Viscosupplementation

Cochrane Database of Systematic Reviews
Viscosupplementation for the treatment of osteoarthritis of

the knee (Review)
Bellamy N, Campbell J, Welch V, Gee TL, Bourne R, Wells GA
Bellamy N, Campbell J, Welch V, Gee TL, Bourne R, Wells GA.

Viscosupplementation for the treatment of osteoarthritis of the knee.
Cochrane Database of Systematic Reviews 2006, Issue 2. Art. No.: CD005321.
DOI: 10.1002/14651858.CD005321.pub2.
www.cochranelibrary.com
Viscosupplementation for the treatment of osteoarthritis of the knee (Review)

Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
TABLE OF CONTENTS
HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44
AUTHORS’ CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51
ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52
REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52
CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 71
DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 225
Analysis 1.1. Comparison 1 Adant versus Hyalgan, Outcome 1 Patient global assessment (number of patients
excellent/good). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 278
Analysis 1.2. Comparison 1 Adant versus Hyalgan, Outcome 2 Safety: number of painful injections. . . . . . . 279
Analysis 2.1. Comparison 2 Artz versus placebo, Outcome 1 Pain (100 mm VAS). . . . . . . . . . . . . 280
Analysis 2.2. Comparison 2 Artz versus placebo, Outcome 2 Pain score (0-3). . . . . . . . . . . . . . . 281
Analysis 2.3. Comparison 2 Artz versus placebo, Outcome 3 WOMAC pain (0-20 Likert). . . . . . . . . . 281
Analysis 2.4. Comparison 2 Artz versus placebo, Outcome 4 WOMAC function (0-68 Likert). . . . . . . . . 282
Analysis 2.5. Comparison 2 Artz versus placebo, Outcome 5 Lequesne Index (0-24). . . . . . . . . . . . 283
Analysis 2.6. Comparison 2 Artz versus placebo, Outcome 6 Range of motion. . . . . . . . . . . . . . 284
Analysis 2.7. Comparison 2 Artz versus placebo, Outcome 7 Patient global assessment (number of patients improved). 284
Analysis 2.8. Comparison 2 Artz versus placebo, Outcome 8 WOMAC stiffness (0-8 Likert). . . . . . . . . 285
Analysis 2.9. Comparison 2 Artz versus placebo, Outcome 9 Number of survivors (patients not requiring additional
treatment for study knee) 45 to 52 weeks post-injection. . . . . . . . . . . . . . . . . . . . 286
Analysis 2.10. Comparison 2 Artz versus placebo, Outcome 10 Number of clinical failures. . . . . . . . . . 286
Analysis 2.11. Comparison 2 Artz versus placebo, Outcome 11 Safety: total withdrawals overall. . . . . . . . 287
Analysis 2.12. Comparison 2 Artz versus placebo, Outcome 12 Safety: number of patients reporting adverse events (45 to
52 weeks post- injection). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 288
Analysis 2.13. Comparison 2 Artz versus placebo, Outcome 13 Safety: withdrawals due to adverse events. . . . . 288
Analysis 2.14. Comparison 2 Artz versus placebo, Outcome 14 Safety: number of patients with local adverse reaction but
study drug continued. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 289
Analysis 2.15. Comparison 2 Artz versus placebo, Outcome 15 Safety: number of adverse events probably/possibly related
to treatment. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 290
Analysis 2.16. Comparison 2 Artz versus placebo, Outcome 16 Safety: number of serious adverse events (45 to 52 weeks
post-injection). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 290
Analysis 2.17. Comparison 2 Artz versus placebo, Outcome 17 Safety: total withdrawals overall (knees). . . . . . 291
Analysis 3.1. Comparison 3 Artzal versus Hylan G-F 20 (Also see Hylan G-F 20 versus hyaluronan, NRD-101 versus Artz,
SLM-10 versus Artz), Outcome 1 Pain on weight bearing (0-100 mm VAS). . . . . . . . . . . . . 292
SLM-10 versus Artz), Outcome 2 Lequesne Index (0-24). . . . . . . . . . . . . . . . . . . 293
SLM-10 versus Artz), Outcome 3 Number of clinical failures. . . . . . . . . . . . . . . . . . 294
SLM-10 versus Artz), Outcome 4 Number of survivors (patients not requiring additional treatment for study knee)
(45 to 52 weeks post-injectio. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 294
SLM-10 versus Artz), Outcome 5 Safety: number of patients withdrawn due to adverse events (45 to 52 weeks post-
injection). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 295
Viscosupplementation for the treatment of osteoarthritis of the knee (Review) i
Analysis 3.6. Comparison 3 Artzal versus Hylan G-F 20 (Also see Hylan G-F 20 versus hyaluronan, NRD-101 versus
Artz, SLM-10 versus Artz), Outcome 6 Safety: number of adverse events related to treatment (45 to 52 weeks post-
injection). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 295
Analysis 3.7. Comparison 3 Artzal versus Hylan G-F 20 (Also see Hylan G-F 20 versus hyaluronan, NRD-101 versus
Artz, SLM-10 versus Artz), Outcome 7 Safety: number of patients reporting adverse events (45 to 52 weeks post-
injection). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 296
Analysis 4.1. Comparison 4 BioHy (Arthrease, Euflexxa) versus placebo, Outcome 1 Safety: total withdrawals overall. 296
Analysis 4.2. Comparison 4 BioHy (Arthrease, Euflexxa) versus placebo, Outcome 2 Safety: number of adverse events for
injection site pain. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 297
Analysis 5.1. Comparison 5 BioHy (Arthrease, Euflexxa) versus Hylan G-F 20 (Synvisc), Outcome 1 WOMAC pain (0-
100 mm VAS). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 298
Analysis 5.2. Comparison 5 BioHy (Arthrease, Euflexxa) versus Hylan G-F 20 (Synvisc), Outcome 2 WOMAC physical
function (0-100 mm VAS). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 299
Analysis 5.3. Comparison 5 BioHy (Arthrease, Euflexxa) versus Hylan G-F 20 (Synvisc), Outcome 3 WOMAC stiffness
(0-100 mm VAS). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 300
Analysis 5.4. Comparison 5 BioHy (Arthrease, Euflexxa) versus Hylan G-F 20 (Synvisc), Outcome 4 WOMAC pain
(number of patients symptom free: VAS score below 20 mm). . . . . . . . . . . . . . . . . . 301
Analysis 5.5. Comparison 5 BioHy (Arthrease, Euflexxa) versus Hylan G-F 20 (Synvisc), Outcome 5 WOMAC function
(number of patients symptom free: VAS score below 20 mm). . . . . . . . . . . . . . . . . . 301
Analysis 5.6. Comparison 5 BioHy (Arthrease, Euflexxa) versus Hylan G-F 20 (Synvisc), Outcome 6 Patient assessment of
treatment (number of patients very satisfied or satisfied). . . . . . . . . . . . . . . . . . . . 302
Analysis 5.7. Comparison 5 BioHy (Arthrease, Euflexxa) versus Hylan G-F 20 (Synvisc), Outcome 7 Rescue medication
usage (number of patients using acetaminophen). . . . . . . . . . . . . . . . . . . . . . 303
Analysis 5.8. Comparison 5 BioHy (Arthrease, Euflexxa) versus Hylan G-F 20 (Synvisc), Outcome 8 Safety: total
withdrawals overall. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 304
Analysis 5.9. Comparison 5 BioHy (Arthrease, Euflexxa) versus Hylan G-F 20 (Synvisc), Outcome 9 Safety: withdrawals
due to adverse events. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 304
Analysis 5.10. Comparison 5 BioHy (Arthrease, Euflexxa) versus Hylan G-F 20 (Synvisc), Outcome 10 Safety: withdrawals
due to lack of efficacy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 305
Analysis 5.11. Comparison 5 BioHy (Arthrease, Euflexxa) versus Hylan G-F 20 (Synvisc), Outcome 11 Safety: number of
patients with serious adverse events. . . . . . . . . . . . . . . . . . . . . . . . . . . 305
patients with joint effusion. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 306
patients reporting adverse events. . . . . . . . . . . . . . . . . . . . . . . . . . . . 306
Analysis 6.1. Comparison 6 Durolane versus placebo, Outcome 1 Responder: reduction in the WOMAC pain score of at
least 40% with an absolute improvement of at least 5 points. . . . . . . . . . . . . . . . . . 307
Analysis 6.2. Comparison 6 Durolane versus placebo, Outcome 2 Responder: patients only with knee OA, reduction in
WOMAC pain score of at least 40%, abs improvement 5 points. . . . . . . . . . . . . . . . . 308
Analysis 6.3. Comparison 6 Durolane versus placebo, Outcome 3 WOMAC pain (change from baseline; 0 to 20 Likert). 309
Analysis 6.4. Comparison 6 Durolane versus placebo, Outcome 4 WOMAC stiffness (change from baseline; 0 to 8
Likert). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 310
Analysis 6.5. Comparison 6 Durolane versus placebo, Outcome 5 WOMAC physical function (change from baseline; 0 to
68 Likert). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 311
Analysis 6.6. Comparison 6 Durolane versus placebo, Outcome 6 Safety: total withdrawals overall. . . . . . . . 312
Analysis 6.7. Comparison 6 Durolane versus placebo, Outcome 7 Safety: withdrawals due to inefficacy. . . . . . 312
Analysis 6.8. Comparison 6 Durolane versus placebo, Outcome 8 Safety: withdrawals due to adverse events. . . . 313
Analysis 6.9. Comparison 6 Durolane versus placebo, Outcome 9 Safety: number of patients affected by device-related
adverse events. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 313
Analysis 6.10. Comparison 6 Durolane versus placebo, Outcome 10 Safety: number of patients with adverse events related
to injection only. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 314
Analysis 6.11. Comparison 6 Durolane versus placebo, Outcome 11 Safety: number of patients with non-serious treatment-
related adverse events. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 314
Viscosupplementation for the treatment of osteoarthritis of the knee (Review) ii
Analysis 6.12. Comparison 6 Durolane versus placebo, Outcome 12 Safety: number of patients with non-serious adverse
events. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 315
Analysis 6.13. Comparison 6 Durolane versus placebo, Outcome 13 Safety: number of patients with treated unrelated
adverse events. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 315
Analysis 6.14. Comparison 6 Durolane versus placebo, Outcome 14 Safety: number of patients with serious treatment-
unrelated adverse events. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 316
Analysis 7.1. Comparison 7 Fermathron versus Hyalart, Outcome 1 Pain (0-100 mm VAS). . . . . . . . . . 316
Analysis 7.2. Comparison 7 Fermathron versus Hyalart, Outcome 2 Lequesne Index (0-24). . . . . . . . . . 317
Analysis 7.3. Comparison 7 Fermathron versus Hyalart, Outcome 3 Patient global assessment (number of patients much
better/better). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 318
Analysis 7.4. Comparison 7 Fermathron versus Hyalart, Outcome 4 Safety: number of related adverse events. . . . 318
Analysis 8.1. Comparison 8 Hyalgan versus placebo, Outcome 1 Pain on weight bearing (walking) (0-100 mm VAS). 319
Analysis 8.2. Comparison 8 Hyalgan versus placebo, Outcome 2 Pain spontaneous (0-100 mm VAS). . . . . . . 321
Analysis 8.3. Comparison 8 Hyalgan versus placebo, Outcome 3 Pain at rest (0-100 mm VAS). . . . . . . . . 322
Analysis 8.4. Comparison 8 Hyalgan versus placebo, Outcome 4 Pain at night (0-100 mm VAS). . . . . . . . 323
Analysis 8.5. Comparison 8 Hyalgan versus placebo, Outcome 5 WOMAC pain (0-100 mm VAS). . . . . . . 324
Analysis 8.6. Comparison 8 Hyalgan versus placebo, Outcome 6 Number of joints improved for walking pain. . . 325
Analysis 8.7. Comparison 8 Hyalgan versus placebo, Outcome 7 Number of joints improved for pain under load. . 326
Analysis 8.8. Comparison 8 Hyalgan versus placebo, Outcome 8 Number of knee joints without rest pain. . . . . 327
Analysis 8.9. Comparison 8 Hyalgan versus placebo, Outcome 9 Number of knee joints without night pain. . . . 328
Analysis 8.10. Comparison 8 Hyalgan versus placebo, Outcome 10 Number of joints with improvement in pain on
touch. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 328
Analysis 8.11. Comparison 8 Hyalgan versus placebo, Outcome 11 Number of patients with moderate/marked pain. 329
Analysis 8.12. Comparison 8 Hyalgan versus placebo, Outcome 12 Pain (number of patients improved). . . . . 330
Analysis 8.13. Comparison 8 Hyalgan versus placebo, Outcome 13 WOMAC function (0-100 mm VAS). . . . . 331
Analysis 8.14. Comparison 8 Hyalgan versus placebo, Outcome 14 Lequesne Index (0-24). . . . . . . . . . 332
Analysis 8.15. Comparison 8 Hyalgan versus placebo, Outcome 15 Flexion (degrees). . . . . . . . . . . . 333
Analysis 8.16. Comparison 8 Hyalgan versus placebo, Outcome 16 Synovial fluid volume (ml). . . . . . . . . 334
Analysis 8.17. Comparison 8 Hyalgan versus placebo, Outcome 17 Joint space width (mm). . . . . . . . . . 335
Analysis 8.18. Comparison 8 Hyalgan versus placebo, Outcome 18 Patient global assessment (number of patients
improved). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 336
Analysis 8.19. Comparison 8 Hyalgan versus placebo, Outcome 19 Patient global assessment (number of joints fairly
good/good/very good). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 337
Analysis 8.20. Comparison 8 Hyalgan versus placebo, Outcome 20 Safety: total withdrawals overall. . . . . . . 338
Analysis 8.21. Comparison 8 Hyalgan versus placebo, Outcome 21 Safety: withdrawals due to lack of efficacy. . . . 339
Analysis 8.22. Comparison 8 Hyalgan versus placebo, Outcome 22 Safety: withdrawals due to painful injection. . . 340
Analysis 8.23. Comparison 8 Hyalgan versus placebo, Outcome 23 Safety: number of patients with local adverse reaction
and study drug discontinued. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 340
Analysis 8.24. Comparison 8 Hyalgan versus placebo, Outcome 24 Safety: number of patients with local adverse reaction
but study drug continued. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 341
Analysis 8.25. Comparison 8 Hyalgan versus placebo, Outcome 25 Safety: number of patients discontinued due to adverse
events. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 341
Analysis 8.26. Comparison 8 Hyalgan versus placebo, Outcome 26 Safety: number of patients with serious or severe adverse
events. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 342
Analysis 8.27. Comparison 8 Hyalgan versus placebo, Outcome 27 Safety: number of knee joints with local adverse
reaction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 343
Analysis 8.28. Comparison 8 Hyalgan versus placebo, Outcome 28 Safety: number of patients with injection site pain or
painful intra-articular injection. . . . . . . . . . . . . . . . . . . . . . . . . . . . 343
Analysis 8.29. Comparison 8 Hyalgan versus placebo, Outcome 29 Safety: number of patients with local joint pain or
swelling. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 344
Analysis 8.30. Comparison 8 Hyalgan versus placebo, Outcome 30 Safety: number of patients with local skin rash or
ecchymosis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 344
Viscosupplementation for the treatment of osteoarthritis of the knee (Review) iii

Analysis 8.31. Comparison 8 Hyalgan versus placebo, Outcome 31 Safety: number of patients with gastrointestinal
complaints. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 345
Analysis 8.32. Comparison 8 Hyalgan versus placebo, Outcome 32 Safety: number of patients with pruritis (local). . 345
Analysis 8.33. Comparison 8 Hyalgan versus placebo, Outcome 33 Safety: number of patients with treatment related
adverse events. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 346
Analysis 8.34. Comparison 8 Hyalgan versus placebo, Outcome 34 Safety: number of patients reporting adverse events. 347
Analysis 8.35. Comparison 8 Hyalgan versus placebo, Outcome 35 Number of patients with none/slight/mild pain. . 347
Analysis 8.36. Comparison 8 Hyalgan versus placebo, Outcome 36 Joint space width (mm) (after three courses of treatment
and stratified subgroups). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 348
Analysis 9.1. Comparison 9 Hyalgan versus arthroscopy, Outcome 1 Pain (0-10 cm VAS). . . . . . . . . . 349
Analysis 9.2. Comparison 9 Hyalgan versus arthroscopy, Outcome 2 Knee Society Function scale. . . . . . . . 350
Analysis 9.3. Comparison 9 Hyalgan versus arthroscopy, Outcome 3 Lequesne Index (0-24). . . . . . . . . . 351
Analysis 9.4. Comparison 9 Hyalgan versus arthroscopy, Outcome 4 Clinical outcome (number of patients requiring
further intervention). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 352
Analysis 9.5. Comparison 9 Hyalgan versus arthroscopy, Outcome 5 Safety: total withdrawals overall. . . . . . . 352
Analysis 9.6. Comparison 9 Hyalgan versus arthroscopy, Outcome 6 Safety: number of patients with pain at injection
site. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 353
Analysis 10.1. Comparison 10 Hyalgan versus NSAID, Outcome 1 Pain after 50 foot walk (0-100 mm VAS). . . . 353
Analysis 10.2. Comparison 10 Hyalgan versus NSAID, Outcome 2 Number of patients with moderate or marked pain. 354
Analysis 10.3. Comparison 10 Hyalgan versus NSAID, Outcome 3 Number of patients with none/slight/mild pain. 355
Analysis 10.4. Comparison 10 Hyalgan versus NSAID, Outcome 4 Safety: total withdrawals overall. . . . . . . 355
Analysis 10.5. Comparison 10 Hyalgan versus NSAID, Outcome 5 Safety: withdrawals due to lack of efficacy. . . . 356
Analysis 10.6. Comparison 10 Hyalgan versus NSAID, Outcome 6 Safety: number of patients withdrawn due to
gastrointestinal events. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 356
Analysis 10.7. Comparison 10 Hyalgan versus NSAID, Outcome 7 Safety: number of patients withdrawn due to injection
site pain. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 357
Analysis 10.8. Comparison 10 Hyalgan versus NSAID, Outcome 8 Safety: number of patients with injection site pain. 357
Analysis 10.9. Comparison 10 Hyalgan versus NSAID, Outcome 9 Safety: number of patients with local joint pain or
swelling. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 358
Analysis 10.10. Comparison 10 Hyalgan versus NSAID, Outcome 10 Safety: number of patients with local skin rash. 358
Analysis 10.11. Comparison 10 Hyalgan versus NSAID, Outcome 11 Safety: number of patients with gastrointestinal
complaints. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 359
Analysis 10.12. Comparison 10 Hyalgan versus NSAID, Outcome 12 Safety: number of patients with pruritis (local). 359
Analysis 11.1. Comparison 11 Hyalgan versus methylprednisolone acetate, Outcome 1 Spontaneous pain intensity (0-100
mm VAS). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 360
Analysis 11.2. Comparison 11 Hyalgan versus methylprednisolone acetate, Outcome 2 Number of joints with moderate or
severe walking pain. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 361
Analysis 11.3. Comparison 11 Hyalgan versus methylprednisolone acetate, Outcome 3 Number of patients with moderate
or severe pain under load. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 362
Analysis 11.4. Comparison 11 Hyalgan versus methylprednisolone acetate, Outcome 4 Number of joints with moderate or
severe pain under load. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 363
Analysis 11.5. Comparison 11 Hyalgan versus methylprednisolone acetate, Outcome 5 Number of patients with at least
moderate or greater night pain. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 364
Analysis 11.6. Comparison 11 Hyalgan versus methylprednisolone acetate, Outcome 6 Number of patients with moderate
or greater rest pain. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 365
Analysis 11.7. Comparison 11 Hyalgan versus methylprednisolone acetate, Outcome 7 Function: range of motion (flexion
in degrees). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 366
Analysis 11.8. Comparison 11 Hyalgan versus methylprednisolone acetate, Outcome 8 Patient global (number of patients
very good or good, excellent or /good). . . . . . . . . . . . . . . . . . . . . . . . . . 367
Analysis 11.9. Comparison 11 Hyalgan versus methylprednisolone acetate, Outcome 9 Safety: total withdrawals overall. 368
Analysis 11.10. Comparison 11 Hyalgan versus methylprednisolone acetate, Outcome 10 Safety: number of patients
withdrawn due to lack of efficacy. . . . . . . . . . . . . . . . . . . . . . . . . . . . 369
Viscosupplementation for the treatment of osteoarthritis of the knee (Review) iv

Analysis 11.11. Comparison 11 Hyalgan versus methylprednisolone acetate, Outcome 11 Safety: number of patients
withdrawn due to adverse events. . . . . . . . . . . . . . . . . . . . . . . . . . . . 369
Analysis 11.12. Comparison 11 Hyalgan versus methylprednisolone acetate, Outcome 12 Safety: number of patients with
local or systemic reactions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 370
Analysis 11.13. Comparison 11 Hyalgan versus methylprednisolone acetate, Outcome 13 Safety: number of joints with
local reactions but continued in trial. . . . . . . . . . . . . . . . . . . . . . . . . . . 370
Analysis 12.1. Comparison 12 Hyalgan versus triamcinolone hexacetonide, Outcome 1 Pain on nominated activity (0-100
mm VAS). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 371
Analysis 12.2. Comparison 12 Hyalgan versus triamcinolone hexacetonide, Outcome 2 Pain at rest (0-100 mm VAS). 372
Analysis 12.3. Comparison 12 Hyalgan versus triamcinolone hexacetonide, Outcome 3 Pain at night (0-100 mm VAS). 373
Analysis 12.4. Comparison 12 Hyalgan versus triamcinolone hexacetonide, Outcome 4 Safety: total withdrawals overall. 374
Analysis 12.5. Comparison 12 Hyalgan versus triamcinolone hexacetonide, Outcome 5 Safety: wIthdrawals due to lack
efficacy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 375
Analysis 12.6. Comparison 12 Hyalgan versus triamcinolone hexacetonide, Outcome 6 Safety: wIthdrawals due to adverse
events. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 376
Analysis 13.1. Comparison 13 Hyalgan versus mucopolysaccharide polysulfuric acid ester, Outcome 1 Pain (0-30)
change. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 377
Analysis 13.2. Comparison 13 Hyalgan versus mucopolysaccharide polysulfuric acid ester, Outcome 2 Function (0-30)
change. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 377
Analysis 13.3. Comparison 13 Hyalgan versus mucopolysaccharide polysulfuric acid ester, Outcome 3 Range of motion (0-
10) change. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 378
Analysis 13.4. Comparison 13 Hyalgan versus mucopolysaccharide polysulfuric acid ester, Outcome 4 Total Larson rating
score (0-77) change. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 379
Analysis 13.5. Comparison 13 Hyalgan versus mucopolysaccharide polysulfuric acid ester, Outcome 5 Patient global
(number of patients symptom free or markedly improved). . . . . . . . . . . . . . . . . . . 379
Analysis 13.6. Comparison 13 Hyalgan versus mucopolysaccharide polysulfuric acid ester, Outcome 6 Safety: total
Analysis 13.7. Comparison 13 Hyalgan versus mucopolysaccharide polysulfuric acid ester, Outcome 7 Safety: adverse events
due to study medication. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 381
Analysis 14.1. Comparison 14 (Hyalgan plus exercise plus ultrasound) versus control warmup exercise, Outcome 1 Pain (0-
10 cm VAS). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 382
Analysis 14.2. Comparison 14 (Hyalgan plus exercise plus ultrasound) versus control warmup exercise, Outcome 2
Lequesne Index (0-26). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 383
Analysis 14.3. Comparison 14 (Hyalgan plus exercise plus ultrasound) versus control warmup exercise, Outcome 3 Range
of motion (degrees). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 384
Analysis 14.4. Comparison 14 (Hyalgan plus exercise plus ultrasound) versus control warmup exercise, Outcome 4
Ambulation speed (metres per minute). . . . . . . . . . . . . . . . . . . . . . . . . . 385
Analysis 14.5. Comparison 14 (Hyalgan plus exercise plus ultrasound) versus control warmup exercise, Outcome 5 Safety:
total withdrawals overall. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 386
Analysis 15.1. Comparison 15 (Hyalgan plus exercise plus ultrasound) versus exercise, Outcome 1 Pain (0-10 cm VAS). 387
Analysis 15.2. Comparison 15 (Hyalgan plus exercise plus ultrasound) versus exercise, Outcome 2 Lequesne Index (0-
26). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 388
Analysis 15.3. Comparison 15 (Hyalgan plus exercise plus ultrasound) versus exercise, Outcome 3 Range of motion
(degrees). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 389
Analysis 15.4. Comparison 15 (Hyalgan plus exercise plus ultrasound) versus exercise, Outcome 4 Ambulation speed
(metres per minute). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 390
Analysis 15.5. Comparison 15 (Hyalgan plus exercise plus ultrasound) versus exercise, Outcome 5 Safety: total withdrawals
overall. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 391
Analysis 16.1. Comparison 16 (Hyalgan plus exercise plus ultrasound) versus (exercise plus ultrasound), Outcome 1 Pain
(0-10 cm VAS). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 392
Analysis 16.2. Comparison 16 (Hyalgan plus exercise plus ultrasound) versus (exercise plus ultrasound), Outcome 2
Lequesne Index (0-26). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 393
Viscosupplementation for the treatment of osteoarthritis of the knee (Review) v

Analysis 16.3. Comparison 16 (Hyalgan plus exercise plus ultrasound) versus (exercise plus ultrasound), Outcome 3 Range
of motion (degrees). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 394
Analysis 16.4. Comparison 16 (Hyalgan plus exercise plus ultrasound) versus (exercise plus ultrasound), Outcome 4
Ambulation speed (metres per minute). . . . . . . . . . . . . . . . . . . . . . . . . . 395
Analysis 16.5. Comparison 16 (Hyalgan plus exercise plus ultrasound) versus (exercise plus ultrasound), Outcome 5 Safety:
total withdrawals overall. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 396
Analysis 17.1. Comparison 17 Hyalgan versus conventional therapy (three courses of treatment), Outcome 1 Pain overall
(0-100 mm VAS). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 397
Analysis 17.2. Comparison 17 Hyalgan versus conventional therapy (three courses of treatment), Outcome 2 Lequesne
Index (0-24). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 397
Analysis 17.3. Comparison 17 Hyalgan versus conventional therapy (three courses of treatment), Outcome 3 Joint space
width (mm). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 398
Analysis 17.4. Comparison 17 Hyalgan versus conventional therapy (three courses of treatment), Outcome 4 Quality of life
(AIMS: total of 12 items). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 399
Analysis 17.5. Comparison 17 Hyalgan versus conventional therapy (three courses of treatment), Outcome 5 Arthroscopy
overall assessment (0-100 mm VAS). . . . . . . . . . . . . . . . . . . . . . . . . . . 399
Analysis 17.6. Comparison 17 Hyalgan versus conventional therapy (three courses of treatment), Outcome 6 SFA scoring
(0-100 mm VAS). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 400
Analysis 17.7. Comparison 17 Hyalgan versus conventional therapy (three courses of treatment), Outcome 7 Safety: total
withdrawals. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 401
Analysis 18.1. Comparison 18 Hyalgan versus Hylan G-F 20, Outcome 1 Safety: number of patients with local reaction
(acute inflammation and pain). . . . . . . . . . . . . . . . . . . . . . . . . . . . . 401
Analysis 19.1. Comparison 19 Hyalgan versus Hyalgan, Outcome 1 Patient global (number of patients assessing response
as satisfactory). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 402
Analysis 20.1. Comparison 20 Hylan G-F 20 versus placebo, Outcome 1 Pain on weight bearing (0-100 mm VAS). . 403
Analysis 20.2. Comparison 20 Hylan G-F 20 versus placebo, Outcome 2 Pain walking (0-100 mm VAS). . . . . 404
Analysis 20.3. Comparison 20 Hylan G-F 20 versus placebo, Outcome 3 WOMAC pain. . . . . . . . . . . 405
Analysis 20.4. Comparison 20 Hylan G-F 20 versus placebo, Outcome 4 Pain at night (0-100 mm VAS). . . . . 406
Analysis 20.5. Comparison 20 Hylan G-F 20 versus placebo, Outcome 5 Pain at rest (0-100 mm VAS). . . . . . 407
Analysis 20.6. Comparison 20 Hylan G-F 20 versus placebo, Outcome 6 Pain overall (0-100 mm VAS). . . . . . 408
Analysis 20.7. Comparison 20 Hylan G-F 20 versus placebo, Outcome 7 WOMAC physical function. . . . . . 409
Analysis 20.8. Comparison 20 Hylan G-F 20 versus placebo, Outcome 8 Lequesne Index (0-24). . . . . . . . 410
Analysis 20.9. Comparison 20 Hylan G-F 20 versus placebo, Outcome 9 Function: improvment in most painful knee
movement (0-100 mm VAS). . . . . . . . . . . . . . . . . . . . . . . . . . . . . 411
Analysis 20.10. Comparison 20 Hylan G-F 20 versus placebo, Outcome 10 15 metre walking time. . . . . . . 412
Analysis 20.11. Comparison 20 Hylan G-F 20 versus placebo, Outcome 11 WOMAC stiffness (2 to 10 Likert). . . 413
Analysis 20.12. Comparison 20 Hylan G-F 20 versus placebo, Outcome 12 Patient global assessment (0-100 mm VAS;
where 100 is worst severity). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 414
Analysis 20.13. Comparison 20 Hylan G-F 20 versus placebo, Outcome 13 Patient global assessment (number of patients
good or very good) 5 to 13 weeks post-injection. . . . . . . . . . . . . . . . . . . . . . . 415
Analysis 20.14. Comparison 20 Hylan G-F 20 versus placebo, Outcome 14 Patient global evaluation of efficacy due to
treatment. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 415
Analysis 20.15. Comparison 20 Hylan G-F 20 versus placebo, Outcome 15 Physician global assessment (0-100 mm VAS;
Analysis 20.16. Comparison 20 Hylan G-F 20 versus placebo, Outcome 16 Number of survivors (patients not requiring
additional treatment for study knee). . . . . . . . . . . . . . . . . . . . . . . . . . . 418
Analysis 20.17. Comparison 20 Hylan G-F 20 versus placebo, Outcome 17 Number of clinical failures. . . . . . 419
Analysis 20.18. Comparison 20 Hylan G-F 20 versus placebo, Outcome 18 Need for paracetamol (pill count). . . 420
Analysis 20.19. Comparison 20 Hylan G-F 20 versus placebo, Outcome 19 Safety: total withdrawals overall. . . . 421
Analysis 20.20. Comparison 20 Hylan G-F 20 versus placebo, Outcome 20 Safety: number of patients withdrawn due to
noncomplinance. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 422
Analysis 20.21. Comparison 20 Hylan G-F 20 versus placebo, Outcome 21 Safety: number of patients with local
reaction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 422
Viscosupplementation for the treatment of osteoarthritis of the knee (Review) vi
Analysis 20.22. Comparison 20 Hylan G-F 20 versus placebo, Outcome 22 Safety: number of patients with local adverse
reactions but study drug continued. . . . . . . . . . . . . . . . . . . . . . . . . . . 423
Analysis 20.23. Comparison 20 Hylan G-F 20 versus placebo, Outcome 23 Safety: number of patients with one or more
probable or possible related systemic adverse events. . . . . . . . . . . . . . . . . . . . . . 423
Analysis 20.24. Comparison 20 Hylan G-F 20 versus placebo, Outcome 24 Safety: number of patients reporting systemic
reactions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 424
Analysis 21.1. Comparison 21 Hylan G-F 20 versus NSAID, Outcome 1 Pain on motion (0-100 mm VAS). . . . 425
Analysis 21.2. Comparison 21 Hylan G-F 20 versus NSAID, Outcome 2 WOMAC pain (0-100 mm VAS). . . . 426
Analysis 21.3. Comparison 21 Hylan G-F 20 versus NSAID, Outcome 3 Pain at rest (0-100 mm VAS). . . . . . 427
Analysis 21.4. Comparison 21 Hylan G-F 20 versus NSAID, Outcome 4 Pain at night (0-100 mm VAS). . . . . 428
Analysis 21.5. Comparison 21 Hylan G-F 20 versus NSAID, Outcome 5 Pain overall (0-100 mm VAS). . . . . . 429
Analysis 21.6. Comparison 21 Hylan G-F 20 versus NSAID, Outcome 6 WOMAC function (0-100 mm VAS). . . 430
Analysis 21.7. Comparison 21 Hylan G-F 20 versus NSAID, Outcome 7 Lequesne Index (0-24). . . . . . . . 430
Analysis 21.8. Comparison 21 Hylan G-F 20 versus NSAID, Outcome 8 Patient overall assessment of treatment (number
of patients excellent, very good, good). . . . . . . . . . . . . . . . . . . . . . . . . . 431
Analysis 21.9. Comparison 21 Hylan G-F 20 versus NSAID, Outcome 9 Safety: total withdrawals overall. . . . . 432
Analysis 21.10. Comparison 21 Hylan G-F 20 versus NSAID, Outcome 10 Safety: number of patients with local
reactions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 433
Analysis 21.11. Comparison 21 Hylan G-F 20 versus NSAID, Outcome 11 Safety: number of patients with probable or
possible related systemic adverse events. . . . . . . . . . . . . . . . . . . . . . . . . . 433
Analysis 21.12. Comparison 21 Hylan G-F 20 versus NSAID, Outcome 12 Safety: withdrawals due to adverse events. 434
Analysis 22.1. Comparison 22 (Hylan G-F 20 + NSAID + arthrocentesis) versus (NSAID + arthrocentesis), Outcome 1
Pain on motion (0-100 mm VAS). . . . . . . . . . . . . . . . . . . . . . . . . . . . 435
Pain at rest (0-100 mm VAS). . . . . . . . . . . . . . . . . . . . . . . . . . . . . 436
Pain at night (0-100 mm VAS). . . . . . . . . . . . . . . . . . . . . . . . . . . . . 437
Pain overall (0-100 mm VAS). . . . . . . . . . . . . . . . . . . . . . . . . . . . . 438
Patient overall assessment of treatment (number of patients excellent, very good, or good). . . . . . . . 439
Safety: total withdrawals overall. . . . . . . . . . . . . . . . . . . . . . . . . . . . 439
Analysis 23.1. Comparison 23 Hylan G-F 20 versus betamethasone, Outcome 1 Safety: total withdrawals overall. . 440
Analysis 23.2. Comparison 23 Hylan G-F 20 versus betamethasone, Outcome 2 Safety: wIthdrawals due to lack of
efficacy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 440
Analysis 23.3. Comparison 23 Hylan G-F 20 versus betamethasone, Outcome 3 Safety: wIthdrawals due to acute local
reaction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 441
Analysis 24.1. Comparison 24 Hylan G-F 20 versus triamcinolone hexacetonide, Outcome 1 WOMAC pain walking on a
flat surface (Question 1: 0-4 Likert). . . . . . . . . . . . . . . . . . . . . . . . . . . 441
Analysis 24.2. Comparison 24 Hylan G-F 20 versus triamcinolone hexacetonide, Outcome 2 WOMAC physical function
subscale (0-68 Likert). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 442
Analysis 24.3. Comparison 24 Hylan G-F 20 versus triamcinolone hexacetonide, Outcome 3 WOMAC total score (0-96
Likert). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 443
Analysis 24.4. Comparison 24 Hylan G-F 20 versus triamcinolone hexacetonide, Outcome 4 Patient global overall
assessment (0-100 mm VAS). . . . . . . . . . . . . . . . . . . . . . . . . . . . . 444
Analysis 24.5. Comparison 24 Hylan G-F 20 versus triamcinolone hexacetonide, Outcome 5 Number of responders
(greater than or equal to one category on WOMAC pain Q1). . . . . . . . . . . . . . . . . . 445
Analysis 24.6. Comparison 24 Hylan G-F 20 versus triamcinolone hexacetonide, Outcome 6 Analgesic usage. . . . 446
Analysis 24.7. Comparison 24 Hylan G-F 20 versus triamcinolone hexacetonide, Outcome 7 Safety: total withdrawals
overall. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 446
Analysis 24.8. Comparison 24 Hylan G-F 20 versus triamcinolone hexacetonide, Outcome 8 Safety: withdrawals due to
adverse event. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 447
Viscosupplementation for the treatment of osteoarthritis of the knee (Review) vii
Analysis 24.9. Comparison 24 Hylan G-F 20 versus triamcinolone hexacetonide, Outcome 9 Safety: withdrawals due to
lack of efficacy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 447
Analysis 25.1. Comparison 25 Hylan G-F 20 versus physical therapy, Outcome 1 Spontaneous pain (0-100 mm VAS). 448
Analysis 25.2. Comparison 25 Hylan G-F 20 versus physical therapy, Outcome 2 WOMAC pain. . . . . . . . 449
Analysis 25.3. Comparison 25 Hylan G-F 20 versus physical therapy, Outcome 3 WOMAC physical function. . . 450
Analysis 25.4. Comparison 25 Hylan G-F 20 versus physical therapy, Outcome 4 SF-36 pain. . . . . . . . . 451
Analysis 25.5. Comparison 25 Hylan G-F 20 versus physical therapy, Outcome 5 SF-36 physical functioning. . . . 452
Analysis 26.1. Comparison 26 (Hylan G-F 20 + physiotherapy) versus physiotherapy, Outcome 1 Lequesne Index (0-
24). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 453
Analysis 26.2. Comparison 26 (Hylan G-F 20 + physiotherapy) versus physiotherapy, Outcome 2 Safety: total withdrawls
overall. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 454
Analysis 26.3. Comparison 26 (Hylan G-F 20 + physiotherapy) versus physiotherapy, Outcome 3 Safety: number of
patients with adverse events. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 454
Analysis 27.1. Comparison 27 Hylan G-F 20 versus progressive knee exercises, Outcome 1 Pain during activity. . . 455
Analysis 27.2. Comparison 27 Hylan G-F 20 versus progressive knee exercises, Outcome 2 Pain at rest. . . . . . 456
Analysis 27.3. Comparison 27 Hylan G-F 20 versus progressive knee exercises, Outcome 3 Pain during climbing stairs. 457
Analysis 27.4. Comparison 27 Hylan G-F 20 versus progressive knee exercises, Outcome 4 Pain during transfer activity. 458
Analysis 27.5. Comparison 27 Hylan G-F 20 versus progressive knee exercises, Outcome 5 Walking distance. . . . 459
Analysis 27.6. Comparison 27 Hylan G-F 20 versus progressive knee exercises, Outcome 6 Range of motion (degrees). 460
Analysis 27.7. Comparison 27 Hylan G-F 20 versus progressive knee exercises, Outcome 7 Hospital for Special Surgery
Knee Score (100 points). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 461
Analysis 27.8. Comparison 27 Hylan G-F 20 versus progressive knee exercises, Outcome 8 Safety: total withdrawals
overall. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 462
Analysis 28.1. Comparison 28 Hylan G-F 20 versus appropriate care, Outcome 1 WOMAC pain (0-20 Likert). . . 462
Analysis 28.2. Comparison 28 Hylan G-F 20 versus appropriate care, Outcome 2 WOMAC pain (0-100 mm VAS). 463
Analysis 28.3. Comparison 28 Hylan G-F 20 versus appropriate care, Outcome 3 Pain on walking (0-100 mm VAS). 463
Analysis 28.4. Comparison 28 Hylan G-F 20 versus appropriate care, Outcome 4 WOMAC function (0-68 Likert). 464
Analysis 28.5. Comparison 28 Hylan G-F 20 versus appropriate care, Outcome 5 WOMAC function (0-100 mm VAS). 465
Analysis 28.6. Comparison 28 Hylan G-F 20 versus appropriate care, Outcome 6 Lequesne Index (0-24). . . . . 465
Analysis 28.7. Comparison 28 Hylan G-F 20 versus appropriate care, Outcome 7 WOMAC total score (0-100 mm
VAS). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 466
Analysis 28.8. Comparison 28 Hylan G-F 20 versus appropriate care, Outcome 8 Patient global assessment (number of
patients improved in study knee). . . . . . . . . . . . . . . . . . . . . . . . . . . . 466
Analysis 28.9. Comparison 28 Hylan G-F 20 versus appropriate care, Outcome 9 Patient global evaluation of effectiveness
(good or satisfactory). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 467
Analysis 28.10. Comparison 28 Hylan G-F 20 versus appropriate care, Outcome 10 Number of responders (20% decrease
in pain on walking). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 467
Analysis 28.11. Comparison 28 Hylan G-F 20 versus appropriate care, Outcome 11 Safety: total withdrawals overall. 468
Analysis 28.12. Comparison 28 Hylan G-F 20 versus appropriate care, Outcome 12 Safety: wIthdrawals due to lack of
effectiveness. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 468
Analysis 28.13. Comparison 28 Hylan G-F 20 versus appropriate care, Outcome 13 Safety: wIthdrawals due to adverse
events. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 469
Analysis 28.14. Comparison 28 Hylan G-F 20 versus appropriate care, Outcome 14 Safety: number of patients reporting
mild, moderate or severe side effects at month 12. . . . . . . . . . . . . . . . . . . . . . 469
Analysis 28.15. Comparison 28 Hylan G-F 20 versus appropriate care, Outcome 15 Safety: total number of patients
reporting side effects from baseline. . . . . . . . . . . . . . . . . . . . . . . . . . . 470
Analysis 28.16. Comparison 28 Hylan G-F 20 versus appropriate care, Outcome 16 Safety: number of patients with
gastrointestinal adverse events. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 470
Analysis 29.1. Comparison 29 Hylan G-F 20 versus gaseous oxygen, Outcome 1 Pain under load (0-100 mm VAS). . 471
Analysis 29.2. Comparison 29 Hylan G-F 20 versus gaseous oxygen, Outcome 2 Pain at rest (0-100 mm VAS). . . 472
Analysis 29.3. Comparison 29 Hylan G-F 20 versus gaseous oxygen, Outcome 3 WOMAC pain (0-20 Likert). . . 473
Analysis 29.4. Comparison 29 Hylan G-F 20 versus gaseous oxygen, Outcome 4 WOMAC physical function (0-68
Likert). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 474
Viscosupplementation for the treatment of osteoarthritis of the knee (Review) viii
Analysis 29.5. Comparison 29 Hylan G-F 20 versus gaseous oxygen, Outcome 5 WOMAC stiffness (0-8 Likert). . 475
Analysis 29.6. Comparison 29 Hylan G-F 20 versus gaseous oxygen, Outcome 6 Safety: total number of withdrawals. 476
Analysis 29.7. Comparison 29 Hylan G-F 20 versus gaseous oxygen, Outcome 7 Safety: number of patients having total
knee replacements. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 476
Analysis 30.1. Comparison 30 Hylan G-F 20 versus hyaluronan (Also see Artzal, BioHy (Arthrease), Hyalgan and Orthovisc
versus Hylan G-F 20), Outcome 1 Pain on weight bearing (0-100 mm VAS). . . . . . . . . . . . . 477
versus Hylan G-F 20), Outcome 2 Pain at night (0-100 mm VAS). . . . . . . . . . . . . . . . 478
versus Hylan G-F 20), Outcome 3 Function: improvement in knee movement (0-100 mm VAS). . . . . . 479
versus Hylan G-F 20), Outcome 4 Patient global evaluation of treatment efficacy (improvement: 0-100 mm VAS). 480
versus Hylan G-F 20), Outcome 5 Safety: total withdrawals overall. . . . . . . . . . . . . . . . 481
versus Hylan G-F 20), Outcome 6 Safety: number of patients with local reactions. . . . . . . . . . . 481
Analysis 31.1. Comparison 31 NRD-101 (Suvenyl) versus placebo (saline plus oral placebo), Outcome 1 Pain (0-100 mm
VAS) change between baseline and 45 to 52 weeks post-injection. . . . . . . . . . . . . . . . . 482
Analysis 31.2. Comparison 31 NRD-101 (Suvenyl) versus placebo (saline plus oral placebo), Outcome 2 Lequesne Index
(0-100 modified scale) change between baseline and 45 to 52 weeks post-injection. . . . . . . . . . . 483
Analysis 31.3. Comparison 31 NRD-101 (Suvenyl) versus placebo (saline plus oral placebo), Outcome 3 Patient global
assessment (0-100 mm VAS) change between baseline and 45 to 52 weeks post-injection. . . . . . . . . 483
Analysis 31.4. Comparison 31 NRD-101 (Suvenyl) versus placebo (saline plus oral placebo), Outcome 4 Percentage of
painful days (0-100 mm VAS) change between baseline and 45 to 52 weeks post-injection. . . . . . . . 484
Analysis 31.5. Comparison 31 NRD-101 (Suvenyl) versus placebo (saline plus oral placebo), Outcome 5 Patient assessment
of treatment efficacy (no. of patients rating very good or good versus mod, bad or very bad. . . . . . . . 484
Analysis 31.6. Comparison 31 NRD-101 (Suvenyl) versus placebo (saline plus oral placebo), Outcome 6 Joint space width
(percentage of progressors: joint space narrowing greater than 0.5 mm). . . . . . . . . . . . . . . 485
Analysis 31.7. Comparison 31 NRD-101 (Suvenyl) versus placebo (saline plus oral placebo), Outcome 7 Safety: total
Analysis 31.8. Comparison 31 NRD-101 (Suvenyl) versus placebo (saline plus oral placebo), Outcome 8 Safety: withdrawals
due to inefficacy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 486
Analysis 31.9. Comparison 31 NRD-101 (Suvenyl) versus placebo (saline plus oral placebo), Outcome 9 Safety: number of
withdrawals due to adverse events. . . . . . . . . . . . . . . . . . . . . . . . . . . . 486
Analysis 31.10. Comparison 31 NRD-101 (Suvenyl) versus placebo (saline plus oral placebo), Outcome 10 Safety: number
of patients reporting knee pain during or after IA injection. . . . . . . . . . . . . . . . . . . 487
Analysis 31.11. Comparison 31 NRD-101 (Suvenyl) versus placebo (saline plus oral placebo), Outcome 11 Safety: number
of patients reporting diarrhoea. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 487
Analysis 32.1. Comparison 32 NRD-101 (Suvenyl) versus Diacerein, Outcome 1 Pain (0-100 mm VAS) change between
baseline and 45 to 52 weeks post-injection. . . . . . . . . . . . . . . . . . . . . . . . . 488
Analysis 32.2. Comparison 32 NRD-101 (Suvenyl) versus Diacerein, Outcome 2 Lequesne Index (0-100 modified scale)
change between baseline and 45 to 52 weeks post-injection. . . . . . . . . . . . . . . . . . . 488
Analysis 32.3. Comparison 32 NRD-101 (Suvenyl) versus Diacerein, Outcome 3 Patient global assessment (0-100 mm
Analysis 32.4. Comparison 32 NRD-101 (Suvenyl) versus Diacerein, Outcome 4 Percentage of painful days (0-100 mm
Analysis 32.5. Comparison 32 NRD-101 (Suvenyl) versus Diacerein, Outcome 5 Patient assessment of treatment efficacy
(no. of patients rating very good or good versus mod, bad or very bad. . . . . . . . . . . . . . . 490
Analysis 32.6. Comparison 32 NRD-101 (Suvenyl) versus Diacerein, Outcome 6 Joint space width (percentage progressors:
joint space narrowing greater than 0.5 mm). . . . . . . . . . . . . . . . . . . . . . . . 490
Analysis 32.7. Comparison 32 NRD-101 (Suvenyl) versus Diacerein, Outcome 7 Safety: total withdrawals overall. . 491
Analysis 32.8. Comparison 32 NRD-101 (Suvenyl) versus Diacerein, Outcome 8 Safety: withdrawals due to inefficacy. 491
Viscosupplementation for the treatment of osteoarthritis of the knee (Review) ix

Analysis 32.9. Comparison 32 NRD-101 (Suvenyl) versus Diacerein, Outcome 9 Safety: number of withdrawlals due to
adverse events. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 492
Analysis 32.10. Comparison 32 NRD-101 (Suvenyl) versus Diacerein, Outcome 10 Safety: number of patients reporting
knee pain during or after IA injection. . . . . . . . . . . . . . . . . . . . . . . . . . 492
Analysis 32.11. Comparison 32 NRD-101 (Suvenyl) versus Diacerein, Outcome 11 Safety: number of patients reporting
diarrhoea. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 493
Analysis 33.1. Comparison 33 NRD-101 (Suvenyl) versus Artz (end of treatment), Outcome 1 Spontaneous pain (number
of patients improved). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 493
Analysis 33.2. Comparison 33 NRD-101 (Suvenyl) versus Artz (end of treatment), Outcome 2 Pain during the night
(number of patients improved). . . . . . . . . . . . . . . . . . . . . . . . . . . . . 494
Analysis 33.3. Comparison 33 NRD-101 (Suvenyl) versus Artz (end of treatment), Outcome 3 Pressure pain (number of
patients improved). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 494
Analysis 33.4. Comparison 33 NRD-101 (Suvenyl) versus Artz (end of treatment), Outcome 4 Passive movement pain
(number of patients improved). . . . . . . . . . . . . . . . . . . . . . . . . . . . . 495
Analysis 33.5. Comparison 33 NRD-101 (Suvenyl) versus Artz (end of treatment), Outcome 5 Passive flexion (degrees). 495
Analysis 33.6. Comparison 33 NRD-101 (Suvenyl) versus Artz (end of treatment), Outcome 6 Passive extension
(degrees). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 496
Analysis 33.7. Comparison 33 NRD-101 (Suvenyl) versus Artz (end of treatment), Outcome 7 Patient global assessment. 496
Analysis 33.8. Comparison 33 NRD-101 (Suvenyl) versus Artz (end of treatment), Outcome 8 Safety: total withdrawals
overall. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 497
Analysis 33.9. Comparison 33 NRD-101 (Suvenyl) versus Artz (end of treatment), Outcome 9 Safety: number of adverse
events. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 497
Analysis 34.1. Comparison 34 Orthovisc versus placebo, Outcome 1 WOMAC pain (5 to 25 Likert). . . . . . 498
Analysis 34.2. Comparison 34 Orthovisc versus placebo, Outcome 2 WOMAC pain (number of patients who
improved). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 499
Analysis 34.3. Comparison 34 Orthovisc versus placebo, Outcome 3 WOMAC pain (number of patients who achieved
greater than 5 unit improvement (relative to baseline score)). . . . . . . . . . . . . . . . . . 499
Analysis 34.4. Comparison 34 Orthovisc versus placebo, Outcome 4 Number of patients with a 20% improvement from
baseline in WOMAC pain score. . . . . . . . . . . . . . . . . . . . . . . . . . . . 500
Analysis 34.7. Comparison 34 Orthovisc versus placebo, Outcome 7 WOMAC pain on standing (0 to 100 mm VAS;
change from baseline). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 503
Analysis 34.8. Comparison 34 Orthovisc versus placebo, Outcome 8 WOMAC physical function (17 to 85 Likert). . 504
Analysis 34.9. Comparison 34 Orthovisc versus placebo, Outcome 9 Range of motion: flexion (degrees). . . . . 505
Analysis 34.10. Comparison 34 Orthovisc versus placebo, Outcome 10 25 metre walking time (sec). . . . . . . 505
Analysis 34.11. Comparison 34 Orthovisc versus placebo, Outcome 11 Knee circumference (mm). . . . . . . 506
Analysis 34.12. Comparison 34 Orthovisc versus placebo, Outcome 12 WOMAC stiffness (2 to 10 Likert). . . . 507
Analysis 34.13. Comparison 34 Orthovisc versus placebo, Outcome 13 WOMAC total score (0 to 100 mm VAS; change
from baseline). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 508
Analysis 34.14. Comparison 34 Orthovisc versus placebo, Outcome 14 Patient global assessment (0 to 100 mm VAS; where
100 is worst severity). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 509
Analysis 34.15. Comparison 34 Orthovisc versus placebo, Outcome 15 Patient global assessment (0 to 100 mm VAS;
Analysis 34.16. Comparison 34 Orthovisc versus placebo, Outcome 16 Patient global assessment (number patients rating
treatment as effective or very effective). . . . . . . . . . . . . . . . . . . . . . . . . . 511
Analysis 34.17. Comparison 34 Orthovisc versus placebo, Outcome 17 Physician global assessment (0 to 100 mm VAS;
Analysis 34.18. Comparison 34 Orthovisc versus placebo, Outcome 18 Physician global assessment (0 to 100 VAS; change
from baseline). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 513
Analysis 34.19. Comparison 34 Orthovisc versus placebo, Outcome 19 Synovial fluid effusion volume (ml). . . . 514
Viscosupplementation for the treatment of osteoarthritis of the knee (Review) x
Analysis 34.20. Comparison 34 Orthovisc versus placebo, Outcome 20 Interleukin 6 level in the synovial fluid (pg/ml). 514
Analysis 34.21. Comparison 34 Orthovisc versus placebo, Outcome 21 Interleukin 8 level in the synovial fluid (pg/ml). 515
Analysis 34.22. Comparison 34 Orthovisc versus placebo, Outcome 22 Tumor necrosis factor alpha levels in synovial
fluid. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 515
Analysis 34.23. Comparison 34 Orthovisc versus placebo, Outcome 23 Safety: total withdrawals overall. . . . . . 516
Analysis 34.24. Comparison 34 Orthovisc versus placebo, Outcome 24 Safety: withdrawals due to lack of efficacy. . 517
Analysis 34.25. Comparison 34 Orthovisc versus placebo, Outcome 25 Safety: number of patients with treatment related
adverse events. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 517
Analysis 34.26. Comparison 34 Orthovisc versus placebo, Outcome 26 Safety: number of patients withdrawn due to
noncompliance. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 518
Analysis 34.27. Comparison 34 Orthovisc versus placebo, Outcome 27 Safety: number of patients with reported
musculoskeletal adverse events. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 518
Analysis 34.28. Comparison 34 Orthovisc versus placebo, Outcome 28 Safety: number of patients with general body
adverse events. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 519
Analysis 34.29. Comparison 34 Orthovisc versus placebo, Outcome 29 Safety: number of patients with local skin rash. 519
Analysis 34.30. Comparison 34 Orthovisc versus placebo, Outcome 30 Safety: number patients with gastrointestinal
complaints. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 520
Analysis 34.31. Comparison 34 Orthovisc versus placebo, Outcome 31 Safety: number of patients with reported respiratory
adverse events. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 520
Analysis 34.32. Comparison 34 Orthovisc versus placebo, Outcome 32 Safety: number of patients with nervous system
adverse events. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 521
Analysis 34.33. Comparison 34 Orthovisc versus placebo, Outcome 33 Safety: number of patients with urinary adverse
events. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 521
Analysis 34.34. Comparison 34 Orthovisc versus placebo, Outcome 34 Safety: number of patients withdrawn due to local
adverse events. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 522
Analysis 35.1. Comparison 35 Orthovisc versus betamethasone, Outcome 1 WOMAC function (0-100 mm VAS). . 522
Analysis 35.2. Comparison 35 Orthovisc versus betamethasone, Outcome 2 Flexion (degrees). . . . . . . . . 523
Analysis 35.3. Comparison 35 Orthovisc versus betamethasone, Outcome 3 Patient global assessment (number of patients
good or very good). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 524
Analysis 35.4. Comparison 35 Orthovisc versus betamethasone, Outcome 4 Safety: total withdrawals overall. . . . 524
Analysis 35.5. Comparison 35 Orthovisc versus betamethasone, Outcome 5 Safety: number of patients withdrawn due to
adverse events. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 525
Analysis 35.6. Comparison 35 Orthovisc versus betamethasone, Outcome 6 Safety: number of patients with local adverse
events. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 525
Analysis 35.7. Comparison 35 Orthovisc versus betamethasone, Outcome 7 Safety: number of patients with systemic
adverse events. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 526
Analysis 36.1. Comparison 36 Orthovisc versus 6-methylprednisolone acetate, Outcome 1 Pain on weight bearing (0-100
mm VAS). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 526
Analysis 36.2. Comparison 36 Orthovisc versus 6-methylprednisolone acetate, Outcome 2 Pain at rest (0-100 mm
VAS). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 527
Analysis 36.3. Comparison 36 Orthovisc versus 6-methylprednisolone acetate, Outcome 3 Pain on walking (0-100 mm
VAS). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 528
Analysis 36.4. Comparison 36 Orthovisc versus 6-methylprednisolone acetate, Outcome 4 Lequesne Index (0-24). . 529
Analysis 36.5. Comparison 36 Orthovisc versus 6-methylprednisolone acetate, Outcome 5 Flexion (active range in
degrees). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 530
Analysis 36.6. Comparison 36 Orthovisc versus 6-methylprednisolone acetate, Outcome 6 Safety: total withdrawals
overall. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 531
Analysis 36.7. Comparison 36 Orthovisc versus 6-methylprednisolone acetate, Outcome 7 Safety: number of patients
withdrawn due to increased pain. . . . . . . . . . . . . . . . . . . . . . . . . . . . 531
reporting musculoskeletal adverse events. . . . . . . . . . . . . . . . . . . . . . . . . 532
reporting skin adverse events. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 532
Viscosupplementation for the treatment of osteoarthritis of the knee (Review) xi
reporting gastrointestinal adverse events. . . . . . . . . . . . . . . . . . . . . . . . . 533
reporting general adverse events. . . . . . . . . . . . . . . . . . . . . . . . . . . . 533
reporting knee pain after injection. . . . . . . . . . . . . . . . . . . . . . . . . . . 534
Analysis 37.1. Comparison 37 Orthovisc versus (Orthovisc plus triamcinolone acetonide), Outcome 1 Pain (0-100 mm
VAS). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 534
Analysis 37.2. Comparison 37 Orthovisc versus (Orthovisc plus triamcinolone acetonide), Outcome 2 WOMAC pain (0-
20 Likert). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 536
Analysis 37.3. Comparison 37 Orthovisc versus (Orthovisc plus triamcinolone acetonide), Outcome 3 WOMAC physical
function (0-68 Likert). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 537
Analysis 37.4. Comparison 37 Orthovisc versus (Orthovisc plus triamcinolone acetonide), Outcome 4 50 foot walking
time (seconds). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 538
Analysis 37.5. Comparison 37 Orthovisc versus (Orthovisc plus triamcinolone acetonide), Outcome 5 Range of motion
(degrees). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 539
Analysis 37.6. Comparison 37 Orthovisc versus (Orthovisc plus triamcinolone acetonide), Outcome 6 WOMAC stiffness
(0-8 Likert). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 540
Analysis 37.7. Comparison 37 Orthovisc versus (Orthovisc plus triamcinolone acetonide), Outcome 7 WOMAC total
score (0-96 Likert). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 541
Analysis 37.8. Comparison 37 Orthovisc versus (Orthovisc plus triamcinolone acetonide), Outcome 8 Safety: total
Analysis 37.9. Comparison 37 Orthovisc versus (Orthovisc plus triamcinolone acetonide), Outcome 9 Safety: withdrawals
due to lack of efficacy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 542
Analysis 37.10. Comparison 37 Orthovisc versus (Orthovisc plus triamcinolone acetonide), Outcome 10 Safety: number of
patients reporting adverse events (local reactions). . . . . . . . . . . . . . . . . . . . . . 543
Analysis 38.1. Comparison 38 Orthovisc versus (Orthovisc plus lidocaine trigger point injection)(1 week post-injection),
Outcome 1 Pain at rest (0 to 4 point scale). . . . . . . . . . . . . . . . . . . . . . . . 543
Outcome 2 Pain/restrictions walking (0 to 4 point scale). . . . . . . . . . . . . . . . . . . . 544
Outcome 3 Pain/restrictions going up or down stairs (0 to 4 point scale). . . . . . . . . . . . . . 544
Outcome 4 Range of motion (degrees). . . . . . . . . . . . . . . . . . . . . . . . . . 545
Outcome 5 Safety: total withdrawals overall. . . . . . . . . . . . . . . . . . . . . . . . 545
Analysis 39.1. Comparison 39 Orthovisc versus physical therapy, Outcome 1 Spontaneous pain (0-100 mm VAS). . 546
Analysis 39.2. Comparison 39 Orthovisc versus physical therapy, Outcome 2 WOMAC pain. . . . . . . . . 547
Analysis 39.3. Comparison 39 Orthovisc versus physical therapy, Outcome 3 WOMAC physical function. . . . . 548
Analysis 39.4. Comparison 39 Orthovisc versus physical therapy, Outcome 4 SF-36 pain. . . . . . . . . . . 549
Analysis 39.5. Comparison 39 Orthovisc versus physical therapy, Outcome 5 SF-36 physical functioning. . . . . 550
Analysis 40.1. Comparison 40 (Orthovisc + physiotherapy) versus physiotherapy, Outcome 1 Activity pain (0-100 mm
VAS). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 551
Analysis 40.2. Comparison 40 (Orthovisc + physiotherapy) versus physiotherapy, Outcome 2 Spontaneous pain (0-100
mm VAS). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 552
Analysis 40.3. Comparison 40 (Orthovisc + physiotherapy) versus physiotherapy, Outcome 3 Night pain (0-100 mm
VAS). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 553
Analysis 40.4. Comparison 40 (Orthovisc + physiotherapy) versus physiotherapy, Outcome 4 Lequesne (0-24). . . 554
Analysis 40.5. Comparison 40 (Orthovisc + physiotherapy) versus physiotherapy, Outcome 5 25 m walk time (sec). . 555
Analysis 40.6. Comparison 40 (Orthovisc + physiotherapy) versus physiotherapy, Outcome 6 Flexion (degrees). . . 556
Analysis 40.7. Comparison 40 (Orthovisc + physiotherapy) versus physiotherapy, Outcome 7 Patient global assessment
(number of patients evaluating treatment as effective or very effective). . . . . . . . . . . . . . . 557
Viscosupplementation for the treatment of osteoarthritis of the knee (Review) xii

Analysis 40.8. Comparison 40 (Orthovisc + physiotherapy) versus physiotherapy, Outcome 8 Safety: total withdrawals
overall. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 557
Analysis 40.9. Comparison 40 (Orthovisc + physiotherapy) versus physiotherapy, Outcome 9 Safety: number of patients
with local reactions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 558
withdrawn due to adverse events. . . . . . . . . . . . . . . . . . . . . . . . . . . . 559
with systemic adverse events. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 560
Analysis 41.1. Comparison 41 (Orthovisc + physiotherapy) versus (Hylan G-F 20 + physiotherapy), Outcome 1 Lequesne
Index (0-24). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 561
Analysis 42.1. Comparison 42 Orthovisc versus hylan G-F 20, Outcome 1 WOMAC pain (0-20 or 5-25 Likert). . 562
Analysis 42.2. Comparison 42 Orthovisc versus hylan G-F 20, Outcome 2 Spontaneous pain (0-100 mm VAS). . . 563
Analysis 42.3. Comparison 42 Orthovisc versus hylan G-F 20, Outcome 3 SF-36 pain. . . . . . . . . . . . 564
Analysis 42.4. Comparison 42 Orthovisc versus hylan G-F 20, Outcome 4 Hospital for Special Surgery Knee Score. . 565
Analysis 42.5. Comparison 42 Orthovisc versus hylan G-F 20, Outcome 5 Pain during activity (Hospital for Special
Surgery). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 566
Analysis 42.6. Comparison 42 Orthovisc versus hylan G-F 20, Outcome 6 Pain at rest (Hospital for Special Surgery). 567
Analysis 42.7. Comparison 42 Orthovisc versus hylan G-F 20, Outcome 7 Pain during climbing stairs (Hospital for Special
Surgery). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 568
Analysis 42.8. Comparison 42 Orthovisc versus hylan G-F 20, Outcome 8 Pain during transfer activity (Hospital for
Special Surgery). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 569
Analysis 42.9. Comparison 42 Orthovisc versus hylan G-F 20, Outcome 9 WOMAC physical function (0-68 or 17-85
Likert). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 570
Analysis 42.10. Comparison 42 Orthovisc versus hylan G-F 20, Outcome 10 SF-36 physical functioning. . . . . 571
Analysis 42.11. Comparison 42 Orthovisc versus hylan G-F 20, Outcome 11 Range of motion (degrees). . . . . 572
Analysis 42.12. Comparison 42 Orthovisc versus hylan G-F 20, Outcome 12 Walking distance. . . . . . . . . 573
Analysis 42.13. Comparison 42 Orthovisc versus hylan G-F 20, Outcome 13 Patient global assessment (0-100 mm VAS
Analysis 42.14. Comparison 42 Orthovisc versus hylan G-F 20, Outcome 14 Physician global assessment (0-100 mm VAS
Analysis 42.15. Comparison 42 Orthovisc versus hylan G-F 20, Outcome 15 WOMAC stiffness (0-8 or 2-10 Likert). 576
Analysis 42.16. Comparison 42 Orthovisc versus hylan G-F 20, Outcome 16 Synovial fluid intercellular adhesion molecule-
1 (ICAM-1). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 577
Analysis 42.17. Comparison 42 Orthovisc versus hylan G-F 20, Outcome 17 Synovial fluid vascular cell adhesion molecule-
1 (VCAM-1). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 577
Analysis 42.18. Comparison 42 Orthovisc versus hylan G-F 20, Outcome 18 Safety: total withdrawals overall. . . 578
Analysis 42.19. Comparison 42 Orthovisc versus hylan G-F 20, Outcome 19 Safety: withdrawals due to lack of efficacy. 578
Analysis 42.20. Comparison 42 Orthovisc versus hylan G-F 20, Outcome 20 Safety: number of patients with local adverse
event. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 579
Analysis 42.21. Comparison 42 Orthovisc versus hylan G-F 20, Outcome 21 Safety: withdrawals due to noncompliance. 579
Analysis 43.1. Comparison 43 Orthovisc versus Orthovisc, Outcome 1 WOMAC total score (0 to 100 mm VAS; change
from baseline). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 580
Analysis 43.2. Comparison 43 Orthovisc versus Orthovisc, Outcome 2 Patient global assessment (0 to 100 mm VAS;
Analysis 43.3. Comparison 43 Orthovisc versus Orthovisc, Outcome 3 Physician global assessment (0 to 100 mm VAS;
Analysis 43.4. Comparison 43 Orthovisc versus Orthovisc, Outcome 4 WOMAC pain on standing (0 to 100 mm VAS;
Analysis 43.5. Comparison 43 Orthovisc versus Orthovisc, Outcome 5 Number of patients with a 20% improvement from
Viscosupplementation for the treatment of osteoarthritis of the knee (Review) xiii

Analysis 43.8. Comparison 43 Orthovisc versus Orthovisc, Outcome 8 Safety: total withdrawals overall. . . . . . 586
Analysis 43.9. Comparison 43 Orthovisc versus Orthovisc, Outcome 9 Safety: total withdrawals due to lack of efficacy. 587
Analysis 43.10. Comparison 43 Orthovisc versus Orthovisc, Outcome 10 Safety: number of patients reporting adverse
events. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 587
Analysis 43.11. Comparison 43 Orthovisc versus Orthovisc, Outcome 11 Safety: number of patients with gastrointestinal
adverse events. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 588
Analysis 43.12. Comparison 43 Orthovisc versus Orthovisc, Outcome 12 Safety: number of patients with general body
adverse events. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 588
Analysis 43.13. Comparison 43 Orthovisc versus Orthovisc, Outcome 13 Safety: number of patients with infections. 589
Analysis 43.14. Comparison 43 Orthovisc versus Orthovisc, Outcome 14 Safety: number of patients with musculoskeletal
adverse events. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 589
Analysis 43.15. Comparison 43 Orthovisc versus Orthovisc, Outcome 15 Safety: number of patients with nervous system
adverse events. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 590
Analysis 43.16. Comparison 43 Orthovisc versus Orthovisc, Outcome 16 Safety: number of patients with respiratory
adverse events. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 590
Analysis 43.17. Comparison 43 Orthovisc versus Orthovisc, Outcome 17 Safety: number of patients with skin adverse
events. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 591
Analysis 44.1. Comparison 44 Replasyn versus placebo, Outcome 1 Safety: Number of patients with local adverse reaction
but study drug continued. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 591
Analysis 45.1. Comparison 45 SLM-10 versus Artz (end of treatment), Outcome 1 Pain in movement (number of patients
improved). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 592
Analysis 45.2. Comparison 45 SLM-10 versus Artz (end of treatment), Outcome 2 Pain when resting (number of patients
improved). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 592
Analysis 45.3. Comparison 45 SLM-10 versus Artz (end of treatment), Outcome 3 Pressure pain (number of patients
improved). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 593
Analysis 45.4. Comparison 45 SLM-10 versus Artz (end of treatment), Outcome 4 Patient global assessment (number of
patients better or much better). . . . . . . . . . . . . . . . . . . . . . . . . . . . . 593
Analysis 45.5. Comparison 45 SLM-10 versus Artz (end of treatment), Outcome 5 Safety: total withdrawals overall. . 594
Analysis 45.6. Comparison 45 SLM-10 versus Artz (end of treatment), Outcome 6 Safety: local adverse events related to
study drug resulting in withdrawals. . . . . . . . . . . . . . . . . . . . . . . . . . . 594
Analysis 45.7. Comparison 45 SLM-10 versus Artz (end of treatment), Outcome 7 Safety: local adverse events no specific
causal relationship to study drug and continuation in trial. . . . . . . . . . . . . . . . . . . 595
Analysis 46.1. Comparison 46 Suplasyn versus placebo: 1 week post-injection, Outcome 1 Pain after walking (0-10 cm
VAS). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 595
Analysis 46.2. Comparison 46 Suplasyn versus placebo: 1 week post-injection, Outcome 2 WOMAC pain (0-10 cm
VAS). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 596
Analysis 46.3. Comparison 46 Suplasyn versus placebo: 1 week post-injection, Outcome 3 Pain at rest (0-10 cm VAS). 596
Analysis 46.4. Comparison 46 Suplasyn versus placebo: 1 week post-injection, Outcome 4 WOMAC function (0-10 cm
VAS). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 597
Analysis 46.5. Comparison 46 Suplasyn versus placebo: 1 week post-injection, Outcome 5 Walk time (sec). . . . . 597
Analysis 46.6. Comparison 46 Suplasyn versus placebo: 1 week post-injection, Outcome 6 Safety: total withdrawals
overall. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 598
Analysis 47.1. Comparison 47 Suplasyn versus NSAID: 1 week post-injection, Outcome 1 Pain after walking (0-10 cm
VAS). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 598
Analysis 47.2. Comparison 47 Suplasyn versus NSAID: 1 week post-injection, Outcome 2 WOMAC pain (0-10 cm
VAS). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 599
Analysis 47.3. Comparison 47 Suplasyn versus NSAID: 1 week post-injection, Outcome 3 Pain at rest (0-10 cm VAS). 599
Analysis 47.4. Comparison 47 Suplasyn versus NSAID: 1 week post-injection, Outcome 4 WOMAC function (0-10 cm
VAS). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 600
Analysis 47.5. Comparison 47 Suplasyn versus NSAID: 1 week post-injection, Outcome 5 Walk time (sec). . . . 600
Viscosupplementation for the treatment of osteoarthritis of the knee (Review) xiv

Analysis 47.6. Comparison 47 Suplasyn versus NSAID: 1 week post-injection, Outcome 6 Safety: total withdrawals
overall. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 601
Analysis 48.1. Comparison 48 (Suplasyn + NSAID) versus NSAID: 1 week post-injection, Outcome 1 Pain after walking
(0-10 cm VAS). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 601
Analysis 48.2. Comparison 48 (Suplasyn + NSAID) versus NSAID: 1 week post-injection, Outcome 2 WOMAC pain (0-
10 cm VAS). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 602
Analysis 48.3. Comparison 48 (Suplasyn + NSAID) versus NSAID: 1 week post-injection, Outcome 3 Pain at rest (0-10
cm VAS). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 602
Analysis 48.4. Comparison 48 (Suplasyn + NSAID) versus NSAID: 1 week post-injection, Outcome 4 WOMAC function
(0-10 cm VAS). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 603
Analysis 48.5. Comparison 48 (Suplasyn + NSAID) versus NSAID: 1 week post-injection, Outcome 5 Walk time (sec). 603
Analysis 48.6. Comparison 48 (Suplasyn + NSAID) versus NSAID: 1 week post-injection, Outcome 6 Safety: total
Analysis 49.1. Comparison 49 Zeel compositum versus Hyalart (end of treatment (5 weeks)), Outcome 1 Pain during
movement (0-100 mm VAS ). . . . . . . . . . . . . . . . . . . . . . . . . . . . . 604
Analysis 49.2. Comparison 49 Zeel compositum versus Hyalart (end of treatment (5 weeks)), Outcome 2 Pain during the
night (0-100 mm VAS). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 605
Analysis 49.3. Comparison 49 Zeel compositum versus Hyalart (end of treatment (5 weeks)), Outcome 3 Patient global:
number of patients with noticeable improvements in symptoms. . . . . . . . . . . . . . . . . 605
Analysis 49.4. Comparison 49 Zeel compositum versus Hyalart (end of treatment (5 weeks)), Outcome 4 Patient assessment
of improvement (0-100 mm VAS). . . . . . . . . . . . . . . . . . . . . . . . . . . 606
Analysis 49.5. Comparison 49 Zeel compositum versus Hyalart (end of treatment (5 weeks)), Outcome 5 Patient assessment
of tolerance (0-100 mm VAS). . . . . . . . . . . . . . . . . . . . . . . . . . . . . 606
Analysis 49.6. Comparison 49 Zeel compositum versus Hyalart (end of treatment (5 weeks)), Outcome 6 Safety: number
of patients with side effects. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 607
Analysis 49.7. Comparison 49 Zeel compositum versus Hyalart (end of treatment (5 weeks)), Outcome 7 Safety: number
of patients withdrawn due to lack of efficacy. . . . . . . . . . . . . . . . . . . . . . . . 607
Analysis 50.1. Comparison 50 HA/hylan versus placebo, Outcome 1 Pain on weight bearing (0-100 mm VAS). . . 608
Analysis 50.2. Comparison 50 HA/hylan versus placebo, Outcome 2 Pain at rest (0-100 mm VAS). . . . . . . 611
Analysis 50.3. Comparison 50 HA/hylan versus placebo, Outcome 3 WOMAC pain. . . . . . . . . . . . 612
Analysis 50.4. Comparison 50 HA/hylan versus placebo, Outcome 4 WOMAC physical function. . . . . . . . 613
Analysis 50.5. Comparison 50 HA/hylan versus placebo, Outcome 5 Lequesne Index (0-24). . . . . . . . . . 615
Analysis 50.6. Comparison 50 HA/hylan versus placebo, Outcome 6 Patient global assessment (number of patients
improved). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 616
Analysis 50.7. Comparison 50 HA/hylan versus placebo, Outcome 7 Flexion (degrees). . . . . . . . . . . . 618
Analysis 50.8. Comparison 50 HA/hylan versus placebo, Outcome 8 Safety: total withdrawals overall. . . . . . 619
Analysis 50.9. Comparison 50 HA/hylan versus placebo, Outcome 9 Safety: number of patients with local adverse reaction
and study drug discontinued. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 621
Analysis 50.10. Comparison 50 HA/hylan versus placebo, Outcome 10 Safety: number of patients with local adverse
reaction but study drug continued. . . . . . . . . . . . . . . . . . . . . . . . . . . 621
Analysis 50.11. Comparison 50 HA/hylan versus placebo, Outcome 11 Safety: number of patients discontinued due to
adverse events. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 622
Analysis 50.12. Comparison 50 HA/hylan versus placebo, Outcome 12 Safety: withdrawals due to lack of efficacy. . 623
Analysis 50.13. Comparison 50 HA/hylan versus placebo, Outcome 13 Safety: number of adverse events for injection site
pain. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 624
Analysis 50.14. Comparison 50 HA/hylan versus placebo, Outcome 14 Safety: number of adverse events local skin rash. 624
Analysis 50.15. Comparison 50 HA/hylan versus placebo, Outcome 15 Safety: number of patients with gastrointestinal
complaints. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 625
Analysis 50.16. Comparison 50 HA/hylan versus placebo, Outcome 16 Safety: number of patients with treatment related
adverse events. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 626
Analysis 50.17. Comparison 50 HA/hylan versus placebo, Outcome 17 Safety: number of patients with possible study
medication related events. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 627
Analysis 50.18. Comparison 50 HA/hylan versus placebo, Outcome 18 Safety: number of serious adverse events. . . 627
Viscosupplementation for the treatment of osteoarthritis of the knee (Review) xv
Analysis 50.19. Comparison 50 HA/hylan versus placebo, Outcome 19 Safety: number of adverse events probably or
possibly related to treatment. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 628
Analysis 50.20. Comparison 50 HA/hylan versus placebo, Outcome 20 Safety: number of patients reporting adverse
events. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 629
Analysis 51.1. Comparison 51 HA/hylan versus NSAID, Outcome 1 Pain after walking (0-100 mm VAS). . . . . 629
Analysis 51.2. Comparison 51 HA/hylan versus NSAID, Outcome 2 Patient general satisfaction wtih treatment (excellent
or good vs satisfactory or bad). . . . . . . . . . . . . . . . . . . . . . . . . . . . . 630
Analysis 51.3. Comparison 51 HA/hylan versus NSAID, Outcome 3 Safety: total withdrawals overall. . . . . . 631
Analysis 51.4. Comparison 51 HA/hylan versus NSAID, Outcome 4 Safety: number of withdrawals due to inefficacy. 632
Analysis 52.1. Comparison 52 HA/hylan versus Methylprednisolone acetate, Outcome 1 Function: range of motion (active
flexion in degrees). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 632
Analysis 53.1. Comparison 53 HA versus HA, Outcome 1 Pain in movement (number of patients improved). . . . 633
Analysis 53.2. Comparison 53 HA versus HA, Outcome 2 Pressure pain (number of patients improved). . . . . 634
Analysis 53.3. Comparison 53 HA versus HA, Outcome 3 Lequesne Index (0-24). . . . . . . . . . . . . 635
Analysis 53.4. Comparison 53 HA versus HA, Outcome 4 Patient global assessment. . . . . . . . . . . . 636
ADDITIONAL TABLES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 636
APPENDICES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 758
FEEDBACK . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 759
WHAT’S NEW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 760
HISTORY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 760
CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 761
DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 761
SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 761
NOTES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 762
INDEX TERMS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 762
Viscosupplementation for the treatment of osteoarthritis of the knee (Review) xvi

[Intervention Review]
Viscosupplementation for the treatment of osteoarthritis of

the knee
Nicholas Bellamy1 , Jane Campbell2 , Vivian Welch3 , Travis L Gee4 , Robert Bourne2 , George A Wells5
1 Centre of National Research on Disability and Rehabilitation Medicine, Mayne Medical School, The University of Queensland,
Brisbane, Australia. 2 Department of Medicine, London Health Sciences Center, London, Canada. 3 Bruyère Research Institute, Uni-
versity of Ottawa, Ottawa, Canada. 4 Centre of National Research on Disability and Rehabiliation Medicine, University of Queensland,
Brisbane, Australia. 5 Department of Epidemiology and Community Medicine, University of Ottawa, Ottawa, Canada
Contact address: Nicholas Bellamy, Centre of National Research on Disability and Rehabilitation Medicine, Mayne Medical School,
The University of Queensland, Level 3, Herston Road, Brisbane, Queensland, 4006, Australia. n.bellamy@uq.edu.au.
Editorial group: Cochrane Musculoskeletal Group.

Publication status and date: Unchanged, published in Issue 1, 2010.
Review content assessed as up-to-date: 20 February 2006.
Citation: Bellamy N, Campbell J, Welch V, Gee TL, Bourne R, Wells GA. Viscosupplementation for the treatment of osteoarthritis
of the knee. Cochrane Database of Systematic Reviews 2006, Issue 2. Art. No.: CD005321. DOI: 10.1002/14651858.CD005321.pub2.
ABSTRACT
Background
Osteoarthritis (OA) is the most prevalent chronic joint disorder worldwide and is associated with significant pain and disability.
Objectives
To assess the effects of viscosupplementation in the treatment of OA of the knee. The products were hyaluronan and hylan derivatives
(Adant, Arthrum H, Artz (Artzal, Supartz), BioHy (Arthrease, Euflexxa, Nuflexxa), Durolane, Fermathron, Go-On, Hyalgan, Hylan
G-F 20 (Synvisc Hylan G-F 20), Hyruan, NRD-101 (Suvenyl), Orthovisc, Ostenil, Replasyn, SLM-10, Suplasyn, Synject and Zeel
compositum).
Search methods
MEDLINE (up to January (week 1) 2006 for update), EMBASE, PREMEDLINE, Current Contents up to July 2003, and the Cochrane
Central Register of Controlled Trials (CENTRAL) were searched. Specialised journals and reference lists of identified randomised
controlled trials (RCTs) and pertinent review articles up to December 2005 were handsearched.
Selection criteria
RCTs of viscosupplementation for the treatment of people with a diagnosis of OA of the knee were eligible. Single and double-blinded
studies, placebo-based and comparative studies were eligible. At least one of the four OMERACT III core set outcome measures had
to be reported (Bellamy 1997).
Data collection and analysis
Each trial was assessed independently by two reviewers for its methodological quality using a validated tool. All data were extracted by
one reviewer and verified by a second reviewer . Continuous outcome measures were analysed as weighted mean differences (WMD)
with 95% confidence intervals (CI). However, where different scales were used to measure the same outcome, standardized mean
differences (SMD) were used. Dichotomous outcomes were analyzed by relative risk (RR).
Viscosupplementation for the treatment of osteoarthritis of the knee (Review) 1
Main results
Seventy-six trials with a median quality score of 3 (range 1 to 5) were identified. Follow-up periods varied between day of last injection
and eighteen months. Forty trials included comparisons of hyaluronan/hylan and placebo (saline or arthrocentesis), ten trials included
comparisons of intra-articular (IA) corticosteroids, six trials included comparisons of nonsteroidal anti-inflammatory drugs (NSAIDs),
three trials included comparisons of physical therapy, two trials included comparisons of exercise, two trials included comparisons of
arthroscopy, two trials included comparisons of conventional treatment, and fifteen trials included comparisons of other hyaluronans/
hylan. The pooled analyses of the effects of viscosupplements against ’placebo’ controls generally supported the efficacy of this class
of intervention. In these same analyses, differential efficacy effects were observed for different products on different variables and at
different timepoints. Of note is the 5 to 13 week post injection period which showed a percent improvement from baseline of 28 to
54% for pain and 9 to 32% for function. In general, comparable efficacy was noted against NSAIDs and longer-term benefits were
noted in comparisons against IA corticosteroids. In general, few adverse events were reported in the hyaluronan/hylan trials included
in these analyses.
Authors’ conclusions
Based on the aforementioned analyses, viscosupplementation is an effective treatment for OA of the knee with beneficial effects: on
pain, function and patient global assessment; and at different post injection periods but especially at the 5 to 13 week post injection
period. It is of note that the magnitude of the clinical effect, as expressed by the WMD and standardised mean difference (SMD)
from the RevMan 4.2 output, is different for different products, comparisons, timepoints, variables and trial designs. However, there
are few randomised head-to-head comparisons of different viscosupplements and readers should be cautious, therefore, in drawing
conclusions regarding the relative value of different products. The clinical effect for some products, against placebo, on some variables
at some timepoints is in the moderate to large effect-size range. Readers should refer to relevant tables to review specific detail given the
heterogeneity in effects across the product class and some discrepancies observed between the RevMan 4.2 analyses and the original
publications. Overall, the analyses performed are positive for the HA class and particularly positive for some products with respect to
certain variables and timepoints, such as pain on weight bearing at 5 to 13 weeks postinjection.
In general, sample-size restrictions preclude any definitive comment on the safety of the HA class of products; however, within the
constraints of the trial designs employed no major safety issues were detected. In some analyses viscosupplements were comparable in
efficacy to systemic forms of active intervention, with more local reactions but fewer systemic adverse events.
In other analyses HA products had more prolonged effects than IA corticosteroids. Overall, the aforementioned analyses support the
use of the HA class of products in the treatment of knee OA.
PLAIN LANGUAGE SUMMARY

Viscosupplementation for the treatment of osteoarthritis of the knee
Osteoarthritis (OA) is the most common form of chronic arthritis worldwide. Hyaluronan and hylan (HA) products provide opportunity
to treat OA in individual knee joints. To evaluate the efficacy, effectiveness and safety of HA products, in knee OA, we have conducted
a systematic review using Cochrane methodology. The analyses support the contention that the HA class of products is superior to
placebo. There is considerable between-product, between-variable and time-dependent variability in the clinical response. The clinical
effect for some products against placebo on some variables at some time points is in the moderate to large effect size range. In general,
sample size restrictions preclude any definitive comment on the safety of the HA class of products, however, within the constraints of
the trial designs employed, no major safety issues were detected. The analyses suggest that viscosupplements are comparable in efficacy
to systemic forms of active intervention, with more local reactions but fewer systemic adverse events, and that HA products have more
prolonged effects than IA corticosteroids. Overall, the aforementioned analyses support the use of the HA class of products in the
treatment of knee OA.

BACKGROUND that public funding should not support viscosupplementation for
the treatment of knee OA, in March 2003 (MSAC 2003). Choi et
Of all of the specific joint diseases osteoarthritis (OA) is the most al. concluded from their meta-analysis of seven placebo-controlled
frequent cause of rheumatic complaints. OA of the knee is a major trials that viscosupplementation significantly reduced pain in pa-
cause of pain and disability. Guidelines for the management of tients with knee OA, for a period of 5 to 10 weeks after the last
knee OA have been reported in four publications (ACR Guidelines injection (Choi 1999). Lo et al.’s meta-analysis of 18 trials of HA
2000; Jordan 2003; Pendleton 2000; Walker-Bone 2000). against IA placebo, using a hierarchical algorithm to select vari-
Viscosupplementation is an intra-articular (IA) therapeutic ables and timepoints from different trials to charcterise the clinical
modality for the treatment of knee OA based on the physiologic response across variables, timepoints, and studies to the HA class
importance of hyaluronan in synovial joints. Its therapeutic goal is as a whole, indicated that HA had a small effect when compared
to restore the viscoelasticity of synovial hyaluronan, decrease pain, to placebo (Lo 2003; Bernstein 2004; Hou 2004). The evidence
improve mobility and restore the natural protective functions of from Arrich et al.’s systematic review and meta-analysis of 22 tri-
als of HA against placebo suggested that HA was not clinically
hyaluronan in the joint. The short-term mode of action of visco-
supplementation is believed to be based on the pain-relieving ef- effective and that it could be associated with an increased risk of
fect of the elastoviscous fluid in the affected joint. In the long term, adverse events. The most recent meta-analysis by Modawal 2005,
the restoration of joint mobility due to relief of pain is thought based on nine randomised, double-blind, placebo-controlled tri-
to trigger a sequence of events which restores the trans-synovial als, reported that viscosupplementation was moderately effective
flow and subsequently the metabolic and rheological homeostases in relieving OA knee pain at five to seven and eight to ten weeks
after the last injection but not at 15 to 22 weeks.
of the joint.
Given this diversity of opinion there is, therefore, a rational basis
The principle of viscosupplementation was pioneered by Balazs
for performing a Cochrane review of viscosupplementation in knee
and coworkers (Balazs 1982; Denlinger 1998; Peyron 1974; Weiss
OA.
1999). There are now several different formulations of viscosup-
plements (hyaluronan and hylan) produced by different manu-
facturers and of widely different molecular weights. This differ-
ence in molecular weight (MW) is thought to be of importance OBJECTIVES
with respect to the volume/amount and number of injections, the
To assess the effects of viscosupplementation in the treatment
residue time in the joint and biologic effects. Aviad and Houpt
of OA of the knee. The products were hyaluronan and hylan
found no correlation between MW and efficacy (Aviad 1994). Lo
derivatives of widely different molecular weights and formulation
et al. reported that at a higher MW HA may have greater effects,
(Adant, Arthrum H, Artz (Artzal, Supartz), BioHy (Arthrease,
but the heterogeneity of the trials used in this meta-analysis lim-
Euflexxa, Nuflexxa), Durolane, Fermathron, Go-On, Hyalgan,
ited this conclusion (Lo 2003). Based on results observed in vitro,
Hylan G-F 20 (Synvisc Hylan G-F 20), Hyruan, NRD-101,
Maneiro et al. concluded that HA products were different due to
Orthovisc, Ostenil, Replasyn, SLM-10, Suplasyn, Synject and Zeel
differences in biological activity that resulted from the difference
compositum).
in MW (Maneiro 2004).
Viscosupplementation as treatment for knee OA has been the

focus of several review publications (Aggarwal 2004; Altman METHODS
2003; Altman 2000; Ayral 2001; Brandt 2000; Collange 1999;
Dougados 2000; Espallargues 2003; Gossec 2006; Haraoui
2002; Hochberg 2000; Kelly 2003; Khanuja 2003; Kirwan
1997; Kirwan 2001; Lussier 1996; Maheu 1994; Maheu 1995; Criteria for considering studies for this review
Maheu 2003; Marshall 2000; MSAC 2003; Moreland 2003;
Moskowitz 2000; Peyron 1993; Tehranzadeh 2005; Uebelhart
1999; Watterson 2000). Four meta-analyses have been reported Types of studies
(Arrich 2005; Lo 2003; Modawal 2005; Wang 2004). A fifth meta- All randomised controlled clinical trials using one or more visco-
analysis has been reported only as an abstract (Choi 1999). These supplements.
publications employ different methodologies and have shown con-
flicting results. The review by Espallargues and Pons concluded
that a hylan (Hylan G-F 20) was a safe and well-tolerated ther- Types of participants
apy in the short term, but they recommended further work on Participants were males and/or females with a diagnosis of OA of
the effect of multiple courses of hylan (Espallargues 2003). The the knee. Diagnosis was classified as one of the following (any one
Medical Services Advisory Committee (Australia) recommended of the diagnostic criteria below):

a) diagnosis according to published ACR classification criteria ( week 29 2003 (n = 255)), PREMEDLINE (to 21 July 2003
Altman 1986); (n = 8)), Current Contents (to 17 September 2000 (n = 36)),
b) diagnosis according to the algorithm developed by Altman ( and the Cochrane Central Register of Controlled Trials (CEN-
Altman 1991); TRAL) (to the second quarter 2003 (n = 52)) were searched.
c) diagnosis on the basis of detailed clinical and/or radiographic The electronic search was supplemented by handsearches of bib-
information. liographic references and abstracts published in conference pro-
ceedings or in special issues of specialized journals, up to the
Types of interventions end of December 2005. One reviewer (JC) handsearched all rel-
evant journals at The University of Western Ontario, London,
All viscosupplements used for the treatment of OA of the knee in
Canada. The journals that were handsearched were: Acta Ortho-
humans.
pedica Scandinavica, Acta Rheumatologica Scandinavica, American
Control treatments included: placebo (saline, arthrocentesis) and
Journal of Orthopedics, American Journal of Sports Medicine, Annals
active treatment.
of the Rheumatic Diseases, Arthritis Care & Research, Arthritis &
Rheumatism, Arthroscopy, Bailliere’s Clinical Rheumatology, British
Types of outcome measures Journal of Clinical Practice, British Journal of Rheumatology (now
The OMERACT III core set of outcome measures was considered Rheumatology), British Journal of Sports Medicine, British Medical
for analysis (Bellamy 1997): Journal (now BMJ), Bulletin - Hospital for Joint Diseases, Bulletin
a) pain; on the Rheumatic Diseases, Clinical and Experimental Rheumatol-
b) physical function; ogy, Clinical Therapeutics, Current Medical Research and Opinion,
c) patient global assessment; Current Orthopaedics, Current Therapeutic Research Clinical and
d) joint imaging (for studies of one year or longer). Experimental, Drugs, Drug and Therapeutics Bulletin, JAMA, The
The minimum criterion for inclusion of the trial in the systematic Journal of Bone and Joint Surgery (American and British), Journal
review was the adequate reporting of at least one of the outcome of Bone and Mineral Research, Journal of Orthopaedic and Sports
variables a) or b) or c). Information regarding other outcome mea- Physical Therapy, Journal of Orthopaedic Research, Journal of Or-
sures was extracted and analysed when feasible. thopedic Rheumatology, Netherlands Journal of Medicine, New Eng-
The following variables were included for assessment of adverse land Journal of Medicine, Orthopedics, Orthopaedic Review, Physio-
reactions to IA injection: therapy Practice, Physiotherapy Theory and Practice, Rheumatology
1) by procedure; and Physical Medicine, Rheumatology and Rehabilitation, Rheuma-
a) infection; tology International, Scandinavian Journal of Rheumatology, Sem-
b) needle breakage or separation; inars in Arthritis and Rheumatism, The Journal of Musculoskele-
c) hypersensitivity to local anaesthetic or preservative; tal Medicine, The Journal of Rheumatology and the Lancet. Refer-
d) discomfort at site of injection; ence lists were handsearched for further identification of published
2) by viscosupplement; work and presentations at scientific meetings (e.g. American Col-
a) swelling; lege of Rheumatology (ACR), The Asia Pacific League of Asso-
b) pain; ciations for Rheumatology (APLAR), European League Against
3) by toxicity-related withdrawals; Rheumatism (EULAR), International League of Associations for
4) by total number of withdrawals and dropouts. Rheumatology (ILAR), Pan-American League of Associations for
Rheumatology (PANLAR), OsteoArthritis Research Society Inter-
national (OARSI), American Academy of Orthopaedic Surgeons
Search methods for identification of studies (AAOS)). There were no language restrictions.
Industry representatives were contacted requesting reports on ad-
MEDLINE and EMBASE were used initially to identify all clinical
ditional studies of their products that might meet eligibility crite-
trials relating to the use of viscosupplementation therapy in OA.
ria.
MEDLINE searches for clinical trials were based on the Cochrane
The search strategy used is in Appendix 1.
search strategy (Dickerson 1994; Haynes 1994). The MeSH head-
ing osteoarthritis (degenerative arthritis, gonoarthrosis) (all sub-
headings) was added to the search. Similar searches were prepared
for the other databases. The lists of references of retrieved pub-
Data collection and analysis
lications were also manually checked to add any citations missed Selection of trials
by the electronic searches. Abstracts from scientific meetings were Inclusion criteria were based on the characteristics of interest. The
included if enough information was available in the abstract. inclusion criteria were:
MEDLINE (1966 to week 2 July 2003 (n = 156 identified)(for a) diagnosis of OA of the knee in participants as specified earlier;
update to January (week 1) 2006 (n=92)), EMBASE (1988 to b) randomised controlled trial design;

c) specification of comparative treatment; (I) while worsening is indicated by (W). Only if a comparison
d) published data on relevant outcome measures; resulted in a statistically significant difference and baseline values
e) statistical analysis including intention-to-treat approach. were reported was the clinical relevance (i.e. NNT or benefit) re-
Data collection ported in the text.
Data from the trials were extracted by one reviewer (JC) and veri- In other additional tables the results of analyses for continuous
fied by a second reviewer (VR). For the update one reviewer (JC) outcome measures based on effect size (SMD) are presented to
extracted the data and a second reviewer (NB) verified the data allow reviewers an alternate appreciation of the magnitude of the
extraction. Trials were not blinded as to authors or institutions. effect (compared with WMD).
Every effort was made to obtain translations. If the change of the standard deviation (SD) was reported in the
A data collection form was developed to use for data collection publication the quadratic formula was used to convert the change
and subsequent entry into Review Manager (RevMan) 4.2.8. SD to the raw SD; ρ was set at 0.4, a conservative estimate of the
Data synthesis correlation between baseline and post-test scores. This value for ρ
Quantitative data were analysed as unadjusted post-test scores closely approximates values for ρ generated from analyses based
(Lund 1988). Selected timepoints defined a priori and reflecting on PMA data of Hylan G-F 20 trials reporting both interval and
short-term, intermediate-term and long-term follow-up were: 1 to change scores. If median rather than mean values were reported
4 weeks postinjection (with respect to the last injection), 5 to 13 the median was extracted. If the range was reported the SD was
weeks postinjection, 14 to 26 weeks postinjection and 45 to 52 calculated as range divided by 4.
weeks postinjection. If two follow-up assessments were completed In comparisons of two hyaluronans the ’new’ hyaluronan was con-
within one of the defined timepoints the results of the later of the sidered the treatment and the ’old’ marketed hyaluronan was con-
two assessments were selected for inclusion. For continuous out- sidered the control.
come data measured on the same scale weighted mean differences Cochrane policy is, where possible, to avoid the use of proprietary
(WMD) were calculated. When pain and function were measured names of products under review. In the case of this viscosupple-
on different scales we defined a hierarchy of pain and function mentation review, an exception has been made, for purposes of
measures then used standardized mean differences (SMD) to pool clarity, and to permit consumers to more easily identify the prod-
across RCTs (Hedges 1985; Petitti 1994). In the event, a variable- ucts being reviewed. HA products are normally identified by their
by-variable approach to data extraction was pursued in order to proprietary names since this is the only exclusive label that allows
avoid any potential bias resulting from the hierarchical approach, readers/consumers a common language to understand which prod-
which might have excluded more or less responsive variables from uct is being described. We consider this preferable to circuitous de-
consideration. The SMD controls for different units by calculat- scriptions based on method of manufacture and molecular weight.
ing an effect size by dividing the mean difference between treat- In this particular review, we have described the products accord-
ment and control by the standard deviation. For all pooled out- ing to the names commonly used by manufacturers, providers and
comes, heterogeneity was tested with a chi square test. A fixed-ef- consumers.
fect model was used unless heterogeneity was significant (P value < Evaluation of the data was by meta-analysis using RevMan 4.2.8).
0.10), in which case a random-effects (RE) model was used. Since Readers should note that the analyses that follow were based on
the RevMan Analyses window in RevMan 4.2.8 only permits one secondary, not primary, data and only use statistical methods con-
model to be set for an outcome, the text results present the correct tained within RevMan 4.2.8 software. As a result, some analyses
model. If there is only one trial in a comparison the default is a may differ in level of significance (in either direction) from that
fixed-effect model. Only P values less than 0.05 are reported in reported in the original publication, based on primary data and
the text of the Results section. other analytic techniques. These differences are apparent in some
For categorical outcome data with two categories, relative risk (RR) comparisons based on only a single study but may not be evident
was calculated (Petitti 1994). to the reader in comparisons based on meta-analyses where data
In the Additional Tables section, clinical relevance tables are pro- from multiple studies were combined. Results and interpretations
vided. For dichotomous outcome measures, the number needed may need to take into account these analytic differences, which
to treat (NNT) has been provided. The NNT was calculated as are summarised in Additional Table 1. This is potentially a generic
one divided by the risk difference. For continuous outcome mea- issue and not necessarily limited to this particular review.
sures, the absolute benefit and the relative difference in the change
from baseline are presented. The absolute benefit was calculated as
the improvement in the treatment group (followup mean minus
baseline line) less the improvement in the control group (followup RESULTS
mean minus baseline mean). The relative difference in the change
from baseline was calculated as the absolute benefit divided by the
baseline mean of the control group. Improvement is indicated by Description of studies

The following information was systematically extracted. a description of withdrawals or dropouts (1 point). Two additional
Trial methodology: points are given if the method of randomisation was described and
randomisation; it was appropriate (e.g. computer generated) (1 point), and if the
controlled; method of double blinding was described and it was appropriate
blinding: single, double, masked observer; (e.g. identical placebo) (1 point). Two points can be deducted
design: parallel-group, cross-over; if the method of randomisation was inappropriate (e.g. patients
number of centres; randomised according to date of birth) (-1 point), or if the method
stratification variables; of blinding was inappropriate (e.g. comparison of an oral tablet
washout utilization; versus IA injection with no double dummy) (-1 point).
type of analysis: per protocol, intent to treat.
Characteristics of the study population:
country where trial was completed; Effects of interventions
mean age;
Results are presented by product. An independent evaluation by
percentage of female patients;
product is recommended rather than a by-class meta-analysis since
mean disease duration;
these products differ in their MW, concentration, treatment sched-
number randomised;
ules, and mode of production (Altman 2003; Blue Cross 1998).
inclusion/exclusion criteria;
Furthermore, since the response is time-dependent, and may dif-
baseline values of outcomes.
fer between outcome variables, the response has been presented
Interventions:
on a by-product, by-variable and by-time basis for each individual
description of experimental and control treatments;
product. At the end of the product-by-product evaluation there is
concurrent therapy usage.
a section based on the by-class (pooled) results. Readers are cau-
Outcomes:
tioned to note the many differences in study design while reading
primary (when reported, a dash line followed);
the results of this analysis. The Discussion section addresses some
secondary outcomes.
of these issues.
In notes:
Product - Adant
Jadad score: randomisation (R), blinding (B), description of with-
Description of studies
drawals/dropouts (W) (Jadad 1996);
One RCT was included: a comparison of Adant and another
presence/absence of effusion;
hyaluronan (Roman 2000).
if bilateral disease, selection criteria for injected joint(s);
Roman et al. reported a six-month, parallel-group, blind RCT
trial affiliation with industry (e.g. sponsorship, authorship, statis-
performed at a single centre comparing five weekly injections of
tical analysis).
Adant (Treatment: MW 900,000 D biotechnically obtained) to
Allocation concealment was evaluated using the following criteria:
five weekly injections of Hyalgan (Control: MW 800,000 D ob-
1) adequately concealed trials (i.e. central randomisation; num-
tained from rooster crest) in 49 patients with OA of the knee
bered or coded bottles or containers; drugs prepared by the phar-
(Roman 2000). The authors concluded that the efficacy of Adant
macy; serially numbered, opaque sealed envelopes; or other de-
was greater than with Hyalgan at three months after treatment.
scription that contained elements convincing of concealment), 2)
They reported that maximum improvement was seen at five weeks
inadequate (i.e. alternation or reference to case record numbers
with response decreasing over time resulting in almost 75% of pa-
or to dates of birth), and 3) unclear (i.e. authors either did not
tients reporting only ’fair’ or ’no’ clinical response at six months
report an allocation concealment approach at all or reported an
postinjection. Pain at the injection site was almost twice as great
approach that did not fall into one of the above two categories)
with Adant. The Jadad score for this study was 3 out of a max-
(Schulz 1995).
imum of 5; specific details of blinding and randomisation were
not reported in the publication. The randomisation allocation was
1.6:1 (e.g. n = 30:19) in favour of the Adant group. Allocation
Risk of bias in included studies concealment was unclear (i.e. not reported).
Methodological quality was assessed by two reviewers (NB and In this RCT several design issues were noted: 1) one and a half
JC). A third reviewer (GW) re-evaluated these assessments and times as many patients were randomised to the Adant group com-
acted as adjudicator in cases of disagreement. The quality of the pared to the Hyalgan group; 2) eighty-four percent of the patients
methodology of the trials was rated by the criteria recommended by were female; 3) no exclusion criteria were reported in the Mate-
Jadad et al. (Jadad 1996). Briefly, this instrument has a maximum rials and Methods section of the publication; 4) details regarding
score of 5 points. A score of one point is given for each of the presence or absence of effusion, uni- or bilateral disease, OA di-
following: if the study was described as randomised (1 point), if agnosis criteria and disease duration were not published; 5) effi-
the study was described as double blind (1 point), and if there was cacy was assessed only by the patient subjective assessment, the

details of which were not published. However, injection technique rected to the Hylan G-F 20, NRD-101 and SLM-10 sections for
was standardised and the effect of concomitant analgesic and/or results based on these products. With respect to methodological
anti-inflammatory drugs was considered. Although the authors at- quality, the average Jadad score was 4.3 out of 5 with three tri-
tributed the ’greater efficacy’ with Adant at three months and the als scoring 5 (Day 2004; Karlsson 2002; Puhl 1993), three tri-
higher incidence of pain at the injection site to its greater viscos- als scoring 4 (Lohmander 1996; Shichikawa 1983a; Shichikawa
ity and volume, there were no statistically significant differences 1983b) and one trial scoring 3 (Wu 1997). Allocation conceal-
between the products in either the efficacy or safety profiles. ment was adequate in three trials (Puhl 1993; Shichikawa 1983a;
Four trials were excluded: Couceiro 2003; Guerrero 1999; Shichikawa 1983b) and unclear (not reported) in four trials (Day
Guerrero 1999a; Novaes 2005. One trial is awaiting assessment: 2004; Karlsson 2002; Lohmander 1996; Wu 1997). Two ran-
Blanco Garcia 2004. domised, double-blind, placebo-controlled, multicentre trials have
Adant versus placebo: no trials included. been completed: one in France (Bourgeois (Artz)) and one in
Adant versus corticosteroid: no trials included. the United Kingdom (Byrd (Artz)) but have only been published
Adant versus NSAID: no trials included. as part of the Food and Drug Administration Pre-Market Ap-
Adant versus other hyaluronan proval Package (Number P980044, Docket #01M-0342). Seven-
Efficacy teen studies, reported between 1982 and 2005, were excluded
The only efficacy outcome measure extracted from this trial (Arizono 1997; Dahlberg 1994; Fuji 1994; Hashimoto 1992;
(Roman 2000) was patient global assessment (e.g. number of pa- Honma 1989; Igarashi 1983; Iseki 1983; Iwasaki 1993; Kawakami
tients excellent or good) (Table 2). At each of the three timepoints 1993; Namiki 1982; Oshima 1983; Shibata 1993; Suzu 1990;
there were no statistically significant differences between the two Takeuchi 1993; Tang 2004; Tang 2005; Yoh 1989).
groups: at 1 to 4 weeks postinjection, 43% of the Adant patients Day et al. reported an 18-week, placebo-controlled, double-blind
and 37% of the Hyalgan patients were excellent or good; at 5 to RCT performed at 17 centres in Australia comparing five weekly
13 weeks postinjection, 50% of the Adant patients and 21% of injections of Artz to five weekly injections of saline in 240 pa-
the Hyalgan patients were excellent or good; and at 14 to 26 weeks tients with OA of the knee (Day 2001; Day 2004). A significant
postinjection, 33% of the Adant patients and 16% of the Hyalgan difference between the two comparison groups for each outcome
patients were excellent or good. measure evaluated was reported. A total of 482 adverse events were
The RevMan analysis differed from the publication analysis. The reported but only 81 were possibly, probably or definitely related
publication reported a significant difference in favour of Adant to study medication (Artz n = 50, saline n = 31). Tolerability was
compared to Hyalgan at three months in the number of patients reported as being excellent since approximately 95% of patients
rating the improvement as excellent or good (P value < 0.05) completed the full treatment schedule. Injection site pain and in-
whereas RevMan reported a P value of 0.07. flammation, that was mild and of short duration, was the most
Safety frequent adverse event and occurred in approximately 10% of pa-
The number of patients reporting painful injections was almost tients.
twice as high in the Adant group (6/30, 20%) versus Hyalgan (2/ In the Discussion of the Day RCT (Day 2004) the authors sug-
19, 11%). This difference was not statistically significant (Table gested that their positive result, in comparison to the Lohmander
3). RCT (Lohmander 1996), may have been due to the inclusion cri-
The RevMan analysis differed from the publication analysis. The teria. Specifically, only patients with unilateral, mild-to-moderate
publication reported a significant difference in favour of Hyalgan disease, with no patellofemoral OA or clinically large effusions,
compared to Adant in the number of patients with painful infil- and who were not morbidly obese were entered into the trial. Both
trations (P value < 0.001) whereas RevMan detected a P value of lateral and medial approaches were utilised for IA injections in this
0.4. trial. However, the same approach was used for all injections in
Product - Arthrum H one patient.
Description of studies Karlsson et al. reported a one-year, placebo-controlled, parallel-
One trial was excluded: Bardin 2004. group, double-blind RCT performed at 19 centres in Sweden com-
Product - Artz (Artzal, Supartz) paring three weekly injections of Artzal (Astra Lakemedel) to three
Description of studies weekly injections of Hylan G-F 20 (Roche) and three weekly in-
Nine trials of Artz (Seikagaku Corporation) have been included. jections of placebo (phosphate-buffered saline solution) in 210 pa-
Seven included comparisons of Artz against placebo (Day 2004; tients with OA of the knee (Karlsson 2002). All patients, regard-
Karlsson 2002; Lohmander 1996; Puhl 1993; Shichikawa 1983a; less of treatment, showed clinical improvement during the first 26
Shichikawa 1983b; Wu 1997) and three included comparisons weeks of the treatment. Neither hyaluronan/hylan product pro-
of Artz against three other hyaluronan/hylan products: Hylan G- duced a longer duration of clinical benefit than placebo. How-
F 20 (Karlsson 2002), NRD-101 (Tsukamoto 1995 (abstract); ever, a significantly longer duration of clinical benefit was achieved
Yamamoto 1994) and SLM-10 (Kawabata 1993). Readers are di- when data from the two hyaluronan products were pooled. No

serious adverse events due to the treatments were reported. Treat- 1996) in that patients older than 60 y with a Lequesne score greater
ment was discontinued due to adverse events in similar numbers of than 10 were the most likely to benefit from treatment. Local reac-
patients in each of the treatment groups. In this review the Karls- tions at the injection site were reported in similar numbers in both
son 2002a reference refers to the Artzal versus placebo comparison groups (Artz n = 4, vehicle n = 5) and all were of short duration
(Karlsson 2002a (AvP), the Karlsson 2002b reference refers to the and minor severity.
Hylan G-F 20 versus placebo comparison (Karlsson 2002b (SvP)) This well-designed trial excluded patients with excessive (greater
and the Karlsson 2002c reference refers to the Artzal versus Hylan than 100 ml) joint effusion (Puhl 1993).
G-F 20 comparison (Karlsson 2002c (AvS)). Shichikawa et al. reported a five-week, parallel-group, double-
The Karlsson RCT (Karlsson 2002) inclusion criteria were based blind RCT performed at 38 centres in Japan comparing five weekly
on the Lohmander RCT (Lohmander 1996): patients aged 60 injections of Artz (1.0% sodium hyaluronate) plus one placebo
years or above, with a baseline Lequesne Index above 10, and ra- tablet (lactose coated) administered three times daily after ev-
diographically verified OA as Ahlback grade I-II. A Lequesne score ery meal to five weekly injections of suspending vehicle (0.25
of 8 to 10 points represents severe handicap. Surgery is indicated mg, 0.01% sodium hyaluronate) plus one placebo tablet (lactose
for scores of 10 to 12 points and higher. An Ahlback Stage I is coated) administered three times daily after every meal in 228 pa-
classified as narrowing of the joint space (with or without sub- tients with OA of the knee (Shichikawa 1983a). Statistically sig-
chondral sclerosis); joint space narrowing is defined by a space nificant differences in favour of Artz compared to control were
inferior to 3 mm or inferior to the half of the space in the other reported for final effectiveness and usefulness. No systemic adverse
compartment (or in the homologous compartment of the other events were reported. Local reactions were reported by four pa-
knee). An Ahlback Stage II is classified as “obliteration of the joint tients in the control group and one patient in the Artz group. One
space” (Karlsson 2003d, Magilavy 2003). patient in the control group had treatment discontinued due to
Lohmander et al. reported a 20-week, placebo-controlled, dou- side effects.
ble-blind RCT performed at eight centres in Denmark, Finland, The following design issues were noted: 1) follow-up was lim-
Norway and Sweden comparing five weekly injections of Artzal ited to one week after final injection; 2) patients with severe joint
to five weekly injections of saline in 240 patients with OA of the space narrowing and marked retention of synovial effusion were
knee (Lohmander 1996). Prior to code break, patient data were excluded; 3) patients recorded in symptom diaries at 10:00 daily;
stratified by age (40 to 60 y, 61 to 75 y) and Lequesne algofunc- 4) authors attributed some of the local pain to injection procedure
tional index score (4 to 10, greater than 10). Although both groups (Shichikawa 1983a).
improved from baseline at the end of the study there was no dif- Shichikawa et al. reported a five-week, parallel-group, double-
ference between the two groups. However, when the two stratifi- blind RCT performed at 16 centres in Japan comparing five
cation variables were utilised in the analyses Artzal was found to weekly injections of Artz (0.5% sodium hyaluronate) plus two
be more effective than saline in older (greater than 60 y) patients placebo tablets (sugar coated lactose) administered three times
with more severe symptoms (Lequesne greater or equal to 10). daily to five weekly injections of suspending vehicle (0.01%
Although no serious adverse events were reported seven patients sodium hyaluronate solution) plus two placebo tablets (sugar
(Artz n = 2, saline n = 5) withdrew from the trial due to adverse coated lactose) administered three times daily in 107 patients with
events. Severity of injection-site swelling was significantly greater OA of the knee (Shichikawa 1983b). Statistically significant dif-
in the Artz group. Dr. S. Lohmander kindly provided unpublished ferences in favour of Artz compared to control were reported for
data from the trial for this review. final effectiveness, pain in motion and usefulness. Treatment was
The well-designed Lohmander RCT (Lohmander 1996) had a discontinued in three patients (Artz n = 1, control n = 2) due to
pretrial meeting to standardize the injection procedure and assess- adverse events.
ment procedures. The discussion of this report summarises some The following design issues were noted: 1) follow-up was limited
of the difficulties in interpreting trials of HA. This is one of the few to one week after final injection; 2) patients with moderate-to-
trials which stratified patients based on baseline age and Lequesne severe joint space narrowing and synovial effusion were excluded
Index scores. (Shichikawa 1983b).
Puhl et al. reported an 18-week, parallel-group, double-blind RCT Wu et al. reported a 26-week, placebo-controlled, double-blind
performed at 25 centres in Germany comparing five weekly injec- RCT performed at a single centre in China comparing five weekly
tions of Artz to five weekly injections of suspending vehicle (0.25 injections of Artz to five weekly injections of the solvent for Artz
mg of sodium hyaluronate per 2.5 ml) in 209 patients with OA in 90 patients with OA of the knee (Wu 1997). Statistically signifi-
of the knee (Puhl 1993). A statistically significant difference was cant efficacy was reported for Artz compared to placebo beginning
reported in the Lequesne Index (the primary outcome measure) in one week after the fifth injection and lasting up to three months.
favour of the Artz group from the third injection to the end of the During the six-month trial no adverse events were reported.
trial. In a subsequent publication (Puhl 1997) a subgroup analysis The following design issue was noted: 1) patients with marked
confirmed the findings of the Lohmander et al. trial (Lohmander joint space narrowing and large amounts of synovial effusion were

excluded (Wu 1997). knee) (Karlsson 2002a (AvP)).
Artz versus placebo Safety
Efficacy There was no statistically significant difference in the number of
With respect to the placebo comparisons at 1 to 4 weeks postin- withdrawals, overall, at 1 to 4 weeks postinjection (Shichikawa
jection, there were no statistically significant differences between 1983a; Shichikawa 1983b); at 5 to 13 weeks postinjection (Day
Artz and placebo for the following outcome measures: pain (0 to 2004; Puhl 1993); or at 14 to 26 weeks postinjection (Lohmander
3 scale) (Shichikawa 1983b); pain (0 to 100 mm VAS) (Karlsson 1996). There was no statistically significant difference in the
2002a (AvP); Lohmander 1996; Puhl 1993); Lequesne Index (0 number of withdrawals due to adverse events at 1 to 4 weeks
to 24) (Puhl 1993); and range of motion (degrees) (Shichikawa postinjection (Shichikawa 1983a; Shichikawa 1983b); at 5 to 13
1983b). There was a statistically significant difference in favour of weeks postinjection (Day 2004); at 14 to 26 weeks postinjection
Artz for patient global assessment (RR 1.17; 95% CI 1.04 to 1.32, (Lohmander 1996); or at 45 to 52 weeks postinjection (Karlsson
P value 0.008) (Lohmander 1996; Shichikawa 1983a; Shichikawa 2002a (AvP)). There were no statistically significant differences in
1983b). With the exception of the Lohmander trial (Lohmander the number of participants withdrawn overall at 5 to 13 or at 14
1996), the NNT for patient global assessment was between 5 and to 26 weeks postinjection. The number of adverse events probably
11 patients.(Table 4;Table 5) or possibly related to treatment was statistically greater in the Artz
The RevMan analysis differed from the Puhl et al. publication group compared to the saline group at 5 to 13 weeks postinjection
analysis (Puhl 1993). The publication reported a statistically sig- (RR 1.59; 95% CI 1.12 to 2.26, P value 0.009) (Day 2004; Puhl
nificant difference in favour of Artz compared to placebo for the 1993), but there was no difference at 45 to 52 weeks postinjec-
Lequesne Index at 1 to 4 weeks postinjection (P value 0.043) com- tion (Karlsson 2002a (AvP)). There was no statistically significant
pared to the RevMan analysis (P value 0.7). difference in the number of patients with local adverse events in
At 5 to 13 weeks postinjection, there were no statistically signifi- whom the study treatment was continued at 1 to 4 weeks postin-
cant differences between Artz and placebo for: WOMAC OA In- jection (Shichikawa 1983a). In Karlsson’s trial (Karlsson 2002a
dex pain (0 to 20) (Day 2004); WOMAC OA Index physical func- (AvP)) at 45 to 52 weeks postinjection there was no statistically
tion (0 to 68) (Day 2004); Lequesne Index (Puhl 1993); and pa- significant difference in the number of patients reporting adverse
tient global assessment (Lohmander 1996; Puhl 1993). However, events or in the number of serious adverse events. In Wu’s study
Artz was better than placebo for pain (100 mm VAS) (WMD - (Wu 1997), no side effects developed over a six-month period.
4.55; 95% CI -9.09 to 0.00, P value 0.05) (Karlsson 2002a (AvP); Artz versus corticosteroid: No trials included.
Lohmander 1996; Puhl 1993). Artz was between 5 and 20% more Artz versus NSAID: No trials included.
effective than saline in relieving pain at 5 to 13 weeks postinjec- Artz versus other hyaluronan
tion. One RCT included was a comparison of Artzal and Hylan G-F
The RevMan analysis differed from the Day et al. publication anal- 20 (Karlsson 2002c (AvS)). Readers are directed to the NRD-101
ysis (Day 2004). The publication reported statistically significant and SLM-10 sections for results based on comparisons of Artz and
between-group differences in WOMAC pain (P value 0.045) and these products.
WOMAC stiffness (P value 0.024) in favour of the Artz group Efficacy
compared to the placebo group, whereas the RevMan analysis did With respect to the Artzal comparison against Hylan G-F 20
not detect a significant difference (WOMAC pain P value 0.07, (Karlsson 2002c (AvS)), there were no statistically significant dif-
WOMAC stiffness P value 0.07). The RevMan analysis differed ferences between the two products in pain on weight bearing (0
from the Puhl et al. publication analysis (Puhl 1993). The pub- to 100 mm VAS) at the three assessment times: 1 to 4, 5 to 13, or
lication reported a statistically significant difference in favour of 14 to 26 weeks postinjection. There was no statistically significant
Artz compared to placebo for the Lequesne Index at 5 to 13 weeks difference between the two products in the Lequesne Index at 14
post injection (P value 0.0053) compared to the RevMan analysis to 26 weeks postinjection. There were no statistically significant
which did not (P value 0.5). differences between the two products in the number of clinical
At 14 to 26 weeks postinjection, no statistically significant dif- failures either at 14 to 26 or 45 to 52 weeks postinjection, or
ferences were found between Artz and placebo for the Lequesne in the number of survivors (i.e. patients not requiring additional
Index or pain (100 mm VAS) (Karlsson 2002a (AvP); Lohmander treatment to study knee) at 45 to 52 weeks postinjection.(Table
1996). However, more patients improved in the Artz than placebo 6; Table 7)
group for patient global assessment (Lohmander 1996). The num- Safety
ber of clinical failures was higher in the saline group (11%) versus
Artzal (2%) (Karlsson 2002a (AvP)). There were no statistically significant differences between Artzal
At 45 to 52 weeks postinjection there was no statistically significant and Hylan G-F 20 at 45 to 52 weeks postinjection in the number
difference in the number of clinical failures or in the number of of patients withdrawn due to adverse events, the number of adverse
survivors (i.e. patients not requiring additional treatment for study events related to treatment, or the number of patients reporting

adverse events. randomisation and blinding both were reported in the publica-
Product - Biohy (Arthrease, Euflexxa, Nuflexxa) tion. Allocation concealment was adequate. One should note that
Description of studies this trial was designed and powered to test for non-inferiority. Fer-
Two trials of BioHy have been included. One trial included a com- ring Pharmaceuticals Inc. kindly provided the means and standard
parison against placebo (Tamir 2001) and the other trial included errors for the WOMAC OA Index stiffness and physical function
a comparison against Hylan G-F 20 (Kirchner 2006; Thompson subscales for the ITT population. Biotechnology General (Israel)
2002 (abstract)). Ltd. kindly provided the poster of this trial that was presented at
Tamir et al. reported a 20-week, placebo-controlled, single-blind, the OARSI 2002 Congress as well as an Excel file of the WOMAC
open-label RCT performed at a single orthopaedic clinic in Turkey OA Index pain subscale data.
comparing three weekly injections of BioHy (Bio-Technology BioHy versus placebo
General, manufactured by bacterial fermentation of the non- Efficacy
hemolytic strain of Streptococcus zooepidemicus) to three weekly No efficacy results have been extracted from this trial (Tamir
injections of phosphate-buffered saline in 49 patients with OA of 2001). Pain and stiffness results were reported as change but nei-
the knee (Tamir 2001). The authors reported that this feasibility ther baseline values nor measures of dispersion were reported.
study was not sufficiently powered to detect between-group dif-
ferences. However, they found a ’favourable trend’ for BioHy in Safety
decreasing pain. With respect to safety, they reported that BioHy There were no statistically significant differences in the safety pro-
was well tolerated and no HA-related adverse events were found. file of BioHy and placebo. There were a similar number of with-
With respect to methodological quality, it scored 3 out of 5 on the drawals overall in both groups: BioHy 12% and placebo 17%.
Jadad scale; specific details of randomisation were not reported in The difference in the percentage of patients in the BioHy group
the publication. Allocation concealment was unclear. (72%) who reported knee pain immediately after the injection,
In this RCT, several design issues were noted: 1) patients with which was related to the injection procedure, was not significantly
more than 15 ml of aspirated synovial fluid (SF) were excluded; different from that in the placebo group (46%). No systemic ad-
2) concurrent and escape medication such as paracetamol and verse events were reported in either group.
NSAIDs were permitted throughout the trial; 3) although the BioHy versus corticosteroid: no trials included.
AAOS MODEMS arthritic module was utilised for assessing pain, BioHy versus NSAID: no trials included.
stiffness and physical function, all the pain variables were assessed BioHy versus other hyaluronan
and scored by the investigator and not by the patient; 4) in re- One RCT was included comparing Euflexxa (syn: Arthrease,
porting the results the authors did not provide baseline means, BioHy) and Hylan G-F 20 (Kirchner 2006; Thompson 2002 (ab-
rather they reported change in mean categorical scores without stract)).
any measure of dispersion excluding this trial from the analysis; 5) Efficacy
the trial was found to be under powered. There were no statistically significant differences in the WOMAC
The Thompson et al. trial, first published as an abstract ( OA Index pain subscale either at 1 to 4 or 5 to 13 weeks
Thompson 2002), has now been reported as a full-length article postinjection. There were statistically significant differences in the
by Kirchner and Marshall (Kirchner 2006). Kirchner and Mar- WOMAC OA Index physical function subscale in favour of Eu-
shall reported a 12-week, parallel-group, double-blind, multicen- flexxa compared to Hylan G-F 20 both at 1 to 4 weeks postin-
tre RCT performed at 10 centres in Germany comparing three jection (WMD -5.10; 95% CI -9.54 to -0.66, P value 0.02), and
weekly injections of Euflexxa (Arthrease) to three weekly injec- at 5 to 13 weeks postinjection (WMD -5.40; 95% CI,-9.83 to -
tions of Hylan G-F 20 in 321 patients with OA of the knee. For 0.97, P value 0.02). Euflexxa was 3% more effective than Hylan
the primary outcome measure, the WOMAC OA Index pain sub- G-F 20 in improving WOMAC physical function. There were no
scale, both groups reported statistically significant improvements statistically significant differences in the WOMAC stiffness sub-
from baseline. In addition, the criteria for non-inferiority were scale either at 1 to 4 or at 5 to 13 weeks postinjection. There
met. With regards to secondary outcome measures, statistically was no statistically significant difference in the number of patients
significant differences favoured Euflexxa for patient global satis- symptom-free (VAS score for the average of the five WOMAC
faction and the number of patients requiring acetaminophen for pain questions less than 20 mm) in the WOMAC OA Index pain
rescue analgesia. With respect to safety, a statistically significant subscale at 5 to 13 weeks postinjection (Euflexxa 63%, Hylan G-F
difference was detected in the number of joint effusions; 0.6% in 20 52%). There was a statistically significant difference in favour
the Euflexxa group compared to 8.1% in the Synvisc group. The of Euflexxa compared to Hylan G-F 20 for the number of pa-
authors concluded that the effectiveness of Euflexxa was not infe- tients who were symptom-free based on the WOMAC OA Index
rior to that of Synvisc, but due to the higher incidence of effusions physical function subscale at 5 to 13 weeks postinjection (Euflexxa
that Euflexxa had a safety advantage. 64%, Hylan G-F 20 47%) (RR 1.36; 95% CI 1.11 to 1.66, P
This trial scored 5 out of 5 on the Jadad scale; specific details of value 0.003). There was no statistically significant difference in

the number of patients that assessed the treatment as ’very satis- by the inclusion of patients with OA at other sites since an analysis
fied or satisfied’ (Euflexxa 81%, Hylan G-F 20 75%). There were based only on patients with knee OA showed a greater response to
statistically significant differences in favour of Euflexxa compared Durolane than placebo. With respect to methodological quality,
to Hylan G-F 20 for the number of patients using acetaminophen the trial scored 5 out of 5 on the Jadad scale achieving points for
(rescue medication) both at 1 to 4 weeks postinjection (RR 0.72, both randomisation and blinding details. Allocation concealment
95% CI 0.57 to 0.91, P value 0.006), and at 5 to 13 weeks postin- was adequate.
jection (RR 0.71; 95% CI 0.56 to 0.89, P value 0.003), and also The statistical analyses were performed using the change from
during the trial (RR 0.83; 95% CI 0.71 to 0.97, P value 0.02). baseline since raw means and standard deviations for unadjusted
The RevMan analysis differed from the publication analysis for post-test scores were not available.
several analyses. The publication reported no statistically signifi- One trial is awaiting assessment: Sinha 2003.
cant difference between groups in the WOMAC OA Index phys- One trial was excluded: Akermark 2004.
ical function subscale. RevMan detected a statistically significant Durolane versus placebo
difference both at 1 to 4 and 5 to 13 weeks postinjection (P value Efficacy
0.02). The publication reported a statistically significant differ- The primary outcome measure for this trial was a positive response
ence in the number of patients that were symptom-free with re- to treatment where a responder was defined “as a reduction in the
spect to the WOMAC OA Index pain subscale (95% CI 0.3 to WOMAC pain score of at least 40% with an absolute improve-
21.7, P value 0.038) whereas RevMan did not detect a statistically ment of at least 5 points compared with baseline for the study knee
significant difference (RR 1.21; 95% CI 1.00 to 1.46, P value at the final visit”. There were no statistically significant differences
0.05). The P value for the number of patients who required res- between Durolane and saline at any of the follow-up assessments:
cue medication during the study was smaller in the publication at week 2; week 6; week 13 or week 26. However, when the analysis
(0.013) compared to RevMan (0.02). The publication reported a was based only on patients with knee OA, a statistically significant
statistically significant difference in favour of Euflexxa compared difference in favour of Durolane was found at week 6 (RR 1.53;
to Hylan G-F 20 for the number of patients that assessed the treat- 95% CI 1.05 to 2.23, P value 0.03) (NNT was 7); but not at any
ment as ’very satisfied’ (P value 0.03) whereas RevMan detected of the other follow-up assessments: at week 2, week 13 or week
no difference in the number ’very satisfied or satisfied’ (P value 26.
0.23). Table 8; Table 9 Readers should note that the following efficacy results are based
Safety on change from baseline scores not unadjusted post-test scores. A
There was no statistically significant difference between the two statistically significant difference was detected in favour of saline
groups for the following safety outcomes: total withdrawals over- for WOMAC OA Index pain subscale at week 2 (WMD 0.74;
all, withdrawals due to adverse events, withdrawals due to lack of 95% CI 0.02 to 1.46, P value 0.04). Saline was 2% more effective
efficacy (none in either group), number of patients with serious than Durolane in improving pain. This differed from the publi-
adverse events, number of patients reporting adverse events (Eu- cation which reported no significant between-group difference. A
flexxa 34%, Hylan G-F 20 40%). There was a statistically sig- statistically significant difference was detected in favour of saline
nificant difference in the number of patients with joint effusion for WOMAC OA Index stiffness subscale at week 2 (WMD 0.51;
(Euflexxa 0.6%, Hylan G-F 20 8%) (RR 0.08; 95% CI 0.01 to 95% CI 0.16 to 0.86, P value 0.005). Saline was 4% better than
0.58, P value 0.01). The RevMan P value for this last comparison Durolane in improving stiffness. The original publicaton reported
differed from the publication P value of 0.0015.Table 10 statistically significant between-group differences both at 2 and
Product - Durolane (NASHA - non-animal stabilized 6 months. No statistically significant difference was detected for
hyaluronic acid) the WOMAC OA Index physical function subscale at any of the
Description of studies timepoints. This RevMan analysis differed from the publication
One RCT was included comparing Durolane to placebo (Altman in which a statistically significant between-group difference was
2004). reported at 2 weeks.(Table 11; Table 12)
Altman et al. reported a 26-week, placebo-controlled, double- Safety
blind RCT performed at 18 centres in Canada (6 centres), Sweden
(5 centres), and the United States (7 centres) comparing a single There were no statistically significant differences in the safety out-
injection of Durolane (synthesized by Streptococci, 60 mg) to a comes reported: total withdrawals overall; withdrawals due to in-
single injection of saline (identical buffered sodium chloride ve- efficacy; withdrawals due to adverse events; number of patients
hicle) in 347 patients with OA of the knee (Altman 2004). The affected by device-related adverse events; number of patients with
authors reported that although WOMAC scores and quality of adverse events related to injection only; number of patients with
life improved in both groups, there were no between-group differ- non-serious treatment-related adverse events; number of patients
ences. There were few treatment-related adverse events. The au- with non-serious adverse events; number of patients with treated
thors proposed that the efficacy data may have been confounded unrelated adverse events, and number of patients with serious

treatment-unrelated adverse events.(Table 13) ated.
Product - Fermathron
Product - Go-On
Description of studies
One RCT was included comparing Fermathron to another There were no RCTs of Go-On available (correspondence from
hyaluronan (McDonald 2000). Rotta Research Laboratorium July 1, 2004).
McDonald et al. reported a six-month, parallel-group, double-
blind RCT performed at 12 centres in Germany comparing five Product - Hyalgan
weekly injections of Fermathron (Fermentech Medical Ltd., man-
ufactured by bacterial fermentation) to five weekly injections of Description of studies
Hyalart (Fidia SpA, obtained from rooster combs) in 256 patients
with OA of the knee (McDonald 2000). The authors reported Twenty-nine randomised controlled trials have been included
that the products were similar in efficacy and that both were well with Hyalgan (marketed also as Hyalart and Polyreumin)
tolerated. With respect to methodological quality, the trial scored (Fidia Pharmaceutical Corporation, Italy, derived from rooster
5 out of 5 on the Jadad scale achieving points for both randomisa- combs): 14 included comparisons against placebo (Altman 1998;
tion and blinding details. Allocation concealment was adequate. Bragantini 1987; Bunyaratavej 2001; Carrabba 1995; Corrado
This was a well-designed and reported ’non-inferiority’ study of 1995; Creamer 1994; Dougados 1993; Formiguera Sala 1995;
two HA products. The importance of escape medication was ad- Grecomoro 1987; Henderson 1994; Huskisson 1999; Jubb 2003;
dressed in the study design. Patients kept a daily diary which was St. J. Dixon 1988; Tsai 2003), one was a comparison against no
declared as the secondary performance variable. Moreover, the au- treatment (Miltner 2002; Schneider 1997), one was a comparison
thors investigated the correlation between the route of injection against arthroscopic washout (Forster 2003), one was a compar-
(knee straight or bent, medial or lateral approach) with the local ison against exercise, exercise and ultrasound, and no treatment
adverse event incident rate. They found that the lowest risk was with only warmup exercises (Huang 2005), three were compar-
associated with a lateral approach to a straight knee (Jones 1993). isons against other hyaluronan products (McDonald 2000; Roman
Source of HA (i.e. bacterial fermentation versus rooster combs) 2000; Brown 2003), five were comparisons against corticosteroids
did not affect the results. (Frizziero 2002; Leardini 1987; Leardini 1991; Pietrogrande 1991,
One trial is awaiting assessment: Sinha 2003. against methylprednisolone acetate; Jones 1995, against triamci-
Fermathron versus placebo: no trials included. nolone acetate), one was a comparison against NSAID (Altman
Fermathron versus corticosteroid: no trials included. 1998), one was a comparison against a homeopathic preparation
Fermathron versus NSAID: no trials included. (Zeel Compositum) (Nahler 1998) (readers are directed to the
Fermathron versus other hyaluronan Zeel product section), one was a comparison against mucopolysac-
caride polysulfuric acid ester (Graf 1993), one was a comparison
Efficacy against conventional therapy (Listrat 1997) and one was a com-
parison of treatment regimens (Karras 2001). Except for three
The three efficacy outcome measures extracted from this trial were trials (Brown 2003; Karras 2001; Tsai 2003) which have been
pain (0 to 100 mm VAS), the Lequesne Index (0 to 24), and published as abstracts the remaining trials have been published
patient global assessment (very good, good, average, poor, very as journal articles. In three trials, Hyalgan was the control inter-
poor). No statistically significant differences were found between vention (McDonald 2000; Nahler 1998; Roman 2000). The fre-
the two products for pain or the Lequesne Index at 1 to 4 or 5 to quency of injection varied between studies (3, 4 and 5 weekly in-
13 weeks postinjection. No statistically significant difference was jections). Considering only the 26 trials in which Hyalgan was des-
found in the number of responders at 5 to 13 weeks postinjection ignated the experimental intervention (i.e. excluding McDonald
with 72.4% in the Hyalart group and 69.6% in the Fermathron 2000; Nahler 1998; Roman 2000), with respect to methodolog-
group that reported feeling better or much better.(Table 14; Table ical quality the average Jadad score was 2.81 out of 5 with one
15) trial scoring 5 (Henderson 1994), 7 trials scoring 4 (Altman 1998;
Bunyaratavej 2001; Frizziero 2002; Huskisson 1999; Jones 1995;
Safety Jubb 2003; St. J. Dixon 1988), 6 trials scoring 3 (Carrabba 1995;
Corrado 1995; Formiguera Sala 1995; Forster 2003; Grecomoro
There was no statistically significant difference in the number of 1987; Huang 2005), 10 trials scoring 2 (Bragantini 1987; Creamer
related adverse events (Fermathron 21% versus Hyalart 14%). 1994; Dougados 1993; Graf 1993; Karras 2001; Leardini 1987;
. Leardini 1991; Listrat 1997; Pietrogrande 1991; Tsai 2003) and 2
These results confirmed the results of the publication indicating trials scoring 1 (Brown 2003; Miltner 2002). Again, considering
that the two products were similar in performance and well toler- only the 26 trials in which Hyalgan was designated the experimen-

tal intervention allocation concealment was adequate in three tri- F 20. The protocol called for a sample size of 100 patients with
als (Forster 2003; Frizziero 2002; Huang 2005) and unclear (not 50 to be randomised to each group. The trial was designed to last
reported) in 23 trials. six months. The number of patients that developed an acutely in-
Twenty-three studies were excluded (Aglas 1997; Carrabba flamed painful knee was 6 out of 29 in the Hylan G-F 20 group
1992; D’Agnolo 1988; Dahlberg 1994; Frizziero 1993; Frizziero compared to 0 of 25 in the Hyalgan group. Statistically signifi-
1997; Frizziero 1998; Grecomoro 1992; Hamburger 2004; cant improvement in WOMAC pain and function was found for
Kotz 1999; Mazzocato 1987; Mensitieri 1995; Milini 1989; Hyalgan while a trend of improvement was found for Hylan G-F
Pasquali Ronchetti 2001; Pavelka 2002; Pipino 1990; Punzi 20.
1988; Rao 2001; Scali 1995; Sieliwonczyk 1997; Turajane 2005; Two study design points were noted: 1) this RCT was conducted
Turajane 2005a; Zamora-Quezada 2004). Four trials are await- in a clinical practice setting; 2) randomisation was based on the
ing assessment (Garcia 2004; Joergensen 2005; Stitik 2004; consultant to whom the patient was referred.
NCT00130468). Bunyaratavej et al. reported a six-month, placebo-controlled,
Altman et al. reported a 26-week, placebo- and naproxen-con- double-blind RCT performed at three centres in Asia (China,
trolled, double-blind, double-dummy, stratified, parallel-group Malaysia, Thailand) comparing four weekly injections of Hyalgan
RCT performed at 15 centres in the United States comparing five to four weekly injections of saline in 49 patents with OA of the
weekly injections of Hyalgan plus oral placebo twice daily to five knee (Bunyaratavej 2001). Statistically significant differences in
weekly injection of saline plus oral placebo or naproxen 500 mg favour of Hyalgan were reported one month after treatment as
twice daily in 495 patients with OA of the knee (Altman 1998). reflected by decreased pain and increased joint mobility. No local
Only 67% of the patients completed the trial. Hyalgan was more or systemic adverse events related to treatment were observed. No
efficacious (pain relief and improved function) than placebo and measure of dispersion was reported for the saline group for pain
as effective as naproxen with fewer side effects. Injection site pain on active movement nor for either treatment group for day pain at
was more common in the Hyalgan group while gastrointestinal baseline. Consequently, this review includes safety but not efficacy
adverse events were more common in the naproxen group. data.
Several design issues are noted: 1) the placebo group received active This was one of two RCT where a four-injection schedule of
treatment in the form of 4 g of acetaminophen and arthrocentesis Hyalgan was followed. In addition, acetaminophen (paracetamol)
with synovial fluid aspiration if necessary; 2) the naproxen group up to 3000 mg daily was permitted.
did not receive arthrocentesis, they received a subcutaneous injec- Carrabba et al. reported a six-month, placebo- and arthrocente-
tion; 3) a training video was provided to all sites; 4) one criterion sis-controlled, double-blind, parallel-group RCT performed at a
of success was defined as an effect size of 0.25 of the standard de- single centre in Italy comparing three dose schedules of Hyalgan
viation or 6 mm; 5) the data for all secondary outcome measures (one, three and five weekly injections) to five weekly arthrocentesis
was analysed only for those patients who completed the 26 weeks or five weekly injections of saline in 100 patients with OA of the
of follow-up since the intent-to-treat analysis detected only a 1.5 knee (Carrabba 1995). All five groups received arthrocentesis at
mm difference between the Hyalgan and placebo groups in the the baseline visit. A significantly superior effect of five and three
primary outcome measure (pain during the 50-foot walk test); and injections of Hyalgan was shown in comparison with placebo,
6) escape analgesia, as 500 mg acetaminophen up to 4000 mg/day, arthrocentesis and one injection of Hyalgan. Four patients re-
was permitted. Analyses showed no statistically significant differ- ported minor local reactions after injection (one patient each in
ences between the three arms of the trial. the arthrocentesis group, the one, three and five injection Hyalgan
Bragantini et al. reported a 60-day, placebo-controlled, single- groups). This review does not report results based on the one injec-
blind, parallel-group RCT performed at a single centre in Italy tion Hyalgan arm. The 1995 reference refers to the five injection
comparing three weekly injections of Hyalgan (both 20 mg and Hyalgan versus saline comparison (Carrabba 1995); the 1995a ref-
40 mg) to three weekly injections of saline in 55 patients with OA erence refers to the three injection Hyalgan versus saline compari-
of the knee (Bragantini 1987). Both dosage levels of Hyalgan were son (Carrabba 1995a); the 1995b reference refers to the five injec-
significantly superior to placebo. Four patients experienced local tion Hyalgan versus arthrocentesis comparison (Carrabba 1995b);
pain and burning after injection with Hyalgan but these reactions and the 1995c reference refers to the three injection Hyalgan ver-
resolved within a short time. In this review, we have only used the sus arthrocentesis comparison (Carrabba 1995c).
Hyalgan 20 mg arm for comparison against saline. In this RCT paracetamol (acetaminophen) was permitted. How-
Brown and Beinat reported a six-week, parallel-group, RCT per- ever, only 15% of the patients used it at baseline, and there was
formed at a single centre in England comparing five weekly in- no change in usage over the duration of the trial.
jections of Hyalgan to three weekly injections of Hylan G-F 20 Corrado et al. reported a two-month, placebo-controlled, double-
in 54 patients with OA of the knee (Brown 2003). This trial was blind RCT performed at a single centre in Italy comparing five
discontinued, with about 50% of enrolment completed, due to weekly injections of Hyalgan to five weekly injections of placebo
a high frequency of acute inflammatory reactions with Hylan G- (water, sodium chloride, sodium phosphate) in 40 patients with

OA of the knee (Corrado 1995). A significant difference in favour 2) study population consisted of 36 patients, but 40 joints; 3)
of Hyalgan was reported for pain and range of motion. Two pa- four patients were recruited twice: two receiving placebo in one
tients experienced ’accidental trauma’ to the knee during treat- knee and Hyalgan in the other, one patient receiving Hyalgan in
ment. separate knees at both times, one patient receiving placebo in the
In order to study the possible anti-inflammatory activity of same knee on two occasions; and 4) the treatment in the second
Hyalgan, Corrado et al. completed a biochemical assessment of knee took place some time after the first knee was treated.
synovial fluid and plasma. Forster and Straw reported a one-year, parallel-group RCT per-
Creamer et al. reported a nine-week, placebo-controlled, single- formed at a single centre in England comparing five weekly injec-
blind, blind-observer RCT performed at a single centre in Eng- tions of Hyalgan to arthroscopic washout (two litres 0.9% saline
land comparing five weekly injections of Hyalgan to five weekly at least) with either general or spinal anaesthesia in 38 patients
injections of saline in 12 patients with bilateral OA of the knee with OA of the knee (Forster 2003; Forster 2003a). No signifi-
(Creamer 1994). This study investigated the mode of action of cant differences between the two groups were found in any of the
HA. It was not designed to assess clinical efficacy. No beneficial clinical outcome measures at any assessment point. Two patients
clinical effect was found for Hyalgan as compared to placebo. in the Hyalgan group reported pain at the injection site following
Twelve adverse events were reported by seven patients. Five local one injection.
reactions (pain and swelling), graded as severe, occurred in three Dr. Forster kindly provided an Excel data file from which we cal-
Hyalgan-treated knees and two placebo-treated knees. culated means and standard deviations.
Several design issues were noted: 1) each patient acted as his/her Frizziero and Pasquali Ronchetti reported a six-month, parallel-
own control; 2) paracetamol up to 4 g daily was permitted; 3) group, single-blind RCT performed at a single centre in Italy com-
imaging assessments, both MRI and 99m Tc scintigraphic bone paring five weekly injections of Hyalgan to three weekly injections
scans, were performed; and 4) four of the treated knees and six of of methylprednisolone acetate in 99 patients with primary or sec-
the placebo knees had only patellofemoral disease. ondary OA of the knee (Frizziero 2002). The authors found an
Dougados et al. reported a one-year, placebo-controlled, single- initial statistically significant difference in favour of methylpred-
blind RCT performed at a single centre in France comparing four nisolone acetate at day 35 but not at day 180. The clinical effect
weekly injections of Hyalectin to four weekly injections of the with Hyalgan appeared more gradually but lasted longer than that
vehicle in 110 patients with OA of the knee (Dougados 1993). of methylprednisolone acetate. Arthroscopic evaluations showed
Greater improvement was found in the Hyalectin group compared that Hyalgan was superior to methylprednisolone acetate in reduc-
to the placebo group for pain and function (Lequesne) in the ing the extent and grade of cartilage damage. No adverse events
early assessment and for physician’s overall assessment of efficacy were reported in the Hyalgan group compared to two patients in
and the Lequesne Index in the long term. Nine patients did not the methylprednisolone acetate group, one resulting in withdrawal
receive all four injections: four in the Hyalectin group (two due from the trial.
to painful injection, one lack of efficacy, and one improved) and This RCT was one of the trials which examined the structural
five in the placebo group (one due to painful injection, one lack effects of Hyalgan using both arthroscopic and microarthroscopic
of efficacy, three due to reasons unrelated to treatment (traumatic examinations.
hemarthrosis in one, refusal to continue in two). Graf et al. reported a six-month, verum-controlled, single-blind
Several design issues were noted: 1) this RCT followed a four RCT performed at a single centre in Germany comparing Hyalgan
injection schedule of Hyalgan; 2) one-sided tests were used in once per week (seven injections) to mucopolysaccharide polysul-
the statistical analysis; and 3) the physician that administered the furic acid (MPA) ester twice per week (13 injections) in 60 pa-
injection also completed the clinical assessment. Fidia Spa kindly tients with OA of the knee (Graf 1993). At the end of the treat-
provided an in-house report of this trial. ment phase the improvement in the modified total Larson rating
Formiguera Sala and Esteve de Miguel reported a 90-day, placebo- score was significantly better in the Hyalgan group. The authors
controlled, double-blind RCT performed at a single centre in reported a more rapid onset of pain relief with Hyalgan. At the end
Spain comparing five weekly injections of Hyalgan to five weekly of the trial significantly more patients in the Hyalgan group were
injections of saline in 36 patients with OA of the knee (Formiguera symptom free or markedly improved. There was a causal relation-
Sala 1995). There were no significant differences between the ship with study medication for six adverse events in the Hyalgan
groups at day 35. However, at day 90, statistically significant dif- group and for two adverse events in the MPA group.
ferences in favour of Hyalgan were reported for pain outcome This RCT was the only trial where a seven injection schedule of
measures. Three patients in each group reported pain that “could Hyalgan was followed.
be attributed to the route of administration and the individual Grecomoro et al. reported a 60-day, placebo-controlled, double-
idiosyncrasies of the patients”. blind RCT performed at a single centre in Italy comparing three
Several design issues were noted: 1) the supero-external approach weekly injections of Hyalgan to three weekly injections of phos-
with the patient in a supine position was followed for injections; phate buffer in 34 patients with OA of the knee (Grecomoro

1987). A significant difference between treatments was reported centre in England comparing five weekly injections of Hyalgan
for all the clinical variables assessed. In the Hyalgan group, pain re- to five weekly injections of saline in 100 patients with OA of the
lief was both rapid and long lasting. No ’untoward signs or symp- knee (Huskisson 1999). Superiority of Hyalgan over placebo was
toms’ were reported. Two patients withdrew early in the placebo demonstrated. Local reactions occurred in similar numbers in each
group for reasons unrelated to treatment. group: seven patients in each group reported flare at the joint while
In this RCT results were based on 40 joints of 34 patients. effusion was present in three patients in the placebo group and
Henderson et al. reported a five-month, placebo-controlled, dou- one patient in the Hyalgan group.
ble-blind RCT performed at a single centre in England compar- This trial was conducted in England to readdress the efficacy of
ing five weekly injections of Hyalgan to five weekly injections of Hyalgan over placebo (see: Henderson 1994). Fidia Spa kindly
vehicle in 91 patients with OA of the knee (Henderson 1994). Pa- provided an in-house statistical report providing means and stan-
tients were stratified into two groups based on radiological sever- dard deviations for pain on walking for all randomised patients
ity. In this review, the reference to Henderson 1994 refers to for this trial.
the milder severity group; while Henderson 1994a refers to the Jones et al. reported a six-month, double-blind, parallel-group
more severe group. No significant differences were found between RCT performed at a single centre in England comparing five
the two groups. The rate of return to previously prescribed or weekly injections of Hyalgan to one injection of triamcinolone
other NSAIDs or analgesia was significantly slower in the Hyalgan hexacetonide followed by four injections of saline in 63 patients
treated group in the subgroup of patients with mild disease. Local with bilateral OA of the knee (Jones 1995). Active treatment,
reactions (pain and swelling) were observed in 47% of the patients which was randomised, was always given to the worst knee. The
in the Hyalgan group compared to 22% in the placebo group. placebo therapy was not randomised, and, therefore, no data were
Several design issues were noted: 1) all but one patient had bilateral extracted for comparisons between Hyalgan and saline. No sta-
disease; 2) a clinical metrologist was used; 3) injections were into tistically significant differences were found between the groups in
the patello-femoral space with a medial approach; and 4) there the intention-to-treat analysis. However, in the completer analysis
was a high percentage of withdrawals (38%). significantly less pain was seen in the Hyalgan group with other
Huang et al. reported a one-year, single-blind RCT performed at parameters showing a similar trend in favour of Hyalgan. Sixty-
a single centre in Taiwan comparing isokinetic muscular strength- eight percent of the patients dropped out of the study, the majority
ening exercises alone to: 1) isokinetic exercise and pulse ultrasound due to lack of efficacy. By week 29 only 26% of the triamcinolone
treatment for painful periarticular soft tissue, 2) isokinetic exercise, hexacetonide patients and 38% of the Hyalgan patients remained
pulse ultrasound treatment for painful periarticular soft tissue and in the trial.
intraarticular Hyalgan 5 weekly injections, and 3) no treatment Jubb et al. reported a one-year, placebo-controlled, double-blind
other than warmup exercises (Huang 2005). All three active treat- RCT performed at 17 centres in the United Kingdom comparing
ment groups showed significantly reduced pain and disability and three weekly injections of Hyalgan to three weekly injections of
increased muscle peak torques after treatment and at the end of saline (vehicle placebo) in 408 patients with OA of the knee (Jubb
the study. The active treatment group including Hyalgan showed 2001a; Jubb 2001b; Jubb 2001c; Jubb 2001d; Jubb 2003). The
the greatest increase in walking speed and decrease in disability treatment schedule was repeated twice more at four-monthly in-
after treatment and at the one-year follow-up. The authors con- tervals. The aim of the study was to investigate structural changes
cluded that an “integrated therapy including ultrasound, isoki- as measured by joint space narrowing (the primary outcome). Sta-
netic strengthening exercise, and intraarticular hyaluronan ther- tistically significant differences in favour of Hyalgan were found
apy is suggested for the management of knee OA”. During the for the pain outcome measures. Since the primary analysis did
treatment phase, nine patients withdrew from the study due to not show any differences between the two groups with respect to
intolerable pain induced to the prescribed exercise, while three joint space narrowing, the authors performed a subgroup analysis
patients withdrew because of muscle weakness. During the one- based on baseline joint space width. Those patients with radio-
year follow-up period, 13 patients were lost to follow-up. logically milder disease (less than 4.6 mm) had less progression of
This trial used the same physiatrists (who were blinded to treat- joint space narrowing when treated with Hyalgan. A total of 7.2%
ment) to perform all the evaluations. Measurement of knee range of the Hyalgan patients and 3% of the saline patients withdrew
of motion was standardised. All patients received warmup exercises prematurely due to adverse events; 2.4% and 1.5%, respectively,
with 20 minutes of hot packs application followed by passive range due to local adverse events. Local effects were reported by 36.1%
of motion exercises on an electric stationary bicycle for 5 minutes of the Hyalgan patients and 27.5% of the saline patients. Serious
to both knees before commencing the muscle strengthening exer- adverse events, all due to concomitant disease, were reported by
cises. Fidia Spa kindly provided page proofs of a manuscript which 13% of the Hyalgan patients and 7% of the saline patients.
was in press. In the Tables of Comparisons and data Jubb 2003 entries refer to
Huskisson and Donnelly reported a six-month, placebo-con- the full journal publication; Jubb 2001a entries refer to the primary
trolled, blind-observer, parallel-group RCT performed at a single analysis population; Jubb 2001b entries refer to the subgroup with

joint space width equal or greater than 4.6 mm; Jubb 2001c entries performed at a single centre in Germany comparing five weekly
refer to the subgroup with joint space width less than 4.6 mm. injections of Hyalart in the impaired knee to no treatment in the
Since reduction of joint space width was the primary efficacy contralateral, untreated knee in 43 patients with OA of the knee
outcome measure in this trial evaluation was based on comput- (Miltner 2002; Schneider 1997). The objective of this trial was
erised digital image analysis of anteroposterior weight-bearing ra- to assess the effect of Hyalart on total work and isokinetic muscle
diographs. The trial also addressed the safety of repeated cycles of strength. This pilot study showed that Hyalart was effective with
Hyalgan. Fidia Spa kindly provided an in-house statistical report regard to both clinical outcomes (e.g. relieving pain and improving
for pain on walking. function) as well as to functional outcomes (e.g. peak torque and
Karras et al. reported a one-year, parallel-group RCT performed at total work). Schneider et al. published a preliminary evaluation of
a single centre in Greece comparing five weekly injections every six this trial in German based on 18 patients (Schneider 1997).
months of Hyalgan to three weekly injections every three months Several design issues were noted: 1) all patients had bilateral dis-
of Hyalgan in 200 patients with OA of the knee (Karras 2001). The ease; 2) the control group received no treatment; and 3) follow-
objective was to compare the effectiveness of the two regimens. up was limited to one week after the final injection.
The authors reported that the three-injection regimen was more Pietrogrande et al. reported a 60-day, open, parallel-group RCT
effective than the five-injection regimen. Except for three cases of performed at three centres in Italy comparing five weekly injections
local pain there were no side effects reported. of Hyalgan to three weekly injections of 6-methylprednisolone
Leardini et al. reported a one-year, single-blind, parallel-group acetate in 90 patients with OA of the knee (Pietrogrande 1991).
RCT performed at a single centre in Italy comparing three weekly Although both treatments reduced the disease symptoms 6-MPA
injections of Hyalgan to three weekly injections of methylpred- had a more rapid action that did not last as long as that of Hyalgan.
nisolone acetate (MPA) in 36 patients with OA of the knee At the final assessment significant differences were found between
(Leardini 1987). No statistically significant differences were found the treatments for most outcome measures. One patient in the
between the two groups in the clinical assessments. Local reactions Hyalgan group had a local reaction which resolved spontaneously
were reported in three patients in the MPA group compared to but the patient was withdrawn due to lack of efficacy. No systemic
four patients in the Hyalgan group. adverse reactions were reported in either group.
This trial reported results on 40 joints of 36 patients (four with St. J. Dixon et al. reported a 48-week, placebo-controlled, double-
bilateral disease). blind, parallel-group RCT performed at three centres in England
Leardini et al. reported a 60-day, open, parallel-group RCT per- comparing Hyalgan (up to eleven injections over 23 weeks) to ve-
formed at a single centre in Italy comparing three weekly injections hicle (0.2 mg sodium hyaluronate) in 63 patients with OA of the
of Hyalgan to three weekly injections of 6-methylprednisolone knee (St. J. Dixon 1988). Knee pain was significantly reduced in
acetate (6-MPA) in 40 patients with OA of the knee (Leardini the Hyalgan group compared to the placebo group. No between-
1991). Assessments, completed one week after the end of treat- group difference was found for function as measured by activities
ment, showed that Hyalgan was comparable to 6-MPA. In the of daily living. Possible treatment-related (Hyalgan) adverse events
longer term significant differences were found in favour of Hyalgan occurred in three patients: hemarthrosis developed in one patient,
for the pain outcomes. All patients completed the treatment sched- effusion volume increased in one patient, and phlebitis developed
ule. No local or systemic reactions were reported. in one patient. Ten patients did not complete the trial. Five pa-
In this trial, all patients were kept ’at rest’ for two days after injec- tients in the placebo group withdrew early because of increased
tion. pain; while five patients withdrew early in the Hyalgan group: one
Listrat et al. reported a one-year, open, parallel-group RCT per- because of a torn meniscus, one because knee was painless, one
formed at a single centre in France comparing three weekly injec- had increased pain, one defaulted and one had a hemarthrosis. No
tions of Hyalgan every three months for a total of nine injections measure of dispersion was reported for pain on movement, pain
to conventional therapy in 39 patients with OA of the knee (Listrat at rest, or activities of daily living and, consequently, efficacy data
1997). All patients underwent knee arthroscopy before randomi- are not included in this review. Only safety data are included in
sation. A statistically significant difference in favour of Hyalgan this review.
was found for the quality of life index. A statistically significant This is the only RCT where up to 11 injections of Hyalgan were
difference for two of three structural parameters was found in used. Fidia Spa kindly provided an in-house clinical report for pain
favour of Hyalgan. Forty percent of the Hyalgan patients reported on movement and rest pain.
transient local reactions (pain) associated with the injection. Tsai et al. reported a 25-week, placebo-controlled, multicentre,
This study evaluated the potential structure-modifying effects double-blind RCT performed in Taiwan comparing five weekly
of Hyalgan. The arthroscopy was videotaped and assessed by a injections of Hyalgan to five weekly injections of saline in 200
blinded assessor. The primary efficacy outcomes were the arthro- patients with OA of the knee (Tsai 2003). Statistically significant
scopic parameters. differences were found in favour of Hyalgan for pain on 50-foot
Miltner et al. reported a seven-week, right to left comparison RCT walk, WOMAC OA Index pain and physical function. No differ-

ences between treatments were reported in adverse event occur- Index pain, measured on a 0 to 100 mm VAS, between Hyalgan
rence. and placebo at 1 to 4 weeks or at 5 to 13 weeks postinjection.
Fidia Spa kindly provided an in-house report (Lin 2004) as only There was a statistically significant difference in favour of Hyalgan
an abstract, based on this trial, had been published in 2003 (Tsai compared to saline at 14 to 26 weeks postinjection (WMD -5.66;
2003). 95% CI -10.06 to -1.26, P value 0.01) (Lin 2004, Tsai 2003) with
Hyalgan versus placebo Hyalgan being 14% more effective than saline.
Pain was measured using several dichotomous outcome measures.
Efficacy There were statistically significant differences in favour of Hyalgan
Table 16; Table 17; Table 18 compared to placebo for the number of joints improved for walk-
Based on 14 comparisons, there was a statistically significant differ- ing pain at the end of treatment (RR 1.68; 95% CI 1.02 to 2.78, P
ence in pain on weight bearing, measured on a 0 to 100 mm VAS, value 0.04) (Bragantini 1987); at 1 week postinjection (RR 3.60;
in favour of Hyalgan compared to placebo at 1 to 4 weeks postin- 95% CI 1.48 to 8.78, P value 0.005) (Grecomoro 1987); and
jection (WMD (random-effects model) -6.20; 95% CI -11.02 to at 5 to 13 weeks postinjection (RR 2.30; 95% CI 1.26 to 4.19,
-1.38, P value 0.009). Hyalgan was 2 to 31% more effective than P value 0.006) (Bragantini 1987). The NNT for walking pain
placebo in improving pain. Based on 10 comparisons, there was a was 2 to 3. Similarly, statistically significant differences in favour
statistically significant difference in favour of Hyalgan compared of Hyalgan compared to placebo were found for the number of
to placebo at 5 to 13 weeks postinjection (WMD (random-ef- joints improved for pain under load at the end of treatment (RR
fects model) -9.04; 95% CI -14.10 to -3.98; P value 0.0005). 0.37; 95% CI 0.19 to 0.73, P value 0.004) (Bragantini 1987);
Hyalgan was 18 to 44% more effective than placebo in improv- at 1 week postinjection (RR 3.60; 95% CI 1.48 to 8.78, P value
ing pain. There was a statistically significant difference in favour 0.005) (Grecomoro 1987); and at 5 to 13 weeks postinjection (RR
of Hyalgan compared to placebo at 14 to 26 weeks postinjection 0.25; 95% CI 0.10 to 0.60, P value 0.002) (Bragantini 1987). The
(WMD -4.12; 95% CI -6.97 to -1.27, P value 0.005) (Altman NNT for pain under load was 2.
1998; Huskisson 1999; Jubb 2003; Tsai 2003). Hyalgan was 3 to There was no statistically significant difference in pain, expressed
26% more effective than placebo in improving pain. There was no as the number of patients improved, at 5 to 13 weeks postinjection.
statistically significant difference at 45 to 52 weeks postinjection The RevMan analysis differed from the publication analysis where
(Dougados 1993; Jubb 2003; St. J. Dixon 1988). the P value was 0.04 (chi square test). A significant difference in
There was a statistically significant difference in spontaneous pain, favour of Hyalgan compared to placebo was found at 32 weeks
measured on a 0 to 100 mm VAS, in favour of Hyalgan compared postinjection (RR 1.36; 95% CI 1.06 to 1.75, P value 0.02) (Jubb
to placebo at 1 to 4 weeks postinjection (WMD -23.88; 95% 2003). The NNT for patient global assessment was 9.
CI -33.50 to -14.25, P value < 0.00001), and at 5 to 13 weeks There was no statistically significant difference in the number of
postinjection (WMD (random-effects model) -22.28; 95% CI patients who had moderate to marked pain or in those who had
-38.88 to -5.68, P value 0.009) (Bragantini 1987; Grecomoro none to slight to mild pain at 14 to 26 weeks postinjection (Altman
1987). Hyalgan was 38 to 67% more effective than placebo in 1998).
improving pain. There were no statistically significant differences in the number
There was a statistically significant difference in pain at rest, mea- of knee joints without night pain at 1 to 4 or at 5 to 13 weeks
sured on a 0 to 100 mm VAS, in favour of Hyalgan compared postinjection (Creamer 1994). There were no statistically signif-
to placebo at 1 to 4 weeks postinjection (WMD (random-effects icant differences in the number of participants without rest pain
model) -6.37; 95% CI -11.57 to -1.18, P value 0.02) (Carrabba at 1 to 4 or at 5 to 13 weeks postinjection (Creamer 1994).
1995; Carrabba 1995a; Carrabba 1995b; Carrabba 1995c; There was a statistically significant difference in the number of
Corrado 1995; Dougados 1993; Henderson 1994; Henderson joints with improvement in pain on touch in favour of Hyalgan
1994a; St. J. Dixon 1988), and at 5 to 13 weeks postinjec- compared to placebo (RR 2.25; 95% CI 1.12 to 4.53, P value
tion (WMD -9.65; 95% CI -14.18 to -5.13, P value 0.00003) 0.02) (Grecomoro 1987). The NNT for pain on touch was 2.
(Carrabba 1995; Carrabba 1995a; Carrabba 1995b; Carrabba There were no statistically significant differences in WOMAC OA
1995c; Corrado 1995). Hyalgan was 13 to 116% more effective Index physical function, measured on a 0 to 100 mm VAS, between
than placebo in improving pain. There was no statistically signifi- Hyalgan and saline at 1 to 4, 5 to 13, or 14 to 26 weeks postinjec-
cant difference at 45 to 52 weeks postinjection (Dougados 1993; tion (Lin 2004; Tsai 2003). The RevMan analysis (WMD -4.05;
St. J. Dixon 1988). 95% CI -8.38 to 0.28, P value 0.07) differed from the publication
There was no statistically significant difference in pain at night, analysis where a statistically significant difference was found in
measured on a 0 to 100 mm VAS, between Hyalgan and placebo favour of Hyalgan in WOMAC physical function from baseline
at 5 to 13 weeks post injection (Henderson 1994; Henderson to week 25 (P value 0.0038 (ANOVA)).
1994a). Statistically significant differences in the Lequesne Index, mea-
There were no statistically significant differences in WOMAC OA sured on a 0 to 24 scale, in favour of Hyalgan compared to placebo

were found at 1 to 4 weeks postinjection (WMD -1.50; 95% CI - CI 1.22 to 3.70, P value 0.008) (Bragantini 1987; Creamer 1994).
2.36 to -0.65, P value 0.0006) (Carrabba 1995; Carrabba 1995a; The NNT for patient global assessment was 11.
Carrabba 1995b; Carrabba 1995c; Dougados 1993; Huskisson
1999), and at 5 to 13 weeks postinjection (WMD -2.34; 95% CI - Safety
3.41 to -1.27, P value 0.00002) (Carrabba 1995; Carrabba 1995a;
Carrabba 1995b; Carrabba 1995c; Huskisson 1999). Hyalgan was There were no statistically significant differences in the total num-
11 to 25% more effective than placebo. No statistically significant ber of withdrawals overall at 5 to 13 weeks postinjection (Carrabba
difference was found at 14 to 26 weeks postinjection (Huskisson 1995; Corrado 1995); at 14 to 26 weeks postinjection (Altman
1999) or at 45 to 52 weeks postinjection (Dougados 1993). The 1998; Henderson 1994; Huskisson 1999; Lin 2004); or at 45 at
RevMan analysis (WMD -1.11; 95% CI -2.70 to 0.48, P value 52 weeks postinjection (Dougados 1993; Jubb 2003; St. J. Dixon
0.17) differed from the Dougados publication (Dougados 1993) 1988). There were no statistically significant differences in the
which reported a statistically significant difference (P value 0.046) number of withdrawals due to lack of efficacy during the treat-
in the Lequesne Index at week 52. ment phase (Dougados 1993) or 14 to 26 weeks postinjection
Although not recommended as core-set outcome measures, data (Altman 1998; Huskisson 1999; Lin 2004). A statistically signif-
were extracted on range of motion, synovial fluid volume, and icant difference in favour of placebo compared to Hyalgan was
joint space width. There was no statistically significant difference found in the number of patients with local adverse events that
in flexion, measured in degrees, between Hyalgan and placebo at 1 caused discontinuation of study drug (RR 3.34; 95% CI 1.31 to
to 4 weeks postinjection, but Hyalgan was significantly better than 8.56, P value 0.01) (Altman 1998; Dougados 1993; Henderson
placebo at 5 to 13 weeks postinjection (WMD 7.60; 95% CI 0.46 1994; Jubb 2003). Similarly, there was a statistically significant
to 14.74, P value 0.04) (Corrado 1995). Hyalgan was 6% more difference in favour of placebo compared to Hyalgan found in the
effective in improving flexion than placebo. There were no statis- number of patients with local adverse events but the study drug
tically significant differences in synovial fluid volume, measured was continued (RR 1.42; 95% CI 1.10 to 1.84, P value 0.007).
in ml, between Hyalgan and placebo at 1 to 4 weeks postinjection There was no statistically significant difference in the number of
(Corrado 1995; Creamer 1994; Dougados 1993), or at 5 to 13 patients with serious adverse events at 14 to 26 weeks postinjec-
weeks postinjection (Corrado 1995; Creamer 1994). There was a tion (Huskisson 1999; Lin 2004). There was a trend of more seri-
statistically significant difference in joint space width, measured in ous adverse events in the Hyalgan group compared to the placebo
mm, in favour of Hyalgan compared to placebo at 45 to 52 weeks group at 45 to 52 weeks postinjection (RR 1.85; 95% CI 1.00
postinjection (WMD 0.40; 95% CI 0.03 to 0.77, P value 0.03) to 34.3, P value 0.05) (Dougados 1993, Jubb 2003). There was a
(Jubb 2003). However, when the treatment groups were stratified trend of more patients withdrawing due to adverse events in the
by baseline joint space width, there was no statistically significant Hyalgan group compared to the placebo group (RR 2.35; 95% CI
difference (Jubb 2003). These RevMan analyses differed from the 0.99 to 5.56, P value 0.05) (Huskisson 1999, Jubb 2003). There
Jubb publication (Jubb 2003) analysis where no difference was was no statistically significant difference in the number of knee
found in the total population but a difference in favour of the joints with local adverse events (Bragantini 1987; Creamer 1994).
subgroup with joint space width equal to or greater than 4.6 mm There was no statistically significant difference in the number of
at baseline was reported. patients with injection site pain (Altman 1998; Dougados 1993;
There was no statistically significant difference between Hyalgan Formiguera Sala 1995). There was no statistically significant dif-
and placebo in patient global assessment, measured as number of ference in the number of patients with treatment-related adverse
patients improved, at 1 to 4 weeks postinjection (Corrado 1995; events at 5 to 13 weeks postinjection, 0% in both the Hyalgan
Creamer 1994; Formiguera Sala 1995). A statistically significant and control groups (Formiguera Sala 1995). There was a statisti-
difference was found in favour of Hyalgan compared to placebo cally significant difference in the number of patients with treat-
at 5 to 13 weeks postinjection (RR 2.44; 95% CI 1.43 to 4.16, P ment-related adverse events at 14 to 26 weeks postinjection (RR
value 0.0010) (Corrado 1995; Formiguera Sala 1995). The NNT 2.19; 95% CI 1.18 to 4.07, P value 0.01) (Bunyaratavej 2001;
for patient global assessment was 10. A statistically significant dif- Henderson 1994; Huskisson 1999) but not at 45 to 52 weeks
ference was found in favour of Hyalgan compared to placebo at postinjection. In the Altman trial (Altman 1998) at 14 to 26 week
14 to 26 weeks postinjection (RR 1.24; 95% CI 1.03 to 1.50, P postinjection, there was a statistically significant difference in the
value 0.02) (Henderson 1994; Huskisson 1999; Lin 2004). No number of patients with gastrointestinal complaints in favour of
statistically significant difference was found at 45 to 52 weeks placebo compared to Hyalgan (RR 1.89; 95% CI 1.24 to 2.90,
postinjection in the number of patients rating treatment effective P value 0.003). There was no statistically significant difference in
(Dougados 1993). When patient global assessment was measured the number of patients with local skin rash at 14 to 26 weeks
by the number of joints that were fairly good to very good, a sta- postinjection (Altman 1998).
tistically significant difference in favour of Hyalgan compared to Hyalgan versus arthroscopy
placebo was found at 5 to 13 weeks postinjection (RR 2.12; 95% Table 19

One trial was included which was a comparison of Hyalgan and to 52 weeks postinjection. For pain expressed as the number of
arthroscopy (Forster 2003; Forster 2003a). patients with moderate or severe pain under load (Leardini 1991;
Pietrogrande 1991), there was no statistically significant difference
Efficacy at 1 to 4 weeks postinjection. There was a statistically significant
difference in favour of Hyalgan at 5 to 13 weeks postinjection (RR
In the comparison against arthroscopy, there was no statistically 0.61; 95% CI 0.44 to 0.84, P value 0.003). The NNT for mod-
significant difference between Hyalgan and arthroscopy in pain erate to severe pain under load was 10. For the number of joints
(0 to 10 cm VAS) or in the Lequesne Index (0 to 24) at any with moderate or severe walking pain, no statistically significant
of the four assessments: 1 to 4, 5 to 13, 14 to 26 or 45 to 52 differences were detected at three timepoints: 1 to 4, 5 to 13, or
weeks postinjection. Although there was a statistically significant 45 to 52 weeks postinjection (Leardini 1987). For the number of
difference between groups pre-trial for the Knee Society Function patients with moderate or greater night pain, there was no statisti-
scale score (i.e. Hyalgan group better score), except for the 14 to cally significant difference at 1 to 4 or 5 to 13 weeks postinjection
26 week assessment (WMD 23.50; 95% CI 1.68 to 45.32, P value (Leardini 1991; Pietrogrande 1991). For the number of patients
0.03) (i.e. Hyalgan was 2% more effective than arthroscopy), there with moderate or greater rest pain, there was no statistically sig-
was no statistically significant difference between Hyalgan and nificant difference at 1 to 4 weeks postinjection, but a statistically
arthroscopy at 1 to 4, 5 to 13 or 45 to 52 weeks postinjection. There significant difference in favour of Hyalgan at 5 to 13 weeks postin-
was no statistically significant difference between the number of jection (RR 0.39; 95% CI 0.19 to 0.78, P value 0.008) (Leardini
patients requiring further intervention. 1991; Pietrogrande 1991). The NNT for rest pain was 20.
The RevMan analysis differed from the Forster publication Statistically significant differences in range of motion (flexion) in
(Forster 2003) analysis. The publication reported no difference in favour of Hyalgan were found at 1 to 4 weeks postinjection (WMD
the Knee Society Function scale at six months whereas the RevMan 5.93; 95% CI 0.71 to 11.14, P value 0.03), and at 5 to 13 weeks
analysis detected a statistically significant difference (P value 0.03) post injection (WMD 5.41; 95% CI 0.54 to 10.28, P value 0.03)
in favour of Hyalgan over arthroscopy. (Leardini 1987; Pietrogrande 1991) (i.e. Hyalgan was 2% more
effective than MPA), but no statistically significant difference was
Safety detected at 45 to 52 weeks postinjection (Leardini 1987).
The global assessment, expressed by number of patients good or
There was no statistically significant difference in the number of very good, was not significantly different between groups at 1 to 4
withdrawals overall: Hyalgan 2 out of 19 versus arthroscopy 4 of weeks postinjection (Frizziero 2002; Leardini 1991; Pietrogrande
19. There was no statistically significant difference in the number 1991). There was a statistically significant difference in favour
of patients with pain at the injection site: Hyalgan 2 out of 19 of Hyalgan at 5 to 13 weeks postinjection (WMD 1.86; 95%
versus arthroscopy 0 out of 19. CI 1.26 to 2.75, P value 0.002) (Leardini 1991; Pietrogrande
Hyalgan versus corticosteroid 1991). The NNT for patient global assessment was 7. At 45 to 52
Five RCTs that were included were comparisons of Hyalgan and weeks postinjection, there was no statistically significant difference
IA corticosteroid. (Frizziero 2002).
Four RCT were comparisons of Hyalgan and methylprednisolone One RCT was a comparison of Hyalgan and triamcinolone hex-
acetate (Depomedrol, MPA) (Frizziero 2002; Leardini 1987; acetonide (Jones 1995). Except for pain at night at 14 to 26 weeks
Leardini 1991; Pietrogrande 1991) and one RCT was a compari- postinjection (WMD -20.70; 95% CI -37.74 to -3.66, P value
son of Hyalgan and triamcinolone hexacetonide (Jones 1995). 0.02), there were no statistically significant differences between
treatment detected by the three pain measures: pain on nominated
Efficacy activity, pain at rest, and pain at night (all measured on a 100 mm
Table 20; Table 21 VAS) at the end of treatment or at 14 to 26 weeks postinjection.
There was no statistically significant difference in spontaneous Hyalgan was 26% more effective than triamcinolone hexacetonide
pain intensity (0 to 100 mm VAS) at 1 to 4 weeks postinjection in relieving pain at night at 14 to 26 weeks postinjection. The
(Leardini 1987; Leardini 1991; Pietrogrande 1991). There was a RevMan analysis differed from the Jones publication (Jones 1995)
statistically significant difference in favour of Hyalgan at 5 to 13 analysis. The publication reported significant differences in favour
weeks postinjection (WMD -7.73; 95% CI -12.81 to -2.64, P of Hyalgan in pain on nominated activity and pain at rest at 14 to
value 0.003) (Leardini 1987; Leardini 1991; Pietrogrande 1991). 26 weeks postinjection.
Hyalgan was 11 to 41% more effective than MPA. At 45 to 52
weeks postinjection, there was no statistically significant differ- Safety
ence (Leardini 1987). For pain expressed as the number of joints There were no statistically significant differences in any of the ex-
with moderate or severe pain under load (Leardini 1987), there tracted safety outcomes. There was no difference in the total num-
was no statistically significant difference at 1 to 4, 5 to 13, or 45 ber of withdrawals overall at 1 to 4 weeks postinjection (Frizziero

2002); at 5 to 13 weeks postinjection (Leardini 1991; Pietrogrande One RCT included was a comparison of Hyalgan and naproxen
1991); at 14 to 26 weeks postinjection (Frizziero 2002); or at 45 (Altman 1998).
to 52 weeks postinjection (Leardini 1987). There was no differ-
ence in the number of patients withdrawn due to lack of efficacy Efficacy
at 5 to 13 weeks postinjection (Pietrogrande 1991). There was no
difference in the number of joints with local reactions at 1 to 4 No statistically significant difference was found between Hyalgan
weeks postinjection (Leardini 1987). There was no difference in and naproxen for pain after a 50 foot walk measured on a 100
the number of patients with local or systemic reactions at 5 to 13 mm VAS at any of the three assessment times: 1 to 4, 5 to 13, or
weeks postinjection (Leardini 1991, Pietrogrande 1991). There 14 to 26 weeks postinjection. There was no statistically significant
was no difference in the number of patients withdrawn due to ad- difference in the number of patients with moderate to marked pain
verse events after the first injection in the Frizziero trial (Frizziero at 14 to 26 weeks postinjection or in those with none to slight to
2002). mild pain.
There were no statistically significant differences between Hyalgan
and triamcinolone hexacetonide (Jones 1995) in the total number Safety
of withdrawals overall, in the number of withdrawals due to lack
of efficacy, or in the number of withdrawals due to adverse events There was a statistically significant difference in the number of
at the end of treatment or at 14 to 26 weeks postinjection. patients with gastrointestinal complaints reported in the Hyalgan
Hyalgan versus other IA therapy group (29%) compared to the naproxen group (42%) (RR 0.70;
Table 20; Table 21 95% CI 0.52 to 0.95, P value 0.02). There was a statistically signif-
One RCT included was a comparison of Hyalgan and mu- icant difference in the number of adverse events for injection site
copolysaccharide polysulfuric acid ester (Graf 1993). pain reported in the naproxen group (9%) compared to Hyalgan
(23%) (RR 2.70; 95% CI 1.52 to 4.79, P value 0.0007). There
Efficacy were more adverse events due to local joint pain and swelling re-
ported in the Hyalgan group (13%) than the naproxen group (6%)
The results were presented as change scores. The six-month data (RR 2.09; 95% CI 1.01 to 4.29, P value 0.05).
reported in the publication were not used since it was presented as There were no statistically significant differences for the other
the change from end of treatment not the change from baseline. safety outcome measures: total withdrawals overall, withdrawals
For the Larson rating scale, a higher score indicated improvement. due to lack of efficacy, number of adverse events of local skin rash,
At the end of treatment (week 6), there was a statistically significant or pruritis.
difference in favour of Hyalgan compared to mucopolysaccharide Hyalgan versus conventional therapy
polysulfuric acid ester for pain (0 to 30) (WMD 4.00; 95% CI 0.98 Table 24
to 7.02, P value 0.009), and for the total Larson rating score (0 to One RCT included was a comparison of Hyalgan and conven-
77) (WMD 5.90; 95% CI1.31 to 10.49, P value 0.01). This means tional therapy (Listrat 1997).
that Hyalgan was 25% more effective than mucopolysaccharide
polysulfuric acid ester in relieving pain and 13% more effective in Efficacy
improving ’overall’ function. There was no statistically significant
difference for function (0-30) or for range of motion (0 to 10). The There were no statistically significant differences between Hyalgan
global assessment, expressed by the number of patients symptom and conventional care at 45 to 52 weeks postinjection in overall
free or markedly improved, was significantly better in the Hyalgan pain (measured on 0 to 100 mm VAS) or in function (assessed
group (76%) compared to the mucopolysaccharide polysulfuric by the Lequesne Index). Since the arthroscopic outcome measures
acid ester group (46%) (RR 1.65; 95% CI 1.03 to 2.66, P value were chosen a priori as the primary efficacy variables in this trial,
0.04) at 14 to 26 weeks postinjection. The NNT for patient global their results are also reported. Joint space width, measured in mm,
assessment was 3. was greater at 45 to 52 weeks postinjection, in the Hyalgan group
(WMD 1.10; 95% CI -0.01 to 2.21, P value 0.05). A statisti-
Safety cally significant difference in favour of Hyalgan, at 45 to 52 weeks
postinjection, was found for both the arthroscopy overall assess-
There were no statistically significant differences between Hyalgan ment (0 to 100 mm VAS) (WMD -22.30; 95% CI -40.52 to -
and mucopolysaccharide polysulfuric acid ester at 14 to 26 weeks 4.08, P value 0.02) and the SFA system score (0 to 100 mm VAS)
postinjection either in the total number of withdrawals overall or (WMD -18.20; 95% CI -31.27 to -5.13, P value 0.006). There-
in the number of adverse events due to study medication. fore, Hyalgan was 14 to 22% more effective than conventional
Hyalgan versus NSAID therapy in improving these arthroscopy parameters at 45 to 52
Table 22; Table 23 weeks postinjection. This trial also utilised a quality of life out-

come measure, the Arthritis Impact Measurement Scales (AIMS), CI -2.18 to -1.02, P < 0.00001 and WMD -1.90; 95% CI -2.60
based on the total of 12 items. There was no statistically significant to -1.20, P < 0.00001) (Hyalgan plus exercise plus ultrasound
difference between groups. was 36 to 42% more effective than exercise); Lequesne Index (0
The RevMan analysis differed from the Listrat publication (Listrat to 26) (WMD -2.10; 95% CI -2.50 to -1.70, P < 0.00001 and
1997) analysis. The publication reported a statistically significant WMD -3.30; 95% CI -4.19 to -2.41, P < 0.00001) (Hyalgan
difference in favour of Hyalgan for AIMS (P value 0.047) at 45 to plus exercise plus ultrasound was 42 to 66% more effective than
52 weeks postinjection whereas the RevMan analysis detected no exercise); range of motion (degrees) (WMD 12.00; 95% CI 4.51
difference (P value 0.6). to 19.49, P value 0.002 and WMD 14.00; 95% CI 5.76 to 22.24,
P value 0.0009) (Hyalgan plus exercise plus ultrasound was 21 to
Safety 27% more effective than exercise); and ambulation speed (metres
per minute) (WMD 12.70; 95% CI 10.60 to 14.80, P < 0.00001
Safety, as assessed by total withdrawals overall, was similar in the and WMD 14.00; 95% CI 10.57 to 17.43, P < 0.00001) (Hyalgan
two groups. One patient in the Hyalgan group withdrew because plus exercise plus ultrasound was 18 to 20% more effective than
of lack of pain while two patients in the conventional therapy exercise).
group withdrew: one because of osteotomy performed on the study Safety
knee and one because of relocation. There were no statistically significant differences in the total num-
Hyalgan versus homeopathic treatment ber of withdrawals either during treatment or overall.
Readers are directed to the Zeel section for results based on a Hyalgan plus exercise plus ultrasound versus control warmup ex-
comparison of Zeel compositum and Hyalart (Nahler 1998). ercises
Table 27
Hyalgan plus exercise plus ultrasound versus exercise plus ultra- Efficacy
sound One RCT included was a comparison of Hyalgan plus exercise plus
Table 25 ultrasound and control warmup exercises (Huang 2005). There
Efficacy were statistically significant differences between the two groups
One RCT included was a comparison of Hyalgan plus exercise both at the end of treatment and at the one-year follow-up in
plus ultrasound and exercise plus ultrasound (Huang 2005). There favour of the Hyalgan plus exercise plus ultrasound group for the
were no statistically significant differences between the two groups following outcome measures: pain (0 to 10 cm VAS) (WMD -
either at the end of the treatment or at the one-year follow-up for 2.40; 95% CI -3.08 to -1.72, P < 0.00001 and WMD -4.60; 95%
the following outcome measures: pain (0 to 10 cm VAS); range of CI -5.32 to -3.88, P < 0.00001) (Hyalgan plus exercise plus ultra-
motion (degrees); and the Lequesne Index at the end of treatment. sound was 46 to 89% more effective than control warmup exer-
Statistically significant differences were detected for the following cises); Lequesne Index (0 to 26) (WMD -2.90; 95% CI -3.41 to -
outcome measures in favour of the Hyalgan plus exercise plus ul- 2.39, P < 0.00001 and WMD -5.60; 95% CI -6.38 to -4.82, P <
trasound group: Lequesne Index at one-year follow-up (WMD - 0.00001) (Hyalgan plus exercise plus ultrasound was 34 to 77%
0.80; 95% CI -1.58 to -0.02, P value 0.04) (Hyalgan plus exercise more effective than control warmup exercises); range of motion
plus ultrasound was 77% more effective than exercise plus ultra- (degrees) (WMD 22; 95% CI 16.42 to 27.58, P < 0.00001 and
sound); and ambulation speed (metres per minute) both at the WMD 26; 95% CI 17.14 to 34.86, P < 0.00001) (Hyalgan plus
end of treatment and at one-year follow-up (WMD 5.40; 95% CI exercise plus ultrasound was 20 to 24% more effective than con-
3.99 to 6.81, P < 0.00001 and WMD 5.00; 95% CI 1.58 to 8.42, trol warmup execises); and ambulation speed (metres per minute)
P value 0.004) (Hyalgan plus exercise plus ultrasound was 39% (WMD 19.80; 95% CI 18.17 to 21.43, P < 0.00001 and WMD
more effective than exercise plus ultrasound). 29.20; 95% CI 26.18 to 32.22, P < 0.00001) (Hyalgan plus ex-
Safety ercise plus ultrasound was 29 to 42% more effective than control
There were no statistically significant differences in the total num- warmup exercises).
ber of withdrawals either during treatment or overall. Safety
Hyalgan plus exercise plus ultrasound versus exercise
Table 26 There were no statistically significant differences in the total num-
Efficacy ber of withdrawals either during treatment or overall.
One RCT included was a comparison of Hyalgan plus exercise Hyalgan versus Hyalgan
plus ultrasound and exercise alone (Huang 2005). There were One RCT included was a schedule comparison of Hyalgan (Karras
statistically significant differences between the two groups both at 2001).
the end of treatment and at the one-year follow-up in favour of
the Hyalgan plus exercise plus ultrasound group for the following Efficacy
outcome measures: pain (0 to 10 cm VAS) (WMD -1.60; 95%

There was no statistically significant difference in the number of (Rejaili 2005), and hyaluronan (Atamaz 2005; Bayramoglu 2003;
patients assessing the response as satisfactory between the five in- Karatay 2004; Karatosun 2005a; Kotevoglu 2005 [Orthovisc];
jection Hyalgan schedule (67%) and the three injection Hyalgan Brown 2003 [Hyalgan]; Karlsson 2002c (AvS) [Artzal]; Kirchner
schedule (79%). 2005 (Thompson 2002) [BioHy (Arthrease, Euflexxa, Nuflexxa)];
Wobig 1999 [Artz, Healon]). The draft manuscript for the ab-
Safety stract presented by Moreland et al. (Moreland 1993) was kindly
provided by Biomatrix, Inc. as were the Pre-Market Approval
From the abstract it was not possible to ascertain to which group (PMA) data for the studies by Adams et al. (Adams 1995), Scale
the patients belonged that experienced three cases of local pain. et al. (Scale 1994a (2 inj); Scale 1994b (3 inj)), and Wobig et al.
Hyalgan versus other hyaluronans (Wobig 1998; Wobig 1999). The trials were completed in nine
Readers are directed to the Adant and Fermathron product results countries: Brazil (Rejaili 2005), Canada (Adams 1995; Raynauld
for comparisons of Hyalgan against these two HA products, re- 2002), England (Dickson 2001), France (Kahan 2003a), Ger-
spectively. many (Auerbach 2002; Scale 1994a (2 inj); Scale 1994b (3 inj);
One RCT included was a comparison of Hyalgan and Hylan G-F Wobig 1998; Wobig 1999), Republic of Moldova (Groppa 2001),
20 (Brown 2003). This trial was discontinued on ethical grounds Scotland (Dickson 2001), Turkey (Atamaz 2005; Cubukcu 2004;
due to the frequency of acute inflammatory reactions with Hylan Karatosun 2005), and the United States (Caborn 2004; Leopold
G-F 20 (21%) compared to Hyalgan (0%); this difference was not 2003; Moreland 1993). They were published over a twelve-year
statistically significant. No efficacy data were extracted from the period: 1993 through 2005. Sample size per group varied from
abstract. 10 (Cubukcu 2004; Rejaili 2005) to 253 (Kahan 2003a) while
sample size per trial varied from 20 to 518. One trial was eight
Product - Hylan G-F 20 (Synvisc) weeks in duration (Cubukcu 2004 (Ardic 2001), two trials were
twelve weeks in duration (Dickson 2001; Wobig 1999), four trials
Description of studies were 12 weeks in duration with a telephone interview at 26 weeks
(Adams 1995; Scale 1994a (2 inj); Scale 1994b (3 inj); Wobig
Twenty-four RCTs were included (Adams 1995; Atamaz 2005; 1998), two trials were 24 weeks in duration (Leopold 2003; Rejaili
Auerbach 2002; Bayramoglu 2003; Brown 2003; Caborn 2004; 2005), one trial was 26 weeks in duration (Caborn 2004), one trial
Cubukcu 2004 (abstract - Ardic 2001); Dickson 2001; Groppa was 34 weeks in duration (Moreland 1993), one trial was 36 weeks
2001; Kahan 2003a; Karatay 2004; Karatosun 2005; Karatosun in duration (Kahan 2003a), four trials were 52 weeks in duration
2005a; Karlsson 2002; Kotevoglu 2005; Leopold 2003; Moreland (Atamaz 2005; Auerbach 2002; Groppa 2001; Raynauld 2002),
1993; Raynauld 2002; Rejaili 2005; Scale 1994a (2 inj); Scale and one trial was 18 months in duration (Karatosun 2005).
1994b (3 inj); Kirchner 2005 (abstract - Thompson 2002); Wobig For the six trials that were included in the PMA P940015 (Adams
1998; Wobig 1999). Considering only the 17 trials in which Hylan 1995; Moreland 1993; Scale 1994a (2 inj); Scale 1994b (3 inj);
G-F 20 was designated the experimental intervention, the Jadad Wobig 1998; Wobig 1999), control and Hylan G-F 20 treatments
score ranged from 1 to 5 with an average quality of 3. One trial were prepared in syringes that had identical appearances and which
scored 5 (Moreland 1993), five scored 4 (Dickson 2001; Scale were coded only by random numbers. All subjects participating
1994a (2 inj); Scale 1994b (3 inj); Wobig 1998; Wobig 1999), five in these trials received arthrocentesis with removal of effusion if
scored 3 (Adams 1995; Kahan 2003a; Karatosun 2005; Leopold present. All IA procedures were performed in an identical manner
2003; Raynauld 2002), five scored 2 (Atamaz 2005; Auerbach for treatment and control study groups in these trials. A screen,
2002; Caborn 2004; Cubukcu 2004; Rejaili 2005), and one scored blinding the patient from the procedure, was utilised in four trials
1 (Groppa 2001). Allocation concealment was adequate in nine (Adams 1995; Dickson 2001; Moreland 1993; Wobig 1998).
trials and inadequate (not reported) in eight trials (Atamaz 2005; Twenty-six studies were excluded (Bell 1999; Bellamy 2000; Bruce
Auerbach 2002; Caborn 2004; Cubukcu 2004; Dickson 2001; 2004; Chhabra 2000; Clarke 2001; Evanich 2001; Goorman
Groppa 2001; Karatosun 2005; Rejaili 2005). 2000; Ines 2002; Koyuncu 2003; Legre 2001; Lee 2004; Lussier
Hylan G-F 20 has been compared against IA control treat- 1996; Magobotha 2001; Mathieu 2001; Miller 1999; Myburgh
ment (Ardic 2001; Cubukcu 2004; Dickson 2001; Groppa 2001; 2001; Olszynski 2002; Sripada 1999; Stambuk 2001; Torrance
Karlsson 2002b (SvP); Kotevoglu 2005; Moreland 1993; Scale 2002; Vad 2000; Waddell 2001a; Waddell 2001b; Weiss 1999;
1994a (2 inj); Scale 1994b (3 inj); Wobig 1998; Wobig 1999c Wobig 1999d; Wulwik 2001). Two trials are awaiting assessment
(NEhyl)), IA corticosteroid (Caborn 2004; Leopold 2003), non- (Russell 2003 (Talwalkar 2005); Shariati 2001). These trials have
steroidal anti-inflammatory drug (Adams 1995; Dickson 2001), been published only as abstracts with no extractable data, and at the
IA gaseous oxygen (Auerbach 2002), physiotherapy (Bayramoglu closure of the database for this review no full length manuscripts
2003), appropriate care (Kahan 2003a; Raynauld 2002), exercise have been published.
programme (Karatosun 2005), in combination with arthroscopy Adams et al. reported a 26-week, parallel-group RCT performed

at six centres in Canada comparing three weekly injections of no serious local or systemic adverse events were observed following
Hylan G-F 20 to either NSAID continuation plus three weekly injections. Dr. F. Atamaz kindly provided a copy of the manuscript
control arthrocenteses or NSAID continuation plus three weekly which is in press.
injections of Hylan G-F 20 in 102 patients with OA of the knee This trial used repeat injection but only one injection at six
(Adams 1995). All groups showed significant improvement from months. Although the trial was single-blind, the same physicians
baseline at 12 weeks but did not differ from each other. The two administered the injections and the same observer performed clin-
groups receiving Hylan G-F 20 were significantly better than the ical assessments. Of the 85 patients enrolled, three did not meet
NSAID alone group at Week 26. the inclusion criteria and were not included in the analyses. Local
Several design issues are noted for the Adams et al. RCT (Adams reactions consisting of mild swelling, warmth and pain at the in-
1995). This trial was designed to evaluate viscosupplementation jection site were reported by one patient in the Synvisc group and
with Hylan G-F 20 as a replacement for continuous NSAID ther- three patients in the Orthovisc group, but all four patients had re-
apy. There was no washout period. The concomitant use of ac- lief within a few days after application of cold packs. Paracetamol
etaminophen for analgesia was permitted and recorded by pill up to a maximum of 2 grams daily was permitted during the trial.
counts. However, usage was not reported since it was documented Dr. F. Atamaz kindly provided a manuscript of this trial which has
in different formats by the treating physicians and could not be been accepted for publication in Rheumatology International.
standardised into a single format for purposes of uniform anal- Auerbach et al. reported a one-year, parallel-group RCT performed
ysis. The resumption of NSAID between weeks 12 and 26 was at a single centre in Germany comparing three weekly injections
reported. 55.6% of patients in the Hylan G-F 20 group only re- of Hylan G-F 20 plus an exercise programme to five weekly IA
sumed taking NSAID compared to 84.4% in the NSAID plus injections of gaseous oxygen (three days per week) plus an exercise
Hylan G-F 20 group and 96.8% in the NSAID group. Fifteen per programme in 111 patients with OA of the knee (Auerbach 2002;
cent of the included patients presented with effusion at the first Auerbach 2002a). Both treatments were effective in relieving pain
visit. The Hylan G-F 20 only group may not have been blinded and improving joint function. Pain relief by Hylan G-F 20 and
since they were instructed to discontinue their NSAID. The au- improvement in function by oxygen treatment were shown for
thors addressed this concern in the publication by commenting more severe levels of cartilage damage.
that, “if incomplete blinding introduced a bias, it would be against The Auerbach trial was one of the few trials not published in En-
the Hylan G-F 20-only group in that patients recognized that they glish. Both the thesis (Auerbach 2002a) and the journal article
were discontinuing an active medication, and consequently may (Auerbach 2002) were published in German. An English abstract
have expected their condition to worsen”. The method of assess- was provided in the journal article. It was the only trial in which
ment at 26 weeks was by telephone follow-up which differed from HA was compared to IA injection of gaseous oxygen. The authors
that of baseline (i.e. office visit). A subsequent study showed that studied the relation between treatment effect and severity of car-
there was no significant difference in results obtained by telephone tilage damage.
compared to office visits for the WOMAC 3.0 Osteoarthritis In- Caborn et al. reported a 26-week, parallel group, single-blind RCT
dex (Bellamy 2002). performed at 14 centres in the United States comparing three
Atamaz et al. reported a one-year, parallel-group (three-arm), sin- weekly injections of Hylan G-F 20 to one IA injection of triam-
gle-blind RCT performed at a single centre in Turkey comparing cinolone hexacetonide (Aristospan) in 218 patients with OA of
three weekly injections followed by one additional injection at six the knee (Caborn 2003; Caborn 2004; Lanzer 2002). Treatment
months of Hylan G-F 20 (Synvisc) or hyaluronan (Orthovisc) to with Hylan G-F 20 resulted in a longer duration of effect than
a physical therapy programme five times a week for three weeks triamcinolone hexacetonide. Both treatments were well tolerated
with a series of infrared, short-wave diathermy pulsed patterns and with 10% of patients in each group reporting an adverse event
interferential therapy in 85 patients with OA of the knee (Atamaz that resulted in withdrawal from the trial.
2005). The authors reported significant improvement in all vari- The Caborn et al. trial was single-blind and details regarding the
ables measured in both groups during the follow-up except for method of randomisation were not published (Caborn 2004).
range of motion and the WOMAC OA Index stiffness subscale. The triamcinolone hexacetonide group received only one injec-
Patients in the physical therapy group had greater improvement tion compared to the three injections administered to the Hy-
in pain (at rest, at night, SF-36) and SF-36 social functioning. lan G-F 20 group. Analgesic and NSAID usage were monitored
This improvement was not different between the physical ther- throughout this trial. Patients with effusion of greater than 10 ml
apy group and the Hylan G-F 20 group, but the physical therapy were excluded. Almost 30% of each treatment group had severe
group was superior to the Orthovisc group for non-activity-related radiological ratings while approximately 60% in each group had
pain and functional performance. Based on subgroup analyses, moderate ratings.
the decrease in pain on touch and WOMAC OA Index physical Cubukcu et al. reported an eight-week, placebo-controlled RCT
function was greater in the Hylan G-F 20 group compared to the performed at one centre in Turkey comparing three weekly injec-
Orthovisc group. With respect to safety, the authors reported that tions of Hylan G-F 20 to three weekly injections of saline in 30 pa-

tients with OA of the knee (Cubukcu 2004; Ardic 2001 (abstract)). Kahan et al. reported a nine-month, open-label, parallel-group,
The authors reported a statistically significant between-group dif- RCT performed with 81 rheumatologists (21 hospital based, 60
ference at the end of the trial (i.e. eight weeks) for WOMAC pain, office based) in France comparing three weekly injections of Hylan
WOMAC physical function, night pain, rest pain, walking pain, G-F 20 to conventional treatment in 518 patients with OA of the
need for paracetamol and evaluation of treatment by the patient. knee (Kahan 2003 [article published in French]; Kahan 2003a).
With respect to safety, no patients dropped out of the study and The authors reported that Hylan G-F 20 viscosupplementation
no systemic adverse events were reported. One patient complained was more effective than conventional treatment at no additional
of mild transient local pain in the injected area a day after the first cost.
injection. Details regarding methods of blinding and randomisa- The Kahan et al. trial provided medicoeconomic data on visco-
tion were not reported. supplementation for OA (Kahan 2003a; Kahan 2003). The design
No explanation was given for the unequal group allocation (i.e. was very similar to the Raynauld et al. trial (Raynauld 2002). The
2:1 patients or 3:1 knees). A major limitation of this study is the study was completed under conditions of actual practice.
small sample size particularly in the placebo group. Karatosun et al. reported an eighteen-month, single-blind, parallel
Dickson et al. reported a 12-week, parallel-group, double-blind group, RCT performed at a single centre in Turkey comparing
RCT performed at 18 centres in England and Scotland comparing three weekly injections of Hylan G-F 20 to an exercise programme
three weekly injections of Hylan G-F 20 and dummy capsules that included a series of progressive simple range of motion and
taken once daily to either Diclofenac retard 100 mg taken once resistance exercises for six weeks (Karatosun 2005). The authors
daily and three weekly arthrocenteses or dummy capsules taken reported no statistically significant differences between the two
once daily and three weekly arthrocenteses in 165 patients with groups. However, both groups had improved Hospital for Special
OA of the knee (Dickson 2001). Patients, completing the 12- Surgery scores at the end of the trial. While all patients in the
week study, could enter an open-label study in which they received exercise group completed the trial, 21 patients in the Hylan G-F
treatment with up to four additional courses of Hylan G-F 20 20 did not. With respect to safety, no adverse events were reported
over a one-year period. Hylan G-F 20 was significantly better than that were related to ia injection of Hylan G-F 20.
either diclofenac or arthrocentesis in reducing WOMAC pain. The This trial enrolled only patients with Kellgren-Lawrence Grade III
diclofenac group had significantly more total and gastrointestinal knee OA. All radiographs were evaluated by two of the authors and
adverse events than the Hylan G-F 20 or control groups. concensus had to be reached in order for a patient to be enrolled
The Dickson et al. trial was one of the few trials conducted in gen- in the trial. In addition, 91% of the patients had bilateral knee
eral practice (Dickson 2001). To ensure blinding, all three arms OA. A blinded physical therapist completed patient evaluations.
of the trial received arthrocentesis. The diclofenac sodium dosage Approximately 60 per cent of the Hylan G-F 20 patients com-
of 100 mg daily may be considered by some as subtherapeutic but pleted the trial. The authors acknowledged the “relatively high”
the Diclomax Retard 1993 product label indicated this to be the drop out rate, noting that these patients had statistically signifi-
recommended adult dosage. The mean number of paracetamol cant improvement from baseline. They suggested that the reasons
tablets taken for analgesic rescue medication (3000 mg daily perfor seeking other forms of treatment in this group might have
mitted) was published. been due to their increased satisfaction levels. Dr. Vasfi Karatosun
Groppa and Moshneaga reported a one-year, blind CT performed kindly provided means and standard deviations for the reported
at a single centre in The Republic of Moldova comparing three outcome measures.
weekly injections of Hylan G-F 20 to three weekly injections of Leopold et al. reported a six-month, single-blind, parallel-group,
placebo in 25 patients with OA of knee (Groppa 2001). Courses RCT performed at a single centre in the United States compar-
were repeated at six and 12 months. After the first course, one- ing three weekly injections of Hylan G-F 20 to one injection of
third of the patients treated with Hylan G-F 20 had decreased pain betamethasone sodium phosphate-betamethasone acetate (Cele-
and improved joint function compared to none in the placebo stone Soluspan), which could be repeated during the study, in 100
group. After three courses, 87% of the Hylan G-F 20 patients patients with OA of the knee (Leopold 2003; Redd 2003). No
had moderate or very good effect compared to only 20% of the differences in pain or function were found between the two groups
patients in the control group who had moderate effect. No safety at the six months follow-up. Neither treatment worked well in fe-
data were reported in the abstract. males. One patient in the Hylan G-F 20 group withdrew because
The Groppa trial randomised a sample size of 25 patients (Groppa of an acute local reaction. One-fifth of the study population with-
2001). However, the control group was matched by gender, dis- drew because of a lack of treatment efficacy. Only safety data have
ease duration and x-ray date. The study was designed to address been extracted from this trial. Since the outcome variables had
the important issue of repeat treatment with a second and third results that were not normally distributed, nonparametric statisti-
course repeated at six and 12 months, respectively. Radiography, cal methods were used to analyze the data (e.g. change in median
ultrasonography and scintigraphy with Te 99m were all utilised in outcomes scores).
evaluation. The Leopold et al. trial was an independent trial not funded by

the manufacturer of the hyaluronate-based product under study strengthened by the expertise of an independent, academic Steer-
(Leopold 2003). The injection procedure was standardised by: ing Committee. This ’pragmatic’ study operated under ’a real
1) patient was in the supine position, 2) the injection was made world scenario’. The trial highlighted the difference between radi-
superolaterally into the suprapatellar notch, and 3) patients were ologic grading completed by a central reader and that done by site
encouraged to refrain from strenuous activity for a day. However, investigators. Although Kellgren and Lawrence Grade 4 was an
effusions were aspirated in the HA group whereas they were not in entry exclusion criteria, 20% of the appropriate care plus Hylan
the corticosteroid group. In addition, patients in the corticosteroid G-F 20 group and 33% of the appropriate care without Hylan G-
group were permitted to have one more injection any time during F 20 group were rated as Grade 4 by the central reader. However,
the study. The authors chose not to use the Ahlback radiographic when Grade 4 was used as a covariate there was no significant dif-
grading system, “because three of the four stages include knees ference in the analysis results. Repeat treatment was permitted to
with a completely obliterated joint space”. This was the only trial either or both knees as required during the trial.
to find a gender difference in treatment response. The Rejaili et al. trial was a 24-week, parallel-group RCT per-
Moreland et al. reported a 34-week, parallel-group, double-blind formed at a single centre in Brazil comparing arthroscopy (articu-
RCT performed at five centres in the United States comparing lar lavage and debridement) followed by three weekly postopera-
three weekly injections of Hylan G-F 20 to three weekly arthro- tive injections of Hylan G-F 20 to arthroscopy alone in 20 patients
centeses in 94 patients with OA of the knee (Moreland 1993). with OA of the knee (Rejaili 2005). The authors reported that sta-
This trial had two phases. Phase I lasted 10 weeks, after which tistically significant differences were found in favour of the group
patients could enter Phase II in which all patients received treat- receiving Hylan G-F 20 postoperatively following arthroscopy for
ment with Hylan G-F 20. For this analysis, the Phase II data were pain during rest at night, pain during movement with a 10% over-
not included because, although patient blinding was maintained load of the corporal weight, reduction of pain during the most
during this Phase, treatment was not randomised. Analyses were painful movements of the knee, and in the number of potassium
based on the week eight evaluation endpoint which was two weeks diclofenac tablets ingested daily for pain relief in the affected knee.
after the third injection in Phase I. A statistically significant dif- With respect to safety, it was reported that postinjection synovitis
ference, in favour of Hylan G-F 20, was detected in overall pain did not occur during the trial.
only in a predefined ’flare’ population but not in the ’intent-to- The publication by Scale et al. reported two separate trials (Scale
treat’ population. During the two phases approximately 7% of 1994a (2 inj); Scale 1994b (3 inj)). One was a comparison of two
patients receiving Hylan G-F 20 discontinued treatment due to biweekly injections of Hylan G-F 20 versus two biweekly injections
local adverse reactions (pain or swelling) in the injected knee. of saline in 50 patients with OA of the knee (Scale 1994a (2 inj)),
The Moreland et al. trial was only published as an abstract but an and the other was a comparison of three weekly injections of Hylan
in-house unpublished manuscript allowed this trial to be included G-F 20 versus three weekly injections of saline in 30 patients with
in the review (Moreland 1993). This trial examined the “clinimet- OA of the knee (Scale 1994b (3 inj)). Both studies were 26-week,
ric utility” of identifying a flare population. Despite a four-week parallel-group, double-blind RCTs performed at a single centre
washout of all anti-inflammatory medication, only 30% of pain Germany. Patients were excluded if effusion was present in the
tients demonstrated a flare in pain symptoms. However, patients joint. For most outcome measures, the Hylan G-F 20 treatment
were randomised regardless of flare criteria. The authors noted that showed statistically significant superiority over saline treatment for
the final evaluation for Phase I of the trial was only two weeks after both treatment regimens. The three-injection treatment regimen
completing treatment. This may have minimised any between- was statistically more effective than the two-injection treatment
group differences, and could have maximised the short-term effect regimen. One local, treatment-related, adverse event represented
of arthrocentesis. Acetaminophen usage was permitted through- 1% of all the Hylan G-F 20 injections or 2.5% of all the knees
out the entire trial duration but there was no significant difference treated with Hylan G-F 20 in this study.
between the groups in daily usage. Scale et al. published the first RCTs of Hylan G-F 20. Continu-
Raynauld et al. reported a one-year, open-label, parallel-group, ous outcome measures were transformed into categorical scores.
RCT performed at 14 centres in Canada comparing appropri- ’“Successful treatment’ (i.e. responder) was defined as a score of 0
ate care with Hylan G-F 20 (AC + H) to appropriate care with- to 20 mm on the VAS for the pain and activity reduction outcome
out Hylan G-F 20 (AC) in 255 patients with OA of the knee measures, and a score of 80 to 100 mm for the improvement of the
(Raynauld 2002; Bellamy 2005a; Bellamy 2005b; Hamburger most painful knee movement. Although the journal publication
2005; Raynauld 2005; Raynauld 2005a). For all the primary and reported results based on a combined control group, the PMA
secondary effectiveness outcome measures the AC + H group was report provided results based on the separate randomised control
superior to the AC group. Safety differences favoured the AC + H groups which were used in this review. The three-injection trial
group. randomised 30 patients in total.
The Raynauld et al. trial was an effectiveness study that also in- Wobig et al. reported a 26-week, parallel-group, double-blind
cluded an economic evaluation (Torrance 2002). The study was RCT performed at four centres in Germany comparing three

weekly injections of Hylan G-F 20 to three weekly injections of (random-effects model) -12.54; 95% CI -20.39 to -4.69, P value
saline in 110 patients with OA of the knee (Wobig 1998). Statisti- 0.002) (Karlsson 2002b (SvP); Moreland 1993; Scale 1994a (2
cally significant differences between Hylan G-F 20 and saline treat- inj); Scale 1994b (3 inj); Wobig 1998; Wobig 1999c (NEhyl)).
ment were reported for all outcome measures. No adverse events With the exception of the Karlsson RCT (Karlsson 2002b (SvP)),
were observed in the injected joint after Hylan G-F 20 treatment. Hylan G-F 20 was 4 to 24% more effective than placebo. With
In the Wobig et al. RCT, patients with effusion were excluded five trials, a statistically significant difference in favour of Hylan
(Wobig 1998). Again a categorical analysis was completed based G-F 20 compared to placebo was found at 5 to 13 weeks postin-
on the same responder criteria as Scale et al. above. 98% of the jection (WMD (random-effects model) -22.46; 95% CI -35.24
randomised patients completed all follow-up visits. Only one Hy- to -9.68, P value 0.0006) (Karlsson 2002b (SvP); Scale 1994a (2
lan G-F 20 patient did not participate in the telephone interview inj); Scale 1994b (3 inj); Wobig 1998; Wobig 1999c (NEhyl)).
and one saline patient, who missed the visits at weeks eight and Hylan G-F 20 was 1 to 43% more effective than placebo. At 14
12, did participate in the telephone interview at week 26. to 26 weeks postinjection, there was a statistically significant dif-
The 1999 Wobig publication reported the results of two arms (Hy- ference in favour of Hylan G-F 20 compared to placebo (WMD
lan G-F 20 versus Artz) of a four-arm trial (Artz, Healon, Hylan (random-effects model) -20.70; 95% CI -35.56 to -5.83, P value
G-F 20, nonelastoviscous hylan) (Wobig 1999). This was a 12- 0.006) (Karlsson 2002b (SvP); Scale 1994a (2 inj); Scale 1994b
week, parallel-group, double-blind RCT performed at six centres (3 inj); Wobig 1998). Hylan G-F 20 was 1 to 49% more effective
in Germany comparing three weekly injections of Hylan G-F 20 to than placebo.
either three weekly injections of Artz (Wobig 1999b (Artz)), three Statistically significant differences in favour of Hylan G-F 20 com-
weekly injections of Healon (Wobig 1999a (Healon)), or three pared to placebo were found in pain at night (measured on 0 to
weekly injections of nonelastoviscous (denatured) hylan (Wobig 100 mm VAS) at 1 to 4 weeks postinjection (WMD -8.03; 95%
1999c (NEhyl)) in 109 knees. Considering only the published CI -11.95 to -4.12, P < 0.0001) (Cubukcu 2004; Moreland 1993;
Hylan G-F 20 versus Artz comparison, significantly greater pain- Scale 1994a (2 inj); Scale 1994b (3 inj); Wobig 1998; Wobig
relieving effects were detected in favour of Hylan G-F 20. No sta- 1999c (NEhyl)). Hylan G-F 20 was 13 to 31% more effective
tistically significant differences in the incidence of adverse events than placebo. With five trials, a statistically significant difference in
between these two groups were detected. favour of Hylan G-F 20 compared to placebo was found at 5 to 13
In an attempt to explain the mechanism of action of viscosupple- weeks postinjection (WMD (random-effects model) -13.08; 95%
mentation, the objective of the Wobig et al. trial (Wobig 1999b CI -20.35 to -5.80, P value 0.0004) (Cubukcu 2004; Scale 1994a
(Artz)) was to determine if a correlation existed between clini- (2 inj); Scale 1994b (3 inj); Wobig 1998; Wobig 1999c (NEhyl)).
cal effectiveness and elastoviscosity. Patients were once again cat- Hylan G-F 20 was 28 to 50% more effective than placebo. At 14
egorised as ’symptom-free’ based on the Scale et al. criteria above. to 26 weeks postinjection, based on three trials, there was a statisti-
Descriptions of the seven RCT in which Hylan G-F 20 was the cally significant difference in favour of Hylan G-F 20 compared to
control treatment are found in the other product results sec- placebo (WMD -17.12; 95% CI -23.22 to -11.02, P < 0.00001)
tions: BioHy (Arthrease, Euflexxa, Nuflexxa) (Kirchner 2006, (Scale 1994a (2 inj); Scale 1994b (3 inj); Wobig 1998). Hylan G-
(Thompson 2002 - abstract), Artz (Artzal, Supartz) (Karlsson F 20 was 28 to 96% more effective than placebo.
2002), Hyalgan (Brown 2003), and Orthovisc (Bayramoglu 2003; Statistically significant differences in favour of Hylan G-F 20 com-
Karatay 2005; Karatosun 2005a; Kotevoglu 2005). pared to saline were detected in pain at rest (0 - 100 mm VAS) both
Hylan G-F 20 (Synvisc) versus placebo at 1 to 4 weeks postinjection (WMD -9.44; 95% CI -14.07 to -
Nine RCTs included were comparisons of Hylan G-F 20 and 4.82, P < 0.0001)(Cubukcu 2004; Moreland 1993); and at 5 to 13
placebos (Cubukcu 2004; Dickson 2001; Groppa 2001; Karlsson weeks postinjection (WMD -18.67; 95% CI -23.32 to -14.02, P <
2002b (SvP); Moreland 1993; Scale 1994a (2 inj); Scale 1994b 0.00001) (Cubukcu 2004). Statistically significant differences in
(3 inj); Wobig 1998, Wobig 1999c (NEhyl)). Control treatments favour of Hylan G-F 20 compared to saline were detected in pain
included IA saline, arthrocentesis, arthrocentesis and placebo cap- walking (0-100 mm VAS) at 5 to 13 weeks postinjection (WMD
sules taken once daily, and nonelastoviscous (NE) denatured hylan -13.80; 95% CI -19.74 to -7.86, P < 0.00001) (Cubukcu 2004);
fluid. The current product monograph for Synvisc (Synvisc Hylan but not at 1 to 4 weeks postinjection (Cubukcu 2004; Moreland
G-F 20) indicates administration by IA injection once a week (one 1993). No statistically significant difference was detected at 1 to 4
week apart) for a total of three injections. weeks postinjection in pain overall (0 to 100 mm VAS) (Moreland
1993).
Efficacy Statistically significant differences were detected in WOMAC OA
Table 28; Table 29; Table 30; Table 31 Index pain at 1 to 4 week postinjection (SMD -1.26; 95% CI -
Statistically significant differences in favour of Hylan G-F 20 com- 1.86 to -0.66, P < 0.0001) (Cubukcu 2004; Kotevoglu 2005), at 5
pared to placebo were found in pain on weight bearing (mea- to 13 weeks postinjection (SMD -0.69; 95% CI -1.02 to -0.36, P
sured on 0 to 100 mm VAS) at 1 to 4 weeks postinjection (WMD < 0.0001)(Cubukcu 2004; Dickson 2001; Kotevoglu 2005), and

at 14 to 26 weeks postinjection (WMD -1.09; 95% CI -1.92 to - assessment (measured 0 to 100 mm VAS, where 100 was worst
0.25, P value 0.01)(Kotevoglu 2005). severity) in favour of Hylan G-F 20 compared to saline both at
A statistically significant difference in favour of Hylan G-F 20 was 1 to 4 weeks postinjection (WMD -20.00; 95% CI -33.16 o -
detected in the WOMAC OA Index physical function subscale at 6.84, P value 0.003) and at 5 to 13 weeks postinjection (WMD -
1 to 4 weeks postinjection (WMD (RE) -9.42; 95% CI -18.46 to 20.00; 95% CI -30.57 to -9.43, P value 0.0002); but not at 14 to
-0.37, P value 0.04 (Cubukcu 2004; Kotevoglu 2005), at 5 to 13 26 weeks postinjection (Kotevoglu 2005). Similarly, statistically
weeks postinjection (WMD -11.91; 95% CI -15.06 to -8.76, P significant differences were detected in physican global assessment
< 0.00001) (Cubukcu 2004; Dickson 2001; Kotevoglu 2005), at (measured 0 to 100 mm VAS, where 100 was worst severity) in
14 to 26 weeks postinjection (WMD -17.00; 95% CI -26.90 to - favour of Hylan G-F 20 compared to saline both at 1 to 4 weeks
7.10, P value 0.0008)(Kotevoglu 2005). postinjection (WMD -20.00; 95% CI -37.64 to -2.36, P value
A statistically significant difference in favour of Hylan G-F was 0.03) and at 5 to 13 weeks postinjection (WMD -20.00; 95%
detected in the Lequesne Index at 5 to 13 weeks postinjection CI -36.10 to -3.90, P value 0.01) but not at 14 to 26 weeks
(WMD -1.60; 95% CI -2.99 to -0.21, P value 0.02) (Dickson postinjection (Kotevoglu 2005).
2001). Hylan G-F 20 was 7% more effective than placebo.The No statistically significant difference was noted in the number of
RevMan analysis differed from the publication analysis (Dickson clinical failures at 14 to 26 weeks postinjection: Hylan G-F 20 7%
2001). The publication reported no difference in the Lequesne and Saline 11%, or at 45 to 52 weeks postinjection: Hylan G-F 20
Index at 5 to 13 weeks (P value 0.17) whereas RevMan detected 46% and saline 54% (Karlsson 2002b (SvP)), or in the number
a statistically significant difference in favour of Hylan G-F 20. of survivors (i.e. patients not requiring additional treatment to
No statistically significant difference was detected in the Lequesne study knee): Hylan G-F 20 44% and saline 33% (Karlsson 2002b
Index at 14 to 26 weeks postinjection (Karlsson 2002b (SvP)). (SvP)).
A statistically significant difference in favour of Hylan G-F 20 In the Cubukcu et al. RCT, the need for paracetamol tablets was
compared to placebo was detected in improvement in the most measured by pill counts (means and standard deviations reported).
painful knee movement (0 to 100 mm VAS) both at 1 to 4 weeks The original publication reported a statistically significant differ-
postinjection (WMD 19.29; 95% CI 12.16 to 26.31, P < 0.00001) ence between Hylan G-F 20 and saline at 5 to 13 weeks postinjec-
and at 5 to 13 weeks postinjection (WMD (random-effects model) tion in favour of Hylan G-F 20 (P < 0.05) but no significant differ-
33.87; 95% CI 21.19 to 46.55, P < 0.00001) (Scale 1994a (2 inj); ence at 1 to 4 weeks postinjection (Cubukcu 2004). The RevMan
Scale 1994b (3 inj); Wobig 1998; Wobig 1999c (NEhyl)). software is unable to provide an estimate of this difference.
No statistically significant difference in 15 metre walking time was Considering only the two most homogeneous trials, i.e., the three-
detected between Hylan G-F 20 and saline either at 1 to 4 or 5 to injection trial of Scale (Scale 1994b (3 inj)) and the Wobig trial
13 weeks postinjection (Cubukcu 2004). (Wobig 1998), a statistically significant difference in favour of Hy-
Statistically significant differences were detected in WOMAC OA lan G-F 20 compared to saline was detected in pain on weight
Index stiffness (Likert) at 1 to 4 weeks postinjection (WMD -1.08; bearing (0 to 100 mm VAS) at 1 to 4 weeks postinjection (WMD
95% CI -1.73 to -0.44, P value 0.001), at 5 to 13 weeks postin- -22.00; 95% CI -29.13 to -14.87, P < 0.00001), at 5 to 13
jection (WMD -1.34; 95% CI -2.13 to -0.55, P value 0.0009) weeks postinjection (WMD -35.68; 95% CI -42.81 to -28.55, P
(Cubukcu 2004; Kotevoglu 2005), and at 14 to 26 weeks postin- < 0.00001), and at 14 to 26 weeks postinjection (WMD -21.62;
jection (WMD -1.00; 95% CI -1.89 to -0.11, P value 0.03) 95% CI -30.84 to -12.39, P < 0.00001). A statistically signifi-
(Kotevoglu 2005). cant difference in favour of Hylan G-F 20 compared to saline was
When patient global assessment data were dichotomised into im- detected in pain at night (0 to 100 mm VAS) at 1 to 4 weeks
proved or not improved by classifying responses of ’very poor’, postinjection (WMD -10.64; 95% CI -17.29 to -3.99, P value
’poor’ and ’fair’ as ’not improved’ and ’good’ and ’very good’ as 0.002), at 5 to 13 weeks postinjection (WMD -15.50; 95% CI -
’improved’, more patients in the Hylan G-F 20 group were ei- 21.38 to -9.62, P < 0.00001), and at 14 to 26 weeks postinjection
ther ’very good’ or ’good’ (69%) than in the double control group (WMD -16.20; 95% CI -22.85 to -9.55, P < 0.00001). A statis-
(48%) at 5 to 13 weeks postinjection (RR 1.44; 95% CI 1.01 to tically significant difference in favour of Hylan G-F 20 compared
2.06, P value 0.05) (Dickson 2001). to saline was detected in improvement in the most painful knee
A statistically significant difference in favour of Hylan G-F 20 movement (0 to 100 mm VAS) both at 1 to 4 weeks postinjection
compared to placebo was detected for patient global assessment (WMD 23.97; 95% CI 14.34 to 33.60, P < 0.00001) and at 5 to
of treatment efficacy (0 to 100 mm VAS) both at 1 to 4 weeks 13 weeks postinjection (WMD 40.56; 95% CI 31.11 to 50.01, P
postinjection (SMD 0.70; 95% CI 0.46 to 0.93, P < 0.00001) < 0.00001). A statistically significant difference in favour of Hylan
and at 5 to 13 weeks postinjection (SMD (random effects) 1.54; G-F 20 compared to saline was detected for the variable treatment
95% CI 0.84 to 2.24, P < 0.0001) (Cubukcu 2004; Scale 1994a efficacy (improvement on a 0 to 100 mm VAS) both at 1 to 4
(2 inj); Scale 1994b (3 inj); Wobig 1998; Wobig 1999c (NEhyl)). weeks postinjection (WMD 26.62; 95% CI 17.39 to 35.84, P <
Statistically significant differences were detected in patient global 0.00001) and at 5 to 13 weeks postinjection (WMD 43.85; 95%

CI 34.62 to 53.07, P < 0.00001). 17% more effective than triamcinolone hexacetonide. A statisti-
cally significant difference in favour of Hylan G-F 20 compared to
Safety triamcinolone hexacetonide was found for WOMAC total score
No statistically significant differences were detected in the to- (scored 0-96) (WMD -7.40; 95% CI -12.74 to -2.06, P value
tal number of withdrawals overall at 1 to 4 weeks postinjection 0.007) at 5 to 13 weeks postinjection and (WMD -7.30; 95% CI
(Moreland 1993), at 5 to 13 weeks (Cubukcu 2004; Dickson 2001; -12.76 to -1.84, P value 0.009) at 14 to 26 weeks postinjection.
Wobig 1998; Wobig 1999c (NEhyl), or at 14 to 26 weeks postin- Hylan G-F 20 was 15% more effective than triamcinolone hex-
jection (Kotevoglu 2005). No statistically significant differences acetonide. A statistically significant difference in favour of Hylan
were detected in the number of withdrawals due to adverse events. G-F 20 compared to triamcinolone hexacetonide was found for
The number of local reactions was significantly higher in the Hy- for patient global assessment (scored 0 to 100 mm VAS) (WMD
lan G-F 20 plus arthrocentesis group compared to arthrocente- -13.40; 95% CI -20.03 to -6.77, P value 0.00007) at 5 to 13
sis (RR 30.23; 95% CI 1.86 to 492.59, P value 0.02) (Dickson weeks postinjection and (WMD -15.10; 95% CI -22.17 to -8.03,
2001). P value 0.00003) at 14 to 26 week postinjection. Hylan G-F 20
No significant differences were detected in the number of patients was approximately 23% more effective than triamcinolone hexac-
with local reactions (Cubukcu 2004; Dickson 2001; Kotevoglu etonide.
2005; Moreland 1993; Wobig 1998; Wobig 1999c (NEhyl)); In the Caborn trial (Caborn 2004) there was no statistically sig-
number of patients with local adverse reaction at 1 to 4 weeks nificant difference in the number of responders defined as at least
postinjection but study drug continued (Scale 1994b (3 inj)); a one-point improvement in the WOMAC pain walking on a flat
number of patients with one or more probable or possible related surface at 1 to 4 weeks postinjection. However, there was a sta-
systemic adverse events at 5 to 13 weeks postinjection (Dickson tistically significant difference in favour of Hylan G-F 20 at 5 to
2001); number of patients reporting systemic adverse reactions at 13 weeks postinjection (RR 1.44; 95% CI 1.09 to 1.90, P value
5 to 13 weeks postinjection (Cubukcu 2004; Wobig 1998; Wobig 0.01). The NNT for the number of responders was 5. At 14 to
1999c (NEhyl)); or number of patients withdrawn due to non- 26 weeks postinjection, the RR was 1.44 (95% CI 1.00 to 2.09)
compliance (Kotevoglu 2005). P value 0.05. There was no statistically significant difference in
Hylan G-F 20 (Synvisc) versus corticosteroid analgesic usage between week 0 and prior to week 12 or between
Table 32 week 12 and prior to week 26.
Two RCTs included were comparisons of Hylan G-F 20 and IA
corticosteroid. Safety
One RCT was a comparison of Hylan G-F 20 and betamethasone
sodium phosphate - betamethasone acetate (Leopold 2003). One With respect to the Leopold trial (Leopold 2003), there were no
RCT was a comparison of Hylan G-F 20 and triamcinolone hex- statistically significant differences in the safety outcomes: total
acetonide (Caborn 2004). withdrawals overall; withdrawals due to lack of efficacy; or with-
drawals due to acute local reactions.
Efficacy With respect to the Caborn trial (Caborn 2004), there was a statis-
tically significant difference in favour of Hylan G-F 20 compared
The efficacy outcome measure results in the Leopold trial (Leopold to triamcinolone hexacetonide in the number of withdrawals due
2003) were presented as changes in median scores because the data to lack of efficacy (RR 0.03; 95% CI 0.00 to 0.48, P value 0.01).
were not normally distributed. Therefore, only safety data for this There were no statistically significant differences in the total num-
RCT are reported. ber of withdrawals overall or the number of withdrawals due to
A statistically significant difference in favour of Hylan G-F 20 adverse events.
compared to triamcinolone hexacetonide was found for WOMAC Hylan G-F 20 (Synvisc) versus NSAID
pain walking on a flat surface (scored 0 to 4) in the Caborn trial Table 33
(Caborn 2004) (WMD -0.40; 95% CI -0.65 to -0.15, P value Two trials included were comparisons of Hylan G-F 20 and
0.002) at 5 to 13 weeks postinjection and (WMD -0.40; 95% CI NSAID (Adams 1995; Dickson 2001). In the Adams trial (Adams
-0.68 to -0.12, P value 0.005) at 14 to 26 weeks postinjection. 1995), the early 5 to 13 weeks postinjection follow-up assessment
Hylan G-F 20 was 17% more effective than triamcinolone hexac- was reported as change (improvement) scores, while the 14 to 26
etonide. A statistically significant difference in favour of Hylan G- week follow-up was based on difference scores. The Dickson trial
F 20 compared to triamcinolone hexacetonide was found for the (Dickson 2001) results were reported as change (improvement)
WOMAC physical function subscale (scored 0 to 68) (WMD - scores.
5.00; 95% CI -8.86 to -1.14, P value 0.01) at 5 to 13 weeks postin-
jection and (WMD -5.20; 95% CI -9.10 to -1.30, P value 0.009) Efficacy
at 14 to 26 weeks postinjection. Hylan G-F 20 was, on average,

There were no statistically significant differences in any of the 19.31 to -2.69, P value 0.01); pain at night (WMD -19.00; 95%
efficacy measures scored on a 0 to 100 mm VAS at either 5 to 13 CI -30.09 to -7.91, P value 0.0008); and pain overall (WMD
or 14 to 26 weeks postinjection: pain on motion; pain at rest; pain -15.00; 95% CI -26.09 to -3.91, P value 0.008). Hylan G-F
at night; pain overall (0 to 100 mm VAS) (Adams 1995). 20+NSAID+arthrocentesis was approximately 10% more effective
The RevMan analysis differed from the Adams publication (Adams than NSAID+arthrocentesis. There was no statistically significant
1995) analysis. The publication reported a statistically significant difference in the number of patients reporting that they were ’ex-
difference (P value 0.05) in favour of Hylan G-F 20 over NSAID in cellent, very good, or good’ .
pain at rest at 5 to 13 weeks whereas the RevMan analysis detected
no difference (P value 0.6). Safety
There was a statistically significant difference in favour of Hylan
G-F 20 compared to NSAID in the WOMAC OA Index pain There was no statistically significant difference in the total with-
subscale (0 to 100 mm VAS) (WMD -12.00; 95% CI -23.09 drawals overall.
to -0.91, P value 0.03) at 5 to 13 weeks postinjection (Dickson Hylan G-F 20 (Synvisc) versus physical therapy
2001). Hylan G-F 20 was 16% more effective than NSAID. There One RCT included a comparison of Hylan G-F 20 to physical
were no statistically significant differences in physical function therapy (Atamaz 2005).
measured either on the WOMAC OA Index physical function Efficacy
subscale (0 to 100 mm VAS) or on the Lequesne Index (0 to 24) There was a statistically significant between-group difference in
at 5 to 13 weeks postinjection (Dickson 2001). favour of physical therapy compared to Hylan G-F 20 in spon-
There were no statistically significant differences in the patient taneous pain (0 to 100 mm VAS) at 1 to 4 weeks postinjection
global assessment, measured as the number of patients assessing the (WMD 20.50; 95% CI 10.21 to 30.79, P < 0.0001) (physicl ther-
treatment as excellent, very good or good, either at 5 to 13 weeks apy was 5% more effective than Hylan G-F 20), but not at 5 to
postinjection (Dickson 2001) or at 14 to 26 weeks postinjection 13, 14 to 26, 37, or 45 to 52 weeks postinjection. Statistically
(Adams 1995). significant differences in favour of Hylan G-F 20 were detected
in WOMAC pain (Likert) at 1 to 4 weeks postinjection (WMD
Safety -3.00; 95% CI -4.85 to -1.15, P value 0.001), at 5 to 13 weeks
postinjection (WMD -3.10; 95% CI -5.12 to -1.08, P value 0.003)
There were no statistically significant differences in the following (Hylan G-F 20 was 9% more effective than physical therapy), at
safety outcome measures: total withdrawals overall at 5 to 13 weeks 37 weeks postinjection (WMD -1.90; 95% CI -3.71 to -0.09, P
postinjection (Dickson 2001) or at 14 to 26 weeks postinjection value 0.04) (Hylan G-F 20 was 1% more effective than physical
(Adams 1995); withdrawals due to adverse events at 14 to 26 therapy), and at 45 to 52 weeks postinjection (WMD -5.30; 95%
weeks postinjection (Adams 1995); or the number of patients with CI -7.50 to -3.10, P < 0.00001) (Hylan G-F 20 was 25% more ef-
local reactions at 5 to 13 weeks postinjection (Dickson 2001). fective than physical therapy), but not at 14 to 26 weeks postinjec-
There was a statistically significant difference in favour of Hylan tion. There were no statistically significant differences detected in
G-F 20 compared to NSAID for the number of patients with WOMAC physical function (Likert), SF-36 pain or SF-36 phys-
possible or probable related systemic adverse events at 5 to 13 ical functioning at any of the time-points: 1 to 4, 5 to 13, 14 to
weeks postinjection (RR 0.46; 95% CI 0.25 to 0.83, P value 0.01) 26, 36, or 45 to 52 weeks postinjection.
(Dickson 2001). The NNT was 4.
Hylan G-F 20 (Synvisc) + NSAID versus NSAID alone Safety
The second comparison that was made from the Adams trial ( In the Atamaz et al. RCT, while one patient in the Hylan G-F 20
Adams 1995) was Hylan G-F 20 plus NSAID and arthrocentesis group reported a local reaction which resolved within a few days,
versus NSAID and arthrocentesis alone. no serious local or systemic adverse events were observed following
injections (Atamaz 2005).
Efficacy
Hylan G-F 20 (Synvisc) + physiotherapy versus physiotherapy
There were no statistically significant differences between the two alone
groups at 5 to 13 weeks postinjection for the following pain One RCT included a comparison of Hylan G-F 20 plus physio-
outcomes (0 to 100 mm VAS): pain on motion; pain at rest; therapy to physiotherapy alone (Bayramoglu 2003).
pain at night; or pain overall. There were statistically significant
differences in favour of Hylan G-F 20+NSAID+arthrocentesis Efficacy
compared to NSAID+arthrocentesis at 14 to 26 weeks postin-
jection for pain on motion (WMD -15.00; 95% CI -26.09 to There was no statistically significant difference in the Lequesne
-3.91, P value 0.008); pain at rest (WMD -11.00; 95% CI - Index (scored 0 to 24) either at the end of treatment or at 5 to 13

weeks post injection. under load (P value 0.001), WOMAC pain (P value 0.003), and
WOMAC function (P value 0.001) whereas the RevMan analysis
Safety did not detect any significant differences (pain under load P value
0.2, WOMAC pain P value 0.3, WOMAC function P value 0.2).
There was no statistically significant difference in the number of
total withdrawals overall at 5 to 13 weeks postinjection. Safety
Hylan G-F 20 (Synvisc) versus exercise programme
One RCT included was a comparison of Hylan G-F 20 to an There was no statistically significant difference in the total number
exercise programme (Karatosun 2005). of withdrawals overall or in the number of patients having total
Efficacy knee replacements.
The primary outcome measure for this trial was the Hospital for Hylan G-F 20 (Synvisc) + appropriate care versus appropriate care
Special Surgery Knee Score. There were no statistically significant alone
differences in the Score at any of the assessment times: 1 to 4, 5 to Table 34; Table 35
13, 14 to 26, 45 to 52, or 74 weeks postinjection. By analysing the Two trials included were comparisons of the combination of Hylan
separate categories that make up the Score, the following statisti- G-F 20 and appropriate care (AC) to appropriate care alone (Kahan
cally significant differences were detected in favour of Hylan G-F 2003a; Raynauld 2002).
20 for pain during activity at 1 to 4 weeks postinjection (WMD
1.90; 95% CI 0.19 to 3.61, P value 0.03) (Hylan G-F 20 was Efficacy
53% more effective than exercise); at 5 to 13 weeks postinjec-
tion (WMD 1.70; 95% CI 0.17 to 3.23, P value 0.03) (Hylan A statistically significant difference in favour of Hylan G-F 20 and
G-F 20 was 49% more effective than exercise); and at 14 to 26 AC compared to AC alone was found in the WOMAC OA In-
weeks postinjection (WMD 2.50; 95% CI 0.85 to 4.15, P value dex pain subscale (0 to 20 Likert) at 45 to 52 weeks postinjection
0.003) (Hylan G-F 20 was 27% more effective than exercise). A (WMD -3.16; 95% CI -4.17 to -2.15, P < 0.00001) (Raynauld
statistically significant difference in favour of exercise was detected 2002). The combination group was 22% more effective than AC
for pain during transfer activity at 45 to 52 weeks postinjection alone group. A statistically significant difference in favour of Hy-
(WMD -0.50; 95% CI -0.95 to -0.05, P value 0.03) (exercise was lan G-F 20 and AC compared to AC alone was found in the
10% more effective than Hylan G-F 20). WOMAC OA Index physical function subscale (0 to 68 Likert)
Safety at 45 to 52 weeks postinjection (WMD -9.61; 95% CI -13.09 to
A statistically significant difference was detected in the total with- -6.13, P < 0.00001) (Raynauld 2002). The combination group
drawals overall in favour of the exercise group (RR 43.81; 95% was 22% more effective than AC alone group. The patient global
CI 2.72 to 704.87, P value 0.008). assessment, based on the number of patients improved in the study
Hylan G-F 20 (Synvisc) versus IA gaseous oxygen knee, was statistically better for the Hylan G-F 20 and AC group
One RCT was a comparison of Hylan G-F 20 plus an exercise (73%) compared to AC alone (27%) (RR 2.68; 95% CI 1.98 to
programme to IA gaseous oxygen plus an exercise programme 3.62, P < 0.00001) (Raynauld 2002). The NNT for patient global
(Auerbach 2002; Auerbach 2002a). assessment was 2.
A statistically significant difference in favour of Hylan G-F 20 and
Efficacy AC compared to AC alone was found in the WOMAC OA Index
pain subscale (0 to 100 mm VAS) (WMD -12.70; 95% CI -16.41
A between-group difference was found for pain under load (0 to to -8.99, P < 0.00001) (Kahan 2003a). The combination group
100 mm VAS) at 5 to 13 weeks postinjection in favour of the oxy- was 25% more effective than AC alone. A statistically significant
gen group (WMD 12.83; 95% CI 1.96 to 23.70, P value 0.02) difference in favour of Hylan G-F 20 and AC compared to AC
but no statistically significant differences were found at the other alone was found in the WOMAC OA Index physical function
assessments: end of treatment, 14 to 26 weeks postinjection, or 45 subscale (WMD -13.20; 95% CI -17.02 to -9.38, P < 0.00001)
to 52 weeks postinjection. There were no statistically significant (Kahan 2003a). The combination group was 24% more effective
differences between the groups for pain at rest (0 to 100 mm VAS); than AC alone. A statistically significant difference was found in
WOMAC OA Index pain (0 to 20); or WOMAC OA Index phys- favour of Hylan G-F 20 and AC compared to AC alone in the
ical function (0 to 68) at any of the assessments: end of treatment, Lequesne Index (0 to 24) (WMD -2.20; 95% CI -2.98 to -1.42,
5 to 13, 14 to 26, or 45 to 52 weeks postinjection. P < 0.00001) (Kahan 2003a). The combination group was 18%
The RevMan analysis differed from the Auerbach publication more effective than AC alone. The patient global assessment, based
(Auerbach 2002) analysis. In the publication, statistically signif- on effectiveness rated as good or satisfactory, was statistically better
icant differences were found at 45 to 52 weeks postinjection in for the Hylan G-F 20 and AC group (74%) compared to AC
favour of Hylan G-F 20 compared to IA gaseous oxygen for pain alone (51%) (RR 1.44; 95% CI 1.25 to 1.66, P < 0.00001) (

Kahan 2003a). The NNT for patient global assessment was 4.
The number of responders, defined as those patients with at least Efficacy
a 20% decrease in pain on walking, was significantly higher in the
Hylan G-F 20 and AC group (88%) compared to AC alone (68%) There was no statistically significant difference in pain on weight
(RR 1.30; 95% CI 1.18 to 1.43, P < 0.00001) (Kahan 2003a). bearing (0 to 100 mm VAS) at 1 to 4 weeks postinjection (Karlsson
2002c (AvS), Wobig 1999a (Healon), Wobig 1999b (Artz)), or at
Safety 14 to 26 weeks postinjection (Karlsson 2002c (AvS)). There was a
statistically significant difference in favour of Hylan G-F 20 com-
There was no statistically significant difference in the total with- pared to other hyaluronans at 5 to 13 weeks postinjection (WMD
drawals overall, the number of patients reporting side effects from -6.59; 95% CI -12.46 to -0.73, P value 0.03) (Karlsson 2002c
baseline (Kahan 2003a; Raynauld 2002), or the number of pa- (AvS); Wobig 1999a (Healon); Wobig 1999b (Artz)). There was
tients withdrawn due to adverse events in the Kahan trial (Kahan a statistically significant difference in favour of Hylan G-F 20 in
2003a). The number of patients reporting mild, moderate or se- pain at night (0 to 100 mm VAS) at 1 to 4 weeks postinjection
vere side effects at the end of the study was significantly higher in (WMD -7.07; 95% CI -13.41 to -0.73, P value 0.03), but no
the AC alone group (68%) compared to the Hylan G-F 20 and difference at 5 to 13 weeks postinjection (Wobig 1999a (Healon);
AC group (52%) (RR 0.76; 95% CI 0.61 to 0.94, P value 0.01) Wobig 1999b (Artz)). There was no significant difference in im-
(Raynauld 2002). There was a statistically significant difference provement in knee movement (0 to 100 mm VAS) at 1 to 4 weeks
in the number of patients with gastrointestinal adverse events in postinjection, but there was a statistically significant difference in
favour of the Hylan G-F 20 and AC group compared to AC alone favour of Hylan G-F 20 at 5 to 13 weeks postinjection (WMD
(RR 0.38; 95% CI 0.25 to 0.60, P value 0.00002) (Kahan 2003a; 12.50; 95% CI 2.70 to 22.30, P value 0.01). There was no signif-
Raynauld 2002). Significantly fewer patients withdrew due to lack icant difference in the patient global evaluation of treatment effi-
of effectiveness in the Hylan G-F 20 and AC group (2%) com- cacy (0 to 100 mm VAS) at 1 to 4 or at 5-13 weeks postinjection.
pared to the AC alone group (7%) (RR 0.35; 95% CI 0.14 to When excluding the Healon arm, there was no statistically signif-
0.88, P value 0.03) (Kahan 2003a). icant difference in pain on weight bearing at 1 to 4 or at 5 to 13
Hylan G-F 20 (Synvisc) plus arthroscopy versus arthroscopy alone weeks postinjection (Karlsson 2002c (AvS), Wobig 1999b (Artz)).
One RCT has been a comparison of Hylan G-F 20 following There was no statistically significant difference in pain at night at 1
arthroscopy and arthroscopy alone (Rejaili 2005). to 4 or at 5 to 13 weeks postinjection (Wobig 1999b (Artz)). There
Efficacy was no significant difference in improvement in knee movement
Results have not been reported for the four efficacy outcomes since (0 to 100 mm VAS) at 1 to 4 weeks postinjection. There was a
only means, but not standard deviations, were reported at the 24- significant difference in improvement in knee movement in favour
week follow-up. of Hylan G-F 20 at 5 to 13 weeks postinjection (WMD 17.00;
Safety 95% CI 3.14 to 30.66, P value 0.02). There was no significant
No postinjection synovitis was observed during the trial. With re- difference in patient global evaluation of treatment efficacy at 1 to
spect to the arthroscopy procedure, there were no intra or postop- 4 weeks postinjection. There was a statistically significant differ-
erative complications in the patients. These are the only data that ence in patient global evaluation of treatment efficacy in favour of
were reported with respect to safety. Hylan G-F 20 at 5 to 13 weeks postinjection (WMD 16.00; 95%
Hylan G-F 20 (Synvisc) versus other hyaluronan CI 2.14 to 29.86, P value 0.02).
Table 36
Nine RCTs have been comparisons of Hylan G-F 20 and hyaluro- Safety
nan: 1) Artzal (Karlsson 2002) - readers are directed to the Artz
product results, 2) Artz (Wobig 1999b (Artz)) and Healon (Wobig The safety profile of the three groups (Artz, Healon and Hylan G-F
1999a (Healon)), 3) Hyalgan (Brown 2003) - readers are di- 20) was very similar (Wobig 1999). No patients reported systemic
rected to the Hyalgan product results, 4) Orthovisc (Atamaz 2005; reactions. Two Hylan G-F 20 patients and one Artz patient re-
Bayramoglu 2003; Karatay 2004; Karatosun 2005a; Kotevoglu ported local reactions. One Hylan G-F 20 patient and two Healon
2005) - readers are directed to the Orthovisc product results, and patients withdrew from the trial.
5) Arthrease (Kirchner 2005; Thompson 2002) - readers are di- Product - Hyruan
rected to the BioHy (Arthrease, Euflexxa, Nuflexxa) product re- Description of studies:
sults. Three studies were excluded (Lee 1999; Oberoi 2004; Rastogi
The Wobig 199 trial had two active arms: Artz (Wobig 1999b 2005). One study is awaiting assessment (Lee 2002).
(Artz) and Healon (Wobig 1999a (Healon)). Since Healon is not
indicated for the treatment of knee OA we have completed the Product - NRD-101 (Suvenyl)
analysis both including and excluding this arm.

Description of studies: symptomatic outcome measures were reported as change between
baseline and the final visit for the Pham trial (Pham 2004). There
Two RCTs have been included (Pham 2003 (abstract); Pham 2004 were no statistically significant differences between NRD-101 and
(final publication); Tsukamoto 1995(abstract); Yamamoto 1994 placebo for pain (0-100 mm VAS), the Lequesne Index (0-100
(final publication)). modified scale), patient global assessment (0-100 mm VAS), or
Pham et al. reported a one-year, parallel-group, double-blind, the percentage of painful days (0-100 mm VAS.
placebo-controlled, multicentre (46 rheumatology departments) Data were reported on the percentage of progressors (joint space
RCT performed in France comparing three weekly injections of narrowing greater than 0.5 mm). There was no statistically sig-
NRD-101 plus oral placebo to: 1) three weekly injections of saline nificant difference between NRD 101 + oral placebo 23 of 131
solution plus Diacerein 50 mg twice daily, and 2) three weekly (17.6%) and saline injection + oral placebo 17 out of 85 (20.3%).
IA injections of saline solution plus oral placebo (Pham 2004,
Pham 2003). The objective was to evaluate long-term structural Safety
and symptomatic efficacy of three courses (every three months) No statistically significant differences were detected for the fol-
of three weekly IA injections of NRD-101over a one-year period. lowing safety variables between NRD-101 and placebo: total wi-
No statistically significant between-group differences were found hdrawals overall, withdrawals due to inefficacy, number of with-
for pain. There was a statistically significant deterioration in joint drawals due to adverse events, number of patients reporting knee
space width but no difference between the three groups. The trial pain during or after IA injection, or number of patients reporting
did not find any structural and/or symptomatic effect for NRD- diarrhoea (Pham 2004).
101 and Diacerein. With respect to safety, patients in the NRD- NRD-101 (Suvenyl) versus corticosteroid: no trials included.
101 group had significantly more knee pain during or after intraar- NRD-101 (Suvenyl) versus NSAID (Diacerein)
ticular injection, while patients in the Diacerein group had more
diarrhoea and urine colouration. With respect to methodological Efficacy
quality, the trial scored 5 out of 5 on the Jadad scale achieving Table 39; Table 40
points for both randomisation and blinding details. Allocation
concealment was adequate. Readers should note that the results of the efficacy data on the
The statistical analyses were performed using the change between symptomatic outcome measures were reported as change between
baseline and the final visit since raw means and standard deviations baseline and the final visit for the Pham trial (Pham 2004). There
for unadjusted post-test scores were not available. were no statistically significant differences between NRD-101 and
Yamamoto et al. reported a five-week, parallel-group, double-blind Diacerein for any of the efficacy outcome measures: pain (0-100
RCT performed at 31 centres in Japan comparing five weekly in- mm VAS), Lequesne Index (0-100 modified scale), patient global
jections of NRD-101 (produced by fermentation using Strepto- assessment (0-100 mm VAS) or the percentage of painful days (0-
coccus equi, a type of lactobacilli, Denki Kagaku Kogyo) to five 100 mm VAS).
weekly injections of Artz in 203 patients with OA of the knee Data were reported on the percentage of progressors (joint space
(Tsukamoto 1995; Yamamoto 1994). Statistically significant dif- narrowing greater than 0.5 mm) (Pham 2003). There was no statis-
ferences in favour of NRD-101 were reported for ’final global im- tically significant difference between NRD 101 + oral placebo 23
provement’ and ’usefulness’ but not for evaluation of improvement of 131 (17.6%) and Diacerein + saline injection 16 of 85 (18.9%).
in clinical symptoms. Adverse events were reported for 2 of 100
NRD-101 patients and 3 of 99 Artz patients. Safety
This comparative HA trial was of short duration with the longest A statistically significant difference in favour of NRD-101 com-
assessment only one week postinjection. The 31 trial sites were pared to Diacerein was detected in the number of patients that
all Departments of Orthopedic Surgery. Almost all of the clinical reported diarrhoea (RR 0.22; 95% CI 0.12 to 0.40, P < 0.00001)
evaluations were based on physician ratings rather than on patient (41% versus 9%). A statistically significant difference in favour
ratings. of Diacerein compared to NRD-101 was detected in the number
With respect to methodological quality, the average Jadad score of patients that reported knee pain during or after IA injection
was 5 out of 5; both the Pham trial and the Yamamoto trial scoring (RR 2.51; 95% CI 1.21 to 5.21, P value 0.01) (24% versus 9%).
5. Allocation concealment was adequate for both trials. One trial There were no statistically significant differences between NRD-
was excluded (Kurokawa 1994). 101 and Diacerein for the total withdrawals overall, withdrawals
NRD-101 (Suvenyl) versus placebo due to inefficacy, or the number of withdrawals due to adverse
events (Pham 2004).
Efficacy NRD-101 (Suvenyl) versus other hyaluronans
Table 37; Table 38
Readers should note that the results of the efficacy data on the Efficacy

Table 41; Table 42 been published as abstracts with no extractable data, and at the
For the NRD-101 comparison against Artz (Tsukamoto 1995; closure of the database for this review no full length manuscripts
Yamamoto 1994) there were no statistically significant differences have been published.
between the two products in any measure of efficacy at 1 to 4 weeks Bayramoglu et al. reported a three-month, parallel-group RCT
postinjection: spontaneous pain, pain on pressure, pain during the performed at a single centre in Turkey comparing three weekly in-
night, passive movement pain, passive flexion, passive extension, jections of Orthovisc plus a physical therapy programme to three
and patient global assessment. weekly injections of Hylan G-F 20 plus a physical therapy pro-
gramme to a physical therapy programme alone (deep tissue heat-
Safety ing with short wave diathermy, transcutaneous electrical neuro-
There was a trend of more withdrawals overall in the Artz group muscular stimulation and exercises) in 46 patients with OA of
(15%) compared to the NRD-101 group (6%) (RR 0.40; 95% the knee (Bayramoglu 2003). The authors were particularly in-
CI 0.16 to 1.00, P value 0.05) (Yamamoto 1994). There were a terested in examining the effect of IA HA injection on muscu-
similar number of adverse events reported in the two groups: 2 of lar strength; testing the hypothesis that if patients were relieved
100 in NRD-101 and 3 of 99 in the Artz group. of pain and disability then indirectly they would build stronger
quadriceps muscles. They reported within-group improvement in
Product - Orthovisc the Lequesne score for all three groups but no between-group dif-
ference. No within- or between-group difference was detected in
Description of studies muscular strength. No between-group differences were reported
for range of motion, knee instability, existing deformities and ra-
Fourteen randomised controlled trials of Orthovisc (Anika Ther- diographic grade. No adverse events were associated with the IA
apeutics, Inc., Woburn, MA) have been included. Eleven have hyaluronic acid injections.
been reported as journal articles (Bayramoglu 2003; Brandt 2001; The Bayramoglu et al. RCT had a small sample size. However, it
Karatay 2005a; Karatosun 2005a; Kotevoglu 2005; Neustadt was classified as a pilot study. The presence or absence of effusion,
2005a -3inj; Ozturk 2005; Sezgin 2005; Tascioglu 2003; Tekeoglu usage of rescue and concomitant medications, and OA diagnosis
1998; Yentur 2003), one was the basis of a specialization the- criteria were not reported. There was a difference in the num-
sis (Kalay 1997), one was presented as a poster at the 10th Na- ber of patients with bilateral disease: 100% physical therapy (PT)
tional Rheumatology Congress in Turkey (Guler 1996), and one group, 75% Orthovisc group and 67% Hylan G-F 20 group. No
remains unpublished (Hizmetli 1999). Orthovisc has been com- difference was found with respect to the MW of the HA prod-
pared against placebo (Brandt 2001; Guler 1996; Hizmetli 1999; ucts. Since PT is part of the first line nonpharmacologic therapy
Kotevoglu 2005; Sezgin 2005), arthrocentesis (Neustadt 2005a in the medical management of patients with OA of the knee, the
-3inj), betamethasone (Tekeoglu 1998), 6-methylprednisolone ac- designation of PT alone as a treatment group in comparison to
etate (Tascioglu 2003), in combination with triamcinolone ace- the two combination groups (pharmacologic + nonpharmacologic
tonide (Ozturk 2005), IA hylan (Bayramoglu 2003; Karatay 2004; groups) was a particular interest in this trial.
Karatosun 2005a; Kotevoglu 2005), physical therapy (Bayramoglu Brandt et al. reported a 27-week, placebo-controlled, double-blind
2003; Kalay 1997), and in combination with lidocaine (Yentur RCT performed at 10 centres in the United States comparing three
2003). With the exception of the Brandt RCT (Brandt 2001), weekly injections of Orthovisc to three weekly injections of saline
which was conducted in the United States, and the Neustadt in 226 patients with OA of the knee (Brandt 2001). The authors
RCT (Neustadt 2005a -3inj), which was conducted in Canada examined the influence of contralateral knee pain in a post hoc
and the United States, the other twelve RCT were conducted analysis of patients who completed at least 15 weeks of the trial,
in Turkey. With respect to methodological quality, the average had no major protocol violations, and a WOMAC OA Index pain
Jadad score was 2.9 out of 5, with one trial scoring 5 (Neustadt score less than 12 in the contralateral knee. This ’effectiveness’
2005a -3inj), two trials scoring 4 (Brandt 2001; Hizmetli 1999), population controlled for the severity in the contralateral knee.
three trials scoring 3 (Guler 1996; Kotevoglu 2005; Ozturk 2005), The authors concluded that, in patients with mild to moderate
six trials scoring 2 (Bayramoglu 2003; Kalay 1997; Sezgin 2005; OA of the knee, Orthovisc produced statistically and clinically
Tascioglu 2003; Tekeoglu 1998; Yentur 2003), and one trial scor- significant improvement. No side effects were attributed to treat-
ing 1 (Karatay 2005a). Allocation concealment was adequately ment. The incidence of injection site reaction was similar in both
described in four trials (Brandt 2001; Karatosun 2005a; Neustadt groups: 2.1% Orthovisc and 1.5% saline.
2005a -3inj; Ozturk 2005) and unclear (not reported) in the re- The Brandt et al. RCT did not report the presence or ab-
maining ten trials. Seven trials were excluded (Ates 2001; Birbara sence of effusion or disease duration (Brandt 2001). In this trial,
2004; Koyuncu 2002; Olszynski 2002; Oron 2003; Sepici 2002; acetaminophen was permitted at the recommended treatment
Toh 2002; Toh 2003). Three trials are awaiting assessment (Gur dosage of 1 g four times daily, but was restricted 24 h before as-
2002; Kilinc 2002; Renk[inodot]tepe 20). These trials have only sessment visits. Patients in this trial had a high percentage of bi-

lateral knee disease, but only the index knee received treatment. the Orthovisc group had local pain and swelling which resolved
WOMAC OA Index questionnaires were completed by patients within 24 hours.
for each knee separately. The severity of pain in the contralateral The Kalay trial utilised a two-injection schedule rather than a
knee confounded the outcome measurements in the index knee. three-injection schedule (Kalay 1997). The publication did not
The authors discussed how the pain response may be affected report the presence or absence of effusion or disease duration.
by severity of contralateral knee pain. They also noted the large However, supplemental use of paracetamol as rescue medication
placebo response detected in this trial. Although 78% of the pa- was graded and recorded. Statistically significant decreases in con-
tients randomised completed the trial, results were based only on sumption were seen in both groups at the end of the study com-
the effectiveness population (i.e. 60%). It is of note that no sig- pared to baseline. As well, a statistically significant between-group
nificant difference was detected in the intent-to-treat population difference in favour of Orthovisc was found at the eighth week.
between Orthovisc and placebo. The authors defined a clinically Karatay et al. reported a three-week, parallel group RCT per-
meaningful improvement as a decrease of at least three units in formed at a single centre in Turkey comparing three weekly in-
the WOMAC pain subscale score. They utilised a 1 to 5 scoring jections of Orthovisc to three weekly injections of hylan G-F 20
system for the Likert version of the WOMAC OA Index resulting in 40 patients with OA of the knee (Karatay 2004; Karatay 2005;
in a score range of 5 to 25 for the pain subscale of the Index. Karatay 2005a). The objective of this trial was to evaluate the
Guler et al. reported a 10-week, placebo-controlled, double-blind effects of HA on synovial fluid levels of intercellular adhesion
RCT performed at one centre in Turkey comparing three weekly molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (V-
injections of Orthovisc to three weekly injections of saline in 30 CAM-1). ICAM-1 and VCAM-1 levels were significantly reduced
patients with OA of the knee (Guler 1996). Statistically signifi- in both groups. Both groups showed within-group improvement
cant improvement was reported in the Orthovisc group for the in WOMAC pain and physical function scores with significant
WOMAC pain and physical function subscales, walking time, and within-group improvement being detected for WOMAC stiffness.
acetaminophen usage compared to the saline group. No adverse However, no signiifcant between-group differences were found for
events were reported. any of the outcome measures. Safety was not reported.
The small trial by Guler et al. demonstrated between-group dif- Karatosun et al. reported a one-year, double-blind, parallel-group
ferences (Guler 1996). Of particular note, there was a statistically RCT performed at a single centre in Turkey comparing three
significant decrease in the use of acetaminophen in the Orthovisc weekly injections of Orthovisc to three weekly injections of Hylan
group. Although the abstract reported WOMAC OA Index sub- G-F 20 in 92 patients with OA of the knee (Karatosun 2005a).
scale ranges with the minimum set at zero, it appeared that the The authors reported no statistically significant differences be-
score was based on 1 to 5. tween the groups as both groups improved in the Hospital for Spe-
Hizmetli et al. completed a one-year, placebo-controlled, dou- cial Surgery scores. Both HA products were well tolerated with no
ble-blind RCT in Turkey comparing three weekly injections of complications due to HA injection being reported. Approximately
Orthovisc to saline in 50 patients with OA of the knee (Hizmetli 30% of patients in each group (Orthovisc 30.4% and Hylan G-F
1999). A fourth injection was given at six months. Statistically 20 34.8%) withdrew early from the trial.
significant differences in all subscales of the WOMAC OA Index Patients with advanced (i.e. Kellgren-Lawrence Grade III) bilateral
in favour of Orthovisc were reported. No local or systemic side ef- knee OA were enrolled in this trial. A blinded physical therapist
fects were observed. This unpublished report was kindly provided assessed the efficacy and safety of the therapy. This is one of the
by Anika Therapeutics Inc. longest trials comparing two HA products using the Hospital for
The Hizmetli et al. trial was one of a few unpublished trials in- Special Surgery Knee Score as the primary outcome measure. Dr.
cluded in this review (Hizmetli 1999). The manuscript did not Karatosun kindly provided means and standard deviations for the
report presence or absence of effusion, disease duration, or pres- reported outcome measures.
ence of uni/bilateral disease. The trial addressed repeat treatment Kotevolgu et al. reported a six-month, parallel-group, placebo-
at six months. Analgesics were restricted for the first four weeks of controlled, double-blind RCT performed at a single centre in
the trial. Turkey comparing three weekly injections of Orthovisc to three
Kalay reported a 56-day, parallel-group, open-label RCT per- weekly injections of Synvisc Hylan G-F 20 or saline solution in 78
formed at a single centre in Turkey comparing two weekly injec- patients with OA of the knee without effusion (Kotevoglu 2005).
tions of Orthovisc plus a physical therapy programme to a physical The authors reported that all patients showed clinical improve-
therapy programme (paraffin, short wave, quadriceps exercises) in ment but that neither hyaluronan product was more effective than
40 patients with OA of the knee (Kalay 1997). Statistically sig- the other. With respect to safety, local adverse events were reported
nificant improvement was reported in the Orthovisc group com- by two patients and these (transient pain at injection site or warm
pared to the physical therapy alone group for the following clin- knee lasting for one night) resolved without sequelae. Dr. Nurdan
ical outcome measures: pain, paracetamol usage, walk time, and Kotevoglu kindly provided an Excel worksheet with the means and
patient and investigator evaluation of treatment. Two patients in standard deviations for the WOMAC OA Index, patient global

assessment and physican global assessment; in addition clarified clarified group allocation for withdrawals.
withdrawals. Sezgin et al. reported a four-week, placebo-controlled, single-blind
Neustadt et al. (Neustadt 2005a -3inj) reported a six-month, dou- RCT performed at a single centre in Turkey comparing three
ble-blind, arthrocentesis-controlled RCT performed at 24 centres weekly injections of Orthovisc to three weekly injections of sodium
in Canada and the United States comparing four weekly injec- chloride (0.9%) in 41 patients with OA of the knee (Sezgin 2005).
tions of Orthovisc to either three weekly injections of Orthovisc The objective of this study was to investigate whether hyaluro-
followed by one arthrocentesis or four arthrocenteses without in- nan had any effect on inflammatory cytokines. The authors re-
jection in 372 patients with OA of the knee. The authors reported that hyaluronan significantly decreased IL-6 levels which
ported that there was no statistically significant difference in the correlated with clinical improvement. WOMAC pain, stiffness
primary outcome (greater than or equal to 20% improvement in and physical function scores decreased more in the hyaluronan
the WOMAC OA Index pain subscale score) between the 4-injec- group than the control group, as did flexion, walking time, knee
tion Orthovisc group and the arthrocentesis group. With respect circumference and amount of effusion. With respect to safety, no
to safety, no between group differences were reported in the inci- patients reported any adverse events during or after the treatment;
dence of adverse events. albeit some patients reported short-lasting pain (one or 2 minutes)
For the above RCT, the ITT population was used for safety analy- during the injections.
ses. However, the ”primary planned analysis population“ was the Tascioglu and Oner reported a six-month, parallel-group, open-
evaluable population which was defined as ”patients who received label RCT performed at a single centre in Turkey comparing three
all 4 treatments and at least one followup visit and who had no sig- weekly injections of Orthovisc to three weekly injections of 6-
nificant protocol deviation“. One of the inclusion criteria for this methylprednisolone acetate (6-MPA) in 69 female patients with
trial was that patients had to score less than 150 mm out of 500 OA of the knee (Tascioglu 2003). A significant improvement was
mm on the WOMAC OA Index pain subscale in the contralateral reported in both groups at week four in pain and Lequesne out-
(untreated) knee. In the tables of comparisons and data, the 4 in- come measures. At three months, a significant improvement in
jection schedule comparison is referred to as Neustadt 2005b-4inj, pain and Lequesne was reported in favour of Orthovisc compared
while the 3 injection schedule is referred to as Neustadt 2005a to 6-MPA. By six months, there was no difference between the
-3inj. The analyses were performed using the change from baseline two groups. No serious systemic adverse events were reported that
and absolute means and standard deviations for unadjusted post- could be related to the treatment. Similar percentages of patients
test score were not available from Anika Therapeutics, Inc.. Anika reported knee pain after injection (Orthovisc 21%, 6-MPA 18%).
Therapeutics, Inc. kindly provided additional information regard- There was no significant between-group difference with respect to
ing reasons for discontinuation and a patient tree. Withdrawals adverse events.
were separated into those who withdrew before 8 weeks (n=34) In the Tascioglu and Oner trial paracetamol to a maximum of 3 g
and those who withdrew after 8 weeks (n=78). was permitted but with restriction 48 hours prior to an assessment
Ozturk et al. reported a one-year, parallel-group, single-blind RCT (Tascioglu 2003). The percentage of patients with uni and bilateral
performed at a single centre in Turkey comparing three weekly disease was not reported.
injections of Orthovisc followed by three weekly injections at six Tekeoglu et al. reported a 15-week, parallel-group, open-label
months of the same Orthovisc regimen but in combination with RCT performed in Turkey comparing three weekly injections of
one ml of triamcinolone acetonide (Kenacort-A) prior to the first Orthovisc to three weekly injections of betamethasone in 40 fe-
and fourth injections of Orthovisc after any effusion had been male patients with OA of the knee (Tekeoglu 1998). In the short
aspirated in 47 patients with OA of the knee (Ozturk 2005). The term (week 3), betamethasone was more effective than Orthovisc.
objective of this study was to assess the efficacy and safety of In the long term (week 15), Orthovisc was more effective than
Orthovisc with/without corticosteroid. Repeat treatment occurred betamethasone. No local or systemic reactions were reported.
at the sixth month. In addition, magnetic resonance imaging was The Tekeoglu et al. trial allowed patients to take paracetamol as
used to evaluate the progression of OA. The authors reported that well (Tekeoglu 1998). Again, the percentage of patients with uni
neither treatment showed progression of cartilage damage. With and bilateral disease was not reported. In this RCT, patients were
respect to efficacy, an improvement was reported in all patients for advised to rest for one day after injection ’to avoid overcharging
functional measures but pain decreased more rapidly and to lower the injected joint’.
levels in the combination treatment group. With respect to safety, Yentur et al. reported a 21-day, parallel-group, single-blind
one patient from the combination group and two patients from RCT performed in Turkey comparing three weekly injections of
the Orthovisc group reported adverse events (i.e. local reactions Orthovisc plus trigger point injections with 0.5% lidocaine to
including mild swelling, warmth, pain at the injection site) after three weekly injections of Orthovisc in 34 female patients with OA
the third injection. However, these events resolved within a few of the knee (Yentur 2003). The authors reported that the combi-
days after application of cold packs. Dr. F. Atamaz kindly provided nation therapy group had significantly reduced pain and improved
absolute means and standard deviations for both groups as well as function while pain reduction and function improvement were

not significant in the Orthovisc alone group. Although the authors tients who achieved a greater than five-unit improvement in the
reported that no local or systemic adverse events were observed, WOMAC pain score relative to baseline score by 25 weeks postin-
some patients reported local pain which only lasted for one day jection (Orthovisc 58%, saline 40%) (RR 1.42; 95% CI 1.00 to
and ecchymosis which healed in a few days. Only one patient in 2.02, P value 0.05). The RevMan analysis (P value 0.05) disagreed
the Orthovisc group did not complete the trial. with the publication analysis where a statistically significant dif-
This small trial addressed an interesting question whether injection ference was detected in favour of Orthovisc (P value 0.04). There
of 15 specific trigger points with lidocaine in combination with was no statistically significant difference in the number of patients
hyaluronic acid was more effective than hyaluronic acid alone. In who improved in the WOMAC pain subscale score at 14 to 26
this design, symptoms arising from the soft tissues surrounding weeks postinjection: Orthovisc 92% versus saline 87%.
the knee and not just the joint were treated. A two-day rest period Physical function, as measured by the WOMAC OA Index (scored
after each injection was utilised in the trial. In addition, a blinded 17 to 85), improved significantly with Orthovisc compared to
physician completed all assessments. placebo at three of four follow-up assessments: (WMD -7.20; 95%
Orthovisc versus placebo CI -8.84 to -5.56, P < 0.00001) at 1 to 4 weeks postinjection
(Hizmetli 1999; Kotevoglu 2005; Sezgin 2005); (WMD -12.87;
Efficacy 95% CI -18.60 to -7.14, P < 0.0001) at 5 to 13 weeks postinjec-
Table 43; Table 44; Table 45; Table 46; Table 47 tion; and (WMD -10.88; 95% CI -16.97 to -4.79, P value 0.0005)
A statistically significant difference was detected in pain, as mea- at 14 to 26 weeks postinjection (Hizmetli 1999; Kotevoglu 2005);
sured by the WOMAC OA Index (scored 5 to 25), in favour of but no statistically significant difference was detected at 45 to 52
Orthovisc compared to placebo (WMD (RE) -4.36; 95% CI -7.51 weeks postinjection (Hizmetli 1999). Orthovisc was between 16
to -1.21, P < 0.00001) at 1 to 4 weeks postinjection (Hizmetli and 42% more effective than saline in improving physical func-
1999; Kotevoglu 2005; Sezgin 2005); (WMD -5.40; 95% CI - tion as measured by the WOMAC OA Index physical function
6.92 to -3.89, P < 0.00001) at 5 to 13 weeks postinjection; (WMD subscale.
(RE) -4.41; 95% CI -6.95 to -1.88, P value 0.0007) at 14 to No statistically significant differences were detected in the
26 weeks postinjection (Hizmetli 1999; Kotevoglu 2005); and WOMAC OA Index stiffness subscale (scored 2 to 10) between
(WMD -5.30; 95% CI -7.02 to -3.58, P < 0.00001) at 45 to Orthovisc and saline at 1 to 4 weeks postinjection (Kotevoglu
52 weeks postinjection (Hizmetli 1999). Orthovisc was between 2005; Sezgin 2005). Statistically significant differences were de-
23 and 45% more effective than saline in relieving pain as mea- tected in favour of Orthovisc compared to saline both at 5 to
sured by the WOMAC OA Index pain subscale. Item five of the 13 weeks postinjection (WMD -1.50; 95% CI -2.84 to -0.16, P
WOMAC OA Index pain subscale, pain on standing (measured value 0.03)(Kotevoglu 2005) and at 14 to 26 weeks postinjection
on a 0 to 100 mm VAS), was utilised as a secondary outcome (WMD -1.50; 95% CI -2.71 to -0.29, P value 0.02) (Kotevoglu
measure in the Neustadt et al. RCT. No statistically significant dif- 2005).
ference was detected in this outcome measure between Orthovisc No statistically significant differences were detected in the total
and arthrocentesis (Neustadt 2005a -3inj; Neustadt 2005b-4inj). score for the WOMAC OA Index (scored 0 to 2400 mm VAS)
The proportion of patients achieving a 20% relative and 50 mm between Orthovisc and arthrocentesis either at 5 to 13 or 14 to 26
absolute improvement from baseline in the WOMAC OA Index weeks postinjection (Neustadt 2005a -3inj; Neustadt 2005b-4inj.
pain subscale (measured on a 0 to 500 mm VAS) was the primary ).
outcome measure for the Neustadt et al. RCT. No statistically sig- A statistically significant difference in favour of Orthovisc com-
nificant difference was detected between Orthovisc and arthro- pared to saline was detected both in patient global assessment (0-
centesis either at 5 to 13 weeks postinjection (RE) or at 14 to 26 100 mm, where 100 was worst severity) both at 1to 4 weeks postin-
weeks postinjection. When evaluating the proportion of patients jection (WMD -20.00; 95% CI, -33.22 to -6.78, P value 0.003)
achieving a 40% relative improvement from baseline, a statisti- and at 5 to 13 weeks postinjection (WMD -20.00; 95% CI -30.63
cally significant difference was detected in favour of the Orthovisc to -9.37, P value 0.0002); but not at 14 to 26 weeks postinjection
group compared to arthrocentesis at 5 to 13 weeks postinjection (Kotevoglu 2005). No statistically significant differences was de-
(RR 1.30; 95% CI 1.08 to 1.57, P value 0.006); while a trend was tected between Orthovisc and saline in physican global assessment
detected at 14 to 26 weeks postinjection (RR 1.22; 95% CI 1.00 (0-100 mm, where 100 was worst severity) in the Kotevoglu RCT.
to 1.49, P value 0.05). No statistically significant diference was Similarly, no statistically significant differences were detected in
detected in the 50% relative improvement comparison (Neustadt either the patient or physician global assessments (measured on 0
2005a -3inj; Neustadt 2005b-4inj). to 100 mm VAS) between Orthovisc and arthrocentesis either at
In Brandt’s trial (Brandt 2001), results are presented only for the 5 to 13 or 14 to 26 weeks postinjection (Neustadt 2005a -3inj;
effectiveness population which represents approximately a 40% Neustadt 2005b-4inj).
loss of the initially randomised population. There was a trend Patient satisfaction with treatment was similar in the Orthovisc
in favour of Orthovisc compared to saline in the number of pa- (73%) and saline (33%) groups (Guler 1996); (RR 2.20; 95% CI

1.01 to 4.79, P value 0.05) at 5 to 13 weeks postinjection. more effective than betamethasone in improving physical func-
Results for additional outcome measures utilised in the Sezgin tion. Orthovisc was significantly better than betamethasone for
RCT are as follows. Statistically significant difference were de- patient global assessment (i.e. number of patients good/very good)
tected in favour of Orthovisc compared to saline for range of mo- (RR 1.88; 95% CI 1.04 to 3.39, P value 0.04). The NNT for pa-
tion (measured in degrees) (WMD 4.00; 95% CI 2.02 to 5.98, P < tient global assessment was 3. There was no statistically significant
0.0001)(Orthovisc was 15% more effective than saline in improv- between-group difference for maximum flexion at 5 to 13 weeks.
ing flexion); volume of synovial fluid effusion (WMD -4.00; 95% In the Orthovisc/6-methylprednisolone acetate (6-MPA) compar-
CI -5.66 to -2.34, P < 0.00001) (Orthovisc was 24% more effec- ison (Tascioglu 2003), there were no statistically significant differ-
tive than saline); interleukin 6 level in the synovial fluid (WMD ences between the two groups for any of the pain outcome mea-
-11.90; 95% CI -14.09 to -9.71, P < 0.00001) (Orthovisc was sures (0 to 100 mm VAS), the Lequesne Index (0 to 24), or flexion
6% more effective than saline); and interleukin 8 level in the syn- outcome measures at 1 to 4 weeks postinjection. However, at 5
ovial fluid (WMD -4.80; 95% CI -6.54 to 3.06, P < 0.00001) to 13 weeks postinjection, statistically significant differences were
(Orthovisc; Orthovisc was 42% more effective than saline) (Sezgin detected in all outcome measures, except flexion, in favour of the
2005). No statistically significant differences were detected in 25 Orthovisc group: pain on weight bearing (WMD -15.64; 95% CI
metre walking time (measured in seconds), knee circumference -24.51 to -6.77, P value 0.0006); pain at rest (WMD -7.70; 95%
(measured in mm), tumor necrosis factor alpha levels in synovial CI -13.50 to -1.90, P value 0.009); pain on walking (WMD -
fluid (Sezgin 2005); or WOMAC OA Index stiffness subscale score 18.43; 95% CI -29.19 to -7.67, P value 0.0008); and the Lequesne
(Kotevoglu 2005; Sezgin 2005). Index (WMD -1.40; 95% CI -2.13 to -0.67, P value 0.0002).
Safety Orthovisc was between 25 and 32% more effective than 6-MPA in
relieving pain. Orthovisc was 18% more effective than 6-MPA in
No local or systemic adverse events were observed in the Hizmetli improving function (Lequesne). At 14 to 26 weeks postinjection,
trial (Hizmetli 1999). No complications (e.g. during or after in- statistically significant differences in all outcome measures, except
traarticular injection) were reported in the Guler trial (Guler pain on rest, were detected in favour of the Orthovisc group: pain
1996). on weight bearing (WMD -15.40; 95% CI -25.91 to -4.89, P
The safety data was based on the intention to treat population value 0.004); pain on walking (WMD -14.90; 95% CI -25.91 to
in the Brandt trial (Brandt 2001). There were no statistically sig- -3.89, P value 0.008); Lequesne Index (WMD -1.14; 95% CI -
nificant differences between Orthovisc and saline or arthrocente- 2.16 to -0.12, P value 0.03), and flexion (WMD 5.00; 95% CI
sis in the safety profile for the following outcome measures: to- 0.19 to 9.81, P value 0.04). Orthovisc was between 20 and 31%
tal withdrawals overall (Brandt 2001; Kotevoglu 2005; Neustadt more effective than 6-MPA in relieving pain and between 4 and
2005a -3inj; Neustadt 2005b-4inj; Sezgin 2005); withdrawals due 15% more effective than 6-MPA in improving function.
to lack of efficacy (Brandt 2001; Neustadt 2005a -3inj; Neustadt The RevMan analysis differed from the publication analysis
2005b-4inj; Sezgin 2005); number of patients with local skin (Tascioglu 2003). The publication reported no statistically signif-
rash (Brandt 2001; Neustadt 2005a -3inj; Neustadt 2005b-4inj); icant between-group difference at six months in pain on weight
number of patients with treatment related adverse events (Brandt bearing whereas RevMan detected a statistically significant dif-
2001); number of patients with musculoskeletal adverse events; ference (P value 0.004) in favour of Orthovisc compared to 6-
number of patients with respiratory adverse events; number of MPA. The publication reported no statistically significant be-
patients with general body adverse events; number of patients tween-group difference at six months in pain on walking whereas
with nervous system adverse events (Brandt 2001; Neustadt 2005a RevMan detected a statistically significant difference (P value
-3inj; Neustadt 2005b-4inj); number of patients with local re- 0.008) in favour of Orthovisc compared to 6-MPA. The publi-
action or number of patients withdrawn due to noncompliance cation reported no statistically significant between-group differ-
(Kotevoglu 2005). ence at six months in the Lequesne Index whereas RevMan de-
Orthovisc versus corticosteroid tected a statistically significant difference (P value 0.03) in favour
of Orthovisc compared to 6-MPA. The publication reported no
Efficacy statistically significant between-group difference at six months in
flexion whereas RevMan detected a statistically significant differ-
In the Orthovisc/betamethasone comparison (Tekeoglu 1998), at ence (P value 0.04) in favour of Orthovisc compared to 6-MPA.
1 to 4 weeks postinjection, there were no statistically significant When assessing the combination of trimacinolone acetonide with
differences for: WOMAC OA Index physical function (scored 17 Orthovisc to Orthovisc alone (Ozturk 2005), a statistically signif-
to 85); the number of patients good or very good; and maximum icant difference in favour of the combination group was found for
flexion. At 5 to 13 weeks postinjection, Orthovisc was significantly pain (0 to 100 mm VAS) at 1 to 4 weeks postinjection (WMD
better than betamethasone for WOMAC function (WMD -9.00; 13.00; 95% CI 3.77 to 22.23, P value 0.006) (combination was
95% CI -14.15 to -3.85, P value 0.0006). Orthovisc was 20% 26% more effective than Orthovisc alone), but not at any of the

other time-points: 5 to 13, 14 to 26, 34, or 45 to 52 weeks postin- at 5 to 13, 14 to 26, or 37 weeks postinjection. There were no
jection. A statistically significant difference was detected in favour statistically significant differences between Orthovisc and physical
of the combination treatment group compared to Orthovisc alone therapy in WOMAC OA Index physical function (Likert) at any
for the WOMAC OA Index stiffness subscale (0 to 8 Likert) at 1 of the timepoints: 1 to 4, 5 to 13, 14 to 26, 37, or 45 to 52
to 4 weeks postinjection (WMD 0.80; 95% CI 0.02 to 1.58, P weeks postinjection. There were statistically significant differences
value 0.04), at 34 weeks postinjection (WMD 0.80; 95% CI 0.12 in favour of physical therapy compared to Orthovisc for SF-36
to 1.48, P value 0.02), and at 45 to 52 weeks postinjection (WMD pain at two of the five timepoints: 5 to 13 weeks postinjection
0.80; 95% CI 0.06 to 1.54, P value 0.04) (combination was 20% (WMD -28.20; 95% CI -38.98 to -17.42, P < 0.00001), and 14
more effective than Orthovisc alone), but not at 5 to 13 or 14 to to 26 weeks postinjection (WMD -18.70; 95% CI -31.67 to -
26 weeks postinjection. No statistically significant differences were 5.73, P value 0.005); while a trend was detected at 45 to 52 weeks
noted between the groups for the following outcome measures at postinjection (WMD -12.50; 95% CI -25.03 to 0.03, P value
any of the timepoints: WOMAC OA Index pain subscale (0 to 20 0.05), but not at 1 to 4 or 37 weeks postinjection. Statistically
Likert), WOMAC OA Index physical function subscale (0 to 68 significant differences in favour of physical therapy compared to
Likert), WOMAC OA Index total score (0 to 96 Likert), 50 foot Orthovisc were detected in SF-36 physical functioning at 5 to 13
walking time (seconds), and range of motion (degrees). weeks postinjection (WMD -12.00; 95% CI -23.25 to -0.75, P
Safety value 0.04), and at 45 to 52 weeks postinjection (WMD -22.00;
95% CI -33.76 to -10.24, P value 0.0002), but not at the other
There were no adverse local (e.g. postinjection synovitis) or sys- timepoints: 1 to 4, 14 to 26, or 37 weeks postinjection.
temic reactions reported in either the Orthovisc or betametha-
sone group with all patients completing the trial (Tekeoglu 1998). In the Orthovisc plus physiotherapy versus physiotherapy com-
There were no statistically significant differences in the safety pro- parison (Kalay 1997), there were no statistically significant dif-
file of Orthovisc compared to 6-MPA (Tascioglu 2003). A simi- ferences at 1 to 4 weeks postinjection for: activity pain (VAS);
lar number of patients were withdrawn overall: Orthovisc 6.7% spontaneous pain (VAS); night pain (VAS); 25 m walk time (sec);
and 6-MPA 10%. One patient in each group withdrew due to in- and flexion WMD was not estimable as the SD of the treatment
creased pain. A similar number of patients reported musculoskele- group was zero. At 5 to 13 weeks postinjection, the combination
tal adverse events: Orthovisc 25% and 6-MPA 19%; skin adverse of Orthovisc and physiotherapy was significantly better than phys-
events: Orthovisc 7% and 6-MPA 4%; gastrointestinal adverse iotherapy alone for activity pain (WMD -6.50; 95% CI -11.93 to
events: Orthovisc 11% and 6-MPA 7%; general adverse events: -1.07, P value 0.02) and spontaneous pain (WMD -4.10; 95% CI
Orthovisc 14% and 6-MPA 19%; and knee pain after injection: -7.43 to -0.77, P value 0.02). Orthovisc plus physiotherapy was
Orthovisc 21% and 6-MPA 19%. between 16 and 44% more effective than physiotherapy alone in
In the Orthovisc plus triamcinolone acetonide versus Orthovisc relieving pain. No statistically significant differences were found
alone RCT, a statistically significant difference was detected in for night pain; walk time; and flexion WMD was not estimable
favour of Orthovisc alone for the number of total withdrawals again due to the SD of the treatment group being zero. The num-
overall (RR 0.12, 95% CI 0.02 to 0.88, P value 0.04), but not ber of patients rating the treatment as effective or very effective
for the number of withdrawals due to lack of efficacy or in the was significantly higher in the Orthovisc plus physiotherapy arm
number of patients reporting adverse events (Ozturk 2005). (95%) compared to the physiotherapy group (60%) (RR 1.58;
Orthovisc versus NSAID: no trials included. 95% CI 1.09 to 2.30, P value 0.02). The NNT for patient global
Orthovisc versus physiotherapy assessment was 3.
Three RCT included comparisons of Orthovisc and physical ther- The RevMan analysis differed from the publication analysis. The
apy (Atamaz 2005; Bayramoglu 2003; Kalay 1997). publication reported a statistically significant difference in ac-
tivity pain at day 21 (1 to 4 weeks postinjection) in favour of
Efficacy Orthovisc plus physiotherapy compared to physiotherapy alone
There was a statistically significant difference in spontaneous pain (P value 0.03) whereas RevMan detected no difference (P value
(0 to 100 mm VAS) in favour of physical therapy compared to 0.5). The publication reported a statistically significant difference
Orthovisc at 14 to 26 weeks postinjection (WMD 17.70; 95% CI in night pain at day 56 (5 to 13 weeks postinjection) in favour of
3.70 to 31.70, P value 0.01), but not at any of the other timepoints: Orthovisc plus physiotherapy compared to physiotherapy alone
1 to 4, 5 to 13, 37, or 45 to 52 weeks postinjection (Atamaz 2005). (P value 0.02) whereas RevMan detected no difference (P value
There were statistically significant differences in WOMAC OA 0.7). The publication reported a statistically significant difference
Index pain (Likert) in favour of Orthovisc compared to physical in walk time both at day 21 (P value 0.0049) and day 56 (P value
therapy at 1 to 4 weeks postinjection (WMD -2.00; 95% CI - 0.0001) in favour of Orthovisc plus physiotherapy compared to
3.61 to -0.39, P value 0.02), and at 45 to 52 weeks postinjection physiotherapy alone whereas RevMan detected no difference (P
(WMD -4.30; 95% CI -6.66 to -1.94, P value 0.0004), but not value 0.4 and 0.2).

In the Orthovisc plus physical therapy versus physical therapy OA Index pain score.
comparison (Bayramoglu 2003), there were no statistically signif- Safety
icant differences in the Lequesne Index at the end of treatment at
three weeks or at three months. There were no statistically significant differences in the number of
total withdrawals overall; number of withdrawals due to lack of ef-
Safety ficacy; number of patients reporting adverse events; number of pa-
tients with gastrointestinal adverse events; number of patients with
With respect to safety, two patients in the Orthovisc plus physio- general body adverse events; number of patients with infections;
therapy group (Kalay 1997) experienced local pain and swelling number of patients with musculoskeletal adverse events; number
several hours after the IA injections which resolved in 24 hours of patients with nervous system adverse events; number of patients
with cold application; however, this difference was not statisti- with respiratory adverse events; or number of patients with skin
cally significant. In this trial the treatment schedule differed from adverse events (Neustadt 2005a -3inj; Neustadt 2005b-4inj .
the other four trials, in that only two injections were given on Orthovisc versus other hyaluronans
days 0 and 7. There were no adverse events associated with the IA
hyaluronic acid injections in the second trial (Bayramoglu 2003). Efficacy
There was no statistically detectable difference in the number of In the Atamaz et al. trial (Atamaz 2005), a statistically signifi-
withdrawals overall. No patients in either trial withdrew because cant difference in favour of Orthovisc compared to Hylan G-F 20
of adverse events or experienced any systemic adverse events. were detected for spontaneous pain (0 to 100 mm VAS) at 1 to
In the Atamaz et al. RCT, while three patients in the Orthovisc 4 weeks postinjection (WMD -21.10; 95% CI -33.08 to -9.12, P
group reported local reactions which resolved within a few days, value 0.0006) (Orthovisc was 8% more effective than Hylan G-
no serious local or systemic adverse events were observed (Atamaz F 20). However, a statistically significant difference in favour of
2005). Hylan G-F 20 compared to Orthovisc was detected both at 5 to
Orthovisc plus trigger point injection with lidocaine versus 13 weeks postinjection (WMD 12.90; 95% CI 0.85 to 24.95, P
Orthovisc value 0.04) and at 14 to 26 weeks postinjection (WMD 15.50;
Efficacy 95% CI 0.80 to 30.20, P value 0.04) (Hylan G-F 20 was 33 to
In the one trial included (Yentur 2003), there were statistically 36% more effective than Orthovisc, respectively). No statistically
significant differences in favour of Orthovisc plus lidocaine ver- significant differences were detected at 37 weeks or 45 to 52 weeks
sus Orthovisc alone at one week postinjection for the following postinjection.
outcome measures: pain at rest (WMD -1.73; 95% CI, -2.21 to - In one trial included (Bayramoglu 2003), there were no statis-
1.25, P < 0.00001); pain/restrictions walking (WMD -1.12; 95% tically significant differences between Orthovisc plus a physical
CI, -1.60 to -0.64, P < 0.00001), and pain/restrictions going up or therapy programme versus Hylan G-F 20 plus a physical therapy
down stairs (WMD -1.49; 95% CI, -1.97 to -1.01, P < 0.00001). programme in the Lequesne Index either at the end of the treat-
There was no statistically significant difference in range of motion. ment schedule or at three months.
Safety There were no statistically significant differences between
Only one patient in the Orthovisc alone group did not complete Orthovisc and Hylan G-F 20 in the WOMAC OA Index pain or
the trial (Yentur 2003). physical function subscales at 1 to 4 weeks postinjection (Atamaz
Orthovisc verus Orthovisc 2005; Karatay 2004;Kotevoglu 2005); at 5 to 13 or 14 to 26 weeks
Efficacy postinjection (Atamaz 2005; Kotevoglu 2005); and at 37 or 45 to
In the Neustadt et al. trial, which compared Orthovisc given as a 52 weeks postinjection (Atamaz 2005). There was no statistically
four-injection regimen to Orthovisc given as a three-injection reg- significant difference detected in the WOMAC OA Index stiffness
imen plus one arthrocentesis, statistically significant differences in subscale (Likert scale) either at 1 to 4 weeks postinjection (Karatay
favour of the four-injection regimen were detected in the number 2004; Kotevoglu 2005); 5 to 13 or 14 to 26 weeks postinjection
of patients achieving a 20% relative improvement from baseline in (Kotevoglu 2005).
the WOMAC OA Index pain score at 5 to 13 weeks postinjection There was no statistically significant difference in the patient global
(RR 1.26; 95% CI 1.07 to 1.49, P value 0.005), and in the pa- assessment (100 mm VAS, where 100 was the worst severity) at 1
tient global assessment (measured on a 0 to 100 mm VAS) (WMD to 4, 5 to 13, or 14 to 26 weeks postinjection (Kotevoglu 2005).
-8.80; 95% CI -16.61 to -0.99, P value 0.03)(Neustadt 2005a However, in the physician global assessment (100 mm VAS, where
-3inj; Neustadt 2005b-4inj. No statistically significant differences 100 was the worst severity), there were statistically significant dif-
were detected for any of the other outcome measures: WOMAC ferences in favour of Hylan G-F 20 both at 1 to 4 weeks postinjec-
OA Index pain on standing item, WOMAC OA Index total score, tion (WMD 20.00; 95% CI 7.27 to 32.73, P value 0.002) and at
physician global assessment, or number of patients achieving a 5 to 13 weeks postinjection (WMD 20.00; 95% CI 8.06 to 31.94,
40% or 50% relative improvement from baseline in the WOMAC p=0.001), but not at 14 to 26 weeks postinjection (Kotevoglu

2005). ing by week 8 in the Replasyn group. However, no between-group
In the Karatay et al. trial, there were no statistically significant differences were found in pain on walking, range of motion, the
differences between Orthovisc and Hylan G-F 20 at one week WOMAC functional index, or patient and physician global as-
postinjection for synovial fluid intercellular adhesion molecule-1 sessments. Transient joint pain or swelling was reported in 3 of 19
or synovial fluid vascular cell adhesion molecule-1 (Karatay 2004). Replasyn and 6 of 20 placebo patients.
With respect to the SF-36, statistically significant differences were An abstract is the only publication of this trial.
detected in favour of Hylan G-F 20 compared to Orthovisc in SF- Replasyn versus placebo
36 pain both at 5 to 13 weeks postinjection (WMD -30.80; 95%
CI -43.03 to -18.57, P < 0.00001) and at 14 to 26 weeks postin- Efficacy
jection (WMD -19.80; 95% CI -35.52 to -4.08, P value 0.01) but
not at 1 to 4, 37, or 45 to 52 weeks postinjection (Atamaz 2005). Since no measure of dispersion was reported in the abstract (Cohen
For SF-36 physical functioning, statistically significant differences 1994) this review does not report efficacy data.
were detected in favour of Hylan G-F 20 compared to Orthovisc
both at 5 to 13 weeks postinjection (WMD -20.20; 95% CI - Safety
29.47 to -10.93, P < 0.0001) and at 45 to 52 weeks postinjec-
tion (WMD -23.00; 95% CI -35.97 to -10.03, P value 0.0005) There was no statistically significant difference in the number of
(Atamaz 2005). patients with local adverse reactions: Replasyn 16% versus placebo
In the Karatosun et al. trial (Karatosun 2005a), there were no 30%.
statistically significant differences between Orthovisc and Hylan Replasyn versus corticosteroid: no trials included.
G-F 20 in any of the efficacy outcome measures reported at 1 to Replasyn versus NSAID: no trials included.
4, 5 to 13, 14 to 26, or 45 to 52 weeks postinjection: Hospital for Replasyn versus other hyaluronan: no trials included.
Special Surgery Knee Score (HSSKS), pain during activity (part
of the HSSKS); pain at rest (part of the HSSKS); pain during Product - SLM-10
transfer activity (part of the HSSKS); walking distance; or range
of motion. Description of studies
Safety
One RCT has been included.
There were no adverse events associated with either of the IA Kawabata et al. reported a five-week, parallel-group, single-blind
hyaluronic acid injections (Bayramoglu 2003). No safety out- RCT performed at 23 centres in Japan comparing five weekly
come measures were reported in the Karatay et al. trial (Karatay injections of SLM-10 (developed and produced by fermentation
2004). There were no statistically significant differences in the with Streptococcus zooepidemicus of Lancefield’s group C, Shi-
number of total withdrawals overall (Karatosun 2005a; Kotevoglu seido Co., Ltd.) to five-weekly injections of Artz in 172 patients
2005); number of withdrawals due to lack of efficacy (Karatosun with OA of the knee (Kawabata 1993). No statistically significant
2005a); number of patients wih local adverse events (Atamaz 2005; between-group differences were reported for patients’ impression,
Kotevoglu 2005); number of withdrawals due to noncompliance final global improvement and utility, leading the authors to con-
(Kotevoglu 2005). clude that SLM-10 was as useful as Artz. Adverse events were re-
Product - Ostenil ported in one SLM-10 patient and two Artz patients. The Jadad
score for this trial was 2 out of 5; single-blind and no specific details
Description of studies regarding randomisation were reported. Allocation concealment
was adequate.
One RCT was excluded: Uebelhart 2003. This comparative HA trial was of short duration with the longest
assessment only one week postinjection. In addition, it was single-
Product - Replasyn blind because of differences in the HA; SLM-10 was provided in a
syringe while Artz was provided in an ampoule. The 23 trial sites
Description of studies were all Departments of Orthopedic Surgery. Almost all of the
clinical evaluations were based on attending physician or commit-
One RCT has been reported. tee ratings rather than on patient ratings. The case study commit-
Cohen et al. reported an eight-week, placebo-controlled, double- tee, as well as the attending physician, assessed overall severity, final
blind RCT performed at four centres in Canada and the United global improvement, overall safety and usefulness. Differences in
States comparing three weekly injections of Replasyn to placebo results were noted in assessments made by the attending physician
(not specified) in 39 patients with OA of the knee (Cohen 1994). compared to those made by the committee. In the analysis method
A significant within group difference was found for pain on walk- section of the publication, it reports that ”cases which deviated

from the protocol or those judged to be inappropriate as the sub- and WOMAC function (0 to 10 cm), pain at rest (0 to 100 mm
jects of assessment were excluded from the analysis of correspond- VAS), and walk time (seconds). Of the four groups, three com-
ing assessment item“. However, no definition of appropriateness parisons are reported: (Suplasyn plus lactose) versus (saline plus
was reported. lactose), (Suplasyn plus lactose) versus (NSAID plus saline), and
Five trials were excluded (Minami 1993; Ono 1993; Ono 1993a; (Suplasyn plus NSAID) versus (NSAID plus saline); not reporting
Suzu 1993; Taneda 1993). the combination of (NSAID plus saline) versus placebo (lactose
SLM-10 versus placebo: no trials included. plus saline). With respect to methodological quality, it scored 5
SLM-10 versus corticosteroid: no trials included. out of 5 on the Jadad scale achieving bonus points for providing
SLM-10 versus NSAID: no trials included. details of appropriate randomisation and blinding. Allocation con-
SLM-10 versus other hyaluronan cealment was adequate. An editorial reported the results obtained
from this trial using a factorial design analysis (Felson 2002). Two
Efficacy trials were excluded (Olszynski 2002; Payne 2000).
Table 48 Some design points were noted: 1) a medial approach was utilised
for injections; 2) rescue medication with 2600 mg (650 g x 4)
Regarding the SLM-10 comparison against Artz (Kawabata 1993), of acetaminophen was permitted; 3) a 10-minute home-based re-
significantly more patients improved on pain on pressure in the sistance exercise programme was part of the treatment and was
Artz group (82%) compared to the SLM-10 group (64%) (RR monitored by a patient diary; 4) patients were recruited from a
0.78; 95% CI 0.64 to 0.96, P value 0.02). The NNT for pain on primary care referral centre; 5) no details were published regard-
pressure was 2. No statistically significant between-group differ- ing the presence or absence of effusion, disease duration, and OA
ences were found for pain in movement, pain when resting, and diagnosis criteria. The only significant results reported were based
patient global assessment. on within-group comparisons. No information on rescue medica-
tion usage was reported.
Safety A randomised, double-blind trial comparing three and six in-
jections of Suplasyn is awaiting assessment (Petrella 2002). This
There was no statistically significant difference in the total number trial has only been published as an abstract with no extractable
of withdrawals overall in the Artz group (12%) compared to SLM- data and at the closure of the database for this review no full
10 group (3%). The incidence of local adverse events related to length manuscript had been published. Three trials were excluded
study drug, resulting in withdrawal, was similar in the Artz (3%) (Mazieres 2004; Petrella 2003a; Petrella 2003b).
and the SLM-10 (1%) groups. One patient in each group had a Suplasyn versus placebo
local adverse event with no specific causal relationship to the study
drug and continued in the trial. Efficacy
Table 49
Product - Suplasyn No statistically significant differences were found between Su-
plasyn and placebo for the following outcome measures: pain after
Description of studies walking; WOMAC OA Index pain; WOMAC OA Index physi-
cal function; and walk time. A statistically significant difference,
One RCT has been included. in favour of the placebo group (saline + lactose) compared to the
Petrella et al. reported a 12-week, placebo-controlled, double- treatment group (Suplasyn + lactose), was found for the primary
blind RCT performed at a single centre in Canada comparing outcome measure, pain at rest (WMD 0.83; 95% CI 0.03 to 1.63,
Suplasyn (a bacterial source HA) plus placebo (lactose), placebo P value 0.04). Suplasyn plus lactose was 25% less effective than
(lactose plus saline), NSAID (Arthrotec plus saline), and Suplasyn saline plus lactose in relieving pain at rest.
plus NSAID in 120 patients with OA of the knee (Petrella 2002). The RevMan analysis differed from the publication analysis. The
The authors reported that Suplasyn was superior to placebo alone publication reported that Suplasyn may be superior to placebo for
or NSAIDs alone for pain with physical activity and functional pain with physical activity and functional performance whereas
performance. Suplasyn was as effective as NSAID for resting pain the RevMan analysis detected no difference.
relief. With respect to safety, Petrella reported that two patients had
moderate gastrointestinal irritation resulting in their withdrawal, Safety
and that most adverse events occurred in the NSAID plus saline There was no statistically significant difference in the number of
group. No withdrawals overall: Suplasyn 17% versus placebo 7%.
serious adverse events occurred.
The efficacy outcome measures extracted from this trial were pain Suplasyn versus corticosteroid: no trials included.
after walking (0 to 100 mm VAS), WOMAC pain (0 to 10 cm) Suplasyn versus NSAID

frequent being local inflammation or irritation following the in-
Efficacy jection. One patient withdrew from the study early due to sus-
pected allergic reaction after injection with Hyalart. For this trial,
No statistically significant differences were found between Su- Zeel was the treatment group and Hyalart was the control group.
plasyn and NSAID for: WOMAC OA Index pain; WOMAC OA This is the only RCT in the review comparing homeopathy drug
Index physical function; walk time; pain at rest; and pain after therapy to HA. It was designed as a clinical equivalence study. The
walking. follow-up assessment was short, one week following the treatment.
The RevMan analysis differed from the publication analysis. The As the authors noted, the design was single-blind due to the im-
publication reported that Suplasyn may be superior to NSAID balance in number of injections (Hyalart n = 5 versus Zeel n = 10).
alone for pain relief, pain with physical activity, and functional It was deemed ’unethical’ to equalise the frequency of injections
performance whereas the RevMan analysis detected no difference. with additional injections of a placebo.
Zeel versus placebo: no trials included.
Safety Zeel versus corticosteroid: no trials included.
Zeel versus NSAID: no trials included.
There was no statistically significant difference in the number of Zeel versus other hyaluronans
withdrawals overall: Suplasyn 17% versus NSAID 3%.
Suplasyn + NSAID versus NSAID alone Efficacy
Table 50
Efficacy At the end of treatment (i.e. last injection), there were no statis-
tically significant between-group differences in any of the efficacy
No statistically significant differences were found between Su- outcome measures: pain during movement, pain during the night,
plasyn plus NSAID versus NSAID alone for pain after walking; assessment of improvement, and assessment of tolerance all scored
WOMAC OA Index pain; WOMAC OA Index physical function; on a 0 to 100 mm VAS. There was no statistically significant dif-
pain at rest; and walk time. ference in the number of patients who reported noticeable im-
provement in symptoms: Zeel 87% versus Hyalart 93%.
Safety
Safety
There was no statistically significant difference in the number of
withdrawals overall: Suplasyn plus NSAID 13% versus NSAID There was no statistically significant difference in the number of
alone 3%. patients with side effects: Zeel 11% versus Hyalart 23%; or in the
number of patients withdrawn due to lack of efficacy: Zeel 4%
Suplasyn versus other hyaluronan: no trials included. versus Hyalart 2%.
Product - Hyaluronan (brand name not identified)
Product - Synject Description of studies
One RCT included was a comparison of hyaluronan and different
Description of studies dosages of celecoxib (Wu 2004). The article was published in
One trial was excluded: Alonge 2004. Chinese with an abstract in English. Dr. H. Qian of The University
of Western Ontario, London, Canada, kindly provided an English
Product - Zeel compositum translation of the article.
Wu et al. reported a 16-week, parallel-group, single-blind RCT
Description of studies performed in China comparing hyaluronan to: 1) hyaluronan plus
One RCT included was a comparison of Zeel compositum and low dose celecoxib, 2) hyaluronan plus self-controlled dose cele-
Hyalart (Nahler 1996 [article published in German with English coxib, 3) regular dose celecoxib, and 4) self-controlled celecoxib
abstract]; Nahler 1998). With respect to methodological quality, in 150 patients with OA of the knee (Wu 2004). Outcome mea-
the Jadad score was 4 out of 5. Allocation concealment was unclear. sures included WOMAC Osteoarthritis Index physical function
Nahler et al. reported a five-week, parallel-group, single-blind subscale, degree of satisfaction at the end of treatment, and totally
RCT performed at twelve centres in Germany and Austria com- used dosage of celecoxib. The authors reported that the clinical
paring 10 injections (two injections a week for five weeks) of Zeel symptoms improved by the fourth week in the hyaluronan group,
compositum to five weekly injections of Hyalart in 121 patients at the second week in the hyaluronan plus low dosage celecoxib,
with OA of the knee (Nahler 1998). Both treatments were equally and at the first week in the other three groups. In addition, the
effective in treating patients. Undesirable side effects were reported improvement was maintained until the end of the treatment in all
by 11% of Zeel patients and 23% of Hyalart patients; the most five groups. They concluded that hyaluronan plus self-controlled

celecoxib can improve the clinical symptoms of OA and also sig- 22 trials (WMD (random-effects model) -7.70; 95% CI -11.29
nificantly decrease the amount of required celecoxib to maintain to -4.10, P < 0.0001); at 5 to 13 weeks postinjection, based on
good therapeutic effects. With respect to safety, all patients com- 17 trials (WMD (random-effects model) -13.00; 95% CI -17.77
pleted the trial except seven patients in the hyaluronan group that to -8.23, P < 0.00001); at 14 to 26 weeks postinjection, based
discontinued early because of inefficacy. In addition, no treatment on 9 trials (WMD (random-effects model) -9.04; 95% CI -14.83
was discontinued due to severe side effects in any of the five groups. to -3.24, P value 0.002); but not at 45 to 52 weeks postinjection
The trial scored 2 out of 5 on the Jadad scale; details regarding based on 3 trials.
method of randomisation were not reported and the trial was sin- There was a statistically significant difference in pain at rest (0 to
gle-blind. Details regarding allocation concealment were not re- 100 mm VAS) at 1 to 4 weeks postinjection based on eight trials
ported. (WMD (random-effects model) -5.37; 95% CI -9.90 to -0.85, P
The results of the WOMAC OA Index physical function subscale value 0.02).
were presented as means in Figure 2 with no measure of dispersion There were statistically significant differences in the WOMAC OA
reported. Consequently, we were not able to include this outcome Index pain subscale in favour of HA versus placebo at 1 to 4 weeks
measure in our analyses. postinjection based on six trials (SMD (random-effects model) -
Efficacy 1.22; 95% CI -1.93 to -0.52, P value 0.0007) (Cubukcu 2004;
Hizmetli 1999; Kotevoglu 2005; Petrella 2002; Sezgin 2005; Tsai
A statistically significant difference in favour of regular dose cele- 2003) at 5 to 13 weeks postinjection based on five trials (SMD
coxib compared to hyaluronan was detected in patient general sat- -1.02 (random-effects model); 95% CI -1.57 to -0.47, P value
isfaction with treatment (RR 0.62; 95% CI 0.46 to 0.84, P value 0.003) (Cubukcu 2004; Day 2004; Dickson 2001; Hizmetli 1999;
0.002) (Wu 2004). No statistically significant differences were de- Kotevoglu 2005; Tsai 2003); and at 14 to 26 weeks postinjection
tected for any of the other comparisons: regular dose celecoxib ver- based on three trials (SMD -1.04 (random-effects model); 95% CI
sus hyaluronan plus low dose celecoxib or regular dose celecoxib -1.75 to -0.32, P value 0.005) (Hizmetli 1999; Kotevoglu 2005;
versus hyaluronan plus voluntary dose of celecoxib. Tsai 2003).
Safety There were statistically significant differences in the WOMAC OA
When comparing hyaluronan to regular dose celecoxib, no statis- Index physical function subscale in favour of HA versus placebo
ticaly significant difference was detected in the number of with- at 1 to 4 weeks postinjection based on six trials (SMD -1.02; 95%
drawals due to inefficacy (Wu 2004). CI -1.62 to -0.42, P value 0.0008); at 5 to 13 weeks postinjection
By-class (pooled) analysis based on 6 trials (SMD -0.85; 95% CI -1.31 to -0.39, P value
Table 51; Table 52; Table 53; Table 54 0.0003); and at 14 to 26 weeks postinjection based on three trials
Forty-two trials included comparisons of hyaluronan/hylan and (SMD -0.80; 95% CI -1.37 to -0.24, P value 0.005) (Hizmetli
placebo (Altman 1998; Altman 2004; Ardic 2001; Bragantini 1999; Kotevoglu 2002; Kotevoglu 2005; Tsai 2003).
1987; Brandt 2001; Bunyaratavej 2001; Carrabba 1995; Cohen There was a statistically significant difference in the Lequesne In-
1994; Corrado 1995; Creamer 1994; Cubukcu 2004; Day dex both at 1 to 4 weeks postinjection (WMD -0.82; 95% CI -
2004; Dickson 2001; Dougados 1993; Formiguera Sala 1995; 1.48 to -0.16, P value 0.02) (Carrabba 1995; Dougados 1993;
Grecomoro 1987; Groppa 2001; Guler 1996; Henderson 1994; Huskisson 1999; Puhl 1993); and at 5 to 13 weeks postinjection
Hizmetli 1999; Huskisson 1999; Jubb 2003; Karlsson 2002; (WMD -1.38; 95% CI -2.04 to -0.73, P < 0.0001) (Carrabba
Kotevoglu 2005; Lohmander 1996; Moreland 1993; Neustadt 1995; Dickson 2001; Huskisson 1999; Puhl 1993). There was no
2005a -3inj; Petrella 2002; Pham 2003; Pham 2004; Puhl 1993; statistically significant difference either at 14 to 26 weeks postin-
Scale 1994a (2 inj); Scale 1994b (3 inj); Shichikawa 1983a; jection (Huskisson 1999; Karlsson 2002; Lohmander 1996) or 45
Shichikawa 1983b; St. J. Dixon 1988; Tamir 2001; Tsai 2003; to 52 weeks postinjection (Dougados 1993).
Wobig 1998; Wobig 1999c (NEhyl); Wu 1997). In the figures, With respect to patient global assessment (expressed as the number
the Kotevoglu 2002 citation refers to the Hylan G-F 20 versus of patients improved), there were no statistically significant differ-
saline comparison while the Kotevoglu 2005 citation refers to the ences between HA and placebo at any of the four assessment times:
Orthovisc versus saline comparison. at 1 to 4 weeks post injection (Corrado 1995; Creamer 1994;
In this section, we report only analyses based on multiple studies. Lohmander 1996; Shichikawa 1983a; Shichikawa 1983b); at 5
Analyses based on single products and/or studies can be found in to 13 weeks postinjection (Corrado 1995; Dickson 2001; Guler
the relevant by-product results section. This section is most infor- 1996; Lohmander 1996; Puhl 1993); at 14 to 26 weeks postinjec-
mative when read in combination with the relevant by-product tion (Henderson 1994; Huskisson 1999; Lohmander 1996); and
section(s). at 45 to 52 weeks postinjection (Dougados 1993; Pham 2004).
There was a statistically significant difference in favour of HA There was a statistically significant difference in flexion (degrees)
compared to placebo for pain on weight bearing (0 to100 mm in favour of HA versus placeo at 1 to 4 weeks postinjection (WMD
VAS) at three assessments: at 1 to 4 weeks postinjection, based on 3.87; 95% CI 2.06 to 5.68, P < 0.0001) (Corrado 1995; Sezgin

2005; Shichikawa 1983a; Shichikawa 1983b); and at 5 to 13 weeks reviews and meta-analytic techniques. It is recognized in combin-
postinjection (WMD 7.60; 95% CI 0.46 to 14.74, P value 0.04) ing studies using different designs that any resulting heterogeneity
(Corrado 1995). may be in part or in whole attributable to design elements, or char-
In safety analyses in HA versus placebo comparisons, no statis- acteristics of the patient population, rather than to variability in
tically significant differences were detected in the following: to- the efficacy of the HA product. This heterogeneity can in part be
tal withdrawals overall (1 to 4 weeks, 5 to 13 weeks, 14 to 26 addressed by recognizing the presence and potential determinants
weeks, 45 to 52 weeks postinjection), patients with local adverse of the heterogeneity and conducting the review in a manner that
reaction and study drug discontinued, number of patients with attempts to minimize the influence of any existent heterogeneity.
local adverse reaction but study drug continued, number of pa-
tients discontinued due to adverse events, withdrawals due to lack Previous systematic reviews by Lo et al. (Lo 2003), Wang et al.
of efficacy, number of adverse events due to local skin reaction, (Wang 2004), Arrich et al. (Arrich 2005) and Modawal et al.
number of patients with gastro-intestinal complaints, number of (Modawal 2005) have differed regarding the magnitude of clinical
patients with treatment related adverse events, number of patients benefit of HA products. Lo et al. (Lo 2003), in particular, con-
with possible study medication related events, number of serious cluded that the effect size may be small at the class level. Bernstein
adverse events, number of adverse events probably/possibly related (Bernstein 2004) has drawn attention to the discrepancy between
to treatment, and number of patients reporting adverse events. A the Lo et al. (Lo 2003) and Wang et al. (Wang 2004) commentaries
statistically significant event favouring placebo was noted in the on effect size. Hou and Wang (Hou 2004) have correctly asserted
number of adverse events for injection site pain (RR 1.70; 95%CI that the reviews differ in the approach to effect size estimation,
1.19 to 2.44, P value 0.004). search date and searching source, and in their interpretation of
In comparative studies of HA versus NSAID, no statistically sig- funnel plot distortion. The use of a hierarchy to identify a single
nificant differences were detected in pain on walking at 1 to 4 time point and variable, from each study, in a phenomenon that
weeks post-injection or total withdrawals overall at 14 to 26 weeks is time and variable dependent, may also contribute in part to the
postinjection. small effect size observed in the Lo et al. meta-analysis. Arrich et al.
In comparative studies of HA versus methylprednisolone acetate, reported reasons for discrepancies between their systematic review
statistically significant differences in favour of IA steroid were de- and three other relevant reviews. Some of these discrepancies were
tected in range of motion (degrees of flexion) at 1 to 4 weeks attributable to differences in the literature search, trial selection
postinjection (WMD 3.87; 95%CI 0.36 to 7.37, P value 0.03) criteria, quality scoring, quantitative summary expressed as num-
and 5 to 13 weeks postinjection (WMD 3.66; 95%CI 0.48 to ber of positive trials, use of change scores, and mixing of end (time)
6.83, P value 0.02). points (Arrich 2005). Modawal et al. confirmed that the treatment
In six comparative studies of selected HA products, no statisti- effect was time dependent. Among the limitations of their meta-
cally significant differences were detected between the products analysis, they reported heterogeneity of trials, trial quality, con-
concerned in: pain on movement (number of patients improved) founding by use of rescue analgesia during trial, and lack of in-
(1 to 4 weeks postinjection), pressure pain (number of patients tention-to-treat analyses (Modawal 2005). Brandt (Brandt 2004)
improved) (1 to 4 weeks postinjection), Lequesne Index (1 to 4 reported that Dieppe et al. found a pooled effect size of -0.48 with
weeks and 5 to 13 weeks postinjection), or patient global assess- a confidence interval of -0.72 to -0.23 in an analysis of 11 clinical
ment (1 to 4 weeks, 5 to 13 weeks, 14 to 26 weeks and 45 to 52 trials. It appears, therefore, that the results of the meta-analyses
weeks postinjection). may be, significantly method dependent, and reviewers should be
aware of the nuances associated with the method used in this and
other meta-analyses.
HA products differ in their origin, method of production, molec-

DISCUSSION
ular weights (MW), biologic characteristics, rheologic properties,
This review is current as of the end of December 2005, and con- residence time in the joint and pharmacodynamic properties. As
tains both by-product and by-class analyses. It is comprehensive a consequence, any by-class analysis needs to be approached with
and more current than preceding systematic reviews and avoids due recognition that the products may differ in important respects,
limiting the review to a single product, variable or timepoint, and that this may restrict the valuation of individual products,
or forcing different variables assessed using different instruments particularly where patients have not been randomised to receive
through a hierarchical algorithm in a reductionist manner, that the competing alternatives. The by-class analysis is also less infor-
attempts to obtain a single value capturing complex, dynamic, and mative to clinicians, since practitioners generally seek to make evi-
heterogeneous phenomena. In developing a strategy for conduct- dence-based decisions in treating individual patients with specific
ing this review, we have considered the complexity of the HA class products, and are interested in the time course and dimensionality
of interventions, issues relating to the design, execution, analysis of the clinical response to individual products. In this review, we
and interpretation of clinical trials, and the nuances of systematic have presented both by-product analyses and by-class analyses in

order that readers can make their own judgement regarding in- and hylan in knee OA. Greater standardisation in methodology
dividual products as well as the class as a whole. The provision would facilitate assessment of these trials. Complete descriptions
of separate within-product by-variable and by-time analyses, for of blinding, randomisation, withdrawals and dropout would im-
different comparisons, permits the reader to appreciate the time- prove reporting quality. There was wide variation in the method
dependency of the response and the differential effects detected of assessment of outcome. The distinction between primary and
on different outcome variables. secondary outcome measures was infrequently reported. The util-
isation of local anaesthetic also varied as well as description of the
The clinical epidemiology toolbox contains numerous alternative
injection technique employed. The inclusion/exclusion criterion
approaches to the design, execution and analysis of clinical trials.
of presence of effusion at study entry was variable with some trials
It is our understanding that traditionally, this class of interven-
limiting the entry of subjects with a predefined volume of effu-
tion was considered as a device class and originally was not gen-
sion. Different osteoarthritic populations were included in the tri-
erally subject to the same evaluation guidelines that then existed
als; some subjects had unilateral disease while others had bilateral
for pharmacologic agents. This may explain, in part, the hetero-
disease. Variability was noted in both timing and method (e.g.
geneity in research designs and outcome measurement techniques
office versus telephone) of assessments, and in the opportunity for
used, particularly in some of the earlier studies, a phenomenon,
retreatment. In some trials, a per protocol rather than intent-to-
however, not peculiar to this class of interventions. Our review
treat statistical analysis was reported.
detected differences in at least nineteen areas of trial design in-
cluding: clinical environment, sample size, number of study arms, Safety was reported in variable formats, e.g. number of adverse
number of centres, nature of the placebo comparator, inclusion events per number of injections, number of ’related’ adverse events,
and exclusion criteria, washout period, re-treatment opportunity, number of subjects reporting adverse events, number of serious
concomitant therapy, follow-up schedule, duration of follow-up, adverse events, number of local (injection site) reactions, number
outcome measures, age, gender balance, disease duration, base- of systemic reactions, number of patients withdrawing due to ad-
line pain severity, radiographic grade, treatment schedule, rescue verse events. The denominator for safety analyses was frequently
medication. These differences were sometimes evident, even when based on the intent-to-treat population. However, in some trials
comparing different trials involving the same HA product. it was difficult to ascertain the denominator (patients versus injec-
tions). Ideally, the following should be reported: 1) withdrawals
The nuances of systematic reviews and meta-analysis require due
overall, 2) withdrawals due to all adverse events, 3) withdrawals
consideration of any assumptions, implicit or explicit that are
due to system specific adverse events (e.g. gastrointestinal related
made to combine information and data from diverse sources into
grouped, cardiovascular grouped, etc.), and 4) withdrawals due to
valid and meaningful summary statistics. In particular, it is nec-
lack of efficacy.
essary to be familiar with a number of factors including, but not
limited to the following: RevMan 4.2 software and its operations; Safety of hyaluronan and hylan in the general population for ap-
assumptions, if any, regarding the value of ρ in imputations which proved products in the U.S.A. can be examined by review of the
require converting between change scores and post-test scores; the U.S.A. Food and Drug Administration Manufacturers and User
significance of the test for heterogeneity and its implications both Device Experience (MAUDE) database available online at http:
on the appropriateness of combining studies and the use of fixed- //www.fda.gov/cdrh/maude.html. Large pharmacoepidemiologic
effect versus random-effects models of analysis; the consequence databases are generally better sources of safety data than small in-
of basing analyses on transformed data, for example where dif- dividual clinical trials. An article by Hammesfahr, Knopf and Sti-
ferent outcomes (pain walking, pain at night, global pain) mea- tik reviews the safety data for the three products marketed in the
sured on different instruments, have been filtered through a hi- United States, e.g. Hyalgan, Supartz and Synvisc (Hammesfahr
erarchical algorithm to obtain a single measure of pain suitable 2003). They concluded that HA therapy is a safe treatment for OA
for meta-analysis. This latter issue is particularly concerning given of the knee. In addition, Hamburger et al. also concluded that HA
the differential impact of interventions on different components therapy is a safe treatment for knee OA, but that there may be in-
of the symptom complex and between-instrument differences in terproduct variability in safety profiles (Albert 2005; Hamburger
responsiveness (synonym: sensitivity to change). Other method- 2003; Hamburger 2005; Raynauld 2005a).
ologic issues include the potential for publication bias, and the
The possibility of publication bias exists if reviewers choose to
interpretation of the clinical importance of the observed treatment
exclude unpublished studies. McAuley et al. recommend the in-
effects. In an attempt to address potential publication bias, we
clusion of all reports, grey and published, that meet predefined
have searched abstract books, as well as published manuscripts,
inclusion criteria in meta-analyses (McAuley 2000). In this review,
corresponded with manufacturers, and contacted investigators in
nine included studies (Ardic 2001; Brown 2003; Cohen 1994;
the search for additional information or unpublished studies.
Groppa 2001; Guler 1996; Karras 2001; Moreland 1993; Pham
This review highlights the challenge of interpreting the results 2003; Tsai 2003) were published only as abstracts. However, an in-
of clinical trials of intra-articular (IA) injections of hyaluronan house manuscript by Moreland (Moreland 1993) was provided.

The articles by Hizmetli (Hizmetli 1999) and Lin (Lin 2004) were in this review, the data that could be extracted and the analyses
in-house publications. Two specialization thesis (Auerbach 2002a; that could be performed, and should be interpreted and utilized
Kalay 1997) were included. Published articles have the advantage by readers with the understanding that the review was conducted
of having undergone the peer review process. Frequently, abstracts using the methodology described in the earlier part of this doc-
do not provide enough information to be included in reviews, and, ument, a methodology anchored to the Cochrane review process
consequently, are excluded. using RevMan 4.2 software, and limited potentially by restricted
access to both unpublished studies and primary data. It should
The method of statistical analysis can affect the result. The util-
be recalled that HA products are not generally immediate in their
isation of follow-up (difference) scores, change (improvement)
onset, and that the 5 to 13 week time period may be one of the
scores, or unadjusted post-test (synonym: final value) scores for
more relevant for single course studies, while later periods may be
continuous outcome measures can influence the result. Vick-
particularly relevant for studies allowing more than a single course.
ers and Altman (Vickers 2001), Norman (Norman 1989), Lund
Statistically detectable differences seen in the 1 to 4 week postin-
(Lund 1988) and Stucki et al. (Stucki 1996) have discussed this
jection period represent a relatively early onset of action and are
issue.
not necessarily expected in all responding patients or all studies.
A high placebo effect has been noted in HA clinical trials (Bhogal It should also be noted that statistically detectable improvement
2000). This response may be attributed to a number of factors may not necessarily be detected on all variables or at the same
including: 1) removal of excess synovial fluid, 2) patient expecta- point in time. Function may improve more slowly than pain, and
tion, 3) Hawthorne effect of participating in a clinical trial, or 4) it may be more difficult to detect an effect on night pain than on
active treatment effect of saline and/or arthrocentesis (Kaptchuk walking pain. Finally, comparisons against other efficacious forms
2000). The modulating effects of rescue analgesia and co-therapy of treatment are likely to result in either no statistically detectable
with other OA treatments on outcome variables also should be difference in efficacy or in relatively small differences (cf studies
considered. of HA products against placebo). The inability to show a statisti-
The effect of treating both unilateral and bilateral disease in the cally detectable difference between an HA product and placebo,
same trial is problematic. Generally, efficacy results were based on in at least one key variable such as pain, function or patient global
analyses of the worse joint, while safety results were based on anal- assessment from about 5 to 13 weeks onwards might be regarded
yses of both joints. In some patients both knees received the same with some degree of concern.
intervention, while for other patients they received one interven- RevMan output for continuous data can be in the form of the
tion in one knee and the comparative intervention in the other WMD or SMD. The WMD provides a summary statistic whose
knee. The time between treatment of the knees varied consider- magnitude is related to a number of factors including the treat-
ably with some knees both being treated the same day, while other ment effect and the scale length of the instrument on which the
knees had a 210-day difference between initiation of treatment. underlying data were collected. What constitutes a minimum clin-
The selection of a target joint (e.g. study knee) is one method of ically important difference (MCID) is subject to ongoing debate
resolving this controversy. The problem of analysing the person (Bellamy 1993). The value for the minimum perceptible clinical
versus the joint(s) has been reported in the literature (Sutton 1997; improvement (MPCI) for the WOMAC Index is approximately
Zhang 1996). 10 normalised units (0 to 100). This may serve as one indicator of
Some trials used the Ahlback classification of knee OA. A recent the clinical importance of the WMD for pain, stiffness and func-
publication, suggested that this classification had some ’major lim- tion measured on 0 to 100 normalised unit scales. Tubach and
itations’ (Galli 2004). Even low grade Ahlback grades reflect sub- colleagues have proposed definitions of Minimal Clinically Im-
stantial structural damage. Patients with higher grade structural portant Improvement (MCII) (Tubach 2005), for pain, WOMAC
damage may be generally less responsive to treatment (Barrett function and patient global assessment. In contrast, the SMD pro-
2002; Evanich 2001; Lussier 1996; Magilavy 2003; Toh 2002; vides a summary statistic adjusted by the variance, is of a different
Vad 2003). order of magnitude to the WMD and expresses the effect size as
a unitless measure. What constitutes a small, medium, or large
Limitations of this review are the omission of open trials and case
effect size is a matter for debate. We have used the proposals ad-
series, the omission of studies that failed to meet inclusion crite-
vanced by Cohen (Cohen 1977), and operationalised in a recent
ria, the lack of standard outcome measures restricting pooling op-
publications by Jordan et al. (Jordan 2003), and Mazieres et al.
portunities, and restricted access to source data. Strengths of the
(Mazieres 2001) i.e. small effect size = 0.2, moderate effect size,
review are the inclusion of only randomised controlled trials, the
i.e. clinically recognisable = 0.5, large effect size = 0.8. Other mea-
focus on four core OARSI and OMERACT outcome measures,
sures of clinical value are the percentage superiority in response
and adherence to the principles of Cochrane systematic reviews.
and the NNT. We are not aware of published critical values for
A product-based discussion is followed by a class-based discus- these parameters in OA management. Nevertheless, tables have
sion. All comments are based on the trials that could be included been provided for all the aforementioned parameters, in order that

readers can make informed decisions. It should be noted that the In comparative analyses of Artz and Hylan G-F 20, there were no
magnitude of these parameters differs with product, comparison, statistically significant differences at any of the four time periods
variable and time period. in any of the four efficacy or three safety variables. This analysis
derives from an ostensibly negative study. The two products could
We have observed that in some analyses, the RevMan 4.2 out-
not be differentiated based on this single study.
put differs from the original publication (Table 1). The discrep-
ancies are likely due to the use of secondary data and the statistical
methods available within the software programme. Reviewers are Product - BioHy (Arthrease, Euflexxa, Nuflexxa)
advised to consider these disparities when making product-based
evaluations.
The placebo-controlled study is inconclusive for efficacy, likely as
a result of previously described methodologic issues. There was
Product - Adant no statistically significant between-group difference in the pro-
portion of patients experiencing postinjection pain, or in overall
withdrawals and there were no systemic reactions in either group,
No placebo-controlled trials were included in this review. The providing some support for the safety of
only data that could be included in the review suggested that
Adant is not different to Hyalgan with respect to patient global BioHy within the limits of the available data.
assessment at 1 to 4 weeks, 5 to 13 weeks, and 14 to 26 weeks, No trials of BioHy against either corticosteroid or NSAID ther-
or with respect to the risk of experiencing injection-related pain. apy were reported and no comment can be made on the relative
This review provides some supportive evidence for the efficacy and effectiveness or safety against these two classes of interventions.
safety of Adant, but is based on limited data, and does not include
In comparative analyses of BioHy and Hylan G-F 20, pre-speci-
placebo-controlled trials.
fied criteria for non-inferiority were met. Joint effusion was signif-
icantly less likely in the BioHy group. Statistically significant dif-
ferences in favour of Bio-Hy were detected in the RevMan analyses
Product - Artz (Artzal)
for WOMAC function and number of patients using rescue anal-
gesia at 1 to 4 and 5 to 13 weeks, but not in other efficacy variables
including pain. There were a number of instances in which the
In comparative studies of Artz and placebo included in this re- RevMan analyses differed from the original publication. The two
view, several outcome measures (Lequesne Index, range of motion, products could not be differentiated based on this single study.
WOMAC OA Index), failed to detect a statistically significant dif-
ference at 1 to 4 weeks, 5 to 13 weeks, 14 to 26 weeks and 45 to Product - Durolane
52 weeks, with the exception of patient global assessment at 1 to 4
weeks and 5 to 13 weeks and pain and the number of clinical fail-
ures at 5 to 13 weeks postinjection. Given the inclusion of single The placebo controlled trial of Durolane was essentially negative,
course studies, and the time-dependent dynamics of HA therapy, no statistically significant differences being detected on any effi-
the positive effects of Artz on pain and patient global assessment cacy variable in analyses based on all patients. The RevMan sub-
seen at 5 to 13 weeks postinjection are expected. It is of note that analysis of patients differed from the original publication. On the
statistically significant differences were detected on one pain mea- basis of RevMan analysis of this single study, no comment can be
sure but not another at 5 to 13 weeks. Significant effects on phys- made regarding the relative efficacy of Durolane versus placebo.
ical function cannot be confirmed from these analyses. It should Evaluation of the efficacy of Durolane in patients with isolated
be noted that the original analyses give a more positive result than knee OA requires further study.
the RevMan analyses we have performed. Taken collectively, the Product - Fermathron
data generally support the efficacy of Artz (Artzal).
Analyses supported the safety of Artz, with no statistically signif-
icant differences from placebo being detected for the majority of No trials of Fermathron against placebo were reported and effi-
safety variables. cacy against placebo cannot, therefore, be assessed. No trials of
Fermathron against either corticosteroid or NSAID therapy were
No trials of Artzal against either corticosteroid or NSAID therapy reported and no comment can be made on the relative effective-
were reported and no comment can be made on the relative effec- ness or safety against these two classes of interventions.
tiveness or safety against these two classes of
In comparative analyses of Fermathron and Hyalart, there were no
interventions. statistically significant differences at either of the time periods in

any of the three efficacy variables, or in the safety variable. The two safety variables. Collectively these data support the efficacy and
products could not be differentiated based on this single study. safety of Hyalgan, and show some 5 to 13 week postinjection ad-
vantages in favour of Hyalgan over methylprednisolone.
The comparative study of Hyalgan against NSAID suggests that
Product - Hyalgan Hyalgan is comparable in efficacy to NSAID therapy at 1 to 4
weeks, 5 to 13 weeks, and 14 to 26 weeks postinjection, based on
In comparative studies of Hyalgan and placebo included in this
pain after a 50-feet walk and number of patients with moderate
review, statistically significant differences were detected at 1 to 4
to marked pain. There were significantly fewer patients with gas-
weeks (pain on weight-bearing, spontaneous pain, pain at rest,
trointestinal complaints, but more injection-site pain on Hyalgan;
Lequesne Index, number of joints improved for walking pain,
otherwise there were no statistically detectable differences in sa-
number of joints improved for weight under load), 5 to 13 weeks
fety. Overall, these analyses suggest that Hyalgan is comparable in
(pain on weight-bearing, spontaneous pain, pain at rest, Lequesne
efficacy to NSAID therapy and similar in safety, with the excep-
Index, number of joints improved for walking pain, number of
tion of more injection-site pain events but fewer gastrointestinal
joints improved for weight under load, flexion, patient global as-
adverse events than NSAID.
sessment), 14 to 26 weeks (pain on weight-bearing, WOMAC
pain). Statistically significant differences were not detected for pain The comparative study of Hyalgan against mucopolysaccharide
at rest at 14 to 26 weeks, pain on weight bearing at 45 to 52 polysulfuric acid ester detected statistically significant differences
weeks, night pain, WOMAC pain at 1 to 4 weeks or 5 to 13 weeks, in pain, Larson rating and patient global assessment, but no dif-
WOMAC function, Lequesne Index at 14 to 26 weeks, flexion at ference in function or range of motion. There was no difference
1 to 4 weeks, or patient global assessment at 1 to 4 weeks, 14 to in safety profile. The data are limited and no conclusion can be
26 weeks and 45 to 52 weeks. Many of the aforementioned sta- reached from this review regarding relative efficacy and safety.
tistically significant differences were highly significant, and clin-
The comparative study of Hyalgan versus conventional therapy
ically important (WMD (disregarding sign) for pain (0 to 100
detected statistically significant differences in arthroscopy score
mm) varying from 3.93 to 33.50). Overall, these analyses strongly
but not in clinical outcomes at 45 to 52 weeks. The data are lim-
support the evidence for efficacy of Hyalgan. No statistically sig-
ited, but are of interest in terms of potential structure modification
nificant differences from placebo were detected in the majority
effects.
of safety variables although number of patients with local adverse
events, number of patients with local adverse events that caused Huang et al.’s comparative study of combining Hyalgan therapy
discontinuation, and number of patients with treatment-related with ultrasound and exercise versus physiotherapy programmes
adverse events was significantly greater with Hyalgan. Analyses of without Hyalgan co-therapy, suggested positive clinical benefits in
safety data also support the safety of Hyalgan. some outcome variables both at end of study and 1-year follow-
up. This interesting observation requires confirmation, but may
Comparative studies of Hyalgan against IA methylprednisolone
suggest a role for Hyalgan as a co-therapy, in some patients requir-
suggest that Hyalgan is superior to methylprednisolone at 5 to
ing physical forms of therapy for knee OA.
13 weeks postinjection on spontaneous pain intensity, number of
patients with moderate to severe pain under load, number of pa- Product - Hylan G-F 20 (Synvisc)
tients with moderate or greater rest pain, flexion, patient global
assessment, but with the exception of flexion was not different at 1
to 4 weeks. No statistically significant differences were detected at In comparative studies of Hylan G-F 20 and placebo included in
14 to 26 weeks or 45 to 52 weeks postinjection. These differences this review, statistically significant differences were detected at 1
are probably due to the quick onset but often relatively short dura- to 4 weeks (WOMAC OA Index pain, pain on weight-bearing,
tion of the response to IA corticosteroid treatment. Overall, these night pain, rest pain, improvement in most painful knee move-
analyses suggest that Hyalgan is comparable, or superior in effi- ment, WOMAC OA Index stiffness, WOMAC OA Index physical
cacy to methylprednisolone, notwithstanding that the latter has function, patient global assessment of treatment efficacy, physi-
a faster onset of action but the former a longer duration of ac- cian global assessment), 5 to 13 weeks (WOMAC pain, pain on
tion. Analyses of safety data also supported the safety of Hyalgan, weight-bearing, rest pain, pain walking, night pain, WOMAC
with no statistically significant differences from IA methylpred- OA Index stiffness, WOMAC function, Lequesne Index, improve-
nisolone being detected in safety variables. The comparative study ment in most painful knee movement, patient global assessment
of Hyalgan against IA triamcinolone hexacetonide suggests that of treatment efficacy, physician global assessment), 14 to 26 weeks
Hyalgan is not different in efficacy to triamcinolone hexacetonide, (WOMAC pain, pain on weight-bearing, night pain, WOMAC
except in pain at night at 14 to 26 weeks. Analyses of safety data function). Statistically significant differences were not detected for
supported the safety of Hyalgan, with no statistically significant pain overall , 15 metre walking time, number of clinical failures
differences from IA triamcinolone hexacetonide being detected in or number of survivors. Many of the aforementioned statistically

significant differences were highly significant, and clinically im- in favour of intra-articular gaseous oxygen. The two treatments
portant (WMD (disregarding sign) for pain (0 to 100 mm) vary- could not be differentiated based on this single study.
ing from 8.03 to 35.68). Overall, these analyses strongly support
Two comparative studies of Hylan G-F 20 plus appropriate care
the evidence for efficacy of Hylan G-F 20. Analyses of safety data
versus appropriate care alone both confirm the superiority of
also support the safety of Hylan G-F 20, with no statistically sig-
adding Hylan G-F 20 to appropriate care as assessed by the
nificant differences from placebo being detected in the majority
WOMAC OA Index, Lequesne Index and patient global assess-
of safety variables.
ment. Safety variables either detected no statistically significant
Comparative studies of Hylan G-F 20 against corticosteroid sug- difference or were in favour of Hylan G-F 20 plus appropriate
gest that Hylan G-F 20 is superior to triamcinolone hexace- care. These studies provide strong support for the incorporation
tonide at 5 to 13 weeks, and 14 to 26 weeks post injection on of Hylan G-F 20 into routine clinical care treatment paradigms.
WOMAC pain walking on a flat surface, WOMAC function and
total WOMAC score, but not at 1 to 4 weeks. This difference is
probably due to the quick onset but often relatively short dura- Product - NRD-101
tion of the response to IA corticosteroid treatment. Overall, these
In the comparative study of NRD-101 plus oral placebo versus
analyses suggest that Hylan G-F 20 is comparable in efficacy to
intra-articular saline and oral placebo, performed by Pham (Pham
IA corticosteroid, notwithstanding that the latter has a faster on-
2004), no statistically significant between-group differences were
set of action but the former a longer duration of action. Analyses
detected in pain, Lequesne index, patient global assessment, per-
of safety data also supported the safety of Hylan G-F 20, with
centage of painful days or radiographic progressors. On the basis
no statistically significant differences from IA corticosteroid being
of RevMan analysis of this single study, no comment can be made
detected in the majority of safety variables.
regarding the relative efficacy of NRD-101 versus placebo.
Comparative studies of Hylan G-F20 against NSAID suggest that
In the comparative analyses against Artz, no statistically significant
Hylan G-F 20 is comparable in efficacy to NSAID therapy at 5 to
differences were detected between the products in improvement
13 weeks, and 14 to 26 weeks postinjection, based on the majority
in clinical symptoms or safety. The two products could not be
of variables. There were significantly fewer patients with possible
differentiated based on this single study.
or probable related systemic adverse events on Hylan G-F 20 but
otherwise there were no statistically detectable differences in safety. The comparative study performed by Pham (Pham 2004) detected
Overall, these analyses suggest that Hylan G-F 20 is comparable no statistically significant differences on clinical outcome variables
in efficacy to NSAID therapy and similar or slightly superior in or radiographic progression between NRD-101 and Diacerein.
safety. However, NRD-101 was associated with significantly more local
reactions and Diacerien with significantly more diarrhea. On the
The comparative study of Hylan G-F 20 plus physiotherapy
basis of RevMan analysis of this single study, no comment can be
against physiotherapy alone detected no difference in Lequesne
made regarding the relative efficacy of NRD-101 versus Diacerein.
score or withdrawals but is limited in its scope and generalisability
(Bayramoglu 2003). In contrast, in the comparative study of Hy-
lan G-F20 vs physiotherapy (Atamaz 2005), while there was an
Product - Orthovisc
early effect in favour of physiotherapy at 1 to 4 weeks, other anal-
yses favoured Hylan G-F 20 (WOMAC pain at 1at 4 weeks and In comparative studies of Orthovisc and placebo included in this
5 to 13 weeks, 37 weeks and 45 to 52 weeks). In the comparative review, statistically significant differences in WOMAC pain and
study of Hylan G-F 20 versus an exercise programme (Karatosun WOMAC function were detected at 1 to 4 weeks, 5 to 13 weeks,
2005), statistically significant differences in favour of Hylan G- and 14 to 26 weeks postinjection, WOMAC stiffness at 5 to 13
F 20 were detected in several pain components of the Hospital weeks and 14 to 26 weeks postinjection, and patient global as-
for Special Surgery Knee Score, but not in the overall score at any sessment at 1 to 4 weeks and 5 to 13 weeks postinjection. These
of the time points. There were fewer withdrawals in the exercise analyses support the evidence for efficacy of Orthovisc. Analyses
group. Taken collectively, and recognizing the disparate nature of of safety data also supported the safety of Orthovisc, with no sta-
the physiotherapy interventions and comparisons analysed, Hy- tistically significant differences from placebo being detected in the
lan G-F 20 may be superior to physiotherapy alone or an exercise safety profile.
programme in some knee OA patients with respect to pain relief.
Comparative studies of Orthovisc against corticosteroid suggest
The comparative study of Hylan G-F 20 and intra-articular that Orthovisc is superior to 6-MPA at 5 to 13 weeks and 14 to
gaseous oxygen, detected no statistically significant differences on 26 weeks postinjection and superior to betamethasone at 5 to 13
the majority of variables. Indeed the only variable on which a dif- weeks postinjection. No statistically significant differences were
ference was detected was pain under load at 5 to 13 weeks and was detected at 1 to 4 weeks against either corticosteroid. This time-

dependent difference is probably due to the quick onset but often The comparative study of Orthovisc alone versus Orthovisc plus
relatively short duration of the response to IA corticosteroid treat- co-treatment with trigger point injections (Yentur 2003), sug-
ment. Overall, these analyses suggest that Orthovisc is comparable gested clinical benefit in pain relief with the combination pro-
in efficacy to IA corticosteroids at 1 to 4 weeks and superior at 5 to gramme. No recommendation can be made on the basis of this
13 weeks and 14 to 26 weeks, notwithstanding that the latter have single study, but the concept merits further evaluation in relevant
a faster onset of action but the former a longer duration of action. knee OA patients.
Analyses of safety data also support the safety of Orthovisc, with
The comparison of Orthovisc treatment schedules conducted by
no statistically significant differences from either IA corticosteroid
Neustadt (Neustadt 2005) detected statistically significant differ-
preparation being detected in the safety profile. In the study per-
ences in favour of the 4-injection regimen in WOMAC 20% pain
formed by Ozturk (Ozturk 2005), in which Orthovisc was com-
response at 5 to 13 weeks and in the patient global assessment.
pared in combination with triamcinolone acetonide to Orthovisc
alone, statistically significant differences, in favour of the combi- In a comparative analysis of Orthovisc plus physical therapy versus
nation, were detected for pain (1 to 4 weeks) and WOMAC stiff- Hylan G-F 20 plus physical therapy there were no statistically
ness (1 to 4, 34 and 45 to 52 weeks), although there were fewer significant differences in efficacy or safety. The two products could
withdrawals in the Orthovisc alone group. Given that significant not be differentiated based on this single study.
differences were not noted on the majority of outcome variables,
but acknowledging the apparent clinical benefit of the combina-
tion on some variables, the value of combination therapy merits Product - Replasyn
further evaluation.
No trials of Orthovisc against either NSAID therapy were reported It was not possible to conduct informative analysis of Replasyn
and no comment can be made on the relative effectiveness or safety as part of this review, and therefore no conclusion can be reached
against this class of intervention. regarding efficacy or safety, based on our review. The original pub-
lication, referred to previously, noted a significant difference in
In the comparative study of Orthovisc plus physiotherapy against
only one of six variables.
physiotherapy alone, no statistically significant differences in effi-
cacy variables were detected at 1 to 4 weeks postinjection. Statis-
tically significant differences in favour of Orthovisc were noted in
some, but not all, variables at 5 to 13 weeks postinjection. There Product - SLM-10
were no statistically significant differences in safety profile. These
analyses suggest that adding Orthovisc to physiotherapy may be
beneficial with respect to activity pain and spontaneous pain, at 5 SLM-10 was comparable in efficacy to Artz on three outcome
to 13 weeks postinjection. The more recent study of Orthovisc ver- measures and statistically significantly inferior on pain on pressure.
sus physiotherapy by Atamaz (Atamaz 2005), detected statistically There was no difference in safety profile. This review provides some
significant differences in favour of Orthovisc for spontaneous pain supportive evidence for the efficacy and safety of SLM-10, but is
(14 to 26 weeks), WOMAC pain (1 to 4 and 45 to 52 weeks), SF- based on limited data, and does not include placebo-controlled
36 pain (5 to 13 and 14 to 26 weeks), SF-36 physical function (5 to trials or studies against NSAID, IA corticosteroid or appropriate
13 and 45 to 52 weeks). The comparison of Orthovisc plus phys- care.
iotherapy versus physiotherapy alone (Bayramoglu 2003) failed to
detect between group differences using the Lequesne index. Taken
collectively, the studies of Kalay (Kalay 1997) and Atamaz (Atamaz Product - Suplasyn
2005), suggest that Orthovisc offers clinical benefit compared to
physiotherapy.
No statistically significant differences were detected in our analy-
In a comparative analysis of Orthovisc plus physical therapy ver- ses between Suplasyn and placebo for four of the five efficacy mea-
sus Hylan G-F 20 plus physical therapy (Bayramoglu 2003), sures and for the fifth favoured the control group. No statistically
there were no statistically significant differences in efficacy or sa- detectable differences were noted in the safety profile. The review
fety. Several studies have compared Orthovisc and Hylan G-F 20 does not incontrovertibly support the efficacy of Suplasyn, given
(Atamaz 2005; Bayramoglu 2003; Karatay 2004; Karatosun 2005; negative outcomes for the majority of variables in our RevMan
Kotevoglu 2005). Statistically significant differences have not gen- analyses, which are somewhat at variance with the original pub-
erally been detected, but where detected, the majority have been lication. However, Felson and Anderson (Felson 2002) published
in favour of Hylan G-F20. The two products could not be clearly an editorial on HA injections for OA in the same issue of Archives
differentiated based on these studies. of Internal Medicine in which the Petrella trial (Petrella 2002) was

published. They re-evaluated the data of Petrella analysing it as a Implications for practice
factorial experiment, and noted that Suplasyn had no ”significant
The review presented is comprehensive and permits practitioners
or important clinical effect on pain“ and ”there [were] null results
to more fully consider the therapeutic profile of HA products.
for disability and other outcomes“.
Each analysis addresses a different issue, and practitioners are rec-
No statistically significant differences in efficacy or safety variables ommended to review those analyses specifically relating to their
were detected between Suplasyn and NSAID. The two treatment questions. This should involve examining the original publica-
strategies could not be differentiated based on this single study. tion, the methodology employed in conducting the review, the
results for the product(s) of interest, with attention to the relevant
variables and timepoints. Readers should consider the clinical im-
Product - Zeel compositum portance as well as the statistical significance of any differences
detected. Readers should be aware that the results of our review
derive from a defined approach to the analysis of selected stud-
No statistically significant differences in efficacy or safety variables ies, that selected studies vary in quality and that the analyses do
were detected between Zeel compositum and Hyalart. The two not consider studies excluded from consideration. Nevertheless,
products could not be differentiated based on this study. the approach is traditional, follows Cochrane guidelines and uses
RevMan 4.2 software.
Product - Hyaluronan (brand name not identified)
Controversy in the existing literature is part due to a combination
The interpretation of the study reported by Wu (Wu 2004) is
of the heterogeneous time-dependant nature of the response to the
problematic since the exact nature of the HA product could not
HA class of products, diversity in protocol design in the contribut-
be identified. The authors concluded that HA plus self-controlled
ing studies, and the different approaches taken to the conduct of
celecoxib could improve the clinical symptoms of knee OA. We
systematic reviews. We have attempted to dissect out the effect of
are not able to reach a conclusion based on this study due to lack
these issues by performing multiple analyses on a by-product, by-
of sufficient information.
comparison, by-variable, by-timepoint basis. While this does not
By-class analyses provide a single answer to questions of efficacy, effectiveness and
safety, the analyses permit the complexity of the HA effect to be
The pooled analyses address issues relating to class characteris-
appreciated.
tics and may not be shared to the same extent by each individual
HA product. Readers including practitioners, regulators and third The analyses suggest that there is considerable heterogeneity in
party payers should be cautious in extrapolating from the class to the clinical response, such that there are differential therapeutic
an individual product or vice versa, as the class-based analysis may effects by different HA products, on different variables and that
either under-estimate or over-estimate the performance of individ- the response is time dependent. For example, when pain on weight
ual component products. For product-based information, read- bearing at 5 to 13 weeks postinjection is considered the evidence is
ers are referred to the relevant preceding sections. Only compar- very supportive of therapeutic benefit over placebo, and the effect
isons against placebo are discussed, because of the relatively large size (SRM) may be as high as 0.94 depending on the product and
number of studies available for some of these analyses. The other is 0.61 for the HA class in general. Given that effect sizes can be
comparisons were limited, in some cases, by a relative paucity of classified as small (0.2), medium (0.5) or large (0.8), these analyses
studies. suggest a range of effect sizes up to large product-based effect on
pain on weight bearing, and a moderate class-based effect on pain
Statistically significant differences were detected between HA and
on weight bearing.
placebo at 1 to 4 weeks (WOMAC pain, pain on weight bearing,
pain at rest, WOMAC function, Lequesne Index, flexion), 5 to 13 The dynamics of the response are such that a statistically signifi-
weeks (pain on weight bearing, WOMAC pain, WOMAC func- cant, clinically important, effect 1 to 4 weeks postinjection versus
tion, Lequesne Index, flexion), and 14 to 26 weeks (pain on weight placebo is not necessarily achievable, but should be evident by the
bearing, WOMAC pain, WOMAC function, flexion) postinjec- 5 to 13 week time point. Nevertheless, early responses are observed
tion. Apart from a higher incidence of injection site pain, no sta- in some comparisons. In contrast, in comparisons against placebo
tistically significant differences versus placebo were noted in the there may be a more durable, albeit slower response compared to
safety profile variables. These data generally support the evidence IA corticosteroids. In long-term studies, the effects of combining
for the efficacy and safety (versus placebo) of the HA class of in- single course with repeat treatment studies in our analyses deserve
tervention. due consideration, particularly when reviewing the late stage end-
points, for example 45 to 52 weeks. In single course studies the
last course may have been almost one year prior when a persisting
AUTHORS’ CONCLUSIONS effect might not be expected, while in repeat-course studies the last

course may have been recent, or even 5 to 13 weeks prior, when a trials (up to one year) including repeat course studies, head-to-
clinical benefit might well be anticipated. These nuances deserve head comparisons of different HA products, effectiveness, cost-
due recognition since they account for some of the diversity in the effectiveness and cost-utility studies, studies of different OA sub-
responses reported in the literature. groups, dissection of the determinants of the response to HA prod-
ucts, exploration of the apparently differential effect of HA prod-
These issues notwithstanding, HA products generally appear su-
ucts on different variables. The aforementioned studies should
perior to placebo on multiple efficacy variables, providing support
follow OARSI and other similar guidelines for the conduct and
for the use of those HA products for which the effect is not only
design of OA studies. The use of standardized outcome measures
statistically significant but also clinically important. These bene-
is encouraged to facilitate meta-analyses and between trial com-
fits appear to be achievable without attributable systemic adverse
parisons.
events but with occasional local reactions which tend, for the most
part, to be relatively transient, resolving without sequelae either
spontaneously or with simple intervention. It should be noted that
this review is not the premier source of safety data, since sample
sizes are relatively small in the trials reported, particularly for de-
tecting less frequent or even rare adverse events. Readers are re- ACKNOWLEDGEMENTS
ferred to the general literature and the surveillance literature for
The authors are grateful to Jessie McGowan for conducting the
a more comprehensive appreciation of safety issues. Nevertheless,
search strategy. We acknowledge the translation of the Wu 2004
based on the evidence reviewed, HA products appear in general to
article by Dr. Hua Qian, MD, PhD, The Robarts Research In-
be safe.
stitute, The University of Western Ontario. We acknowledge the
assistance of former Musculoskeletal Review Group Co-ordinator
Implications for research Maria Judd and current Musculoskeletal Review Group Co-ordi-
The following types of studies would be informative: long-term nator Lara Maxwell for their guidance in completing this review.
REFERENCES
References to studies included in this review Atamaz 2004 {published data only}
Atamaz F, Kirazli Y, Akkoc Y. A comparative study between
Adams 1995 {published data only}
intra-articular hylan G-F 20 and Na-hyaluronate and
∗
Adams ME, Atkinson MH, Lussier AJ, Schulz JI,
physical therapy in the management of knee osteoarthritis.
Siminovitch KA, Wade JP, Zummer M. The role of
Annals of the Rheumatic Diseases 2004;EULAR, Berlin,
viscosupplementation with hylan G-F 20 (Synvisc) in
June 9-12.
the treatment of osteoarthritis of the knee: a Canadian
multicenter trial comparing hylan G-F 20 alone, hylan G-F Atamaz 2005 {unpublished data only}
20 with non-steroidal anti-inflammatory drugs (NSAIDs) Atamaz F, Kirazli Y, Akkoca Y. A comparison of two different
and NSAIDs alone. Osteoarthritis and Cartilage 1995;3: intra-articular hyaluronan drugs and physical therapy in
213–6. the management of knee osteoarthritis. Rheumatology
Altman 1998 {published data only} International 2006;26(10):873–8.
∗
Altman RD, Moskowitz R, the Hyalgan Study Group. Auerbach 2002 {published data only}
Intraarticular sodium hyaluronate (Hyalgan) in the Auerbach B, Melzer C. Cross-linked hyaluronic acid
treatment of patients with osteoarthritis of the knee: a in the treatment of osteoarthritis of th eknee - results
randomized clinical trial [published erratum appears in J of a prospective randomized trial [Die Behandlung
Rheumatol 1999;26:1216]. The Journal of Rheumatology der Gonarthrose mit hochvernetzter Hyaluronsaure –
1998;25(11):2203–12. Ergebnisse einer prospektiven randomisierten Studie].
Altman 2004 {unpublished data only} Zentralblatt fur Chirurgie 2002;127(10):895–9.
Altman RD, Akermark C, Beaulieu AD, Schnitzer T for the Auerbach 2002a {published data only}
Durolane International Study Group. Efficacy and safety ∗
Auerbach B. [Ergebnisse einer prospektiven randomisierten
of a single intra-articular injection of non-animal stabilized Studie zur Wirksamkei hochvernetzter Hyaluronsaure bei
hyaluronic acid (NASHA) in patients with osteoarthritis of der Behandlung der Gonarthrose]. Inaugural-Dissertation
the knee. Osteoarthritis and Cartilage 2004;12(8):642–9. zur Erlangung des Grades eines Doktors der Medizin des
Ardic 2001 {published data only} Fachbereichs Humanmedizin der Justus-Liebig-Universitat
∗
Ardic F, Bolulu D, Topuz O, Cubukcu S. Efficacy of intra- Giessen 2002.
articular hyaluronic acid injections in knee osteoarthritis. Bayramoglu 2003 {published data only}
Annals of the Rheumatic Diseases 2001;60 Suppl (1):232. ∗
Bayramoglu M, Karatas M, Cetin N, Akman N.
Comparison of two different viscosupplements in knee Corrado 1995 {published data only}
osteoarthritis - a pilot study. Clinical Rheumatology 2003; ∗
Corrado EM, Peluso GF, Gigliotti S, de Durante C,
22:118–2. Palmieri D, Savoia M, Oriani GO, Tajana GF. The
Bragantini 1987 {published data only} effects of intra-articular administration of hyaluronic
∗
Bragantini A, Cassini M, De Bastiani G. Controlled acid on osteoarthritis of the knee: a clinical study with
single-blind trial of intra-articularly injected hyaluronic acid immunological and biochemical evaluations. European
(Hyalgan) in osteo-arthritis of the knee. Clinical Trials Journal of Rheumatology and Inflammation 1995;15(1):
Journal 1987;24(4):333–40. 47–56.
Brandt 2001 {published data only} Creamer 1994 {published data only}
∗
Brandt KD, Block JA, Michalski JP, Moreland LW, ∗
Creamer P, Sharif M, George E, Meadows K, Cushnaghan
Caldwell JR, Lavin PT, the ORTHOVISC Study Group. J, Shinmei M, Dieppe P. Intra-articular hyaluronic acid in
Efficacy and safety of intraarticular sodium hyaluronate osteoarthritis of the knee: an investigation into mechanisms
in knee osteoarthritis. Clinical Orthopaedics and Related of action. Osteoarthritis and Cartilage 1994;2:133–40.
Research 2001;385:130–43. Cubukcu 2004 {published data only}
Brown 2003 {published data only} Cubukcu D, Ardic F, Karabulut N, Topuz O. Hylan G-F
∗
Brown DJ, Beinat L. Safety and efficacy of an hyaluronan 20 efficacy on articular cartilage quality in patients with
of 500-730 KDa and Hylan G-F 20 in clinical practice. knee osteoarthritis: clinical and MRI assessment. Clinical
Osteoarthritis and Cartilage 2003;11 Suppl (A):118. Rheumatology 2005;24(4):336–41.
[OARSI October 2003 Berlin]
Day 2001 {unpublished data only}
Bunyaratavej 2001 {published data only}
Day R, Brooks P, Petersen M, The Australian Multicentre
∗
Bunyaratavej N, Chang KM, Subramanian N. Treatment
Trial Group. A randomised multicentre parallel group study
of painful osteoarthritis of the knee with hyaluronic acid
of the effectiveness and tolerance of intra-articular injections
results of a multicenter Asian study. Journal of the Medical
of sodium hyaluronate in osteoarthritis of the knee.
Association of Thailand 2001;84 Suppl (2):576–81.
Day 2004 {published data only}
Caborn 2003 {published data only} ∗
Day R, Brooks P, Conaghan PG, Petersen M for the
Caborn DN. Efficacy and tolerability of hylan G-F 20
Multicenter Trial Group. A double blind, randomized,
compared to intra-articular triamcinolone hexacetonide in
multicenter, parallel group study of the effectiveness and
patients with osteoarthritis of the knee in a randomized,
tolerance of intraarticular hyaluronan in osteoarthritis of the
evaluator-blinded study. Annals of the Rheumatic Diseases
knee. The Journal of Rheumatology 2004;31(4):775–82.
2003;EULAR, Lisbon, Portugal,June 18-21.
Caborn 2004 {published data only} Dickson 2001 {published and unpublished data}
∗
Caborn D, Rush J, Lanzer W, Parenti D, Murray C on
∗
Dickson DJ, Hosie G, English JR, and the Primary Care
Behalf of the Synvisc 901 Study Group. A randomized, Rheumatology Society. A double-blind, placebo-controlled
single-blind comparison of the efficacy and tolerability of comparison of hylan G-F 20 against diclofenac in knee
hylan G-F 20 and triamcinolone hexacetonide in patients osteoarthritis. Journal of Clinical Research 2001;4:41–52.
with osteoarthritis of the knee. The Journal of Rheumatology Dougados 1993 {published and unpublished data}
2004;31(2):333–43. ∗
Dougados M, Nguyen M, Listrat V, Amor B. High
Carrabba 1995 {published data only} molecular weight sodium hyaluronate (hyalectin) in
∗
Carrabba M, Paresce E, Angelini M, Re KA, Torchiana osteoarthritis of the knee: a 1 year placebo-controlled trial.
EEM, Perbellini A. The safety and efficacy of different dose Osteoarthritis and Cartilage 1993;1:97–103.
schedules of hyaluronic acid in the treatment of painful Formiguera Sala 1995 {published data only}
osteoarthritis of the knee with joint effusion. European ∗
Sala S, de Miguel RE. Intra-articular hyaluronic acid in
Journal of Rheumatology and Inflammation 1995;15(1): the treatment of osteoarthritis of the knee: a short term
25–31. study. European Journal of Rheumatology and Inflammation
Carrabba 1995a {published data only} 1995;15(1):33–8.
Reference same as Carrabba 1995, multiple arm trial.
Forster 2003 {published and unpublished data}
Carrabba 1995b {published data only} ∗
Forster MC, Straw R. A prospective randomised
Reference same as Carrabba 1995, multiple arm trial. trial comparing intra-articular Hyalgan injection and
Carrabba 1995c {published data only} arthroscopic washout for knee osteoarthritis. The Knee
Reference same as Carrabba 1995, multiple arm trial. 2003;10:291–3.
Cohen 1994 {published data only} Forster 2003a {published and unpublished data}
∗
Cohen MA, Shiroky JB, Ballachey ML, Neville C, Esdaile Forster MC, Straw R, Rowles JM. A prospective randomised
JM. Double-blind randomized trial of intra-articular (I/A) trial comparing intra-articular sodium hyaluronate injection
hyaluronate in the treatment of osteoarthritis of the knee. and arthro-scopic washout for knee osteoarthritis. The
Arthritis & Rheumatism 1994;37 Suppl 6:R31. Journal of Bone and Joint Surgery 2003;85-B Suppl (II):103.
Frizziero 2002 {published data only} Jubb 2001a {published data only}
∗
Frizziero L, Pasquali Rochetti I. Intra-articular treatment Jubb RW, Piva S, Beinat L, Dacre J, Gishen P on behalf
of osteoarthritis of the knee: an arthroscopic and clinical of the UK Hyalgan Study Group. Effect of sodium
comparison between sodium hyaluronate (500-730 kDa) hyaluronate (500-730 KDa, HyalganR) on joint space width
and methylprednisolone acetate. Journal of Orthopaedics in osteoarthritis of the knee. The Journal of Rheumatology
and Traumatology 2002;3:89–96. 2001;28 Suppl (63):8.
Graf 1993 {published data only} Jubb 2001b {published data only}
∗
Graf J, Neusel E, Schneider E, Niethard FU. Intra- Jubb RW, Piva S, Beinat L, Dacre J, Gishen P for the
articular treatment with hyaluronic acid in osteoarthritis UK Hyalgan Study Group. Structure modifying study of
of the knee joint: a controlled clinical trial versus hyaluronan (500-730 KDa, HyalganR) on osteoarthritis of
mucopolysaccharide polysulfuric acid ester. Clinical and the knee. Osteoarthritis and Cartilage 2001;9 Suppl (B):16.
Experimental Rheumatology 1993;11:367–72. Jubb 2001c {published data only}
Grecomoro 1987 {published data only} Jubb RW, Piva S, Beinat L, Dacre J, Gishen P. Structure
∗
Grecomoro G, Martorana U, Di Marco C. Intra-articular modifying study of hyaluronan (500-730 KDa, HyalganR)
treatment with sodium hyaluronate in gonarthrosis: a on osteoarthritis of the knee. Arthritis & Rheumatism 2001;
controlled clinical trial versus placebo. Pharmatherapeutica 44 Suppl (9):155.
1987;5(2):137–41. Jubb 2001d {published data only}
Groppa 2001 {published data only} Jubb RW, Piva S, Beinat L, Dacre J, Gishen P, on behalf of
∗
Groppa LG, Moshneaga M. Studying of the efficiency the UK Hyalgan Study Group. Structure modification in
of the Synvisc in osteoarthrosis. Annals of the Rheumatic osteoarthritis with intra-articular sodium hyaluronate of
Diseases 2001;60 Suppl (1):230. mol. 500-730 KDA. Annals of the Rheumatic Diseases 2001;
60 Suppl (I):46.
Guler 1996 {published data only}
∗
Guler M, Kuran B, Parlar D, Guler M, Saglam H, Yapici Jubb 2003 {published and unpublished data}
S, Guzeloglu S, Ozgul Mese F, Bonveval F. Clinical trial
∗
Jubb RW, Piva S, Beinat L, Dacre J, Gishen P. A one-year,
of intra-articular injection of hyaluronic acid in patients randomised, placebo (saline) controlled clinical trial of 500-
with osteoarthritis of the knee. X National Rheumatology 730 kDa sodium hyaluronate (Hyalgan) on the radiological
Congress, Turkey. October 29–November 3, 1996. change in osteoarthritis of the knee. International Journal of
Clinical Practice 2003;57(6):467–74.
Henderson 1994 {published data only}
Kahan 2001 {published data only}
∗
Henderson EB, Smith EC, Pegley F, Blake DR. Intra-
Kahan A, Guemas E, Lieu PL. Patients with knee
articular injections of 750 kD hyaluronan in the treatment
osteoarthritis treated by hylan G-F 20 versus usual
of osteoarthritis: a randomised single centre double-blind
treatments: a medico-economic, prospective, randomised
placebo-controlled trial of 91 patients demonstrating lack of
large scale trial in France, efficacy and safety outcomes.
efficacy. Annals of the Rheumatic Diseases 1994;53:529–34.
Annals of the Rheumatic Diseases 2001;60 Suppl (1):232.
Henderson 1994a {published data only} Kahan 2003 {published data only}
See Henderson 1994. Kahan A, Lleu P-L, Salin L. Prospective randomised study
Hizmetli 1999 {unpublished data only} comparing the medico-economic benefits of hylan GF-
∗
Hizmetli S, Kocagil S, Kaptanoglu E, Elden H, Nacitarhan 20 versus conventional treatment in knee osteoarthritis
V. The efficacy and safety of intra-articular hyaluronic acid [Etude prospective randomisee comparant le benefice
in osteoarthritis of the knee: a prospective, double-blind medico–economique de Synvisc a celui des traitements
trial. usuels chez des patients souffrant de gonarthrose]. Revue du
Huang 2005 {published and unpublished data} rhumatisme 2003;70:588–94.
Huang M-H, Yang R-C, Lee C-L, Chen T-W, Wang M-C. Kahan 2003a {published data only}
Preliminary results of integrated therapy for patients with ∗
Kahan A, Lleu P-L, Salin L. Prospective randomized study
knee osteoarthritis. Arthritis Care & Research 2005;53(6): comparing the medicoeconomic benefits of Hylan G-F 20
812–20. vs. conventional treatment in knee osteoarthritis. Joint Bone
Huskisson 1999 {published and unpublished data} Spine 2003;70:276–81.
∗
Huskisson EC, Donnelly S. Hyaluronic acid in the Kalay 1997 {published data only}
treatment of osteoarthritis of the knee. Rheumatology 1999; ∗
Kalay S. The effectiveness of intraarticular hyaluronic acid
38:602–7. treatment in primary gonarthrosis [specialization thesis].
Jones 1995 {published data only} Ankara, Turkey: Ministry of Health, Republic of Turkey,
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Jones AC, Pattrick M, Doherty S, Doherty M. Intra- 1997.
articular hyaluronic acid compared to intra-articular Karatay 2004 {published data only}
triamcinolone hexacetonide in inflammatory knee Karatay S, Kiziltunc A, Yildirim K, Karanfil RC, Senel K.
osteoarthritis. Osteoarthritis and Cartilage 1995;3:269–73. Effects of different hyaluronic acid products on synovial
fluid levels of intercellular adhesion molecule-1 and vascular Kawabata 1993 {published data only}
cell adhesion molecule-1 in knee osteoarthritis. Annals of ∗
Kawabata M, Igarashi M, Mikami R, Ninomiya S,
Clinical & Laboratory Science 2004;34(3):330–5. Oda H, Hoshino Y, Yamamoto S, Kurokawa T, Ogawa
Karatay 2005 {published data only} N. Clinical evaluation of SLM-10 (sodium hyaluronate
Karatay S, Kiziltunc A, Yildirim K, Karanfil RC, Senel K. injection) in patients with osteoarthritis of the knee - a
Effects of different hyaluronic acid products on synovial mutli-center comparative trial with Artz as control drug.
fluid NO levels in knee osteoarthritis. Osteoporosis Japanese Pharmacology & Therapeutics 1993;21(1):257–83.
International 2005;16(3):S71. Kirchner 2005 {published data only}
Karatay 2005a {published data only}
Kirchner 2005 {published data only}
Karatay S, Yildirim K, Yildiz L, Karanfil RC, Senel K. The ∗
Kirchner M, Marshall D. A double-blind randomized
effect of hyaluronic acid on levels of IFG-1 and IGFBP-
controlled trial comparing alternate forms of high molecular
3 in synovial fluids of patients with knee osteoarthritis.
weight hyaluronan for the treatment of osteoarthritis of the
Osteoporosis International 2005;16(3):S72.
knee. Osteoarthritis and Cartilage 2006;14(2):154–62.
Karatosun 2005 {published and unpublished data}
Karatosun V, Unver B, Gocen Z, Sen A, Gunal I. Intra- Kirchner 2006 {published and unpublished data}
articular hyaluronic acid compared with progressive knee Kirchner M, Marshall D. A double-blind randomized
exercises in osteoarthritis of the knee: a prospective controlled trial comparing alternate forms of high molecular
randomized trial with long-term follow-up. Clinical & weight hyaluronan for the treatment of osteoarthritis of the
Experimental Rheumatology 2005. knee. Osteoarthritis and Cartilage 2006;14(2):154–62.
Karatosun 2005a {published data only} Kotevoglu 2002 {published data only}
Karatosun V, Unver B, Gocen Z, Sen A. Comparison of two Kotevoglu N, Iyibozkurt P, Hiz O, Kuran B.
hyaluronan drugs in patients with advanced osteoarthritis Viscosupplementation treatment for osteoarthritis of the
of the knee. A prospective, randomized, double-blind knee. Annals of the Rheumatic Diseases 2002;61 Suppl.
study with long term follow-up. Clinical and Experimental
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Kotevoglu N, Iybozkurt PC, Hz O, Toktas H, Kuran
Karlsson 1999 {published data only} B. A prospective randomised controlled clinical trial
Karlsson J, Selin-Sjogren L. A comparison of two hyaluronan comparing the efficacy of different molecular weight
drugs and placebo in patients with mild to moderate hyaluronan solutions in the treatment of knee osteoarthritis.
osteoarthritis of the knee - a controlled, randomised, Rheumatology International 2005;4.
parallel-design multicenter study. Acta orthopaedica
Scandinavica 1999;70 Suppl (287):62. Lanzer 2002 {published data only}
Lanzer WL, Schuster R. A randomized, single-blind
Karlsson 2002 {published data only}
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Karlsson J, Sjogren LS, Lohmander LS. Comparison of
20 and Aristospan Triamcinolone Hexacetonide in patients
two hyaluronan drugs and placebo in patients with knee
with osteoarthritis (OA) of the knee. American Academy
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of Orthopaedic Surgeons Annual Meeting. Dallas, Texas:
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Karlsson 2002a (AvP) {published data only} Leardini 1987 {published data only}
See Karlsson 2002.
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Leardini G, Franceschini M, Mattara L, Bruno
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See Karlsson 2002. (Hyalgan) in gonarthrosis. A controlled study comparing
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See Karlsson 2002.
Karlsson 2003d {published data only} Leardini 1991 {published data only}
Karlsson J, Sjogren LS, Lohmander S. Comparison of
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Leardini G, Mattara L, Franceschini M, Perbellini A. Intra-
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parallel-design multicentre study. Rheumatology 2003;42 acetate. Clinical and Experimental Rheumatology 1991;9:
(10):1262–3. 375–81.
Karras 2001 {published data only} Leopold 2003 {published data only}
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Karras D, Basilakos J, Diaourta V, Kedikoglou S, ∗
Leopold SS, Redd BB, Warme WJ, Wehrle PA, Pettis PD,
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intraarticular infusion of hyaluronan (Hyalart, Fidia, SPA) injections for the treatment of osteoarthritis of the knee. A
in knee osteoarthritis. The Journal of Rheumatology 2001;28 prospective, randomized trial. The Journal of Bone and Joint
Suppl (63):6. Surgery 2003;85-A(7):1197–203.
Lin 2004 {unpublished data only} Neustadt 2005 {published data only}
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Lin C-C, Tsai C-L, Lee C-H, Chang C-C, Chen S-C, Neustadt DH, Caldwell JR, Burnette MC, Block JA,
Lai C-H, Beinat L. Efficacy and safety of intra-articular Bhirangi K, Lavin PT, Broderick JN. Intra-articular high
injections of sodium hyaluronate (Hyalgan) in the treatment molecular weight hyaluronan (Orthovisc) is effective in
of osteoarthritis of the knee. A randomized, controlled trial. the treatment of pain of knee osteoarthritis. Annals of the
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Vienna, Austria.
Listrat 1997 {published data only}
∗
Listrat V, Ayral X, Patarnello F, Bonvarlet JP, Simonnet J, Neustadt 2005a -3inj {published and unpublished data}
Amor B, Dougados M. Arthroscopic evaluation of potential Neustadt D, Caldwell J, Bell M, Wade J, Gimbel J. Clinical
structure modifying activity of hyaluronan (Hyalgan) in effects of intraarticular injection of high molecular weight
osteoarthritis of the knee. Osteoarthritis and Cartilage 1997; hyaluronan (Orthovisc) in osteoarthritis of the knee: a
5:153–60. randomized, controlled multicenter trial. The Journal of
Lohmander 1996 {published data only} Rheumatology 2005;32(10):1928–36.
∗
Lohmander LS, Dalen N, Englund G, Hamalainen M, Neustadt 2005b-4inj {published and unpublished data}
Jensen EM, Karlsson K, et al. Intra-articular hyaluronan
injections in the treatment of osteoarthritis of the knee: a Ozturk 2005 {published data only}
randomised, double blind, placebo controlled multicentre Ozturk C, Atamaz F, Hepguler S, Argin M, Arkun R.
trial. Annals of the Rheumatic Diseases 1996;55:424–31. The safety and efficacy of intraarticular hyaluronan with/
without corticosteroid in knee osteoarthritis: 1-year, single-
McDonald 2000 {published and unpublished data}
blind, randomized study. Rheumatology International 2005
∗
McDonald C, Hantel S, Strohmeier M. A randomised,
February 10;Epub ahead of print.
controlled study to compare the performance and
safety of two sources of sodium hyaluronate given as a Petrella 2002 {published data only}
viscosupplement by intra-articular injection to patients with ∗
Petrella RJ, DiSilvestro MD, Hildebrand C. Effect of
osteoarthritis of the knee. Journal of Clinical Research 2000; hyaluronate sodium on pain and physical functioning
3:41–50. in osteoarthritis of the knee. A randomized, double-
Miltner 2002 {published data only} blind, placebo-controlled clinical trial. Archives of Internal
∗
Miltner O, Schneider U, Siebert CH, Niedhart C, Medicine 2002;162:292–8.
Niethard FU. Efficacy of intrarticular hyaluronic acid in Pham 2003 {published data only}
patients with osteoarthritis - a prospective clinical trial. ∗
Pham T, Le Henanff A, Ravaud P, Dieppe P, Brin S,
Osteoarthritis and Cartilage 2002;10(9):680–6. Paolozzi L, Dougados M. Lack of symptomatic and
Moreland 1993 {published and unpublished data} structural efficacy of a new hyaluronic acid (HA) compund
∗
Moreland LW, Arnold WJ, Saway A, Savory C, Sikes D. (NRD101) when compared to diacerein and placebo
Efficacy and safety of intra-articular hylan G-F 20 (Synvisc), in a one-year controlled study in symptomatic knee
a viscoelastic derivative of hyaluronan, in patients with osteoarthritis. Arthritis & Rheumatism 2003;48 Suppl (9):
osteoarthritis of the knee. Arthritis & Rheumatism 1993;36 698.
Suppl (9):165. Pham 2004 {published data only}
Nahler 1996 {published data only} Pham T, Le Henanff A, Ravaud Ph, Dieppe P, Paolozzi
Nahler von G, Metelmann H, Sperber H. Treatment of L, Dougados M. Evaluation of the symptomatic and
gonarthrosis with Zeel comp. - Results of a randomised, structural efficacy of a new hyaluronic acid compound,
controlled, comparative clinical trial with hyaluronic acid NRD101, in comparison with diacerein and placebo in a
[Behandlung der Gonarthrose mit Zeel comp. – Ergebnisse 1 year randomised controlled study in symptomatic knee
einer randomisierten, kontrollierten klinischen Prufung im osteoarthritis. Annals of the Rheumatic Diseases 2004;63:
Vergleich zu Hyaluronsaure]. Orthopadische Praxis 1996;32 1611–7.
(5):354–9. Pietrogrande 1991 {published data only}
Nahler 1998 {published data only}
∗
Pietrogrande V, Melanotte PL, D’Agnolo B, Ulivi M,
∗
Nahler G, Metelmann H, Sperber H. Treating Benigni GA, Turchetto L, Pierfederici P, Perbellini A.
osteoarthritis of the knee with a homeopathic preparation. Hyaluronic acid versus methylprednisolone intra-articularly
Results of a randomized, controlled, clinical trial in injected for treatment of osteoarthritis of the knee. Current
comparison to hyaluronic acid. Biomedical Therapy 1998; Therapeutic Research 1991;50(5):691–701.
XVI(2):186–91. Puhl 1993 {published data only}
Neustadt 2004 {published data only} ∗
Puhl W, Bernau A, Greiling H, Kopcke W, Pforringer
Neustadt D, Wade J, Gimbel J, Bell M, Caldwell J. Clinical W, Steck KJ, Zacher J, Scharf HP. Intra-articular sodium
effects of intra-articular high molecular weight hyaluronan hyaluronate in osteoarthritis of the knee: a multicenter,
(Orthovisc) in osteoarthritis of the knee. Arthritis & double-blind study. Osteoarthritis and Cartilage 1993;1:
Rheumatism 2004;50 Suppl (9):144. 233–41.
Raynauld 2002 {published and unpublished data} controlled comparative study. Japanese Journal of Clinical
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Raynauld JP, Torrance GW, Band PA, Goldsmith CH, Pharmacology and Therapeutics 1983;14(3):545–58.
Tugwell P, Walker V, Schultz M, Bellamy N. A prospective, St. J. Dixon 1988 {published and unpublished data}
randomized, pragmatic, health outcomes trial evaluating the ∗
St. J. Dixon A, Jacoby RK, Berry H, Hamilton
incorporation of hylan G-F 20 into the treatment paradigm EBD. Clinical trial of intra-articular injection of sodium
for patients with knee osteoarthritis (Part 1 of 2): clinical hyaluronate in patients with osteoarthritis of the knee.
results. Osteoarthritis and Cartilage 2002;10(7):506–17. Current Medical Research and Opinion 1988;11(4):205–13.
Redd 2003 {published data only} Tamir 2001 {published data only}
Redd BB, Leopold SS, Warme WJ, Pettis PD, Wehrle PA, ∗
Tamir E, Robinson D, Koren R, Agar G, Halperin N.
Shott S. Corticosteroid vs. Synvisc injections for knee Intra-articular hyaluronan injections for the treatment of
arthritis: a randomized, controlled trial demonstrating osteoarthritis of the knee: a randomized, double blind,
similar overall efficacy but significant gender-related placebo controlled study. Clinical and Experimental
treatment differences. American Academy of Orthopaedic Rheumatology 2001;19:265–70.
Surgeons. New Orleans: AAOS, Feb.5–9, 2003.
Tascioglu 2003 {published data only}
Rejaili 2005 {published data only} ∗
Tascioglu F, Oner C. Efficacy of intra-articular sodium
Rejaili WA, Chueire AG, Cordeiro JA, Petean FC, De hyaluroante in the treatment of knee osteoarthritis. Clinical
Carvalho Filho G. The evaluation of hilan GF-20 in the Rheumatology 2003;22:112–7.
postoperative knee arthroscopies for arthrosis. Acta Ortop
Tekeoglu 1998 {published data only}
Bras 2005;13(1):20–3. ∗
Tekeoglu I, Adak B, Goksoy T, Tosun N. Effects of intra-
Roman 2000 {published data only} articular injections of sodium hyaluronate (Orthovisc) and
∗
Roman JA, Chismol J, Morales M, Donderis JL. Intra- betamethasone on osteoarthritis of the knee. The Journal of
articular treatment with hyaluronic acid. Comparative Rheumatology & Medical Rehabilitation 1998;9(4):220–4.
study of hyalgan and adant. Clinical Rheumatology 2000;
19:204–6. Thompson 2002 {published data only}
∗
Thompson JI, Huang YW, Zaibel R. Safety and efficacy
Scale 1994a (2 inj) {published and unpublished data}
of fermentation-derived high molecular weight sodium
∗
Scale D, Wobig M, Wolpert W. Viscosupplementation of
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osteoarthritic knees with hylan: a treatment schedule study.
the knee. Osteoarthritis and Cartilage 2002;10 Suppl (A):
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70–1.
Scale 1994b (3 inj) {published and unpublished data} Tsai 2003 {published and unpublished data}
∗
Scale D, Wobig M, Wolpert W. Viscosupplementation of Tsai C-L, Chang C-C, Chen S-C, Beinat L, Piva S.
osteoarthritis knees with hylan: a treatment schedule study. Treatment of knee osteoarthritis in Asian population with
Current Therapeutic Research 1994;55(3):220–32. an intra-articular hyaluronan of MW 500-730 KDa.
Schneider 1997 {published data only} Osteoarthritis and Cartilage 2003;11 Suppl (A):119.
Schneider U, Miltner O, Graf J, Thomsen M, Niethard [OARSI October 2003 Berlin]
FU. The efficacy of hyaluronic acid in patients with Tsukamoto 1995 {published data only}
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pressure, intraarticular temperature and Lequesne score articular higher molecular weight hyaluronic acid (NRD
[Wirkungsweise von Hyaluronsaure bei Gonarthrose beider 101) versus lower molecular weight hyaluronic acid (Artz)
Kniegelenke im Rechts/Links–Vergleich. Untersuchung mit in knee osteoarthritis. Rheumatology in Europe 1995;24
Dynamometrie, Sauerstoffpartialdruck, Temperatur und (EULAR, Amsterdam):333.
Lequesne score]. Zeitschrift Orthop 1997;135:341–7.
Wobig 1998 {published data only}
Sezgin 2005 {published data only} ∗
Wobig M, Dickhut A, Maier R, Vetter G.
Sezgin M, Demirel AC, Karaca C, Ortancil O, Ulkar GB, Viscosupplementation with hyaln G-F 20: a 26-week
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cytokines in knee osteoarthritis?. Rheumatology International knee. Clinical Therapeutics 1998;20(3):410–23.
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Wobig 1999 {published data only}
Shichikawa 1983a {published data only} ∗
Wobig M, Bach G, Beks P, Dickhut A, Runzheimer J,
∗
Shichikawa K. Evaluation of the effect of sodium Schwieger G, Vetter G, Balazs E. The role of elastoviscosity
hyaluronate (SPH) to osteoarthritis of the knee. The in the efficacy of viscosupplementation for osteoarthritis
Ryumachi 1983;23(4):280–90. of the knee: a comparison of hylan G-F 20 and a lower-
Shichikawa 1983b {published data only} molecular-weight hyaluronan. Clinical Therapeutics 1999;
∗
Shichikawa K, Igarashi M, Sugawara S, Iwasaki Y. Clinical 21(9):1549–62.
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Wobig 1999b (Artz) {published and unpublished data} Arizono 1997 {published data only}
∗
See Wobig 1999. ∗
Arizono T, Hara T, Hara Y. Effect of high-molecular-
weight sodium hyaluronate on osteoarthrosis. Orthop Surg
Wobig 1999c (NEhyl) {published data only}
Traumatol 1997;46 Suppl (1):207–10.
See Wobig 1999.
Ates 2001 {published data only}
Wu 1997 {published data only} Ates A, Kinikli G, Turgay M, Duman M.
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Wu JJ, Shih LY, Hsu HC, Chen TH. The double-blind Viscosupplementation with sodium hyaluronate for the
test of sodium hyaluronate (Artz) on osteoarthritis knee. treatment of osteoarthritis. The Journal of Rheumatology
Chinese Medical Journal (Taipei) 1997;59:99–106. 2001;28 Suppl (63):8.
Wu 2004 {published data only} Bagga 2003 {published data only}
Wu H-B, Du J-Y, Yang S-H, Shao Z-W, Xiong X-Q. Bagga H, Burkhardt D, Morris D, Ghosh P, Sambrook P,
Evaluation on the effects of hyaluronan combined with March L. [Long term effects of intra–articular hylan G–F
different dosages of celecoxib for relieving pain and ankylosis 20 (Synvisc) on synovial fluid hyaluronan and sulfated
induced by knee osteoarthritis. Chinese Journal of Clinical glycosaminoglycans levels]. Annals of the Rheumatic DIseases
Rehabilitation [Zhongguo lin Chuang Kang fu] 2004;8(26): 2003;EULAR, Lisbon, Portugal, June 18-21.
5491–3.
Bardin 2004 {published data only}
Yamamoto 1994 {published data only} Bardin T, Kieffer P, Hassaynia K, Vincent P, Vincent Aubrey
∗
Yamamoto M, Sugawara Y, Tsukamoto Y, Motegi M, Iwata F. [A large study phase IV of intraarticular arthrum H in
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high molecular weight sodium hyaluronate (NRD 101) on Suppl (2):145.
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Therapeutics 1994;22(9):4059–87. Barrett JP, Siviero P. [Retrospective study of outcomes in
Hyalgan–treated patients with osteoarthritis of the knee].
Yentur 2003 {published data only} Clinical Drug Investigation 2002;23:87–97.
Yentur EA, Okcu G, Yegul I. The role of trigger point
Bell 1999 {published data only}
therapy in knee osteoarthritis. The Pain Clinic 2003;15(4):
Bell M, Fallaha M, Lenczner E, Ranger P, Welsh P.
385–90.
Viscosupplementation with hylan G-F 20 in total knee
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(POAK)]. The Knee 2005;12:57–62. Frizziero 1998 {published data only}
Conrozier 2003 {published data only} Frizziero L, Govoni E, Bacchini P. Intra-articular hyaluronic
Conrozier T, Mathieu P, Schott A-M, Laurent I, Hajri acid in the treatment of osteoarthritis of the knee: clinical
T, Crozes P, et al Meignan F, Noel E, Rozand Y, Savoye and morphological study. Clinical and Experimental
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knee osteoarthritis? [Existe–t–il des facteurs predictifs de ∗
Fuji T, Matsui S, Fujita S, Hirota S. Clinical effect of
l’efficacite a long terme de la viscosupplementation par intra-articular injection of sodium hyaluronate (Artz) on
hylane GF–20 dans la gonarthrose?]. Revue du rhumatisme osteoarthritis of the knee. A study comparing between
2003;70:253–8. independently using and combined using local anesthetic.
Couceiro 2003 {published data only} Japanese Journal of Medicine and Pharmaceutical Sciences
Couceiro JM, Coton F, Fernandez A, Collado A, Usabiaga 1994;32(3):507–13.
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Multicenter clinical trial on the efficacy of intra-articular Goorman SD, Watanabe TK, Miller EH, Perry C.
hyaluronic acid (Adant) in osteoarthritis of the knee Functional outcome in knee osteoarthritis after treatment
[Estudio multicentrico de la eficacia del tratamiento with hylan G-F 20: a prospective study. Archives of Physical
intraarticular con acido hialuronico (Adant) en artrosis de Medicine and Rehabilitation 2000;81:479–83.
rodilla]. Revista Espanola de Reumatologia 2003;320(2): Grecomoro 1992 {published data only}
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Grecomoro G, Piccione F, Letizia G. Therapeutic
D’Agnolo 1988 {published data only} synergism between hyaluronic acid and dexamethasone in
D’Agnolo B, Perbellini A. Intra-articular hyaluronic acid the intra-articular treatment of osteoarthritis of the knee:
treatment in gonarthritis. Results of an open trial on 30 a preliminary open study. Current Medical Research and
patients. Reumatismo 1988;40:57–64. Opinion 1992;13(1):49–55.
Dahlberg 1994 {published data only} Guerrero 1999 {published data only}
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Dahlberg L, Lohmander LS, Ryd L. Intraarticular Guerrero R, Sanchez-Pernaute O, Acebes C, Llorens MA,
injections of hyaluronan in patients with cartilage Mas S, Palacios I, et al. Modification of synovial cartilage
abnormalities and knee pain. A one-year double-blind, markers after repetitive intraarticular administration of
placebo-controlled study. Arthritis & Rheumatism 1994;37 hyaluronate (Adant) in knee OA patients. Arthritis &
(4):521–8. Rheumatism 1999;42 Suppl (9):253.
Evanich 2001 {published data only} Guerrero 1999a {published data only}
Evanich JD, Evanich CJ, Wright MB, Rydlewicz JA. Guerrero R, Herreo-Beaumont G, Acebes C, Sanchez-
[Effficacy of intraarticular hyaluronic acid injections in knee Pernaute O, Llorens MA, Blazquez AB, Palacios I,
osteoarthritis]. Clinical Orthopaedics and Related Research Egido J, Vivanco F. Cartilage turnover and symptomatic
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[Retrospective comparative analysis of the safety and efficacy Kolarz G, Kotz R, Hochmayer I. [Long–term benefits
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Osteoarthritis and Cartilage 2004;12 Suppl (2):146. hyaluronate (Hyalgan) in patients with osteoarthritis of the
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Iseki F, Hosokawa M, Shibata H, et al. Clinical study weight sodium hyaluronate (NRD101) on osteoarthritis of
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Therapeutics 1983;11(8):401(3283)–15(97). Lee 1999 {published data only}
Iwasaki 1993 {published data only} Lee S-S, Joo Y-S, Kim W-U, Park S-H, Cho C-S, Kim H-Y,
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Usefulness of sodium hyaluronate (Artz) in osteoarthritis (sodium hyaluronate) in patients with osteoarthritis of the
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combination therapy with a local anesthetic. Medical Lee 2004 {published data only}
Consultation & New Remedies 1993;30(8):1469–76. Lee S, Park D, Chmell SJ. Viscosupplementation with hylan
Johnson 2004 {published data only} G-F 20 (Synvisc). The Journal of Knee Surgery 2004;17(2):
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Mayrhofer F, Rainer F, Ramach W, Singer F, Metz M. 83-A(9):1619–23.
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Punzi L, Schiavon F, Ramonda R, Malatesta V, Gambari P,
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Russell 1992 {published data only}
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Russell IJ, Michalek JE, Lawrence VA, Lessard JA,
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the treatment of patients with osteoarthritis of the knee: intervention (NI) controlled, trial of intra-articular (IA)
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Diseases 2003;EULAR, Lisbon, Portugal, June 18-21.
features of osteoarthritis of the knee. Annals of the Rheumatic
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Sieliwonczyk 1997 {published data only}
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intra–articular steroids at 6 months]. American Academy of ∗
Torrance GW, Raynauld JP, Walker V, Goldsmith CH,
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Suzu F, Hirasawa Y. A study of the effect of high molecular
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Takeuchi 1993 {published data only}
Takeuchi H, Yamaguchi I, Morita S, Kawagoe S, Chosa E, Vad 2000 {published data only}
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Taneda 1993 {published data only}
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Taneda Y, Matsui N, Nakane K, Takai Y, Suzuki H, Hongoh
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Tang SF, Chen CP, Chen MJ, Pei Y-C, Lau Y-C,
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osteoarthritis]. Archives Physical Medicine and Rehabilitation
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Waddell 2001b {published data only}
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patients after intraarticular knee injection of hyaluronan]. 49.
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Waddell D, Rein A, Panarites C, Coleman PM, Weiss C.
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Annals of the Rheumatic Diseases 2003;EULAR, Lisbon, replacement surgery with intra–articular hyaluronic acid
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Indicates the major publication for the study

CHARACTERISTICS OF STUDIES
Characteristics of included studies [ordered by study ID]
Adams 1995
Methods Randomised
Controlled
Trial
2/3-arms blinded
Hylan G-F 20
group not blinded
Blinded assessor
Screen blinded patient
Parallel-group
Multicentre
No washout
Efficacy analysis: Per protocol: n=93
Safety analysis:
ITT
Participants Country:
Canada
Mean age:61
% Female:65
Mean disease duration:6 y
Disease duration
statistically significantly
longer for NSAID only group
Duration:12 wk
Telephone follow-up at 26 weeks
Number
randomised:102
(NSAID 34, HA 31, NSAID+HA 37)
Inclusion:
18-75 y
chronic, idiopathic knee OA on radiographic examination
Kellgren and Lawrence Grade 1 to 3 in no more than 2 compartments and not 3 in
patellofemoral
4 of 6: ESR<30mm/h, RF<1:160,
morning stiffness<=30 min, crepitus on active motion, tenderness of bony margins, MD
absence of rheumatoid disease
tolerant of NSAID for at least 30 days
using joint actively on daily basis
score >50/100 on VAS for pain on motion with weight bearing
Exclusion:
serious systemic disease, depression or neuroses
acute synovitis
excessive effusion
clinically obese

Adams 1995 (Continued)
varus/valgus of >15
pregnant or not using effective contraception
chronic daily steroid therapy
surgery or joint injection within previous 3 mths
Baseline values:
pain on motion
NSAID: 63
Hylan G-F 20: 61
NSAID+Hylan G-F 20: 60
Interventions Usual
NSAID-only + 3 weekly arthrocentesis
(NSAID-only group)
Hylan G-F 20
(2 ml) 3 weekly injections + arthrocentesis
(Hylan G-F only group),
Usual NSAID+ Hylan G-F20
(2 ml) 3 weekly injections + arthrocentesis
(Hylan G-F 20 +
NSAID group)
Concurrent therapy:
acetaminophen usage for analgesia documented in weekly diaries (pill counts)
Outcomes Pain on motion with weight bearing (100 mm VAS)-----------------

Pain at rest, night, restriction of activity, pt’s overall assessment of arthritic pain, pain during
50 foot walk, medial and lateral joint tenderness, evaluator’s overall assessment of treatment
: 100 mm VAS;
level of activity for each of standing, sitting, walking, climbing stairs (1=never able to
perform,2=occa-
sionally able to perform,3=fre-
quently able to
perform); pt. pain severity (1=none,
2=only on starting activity after rest,3=during day when active,4=during day at rest,5=all
day and waking pt at night); support used; level of activity for running; 50 foot walk time,
evaluator scored effusion, medial and lateral joint tenderness, pain while walking, overall
assessment, 50 foot walk time on 100 mm VAS
Assessments:
Wk 0,
1(baseline),
2,3,7,12,26
Notes Jadad’s:3/5
R-2,B-0,W-1
13 pts had bilateral OA,
both treated but only most painful evaluated for efficacy while both evaluated for safety.
Arthrocentesis with removal of effusion if present before treatment.
15% subjects presented wtih an effusion.
Incomplete blinding of hylan G-F 20 only group with instruction to discontinue NSAID
therapy may have introduced bias.

Adams 1995 (Continued)
Work supported by Biomatrix, Inc.
Risk of bias
Bias Authors’ judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
Altman 1998
Methods Randomised
Controlled
Trial
Double-blind
Masked observer
Parallel-group
Multicentre (n=15)
Double-dummy
Stratified by pain severity
Placebo and
naproxen controlled
2 week washout
Both per protocol n=333 (HA 105, PL 115,
naproxen 113) and post-hoc ITT analyses
United States
Mean age:64
% Female:58
Mean disease duration:NR
Duration:26 wk
Number randomised:495
(HA 164, PL 168, naproxen 163)
Inclusion:
>= 40 y
knee OA (ACR criteria)
knee pain >= 1 y
knee pain >= 20/100 mm VAS on 50 foot walk
pain >= 20 mm on >= 1 WOMAC pain items
moderate or marked pain on 6 point categorical scale
xray >= 1 osteophyte and Kellgren and Lawrence Grade 2 to 3
no prior IA HA within 1 y
no other IA injection within 3 mth
Exclusion:
NR
Baseline values:
50 foot walk pain HA: 54
PL: 55

Altman 1998 (Continued)
Naproxen: 54
Interventions Hyalgan 2 ml (20 mg) 5 weekly injections in

saline vehicle
+lidocaine and SF aspiration
+oral placebo bid
Placebo=lidocaine + SF aspiration
+ 2 ml saline 5 weekly injections
+oral placebo bid
naproxen 500 mg bid + lidocaine ( 5 weekly sham injection) + SF aspirated only if effusion
Concurrent therapy:
acetaminophen 2000 mg daily per-
mitted, aspirin <=
650 mg permitted
Outcomes Pain on 50 foot walk on 10 cm VAS immediately after walk-----------------

Pt. and observer global assess-
ments of knee pain six point categorical scale
(none,slight,mild,
moderate,
marked)
50 foot walk time
WOMAC VAS
heel to buttock distance (cm)
knee range of motion (degrees)
by goniometry
midpatellar knee circumference
synovial effusion (presence/absence)
acetaminophen tablet count
overall evaluation of treatment by pt. and observer
Notes Jadad’s:4/5
R-1,B-2,W-1
Worse knee selected for study if bilateral.
Sponsored by Fidia Pharma-
ceutical Corporation.
R. Fiorentini (Fidia) provided guidance. F. Dosey & F.
Patarnello (Fidia) provided statistical support. D. Westcott (Fidia) provided secretarial
assistance.
Comparison of the decrease from baseline from the HA versus PL revealed a difference of
only 1.5 mm, which was not statistically significant, therefore because statistical significance
for this ITT analysis was not achieved, the data for all 2o effectiveness variables was analysed
only for completers (333/495)
Risk of bias

Allocation concealment (selection bias) Unclear risk B - Unclear
Altman 2004
Methods Randomised
Controlled
Trial
Double blind
Multicentre (n=18)
1 wk washout NSAID
Canada (6 sites),
Sweden (5 sites),
United States (7 sites)
Mean age: 63.1
% Female: 55
Mean disease
duration: 5.75 y
Duration: 26 wk
Number randomised: 347
(HA 173, PL 174)
Inclusion:
OA of the knee as defined by the ACR criteria that was refractory to non-pharmacologic
therapies,
a WOMAC pain subscale score greater than or equal to 7 in one knee and no greater than
15 in either knee (range 0 to 20 Likert scale),
significant knee pain in the signal knee for the majority of the preceding 3 mth,
pts had to be normally active and able to walk 50 m unaided
Exclusion:
Isolated patello-
femoral OA, use of systemic steroids, glucosamine or chondroitin within the past 3 mth,
intra-articular injection into the knee of corticosteroids in the past 3 mth or intra-articular
HA within the last 9 mth,
treatment with oral or topical NSAIDs during the previous wk,
use of topical non-NSAIDs within the previous 3 days,
arthroscopy or other surgical procedure within the last 12 mth and anticoagulant treatment
(except acetylsalicyclic acid less than or equal to 325 mg per day),
presented with a systemic active inflammatory condition or infection,
septic knee arthritis within the previous 3 month,
significant venous or lymphatic stasis of the legs, active skin disease or infection at the
injectione site, or any other medical condition rendering the pt unsuitble for inclusion
according to the investigator, pregnant or breast-feeding women and those of childbearing
potential not practicicing adequate contraception
Baseline values:
WOMAC pain:
HA: 9.90, PL 10.42
WOMAC stiffness

HA: 3.91, PL 4.30

WOMAC function
HA: 30.70
PL: 32.16
Pt global
HA: 3.23
PL: 3.17
SF-36 physical component summary
HA: 33.54,
PL: 32.91
SF-36 mental component summary
HA: 55.55,
PL: 55.92
Interventions NASHA (non-animal stabilized hyaluronic acid) Durolane, a single 3 ml injection con-
taining HA 60 mg in buffered sodium chloride 0.9% (pH 7),
Placebo: saline, identifical buffered sodium chloride vehicle
Both NASHA and saline supplied in identical 3 ml syringes; an 18-22 G needle
Concurrent therapy: acetaminophen (paracetamol maximum daily dose 4 g) was permitted
as rescue medication except during the 48 h period prior to each study visit
Outcomes Responder (positive response to treatment) was defined as a reduction in the WOMAC
pain score of at least 40% with an absolute improvement of at least 5 points compared with
baseline for the study knee at the final visit------------
WOMAC stiffness, WOMC physical function score,
pt assessment of global disease status ona 5-point scale,
SF-36
Notes Jadad’s: 5/5

R-2, B-2, W-1
This study was supported by Q-Med AB, Uppsala, Sweden.
Formal statistical comparison of groups at baseline not completed, but authors noted there
was a trend towards higher WOMAC pain, stiffness and function scores in PL group and
also more females than males in the PL group, and also higher incidence of joint effusion
in PL group
Risk of bias

Ardic 2001
Methods See
Cubukcu 2004
Participants
Interventions
Outcomes
Notes
Risk of bias
Allocation concealment (selection bias) Unclear risk D - Not used
Atamaz 2004
Methods See
Atamaz 2005
Participants
Interventions
Outcomes
Notes
Risk of bias
Atamaz 2005
Methods Controlled
Trial
Single blind
Single centre
1 wk washout
Turkey
Mean age: 60.5
% Female: 81.7
Mean disease duration: NR

Atamaz 2005 (Continued)
Number enrolled: 85 of whom 3 did not meet inclusion criteria leaving number randomised:
82
(Group 1 - 40;
Group 2 - 42)
Inclusion:
age 40 to 80 y,
clinically (criteria of the ACR) and radiological (grade 2 or 3 on Kellgen-Lawrence) OA of
the knee for at least 6 months duration
Exclusion:
had received intra-articular injection in the joint and/or attended to physiotherapy on the
affected knee within 6 months prior to study, history of allergy or hypersensitive to drugs
or eggs, ascertained or suspected pregnancy or lactating, known or suspected joint infection
or a specific condition (neoplasm, diabetes mellitus, paresis, osteonecrosis, recent trauma)
or poor general health status that would interfere with the functional assessments during
the study
Baseline values:
WOMAC pain
OR: 13.4
SY: 12.4
PT: 14.2
Spontaneous pain (VAS)
OR: 70.3
SY: 85.0
PT: 93.5
SF-36 pain
OR: 36.4
SY: 25.6
PT: 29.6
WOMAC function
OR: 41.5
SY: 58.3
PT: 49.9
SF-36 physical function
OR: 44.5
SY: 35.5
PT: 31.7
15 meter walking time
OR: 24.4
SY: 22.8
PT: 22.5
Range of motion
OR: 118.6
SY: 123.0
PT: 121.3
Stiffness (minutes)
OR: 9.6
SY: 6.5
PT: 10.5

Atamaz 2005 (Continued)
Peripheral measurement of knee (centimetre)

OR: 42.6
SY: 41.0
PT: 41.2
Interventions Group I: (hyaluronan or hylan G-F 20):

HA intraarticular injection (Orthovisc 15 mg/2 ml) or hylan G-F 20 (Synvisc 16 mg/2
ml) 3 weekly injections at day 0, 7, 14 and then on 6th month for a total of 4 injections;
if effusion present joint was aspirated; all injections given by same physicians using aseptic
procedures
Group II: Physical therapy five times a week at day 3 weeks with a series of infrared, short-
wave diathermy pulsed patterns and interferential therapy; each of which were continued
approximately 20 seconds with a total one hour
Concurrent therapy:
Paracetamol (to a maxium of 2 g daily) as considered appropriate by the physician
Outcomes Range of motion (flexion with a goniometer), time to walk a distance of 15 m (seconds)
, amount of soft tissue swelling and swelling and synovial effusion (measured by a meter
on volar patellar area and noted if patellar click sign was present b bimanual examination)
, spontaneous day pain (100 mm VAS), night pain, pain at rest, pain on movement, pain
on touch assessed by a 4-point scoring system where 0= no pain, 1= slight pain, 2=
moderate pain, 3=strong pain,
WOMAC OA Index, SF-36

R-1, B-0, W-1
No industry funding; supported by University.
Risk of bias
Auerbach 2002
Methods Randomised
Controlled
Trial
Germany
Mean age: 47
% Female: 51
Disease duration: NR
Duration: 1 y
(HA 56, O2 53)
Inclusion: NR

Auerbach 2002 (Continued)
Exclusion: NR
Baseline values:
Rest pain:
GF: 29.03
O2: 28.89
Movement pain:
GF: 58.57
O2: 47.40
WOMAC Pain
GF: 8.2
O2: 6.8
WOMAC Function
GF: 22.5
O2: 20.6
WOMAC Stiffness:
GF: 2.7
O2: 2.7
Interventions Hylan G-F 20 3 weekly injections + exercise programme,

IA gaseous oxygen + exercise programme
Outcomes Pain at rest and under strain (100 mm VAS),

WOMAC OA Index,
Lysholm score,
Tegner Activity Index
Notes Jadad’s:2/5
R-1,B-0,W-1
Risk of bias
Auerbach 2002a
Methods See Auerbach 2002.
Participants
Interventions
Outcomes
Notes
Risk of bias

Auerbach 2002a (Continued)
Bayramoglu 2003
Methods Randomised
Controlled
Trial (Pilot study)
Parallel-group
Blinded technician (muscle strength)
Single centre
Per protocol n=37 (OR 16, GF 12, PT 9)
Turkey
Mean age: 62
% Female: 95
Mean disease duration: 5.8 y
Duration: 3 mth
(OR 16, GF 15,
PT 15)
Inclusion:
presence of definite osteo-
phytes in medial and/or lateral tibiofemoral compartment,
pain and/or difficulty in activities of daily living due to knee OA
Exclusion:
ia corticosteroid injection into either knee within 3 mth prior to study,
uncomplicated knee surgery within 6 mth of study,
complicated knee surgery within previous y,
bilateral or unilateral TKA,
history of avascular necrosis, RA or any other systemic inflam-
matory arthropathy,
periarticular fracture,
Paget’s disease,
villonodular synovitis, joint infection, ochronosis, neuropathic arthropathy, acromegaly,
hemochroma-
tosis, gout or recurrent pseudogout and osteopetrosis
Baseline values:
Lequesne
OR: 12.4
GF: 12.8
PT: 11.6
Interventions Orthovisc once per wk for 3 wk plus 3 wk physical therapy programme,

Hylan G-F 20 once per wk for 3 wk plus 3 wk PT,
PT alone (deep tissue heating with short-wave diathermy, TENS and exercises.

Bayramoglu 2003 (Continued)
All groups were to continue resistive exercises at home.
Outcomes Lequesne Index

Range of motion
static knee stability in frontal and sagittal planes, existing deformities assessed,
x-ray Kellgren and Lawrence grading,
flexor and extensor muscle strength by computerised isokinetic dynamometer
Notes Jadad’s:2/5
R-1,B-0,W-1
From publication, blinded technician only assessed muscle strength outcome.
Bilateral OA in 12 OR, 8 GF, 9 PT
and injections performed ”accordingly“.
Risk of bias
Bragantini 1987
Methods Randomised
Controlled
Trial
Single-blind
Parallel-group
Single centre
3 mth washout of IA treatments
Per protocol
analysis, n=52
Italy
Mean age:57
% Female:75
Mean disease
duration:44%
1-5 y
Duration:60 days
[57 joints:HA40 20, HA20 19, PL 18]
Inclusion:
knee OA on basis of clinical & radiological
(Kellgren Grade 2 to 4)
findings
Exclusion:
NR

Bragantini 1987 (Continued)
Interventions Hyalgan 40 mg
3 weekly injections
Hyalgan 20 mg
3 weekly injections
Placebo = saline 2 ml 3 weekly injections
Concurrent therapy:
Not reported
Outcomes Spontaneous pain on 10 cm VAS, walking and under load pain on 1-5 scale
(1=none, 5=severe), pt. and MD global assessment on 1-5 scale (1=very poor, 5=very good)
Notes Jadad’s:2/5
R-1,B-0,W-1
5 pt had bilateral OA - knees treated at different times.
A. Perbellini (Fidia S.p.A.)
C. Baggio and E. Palin provided statistical analysis. A. Babolin provided secretarial assistance
Risk of bias
Brandt 2001
Methods Randomised
Controlled
Trial
Parallel-group
Double blind
Masked observer
Adverse events monitor
Placebo-controlled
Multicentre (n=10)
2 wk washout
Per protocol analysis, n=181
Post-hoc retrospective subgroup effectiveness population, n=135 (OR 66, PL 69)
ITT (safety)
United States
Mean age: 66
% Female: 63
Duration: 27 wk
(OR 114, PL 112)
Inclusion:

Brandt 2001 (Continued)
idiopathic knee OA
Kellgren and Lawrence Grade 2 or 3
significant pain (WOMAC pain >= 13/20) in index knee
WOMAC pain <13/20 in contra-
lateral knee
able to walk 50 ft unassisted
discontinue anal-
gesics (2 wk) and NSAIDS for 5 half-lives
not pregnant or planning a pregnancy
Exclusion:
contralateral knee WOMAC pain score >= 13/20
contralateral knee Kellgren and Lawrence < Grade 4 in either knee
initiation of quads exercise within 4 mths
oral or IM steroid use within 2 mth
IA injection of HA within 21 y
allergy to lidocaine
clinically signifi-
cant comorbidity (renal/hepatic) or abnormal lab tests
treatment with anticoagulants, immunosuppressives or muscle
relaxants
inability to tolerate aceta-
minophen
Baseline values:
WOMAC pain
OR:16.4, PL:16.3
WOMAC stiffness
OR: 7.0, PL: 6.8
WOMAC function
OR: 54.8,PL:54.5
Interventions Orthovisc 15 mg/ml

2 ml once per week
3 weekly injections
plus 1% lidocaine HCI 3-5 ml
Placebo: Saline 2 ml 3 weekly injections
plus 1% lidocaine HCI 3-5 ml
Concurrent therapy:
acetaminophen max
of 4 g/day; however not 24 hr before visit
Outcomes WOMAC pain (5-25)

pain on standing
pt and investigator global assessment
WOMAC stiffness (2-10) and function (17-85)
pain after a 50 foot walk (1=none,2=mild,3=moderate,4=severe,5=extreme)
time to walk 50’
vital signs, labs, MedDRA adverse events

Brandt 2001 (Continued)

R-1,B-2,W-1
Treated index knee exclusively
Bilateral OA in 89 OR and 99 PL pts.
Effectiveness population: completed minimum of 15 wks, no major protocol violations,
WOMAC pain score for contra-
lateral knee <12
Severity of contra lateral knee pain confounded out-
come measure-
ment in the index knee.
Supported in part by a grant from Anika Thera-
peutics, Inc. Data management and statistical analyses by Boston Bio-
statistics, Inc.
Risk of bias
Brown 2003
Methods Randomised
Controlled
Trial
Parallel-group
Unblinded
England
Mean age: NR
% Female: NR
Duration: 6 wk
(Planned 6 mth)
(HA 25, GF 29)
Planned: 100
(HA 50, GF 50)
Inclusion:
knee OA
Exclusion: NR
Baseline values:
NR
Interventions Hyalgan
5 weekly injections
Hylan G-F 20

Brown 2003 (Continued)
3 weekly injections
Outcomes WOMAC OA Index
Notes Jadad’s:1/5
R-1,B-0 ,W-0
Trial discontinued due to safety concerns with Hylan G-F 20.
Risk of bias
Bunyaratavej 2001
Methods Randomised
Controlled
Trial
Double-blind
Masked observer
Placebo-controlled
Multicentre (n=3)
2 wk washout of NSAIDs
Participants Countries:
Thailand,
Hong Kong,
Malaysia
Mean age: 60
% Female: 78
Mean disease duration: 33 mth
Duration: 6 mth
(HA 24, PL 25)
[59 screened but 10 not eligible]
Inclusion:
male and female
patients between 50 to 75 yr of age
mono or bilateral congenital or locally acquired painful OA of the knee
pain on movement >40 mm on VAS scale
meet clinical and radiological ACR criteria within previous 6 mth
Exclusion:
patients with rapid, destructive or evolving arthritis requiring surgery within the following
few months
patients treated with intra-articular injection (e.g. steroids or chondroprotectives) within
previous 3 mth
patiens treated with NSAIDs in previous 7 days

Bunyaratavej 2001 (Continued)
those with painful knee conditions not due to OA such as Sudeks atrophy, i-a neoplasm,
villonodular synovitis and Paget’s disease and those with recent knee trauma
pregnant women and women of child bearing age
Interventions Hyalgan 20 mg/

2 ml
4 injections
(Days 0, 7, 14 and 21)
Saline solution
2 ml
Concurrent therapy: paracetamol maximum of six 500 mg tablets daily and number taken
recorded
Outcomes Pain on movement (100 mm VAS), day pain (100 mm VAS), night pain, pain on touch, joint
circumference (mm), intake of paracetamol tablets (mg/day), overall efficacy judgement by
patient and investigator
morning stiffness
joint extension

R-1,B-2,W-1
If bilateral, only the most severely affected knee was treated
Risk of bias
Caborn 2003
Methods See Caborn 2004.
Participants
Interventions
Outcomes
Notes
Risk of bias

Caborn 2004
Methods Randomised
Controlled
Trial
Single-blind
(Blinded evaluator)
Parallel-group
Multicentre (n=14)
ITT analysis n=215,
Safety analysis n=216,
Valid for efficacy n=177
United States
Mean age: 63
% Female: 57
Duration: 26 wk
(HA 113, TH 105)
Inclusion:
ambulatory males and females
>= 40 yrs of age
in generally good health
diagnosed with knee OA (ACR criteria) at least 3 mth prior to study entry, required to have
been taking analgesics/
NSAIDs to control knee pain at least 3 days/wk for a minimum of 2 mth before study
entry
score >= 2 on Q1 of WOMAC Pain subscale at screening,
score of 50-90/100 mm VAS on both pt and investigator overall assessment,
females of child-
bearing potential required to use adequate means of contraception.
Exclusion:
any unstable medical condition,
acute synovitis, allergy to avian products/hyaluronan-based injection components/corti-
costeroid injections/acetaminophen, inflamatory arthropathy or infection in the area of the
injection site, a clinical diagnosis of primarily patello-
femoral knee pain,
effusion of >10 ml at screening or baseline,
venous or lymphatic statis in the leg,
claudication or peripheral vascular disease, malignancy within 5 y, diabetic neuropathy or
related infections, laboratory abnormalities
use of glucosamine and/or chondroitin sulfate prohibited,
exposure to prior viscosupplementation in target knee,
oral corticosteroids or IA corticosteroid injection of a target knee within 3 mth of screening
or a nontarget joint within 4 wk,
pts with a history of target joint arthroplasty
Baseline values:
WOMAC Pain Ql:
HA: 2.12

Caborn 2004 (Continued)
TH: 2.15
Pt VAS score:
HA: 68.4
TH: 67.3
Iv VAS score:
HA: 69.0
TH: 69.6
WOMAC Pain:
HA: 10.7
TH: 10.4
WOMAC Stiffness:
HA: 4.7
TH: 4.9
WOMAC Function
HA: 38.6
TH: 37.9
WOMAC Total:
HA: 54.0
TH: 53.1
% pt analgesics:
HA: 98.2
TH: 97.1
Interventions Hylan G-F 20

(Synvisc) three weekly injections.
Triamcinolone hexacetonide (Aristospan) a single ia injection of 40 mg (2 ml of a 20 mg/
ml suspension).
Injection approach not standardised.
18-22 gauge needle used. Subcutaneous local anaesthetics and anaesthetic skin spray were
permitted.
Concurrent therapy: Medications for preexisting conditions were permitted. Except for
within 24 h of study visit, the following oral pain medications were allowed: acetaminophen
(up to 4000 mg/day); analgesics or short-acting NSAID with a washout of at least 24 h
(according to product labelling) for pain other than in the target knee, but not for more
than 3 consecutive days or 10 days per month, and low dose aspirin (<= 325 mg/day) for
antithrombotic prophylaxis.
NSAID with once-daily dose regimens were prohibited.
Longer-acting analgesics and NSAID (e.g. rofecoxib) were to be discontinued at least 7
days before baseline and not permitted during the study
Outcomes Pain walking on a flat surface (WOMAC Pain Q1), Pt and investigator overall assessments
(0-100 mm VAS)
-----------------------
WOMAC total score (0-96),
WOMAC pain
(0-20), WOMAC stiffness (0-8),
WOMAC physical function subscale (0-68),
use of analgesics, rate of early withdrawals, responder rate (pt improved from baseline by
at least one point on WOMAC Q1 at a given visit)

Caborn 2004 (Continued)
Notes Jadad’s:2/5
R-1,B-0,W-1
If effusion present, aspirated and assessed for infection & crystals.
Fourth author, D. Parenti is Asst. VP of Musculoskeletal Products, McNeil Pharmaceuticals,
5th author, C.W. Murray is Director of Musculoskeletal Products, Wyeth Pharmaceuticals
Risk of bias
Carrabba 1995
Methods Randomised
Controlled
Trial
Double-blind
Blind observer
Parallel-group
Placebo- and arthrocentesis- controlled
Single centre
ITT analysis
(5 inj HA versus PL)
Italy
Mean age: 60
% Female:63
Mean disease
duration: NR
Duration:60 days
Phase 1, 6 mth Phase 2
(20/group)
Inclusion:
>= 40 y
ACR diagnosis of knee OA
clinical history of
painful knee OA for > 6 mth
+ knee effusion (> 3 ml)
pain on movement (> 40/100 mm VAS)
Exclusion:
generalised OA
secondary knee OA
known or suspected joint infection
poor general health status or specific condition that would interfere with functional assess-

Carrabba 1995 (Continued)
ments
arthrocentesis and/or IA injection within 3 mth
very severe knee OA (planned intra-medicinal product)
Baseline values:
pain on movement
PL: 64.4, AR:64.5
HA1:61.7,HA3:
64.1,HA5: 63.3
Lequesne
PL:14.5,AR:14.3
HA1:14.0,HA3:
14.9, HA5:15.0
pain at rest
PL:45.6,AR:43.3
HA1:40.5, HA3:
44.7, HA5:43.6
Interventions Hyalgan 20mg/2 ml 1 injection and arthrocentesis + 4 weekly arthrocentesis,

Hyalgan 20mg/2 ml and arthro-
centesis + 2 HA weekly injections+
2 arthrocentesis,
Hyalgan 20mg/2
ml and arthro-
centesis + 4 HA weekly injections,
Arthrocentesis=5 weekly arthrocentesis,
Placebo= Arthro-
centesis and 2 ml
saline + 4 weekly saline injections
Concurrent therapy:
paracetamol permitted
Outcomes pain at rest by pt on 100 mm VAS

pain on movement by pt
on 100 mm VAS
Lequesne Index
----------------------
Range of motion by goniometer (flexion)
daily paracet-
amol consumption
presence
joint effusion (volume)
global pt and observer assessment of treatment efficacy
Notes Jadad’s:3/5
R-1,B-1,W-1
Effusions
aspirated at Visit 1, but no aspira-
tion at other visits except Day 35 (one wk after last injection) and 2 mth after beginning
of study.

Carrabba 1995 (Continued)
Dr. G.B. Guillou and Dr. E. Maheu assisted in preparing paper. J.M. Grouin (Fidia France)
provided statistical analysis
Risk of bias
Carrabba 1995a
Methods See Carrabba 1995 (HA 3 inj versus Placebo)
Participants
Interventions
Outcomes
Notes
Risk of bias
Carrabba 1995b
Methods See Carrabba

1995 (HA 5 inj versus Arthrocentesis)
Participants
Interventions
Outcomes
Notes
Risk of bias

Carrabba 1995c
Methods See Carrabba

1995 (HA 3 inj versus
Arthrocentesis)
Participants
Interventions
Outcomes
Notes
Risk of bias
Cohen 1994
Methods Randomised
Controlled
Trial
Double-blind
Blinded assessor
Placebo- controlled
Multicentre (n=4)
Participants Country: Canada and USA

Mean age: NR
% Female: NR
Duration: 8 wk
Number randomised:
(HA 19, PL 20)
Inclusion:
NR
Exclusion:
NR
Baseline values:
NR
Interventions Replasyn/
Hyalgan (20 mg)
3 weekly injections
Placebo (not specified)

Cohen 1994 (Continued)
Outcomes Knee pain when walking (100 mm VAS),

Range of motion,
WOMAC OA functional Index,
Pt and MD overall global
Notes Jadad’s:4/5
No baseline differences between groups.
Supported by a grant from Bioniche Pharm-
aceuticals, London, ON, Canada.
Risk of bias
Corrado 1995
Methods Randomised
Controlled
Trial
Double-blind
Efficacy analysis:
per protocol n=35, tolerance analysis, ITT
Italy
Mean age:61
% Female:78
Mean disease
duration:
Duration:60 days
(PL 19 / HA 21)
Inclusion:
>40 y
clinically & radio-
logically OA knee (Altman criteria) of at least 6 mth duration
>= 3 ml effusion
pain on movement >40
mm on VAS
Exclusion:
NR
Baseline values:
pain on movement
PL:62.3, HA:68.7
pain at rest

Corrado 1995 (Continued)
PL:16.8, HA:22.8
flexion
PL:113.3,
HA:114.7
Interventions Hyalgan 20 mg/2 ml after arthro-

centesis at baseline 5 weekly injections,
Placebo=0.2mg/2 ml (2 ml water with 17 mg sodium chloride, 0.1 mg monobasic sodium
phosphate, 1.2 mg bibasic sodium phosphate) 5 weekly injections
Concurrent therapy:
no painkillers during treatment
Outcomes pain on movement (100 mm VAS)-----------

pain at rest (VAS)
joint mobility on flexion
efficacy of treatment by pt and MD on 5 point scale (0=none,1=poor,2=fair,3=good,4=
excellent)
volume of joint effusion
immunological and biochemical
evaluations
Notes Jadad’s:3/5
R-1,B-1,W-1
All pts had effusion at baseline
Risk of bias
Creamer 1994
Methods Randomised
Controlled
Trial
Single-blind
Blind observer
Parallel-group
Single centre
Each pt own control
ITT analysis
England
Mean age:72
% Female:100
Mean disease

Creamer 1994 (Continued)
duration:22 y
Duration:9 wk
(HA 12 knees,
PL 12 knees)
Inclusion:
use-related pain in both knees
no steroid injection at least 3 mths prior to study
xray evidence of OA (joint space narrowing + sclerosis
or osteophytosis,
Kellgren and Lawrence Grade 2 to 4)
presence of bi-
lateral synovial
effusions as judged clinically
Exclusion:
NR
Baseline values:
rest pain
HA:10/12,
PL: 10/12
night pain
HA:7/12, PL:9/12
EMS
HA:10, PL:6 min
Inactivity stiffness
HA:4.1,PL:4.0min
Interventions Hyalgan (20mg/2 ml) 5 weekly injections

Placebo= 2 ml
saline 5 weekly injections
Concurrent therapy:
paracetamol 4000 mg daily permitted
Outcomes use-related pain (100 mm VAS)

rest and night pain (present/absent)
duration of early morning stiffness and inactivity
stiffness
pt opinion of disease severity
(none,mild,moderate,severe)
pt choice of worse knee
pt preferred treatment
pt overall change in each knee
Synovial fluid keratan sulfate
RF, CRP, plasma
viscosity, chondroitin sulfate 3B3, CPII
Notes Jadad’s:2/5
R-1,B-0,W-1
All bilateral knee OA with effusions

Creamer 1994 (Continued)
synovial fluid aspirated prior to each

injection
Wk 0-4 max 5ml
Wk 5 and 9 aspira-
ted to dryness.
Study not designed to assess clinical efficacy (cf small patient numbers and advanced disease)
Work was partially supported by a grant from Fidia SpA.
Risk of bias
Cubukcu 2004
Methods Randomised
Controlled
Trial
Placebo controlled
Single centre
Turkey
Mean age: 55.1
% Female: 80
Duration: 8 wk
(HA 20 (30 knees), PL 10 (10 knees))
Inclusion:
fulfill ACR criteria for knee OA with radiological evidence and symptoms
knee pain persisting for more than one year and pain >40/100 (VAS) for more than 15
days in the last month
Exclusion:
any other serious systemic diseases, depression, avian allergy, other arthropathies, neo-
plasms, recent trauma, knee instability, effusion in the knee, a varus or valgus deformity of
>15 degrees, flexion contracture of >20 degrees,
had received intraarticular corticosteroids within the 6 mth prior to start of study
Baseline values:
Walking pain
HA: 71.0,
PL: 67.0
Night pain
HA: 45.0
PL: 54.0
Rest pain
HA: 46.7

Cubukcu 2004 (Continued)
PL: 51.0
Need for paracetamol
HA: 1.0
PL: 0.9
WOMAC pain
HA: 15.7
PL: 17.6
WOMAC stiffness
HA: 6.3
PL: 6.1
WOMAC function
HA: 49.6
PL: 47.8
15 m walk time
HA: 20.6
PL: 17.9

(2 ml 10 mg/ml) (Synvisc) 3 weekly injections,
Saline 2 ml
3 weekly injections
Both medial approach, after injection, knees wrapped with bandage and patients instructed
to rest for 24h.
Concurrent therapy: Paracetamol permitted for analgesia. No additional physiotherapy or
anti-inflammatory drugs
Outcomes Pain at rest, at night and on walking (0-100 mm VAS), WOMAC pain (5-25), WOMAC
stiffness (2-10), WOMAC physical function (17-85), walking time for 15 m, need for
paracetamol, evaluation of treatment by patient (1=treatment is not effective, 2=less effec-
tive, 3=effective, and 4=very effective)

R-1, B-0, W-1
If bilateral, both knees injected.
Risk of bias
Day 2001
Methods See Day 2004
Participants
Interventions

Day 2001 (Continued)
Outcomes
Notes
Risk of bias
Day 2004
Methods Randomised
Controlled
Trial
Double-blind
Parallel-group
Multicentre (n=17)
1 wk washout
Efficacy analysis:
both per protocol n=208, modified ITT n=223
Safety analysis:
ITT, n=223
Australia
Mean age: 62
% Female: 56
Duration:18 wk
(HA - 116, PL 124)
Inclusion:
40-75 y
BMI < 40
appropriate contraception
mild to moderate idiopathic painful femoro-tibial OA knee defined by:
knee pain while standing, walking and/or in motion of at least 3 mth duration, >=1 features
on xray in past 6 mth: femoro-tibial, osteophytes, osteosclerosis of femoral or tibial endplates
or JSN
unilateral or predominantly unilateral symptomatology
informed written consent
willing to discontinue current OA treatment for study
Exclusion:
pregnant and lactating females
severe malalignment of knee
severe, tight effusion
clinical manifestations of OA of the hip and/or history of joint replacement in lower

Day 2004 (Continued)
extremities
history of surgery on knee within last 12 mth or arthroscopy within last 6 mth
IA injection or treatment with long-acting OA therapy in previous 3 mth
Baseline values:
WOMAC pain
HA: 7.96
PL: 8.68
WOMAC function
HA: 28.07
PL: 31.25
WOMAC stiffness
HA: 3.70
PL: 3.79
Interventions Artz (25mg/2.5 ml)

5 weekly injections
local anesthesia 1% xylocaine,
Placebo= phosphate buffered saline vehicle (2.5 ml) 5 weekly injections
Concurrent therapy:
paracetamol, standard physical therapy exercises
permitted
Outcomes WOMAC -----------

Lequesne Index
knee examination (4 point categorical scale for pain, stiffness, effusion and range of motion)
pt and MD global assessment
paracetamol consumption
Notes Jadad’s:5/5
R-2,B-2,W-1
Bilateral disease in 66% Artz and 64% PL.
Effusions were aspirated.
Work was supporated by Seikagaku Corporation. Test medications provided by Seikagaku.
A CRO,
Omnicare Clinical Research, was responsible for management, monitoring and safety re-
porting of study. Study statistician was Dr. Philip McCloud and associates of the Monash
University Statistical Consuting Group
Risk of bias

Dickson 2001
Methods Randomised
Controlled
Trial
Double-blind
Blind observer
Parallel-group
Multicentre
(n=18)
3-7 day washout
Efficacy analysis:
both ITT n=165 and per protocol n=134
Safety analysis:
ITT
England and
Scotland
Mean age:63
% Female:53
Mean disease
duration:NR
Duration:12 wk
(HA - 53, DI - 55, CN - 57)
Inclusion:
35-80 y
radiologically
confirmed knee OA (tibofemoral compartment) and no other OA joint likely to warrant
escape analgesia
knee had to be most painful joint
xray report <2 y
end of washout 2/5 WOMAC pain >40/100 mm VAS
Exclusion:
bed ridden pts
pts in wheelchair
or unable to walk 50 steps unaided
other jt disease
clinically significant renal, hepatic or haematological disorders
any contraindication to study treatments
Baseline values:
WOMAC pain
HA:59, DI:61, CN:58
WOMAC function
HA: 54, DI: 56,
CN: 56
Lequesne
HA: 13.9, DI: 13.9
CN: 14.5

Dickson 2001 (Continued)
Interventions Hylan G-F 20 (2 ml) 3 weekly injections+arthro-

centesis + placebo capsules od
Diclofenac retard
100 mg od + arthrocentesis
Control: Arthro-
centesis + placebo capsules od
Concurrent therapy:
paracetamol 3000 mg daily permitted
Outcomes WOMAC pain subscale-----------

WOMAC stiffness
and function
Lequesne Index
pt. and blinded observer overall opinion of treatment (5-pt verbal scale:very
poor, poor, fair,
good,very good)
Assessments:
Wk 0,1,2,4,8,12
Notes Jadad’s:4/5
R-1,B-2,W-1
17 bilateral
injections
target knee
Arthrocentesis removing all joint
fluid in all 3 groups.
At end of 12 DBRCT, patients could enter an open label one-year extension study in which
they could receive up to four repeat courses of Hylan G-F 20.
Syntex Pharma-
ceuticals Ltd. and Roche Products Ltd provided financial support. Biomatrix, Inc. supplied
hylan G-F 20 and Dr. Arnold Goldman provided statistical analysis
Risk of bias

Dougados 1993
Methods Randomised
Controlled
Trial
Single-blind
Parallel-group
Multicentre
Placebo- controlled
Efficacy analysis:
per protocol n=95, ITT done to check consistency of
per protocol
France
Mean age: 68
% Female:71
Mean disease duration:
Duration: 1 y
(HA 55, PL 55)
Inclusion:
ACR criteria for
knee OA
Femorotibial localisation of disease
+ knee effusion
painful knee (>= 40/100 mm VAS)
stable dose of OA therapy for 3 mth
NSAID, analgesics, physiotherapy stable for one mth
Exclusion:
serious concomitant illness
secondary OA of knees by ACR
knee with prothesis
any IA surgery of evaluated knee,
menisectomy in 10 y prior
any extra-articular surgery of evaluated knee,
osteotomy last 2 y
arthrocentesis of evaluated knee in previous 3 mth
Baseline values:
Lequesne
HA:11.6, PL:10.9
Pain at rest
HA:31.4, PL:28.0
Pain after exercise
HA:67.6, PL:61.9
Interventions Hyalgan (20 mg/2ml) 4 weekly injections

Placebo:saline vehicle (2 ml) 4 weekly injections
Concurrent therapy:
previous treatment continued at same dose schedule; between Wks 7-52, corticosteroid
injection, SF aspira-
tion, total knee re-
Dougados 1993 (Continued)
placement allowed
Outcomes degree of inflam-

mation by presence and amount of synovial fluid effusion by
arthrocentesis----
pain at rest and after exercise on 100 mm VAS
Lequesne Index
overall pt and MD assessment
requirement for local therapies between Wk 7 & Wk 52 (number and time)
Notes Jadad’s:2/5
R-1,B-0,W-1
The MD who did injection was also the assessor and therefore may not have remained
blind.
Dr. G.B. Buillou and J.M. Grouin (Fidia, France) provided statistical analysis. Helpful
assistance from: V. Figeac, C. Strauss, C. Kubiak, and N. Chevalier
Risk of bias
Formiguera Sala 1995
Methods Randomised
Controlled
Trial
Double-blind
Placebo- controlled
Single centre
Washout
ITT analysis
Spain
Mean age: 62
% Female:73
Mean disease
duration:
Duration:90 days
[40 jts: HA 20, PL 20]
Inclusion:
adult pt. with mono or bilateral knee OA
painful limitation
of movement
narrowing of femorotibial space and osteophytes, subchondral sclerosis or cysts

Formiguera Sala 1995 (Continued)
Exclusion:
secondary knee OA
nonarthritic arthropathies
large volume of joint effusion
severe systemic diseases
pregnancy or lactation
inexplicable biochemical or
haematological
abnormalities
Interventions Hyalgan (20mg/2ml)

5 weekly injections
Placebo: saline
(2 ml) 5 weekly
injections
Concurrent therapy:
not reported
Outcomes pain on walking--

spontaneous pain, pain on load, pain on palpation:100 mm VAS
active and passive
flexion in degrees
pt and MD overall judgement on evolution of disease
standard severity scale (0-25) for level of pain, max
distance walked and activities of daily living
Notes Jadad’s:3/5
R-1,B-1,W-1
Most cases ”dry“ knees.
4 pts bilateral knee OA with second knee treated some time after first
Risk of bias
Forster 2003
Methods Randomised
Controlled
Trial
Single centre
Parallel-group
England
Mean age: 62

Forster 2003 (Continued)
% Female: NR
Duration: 1 yr
(HA 19, AR 19)
Inclusion:
Symptomatic knee OA with radiographic evidence of some remaining joint space on weight
bearing films
Be fit for regional or general anaesthesia.
Exclusion:
Pts with mechanical symptoms
IA injection within last 6 mths
Previous arthro-
scopic surgery
Hypersensitivity to avian proteins
Baseline:
Pain
HA: 7.6
AR: 7.5
Lequesne
HA: 10.5
AR: 13.0
Knee Society ftn:
HA: 65
AR: 45
20 mg
5 weekly injections
Arthroscopic washout with either general or spinal anaesthesia 2 l 0.9% saline at least
Outcomes Pain (10 cm VAS)

Function score from the Knee Society rating system
Lequesne
Notes Jadad’s:3/5
R-2,B-0,W-1
The Knee Society function score was significantly worse in the AR group at baseline
Risk of bias

Forster 2003a
Methods See Forster 2003
Participants
Interventions
Outcomes
Notes
Risk of bias
Frizziero 2002
Methods Randomised
Controlled
Trial
Single-blind
Blinded assessor for
arthroscopic assessment.
Parallel-group
Single centre
Italy
Mean age: 50
% Female: 53
Mean disease
duration: 25 mth
Duration: 6 mth
(HA 52, MP 47)
Inclusion:
Outpatient re-
ferred to Rheumatology
Unit for OA over a 3 yr period
Primary OA or OA secondary to traumatic events to the knee.
Kellgren and
Lawrence Grades I to III
Fulfill clinical and radiological criteria of ACR
Exclusion:
Pt judged not
controllable or
unreliable.
Presence of severe concom-

Frizziero 2002 (Continued)
itant diseases,
suspected joint infection.
Concomitant treatment with NSAID
IA steroid treatment in previous 3 mth
Pregnancy and breast feeding
Baseline:
Pain after spontaneous movement:
HA: NR
MP: NR
Pain after forced movement
HA: NR
MP: NR
(20 mg/2ml)
5 weekly injections
Methylpredniso-
lone acetate
3 weekly injections
Outcomes Noctural pain,

pain at rest,
pain on spontan-
eous or forced
movement,
pain on touch (all on 100 mm VAS)
morning stiffness (min),
joint motion
(max active flexion/extension)
pt and MD opinion of efficacy (0=poor (unsatisfactory),
1=scarce,2=fair,
3=good,4=excel-
lent)
use of analgesic
or NSAID
cartilage damage (modified version of the Outer-
bridge & Noyes scales): degree of cartilage damage (5 point scale) and extent of cartilage
lesions
(6 point scale)
Notes Jadad’s:4/5
R-2,B-1,W-1
When OA was bilateral, most severely affected knee selected for treatment
Risk of bias

Frizziero 2002 (Continued)
Graf 1993
Methods Randomised
Controlled
Trial
Single-blind
Parallel-group
Verum- controlled
ITT analysis
Germany
Mean age: NR
% Female:55
Mean disease
duration:
Duration: 6 mth
(HA 33, MPA 27)
Inclusion:
outpatients
>= 18 y
clinical & radiological signs of OA
written informed consent
Exclusion:
radiographically
no cartilage lesions
arthropathy other than OA
tubercular osteopathy
peripheral neuropathy with pain
severe, decompensated
concomitant disease
pregnant/nursing
recd IA corticosteroids in last 3 mth or NSAID within 14 days
Baseline values:
pain
HA: 14.1,
MPA: 16.2
function
HA: 18.0,
MPA: 16.9
ROM
HA: 8.8,
MPA: 8.7
Larson

Graf 1993 (Continued)
HA: 45.7,
MPA: 46.6
Interventions Hyalgan (20mg/2ml) once a wk for 6 wk - 7 injections

Mucopolysacchar-
ide polysulfuric
acid ester (MPA)
50mg/1 ml twice/wk -
13 injections over 6 weeks
Concurrent therapy:
no additional anal-
gescis, NSAIDS, physical therapy
Outcomes Larson rating scale shortened (77 points:pain severity (0-30), ROM (0-10), function (0-
30), anatomy (0-7))
extension deficit
crepitation
ligament loosening
extensor & flexor
muscle strength
pt & MD global:
unchanged,
slightly improved,
significantly
improved, and
symptom-free
Notes Jadad’s:2/5
R-1,B-0,W-1
Risk of bias
Grecomoro 1987
Methods Randomised
Controlled
Trial
Double-blind
Parallel-group
Placebo- controlled
Single centre,
ITT analysis

Grecomoro 1987 (Continued)
Participants Country: Italy

Mean age:65
% Female:56
Duration:60 days
[40 jts: HA 20, PL 20]
Inclusion:
gonarthrosis
pain with clinical signs, e.g. limitation of joint function and of unaided walking
Exclusion:
NR

3 weekly injections
Placebo: phosphate buffer
2 ml 3 weekly injections
Concurrent therapy:
not reported
Outcomes spontaneous pain intensity VAS -----------------

pain on touch
pain under load
pain while walking (1=none,
2=mild,3=moder-
ate,4=severe,5=
very severe)
Notes Jadad’s:3/5
R-1,B-1,W-1
6 pts had bilateral disease each knee ran-
domised
Risk of bias
Groppa 2001
Methods Blind
Controlled
Trial
Republic of Moldova
Mean age: 61

Groppa 2001 (Continued)
% Female: 64
Duration: 1 y
(HA -?, PL-?)
Inclusion:NR
Exclusion:NR
Baseline values:
NR

3 weekly injections
Placebo
3 weekly injections
Repeat courses given at 6 and 12 months.
Outcomes Pain
Lequesne
Volume of movement on affected joints
xray parameters
functional methods (US, scintigraphy with Te99m)
Notes Jadad’s:1/5
R-0,B-1,W-0
Risk of bias
Guler 1996
Methods Randomised
Controlled
Trial
Double-blind
Placebo- controlled
Parallel-group
ITT analysis
Turkey
Mean age: NR
% Female: NR
Mean disease
duration: NR
Duration: 10 wk

Guler 1996 (Continued)
(HA 15, PL 15)
Inclusion:
Exclusion:
Baseline values:
WOMAC pain
HA: 16.87
WOMAC stiffness
HA: 6.47
WOMAC function
HA: 59.00
Interventions Orthovisc 15 mg/ml

2 ml once per week for 3 weeks
Placebo: physiologic saline 2 ml
Concurrent therapy: acetaminophen use recorded
Outcomes WOMAC
pain(5-25),
stiffness (2-10)
function (17-85)
-----------------------
quantity of acetaminophen use
time for 15 meter walk
range of joint mobility
patella ciricumference
pt assessment of degree of
arthrosis
satisfaction with
treatment

R-1,B-1,W-1
Risk of bias

Henderson 1994
Methods Randomised
Controlled
Trial
Double-blind
Blinded metrologist
Parallel-group
Placebo- controlled
Single centre,
2 wk washout
Per protocol analysis: n=84
England
Mean age: 65
% Female: 69
Mean disease
duration:NR
Duration:5 mth
(HA 45, PL 46)
Inclusion:
clinical history of knee OA
radiological evidence of knee OA (Kellgren and
Lawrence 1-4)
pain in at least one knee >= 30 mm on a VAS for at least 1/5 activities in prior 2 wk
Exclusion:
pts with inflammatory bowel disease, anserine bursitis or pain referred from other structures
(e.g. ipsilateral hip or lumbar spine)
Baseline values:
pain on active
movement
HA: mild 43.7
moderate 48.5
PL: mild 53.0
moderate 49.3
pain at rest
HA: mild 20.8
moderate 25.2
PL: mild 30.3
moderate 38.9
Interventions Hyalgan (20mg/2ml) 5 weekly injections

Placebo:saline 2 ml 5 weekly injections
Concurrent therapy:
paracetamol permitted
Outcomes daily VAS pain in the am, pm, getting up from chair, climbing stairs, painful activity, at rest
for 20 min, active and passive movement, patellofemoral tenderness, flexion by goniometer,
morning stiffness (min), interference with activity of daily living, escape analgesia count,
pt and metrologist global assessment

Henderson 1994 (Continued)
Notes Jadad’s:5/5
R-2,B-2,W-1
Most affected knee studied.
90 pts had bilateral disease
Effusions aspirated to dryness
Stratification by
xray severity
Risk of bias
Henderson 1994a
Methods See Henderson 1994 (severity group 2)
Participants
Interventions
Outcomes
Notes
Risk of bias
Hizmetli 1999
Methods Randomised
Controlled
Trial
Double-blind
Placebo- controlled
2 wk washout
Per protocol analysis (n=40)
Turkey
Mean age: 56
% Female: 68

Hizmetli 1999 (Continued)
Mean disease
duration:
Duration: 1 yr
(HA 25, PL 25)
Inclusion:
knee OA according to ACR criteria
Kellgren and Lawrence Grades 1 and 2
Exclusion:
pts who had undergone extra- or intra-articular surgery, arthrocentesis & physical therapy
Baseline values:
WOMAC pain
HA: 17.75
PL: 17.45
WOMAC stiffness
HA:5.65, PL:5.55
WOMAC function
HA:53.15,
PL:52.00
Interventions Hyaluronic acid

2 ml
Placebo: sterile physiological saline 2 ml
Injections done on 1st,2nd,3rd wks one wk apart and a 4th injection at 6 mth
Concurrent therapy: no analgesics, NSAIDs, steroids first 4 wks of study
Outcomes WOMAC
pain (5-25)
stiffness (2-10)
function (17-85)

R-1,B-2,W-1
clinical evaluation and injection done by 2 different researchers
Although report states that WOMAC mean and sd are presented in tables, wonder if the
sd is really se due to their small values
Risk of bias

Huang 2005
Methods Randomised
Controlled
Trial
Single-blind
Single centre
Blinded physiatrists
Taiwan
Mean age: 65.0
% Female: 80.7
Mean disease duration: range 5 mth to 12 y
Duration: 1 y
(35 in each of 4groups)
Inclusion:
patients with bilateral moderate knee OA (Altman grade II)
Exclusion:
Not reported
Baseline values:
Range of motion
EX: 103
EX+US: 104
EX+US+HA: 103
CT: 101
Pain (10 cm VAS)
EX: 5.3
EX+US: 5.5
EX+US+HA: 5.6
CT: 5.4
Lequesne Index
EX: 7.6
EX+US: 7.4
EX+US+HA: 7.5
CT: 7.4
Ambulation speed (metres/minute)
EX: 72.6
EX+US: 71.3
EX+US+HA: 72.4
CT: 73.9
Mean peak torque at 60 degrees/second
EX: 230.4
EX+US: 232.7
EX+US+HA: 230.4
CT: 229.3
Mean peak torque at 180 degrees/second
EX: 181.5
EX+US: 183.3
EX+US+HA: 180.1
CT: 182.3

Huang 2005 (Continued)
Interventions 1) EX: isokinetic muscular strengthening exercises,

2) EX+US: isokinetic exercise and pulse ultrasound treatment for painful periarticular soft
tissue,
3) EX+US+HA: isokinetic exercise, pulse ultrasound treatment for painful periarticular soft
tissue and intra-
articular Hyalgan 20 mg/2ml 5 weekly injections,
4) CT: no treatment other than warmup exercises.
Patients received treatments 3 times weekly for 8 weeks. Patients in all groups received a
warmup exercise with 20 minutes of hot packs and underwent passive range of motion
exercises on an electric stationary bike (20 cycles per minute) for 5 minutes to both knees
before undergoing muscle strengthening exercises.
Concurrent therapy: None reported.
Outcomes Active range of motion (standardised method for flexion, extension, excursion range),
Pain severity by 10 cm VAS (0=no pain, 10=maximum pain) after patient had remained in
a weight-bearing position (walking or standing) for 5 minutes,
Disability by the Lequesne Index (score: 1-3 mild dysfunction, less than 7 functional status
acceptable for isokinetic exercise, maximum score 26),
Ambulation speed - 50 metres on treadmill at self-selected pace - walking time,
Muscle peak torque of knee flexion and extension with an isokinetic dynamometer

R-2, B-0, -1
Supported by a project grant from the National Science Counil of Taiwan
Risk of bias
Huskisson 1999
Methods Randomised
Controlled
Trial
Blind observer
Parallel-group
Placebo- controlled
Single centre,
Principal efficacy criteria: ITT
all other efficacy: per protocol n=81
England
Mean age: 65
% Female: 67
Huskisson 1999 (Continued)
Duration:6 mth
(HA 50, PL 50)
Inclusion:
fully ambulant
mono or bilateral knee OA
Grade 2 to 3 Kellgren and Lawrence within 6 mth prior
consistent pain for 3 mth prior
moderate or severe pain on walking at screen and baseline visits
Exclusion:
Grade 4 Kellgren and Lawrence
serious functional impair-
ment at knee
associated OA of hip that interferes with knee assessment
OA of any other jt that affect knee assessment
psoriasis
radiographic evidence of sacroilitis or any other joint disease other than OA
known or suspected jt infection
poor general health or other conditions preventing hospital attendance
skin conditions overlying jt affecting injection
painful knee conditons other than OA
severe hepatic or renal disease or major medical
conditions
use of IA steroid or radiocolloid within 3 mth
Baseline values:
pain on walking
HA:65.8, PL:61.9
Lequesne
HA:13.4, PL:14.0
Interventions Hyalgan (20mg/2 ml) 5 weekly injections

Placebo: saline
2 ml 5 weekly injections
Concurrent therapy:
Existing analgesic & NSAID continued as considered appro-
priate by referring physician
Outcomes pain on walking (100 mm VAS)

Lequesne ---------
knee pain at rest (100 mm VAS)
joint tenderness,
swelling (4 point:
none,mild,mod-
erate, severe)
am stiffness, in-
activity stiffness
(min), pt. global impression (excellent, fair,
poor, useless)
satisfaction index

Huskisson 1999 (Continued)
Notes Jadad’s:4/5
R-1,B-2,W-1
Effusions aspirated
Risk of bias
Jones 1995
Methods Randomised
Controlled
Trial
Double-blind
Parallel-group
Both per protocol and ITT analyses
England
Mean age:71
% Female:62
Duration:6 mth
(HA 32, TH 31)
Inclusion:
bilateral effusions
bilateral sympto-
matic knee OA
(ARA criteria)
self-selected knee pain average of >30 mm during 2 wk run-in
Exclusion:
Coexistent rheumatological or serious medical disease
Baseline values:
pain on nomina-
ted activity
HA:77.2, TH:75.8
pain at rest
HA:53.2, TH:55.3
pain at night
HA:57.8, TH:62.2
Interventions Hyalgan (20mg)

5 weekly injections
Triamcinolone hexacetonide 20 mg followed by 4 placebo (1 ml of 0.9% saline) injections
Concurrent therapy:

Jones 1995 (Continued)
Paracetamol per-
mitted
Outcomes pain on self-selected activity (10 cm VAS)-----------------

pain at rest, night
duration of stiffness
range of motion
joint effusion
local heat
synovial thickening
joint line and periarticular tenderness
xray score
synovial fluid volume
Notes Jadad’s:4/5
R-1,B-2,W-1
Active treatment was always given to worse knee with contra-
lateral knee re-
ceiving 5 placebo
injections
Joint aspirated to dryness before
injection.
Study sponsored by Fidia SPA. Drs. B. Guillou and J.M. Grouin of Fidia S.p.A. provided
statistical analysis
Risk of bias
Jubb 2001a
Methods See Jubb 2003
Participants
Interventions
Outcomes
Notes
Risk of bias

Jubb 2001b
Participants
Interventions
Outcomes
Notes
Risk of bias
Jubb 2001c
Participants
Interventions
Outcomes
Notes
Risk of bias
Jubb 2001d
Participants
Interventions
Outcomes
Notes
Risk of bias

Jubb 2001d (Continued)
Jubb 2003
Methods Randomised
Controlled
Trial
Double-blind
Masked-observer
Placebo controlled
Parallel group
Multicentre (n=17)
Primary analysis population n=273
ITT for safety n=408
England
Mean age: 64
% Female: 68
Mean disease duration: 8 y
Duration: 1 y
(HA 208, PL 200)
Inclusion:
primary OA of the knee by ACR criteria,
grade II or III Kellgren and Lawrence in medial tibiofemoral compartment
Exclusion:
OA of the hip or other joint disease severe enough to prevent assess-
ment of knee,
psoriasis, sacro-
ilitis, other joint disease, known or suspected joint infection, disease of skin overlying knee
joint that prevented injections, other painful knee conditions or severe concurrent illnesses,
ia corticosteroid or radiocolloid treatment in 3 mths before study or ia or new/rearrange-
ment surgical procedures on legs,
evidence of clinically important axial deviation of the legs (valgus or varus deformities),
history of allergic reactions to avian proteins, pregnant or breast-feeding
Baseline values:
JSW
HA: 4.9
PL: 4.5
JSW>=4.6 mm
HA: 5.9
PL: 5.9
JSW<4.6 mm
HA: 3.5
PL: 3.4

Jubb 2003 (Continued)
Interventions Hyalgan (20 mg/2 ml) 3 weekly injections

Placebo: saline
Course was repeated twice more at four-monthly intervals.
Concurrent therapy: Free concomitant use of analgesics and NSAIDs, except indomethacin,
was allowed but regimens had to be stable for at least one month before study entry.
Concurrent treatment with corticosteroids, glucosamine or chondroitin sulphate was not
permitted
Outcomes Mean joint space width at 52 wk by computerised DIA-------------------

pain on walking (VAS),
knee pain (6 point categorical scale), Pt and investigator global impression of efficacy (5
point categorical scale), Lequesene Index, SF-36
Notes Jadad’s:4/5
R-1,B-2,W-1
If bilateral OA, more painful knee was treated.
Subgroups defined by joint space wideth >= or <4.6 mm at baseline.
The trial was supported by a grant from Fidia SpA, Abano Terme, Italy.
Second and third authors are affiliated with Sponsor.
Risk of bias
Kahan 2001
Methods See Kahan 2003a
Participants
Interventions
Outcomes
Notes
Risk of bias

Kahan 2003
Methods See Kahan

2003a
Participants
Interventions
Outcomes
Notes
Risk of bias
Kahan 2003a
Methods Randomised
Controlled
Trial
Open-label
Parallel-group
Multicentre (n=81)
Stratified
Effectiveness
France
Mean age: 66
% Female: 68
Mean disease
duration: 5.9 y
Duration: 9 mth
Number randomised:
518
(HA 258, CT 260)
Inclusion:
>18 y of age
predominantly
femorotibial OA meeting ACR criteria
pain upon walking >= 40/
100 mm VAS
had to have received at least 2 courses of NSAID therapy each at least 10 d long within the
last 3 mth and/or
a symptomatic slow-acting drug taken continu-
ously during the last 2 mth
Exclusion:

Kahan 2003a (Continued)
inflammatory flare in the target knee (effusion with nocturnal pain, local heat or redness,
morning stiffness for longer than 45 min or greater than 50% increase in the VAS pain
score as compared to the previous wk
viscosupple-
mentation in the target knee within the last 3 mth, ia procedure (arthroscopy, lavage, menis-
ectomy, etc.) within the last year,
history of syno-
vectomy, tibial osteotomy, or knee replace-
ment surgery scheduled within the next 9 mth
Baseline values:
Lequesne:
HA 11.1 CT 11.3
WOMAC:
HA 46.3 CT 47.9
Pain walking:
HA 61.1
CT 60.3

3 weekly injections in target knee
(encouraged to stop or spare any other OA treat-
ments) [Synvisc could also be given in other knee]
Conventional treatment for knee OA
Concurrent therapy: NSAID:
HA 87%, CT 82%
Symptomatic slow-acting drugs: HA 69%, CT 76%
Outcomes Lequesne ---------

WOMAC OA Index, SF-12,
medico-
economic evaluation,
pt rating of effectiveness on a 4-category Likert scale
Notes Jadad’s:3/5
R-2,B-0,W-1
Bilateral OA in 72% HA, 76% CT
Synvisc given to both knees in 45 pts.
Second and third authors are affiliated with Boehringer Ingelheim
Risk of bias

Kalay 1997
Methods Randomised
Controlled
Trial
Open-label
Parallel-group
1 wk washout
ITT analysis
Turkey
Mean age: 61
% Female: 78
Duration: 56 days
(HA 20, PT 20)
Inclusion:
idiopathic OA according ACR criteria
AP xray Kellgren and Lawrence 2 or 3 study knee and <4 other knee
>40 yr
walk 25 m without help
stop all NSAIDs and muscle relaxants 1 wk before study
Exclusion:
ia inj or important trauma episode within last 3 mths
oral or im steroid episode within last 2 mths
HA inj within last 12 mths
start of quadriceps exercise program in last 4 mths
presence of fixed flexion contracture at knee >10 degrees
valgus/varus >15 degrees on standing knee xrays
anticoagulant treatment
knee surgery episode
joint diseases: secondary OA or inflammatory jt disease, pseudo
-gout attack in last 3 mths, FM, intrajoint tumor, excessive symptoms in same hip or other
knee that may interfere with study, anserine bursitis
functional damages: hemi-
paresis episode
others: multiple i-a inj or aspiration,liver or kidney disease, pregnancy, lacta-
tion, insufficient contraception, peripheral neuropathy or vascular inadequacy, osteonecro-
sis, immune suppresive disease, diabetes mellitus
Baseline values:
spontaneous pain
HA:2.61, PT:2.21
activity pain
HA:4.68, PT:3.71
night pain
HA:2.43, PT:2.17
25 m walk time
HA:22.4, PL:18.6

Kalay 1997 (Continued)
Interventions Sodium hyaluronate 1.5% 15 mg/ml

2 ml Orthovisc
2 weekly injections
+ 5 days/wk for a total of 10 sessions in-patient physical therapy program (paraffin, short
wave, quadriceps exercises) directed towards knees
Physical therapy program only
Concurrent therapy:
Paracetamol per-
mitted
Outcomes spontaneous pain, pain during daily activities and night pain (0-4:
0=none,1=light, 2=medium, 3=
strong, 4=very
strong and 100 mm VAS)
paracetamol use
morning stiffness (min)
range of motion: flexion/extension goniometer
knee circumfer-
ence
25 metre walk time
pt global (1-4)
MD global (1-4)
(1=ineffective,2=
slightly effective,
3=effective, 4=
very effective)
side effects

R-1,B-0,W-1
If bilateral OA, more symptomatic knee in study
Risk of bias
Karatay 2004
Methods Randomised
Controlled
Trial
Parallel group
Singel centre

Karatay 2004 (Continued)
Participants Country: Turkey

Mean age: 61.5
% Female: 70
Duration: 3 wk
(Orthovisc 20, Hylan G-F 20 20)
Inclusion:
fulfill ACR criteria for knee OA,
Kellgren-Lawrence grade II or III
Exclusion:
use of analgesic or NSAID,
pts with concomitant rheumatological disease, active synovitis, surgical or arthroscopic
interventions or ia steroid or HA treatment during the past 6 mth
Baseline values:
WOMAC pain:
OR: 11.2
GF: 10.8
WOMAC stiffness
OR: 3.8
GF: 3.6
WOMAC function
OR: 35
GF: 31.9
ICAM-1
OR: 19.2
GF: 17.8
VCAM-1
OR: 40.5
GF: 37.8
Interventions Orthovisc
2 ml, 30 mg
(Anika Therapeutics)
3 weekly injections;
Hylan G-F 20
Synvisc
2 ml, 16 mg
(Wyeth)
3 weekly injections
Concurrent therapy: None permitted as per exclusion criteria
Outcomes WOMAC OA Index

pain (0-20),
stiffness (0-8),
physical function (0-68)
biochemical measurements:
sICAM-1 and sVCAM-1 in SF samples

Karatay 2004 (Continued)

R-1, B-0, W-0
No baseline differences between groups of demographic features, clinical indices or lab
values
Risk of bias
Karatay 2005
Methods See Karatay 2004.
Participants
Interventions
Outcomes
Notes
Risk of bias
Karatay 2005a
Methods See Karatay 2004.
Participants
Interventions
Outcomes
Notes
Risk of bias

Karatosun 2005
Methods Randomised
Controlled
Trial
Parallel group
Blinded physical therapist
Single centre
Turkey
Mean age: 56.6
% Female: 86
Duration: 18 mth
(200 knees)
(HA 52, PE 53)
Inclusion:
primary OA of the knee as defined by ACR criteria,
Kellgren Law-
rence grade III with joint space narrowing and sclerosis of the subchondral bone
Exclusion:
radiographic appearance of pseudocysts as defined by Kellgren Law-
rence Grade IV,
unable to discontinue NSAID for duration of study,
previous fracture around the knee,
inflammatory arthritis, previous intraarticular injections or any other invasive procedure
in the knee,
significant comorbidity (renal, hepatic or heart disease),
chicken or egg allergy
Baseline values:
pain during activity
HA: 4.0, PE: 4.5
pain at rest
HA: 7.8, PE: 9.1
pain during climbing stairs
HA: 2.5, PE: 2.5
pain during transfer activity
HA: 2.9, PE: 3.1
walking distance
HA: 8.1, PE: 7.9
range of motion
HA: 113.2,
PE: 114.4
total HSS score
HA: 62.6,
PE: 65.4

(Synvisc) 3 weekly injections at baseline, Week 1 and Week 3,
Exercise programme included a series of progressive, simple range of motion and resistance

Karatosun 2005 (Continued)
exercises for 6 wk. Home-based regimen but patients came to hospital at baseline and weeks
1, 2, 3 and 6 to learn the exercises
Outcomes Knee function evaluated by the Hospital for Special Surgery knee score criteria that is based
on a total of 100 points with the score divided into 7 categories: pain, function, range of
motion, muscle, strength, flexion deformity, instability, and subtractions. scores 85-100
excellent, 84-70 good, 60-69 fair and less than 60 poor-----------------
pain during activity, pain at rest,
pain during climbing stairs, pain during transfer activity, walking distance and range of
motion all but walking distance and ROM are graded by HSS score (i.e. pain)

R-2, B-0, W-1
95 patients had bilateral OA; 48 in the HA group and 47 in the PE group. 10 patients had
unilateral OA: 4 HA and 6 PE
Risk of bias
Karatosun 2005a
Methods Randomised
Controlled
Trial
Parallel group
Double blind
15 day washout of NSAID
Turkey
Mean age: 60.55
% Female: 81.5
Mean disease
duration: NR
Duration: 1 y
(184 knees)
(OR 46, GF 46)
Inclusion:
primary OA of the knee as defined by ACR criteria,
all seeking treatment,
Kellgren-
Lawrence stage III OA with joint space narrowing and sclerosis of subchondral bone
Exclusion:
any pt with radiographic appearance of pseudocysts was defined as Kellgren-

Karatosun 2005a (Continued)
Lawrence grade IV,

if pt could not discontinue NSAID beginning 15 days prior to the study due to presence
of other diseases,
previous fracture around the knee, joint effusion, inflammatory arthritis, previous intraar-
ticular injection or any other invasive procedure in the knee,
significant comorbidity (renal, hepatic or heart disease),
chicken or egg allergy
Baseline values:
pain at activity
OR: 4.4, GF 5.2
pain at rest
OR: 9.1, GF 8.1
pain during climbing stairs
OR: 2.1, GF 2.1
pain during transfer activities
OR: 2.5, GF 2.6
walking distance
OR: 5.4, GF 8.3
range of motion
OR: 113.0,
GF: 114.4
total HSS score
OR: 67.7,
GF: 70.1
3 weekly injections,
Hylan G-F 20
(Synvisc) 3 weekly injections
Concurrent therapy: NSAID not permitted
Outcomes Hospital for Special Surgery Knee Score which includes pain at activity, pain at rest, pain
during climbing stairs, pain during transfer activities, walking distance, and range of motion

R-2, B-2, W-1
All radiographs (AP, lateral and Merchant) evaluated by 2 orthoopaedic surgeons and if
consensus not achieved pt not included.
Statistically significant difference at baseline in walking distance
Risk of bias

Karlsson 1999
Methods See Karlsson 2002a
Participants
Interventions
Outcomes
Notes
Risk of bias
Karlsson 2002
Participants
Interventions
Outcomes
Notes
Risk of bias
Karlsson 2002a (AvP)
Methods Randomised
Controlled
Trial
Double-blind
Parallel-group
Multicentre (n=19)
2 wk washout
Both per protocol n=210 (Artzal 76, Synvisc 77, PL 57) and
ITT n=242 (Artzal 90, Synvisc 86, PL 66) analyses completed
PP analysis planned a priori as high drop-out rate expected.

Karlsson 2002a (AvP) (Continued)
Sweden
Mean age: 71
% Female: 65
Duration: 1 yr
(Artzal 92
Synvisc 88
Placebo 66)
Inclusion:
age at least 60 y
Lequesne Index score at least 10
weight bearing pain at least 40/100 mm VAS
normal general physical exam
dominant pain in one knee due to OA
radiologically verified OA of grade I or II by Ahlback criteria
(50-100% joint space narrowing but no bone erosion)
Exclusion:
bone attrition in either knee (Ahlback grade III to V)
previous ia fracture of knee
RA or other inflammatory joint disease as defined by ACR criteria
ia injections of steroids or HA or other invasive procedure (arthroscopy, arthrography,
surgery) in knee less than 6 mths prior to study
known alcohol or drug abuse
known allergy to any substance related to study
(disinfectants, adhesives)
any clinically relevant haematological or known clinical chemistry values outside the refer-
ence values
any disabling problem of the musculoskeletal system or other organ system which could
interfere with the assessment of efficacy
Baseline values:
Weight bearing pain:
A: 64
S: 63
PL: 65
Total WOMAC
A: 48.7
S: 48.7
PL: 48.9
Total Lequesne:
A: 13.9
S: 13.4
PL: 13.6
Interventions Artzal 2.5 ml (1% hyaluronan, Astra Lakemedel)

3 weekly injections (7 days apart)
Synvisc 2.0 ml (0.8% hyaluronan, Roche) 3 weekly injections (7 days apart)
Placebo (phosphate-

Karlsson 2002a (AvP) (Continued)
buffered saline solution - 3 ml solution in 5 ml ampoules, Astra Lakemedel) 3 weekly

injections (7 days apart)
Concurrent therapy: Paracetamol (acetaminophen) up to 4 g/day permitted; analgesics not
permitted 12 h prior to clinical assessment; pt recoded use of analgesics on diary card during
wk 0-26
Outcomes Wk 0-26 primary outcome was weight bearing pain and Wk 0-52 was duration of clinical
benefit
Clinical failure defined as use of concurrent treatment for study knee, i.e. more than 4g/
day, surgery or new injections.
*******************
Patient rated weight bearing pain, resting pain and maximum pain of knee on 100 mm
VAS
WOMAC OA Index (Likert), SF 36, global evaluation of overall response to treatment at
Wk 26 (8-point ordinal scale),
Examiner completed the Lequesne Index,
evaluated change in intake of concurrent analgesic medication (much more, more, un-
changed, less, much less),
Notes Jadad’s:5/5
R-2,B-2,W-1
Study was supported by grants from Astra Lakemedel.
Second author affiliated with Clinical Research Medical Dept. of AstraZeneca.
These pts had significant knee pain and impairment as reflected by high WOMAC and
Lequesne scores.
By Wk 26 approx. 20-30% dropouts By Wk 52 approx. 60-70% dropouts
Study pts from a community-
based outpatient
population cared for by family doctors, GPs and orthopaedic surgeons in private practice
Risk of bias
Karlsson 2002b (SvP)
Participants
Interventions
Outcomes
Notes

Karlsson 2002b (SvP) (Continued)
Risk of bias
Karlsson 2002c (AvS)
Participants
Interventions
Outcomes
Notes
Risk of bias
Karlsson 2003d
Participants
Interventions
Outcomes
Notes
Risk of bias

Karras 2001
Methods Randomised
Controlled
Trial
Parallel-group
SIngle centre
Greece
Mean age: NR
% Female: NR
Duration: 1 y
(HA5: NR
HA3: NR )
Inclusion:
Suffering from OA of the knee
Exclusion:
NR
Baseline values:
NR
Interventions Hyalgan 5 weekly injections every 6 months

Hyalgan 3 weekly injections every 3 months
Outcomes Lequesne,
Pain (VAS),
Clinical response by pt and physician.
Notes Jadad’s:2/5
Risk of bias

Kawabata 1993
Methods Randomised
Controlled
Trial
Parallel-group
Multicentre (n=23)
Safety analysis: ITT, n=164,
Pt. impression & global: per proto-
col, n=156
Usefulness: per
protocol, n=159
Japan
Mean age: 67
% Female: 75
Mean disease
duration: NR
Duration: 5 wk
(SLM 87, Artz 85)
Inclusion:
diagnosis of knee OA on basis of clinical and xray
informed consent
pain during movement
xray findings: one of osteophyte, JSN, osteoscl-
erosis
Exclusion:
considered to require an operation
received ia injection of steroid within 2 wks of start
newly administered analgesic, NSAID within 2 wk of start
new PT within 2 wk
pregnant, lactating, or may become pregnant
serious complications such as definite hepatic and renal ftn. disorders
have or have history of hyper-
sensitivity to drug
those judged by the physi-
cian in charge to be inappro-
priate as trial subjects
Baseline values:
movement pain
mild SLM 39%
Artz 35%,
moderate SLM
55%, Artz 61%
severe SLM 6%,
Artz 4%
Interventions SLM-10 (25 mg/2.5 ml)

5 weekly injections
Artz (25 mg/2.5 ml)

Kawabata 1993 (Continued)
5 weekly injections
Concurrent therapy:
”New“ analgesics, NSAIDs, steroids and physiotherapy to be avoided
Outcomes assessment by attending physician:

daily activity dis-
order:standing up from chair,up/
down stairs,
squatting, sitting
up straight (easy,
mild,moderate,
severe), walking ftn disorder, pain
(in movement,
when resting,
pressure), knee jt findings (swel-
ling,feverish
feeling,floating
patella), range of motion: all on 4-point scales (none,mild,mod-
erate,severe), +/- stagnant synovial fluid,
if present, volume
pt’s impression: 7 grades:much
better,better,
slightly better,
unchanged,
slightly worse,
worse, much
worse
pt global improvement : 7 grades:markedly
improved, im-
proved,slightly
improved, un-
changed,slightly
deteriorated, de-
teriorated, mark-
edly deteriorated
overall safety: 3 grades: safe,
continued use
despite some
problem, discon-
tinued due to
problem
usefulness: 7 grades:very use-
ful,useful,slightly
useful,cannot say useful or not,
slightly undesir-
able, undesir-
able, very unde-
sirable

Kawabata 1993 (Continued)
Committee assessment: pain, daily activity disorder, knee jt findings, walking ftn: score/
100,
overall severity: 3 grades (mild >=60/100, moderate 30-50/
100, severe <= 29/100) and global improvement: 7 grades, overall safety & usefulness

R-1,B-0,W-1
Pt observation and assessment done by physician other than physician in charge (injection)
Synovial fluid removed as required.
Significant group difference in baseline +/- of complications.
Artz provided by Seikagaku Corp-
oration.
Risk of bias
Kirchner 2005
Methods Randomised
Controlled
Trial
Parallel-group
Double-blind
Multicentre (n=10)
Germany
Mean age: 63.2
% Female: 64.5
Mean disease duration: 58.9 mth
Duration: 12 wk
(EUF 160, SYN 161)
Inclusion:
either sex,
age 50 to 80 y,
confirmed OA in one or both knees,
clinical evidence of chronic idiopathic OA of the study knee according to criteria of Altman,
radiologically verified OA of the study knee by modified Kellgren-Lawrence (grade 2 or 3),
symptoms in study knee for at least 1 y,
willingness to discontinue all OA treatments other than acetaminophen, moderate to severe
knee pain as reflected by a VAS pain score of 41 to 80 out of 100 mm for the average of
the WOMAC OA Index pain subscale with only one pain item permitted to be below 20
mm or above 80 mm
Exclusion:

Kirchner 2005 (Continued)
secondary OA originating from a known injury to the knee, RA,

history of joint infection, dermatologic disorders or skin infection in proximity to study
knee, osteonecrosis, chronic active fibromyalgia, any inflammatory or metabolic arthrides
and known sensitivity to acetaminophen or hyaluronan,
hyaluronan injection to study knee within 6 mth of screening, corticosteroid injection and
surgery or arthroscopy to study knee within 3 mth of screening, nonambulatory patients:
inability to perform a 50 foot walk test, patients with symptomatic OA of the hip or any
other health condition that would have interfered with study assessments including patients
with uncontrolled hematological, cardiovascular, neoplastic, pulmonary, neurological, re-
nal, hepatic or systemic disease,
clinical lab values: fasting blood glucose concentration greater than 160mg/dl, alkaline
phosphatase greater than 250 U/I, alanine aminotransferase greater than 30 U/I, or aspartate
aminotransferase greater than 30 U/I,
participation in another study during the study period and during the 4 wk prior to study
enrollment
Baseline values:
WOMAC pain
EUF 49.2
SYN 51.9
WOMAC stiffness
EUF 43.2
SYN 47.8
WOMAC function
EUF 47.0
SYN 50.8
WOMAC total
EUF 47.2
SYN 50.8
Interventions Euflexxa (bioengineered 1% sodium hyaluronate)

(20 mg/2 ml)
Synvisc
(16 mg/2 ml)
3 weekly injections
Both groups advised to rest for 24 h following each injection. Before each injection, any
SF that was present was aspirated.
Concurrent therapy:
acetaminophen (500 mg tablets) up to 4 g daily was permitted as rescue medication;
NSAIDs and other non-acetaminophen pain medications were prohibited
Outcomes WOMAC OA Index pain subscale-----------

WOMAC stiffness,
WOMAC physical function,
patient global assessment of treatment, ”Are you satisfied with the results of the injections?
“ with response graded on a 4-point ordinal scale: 1=dissatisfied, 2=slightly satisfied, 3=
satisfied,
4=very satisfied;
patient consumption of acetaminophen for pain relief as quantified by pill counts


R-2, B-2, W-1
Study supported by Ferring Pharmaceuticals, Inc.
Statistical review by W. Huang, PhD, Savient Pharmaceuticals, clinical and regulatory sup-
port by R. Zaibel, Bio-Technology General (Israel) Ltd., editorial assistance in manuscript
preparation provided by BioScience Communications, New York
Risk of bias
Kirchner 2005
Methods See Kirchner 2005 above.
Participants
Interventions
Outcomes
Notes
Risk of bias
Kirchner 2006
Methods See Kirchner 2005 above.
Participants
Interventions
Outcomes
Notes
Risk of bias

Kotevoglu 2002
Methods See
Kotevoglu 2005.
Participants
Interventions
Outcomes
Notes
Risk of bias
Kotevoglu 2005
Methods Randomised
Controlled
Trial
Double blind
Parallel group
Single centre
Placebo and active controlled
Blinded evaluator

Mean age: 59.5
% Female: 88
Duration: 6 mth
Number randomdised:
(Orthovisc 26,
Synvisc 26,
Saline 26)
Inclusion:
patients with knee OA according to ACR criteria,
Kellgren- Lawrence grades II-IV
Exclusion:
renal and hepatic comorbidity,
abnormal lab tests,

Kotevoglu 2005 (Continued)
treatment with anticoagulants or immunosuppressives, intra-articular injection of HA or

steroids within the past 12 mth,
any quadriceps exercise programe within the last 4 mth
Baseline values:
WOMAC pain
OR: 16.5
SYN: 18
PL: 20
WOMAC stiffness
OR: 6.5
SYN: 7
PL: 6
WOMAC function
OR: 52.5
SYN: 55
PL: 59.5
Patient global
OR: 90
SYN: 80
PL: 90
Physician global
OR: 95
SYN: 80
PL: 90
Interventions Synvisc 3 weekly injections,

Orthovisc 3 weekly injections,
Saline 3 weekly injections
All injections injections performed by 2 physicians in anterolateral approach (along the
patellar tendon) with knee in 90 degrees of flexion
Concurrent therapy: aceta-
minophen up to 4 mg/day permitted
Outcomes WOMAC pain (5-25), WOMAC stiffness (2-10), WOMAC physical function (17-85),
patient and physician global assessments on a 0-100 mm VAS scale; for both the question
was, “How do you grade the severity of your (or the patient’s)
knee OA according to a 0-100 scale, 100 being the worst

R-1, B-1, W-1
Patients did not have effusion. In bilateral disease, the more painful knee was treated
Risk of bias

Lanzer 2002
Methods See Caborn 2004.
Participants
Interventions
Outcomes
Notes
Risk of bias
Leardini 1987
Methods Randomised
Controlled
Trial
Single-blind
Parallel-group
Washout
Mth 2: ITT analysis,
Mth 12: Per protocol
Italy
Mean age: 64
% Female:81
Disease
duration: NR
Duration:1 y
(HA 20, MPA 16)
[40 jts: HA 20, MPA 20]
Inclusion:
active gonarthrosis
Kellgren Grade 2 or 3
Exclusion:
no other joint disease
Baseline values:
spontaneous pain
HA:41.3,
MPA: 33.4
passive movement
HA:115.8
MPA:109.0

Leardini 1987 (Continued)
active movement
HA:108.4
MPA:104.2
ring size
HA: 43.0,
MPA: 42.6
# jts.pain under load
HA:18, MPA:19
# jts walking pain
HA:20, MPA:20

Methylpredniso-
lone acetate (MPA) 40 mg/1 ml
(Depo-Medrol)
3 weekly injections
Concurrent therapy:
simple analgesics permitted for most severe pain, no NSAIDs for first 2 mths then allowed
for short periods (<2 wk) between end of mth 2 and mth 12
Outcomes spontaneous pain on VAS

pain under load and on walking (1=absent to 5=
very severe)
active and passive movement in degrees
ring size in cm
Notes Jadad’s:2/5
R-1,B-0,W-1
4 pts had bilateral OA; each knee counted as ’one’ case.
R. Bruno and A. Perbellini, Fidia SpA. C. Baggio and C. Zanetti provided statistical analysis.
A. Babolin provided secretarial assistance
Risk of bias
Leardini 1991
Methods Randomised
Controlled
Trial
Open-label
Parallel-group
ITT analysis

Italy
Mean age: 65
% Female:88
Mean disease duration: 99 mth
(range 12-300)
Duration:60 days
(HA 20, MPA 20)
Inclusion:
painful idiopathic OA of the knee by ARA criteria and radiologically assessed by Kellgren
previous NSAID treatment with poor results suggesting the usefulness of IA treatment
Exclusion:
serious concomitant disorders
ongoing infections
pregnancy
allergy or hypersensitivity to drugs
treatment with any IA drug in last 3 mth
Baseline values:
% pts with strong
pain under load
HA:65, MPA:55
% pts with strong
rest pain
HA:60, MPA:70

6-methylpredniso-
lone acetate (6-MPA) 40 mg/1 ml 3 weekly injections (Depo-
Medrol)
Concurrent therapy:
Analagesic & NSAID
permitted
Outcomes spontaneous pain (100 mm VAS), am stiffness, flexion (degrees)-----------------------

night pain, pain under load, touch pain (0-4:
0=none,1=slight,
2=moderate, 3=
strong, 4 = very
strong)
analgesic or NSAID consumption (0-3: 0=none, 1=
occasional low
doses, 2=regular
low doses, 3 =
regular high doses)
joint effusion volume (ml)
pt and MD global efficacy (0-4: 0 =
unsatisfactory, 1 = poor, 2 = fair,
3 = good, 4 = excellent)

Notes Jadad’s:2/5
R-1,B-0,W-1
Arthrocentesis performed if
effusion present and measured.
Pts kept at rest for 2 days after injection.
A. Perbellini,
Fidia S.p.A.
Risk of bias
Leopold 2003
Methods Randomised
Controlled
Trial
Single-blind
Blinded assessor
Parallel-group
Single centre
USA
Mean age: 65
% Female: 54
Duration: 6 mth
(HA 50, CS 50)
Inclusion:
>18 y
x-ray evidence of symptomatic OA of the knee
dissatisfaction with prior attempts at non-
operative management modalities (e.g.
NSAID, oral
analgesics, nutritional supplements, PT, braces)
symptomatic=
pain with weight
bearing at TB and/or PF with one or more of:
loss of cartilage thickness, osteo-
phyte formation, subchondral sclerosis, cysts
Exclusion:
pregnant
lactating

Leopold 2003 (Continued)
x-ray signs of bone-on-bone

arthritis, chrondrocalcin-
osis,
physical exam showed an insufficiency of collateral ligament or insufficiency of anterior
or posterior cruciate ligament with concomitant symtomatic giving-way of the affected
extremity, or current infection in affected extremity
history of crystalline arthropathy or inflammatory arthritis, neuropathic arthropathy, an ia
injection with any
corticosteroid or any HA within the previous 3 mth
allergy or hyper-
sensitivity to study medications, eggs, feathers, avian proteins, or chickens

3 weekly injections (with effusion aspiration)
Betamethasone sodium phos-
phate-betameth-
asone acetate 2 ml mixed in 4 ml of Marcaine (bupivacaine) and 4 ml of lido-
caine (effusion not aspirated) & could have 2nd injection at any time (48%)
(Celestone
Soluspan)
Concurrent therapy: NSAID permitted but tracked (HA - 64%, CS -56% usage)
Outcomes Modified Knee Society clinical rating scale (100 points),

WOMAC OA Index (Likert),
pain (100 mm VAS)
Notes Jadad’s:3/5
R-2,B-0,W-1
Study was independently funded. Base-
line significant
difference in x-ray severity: more moderate in HA; more mild or severe in CS.
If bilateral, only one knee analysed.
Risk of bias
Lin 2004
Methods See Tsai 2003.
Participants
Interventions
Outcomes

Lin 2004 (Continued)
Notes
Risk of bias
Listrat 1997
Methods Randomised
Controlled
Trial
Per protocol: n=36
France and Italy
Mean age: 62
% Female:67
Duration: 1 y
(HA 20, CT 19)
Inclusion:
primary OA defined by ACR
clinical involvement of medial compartment
active disease justifying local therapy
absence of advanced disease (Kellgren and Lawrence Grade 4)
absence of contraindication of arthroscopy
presence of chondropathy of medial comparment at arthroscopy
Exclusion:
any IA surgery in past 5 y (including arthroscopy)
any IA treatment prescribed in past 3 mths
any concurrent
symptomatic treatment had to be stable for at least one mth before study
Baseline values:
pain
HA:49.2, CT:52.1
Lequesne
HA:8.9, CT:9.4
arthroscopy overall assessment
HA:41.8, CT:52.6
AIMS2
HA:2.6, CT:2.2
Joint space width (mm) HA: 4.5,
CT: 3.5
SFA scoring

Listrat 1997 (Continued)
HA: 26.1,
CT: 39.0
Interventions Hyalgan (20 mg/2ml) 3 weekly injections every 3 mth for total of 9 injections with 1st
injection 1 mth after arthroscopy and last 3 mth before final visit
Conventional therapy but all pts had arthroscopy with lavage 2 litres saline serum
before randomisation
Concurrent therapy: analgesics & NSAID
permitted
Outcomes arthroscopy scored MD overall assess-

ment (100 mm VAS), revised SFA scoring and SFA grading-------
global pain 100 mm VAS
Lequesne Index
AIMS2
analgesic/NSAID score
AP wt bearing knee xrays - joint space narrowing by 7-grade and joint space width (mm)
Notes Jadad’s:2/5
R-1,B-0,W-1
Synovial fluid aspirated before injection.
Imbalance at entry in severity of chondropathy .
Imbalance in amount of rescue treatment.
Study supported by a grant from Fidia S.p.A. and in part from a grant from the Societe
Francaise de Rhumatologie.
Hyalgan supplied by Fidia S.p.A.
Risk of bias
Lohmander 1996
Methods Randomised
Controlled
Trial
Double-blind
Multicentre (n=8)
Placebo- controlled
Stratified
Efficacy analysis: per protocol n=189, safety analysis: ITT, n=239
Participants Country: Denmark, Finland, Norway,

Sweden
Mean age: 58
% Female:56

Lohmander 1996 (Continued)
Mean disease duration:

Duration:20 wk
(HA 120, PL 120)
Inclusion:
40-75 y
symptomatic, radiologically verified knee OA
(Ahlback stage 1 to 2)
knee pain on day of examination >10/100 mm VAS
Lequesne score >= 4 baseline
Exclusion:
significant symptoms of bilateral knee OA
previous IA fracture of knee
RA or other inflammatory arthritis
IA injection of steroids or other invasive procedure in knee in past 6 mth
any other condition that in-
terferes with efficacy assessment or completion of trial
Baseline values:
pain
HA:44.4, PL: 42.3
activity level
HA:60.7, PL:60.7
knee function
HA:51.2, PL:49.3
ROM
HA:33.8, PL:38.5
Lequesne
HA:9.9, PL:9.6
Lysholm
HA:54.1, PL:57.9
Tegner
HA:2.7, PL: 2.6
Clincial exam
HA:20.8, PL:21.0
Interventions Artzal (25 mg/2.5 ml) 5 weekly injections

Placebo:saline 2.5 ml 5 weekly injections
Local anaesthetic used.
Concurrent therapy:
analgesics & NSAID
permitted and monitored.
Outcomes Lequesne index

100 mm VAS for knee pain, ROM, activity level and total knee function-------------
Tegner activity score, Lysholm knee function score
clinical exam
quantity of con-
current medication
pt and examiner global (7 stages:

Lohmander 1996 (Continued)
from much im-

proved to much
worse)
volume of fluid aspirated
number of leuco-
cytes in joint fluid
Notes Jadad’s:4/5
R-1,B-2,W-1
Effusion aspirated before injection
Stratification by age and Lequesne score
into 4 groups:
40-60 y, Lequesne 4-10;
40-60 y,
Lequesne >10,
61-75 y, Lequesne 4-10,
61-75 y, Lequesne >10
Standardisation meeting for injection tech-
nique and assessment procedures.
Work supported by Medical Faculty of Lund University, the Swedish MRC, KaroBio AB
and Astra Lakemedel AB
Risk of bias
McDonald 2000
Methods Randomised
Controlled
Trial
Double-blind
Multicentre (n=12)
2 wk washout
Both ITT n=256
and per protocol, n=233 with publication based on PP.
analyses done
Germany
Mean age: 62
% Female: 61
Mean disease
duration: 4.4 y
Duration:6 mth
(FM 127, HA 129)
McDonald 2000 (Continued)
Inclusion:
radiologically confirmed knee OA (Ahlback 1 to 3) and ACR diagnostic criteria
investigator approval of with-
drawal of analgesic medication
with escape medication being acetaminophen for study
Exclusion:
IA injections or arthroplasty to affected knee in last 3 mth
concomitant medical condi-
tions that could interfere with study assessments such as hip OA
Baseline values:
pain
FM:56.2,HA:57.2
Lequesne
FM:11.2,HA:11.1
Interventions Fermathron 2 ml
5 weekly injections
Hyalart 2 ml
5 weekly injections
Concurrent therapy:
Paracetamol,
Aspirin up to 150 mg
daily
Outcomes Lequesne ---------

use of escape medication by pt daily diary
VAS pain assess-
ment of affected
knee
pt global (very good, good,
average, poor, very poor)
Notes Jadad’s:5/5
R-2,B-2,W-1
First author of publication is affiliated with Fermentech Medical Ltd
Risk of bias

Miltner 2002
Methods Randomised
Controlled
Trial
Single-blind
Blinded clinical assessor
Right/left comparison
Single centre
Stratified on more impaired knee
Germany
Mean age: 67
% Female: 53
Duration: 7 wk
(HA: 24 knees most impaired, 19 knees less impaired;
No treatment: 19 knees most impaired; 24 knees less impaired)
Inclusion:
Adults of both genders with a minimum age of 50 yr
OA of both knees
Radiographic changes = Kell-
gren and Lawrence stage II to III bilat-
erally
Symptomatic gonarthrosis for a minimum of 12 months
Pain during wt bearing >=4/10 cm VAS bilaterally
Lequesene score not different by more than +/- 2 points in total value
Exclusion:
Pts who do not meet all inclusion criteria
Neurological deficits in lower extremities
Underlying diseases such as: primary
inflammatory joint disease, joint infections, crystalline arthritis, ia tumors, axis deviation
of >15o varus or valgus malalignment, ligamentous instability, previous fractures of the
joint, arthroscop-
ic surgery on the knee in the previous 12 mths
IA injections of the knee joint in 3 mth prior to study
Baseline values:
Pain at rest
HA: 3.83
NT: 3.67
Pain wt bearing
HA: 7.57
NT: 7.43
Lequesne
HA: 13.57
NT: 12.48
Interventions Hyalart 20 mg
5 weekly injections
No treatment

Miltner 2002 (Continued)
Concurrent therapy: NSAID & analgesics to be avoided.

Paracetamol 500 mg was permitted as pain medication.
Outcomes Lequesne (max score 26),

pain (10 cm VAS)
isokinetic test (maximum peak torque for extensors and
flexors), total work
Notes Jadad’s:1/5
R-1,B-0,W-0
Baseline difference between groups in initial values for total work of the knee flexor and
extensor. This may be possibly due to the fact that the more impaired knee was entered in
the treatment group more often than in the control group. This trial was piloted by the
trial by Schneider (1997)
Risk of bias
Moreland 1993
Methods Randomised
Controlled
Trial
Double-blind
Blinded assessor
Screen blinded pt
Parallel-group
Multicentre (n=5)
4 wk washout of NSAID but permitted acetaminophen as analgesia
Analysis: ITT
Phase I efficacy:
per protocol
Flare population: n=30 (31 knees)
U.S.A.
Mean age: NR
% Female:67
Mean disease
duration: NR
Duration:34 wk
(HA 46, AR 48)
[104 knees:
HA 52, AR 52]

Moreland 1993 (Continued)
Inclusion:
chronic idiopathic OA of knee confirmed by xray
Kellgren and Lawrence Grade 2 to 4 in no more than 2 compartments
symptoms of inflammation and/or advanced disease which included rest pain during day
of at least moderate severity (>=40/
100 mm VAS) or pain awakening them at night
Exclusion:
pregnant or of childbearing potential not using effective contraception
varus or valgus deformity >=10o
surgery on knee in past 3 mth or planning surgery
chondromalacia as primary contributor to symptoms
<18 y
unavailable for 26 wk follow-up
RA, AS, gout, IBD,
pseudogout,
psoriatic arthritis,
peripheral neuropathy causing pain or diastasis distal to knee
metabolic disease associ-
ated with joint abnormalities
liver disease
cancer
diabetes mellitus, drug abuse
Baseline values:
pain with motion
HA: 69, AR: 70

(2 ml)
3 weekly arthro-
centeses followed by injection
Arthrocentesis
3 weekly
Concurrent therapy:
Acetaminophen
usage for analgesia documented (pill counts)
Outcomes pain with walking, at rest, at night, with motion and overall ( 100 mm VAS)
activity restriction
joint tenderness
(100 mm VAS)
joint effusion (+/-,
volume)
pt and evaluator global assess-
ments (100 mm VAS)
Assessments:
Phase I
Wk 0,2,4,5,6,8,10
Phase II
Wk 10-18,11-19,12-

Moreland 1993 (Continued)
20,16-22,18-26,
26-34
Notes Jadad’s:5/5
R-2,B-2,W-1
If bilateral OA, both knees could be treated and evaluated.
10 pts had both knees treated -
(5 AR, 1 HA, 4 both)
34% patients presented with an effusion.
Each knee randomised
Arthrocentesis with removal of effusion if present.
In Phase II, evaluated repeat treatment with a second course of three hylan G-F 20 injections
but no control group.
Biomatrix, Inc. sponsored work.
Risk of bias
Nahler 1996
Methods See Nahler 1998.
Participants
Interventions
Outcomes
Notes
Risk of bias

Nahler 1998
Methods Randomised
Controlled
Trial
Single-blind
Parallel-group
Multicentre (n=12)
Stratified by pain severity
Equivalence study
Germany and Austria
Mean age: 67
% Female: 80
Mean disease duration: 68% <1 year
Duration: 5 wk
(ZL 57, HY 57)
Inclusion:
presence of primary (idio-
pathic) arthritis verified by:
pain in 1 or 2 knees
a typical xray (medial narrow-
ing of the joint
cavity, peripheral
osteophyte de-
velopment, com-
pact ossification of subchondral bone)
chronic pain in 1 or 2 knee joints for at least 3 mth with no sign of acute inflamma-
tion
written statement of patient consent
Exclusion:
age <35 or >85 y
arthritis resulting from prior defor-
mations, injuries
or metabolic causes (secon-
dary arthritis)
other ailments with symptoms similar to arthritis of the knee such as arthritis of the hip,
varicosis, bone & muscle disorders, RA
signs of acute inflammation (acute active arthritis)
nonambulatory or bedridden pts
pts who stated their intention to change level of physical activity during the study
probable surgical treatment of the arthritic joint in the near future
i-a corticosteroid treatment of the arthritic joint within the past 2 mth
low grade pain (<25 mm on the 100 mm VAS)
a history of aller-
gic reactions to Zeel or Hyalart
serious liver or kidney disease
long term treat-
ment with immu-

Nahler 1998 (Continued)
nosuppressives during last mth

ongoing concom
itant therapy with
analgesics/anti-
inflammatories
Interventions Zeel compositum

10 injections (two 2 ml injections/wk)
Hyalart (2 ml)
5 weekly injection
Concurrent therapy:
Analgesics & anti-
inflammatories
prohibited
Outcomes Pain during active movement on 100 mm VAS (0=pain free, 100=worst pain to date)
pt final assess-
ment of toler-
ance on 100 mm VAS (0=ex-
tremely poorly tolerated, 100= extremely well tolerated)--------pain during night on 100
mm VAS
duration of morning stiff-
ness (min)
maximum dis-
tance capable of walking
time (sec) to walk up and down a stand-
ard series (1 flight) of stairs
final assess-
ment of efficacy
by MD and pt on 100 mm VAS (0=no improve-
ment, 100=ex-
treme improve-
ment)
final assess-
ment of toler-
ance by MD and pt on 100 mm VAS as above
drop-out rate
resulting from inadequate efficacy
reporting of un-
desired side effects (weekly)
Notes Jadad’s:4/5
R-2,B-1,W-1
Risk of bias

Neustadt 2004
Methods See Neustadt 2005a-3inj.
Participants
Interventions
Outcomes
Notes
Risk of bias
Neustadt 2005
Methods See Neustadt 2005a-3inj
Participants
Interventions
Outcomes
Notes
Risk of bias
Neustadt 2005a -3inj
Methods Randomised
Controlled
Trial
Arthrocentesis controlled
Multicentre n=24, (Canada n=3, USA n=21)
Double-blind
7-day washout
NSAID and analgesics
January 2001 to December 2002

Neustadt 2005a -3inj (Continued)
Canada and the United States
Mean age: 176.4
% Female: 47.9
Duration:28 wk
(O4 128,
O3A1 120, and
A4 124)
Inclusion:
greater than or equal to 40 y of age,
willing to discontinue all analgesics and NSAID 7 days before the first injection and for
the duration of the study,
diagnosis of knee OA according to ACR criteria,
Kellgren-Lawrence grade 1,2 or 3,
a summed WOMAC pain score greater than or equal to 200 mm and less than 400 mm
(maximum 500) in the index (treated) knee and less than 150 mm in the contralateral
(untreated) knee
Exclusion:
patients who initiated an exercise or physical therapy program within 3 mth,
oral or parenteral corticosteroid use within 30 days,
intraarticular injection of steroids into the index knee within 90 days,
intraarticulr injection of any hyaluronic substanced within the past 9 mth or operative
arthroscopy within 6 mth,
treatment with anticoagulants,
clinically significant comorbidity (fibromyalgia, peripheral neuropathy, vascular insuffi-
ciency or hemiparesis) severe enough to interferewith accurate evaluation
Baseline values:
(based on evaluable (per protocol) population)
WOMAC pain
index knee
O4: 286.6
O3A1: 289.0
A4: 294.1
contralateral knee
O4: 66.8
O3A1: 69.3
A4: 64.6
Patient global
O4: 67.5
O3A1: 62.4
A4: 64.4
Investigator global
O4: 58.8
O3A1:57.0
A4: 57.6

Neustadt 2005a -3inj (Continued)
Pain on standing
O4: 65.2
O3A1: 65.7
A4: 65.5
Synovial fluid volume (ml)
O4: 0.9
O3A1: 1.0
A4: 0.9
Mean analgesic usage (tablets/day):
O4: 2.08
O3A1: 2.48
A4: 2.05
Interventions 1) O4: Orthovisc 2 ml (30 mg) 4 weekly injections

2) O3A1: Orthovisc 2 ml (30 mg) 3 weekly injections plus one control arthrocentesis
procedure
3) A4: 4 control arthrocentesis
All injections were administered by either lateral or medial approach after instillation of
1% lidocaine hydrochloride solution. If fluid present, joint space aspirated to dryness.
Concurrent therapy: Acetaminophen up to 4 g/day allowed but not permitted for at least
24h prior to each study assessment visit.
NSAIDs and other analgesics not permitted during the study.
Outcomes The proportion of patients achieving a 20% relative and 50 mm absolute improvement
from baseline in WOMAC pain score at weeks 8, 12, 16 and 22 post baseline in the Index
Knee (0-500 mm VAS)
-----------------------
patient global score,
investigator global score and pain on standing score all scored on a 0 to 100 mm VAS

R-2, B-2, W-1
The evaluable poulation (patients who received all 4 treatments and at least one followup
visit and who had no significant protocol deviation) was considered the primary planned
analysis population NOT the intent to treat population.
Screend patients: 888;
Randomised patients: 372;
ITT (safety) O4: 128, O3A1: 119, A4: 123;
Evaluable: 336
O4: 115, O3A1: 107, A4: 114;
Per protocol: 258
O4: 93, O3A1: 76, A4: 89
Risk of bias

Neustadt 2005b-4inj
Methods See Neustadt 2005a-3inj.
Participants
Interventions
Outcomes
Notes
Risk of bias
Ozturk 2005
Methods Randomised
Controlled
Trial
Single-blind
Single centre
7-day washout of NSAID

Mean age: 58.03
% Female: 97.5
Duration: 1 y
(HA: 24, HA+TA: 23)
Inclusion:
OA of the knee according to ACR criteria,
Kellgren-Lawrence grades II or III radiographically confirmed,
pain in affected knee for at least 6 mth
Exclusion:
received intra-
articular injection in the joint and/or attend physiotherapy for the affected knee within 6
mth prior to study,
history of allergy or hypersensitive to drugs or eggs,
ascertained or suspected to be pregnant or lactacting,
known or suspected joint infection or a specific condition (neoplasms, diabetes mellitus,
paresis, osteonecrosis, recent trauma) or poor general health that would interfere with the
functional assessments during the study
Baseline values:
range of motion
HA: 112.0

Ozturk 2005 (Continued)
HA+TA: 118.8
50-foot walking time
HA: 23.7
HA+TA: 22.6
pain (VAS)
HA: 66.7
HA+TA: 72.6
WOMAC pain
HA: 14.3
HA+TA: 16.3
WOMAC stiffness
HA: 4.1
HA+TA: 4.1
WOMAC function
HA: 53.3
HA+TA: 49.0
WOMAC total
HA: 71.8
HA+TA: 69.6
Interventions Orthovisc (2 ml Biomeks) alone 3 weekly injections

(Days 0,7,14) then 3 injections at month 6,
Combined group: same as above but prior to lst and 4th HA injection, effusions aspirated
and then 1 ml triamcinolone acetonid (Kenacort-A, Bristol Myers Squibb)
Concurrent therapy: paracetamol to a maximum of 2 g daily as considered appropriate by
the physician was permitted;
NSAID not permitted.
Outcomes WOMAC OA Index (Likert),

pain (0-100 mm VAS), ROM - flexion only with a goniometer,
50 foot walking time (sec), assessment of effusion (peri-
pheral measurement of knee),
MRI - cartilage evaluated with an eight grade system by 2 independent observers

R-2, B-0, W-1
No statistically significant differences in demographic or clinical data at baseline.
Although 47 patients enrolled, 7 in the HA+TA group were withdrawn as they did not
meet inclusion criteria
Risk of bias

Petrella 2002
Methods Randomised
Controlled
Trial
Double-blind
Placebo- controlled
Parallel-group
2 wk washout all OA medications
ITT analysis
Canada
Mean age: 65.5
% Female: 46
Mean disease
duration: NR
Duration: 12 wk
(30/group)
Inclusion:
radiographic evidence of Grade 1 to 3 medial compartment unilateral knee OA [Grade 1-
23%,
Grade 2 - 45%,
Grade 3 - 32%]
>=3 cm current rest pain
absence of non-OA arthritides
Exclusion:
previous NSAID intolerance
gastrointestinal hemorrhage
peptic ulcer disease
avian allergy
intraarticular injection of HA or corticosteroid in previous 6 mth
regular con-
consumption of ”herbal“ OA products (e.g. glucosamine sulfate)
Baseline values:
WOMAC pain
HA+PL: 3.32
NSAID+PL: 4.22
NSAID+HA: 3.65
PL: 3.62
WOMAC function
HA+PL: 4.10
NSAID+PL: 4.32
NSAID+HA: 3.90
PL: 4.72
Rest pain:
HA+PL:3.29
NSAID+PL:3.34
NSAID+HA:3.60
PL:3.30

Petrella 2002 (Continued)
Baseline xray:
HA+PL: 2.2 (0.3)
NSAID+HA: 2.2 (0.5)
NSAID+PL: 2.3 (0.4)
PL: 2.2 (0.2) based on Altman et al 1987 Arthritis Rheum.
Interventions Suplasyn 20 mg
3 weekly injections
+ placebo (lactose 100 mg po bid)
Suplasyn 20 mg
3 weekly injections + 75 mg diclofenac/
200 ug misoprostol
po bid (Arthrotec)
Saline 2 ml
3 weekly injections + 75 mg diclofenac/
200 ug misoprostol
po bid (Arthrotec)
Saline 2 ml
3 weekly injections
+ placebo (lactose 100 mg po bid)
All pts received 10 min home-based resistance exercise program to be done at least 3x/wk
but preferably most days/wk
Concurrent therapy:
325 mg acetaminophen
Outcomes self-report of cur-

rent pain at rest on VAS
WOMAC OA Index
functional perfor-
mance of self-
paced walking test and a self-
paced stepping test - VAS scale
of pain after completion and performance time
range of motion
VO2 max
Notes Jadad’s:5/5
R-2,B-2,W-1
Unilateral only
Discrepancy between abstract and paper for rest pain mean and sd at baseline and sd at 4
wk. The sd for SPW and SPS pain at wk4 changed as well but WOMAC pain and function
and walk time values did not change.
Results only presented for Week 4 not Week 12.
Study supported by Bioniche Life Sciences Inc.
Dr. Hildebrand is affiliated with Bioniche Life Sciences Inc.
Editorial reports that a factorial design analysis most efficient; a reanalysis found no evidence
that Suplasyn had a signficant or important clinical effect on pain
Risk of bias

Petrella 2002 (Continued)
Pham 2003
Methods See Pham 2004
Participants
Interventions
Outcomes
Notes One author of abstract, S. Brin, affiliated with Aventis, Paris, France
Risk of bias
Pham 2004
Methods Randomised
Controlled
Trial
Double-blind
X-ray scorers blinded
Placebo- controlled
Parallel group
Multicentre (46 rheumatology departments)
Parallel-group
Multicentre
ITT (LOCF)
Repeat treatme
France
Mean age: 64.8
% Female: 68
Duration: 1 y
(NRD+PLDIA 131, PLINJ+DIA
85, PLINJ+PLDIA 85)
Inclusion:

Pham 2004 (Continued)
outpt fulfilling the ACR clinical or radiological criteria for the diagnosis of knee OA,
presenc eof a symptomatic primary painful medial femorotibial knee OA defined by a daily
pain VAS score >30 mm in the previous mth,
medial joint space width >2mm,
radiographic evidence of knee OA, eligibility criteria and quality of radiographic films were
verified by a central reader
Exclusion:
evidence of secondary knee OA (possibly due to injury, inflam-
mation or meta-
bolic rheumatic disease, osteonecrosis, Paget’s disease, villonodular synovitis, haemophilia)
,
prior ia HA treatment, other ia injection including lavage and corticosteroids within the
previous 3 mth,
treatment with diacerein in the 3 mth before inclusion and use of any other anti-os-
teoarthritic drugs in the 2 mth before inclusion,
contraindication to IA injection (anticoagulants, haematological anomalies),
severe knee OA (JSW <2 mm, surgery required on the evaluated knee in the year)
Baseline values:
Pain (0-100)
NRD: 61.7
DIA: 59.6
PL: 59.1
Lequesne
NRD: 11.1
DIA: 10.5
PL: 10.5
Pt global (0-100)
NRD: 59.7
DIA: 59.0
PL: 57.3
% of painful days during previous mth (0-100)
NRD: 85.5
DIA: 83.0
PL: 82.6
JSW (mm)
NRD: 4.5
DIA: 4.5
PL: 4.7
Interventions 1) NRD 101 - 3 courses of 3 IA injections+ oral placebo,

2) IA injections of saline + Diacerein 50 mg twice daily,
3) IA injections of saline + oral placebo
Concurrent therapy: Allowed to take analgesics as rescue drugs but 2-day washout before
evaluation visit; aspirin <500 mg/day allowed; NSAID allowed but 7-day washout requied
before each evaluation visit; no systemic corticosteroid, IA treatment or any potential
symptom modifying drug was allowed during the study
Outcomes Pain (0-100 mm VAS),

Lequesne,

Pham 2004 (Continued)
Pt. global assessment of disease activity (0-100 mm VAS),

% of painful days during previous months (0-100 mm VAS),
use of concomitant treatments (analgesics and NSAIDs) evaluated by numbers of days of
intake between each clinic visit,
pt and investigator global assessment of treatment efficacy (5 point Likert: very good, good,
moderate, bad, very bad),
investigator global assessment of treatment safety on 5 level Likert scale,
Structural:
JSW, Kellgren Lawrence grade,
osteophyte score on antero-posterior X-ray,
% of progressors (joint space narrowing 0.5 mm)

R-2, B-2, W-1
Risk of bias
Pietrogrande 1991
Methods Randomised
Controlled
Trial
Open-label
Parallel-group
Multicentre
ITT analysis
Italy
Mean age: NR
% Female:73
Mean disease
duration: NR
Duration:60 days
(HA 45, MPA 45)
Inclusion:
confirmed radiological signs of knee OA (Kellgren) and presence of pain
Exclusion:
knee joint disease other than OA
severe concomitant diseases or diseases inter-
fering with evaluation of knee joint OA
pregnancy
allergy

Pietrogrande 1991 (Continued)
skin infections
other IA treatments in past 3 mth
Baseline values:
% pt pain under load strong
HA:40, MPA: 64
% pt rest pain strong
HA: 20, MPA: 22
% pt pain on touch strong
HA: 18, MPA: 22
% pt night pain strong
HA: 16, MPA: 11

5 weekly injections
at 7 day intervals
6-methylprednis-
olone acetate
(40mg/1 ml) 3 weekly injections (Depo-Medrol)
Concurrent therapy:
Analgesic & NSAID consumption assessed
Outcomes daytime spon-

taneous pain on
100 mm VAS
morning stiffness (min)
range of motion (goniometer)
pt and MD efficacy
assessment (0=
unsatisfactory,1=poor,2=fair,3=
good,4=excellent)-----------------
night pain, rest pain, pain under load, touch pain (0=absent,1= slight, 2=moder-
ate,3=strong,4= very strong)
NSAID,analgesic
consumption,0-3:0=none,1=occa-
sional,2=continu-
ous low doses,
3=continuous high doses)
effusion volume
(ml)
Notes Jadad’s:2/5
R-1,B-0,W-1
Drugs supplied by Fidia S.p.A.
P. Pierfederici and A. Perbellini, Fidia S.p.A.
Risk of bias

Pietrogrande 1991 (Continued)
Puhl 1993
Methods Randomised
Controlled
Trial
Double-blind
Parallel-group
Multicentre (n=24)
Efficacy analysis: per protocol, n=195, safety analysis: ITT, n=209
Germany
Mean age: 62
% Female: 64
Mean disease
duration: NR
Duration:18 wk
(Wk 18 either in person or
telephone follow-up)
(HA 102, PL 107)
Inclusion:
40-75 y
informed consent
idiopathic OA of knee defined by clinical and xray criteria (Lequesne)
Exclusion:
inflammatory jt disease
ESR>40 mm
RF >1:40
specific arthropathies (chondrocalcinosis, jt effusion >100 ml)
excessive obesity
severe axis deviations or instabilities
protheses of lower limbs
symptomatic hip
IA injection in prior 3 mth
infectious or febrile diseases
joint or skin infections pregnancy
contraindication to paracetamol
Baseline values:
pain
HA:54.1, PL:51.4
Lequesne
HA:10.4, PL:9.4
pain under load
(% pt moderate/ severe)

Puhl 1993 (Continued)
HA:90.5, PL:87.0
pain at rest
(% pt moderate/
severe)
HA:41.1, PL:35.0
pain starting to walk (% pt mod-
erate/severe)
HA: 73.3, PL:63.0
Interventions Artz (25mg/2.5 ml)

5 weekly injections
Placebo:sodium hyaluronate 0.25mg/2.5 ml
5 weekly injections
Concurrent therapy:
Paracetamol up to 1-2 tabs of 500 mg tid daily permitted
Outcomes Lequesne
paracetamol consumption-----
modified Lequesne
pain last week,at rest, under load, starting (100 mm VAS)
crepitation
joint effusion
joint mobility
pt and MD global
efficacy rating
overall tolerance
Notes Jadad’s:5/5
R-2,B-2,W-1
Significantly more females in Artz group (73% versus 55%, P value 0.011)
Retrospective analysis indicated patients >60 y and Lequesne >10 most likely to benefit
from treatment.
Work sponsored by Luitpold Pharma Munich. Statistical evaluations performed by Mr.
Elsasser
Risk of bias

Raynauld 2002
Methods Randomised
Controlled
Trial
Steering Committee blinded
Multicentre (n=14)
Parallel-group
Open-label
ITT analysis
Canada
Mean age: 63
% Female: 70
Duration: 1 y
(AC+H 127, AC 128)
Inclusion:
>40 y
primary diagnosis of radiologically verified OA in study knee
symptomatic (>175/500 WOMAC pain) despite prior treatment with NSAIDs or ac-
etaminophen
ambulatory
willing to participate
sign informed consent
Exclusion:
Grade 4 (Kellgren)
contraindicated per Hylan G-F20 label
inflammatory arthropathies
tense effusion in study knee at baseline
chondrocalcinosis
varus or valgus deformity >12o in study knee
steroid inj in prior 3 mths in study knee
prior viscosupplementation
isolated patello-femoral OA
uncontrolled morbidity particularly that in any joint which would impede measurements
in study knee
Baseline values:
WOMAC pain
AC+H: 11.35
AC: 11.94
WOMAC function
AC+H: 39.54
AC: 40.20
Interventions Appropriate care with hylan G-F20

(AC+H)
Appropriate care without hylan G-F20
(AC)
Concurrent therapy:

Raynauld 2002 (Continued)
Standard care
Outcomes Mean change in WOMAC LK3.0 pain score in study knee baseline to termination--------
% pts improved at termination from baseline for 1) 20% improve-
ment WOMAC pain in study knee, 2) 20% WOMAC pain and either 20% ftn or stiffness
in study knee
pt global assessment of effectiveness for 1) OA in study knee, 2) OA in all jts, 3) overall
health
HRQOL: WOMAC, SF-36, HUI3
safety: pt. self report during telephone inter-
view and global assessments of side effects
Assessments:
Wk0,Mth1,2,4,6,8,19,12 (Wk 0 and
Mth 12 at site; others by telephone interview)

R-2,B-0,W-1
109 AC+H and 108 AC had bilateral knee OA.
Tense effusion at baseline excluded pt.
Although Grade IV xray grade was to be excluded, 20% of AC+H and 33% of AC had
grade IV.
An independent Steering Committee designed the study, developed analysis plan, resolved
methodological issues and interpreted and disseminated results.
A CRO, Innovus Research Inc., managed the study.
Study was funded by Biomatrix, Inc.and Rhone-Poulenc Rorer Canada Inc. Dan Pericak
provided statistical analysis
Risk of bias
Redd 2003
Methods See
Leopold 2003.
Participants
Interventions
Outcomes
Notes
Risk of bias

Redd 2003 (Continued)
Rejaili 2005
Methods Randomised
Controlled
Trial
Single centre
Brazil
Mean age: 54.5
% Female: 80
Duration: 6 mth
(HA 10, AR 10)
Inclusion:
knee arthrosis refractory to conservative treatment with blockage and pain symptoms,
grade 3 Kellgren and Lawrence radiological classification
Exclusion:
NR
Baseline values (preoperative):
Pain in rest
HA 7.90
AR 8.30
Pain with load
HA 8.60
AR 9.20
Pain upon movement
HA 8.40
AR 9.10
Diclofenac used
HA 2.80
AR 2.50
Postoperative values:
Pain in rest
HA 3.20
AR 4.00
Pain with load
HA 3.80
AR 4.50
Pain upon movement
HA 3.90
AR 5.20

Rejaili 2005 (Continued)
Diclofenac usage
HA 0.90
AR 0.80
Interventions Arthroscopy (articular lavage and debridement) plus 3 weekly injections of hylan G-F 20,
Arthroscopy alone
Both groups instructed to stroll first postoperative day. Stitches removed at first visit after
2 weeks at which time the course of Hylan G-F 20 was started.
Concurrent therapy: potassium diclofenac permitted with daily usage recorded
Outcomes VAS (patient saw ”faces“ and colours ranging from blue to red as pain increased while
observer side showed absolute numerical value (0-10)
pain during the night,
pain during movement with a 10% overload of weight on affected knee, pain reduction
during the most painful movements of the knee, daily amount of potassium diclofenac
used to relieve pain of the injured knee, chondral lesions at time of arthroscopy scored by
Noyes and Stabler appud Lemark (grades I to III)

R-1, B-0, W-1
No between group differences at baseline. Statistical analyses completed at Laboratory for
Study Design and Data Analyses of the Dept. of Epidemiology and Public Health of the
Medical School of Sao Jose do rio Preto
Risk of bias
Roman 2000
Methods Randomised
Controlled
Trial
Blind
Parallel-group
ITT analysis
Spain
Mean age: 65
% Female:84
Mean disease
duration:NR
Duration: 6 mth
(AD 30, HY 19)

Roman 2000 (Continued)
Inclusion:
gonarthrosis by clinical and radiological criteria
(Kellgren and Lawrence Grade 2 to 3)
Exclusion:
NR
Interventions Adant (25 mg/2.5 ml) 5 weekly injections

Hyalgan (20 mg/2 ml) 5 weekly injections
Concurrent therapy:
Analgesics and/or
NSAIDs monitored
Outcomes pt efficacy assessment

(clinical improvement crieria rated as: excellent >75, good 50 to 75,
fair 25 to 50, no clinical
response <25)
consumption of analgesic and/or NSAIDS
Notes Jadad’s:3/5
R-1,B-1,W-1
Imbalance in sample size per group.
Risk of bias
Scale 1994a (2 inj)
Methods Randomised
Controlled
Trial
Double-blind
Blinded assessor
Placebo- controlled
Single centre
2 wk washout of NSAID and analgesics.
ITT analysis
Germany
Mean age: 60
%Female:
Study A: 57
(37/65)
Mean disease
duration: 5.6 y

Scale 1994a (2 inj) (Continued)
Duration: 12 wk
Telephone follow-up
at 26 wk
Number randomised:
Study A: 50
(HA 25, PL 25)
Inclusion:
>18 y
male and female
diagnosis of OA of the knee
Grade 2 to 4 Larsen scale
Exclusion:
RA
unreliable
pain under weight bearing <40/100 mm VAS
effusion present in the joint
Baseline group differences:
1) Significantly more pts had Grade 4 xray in PL group
2) females in 2 inj group weighed significantly less than PL group
Interventions Study A:
Hylan G-F 20
2 ml
(2 inj: end of washout and 2 wks later)
Placebo: Phosphate-
buffered saline 2.0 ml
Concurrent therapy:
No medication to treat arthritis pain allowed.
Outcomes weight bearing pain by pt and MD on VAS

night pain pt and MD on VAS
reduction of activity while performing daily tasks (joint mobility) assessed by MD during
examination
improvement in most painful knee movement by pt on VAS
global evaluation of efficacy due to
treatment by pt and MD on VAS
Assessments:
Wk 0,2,4,8,12,26
Notes Jadad’s:4/5
R-1,B-2,W-1
Control groups combined for analyses in publication. Separate group results in PMA.
Excluded pts with effusions.
Arthrocentesis with removal of effusion if present.
If bilateral OA, only most painful knee treated.
Research was supported by Biomatrix, Inc.
Risk of bias

Scale 1994a (2 inj) (Continued)
Scale 1994b (3 inj)
Methods See Scale 1994a

above.
Germany
Mean age: 59
% Female:
Study B: 44
(24/55)
Duration: 12 wk
Telephone follow-up
at 26 wk
(HA 15, Pl 15)
Inclusion/
Exclusion as above (Scale 1994a).
Baseline group differences:
1) Significantly more patients had Grade 4 xray in PL group.
2) 3 inj group had significantly shorter disease duration at baseline

(2 ml) 3 weekly injections
Placebo:
Phosphate-
buffered saline 2.0 ml
Concurrent therapy:
No medication to treat arthritis pain allowed.
Outcomes See Scale 1994a above.

Assessments:
Wk 0,1,2,3,8,12,
26
Notes Jadad’s:4/5
R-1,B-2,W-1
See Scale 1994a above.
Excluded pts with effusions.
Arthrocentesis
with removal of effusion if present.
If bilateral OA only most painful knee treated.
Research was supported by

Scale 1994b (3 inj) (Continued)
Biomatrix, Inc.
Risk of bias
Schneider 1997
Methods See Miltner 2002.
Participants
Interventions
Outcomes
Notes
Risk of bias
Sezgin 2005
Methods Randomised
Controlled
Trial
Single-blind
Turkey
Mean age: 59.7
% Female: 75.6
Duration: 4 wk
(HA 22, PL 19)
Inclusion:
diagnosis of primary gonarthrosis based on modified ACR criteria,
Kellgren-
Lawrence grade II or III on plain x-ray,
presence of effusion in the painful and swollen kne,
total pain score of 15 or over on the WOMAC OA Index,
not receiving NSAIDs

Sezgin 2005 (Continued)
Exclusion:
in the previous year, injection of HA or application of physiotherapy to the knees included
in the study,
administration of ia medicine to the knees included in the study or exposure to trauma
within the previous 3 mth,
oral or intramuscular administration of carticosteroids in the previous 2 mth,
pregnancy or lactation,
history of allergy and the preence of infectious, inflammatory, metabolic or malignant
disease,
presence of OA of the hip and the opposite knee severe enough to affect the evaluation of
functions
Baseline values:
WOMAC pain
HA: 18.9,
PL: 17.2
WOMAC stiffness
HA: 6.5
PL: 4.5
WOMAC function
HA: 64.1
PL: 50.0
Flexion
HA: 95.9
PL: 108.4
Walk time
HA: 43.1
PL: 31.5
Knee circumference
HA: 41.5
PL: 41.3
Effusion volume
HA: 19.0
PL: 18.5
IL-6 in pg/ml
HA: 42.8
PL: 51.7
IL-8 in pg/ml
HA: 20.6
PL: 17.9
TNF-alpha in pg/ml
HA: 77.0
PL: 80.8
(15 mg/ml)
2 ml three weekly injections,
NaCl 0.9% 2 ml three weekly injections
Both groups had any effusion aspirated before injection. All patients recommended to
use bandages and apply cold and rest for 48h. All instructed to do isometric quadriceps
exercises.

Sezgin 2005 (Continued)
Concurrent therapy: acetaminophen permitted but no other analgesics or NSAID allowed
Outcomes IL-6, IL-8, TNF-alpha,

WOMAC OA Index (Likert: pain (5-25), stiffness (2-10), function (17-85)),
flexion,
25 m walking time (sec),
circumference of knee measured in the middle of the patella (cm),
amount of effusion (ml)

R-1, B-0, W-1
Statistically significant poorer values in the HA group verus PL group for WOMAC pain,
stiffness, function, flexion, and walking time
Risk of bias
Shichikawa 1983a
Methods Randomised
Controlled
Trial
Double-blind
Multicentre (n=38)
Safety analysis: ITT, n=219
Efficacy analysis: per protocol, n=208
Japan
Mean age: NR
% Female: NR
Mean disease
duration: NR
Duration:5 wk
(HA 114, PL 114)
Inclusion:
knee OA with clinical symptoms with exercise pain & at least 1/3 radiographic change:
joint space narrowing, sclerosis, bony spur formation
written or oral consent
Exclusion:
severe JSN
marked retention of synovial effuson
IA corticosteroids or any other drug within 2 wk
serious concurrent diseases

Shichikawa 1983a (Continued)
drug allergy
pregnant or lactating females
pt whose info was difficult to obtain
doctors judged unsuitable
Interventions sodium hyaluronate

(25 mg/2.5 ml)
1.0% SPH (Artz)
5 weekly injections
+ placebo tablet 3T/day
Placebo:sodium
hyaluronate
(0.25mg/2.5 ml)
0.01% SPH
5 weekly injections
+ placebo tablet 3T/day
No local anesthesia.
Concurrent therapy:
No ”new“ arthritis treatment permitted. Physio that had been in effect >2 wk continued
but no ”new“ PT
Outcomes pain at rest, walking,up and down stairs, flexion and extension pain,
oppressive pain,
swelling, ballote-
ment of patella,
presence/absence of synovial effu-
sion and volume
range of motion: no symptom, mild,
moderate,
marked
overall severity:
mild, moderate,
severe
diary: VAS pain and
activities of daily living: 10 min walk, up/down
stairs,squat to pick up some-
thing on floor,
sit on floor or ta-
tami, 5 classes:
possible to do as
normal person,
fairly possible to do alone without much difficulty, fairly possible to do alone but often
with difficul-
ty, needed help of others, impos-
sible
subjective change in symptoms (1-7:
excellently im-
proved,improved,fairly improved,
unchanged,

Shichikawa 1983a (Continued)
slightly worsened,
worsened,
markedly wor-
sened)
global effective-
ness (1-7: excel-
lent improvement,
good improve-
ment,fair improvement,
poor improve-
ment,slight aggravation,moderate aggravation,marked aggravation)
overall evaluation: final effectiveness (1-7: excellent improvement,
good improve-
ment, fair improvement,
poor improve-
ment, slight aggravation,
moderate aggravation, ex-
treme aggrava-
tion) + safety (1-3:no side
effect, side effect but drug contin-
ued, drug dis-
continued due to side effect) + usefulness (1-7:
extremely useful,
useful,fairly use-
ful,uncertain,
slightly unfavor-
able,unfavorable,
extremely unfa-
vorable)
Notes Jadad’s:4/5
R-1,B-2,W-1
In case of bilateral OA, worst side ”mainly evaluated“.
Excluded marked synovial effusion.
Synovial effusion aspirated and volume measured. Baseline pain going up and down stairs
significantly more severe in Artz group (p<0.05).
Work sponsored by Seikagaku Corporation.
N. Ogawa in change of statistical analysis.
Risk of bias

Shichikawa 1983b
Methods Randomised
Controlled
Double-blind
Multicentre (n=16)
Safety analysis:
ITT, n=103
Efficacy analysis:
per protocol, n=98
Japan
Mean age: 62
% Female: 83
Mean disease
duration: NR
Duration: 5 wk
(HA 52, PL 55)
Inclusion:
apparent clinical signs with pain on movement
xray at least 1 of joint space narrowing, spur formation, osteosclerosis
consent
Exclusion:
moderate to severe JSN
varus or valgus
deformities
synovial effusion
IA corticosteroid injection in past 2 wk
pregnant or lactating females
hard to communicate
cases thought to be inadequate for trial by doctors in charge
Baseline values:
% pt moderate
walking pain
HA:52, PL:46
ROM
HA:133.4,
PL:128.6
pain score
HA:1.03, PL:1.12
Interventions sodium hyaluronate 5.0 ml of 0.5% SPH solution

5 weekly injections
+ 2 sugar coated lactose pills tid
Placebo: 5.0 ml of 0.01% SPH solution 5 weekly injections
+ 2 sugar coated lactose pills tid
Concurrent therapy:
No ”new“ arthritis therapy permitted

Shichikawa 1983b (Continued)
Outcomes pain: rest, walking, up and down stairs, press, flexion and extension, sense of fever, swelling,
range of motion, ballotement of patella
(4 point scale:
no symptom, mild, moderate, severe)
disturbance of 4 activities of daily living: walk 10 min,
up/down stairs,
squat to pick up
things from floor,
sitting on floor or
tatami: 5 ranks:
can do as the
normal people,
scarcely possible by one-
self and not so in-
convenient,
scarcely possible
by oneself but inconvenience necessary for aid, totally impossible
diary for activities of daily living and pain (knee pain at rest and at the beginning of
motion:0=no pain,1=mild, 2=
painful but mo-
bile,3=painful &
immobile,4=un-
endurable pain & can do nothing)
general improve-
ment (1-7: sig.
improved,moder-ately improved, lightly improved,
no change,lightly worsened, mod-
erately worsened
sig. worsened)
impression by pt
(1-7:sig. improved,fairly
improved,slightly
improved, no
change,slightly
worsened, fairly
worsened, sig.
worsened)
general evalua-
tion (1-7: sig.
improved,moder-ately improved,
slightly improved,
no change, slightly worsened,
moderately worsened, sig.
worsened)
general safety
(1-3: no side
effect,side effect seen but can continue treat-

Shichikawa 1983b (Continued)
ment, stop treat-

ment because of side effect)
usefulness judged on general improvement and general safety: 7 ranks:
extremely useful,
fairly useful,
slightly useful,
cannot judge
whether useful or
not useful,
slightly undesir-
able, fairly unde-
sirable, extremely unde-
sirable
Notes Jadad’s:4/5
R-1,B-2,W-1
Pt with moderate to severe synovial effusion excluded.
If bilateral, evaluation completed on knee fulfilling entry criteria.
Test drug provided by Seikagaku Kogyo Co., Ltd.
Risk of bias
St. J. Dixon 1988
Methods Randomised
Controlled
Trial
Double-blind
Parallel-group
Multicentre (n=3)
Placebo- controlled
Per protocol analysis
England
Mean age: 69
% Female: 54
Mean disease
duration: NR
Duration: 48 wk
(HA 30, PL 33)
Inclusion:
outpatients of either sex and any age

St. J. Dixon 1988 (Continued)
symptomatic OA of one of both knees

informed consent
Exclusion:
inflammatory knee conditions,
e.g. RA, psoriatic, pseudo-
gout or joint infection
OA of the hip which could confuse assessment
poor general health
skin conditions which would deter injection
receiving regular analgesic therapy for reasons other than painful OA of the knee
Interventions Hyalgan (20 mg/2 ml)

up to 11 injections over a 23 week period
Placebo: l/100th of active, e.g. 0.2 mg sodium hyaluronate
Concurrent therapy:
Paracetamol 3000 mg daily permitted
Outcomes pain at rest and on movement (100 mm VAS)

activities of daily living (6 activities
scored 0=no diff-
iculty to 7=activity
impossible, total = 42)
questioned and ex-
amined for local or systemic adverse reactions
Notes Jadad’s:4/5
R-1,B-2,W-1
Dr. M. Massarotti, Dr. D. Massari and Dr. U. Cornelli of Fidia S.p.A. supported study
and supplied clinical trial material. Dr. R. Kohn and Dr. J.F. Harper of Advisory Services,
London helped with trial organisation
Risk of bias

Tamir 2001
Methods Randomised
Controlled
Trial
Single-blind
Parallel-group
Open-label
Placebo- controlled
Single centre
Israel
Mean age: 71
(BH: 71, PL: 70)
% Female: 73
Duration: 20 wk
(BH 25, PL 24)
Inclusion:
adults of either sex
between 60-85 y
evidence of idio-
pathic sympto-
matic clinical OA of the knee as per Altman criteria and radiologically verified
OA of the knee
(stages 2 to 4: Kellgren & Lawrence: BH:
2-6, 3-16, 4-3,
PL: 2-5, 3-11,4-7)
in good general health
no previous history of surgical treatment of joint or arthroscopy or injections to the knee
in 6 mth prior to study start
Exclusion:
pts with knee OA
originating from an i-a fracture, RA, joint infection, other inflammatory & metabolic
arthritis or OA of the hip joint,
pt with significant systemic diseases
allergy or atrophy or skin conditions overlying the joint which could cause adminis-
tration of injections to be problematic,
pt with copious joint exudates (>15 ml of aspirated synovial fluid)
Interventions BioHy 20 mg
(10 mg/ml)
5 weekly injections
Placebo: 2 ml of phosphate buffered saline
5 weekly injections
Concurrent therapy: Para-
cetamol and
NSAIDs were permitted

Tamir 2001 (Continued)
Outcomes pain at rest and during activity-----

stiffness and physical function as per the MODEMS arthritic model (none=1, mild=2,
moderate
=3, severe=4, extreme=5)
[looks like WOMAC]
muscle strength, stiffness, and tenderness of joint upon palpation scored on same scale,
active range of motion:
1= >135.2; 2=90 to 135;
3=45 to 90;
4= <45
Notes Jadad’s:3/5
R-1,B-1,W-1
Third author is affiliated with Bio-Technology General.
Risk of bias
Tascioglu 2003
Methods Randomised
Controlled
Trial
Blinded observer
Open-label
Parallel-group
Single centre
Per protocol n=55 (OR 28, 6-MPA 27)
Turkey
Mean age: 59
% Female: 100
Duration: 6 mth
Number recruited: 69
Inclusion:
ambulant patients with idiopathic OA as per ACR criteria,
Grade II or III
knee OA by Kellgren and Lawrence system,
pain under weight bearing >40/100 mm VAS
Exclusion:
Kellgren-Lawrence Grade IV,
knee joint disease other than OA,
OA of the hip,

Tascioglu 2003 (Continued)
OA of the feet,
serious concomitant systemic diseases,
ia injections within 3 mth prior to study start,
skin infections overlying the joint,
ia fluid effusion,
history of allergy or hypersensitivity to drugs,
treatment with anticoagulants,
previous knee surgery
Baseline values:
Weight bearing pain 100mmVAS
OR: 54.26
6-MPA: 53.10
Walking pain
OR: 67.60
6-MPA: 69.00
Rest pain
OR: 30.43
6-MPA: 29.90
Lequesne
OR: 10.23
6-MPA: 9.86
Flexion
OR: 108.70
6-MPA: 108.06
15 mg/ml
2 ml once per wk for 3 wk,
6-methylprednis-olone acetate
(6-MPA)
40 mg/ml
l ml once per wk for 3 wk
Depo-Medrol
Concurrent therapy: paracetamol (maximum of 3 g/day) but not permitted 48 h before
each injection and clinical assessment
Outcomes Pain at rest, at weight-bearing, and on walking

(100 mm VAS),
Lequesne Index
Flexion (degrees)

R-1,B-0,W-1
Risk of bias

Tekeoglu 1998
Methods Randomised
Controlled
Trial
Parallel-group
Open-label
ITT analysis
Turkey
Mean age: 58
% Female: 100
Mean disease duration: 54 wk
Duration:15 wk
(HA 20, BA 20)
Inclusion:
presence of pain
Kellgren scale
(result:Gr. 2 or 3)
Exclusion:
knee jt disease other than OA
history of allergy, skin infections
other i-a treatments in the 3 mths prior to study
Baseline values:
WOMAC function
HA:45.5, BA:45.6
maximum flexion
HA:110.5,
BA:116.0
Interventions Sodium hyaluronate 20 mg (Orthovisc)

3 injections: 1 every 7 days
Betamethasone 3 mg/ml (Celestone choronodose)
3 injections: 1 every 7 days
Concurrent therapy:
Paracetamol per-
mitted
Outcomes Kellgren and Lawrence rating

intensity of spontaneous pain and clinical severity in terms of pain felt during normal living
activities(1=slight
,2=moderate,3=
severe)
WOMAC function subscale for ADL
(1=none,2=mild,
3=moderate,
4=severe,
5=extreme)
joint flexion in o
NSAID use

Tekeoglu 1998 (Continued)
(0=none,
1=occasional,
2=continuous low doses,
3=continuous high doses)
pt and investigator
judgement of efficacy (0=un-
satisfactory,1=
poor,2=fair,3=
good,4=excellent)
morning stiffness
effusion (presence/absence)
Blood pressure and heart rate,
blood and urine study start and end

R-1,B-0,W-1
When present effusion extracted by arthrosynthesis to dryness
Pt kept in rest for one day after inj
Trial population consisted of all female.
Risk of bias
Thompson 2002
Methods Randomised
Controlled
Trial
Double-blind
Parallel-group
Multicentre (n=10)
Non-inferiority study
Germany
Mean age: NR
% Female: 64.5
Duration: 12 wk
(AR 160, GF20 161)
Inclusion:
Scored a total of between 41-80 mm based on WOMAC OA Index mean pain subscale.
Exclusion:
NR

Thompson 2002 (Continued)
Baseline values:
WOMAC pain:
AR: 49.20
GF20: 51.90
Interventions Arthrease (20 mg/2 ml)

3 weekly injections
Hylan G-F 20
(16mg/2 ml)
3 weekly injections
Concurrent therapy: acetaminophen up to 4 g daily after 1st injection
Outcomes WOMAC OA Index Pain VA -----------------------

Escape medication usage,
pt assessment of treatment (very satisfied, satisfied, slightly satisfied, dissatisfied),
Global WOMAC including stiffness and physical function.

R-1,B-1,W-0
The 3 authors of the abstract are affiliated with industry: J.I. Thompson, DePuy Interna-
tional Ltd.,
Y.W. Huang and R. Zaibel, Biotechnology General.
Risk of bias
Tsai 2003
Methods Randomised
Controlled
Trial
Double-blind
(masked observer)
Placebo- controlled
Parallel-group
Multicentre (n=3 hospitals, 6 investigators)
Both ITT and
per protocol analyses.
Taiwan
Mean age: 65
% Female: 76
Mean disease
duration: 427 days

Tsai 2003 (Continued)
Duration: 25 wk
(HA 100,PL 100)
Inclusion:
>50 years of age,
diagnosed with
knee OA (ACR criteria: >50 y, crepitus, morning stiffness<30 min in duration)
pain >= 40/100 mm VAS on 50 foot walk
radiographic evidence Kellgren Lawrence II to III with predominance in TB compartment
acute disease or trauma leading to secondary OA must have occurred at least 5 y before
study entry
Exclusion:
severe degeneration of knee joint with marked joint narrowing, varus, or valgus deformity
of knee (>12o) or other joint deformities, or other joint disorders (e.g. inflammatory joint
disease, specific arthropathy, severe axis deviations or instabilities, joint or skin infections,
joint prostheses of the lower limbs or symptomatic hip)
ia steroid injections within the 2 wks prior to study entry
Baseline values:
Pain 50’ walk
HA: 47.85
PL: 45.65
WOMAC Pain
HA: 45.73
PL: 45.39
WOMAC Function
HA: 46.54
PL: 45.45
WOMAC Stiffness
HA: 43.35
PL: 44.46
20 mg/2ml
5 weekly injections
Saline 2 ml
5 weekly
injections
Concurrent therapy: acetaminophen permitted as escape medica-
tion up to max 3 g/day but not on the day before study visit
Not permitted:
oral & parenteral corticosteroids, ia corticosteroid injections, NSAIDs or analgesics
other than acetaminophen, topical analgesic preparations, rehabiliation, physical therapy,
acupuncture
Outcomes Pain during 50 foot walk (100 mm VAS)-----------

WOMAC (VAS),
pt and iv overall effectiveness (1-6:1=gravely worsened, 6=
excellent improvement),
acetaminophen
consumption,
Tsai 2003 (Continued)
50 ft walk time, volume of synovial effusion in study knee,

safety

R-1,B-1,W-0
Fourth and fifth authors of abstract are affiliated with Fidia SpA, Italy.
One author of manuscript is affiliated with Fidia S.p.A.
Work supported by a grant from Medpharma.
Risk of bias
Tsukamoto 1995
Methods See Yamamoto 1994
Participants
Interventions
Outcomes
Notes
Risk of bias
Wobig 1998
Methods Randomised
Controlled
Trial
Double-blind
Blinded assessor
Multicentre (n=4)
2 wk washout
of NSAID and analgesics.
ITT analysis

Wobig 1998 (Continued)
Germany
Mean age: 62
% Female: 65
Duration: 12 wk
Telephone follow-up
at 26 wk
(HA 52, PL 54,
HA+PL 4)
[117 knees:
HA 57, PL 60]
Inclusion:
> 18 y
male & female
chronic primary OA of knee of Larsen Grade 1-3
ESR < 40 mm/h
RF < 1:160
daily pain on activity and persistent pain despite use of NSAIDs or analgesics
Exclusion:
pts with effusion in knee
Baseline values:
pt wtbearing pain
HA:71, PL:75
pt night pain
HA:42, PL:47
MD wtbearing
pain
HA:71, PL:75
MD night pain
HA:41, PL:47
MD loss of
activity
HA:59, PL:67

(2 ml)
3 weekly injections
Placebo: phosphate-
buffered saline
2 ml
3 weekly injections
Concurrent therapy:
Standard care per-
mitted: steroids,
NSAIDs, analgesics,
PT, surgery

Wobig 1998 (Continued)
Outcomes pt: pain wt bearing, at rest during night, decrease during most painful movement, treatment
success
MD: extent of pt’s loss of activity while performing difficult daily tasks & treatment success
all above on 100 mm VAS
Assessments:
Wk 0,1,2,3,8,12,
26
Notes Jadad’s:4/5
R-1,B-2,W-1
Local analgesia was optional.
If bilateral OA, only most painful knee treated.
7 pts bilateral - 14 knees: 6 HA , 8 PL. Each knee randomised and analysed independently
for efficacy but for safety these pts. were considered individuals. Time between treatment
of two knees varied from 0 to 153 days.
Pts with effusions excluded.
Arthrocentesis with removal of effusion if present. At baseline, Larsen xray grade III to IV:
HA: 28% versus PL:57%(p<0.05),
duration of OA <1 y: HA: 28% versus PL: 10% (p<0.025)
Work was supported by Biomatrix, Inc.
Risk of bias
Wobig 1999
Methods
Participants
Interventions
Outcomes
Notes
Risk of bias

Wobig 1999a (Healon)
Methods See Wobig 1999
Participants Number randomised:

Healon: 39 knees
Interventions
Outcomes
Notes
Risk of bias
Wobig 1999b (Artz)
Methods Randomised
Controlled
Trial
Double-blind
Blinded assessor
Multicentre (n=6)
2 wk washout
of NSAIDs and analgesics.
Efficacy analysis:
both ITT and per protocol.
Tolerability analysis: ITT
Germany
Mean age: 60
% Female: 51
Duration: 12 wk
Number randomised:
132 pts (148 knees) in 4 arms of trial.
In 2 arms GF/AR:
70 patients
(GF 38, AR 32)
[73 knees:
GF 38, AR 35]
[Healon 39 knees, NE hylan 36 knees]
Inclusion:
> 18 y
primary OA knee (Larsen 1 to 3)

Wobig 1999b (Artz) (Continued)
ESR < 40 mm/h

RF < 1:160
daily, persistent pain despite use of pain relieving
medications
Exclusion:
free of pain in OA knee
detectable effusion in joint at time of first treatment
considered unreliable by the
investigator
Baseline values:
pt wtbearing pain
HA:70, AR:72
MD wtbearing pain
HA:69, PL:72

(2 ml)
Artz
(2 ml)
Healon
Nonelastoviscous denatured hylan fluid
3 weekly injections
Subcutaneous local anesthetic optional in both groups.
Concurrent therapy:
Standard care per-
mitted
Outcomes wt bearing pain by pt and MD on 100 mm VAS

overall treatment response by pt & MD(100mmVAS)
improvement on most painful knee movement by pt 100 mm VAS
Assessments:
Wk 0,1,2,3,8,12
Notes Jadad’s:4/5
R-1,B-2,W-1
Pt with detectable effusion excluded
Arthocentesis with removal of effusion if present.
If bilateral OA both knees could be treated and evaluated. 16 patients had bilateral OA.
Each knee randomised and independently evaluated for efficacy. Time between treatment
of two knees varied from 0 to 23 days but 11/16 had the same day.
4-arm study but only 2 arms reported in publication (Hylan G-F 20 and Artz). Biomatrix,
Inc. provided support for this work and performed all elastoviscosity analyses
Risk of bias

Wobig 1999b (Artz) (Continued)
Wobig 1999c (NEhyl)
Methods See Wobig 1999
Participants Number randomised:

NE hylan fluid:
36 knees
Interventions
Outcomes
Notes
Risk of bias
Wu 1997
Methods Randomised
Controlled
Trial
Double-blind
Placebo- controlled
Single centre
Per protocol analysis: n=111 knees (60 Artz, 51 Placebo)
China
Mean age: 69
% Female: 28
Mean disease
duration: 19 mth
Duration: 26 wk
[116 knees: Artz 62, PL 54]
Inclusion:
adults diagnosed as early OA (mild to moderate) by 4 senior orthopedic surgeons
clinical symptoms with exercise pain, limitation of joint function and radiologic findings
of bone spur, JSN, or osteosclerosis
Exclusion:
steroid IA injection

Wu 1997 (Continued)
functional disturbance of liver and kidney

pregnancy
severe degeneration of knee joints with marked joint narrowing, marked varus or valgus
deformity or a large amount synovial effusion
Baseline values:
% pt moderate
walking pain
Artz: 36, PL:41
% pt mild rest pain
Artz:53, PL:54
Interventions Artz 2.5 ml

5 weekly injections
Placebo:solvent for Artz (sodium chloride phosphate solution) 2.5 ml
5 weekly injections
No local anesthetic drugs.
Concurrent therapy:
No antiinflammatory
agent or physical therapy permitted
Outcomes pain: rest, walking, up/down stairs, flexion and extension, oppressive; swelling, ballote-
ment of patella
(4 grades: no symptoms, mild, moderate,severe symptoms);
synovial fluid (vol), range of motion (degrees), actvities of daily living (walk 10 min, up/
down stairs,squat to pick up some-
thing, sitting on floor) impair-
ment (1:no problem to do,2=
fairly possible to
do alone,3=pos-
sible to do but
often with incon-
venience,4=need
help,5=complete
ly impossible)
radiographic
change (mild,
moderate,severe), general
improvement by pt and MD (1-7:
excellent improvement,
improved, fair
improvement, unchanged,
slightly worsened, wor-
sened, markedly
worsened),
overall evaluation
effectiveness (1-7:excellent improvement, improved, fair improvement, no change, slightly
worsened, wor-
sened, extremely
worsened), usefulness

Wu 1997 (Continued)
(1-7: extremely good, good, fairly

good, uncertain,
slightly unfavor-
able, unfavor-
able, extremely unfavorable), and safety (1-3):no
side effect, side
effect but treat-
ment continued,
stop treatment due to side effect
Notes Jadad’s:3/5
R-1,B-1,W-1
Pts with large amount synovial effusion excluded
Risk of bias
Wu 2004
Methods Randomised
Controlled
Trial
Single-blind
Parallel group
China
Mean age: 67
% Female: 55
Duration: 16 wk
5 groups with 50 per group
1) HA,
2) HA+low dose celecoxib (HALC),
3) HA + self-
selected dose celecoxib (HASCC),
4) celecoxib (CEL), 5) Self-selected celecoxib (SCC)
Inclusion: NR
Exclusion: NR
Baseline values:
WOMAC function
HA: 67.7,
HALC: 68.3,
HASCC: 70.2,

Wu 2004 (Continued)
CEL: 71.3,
SCC: 70.4
Interventions 1) HA 2 ml (10mg/L) 5 weekly injections,

2) HA+low dose celecoxib (one course HA + 100 mg celecoxib once per day for 4 mth),
3) regular dose celecoxib 100 mg/day for 4 mth,
4) HA + self-controlled dose of celecoxib
(one course of HA + celecoxib 100 mg bid) and dosage could be decreased once symptoms
well controlled),
5) voluntary celecoxib 100 mg bid and dosage could be decreased with symptom control
Concurrent therapy: NR
Outcomes WOMAC physical function subscale-----------

weekly dosage of celecoxib,
total dosage of celecoxib,
satisfaction level to the treatment protocol (bad, fine, good, and excellent)
Assessments at baseline, Wks 1,2,4,,8,10,12,14,16

R-1, B-0, W-1
Risk of bias
Yamamoto 1994
Methods Randomised
Controlled
Trial
Double-blind
Blinded assessor.
Parallel-group
Multicentre (n=31)
Safety analysis:
ITT, n=199
Efficacy analysis:
per protocol, n= 182-184
Japan
Mean age: 66
% Female: 78
Mean disease
duration: Not reported
Duration: 5 wk

Yamamoto 1994 (Continued)
(NRD 102, Artz 101)
Inclusion:
knee OA with definite pain or inflammatory symptom & demonstrating on xray 1 of:
osteophyte formation, joint space narrowing,
osteosclerosis
age >=20 < 80 y
if bilateral lesions, only one of lesions which satisfied criteria was selected
Exclusion:
definite 2o knee OA
operation indicated
oral or IV steroid or ia steroid or other drug within 2 wk of start of study
NSAID or new PT within 2 wk
lesion in hip or ankle of affected side
RA
pregnant, breast feeding or possibly pregnant
judged by physician to be in-
appropriate as study subject
Baseline values:
% pt moderate
spontaneous pain
NRD:31, Artz:31
% pt moderate walking disorder
NRD:40, Artz:41
Interventions NRD101 (25 mg/2.5 ml)

5 weekly injections
Artz (25 mg/2.5 ml)
5 weekly injections
No local anesthetics.
Concurrent therapy:
Analgesics, NSAIDs
& physical therapy continued but no ”new“ therapy per-
mitted
Outcomes clinical findings:4 grades of none, mild, moderate, severe for pain:spontaneous, pressure,
night, on passive movement, inflammation: swelling of soft part of jt, floating patella, local
feverish feeling, synovial fluid retention,
activities of daily living disorder: sitting upright, up/down stairs, standing up, squatting,
walking
passive movement: flexion/extension,
drainage: volume
efficacy assessed by MD: overall im-
provement: 7 grades: marked
improvement,
moderate im-
provement,
slight improve-
ment, un-

Yamamoto 1994 (Continued)
changed,slight
aggravation,moderate aggrava-
tion, marked
aggravation)
pt. impression - how they felt about changes in symptoms (very good, good,fair,
cannot say good or not, bad)
comprehensive assessment based on 3: final overall improvement ratings (8 grades: same as
above+
unassessable),
global safety (5 grades: no
adverse reaction,mild AR,
moderate AR,
severe AR,
unassessable),
usefulness (8
grades:very use-
ful,useful,slightly
useful,cannot say useful or not,
slightly undesir-
able, undesirable, very
undesirable, un-
assessable)

R-2,B-2,W-1
MD who did inj
different from MD who did assess-
ment
In case of bilateral OA, only one knee was evaluated.
Bilateral: NRD 53, Artz 44;
Unilateral: NRD 42, Artz 43
Puncture and
drainage done as required.
Artz provided by Seikagaku Corporation. M. Nakajima performed statistical analysis
Risk of bias

Yentur 2003
Methods Randomised
Controlled
Trial
SIngle-blind
Blinded physician completed assessments
Turkey
Mean age: 60.95
% Female: 100
Duration: 21 days
Number randomised:
34
(HA 17, TP+HA 17)
Inclusion:
diagnosis according to ACR criteria,
painful idiopathic knee OA with moderate to very severe pain (pain all the day under weight
bearing or at rest) with x-ray confirmation (Kellgren Lawrence grade 3 - moderate joint
space narrowing, osteophytes, subchondral sclerosis),
all patients were using NSAIDs for more than one year, but stated that they did not have
any beneficial effect
Exclusion:
intraarticular injection or physical therapy at least within the previous 6 mth,
patients who had knee joint diseases other than OA, severe concomitant diseases, diseases
interfering with the evaluation of knee joint function, skin infections, joint instability,
hemorrhagic diathesis or major neuroses
Baseline values:
pain at rest:
HA: weak 2, moderate 4, severe 9, very severe 1
HA+TP: moderate 2, severe 14, very severe 1
knee ROM
HA: 116.2
HA+TP: 103.8
walking
HA+TP: weak 2, moderate 7, severe 8
stairs ascending/
descending
HA+TP: moderate 6,
severe 11
Interventions Orthovisc 2 ml three weekly injections plus at each session following IA injetion, trigger
point (TP) injections with 0.5% lidocaine were performed in relevant TP according to
Travell and SImons’ guide-
lines (rectus femoris, vastus medialis, vastus lateralis, sartorius, adductor longus, tensor
fasciae latae, gracilis, pectineus, iliopsoas, biceps femoris, semitendinosus, semimembra-
nosus, adductor magnus, gastrocnemius, soleus. Local twitch responses were induced on
introducint the needle into the muscle.

Yentur 2003 (Continued)
All patients were kept at rest for 2 days after each injection to avoid overcharging of the
injected joint.
Concurrent therapy:
No other treatment modalities were permitted during the trial
Outcomes Intensity of local pain at rest or during normal daily activities and activit restrictions (squat-
ting, sitting down, ascending and descending stairs, walking, taking off socks, rising from
bed, getting in or out of a car) were evaluated by a 5-point scale (0= no pain, 1=mild, 2=
moderate, 3=severe, 4=very severe),
range of movement (flexion-degrees)

R-1, B-0, W-1
Risk of bias
Characteristics of excluded studies [ordered by study ID]
Study Reason for exclusion
Aglas 1997 Open, prospective study of HA in two subjects conducted in Austria with a 56-month observation period
Akermark 2002 Open, non-blind, prospective study of non-animal stabilised hyaluronic acid (NASHA) (Durolane) in
103 subjects conducted at five centres in Sweden. Primary outcome was frequency of device-related,
unanticipated adverse events. Primary study involved a single injection of 60 mg/3 ml and follow-up was
for 3 months. In extension to primary study, 53 subjects received a second injection approximately 6 mths
after the 1st and were followed up over a 1-month period
Akermark 2004 Open, prospective, 12-week study of non-animal stabilized hyaluronic acid (NASHA) in 149 subjects
conducted in Sweden
Alonge 2004 Open, prospective, 12-week study of Synject in 20 subjects conducted in Nigeria
Angel 2001 Retrospective telephone survey of 69 patients with knee OA who had ia injections of Synvisc conducted
South Australia
Arizono 1997 Not randomised, three-month trial of Artz versus mepivacaine in 38 knees conducted in Japan
Ates 2001 Open, prospective, 21-week study of Orthovisc (five weekly injections) in 21 subjects conducted in Turkey

(Continued)
Bagga 2003 Open, prospective, 6-month study of Hylan G-F 20 in 30 subjects conducted in Australia. Primary end-
points were synovial fluid HA concentration, molecular weight determination, viscosity and sulfated gly-
cosaminoglycan levels
Bardin 2004 Open, prospective, 90-day phase IV trial of Arthrum H in 3349 subjects conducted in France and Spain
Barrett 2002 Uncontrolled, retrospective, 18-month study of Hyalgan in 249 subjects conducted at a single orthopaedic
practice in Florida, USA
Bell 1999 Open, prospective, multicenter, 12-month study in 60 subjects conducted in Canada
Bellamy 2000 Open, prospective, 6-week study of Hylan G-F 20 in 445 subjects conducted in Canada. This was a study
of a learning intervention which tested the impact of an injection skills-acquisition programme for family
physicians
Birbara 2004 Open, multicentre extension study in 190 subjects conducted in Canada and the United States. This is an
extension of the OAK0101 Orthovisc randomised, controlled trial (Neustadt 2004)
Bolgen Cimen Open, prospective, six-month study in 14 female subjects conducted in Turkey
Bruce 2004 Open, controlled, prospective, four-year observational cohort study in 1860 subjects (1301 treated with
Hylan G-F 20 and 559 control) conducted in United States
Carrabba 1992 Open, randomized, 60-day, controlled study comparing Hyalgan and Orgotein (superoxide dismutase) in
118 subjects conducted in three centers in Italy
Chhabra 2000 Open, prospective, six-month study of Hylan G-F 20 in 120 subjects conducted in England
Clarke 2001 See Clarke 2005.
Clarke 2005 Uncontrolled, prospective, 26-week, pilot study of Hylan G-F 20 in 43 subjects with patellofemoral
osteoarthritis of the knee conducted in England
Conrozier 2003 Open, retrospective, 14-month study of Hylan G-F 20 in 155 subjects conducted in France. Objective was
to identify factors predicting efficacy
Couceiro 2003 Open, prospective, non-controlled, six-month, multicentre study of Adant in 112 subjects conducted in
Spain
D’Agnolo 1988 Open, prospective, 60-day study of Hyalgan in 30 subjects conducted in Italy
Dahlberg 1994 Radiographs, obtained in a standardized manner at the time of arthroscopic examination, did not show
any evidence of OA
Evanich 2001 Randomized, single-blind, 26-week controlled trial of Synvisc (hylan G-F 20) and Aristospan 40 mg
(triamcinolone hexacetonide) in 220 subjects with OA of the knee conducted in Seattle, WA. Abstract
reports interim results for over 100 subjects; means and p values up to Week 12

(Continued)
Faraawi 2003 Retrospective telephone survey of 127 patients assessing satisfaction wih hylan G-F 20 therapy. Patients
treated from January 1999 to April 2002. Study conducted in Kitchener, Ontario, Canada
Faus 2002 Open, prospective, one-year study of 35 subjects with severe knee OA conducted in Spain. Ultrasound was
used to measure thickness of articular cartilage of lateral and medial femoral condyles. Femoral articular
cartilage of contralateral knee was used as control group
Frizziero 1993 No clinical outcomes reported in abstract. Six-month study comparing HA versus methylprednisolone in
24 subjects conducted in Italy
Frizziero 1997 No clinical outcome reported in abstract. Six-month study comparing Hyalgan versus methylprednisolone
in 99 subjects conducted in Italy
Frizziero 1998 Open, prospective, six-month, pilot study of 40 subjects conducted in Italy
Fuji 1994 This study addresses the effect of concomitant use of local anesthetic with Artz
Goorman 2000 Open, prospective, six-month, case series of Hylan G-F 20 in 84 subjects conducted in USA
Grecomoro 1992 Study studies synergism between Hyalgan and dexamethasone.
Guerrero 1999 Open, prospective, cohort study of Adant 10 mg/ml, 2.5 ml, five injections, in 20 subjects conducted in
Madrid, Spain. Outcome based on cartilage markers (ACR abstract)
Guerrero 1999a Open, prospective, cohort study of Adant 10 mg/ml, 2.5 ml, five injections, in 20 subjects conducted in
Madrid Spain. Outcome based on cartilage markers (OARSI abstract)
Hamburger 2004 Retrospective review of 171 subjects between 1997-2002 comparing Hyalgan and Synvisc conducted in
New York
Hashimoto 1992 Open, prospective (up to two years and 11 months) study of Artz in 35 knee joints conducted in Japan
Honma 1989 Open, prospective study of Artz in 83 subjects conducted at 13 institutions in Japan
Igarashi 1983 Open, prospective, 40-week study of Artz in 43 subjects conducted at 19 centers in Japan
Ines 2002 Open, prospective, six-month, rheumatology clinical study of Synvisc, triamcinolone hexacetonide and
methylprednisolone acetate with and without joint lavage in 85 subjects of a mixed population (34% OA)
conducted in Portugal
Iseki 1983 Sodium hyaluronate 25 mg versus sodium hyaluronate 1%. Article is in Japanese
Iwasaki 1993 This study addresses the effect of concomitant use of local anesthetic with Artz
Johnson 2004 This was an audit of clinical practice in 40 patients with knee OA who had received Hyalgan conducted
in England

(Continued)
Kawakami 1993 Open, prospective clinical evaluation of Artz in 45 subjects with moderate or severe OA of the knee
conducted in Japan
Kolarz 1995 Randomised, controlled, multicentre, comparative, phase III trial with a masked observer design conducted
in Austria and Germany. Comparison of five intra-articular injections of Hyalgan and 10 intra-articular
injections of the glycosaminoglycan polysulphase (Arteparon). The planned sample size was 144 subjects.
Due to the withdrawal of Arteparon from the Austrian and German markets, the design of the trial was
changed; data from only 53 patients who had completed the first treatment cycle (day 0-35) were analysed
Kolarz 2003 Open, multicenter, observational study conducted at 14 Austrian rheumatologic and orthopedic centers.
108 patients were treated with Hyalgan once weekly for five weeks. A repeat course was administered if
patients continued to fulfill the inclusion criteria but not earlier than month 4
Kotz 1999 Open, multicenter, prospective, 12-month study of Hyalgan in 108 subjects conducted at 14 centers in
Austria
Koyuncu 2002 Open, prospective, one-year study of hyaluronate in 21 subjects conducted in Turkey
Koyuncu 2003 Open, prospective, three-week study of Hylan G-F 20 conducted in Turkey
Kumar 2003 Open, prospective, one-year clinical service study of Hyalgan in 91 subjects conducted at one rheumatology
department in England
Kurokawa 1994 Open, prospective, 12-week study of NRD-101 in 114 subjects conducted in Japan
Lee 1999 Open, prospective, 12-week study of Hyruan in 48 subjects with OA of the knee conducted in Korea.
[English abstract, article in Korean]
Lee 2004 Open, prospective, one-year study of Hylan G-F 20 in 74 patients in an orthopaedic surgery clinic conducted
in the United States
Legre 2001 Study subjects had both osteoarthritis of the knee and calcium pyrophosphate dihydrate (CPPD) deposition
diseases. Open, prospective, six-month study of Hylan GF-20 in 21 subjects conducted in France
Leopold 2002 This is not a randomised controlled trial. Objective of trial was to test hypothesis that the likelihood of
a painful reaction to Hylan G-F 20 did not increase in patients who received more than one course of
treatment. The single course group (n=42) was prospectively followed as part of a randomised trial. The
repeat course group (n=19) was retrospectively identified from a chart review. This was a 15-month, single
centre study conducted in the USA
Lussier 1996 Retrospective review of clinical practice of Hylan G-F 20 in 336 subjects conducted at five Canadian centers
with 2.5 yr follow-up
Magobotha 2001 Open, prospective, six-month study of Hylan G-F 20 in 166 subjects conducted in South Africa
Mathieu 2001 Open, prospective, 14-month study of Hylan GF-20 in 155 subjects conducted in France. Assessed pre-
dictive factors of long-term efficacy

(Continued)
Mazieres 2004 An observational, naturalistic, open-label, multicentre, nine-month study of Suplasyn in 232 subjects
conducted in France
Mazzocato 1987 Open, prospective, 60-day study of Hyalgan in 22 subjects.
Megyeri 1993 Open, prospective, four-week study of sodium hyaluronate 20 mg in 23 subjects conducted in Hungary
Mensitieri 1995 No clinical outcomes reported. Study of Hyalgan, arthrocentesis, and placebo in 60 subjects conducted in
Italy
Milini 1989 Open, prospective, 60-day study of Hyalgan in 23 subjects.
Miller 1999 Open, prospective, one-year study of Hylan G-F 20 in 108 subjects conducted in the USA
Minami 1993 Open, prospective study of SLM-10 in 33 subjects conducted in Japan
Moller 2001 Open, prospective, six-month study of Ostenil in 40 subjects conducted in Spain
Monfort 2000 Open, prospective, three-month study of hyaluronic acid (three injections) in 50 subjects conducted in
Barcelona, Spain. Studied treatment with HA in subjects with gonarthrosis with and without chondrocal-
cinosis
Myburgh 2001 Open, prospective, 24-week case series of Hylan G-F 20 in 18 subjects conducted in South Africa
Namiki 1982 Open, prospective study of Artz in 43 subjects conducted in Japan
Neustadt 2001 Open, prospective, greater than two-year study of intra-articular hyaluronate (five weekly injections) in 92
subjects conducted in Louisville, USA
Neustadt 2003 Open, prospective, two-year study of intra-articular hyaluronate (Hyalgan) in 76 patients (92 knees)
conducted in Louisville, KT, USA. 13 patients had a repeat treatment course
Novaes 2005 Open, prospective, multicentre, four-week study of 25 mg/2.5 ml of hyaluronan (Meiji Seika Kasha, Ltd.,
Tokyo, Japan, MW 900 kDa 5 intraarticular injections) in 365 subjects conducted in seven Latin American
countries
Oberoi 2004 Open, prospective, four-year sudy in 75 subjects of Hyruan plus arthroscopic joint debridement compared
to arthroscopic joint debridement alone conducted in India
Olszynski 2002 Open, prospective, clinical practice study of Synvisc, Suplasyn, Orthovisc and Neovisc in 267 subjects in
a Canadian rheumatology practice
Ono 1993 Open, prospective study in 72 subjects conducted in Japan.
Ono 1993a Open, prospective, multicentre study in 26 subjects conducted in Japan
Oron 2003 Open, prospective, clinical practice study of Orthovisc and Synvisc in 522 subjects conducted in Israel

(Continued)
Oshima 1983 Open, prospective study of Artz in 206 subjects conducted in Japan
Pasquali Ronchetti Randomized, open-label, six-month study of Hyalgan and Depomedrol in 99 subjects conducted at one
centre in Bologna, Italy. This paper reports the structural varibles of the synovial membrane. Clinical and
arthroscopic findings will be the subject of a separate publication
Pavelka 2002 Multicenter, open, prospective, 17-week, observational study of Hyalgan in 601 subjects conducted at 35
centers in the Czech Republic
Pavelka 2002a See Pavelka 2002.
Payne 2000 Randomised, doube blind, placebo-controlled, three-month trial of Suplasyn (three weekly injections) and
saline (three weekly injections) in 46 subjects (40 randomised) conducted in Canada. Both groups given
a programme of flexibility and stretching exercises. Acetaminophen was permitted for pain. The objective
was to test if Suplasyn improved proprioception. No OMERACT efficacy outcome measures were reported.
Primary outcome was absolute angular error measured with an electrogoniometer
Petrella 2003 Retrospective study of 493 patients with unilateral knee OA treated with Suplasyn was conducted over 4.
5 years in London, Canada
Petrella 2003a Cross-sectional, retrospective cohort analysis of 53000 subjects in more than 35 famly practice clinics in
Southwestern Ontario, Canada. Aim is to determine and compare the tolerance and efficacy of intra-articu-
lar viscosupplementation of HA for the treatment of OA with other products for the same indication. Safety
profile of Suplasyn versus other treatment options studied. VAS walking and rest pain, BMI, comorbidity,
global assessment as well as pharmacoeconomic parameters collected
Petrella 2003b A retrospective study of 537 subjects with unilateral OA of the knee treated with Suplasyn conducted over
4.5 years in Canada. 481 subjects received a second series. Improved walking and rest pain reported for
both first- and second-time subjects with low incidence of adverse events and high treatment satisfaction
Petrella 2005 A prospective, naturalistic cohort study of 537 subjects with unilateral OA of the knee treated with Suplasyn
conducted over 6.7 years in Canada. Repeat injection was permitted
Pipino 1990 Open, prospective, 35-day study in 100 subjects.
Punzi 1988 Open, prospective, seven-day, single centre study in mixed study population of 17 subjects (seven OA)
conducted in Italy
Rao 2001 Open, prospective, six-month study of dedicated viscosupplementation clinic ascertaining which patient
groups would derive the most benefit from Hyalgan conducted in England
Rastogi 2005 Open, prospective, six-month study conducted of 30 patients conducted at two orthopaedic centres in
New Delhi. Patients received a series of five Hyruan ia injections (25 mg/2.5 ml)
Russell 1992 Abstract only published. 210 subjects randomised to either HA or Placebo or No-intervention. Two centers
in USA conducted this 14-week study

(Continued)
Scali 1995 Open, prospective, three-month study of Hyalart in 75 subjects conducted in Argentina
Sepici 2002 Open, prospective, case-control, one-month study of Orthovisc in 15 female subjects and 16 age-matched
healthy controls conducted in Turkey
Shibata 1993 Open, case series of Artz in 532 subjects conducted in Japan
Sieliwonczyk 1997 Open, prospective case series.
Singh 2004 See Bruce 2004. This is the same study as the Bruce 2004 reference (Measurement of Outcomes from
Viscosupplementation Effectiveness Study (MOVE)). This is a longitudinal observational cohort study of
1860 subjects conducted in the United States
Sripada 1999 Retrospective pilot study of Hylan G-F 20 and hyaluronan in 100 subjects conducted in the USA
Stambuk 2001 Open, prospective, 12-week study of Hylan G-F 20 in 35 subjects with bilateral knee OA with effusion
conducted in Zagreb, Croatia. Control group was contralateral knee of same subject
Suzu 1990 Open, prospective, 18-month study of ARTZ in 15 subjects conducted in Japan
Suzu 1993 Open, prospective study in 43 subjects conducted in Japan.
Takeuchi 1993 Open, prospective study of 82 subjects conducted in Japan.
Taneda 1993 Open, prospective study of 28 subjects conducted in Japan.
Tang 2004 A case-comparison study of 15 subjects (30 knees) with symptomatic knee OA and 15 age-, mass- and
gender-matched non-OA control subjects (30 knees). Gait patterns and sagittal ground force reaction forces
after intraarticular injection of Artz or 2.5 mL of .01% sodium hyaluronate/ampoule; MW 860 kd was
injected once a week for a total of 5 injections
Tang 2005 Open, prospective study of 25 subjects conducted in Taiwan. HA with a MW of 860 kd (Artz) was injected
once a week for five consecutive weeks. Main purpose of study was to demonstrate if knee muscle strength
could be increased in patients with knee OA after injection of HA
Toh 2002 Open, prospective, 12-week study of Orthovisc in 60 patients conducted in the United Kingdom. Patients
with a minimal to mild loss in joint space are most likely to benefit from HA supplementation
Toh 2003 A prospective cohort of 60 patients received a standard course of ia viscosupplement. Followup was for 12
weeks. WOMAC was outcome. Concluded that only patients with a minimal to mild loss in joint space
on radiological examination are most likely to benefit from ia viscosupplementation (cf not those with
moderate to severe OA changes in joint space)
Torrance 2002 This paper reports the economic results of the trial. The clinical results and health-related quality of life
outcomes for this trial are reported in the Raynauld 2000 manuscript. This prospective, one-year, open-
label health economic trial compared Appropriate Care with Hylan G-F 20 to Appropriate Care without
Hylan G-F 20 in 255 subjects at 14 sites in Canada

(Continued)
Turajane 2005 An uncontrolled, retrospective cohort study of 83 subjects conducted at a single centre in Bangkok,
Thailand between 1998 and 2002. Purpose was to determine the clinical factors that may influence results
of treatment with Hyalgan for subjects who had failed conservative treatment and who were recommended
for surgical treatment
Turajane 2005a A retrospective cohort study carried out between 1998 and 2004 of 109 Kellgren Lawrence grade 4 knee
OA patients who failed conservative treatment. Conducted at a single centre in Bangkok, Thailand. A
pharmacoeconomic analysis of Hyalgan was completed. A second objective was to determine the clinical
indicators for successful outcomes and patient satisfaction
Uebelhart 2003 Retrospective survey of 467 subjects conducted at 23 centres in Switzerland. Previous 15-month data
extracted. Ostenil and Synvisc were the main products evaluated
Vad 2000 Open, prospective, one-year study of knee lavage plus Hylan G-F 20 versus Hylan G-F 20 in 81 subjects
conducted in the USA. Both groups received an eight-week home rehabilitation programme and knee
cryobrace
Vad 2003 Nonrandomized, prospective, one- year study of knee lavage plus Hylan G-F 20 versus Hylan G-F 20
in 81 subjects conducted by a single physician in faculty practice at a major teaching hospital in the
USA. All participants received an 8-week programme of home knee rehabilitation exercise combined with
aquatherapy and use of a knee cryobrace 15 minutes a night
Waddell 2001a Retrospective study from November 1, 1997 to February 29, 2000 of tolerance of Hylan G-F 20 using
fluoroscopically-confirmed injection and effectiveness of retreatment in 598 subjects conducted in the USA
Waddell 2001b Retrospective study from 1997 to 2000 of Hylan G-F 20 to assess the effect of several independent factors
on probability of progression to total knee replacement in 1253 subjects conducted in the USA
Waddell 2001c Pharmacoeconomic model with inputs obtained from peer reviewed medical literature, clinical trial data,
clinical expert opinion, and claims data. A hypothetical cohort of subjects was followed over a three year
period. Analysis conducted from the perspective of a managed care plan
Waddell 2003 Open, prospective, one-year study of hylan G-F 20 in 70 subjects conducted in the USA. Objective was
to evaluate a second course of hylan G-F 20
Waddell 2003a A retrospective, case-control study of 110 who had undergone TKR and 1151 who had not undergone
TKR. Effects of age, gender, BMI, and viscosupplementation with hylan G-F 20 were evaluated on the
probabilit of progression to TKR. Repeat treatment with hylan G-F 20 was also analysed. Conducted in
USA
Waddell 2003b A retrospective, four and a half year study of 1047 patients (1489 knees) who had received at least one
intraarticular injection of hylan G-F 20 conducted at an orthopaedic practice in the USA
Waddell 2003c Open, prospective, 26-week study of Hylan G-F 20 in 85 patients conducted at an orthopaedic practice
in the USA
Weiss 1999 Open, prospective, 12-month study of Hylan G-F 20 in 93 subjects conducted in the USA

(Continued)
Wobig 1999d Open, prospective, 12-week, multicenter study of Hylan G-F 20 in 222 subjects conducted in Germany
Wulwik 2001 Open, prospective, cohort, two-year study of Synvisc in 117 subjects with severe knee OA conducted in
France
Yoh 1989 Open, prospective, six-month study of Artz in 35 subjects conducted in Japan
Zamora-Quezada 2004 Open, prospective study of an electronic data capture system involving Hyalgan in 43 subjects conducted
in the United States
Characteristics of ongoing studies [ordered by study ID]
Anonymous 1999
Trial name or title Orthovisc versus

saline: a double- blind randomised controlled trial
Methods
Participants
Interventions Orthovisc versus

saline
Outcomes
Starting date
Contact information Anika Therapeutics

Press Release
August 1999
Notes
Hempfling 2003
Trial name or title Long-term outcome of synovial fluid substitution with Viscoseal post-
arthroscopy
Prospective, randomised, masked-observer study
Methods
Participants 80 patients with severe pain in knee joint persisting for at least six months (VAS pain greater than 50 mm)
Interventions arthroscopic lavage versus Viscoseal (50 mg/10 ml) one intra-articular injection immediately after arthroscopy

Hempfling 2003 (Continued)
Outcomes Outerbridge,
VAS (investigator)
VAS (pain diary) by patient daily, clinical global impression, problems when walking 100 m, Pain when
walking 100 m, pain at night, safety
Starting date
Contact information Prof. Dr. med. Harald Hempfling, Berufsgenossenschaftliche Unfallklinik, D-82418 Murnau am Staffelsee
Notes
ISRCTN43185756
Trial name or title Comparative study between intraarticular ostenil versus orthovisc
Methods
Participants 73 patients with OA of the knee both male and female.
Interventions Ostenil or Orthovisc a single course
Outcomes WOMAC/VAS pain scale is primary outcome outcome.
Starting date 01/05/2004
Contact information Mr. David Teanby, Consultant Orthopaedic Surgeon, St Helens & Knowsley Hospitals NHS Trust, Whiston
Hospital, Prescot, Merseyside L35 5DR, United Kingdom
Notes Sources of funding: St. Helens & Knowsley Hospitals NHS Trust, NHS R&D Support Funding.
Prospective masked observer RCT.
ISRCTN51421587
Trial name or title Viscosupplementation for osteoarthritis of the knee: protocol for the Swiss viscosupplementation trial (SVIS-
COT)
Methods
Participants Males and females with radiologically confirmed symptomatic OA of the knee for at least six months, with
pain on most days for the previous three months, will be eligible for trial if they fulfill ACR clinical criteria
for OA of the knee; have an ACR functional class rating of II to IV, and have failed to respond sufficiently or
were intolerant to conservative treatment
Interventions Synvisc, Orthovisc or Ostenil

Up to three treatment cycles per knee (one cycle consisting of three injections)

ISRCTN51421587 (Continued)
Outcomes Primary outcome is rate of patients who reach a WOMAC total score of 39 or greater plus the rate of
individuals who have undergone tootal knee replacement surgery after 24 months of follow-up.
Secondary outcomes will be (1) the severity of OA symptoms based on the WOMAC pain sub-scale and the
WOMAC global scale on pain, stiffness and disability, (2) the cost-utility based on health related quality of
life measured by EuroQol and self-reported healthcare utilisation for OA,
(3) the frequency of local side effects, (4) serious adverse events, (5) the rate of surgical interventions for knee
OA other than total knee replacement, and (6) overall mortality
Starting date July 2002
Contact information juni@ispm.unibe.ch

Maya Zullig MD, Research Officer Swiss Federal Office of Social Insurance (OFAS), Berne,
Switzerland
Notes Pilot trial of 600 patients (200/group); main trial 9000 to be randomised
ISRCTN51421587
ISRCTN82192623
Trial name or title Prospective randomised single-blind trial comparing the effectiveness of combined arthroscopic washout
and intra articular hyaluronan injection to intra articular hyaluronan injection and arthroscopic washout in
isolation, for osteoarthritis of knee
Methods
Participants 219 patients
Interventions Arthroscopic washout followed by intra-articular HA injection versus arthroscopic washout and intra-articular
HA injection in isolation
Outcomes
Starting date 01 Jan 2002
Contact information Mr. A. Mohsen

Orthopaedic Department, Hull Royal Infirmary, Anlaby Road,
Hull HU3 2JZ
UK
Tel:+44 01482 328541
Notes End date: 31 Mar 2005

ISRCTN82192623

NCT00130468
Trial name or title A double blind, randomized trial of intra-articular injections of 20 mg of Hyalgan for the treatment of knee
pain due to osteoarthritis (three injection-regimen for efficacy and duration - 20 mg/2ml dose: Tread-20)
Methods
Participants Phase IV randomised, double-blind, placebo controlled, parallel group

Inclusion criteria:
12 criteria:
written consent,
40 yr of age and above,
of sufficient good health to be able to complet 6-month follow-up,
signs and symptoms of OA of at least one knee according to ACR criteria,
Kellgren-Lawrence Grade II or III,
symptoms including knee joint pain, crepitus, swelling, and/or effusion of the knee for at least 6 mths,
pts on analgesic/NSAID VAS pain score after walking on a 50 foot flat surface of greater than or equal to 30
mm but less than 90 mm,
if not taking analgesic/NSAIDVAS pain score after walking of greater than 40 mm but less than 90 mm,
if bilateral knee pain is present, investigator will select the more painful knee
Exclusion criteria:
4 general,
28 musculoskeletal related,
16 concomitant conditions, diseases, medications and/or clinical history related
Outcomes
Starting date
Contact information Suzanne Meeves

Study Director
Sanofi-Aventis
Notes Sponsored by Sanofi-Aventis

ClinicalTrials.gov Identifier:
NCT00130468
NCT00131352
Trial name or title A study of the safety and efficacy of Synvisc in patients with symptomatic osteoarthritis of the knee
Methods
Participants Country: Belgium (4 sites), Czech Republic (4 sites), France (5 sites), Germany (1 site), Netherlands (2 sites)
, United Kingdom (5 sites)
Duration: 26 wk with possible repeat treatment after this time
Inclusion criteria:
age 40 years and above,
pts with symptomatic OA pain of the knee

NCT00131352 (Continued)
Exclusion criteria:
Pts with current or prior conditions or treatment that would impede measurement of efficacy or safety

Placebo
Outcomes Pain relief
Starting date May 2005
Contact information David Perkins

Study Director
Genzyme
Notes Sponsored by Genzyme.

ClinicalTrialsgov. Identifier: NCT00131352
Expected completion: December 2006
NCT00139295
Trial name or title Comparison of the efficacy and safety of Hylastan to methylprednisolone acetate in patients with symptomatic
osteoarthritis of the knee
Methods
Participants Males and females 40 years and above diagnosed with OA of the knee. Have tried but not been sufficiently
helped by conservative treatment such as weight reduction and pain medications. Exclusion: prior or con-
comitant treatments that would impede measuremen tof safety and efficacy
Interventions Hylastan and active control
Outcomes Pain relief
Starting date October 2004
Contact information David Perkins, R.Ph., Study Director, Genzyme
Notes Expected completion: March 2007, Data entry closure: December 2006
NCT00144820
Trial name or title Intra-articular injections of hyaluronan versus 20 MI NaCl versus placebo in treatment of knee osteoarthritis:
a randomised, double-blind, placebo controlled single centre trial
Methods

NCT00144820 (Continued)
Participants Males and females 60 years and above with clinical, radiological and possible arthroscopical verified knee OA;
knee pain on the day of examination scoring more than 20 mm on a VAS at baseline.
Exclusion: less than 60 y, unconsciousness, psychosis, demens, ingestion of drugs that may influence the
results of the clinical examinations, inflammatory diseases of the joints, RA or other inflammatory arthritis as
diagnosed by ACR criteria, contraindication to Hyalgan treatment, previous intra-articular fracture of a knee
joint, infection or skin disease located at the place of injection and invasive procedures done to the knee joint
within previous 2 mth inclusive intra-articular injections of steroids, any other condition that might interfere
with the efficacy assessment or completion of the trial
Interventions 4 weekly injections of :

Hyaluronan (2 ml sodium hyaluronate),
Placebo (2 ml isotonic saline), Excessive saline (20 ml isotonic saline)
Outcomes Pain measured on a VAS on movement; at rest and during the night; KOOS scores; daily consumption of
analgesics; cartilage and bone degradation markers; quadriceps circumference (cm); abililty to bend (degrees
flexion); and stretch (degrees extension); global assessment patient; global assessment investigator
Starting date This study is no longer recruiting patients.
Contact information Charlotte Lundsgaard, MD, Principal Investigator, Copenhagen Trial Unit (CTU), H:S Rigshospitalet. dept.
7102, Copenhagen, Copenhagen 0, 2100, Denmark
Notes 251 consecutive patients were randomised. Results were evaluated at weeks 1,2,3,4,8,12,16 and 26. Biochem-
ical markers for bone and cartilage degradation were measured in urine/blood
Russell 2001
Trial name or title A comparison of Hylan G-F 20 and arthroscopic lavage in the management of osteoarthritis of the knee
Methods
Participants 50 patients with knee OA

Arthroscopic lavage
Outcomes WOMAC
Starting date
Contact information 4 Rural Way, Ty Coch, Swansea

SA2 9NA
Wales
Notes Synvisc group showed greater and more consistent improvement in WOMAC scores at all assessments post
treatment. At 6 months (p<0.05) and 1 yr (p=0.0018)

DATA AND ANALYSES
Comparison 1. Adant versus Hyalgan
No. of No. of
Outcome or subgroup title studies participants Statistical method Effect size
1 Patient global assessment 1 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only
(number of patients
excellent/good)
1.1 1 to 4 weeks post-injection 1 49 Risk Ratio (M-H, Fixed, 95% CI) 1.18 [0.57, 2.41]
1.2 5 to 13 weeks 1 49 Risk Ratio (M-H, Fixed, 95% CI) 2.38 [0.93, 6.09]
post-injection
post-injection
2 Safety: number of painful 1 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only
injections
Comparison 2. Artz versus placebo
No. of No. of
1 Pain (100 mm VAS) 3 Mean Difference (IV, Fixed, 95% CI) Subtotals only
1.1 1 to 4 weeks post-injection 3 507 Mean Difference (IV, Fixed, 95% CI) 0.56 [-3.83, 4.94]
1.2 5 to 13 weeks 3 507 Mean Difference (IV, Fixed, 95% CI) -4.55 [-9.09, -0.00]
post-injection
1.3 14 to 26 weeks 2 312 Mean Difference (IV, Fixed, 95% CI) -0.42 [-6.90, 6.06]
post-injection
2 Pain score (0-3) 1 Mean Difference (IV, Fixed, 95% CI) Subtotals only
2.1 1 to 4 weeks post 1 98 Mean Difference (IV, Fixed, 95% CI) -0.07 [-0.28, 0.14]
-injection
3 WOMAC pain (0-20 Likert) 1 Mean Difference (IV, Fixed, 95% CI) Subtotals only
post-injection
4 WOMAC function (0-68 Likert) 1 Mean Difference (IV, Fixed, 95% CI) Subtotals only
post-injection
5 Lequesne Index (0-24) 3 Mean Difference (IV, Fixed, 95% CI) Subtotals only
post-injection
5.3 14 to 26 weeks 2 397 Mean Difference (IV, Fixed, 95% CI) 0.51 [-0.43, 1.45]
post-injection
6 Range of motion 1 Mean Difference (IV, Fixed, 95% CI) Subtotals only
(number of patients improved)
post-injection
post-injection
8 WOMAC stiffness (0-8 Likert) 1 Mean Difference (IV, Fixed, 95% CI) Subtotals only
post-injection
9 Number of survivors (patients 1 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only
not requiring additional
treatment for study knee) 45 to
52 weeks post-injection
10 Number of clinical failures 1 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only
post-injection
post-injection
11 Safety: total withdrawals overall 5 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only
post-injection
post-injection
post-injection
12 Safety: number of patients 1 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only
reporting adverse events (45 to
52 weeks post- injection)
13 Safety: withdrawals due to 5 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only
adverse events
post-injection
post-injection
post-injection
post-injection
14 Safety: number of patients with 1 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only
local adverse reaction but study
drug continued
15 Safety: number of adverse 3 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only
events probably/possibly
related to treatment
post-injection
post-injection

16 Safety: number of serious 1 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only
adverse events (45 to 52 weeks
post-injection)
(knees)
post-injection
post-injection
Comparison 3. Artzal versus Hylan G-F 20 (Also see Hylan G-F 20 versus hyaluronan, NRD-101 versus Artz,
SLM-10 versus Artz)
No. of No. of
1 Pain on weight bearing (0-100 1 Mean Difference (IV, Fixed, 95% CI) Subtotals only
mm VAS)
1.1 1 to 4 weeks post-injection 1 176 Mean Difference (IV, Fixed, 95% CI) -1.0 [-8.41, 6.41]
post-injection
post-injection
2.1 1 to 4 weeks post-injection 0 0 Mean Difference (IV, Fixed, 95% CI) 0.0 [0.0, 0.0]
2.2 5 to 13 weeks post- 0 0 Mean Difference (IV, Fixed, 95% CI) 0.0 [0.0, 0.0]
injection
post-injection
post-injection
post-injection
treatment for study knee) (45
to 52 weeks post-injectio
withdrawn due to adverse
events (45 to 52 weeks
post-injection)
6 Safety: number of adverse events 1 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only
related to treatment (45 to 52
weeks post- injection)
reporting adverse events (45 to
52 weeks post- injection)

Comparison 4. BioHy (Arthrease, Euflexxa) versus placebo
No. of No. of
post-injection
for injection site pain
post-injection
Comparison 5. BioHy (Arthrease, Euflexxa) versus Hylan G-F 20 (Synvisc)
No. of No. of
1 WOMAC pain (0-100 mm 1 Mean Difference (IV, Fixed, 95% CI) Subtotals only
VAS)
post-injection
2 WOMAC physical function 1 Mean Difference (IV, Fixed, 95% CI) Subtotals only
(0-100 mm VAS)
2.1 1 to 4 weeks post-injection 1 317 Mean Difference (IV, Fixed, 95% CI) -5.10 [-9.54, -0.66]
post-injection
3 WOMAC stiffness (0-100 mm 1 Mean Difference (IV, Fixed, 95% CI) Subtotals only
VAS)
post-injection
4 WOMAC pain (number of 1 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only
patients symptom free: VAS
score below 20 mm)
post-injection
5 WOMAC function (number of 1 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only
patients symptom free: VAS
score below 20 mm)
post-injection
6 Patient assessment of treatment 1 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only
(number of patients very
satisfied or satisfied)
post-injection
7 Rescue medication usage 1 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only
(number of patients using
acetaminophen)
post-injection
7.3 During the trial 1 320 Risk Ratio (M-H, Fixed, 95% CI) 0.83 [0.71, 0.97]
adverse events
10 Safety: withdrawals due to lack 1 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only
of efficacy
serious adverse events
joint effusion
reporting adverse events
Comparison 6. Durolane versus placebo
No. of No. of
1 Responder: reduction in the 2 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only
WOMAC pain score of at
least 40% with an absolute
improvement of at least 5
points
1.1 Week 2 1 346 Risk Ratio (M-H, Fixed, 95% CI) 0.80 [0.59, 1.09]
2 Responder: patients only 1 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only
with knee OA, reduction in
WOMAC pain score of at
least 40%, abs improvement 5
points
3 WOMAC pain (change from 2 Mean Difference (IV, Fixed, 95% CI) Subtotals only
baseline; 0 to 20 Likert)
3.1 Week 2 1 346 Mean Difference (IV, Fixed, 95% CI) 0.74 [0.02, 1.46]
3.2 Week 6 1 346 Mean Difference (IV, Fixed, 95% CI) 0.24 [-0.57, 1.05]
4 WOMAC stiffness (change from 2 Mean Difference (IV, Fixed, 95% CI) Subtotals only
baseline; 0 to 8 Likert)
4.1 Week 2 1 346 Mean Difference (IV, Fixed, 95% CI) 0.51 [0.16, 0.86]
(change from baseline; 0 to 68
Likert)
inefficacy
adverse events
affected by device-related
adverse events
with adverse events related to
injection only
non-serious treatment-related
adverse events
non-serious adverse events
treated unrelated adverse events
serious treatment-unrelated
adverse events
Comparison 7. Fermathron versus Hyalart
No. of No. of
1 Pain (0-100 mm VAS) 1 Mean Difference (IV, Fixed, 95% CI) Subtotals only
1.2 5 to13 weeks 1 233 Mean Difference (IV, Fixed, 95% CI) 0.80 [-4.51, 6.11]
post-injection
post-injection
(number of patients much
better/better)
post-injection
4 Safety: number of related adverse 1 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only
events
post-injection
Comparison 8. Hyalgan versus placebo
No. of No. of
1 Pain on weight bearing (walking) 14 Mean Difference (IV, Random, 95% CI) Subtotals only
(0-100 mm VAS)
1.1 1 to 4 weeks post-injection 14 1398 Mean Difference (IV, Random, 95% CI) -6.20 [-11.02, -1.38]
1.2 5 to 13 weeks 10 1095 Mean Difference (IV, Random, 95% CI) -9.04 [-14.10, -3.98]
post-injection
post-injection
1.4 45 to 52 weeks 3 527 Mean Difference (IV, Random, 95% CI) -2.60 [-7.40, 2.19]
post-injection
2 Pain spontaneous (0-100 mm 2 Mean Difference (IV, Fixed, 95% CI) Subtotals only
VAS)
2.1 1 to 4 weeks post-injection 2 73 Mean Difference (IV, Fixed, 95% CI) -23.88 [-33.50, -14.
25]
2.2 5 to 13 weeks 2 73 Mean Difference (IV, Fixed, 95% CI) -21.03 [-30.26, -11.
post-injection 80]
3 Pain at rest (0-100 mm VAS) 9 Mean Difference (IV, Random, 95% CI) Subtotals only
post-injection
3.3 45 to 52 weeks 2 120 Mean Difference (IV, Random, 95% CI) 1.61 [-5.28, 8.51]
post-injection
4 Pain at night (0-100 mm VAS) 2 Mean Difference (IV, Random, 95% CI) Subtotals only
4.1 1 to 4 weeks post-injection 2 84 Mean Difference (IV, Random, 95% CI) -4.55 [-12.49, 3.39]
VAS)
post-injection
post-injection
6 Number of joints improved for 2 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only
walking pain
6.1 End of treatment 1 37 Risk Ratio (M-H, Fixed, 95% CI) 1.68 [1.02, 2.78]
6.2 1 week post-injection 1 38 Risk Ratio (M-H, Fixed, 95% CI) 3.6 [1.48, 8.78]
post-injection
7 Number of joints improved for 2 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only
pain under load
7.2 1 week post-injection 1 38 Risk Ratio (M-H, Fixed, 95% CI) 3.6 [1.48, 8.78]
post-injection
8 Number of knee joints without 1 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only
rest pain
post-injection
9 Number of knee joints without 1 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only
night pain
post-injection
10 Number of joints with 1 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only
improvement in pain on touch
11 Number of patients with 1 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only
moderate/marked pain
post-injection
12 Pain (number of patients 1 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only
improved)
post-injection
12.2 32 weeks post-injection 1 408 Risk Ratio (M-H, Fixed, 95% CI) 1.36 [1.06, 1.75]
13 WOMAC function (0-100 mm 1 Mean Difference (IV, Fixed, 95% CI) Subtotals only
VAS)
post-injection
post-injection
post-injection
post-injection
post-injection
post-injection
post-injection
15 Flexion (degrees) 1 Mean Difference (IV, Fixed, 95% CI) Subtotals only
post-injection
15.2 5 to 13 weeks 1 35 Mean Difference (IV, Fixed, 95% CI) 7.60 [0.46, 14.74]
post-injection

16 Synovial fluid volume (ml) 3 Mean Difference (IV, Fixed, 95% CI) Subtotals only
post-injection
post-injection
17 Joint space width (mm) 1 Mean Difference (IV, Fixed, 95% CI) Subtotals only
post-injection (after three
courses of treatment)
post-injection (number
of patients improved
(much better/better or
excellent/good))
18.2 5 to 13 2 75 Risk Ratio (M-H, Fixed, 95% CI) 2.44 [1.43, 4.16]
weeks post-injection
(number of patients
improved (excellent/very
good/good/better/somewhat
better)
of patients improved
(better/somewhat/much;
excellent/fair)
post-injection (number of
patients rating treatment
effective)
(number of joints fairly
good/good/very good)
post-injection
post-injection
post-injection
post-injection
of efficacy
21.1 During treatment phase 1 110 Risk Ratio (M-H, Fixed, 95% CI) 1.0 [0.06, 15.59]
post-injection
painful injection
22.1 During treatment phase 1 110 Risk Ratio (M-H, Fixed, 95% CI) 2.0 [0.19, 21.42]

local adverse reaction and study
drug discontinued
drug continued
discontinued due to adverse
events
serious or severe adverse events
post-injection
post-injection
27 Safety: number of knee joints 2 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only
with local adverse reaction
injection site pain or painful
intra-articular injection
local joint pain or swelling
post-injection
local skin rash or ecchymosis
post-injection
gastrointestinal complaints
post-injection
pruritis (local)
post-injection
treatment related adverse events
post-injection
post-injection
post-injection
post-injection
none/slight/mild pain

post-injection
36 Joint space width (mm) (after 2 Mean Difference (IV, Fixed, 95% CI) Subtotals only
three courses of treatment and
stratified subgroups)
post-injection
Comparison 9. Hyalgan versus arthroscopy
No. of No. of
1 Pain (0-10 cm VAS) 1 Mean Difference (IV, Fixed, 95% CI) Subtotals only
1.1 Pre-trial 1 33 Mean Difference (IV, Fixed, 95% CI) 0.10 [-1.39, 1.59]
1.2 1 week post-injection 1 30 Mean Difference (IV, Fixed, 95% CI) 1.20 [-0.88, 3.28]
post-injection
post-injection
post-injection
2 Knee Society Function scale 1 Mean Difference (IV, Fixed, 95% CI) Subtotals only
2.1 Pre-trial 1 33 Mean Difference (IV, Fixed, 95% CI) 22.40 [6.27, 38.53]
post-injection
post-injection
2.5 45 to 52 weeks post 1 25 Mean Difference (IV, Fixed, 95% CI) 23.9 [-1.45, 49.25]
-injection
3.1 Pre-trial 1 33 Mean Difference (IV, Fixed, 95% CI) -1.90 [-4.84, 1.04]
post-injection
post-injection
post-injection
4 Clinical outcome (number of 1 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only
patients requiring further
intervention)
post-injection
post-injection
pain at injection site
Comparison 10. Hyalgan versus NSAID
No. of No. of
1 Pain after 50 foot walk (0-100 1 Mean Difference (IV, Fixed, 95% CI) Subtotals only
mm VAS)
post-injection
post-injection
moderate or marked pain
post-injection
none/slight/mild pain
post-injection
post-injection
of efficacy
post-injection
withdrawn due to
gastrointestinal events
post-injection
withdrawn due to injection site
pain
post-injection
injection site pain
post-injection
local joint pain or swelling
post-injection
local skin rash
post-injection
post-injection
pruritis (local)
post-injection
Comparison 11. Hyalgan versus methylprednisolone acetate
No. of No. of
1 Spontaneous pain intensity 3 Mean Difference (IV, Fixed, 95% CI) Subtotals only
(0-100 mm VAS)
post-injection
post-injection
2 Number of joints with moderate 1 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only
or severe walking pain
post-injection
post-injection
moderate or severe pain under
load
post-injection
4 Number of joints with moderate 1 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only
or severe pain under load
post-injection
post-injection
5 Number of patients with at least 2 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only
moderate or greater night pain
post-injection
moderate or greater rest pain
post-injection
7 Function: range of motion 2 Mean Difference (IV, Fixed, 95% CI) Subtotals only
(flexion in degrees)
post-injection
post-injection
8 Patient global (number of 3 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only
patients very good or good,
excellent or /good)
post-injection
post-injection
post-injection
post-injection
post-injection
withdrawn due to lack of
efficacy
post-injection
events
11.1 After first injection 1 99 Risk Ratio (M-H, Fixed, 95% CI) 0.30 [0.01, 7.24]
local or systemic reactions
post-injection
13 Safety: number of joints with 1 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only
local reactions but continued
in trial
post-injection

Comparison 12. Hyalgan versus triamcinolone hexacetonide
No. of No. of
1 Pain on nominated activity 1 Mean Difference (IV, Fixed, 95% CI) Subtotals only
(0-100 mm VAS)
1.1 End of treatment (week 4) 1 56 Mean Difference (IV, Fixed, 95% CI) -0.20 [-17.39, 16.
99]
1.2 14 to 26 weeks 1 20 Mean Difference (IV, Fixed, 95% CI) -10.0 [-31.83, 11.
post-injection 83]
2 Pain at rest (0-100 mm VAS) 1 Mean Difference (IV, Fixed, 95% CI) Subtotals only
77]
post-injection 12]
3 Pain at night (0-100 mm VAS) 1 Mean Difference (IV, Fixed, 95% CI) Subtotals only
10]
post-injection 66]
4.1 End of treatment (week 4) 1 63 Risk Ratio (M-H, Fixed, 95% CI) 0.73 [0.18, 2.99]
post-injection
5 Safety: wIthdrawals due to lack 1 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only
efficacy
5.2 14 to 26 week 1 63 Risk Ratio (M-H, Fixed, 95% CI) 0.89 [0.49, 1.65]
post-injection
6 Safety: wIthdrawals due to 1 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only
adverse events
post-injection
Comparison 13. Hyalgan versus mucopolysaccharide polysulfuric acid ester
No. of No. of
1 Pain (0-30) change 1 Mean Difference (IV, Fixed, 95% CI) Subtotals only
1.1 End of treatment at week 1 59 Mean Difference (IV, Fixed, 95% CI) 4.0 [0.98, 7.02]
6
2 Function (0-30) change 1 Mean Difference (IV, Fixed, 95% CI) Subtotals only
2.1 End of treatment at week 1 59 Mean Difference (IV, Fixed, 95% CI) 0.60 [-1.95, 3.15]
6
3 Range of motion (0-10) change 1 Mean Difference (IV, Fixed, 95% CI) Subtotals only
3.1 End of treatment at week 1 59 Mean Difference (IV, Fixed, 95% CI) 0.3 [-0.06, 0.66]
6
4 Total Larson rating score (0-77) 1 Mean Difference (IV, Fixed, 95% CI) Subtotals only
change
4.1 End of treatment at week 1 59 Mean Difference (IV, Fixed, 95% CI) 5.9 [1.31, 10.49]
6
patients symptom free or
markedly improved)
post-injection
post-injection
7 Safety: adverse events due to 1 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only
study medication
post-injection
Comparison 14. (Hyalgan plus exercise plus ultrasound) versus control warmup exercise
No. of No. of
1.1 End of treatment 1 66 Mean Difference (IV, Fixed, 95% CI) -2.40 [-3.08, -1.72]
1.2 One-year follow-up 1 60 Mean Difference (IV, Fixed, 95% CI) -4.6 [-5.32, -3.88]
3 Range of motion (degrees) 1 Mean Difference (IV, Fixed, 95% CI) Subtotals only
3.1 End of treatment 1 66 Mean Difference (IV, Fixed, 95% CI) 22.0 [16.42, 27.58]
3.2 One-year follow-up 1 60 Mean Difference (IV, Fixed, 95% CI) 26.0 [17.14, 34.86]
4 Ambulation speed (metres per 1 Mean Difference (IV, Fixed, 95% CI) Subtotals only
minute)
5.1 During treatment 1 70 Risk Ratio (M-H, Fixed, 95% CI) 0.33 [0.04, 3.05]
5.2 Overall 1 70 Risk Ratio (M-H, Fixed, 95% CI) 0.43 [0.12, 1.52]

Comparison 15. (Hyalgan plus exercise plus ultrasound) versus exercise
No. of No. of
minute)
Comparison 16. (Hyalgan plus exercise plus ultrasound) versus (exercise plus ultrasound)
No. of No. of
1.1 End of treatment 1 66 Mean Difference (IV, Fixed, 95% CI) -0.5 [-1.32, 0.32]
1.2 One-year follow-up 1 61 Mean Difference (IV, Fixed, 95% CI) -0.60 [-1.31, 0.11]
3.1 End of treatment 1 66 Mean Difference (IV, Fixed, 95% CI) 6.0 [-0.79, 12.79]
3.2 One-year follow-up 1 61 Mean Difference (IV, Fixed, 95% CI) 6.00 [-2.05, 14.05]
minute)

Comparison 17. Hyalgan versus conventional therapy (three courses of treatment)
No. of No. of
1 Pain overall (0-100 mm VAS) 1 Mean Difference (IV, Fixed, 95% CI) Subtotals only
post-injection 06]
post-injection
3 Joint space width (mm) 1 Mean Difference (IV, Fixed, 95% CI) Subtotals only
post-injection
4 Quality of life (AIMS: total of 1 Mean Difference (IV, Fixed, 95% CI) Subtotals only
12 items)
post-injection
5 Arthroscopy overall assessment 1 Mean Difference (IV, Fixed, 95% CI) Subtotals only
(0-100 mm VAS)
post-injection 08]
6 SFA scoring (0-100 mm VAS) 1 Mean Difference (IV, Fixed, 95% CI) Subtotals only
post-injection
7 Safety: total withdrawals 1 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only
post-injection
Comparison 18. Hyalgan versus Hylan G-F 20
No. of No. of
with local reaction (acute
inflammation and pain)

Comparison 19. Hyalgan versus Hyalgan
No. of No. of
patients assessing response as
satisfactory)
post-injection
Comparison 20. Hylan G-F 20 versus placebo
No. of No. of
1 Pain on weight bearing (0-100 6 Mean Difference (IV, Random, 95% CI) Subtotals only
mm VAS)
1.1 1 to 4 weeks post-injection 6 481 Mean Difference (IV, Random, 95% CI) -12.54 [-20.39, -4.
69]
1.2 5 to 13 weeks 5 385 Mean Difference (IV, Random, 95% CI) -22.46 [-35.24, -9.
post-injection 68]
post-injection 83]
2 Pain walking (0-100 mm VAS) 2 Mean Difference (IV, Fixed, 95% CI) Subtotals only
post-injection 86]
3 WOMAC pain 3 Std. Mean Difference (IV, Fixed, 95% CI) Subtotals only
3.1 1 to 4 weeks post-injection 2 60 Std. Mean Difference (IV, Fixed, 95% CI) -1.26 [-1.86, -0.66]
3.2 5 to 13 weeks 3 170 Std. Mean Difference (IV, Fixed, 95% CI) -0.69 [-1.02, -0.36]
post-injection
3.3 14 to 26 weeks 1 30 Std. Mean Difference (IV, Fixed, 95% CI) -1.09 [-1.92, -0.25]
post-injection
post-injection 38]
post-injection 02]
post-injection 02]
post-injection 76]
post-injection
post-injection
post-injection
9 Function: improvment in most 4 Mean Difference (IV, Fixed, 95% CI) Subtotals only
painful knee movement (0-100
mm VAS)
post-injection
10 15 metre walking time 1 Mean Difference (IV, Fixed, 95% CI) Subtotals only
post-injection
post-injection
11 WOMAC stiffness (2 to 10 2 Mean Difference (IV, Fixed, 95% CI) Subtotals only
Likert)
post-injection
post-injection
post-injection
12 Patient global assessment 1 Mean Difference (IV, Fixed, 95% CI) Subtotals only
(0-100 mm VAS; where 100 is
worst severity)
post-injection
post-injection
12.3 14 to 26 weeks post 1 30 Mean Difference (IV, Fixed, 95% CI) 0.0 [-12.68, 12.68]
injection
(number of patients good
or very good) 5 to 13 weeks
post-injection
14 Patient global evaluation of 5 Std. Mean Difference (IV, Fixed, 95% CI) Subtotals only
efficacy due to treatment
14.1 1 to 4 weeks 5 298 Std. Mean Difference (IV, Fixed, 95% CI) 0.70 [0.46, 0.93]
post-injection
14.2 5 to 13 weeks 5 295 Std. Mean Difference (IV, Fixed, 95% CI) 1.23 [0.97, 1.48]
post-injection
15 Physician global assessment 1 Mean Difference (IV, Fixed, 95% CI) Subtotals only
(0-100 mm VAS; where 100 is
worst severity)

post-injection
post-injection
15.3 14 to 26 weeks post 1 30 Mean Difference (IV, Fixed, 95% CI) -10.00 [-26.38, 6.
injection 38]
treatment for study knee)
post-injection
post-injection
post-injection
18 Need for paracetamol (pill 1 Mean Difference (IV, Fixed, 95% CI) Subtotals only
count)
post-injection
post-injection
post-injection
post-injection
post-injection
20 Safety: number of 1 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only
patients withdrawn due to
noncomplinance
21 Safety: number of patients with 6 Risk Ratio (M-H, Random, 95% CI) Subtotals only
local reaction
local adverse reactions but
study drug continued
post-injection
with one or more probable
or possible related systemic
adverse events
post-injection
reporting systemic reactions
post-injection

Comparison 21. Hylan G-F 20 versus NSAID
No. of No. of
1 Pain on motion (0-100 mm 1 Mean Difference (IV, Fixed, 95% CI) Subtotals only
VAS)
post-injection
post-injection 55]
VAS)
post-injection
post-injection
post-injection
post-injection
post-injection
post-injection
post-injection
VAS)
post-injection
post-injection
8 Patient overall assessment of 2 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only
treatment (number of patients
excellent, very good, good)
post-injection (numbe of
patients very good or good)
of patients excellent/very
good/good)
post-injection
post-injection
local reactions
post-injection
probable or possible related
systemic adverse events
post-injection
adverse events
post-injection
Comparison 22. (Hylan G-F 20 + NSAID + arthrocentesis) versus (NSAID + arthrocentesis)
No. of No. of
1 Pain on motion (0-100 mm 1 Mean Difference (IV, Fixed, 95% CI) Subtotals only
VAS)
post-injection
post-injection
post-injection
post-injection
post-injection
post-injection
post-injection 55]
post-injection
5 Patient overall assessment of 1 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only
treatment (number of patients
excellent, very good, or good)
post-injection
post-injection
Comparison 23. Hylan G-F 20 versus betamethasone
No. of No. of
of efficacy
3 Safety: wIthdrawals due to acute 1 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only
local reaction
Comparison 24. Hylan G-F 20 versus triamcinolone hexacetonide
No. of No. of
1 WOMAC pain walking on a flat 1 Mean Difference (IV, Fixed, 95% CI) Subtotals only
surface (Question 1: 0-4 Likert)
post-injection
post-injection
subscale (0-68 Likert)
post-injection
post-injection
3 WOMAC total score (0-96 1 Mean Difference (IV, Fixed, 95% CI) Subtotals only
Likert)
post-injection
post-injection
4 Patient global overall assessment 1 Mean Difference (IV, Fixed, 95% CI) Subtotals only
(0-100 mm VAS)
post-injection 77]
post-injection 03]
5 Number of responders (greater 1 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only
than or equal to one category
on WOMAC pain Q1)
post-injection
post-injection
6 Analgesic usage 1 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only
6.1 From week 0 to prior to 1 215 Risk Ratio (M-H, Fixed, 95% CI) 1.01 [0.97, 1.06]
week 12
6.2 From week 12 prior to 1 153 Risk Ratio (M-H, Fixed, 95% CI) 0.84 [0.64, 1.11]
week 26
adverse event
of efficacy
Comparison 25. Hylan G-F 20 versus physical therapy
No. of No. of
1 Spontaneous pain (0-100 mm 1 Mean Difference (IV, Fixed, 95% CI) Subtotals only
VAS)
post-injection
post-injection
1.4 37 weeks post-injection 1 40 Mean Difference (IV, Fixed, 95% CI) 1.0 [-9.15, 11.15]
post-injection
2 WOMAC pain 1 Mean Difference (IV, Fixed, 95% CI) Subtotals only
post-injection
post-injection
2.4 37 weeks post-injection 1 40 Mean Difference (IV, Fixed, 95% CI) -1.90 [-3.71, -0.09]
post-injection
post-injection
post-injection
post-injection
4 SF-36 pain 1 Mean Difference (IV, Fixed, 95% CI) Subtotals only
post-injection
post-injection
4.4 37 weeks post-injection 1 40 Mean Difference (IV, Fixed, 95% CI) -7.5 [-17.09, 2.09]
post-injection
5 SF-36 physical functioning 1 Mean Difference (IV, Fixed, 95% CI) Subtotals only
post-injection
post-injection
post-injection
Comparison 26. (Hylan G-F 20 + physiotherapy) versus physiotherapy
No. of No. of
post-injection
2 Safety: total withdrawls overall 1 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only
post-injection
adverse events
Comparison 27. Hylan G-F 20 versus progressive knee exercises
No. of No. of
1 Pain during activity 2 Mean Difference (IV, Fixed, 95% CI) Subtotals only
post-injection
post-injection
post-injection
2 Pain at rest 1 Mean Difference (IV, Fixed, 95% CI) Subtotals only
post-injection
post-injection
post-injection
3 Pain during climbing stairs 1 Mean Difference (IV, Fixed, 95% CI) Subtotals only
post-injection
post-injection
post-injection
4 Pain during transfer activity 1 Mean Difference (IV, Fixed, 95% CI) Subtotals only
post-injection
post-injection
post-injection
5 Walking distance 1 Mean Difference (IV, Fixed, 95% CI) Subtotals only
post-injection
post-injection
post-injection
post-injection
post-injection
post-injection
7 Hospital for Special Surgery 1 Mean Difference (IV, Fixed, 95% CI) Subtotals only
Knee Score (100 points)

post-injection
post-injection
post-injection
Comparison 28. Hylan G-F 20 versus appropriate care
No. of No. of
post-injection
VAS)
2.1 36 weeks post-injection 1 497 Mean Difference (IV, Fixed, 95% CI) -12.70 [-16.41, -8.
99]
3 Pain on walking (0-100 mm 1 Mean Difference (IV, Fixed, 95% CI) Subtotals only
VAS)
15]
4 WOMAC function (0-68 Likert) 1 Mean Difference (IV, Fixed, 95% CI) Subtotals only
post-injection
VAS)
38]
6.1 36 weeks post-injection 1 506 Mean Difference (IV, Fixed, 95% CI) -2.20 [-2.98, -1.42]
mm VAS)
48]
(number of patients improved
in study knee)
9 Patient global evaluation 1 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only
of effectiveness (good or
satisfactory)
10 Number of responders (20% 1 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only
decrease in pain on walking)
11 Safety: total withdrawals overall 2 Risk Ratio (M-H, Random, 95% CI) Subtotals only
of effectiveness
13 Safety: wIthdrawals due to 1 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only
adverse events
reporting mild, moderate or
severe side effects at month 12
15 Safety: total number of patients 2 Risk Ratio (M-H, Random, 95% CI) Subtotals only
reporting side effects from
baseline
gastrointestinal adverse events
Comparison 29. Hylan G-F 20 versus gaseous oxygen
No. of No. of
1 Pain under load (0-100 mm 1 Mean Difference (IV, Fixed, 95% CI) Subtotals only
VAS)
post-injection
post-injection
post-injection
post-injection
post-injection
post-injection
post-injection
post-injection
post-injection
(0-68 Likert)
post-injection
post-injection
post-injection
post-injection
post-injection
post-injection
6 Safety: total number of 1 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only
withdrawals
having total knee replacements
Comparison 30. Hylan G-F 20 versus hyaluronan (Also see Artzal, BioHy (Arthrease), Hyalgan and Orthovisc
versus Hylan G-F 20)
No. of No. of
mm VAS)
post-injection
post-injection
post-injection
2.3 14 to 26 weeks post- 0 0 Mean Difference (IV, Fixed, 95% CI) 0.0 [0.0, 0.0]
injection
3 Function: improvement in knee 2 Mean Difference (IV, Fixed, 95% CI) Subtotals only
movement (0-100 mm VAS)
post-injection
4 Patient global evaluation 2 Mean Difference (IV, Fixed, 95% CI) Subtotals only
of treatment efficacy
(improvement: 0-100 mm
VAS)
post-injection
post-injection
local reactions
post-injection
Comparison 31. NRD-101 (Suvenyl) versus placebo (saline plus oral placebo)
No. of No. of
1 Pain (0-100 mm VAS) change 1 Mean Difference (IV, Fixed, 95% CI) Subtotals only
between baseline and 45 to 52
2 Lequesne Index (0-100 1 Mean Difference (IV, Fixed, 95% CI) Subtotals only
modified scale) change between
baseline and 45 to 52 weeks
post-injection
3 Patient global assessment (0-100 1 Mean Difference (IV, Fixed, 95% CI) Subtotals only
mm VAS) change between
post-injection
4 Percentage of painful days 1 Mean Difference (IV, Fixed, 95% CI) Subtotals only
(0-100 mm VAS) change
efficacy (no. of patients rating
very good or good versus mod,
bad or very bad
6 Joint space width (percentage 1 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only
of progressors: joint space
narrowing greater than 0.5
mm)
inefficacy
9 Safety: number of withdrawals 1 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only
due to adverse events
reporting knee pain during or
after IA injection
reporting diarrhoea

Comparison 32. NRD-101 (Suvenyl) versus Diacerein
No. of No. of
1 Pain (0-100 mm VAS) change 1 Mean Difference (IV, Fixed, 95% CI) Subtotals only
2 Lequesne Index (0-100 1 Mean Difference (IV, Fixed, 95% CI) Subtotals only
modified scale) change between
post-injection
3 Patient global assessment (0-100 1 Mean Difference (IV, Fixed, 95% CI) Subtotals only
mm VAS) change between
post-injection
4 Percentage of painful days 1 Mean Difference (IV, Fixed, 95% CI) Subtotals only
(0-100 mm VAS) change
efficacy (no. of patients rating
very good or good versus mod,
bad or very bad
6 Joint space width (percentage 1 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only
progressors: joint space
narrowing greater than 0.5
mm)
inefficacy
9 Safety: number of withdrawlals 1 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only
due to adverse events
reporting knee pain during or
after IA injection
reporting diarrhoea
Comparison 33. NRD-101 (Suvenyl) versus Artz (end of treatment)
No. of No. of
1 Spontaneous pain (number of 1 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only
patients improved)
2 Pain during the night (number 1 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only
of patients improved)
3 Pressure pain (number of 1 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only
patients improved)
4 Passive movement pain (number 1 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only
of patients improved)
5 Passive flexion (degrees) 1 Mean Difference (IV, Fixed, 95% CI) Subtotals only
6 Passive extension (degrees) 1 Mean Difference (IV, Fixed, 95% CI) Subtotals only
Comparison 34. Orthovisc versus placebo
No. of No. of
1 WOMAC pain (5 to 25 Likert) 3 Mean Difference (IV, Fixed, 95% CI) Subtotals only
post-injection
post-injection
post-injection
patients who improved)
patients who achieved greater
than 5 unit improvement
(relative to baseline score))
post-injection
4 Number of patients with a 20% 2 Risk Ratio (M-H, Random, 95% CI) Subtotals only
improvement from baseline in
WOMAC pain score
4.1 5 to 13 weeks 2 394 Risk Ratio (M-H, Random, 95% CI) 1.15 [0.91, 1.44]
post-injection
post-injection
5 Number of patients with a 40% 2 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only
WOMAC pain score
post-injection
post-injection
WOMAC pain score
post-injection
post-injection
7 WOMAC pain on standing (0 2 Mean Difference (IV, Fixed, 95% CI) Subtotals only
to 100 mm VAS; change from
baseline)
post-injection
post-injection
8 WOMAC physical function (17 3 Mean Difference (IV, Fixed, 95% CI) Subtotals only
to 85 Likert)
post-injection 14]
post-injection 79]
post-injection
9 Range of motion: flexion 1 Mean Difference (IV, Fixed, 95% CI) Subtotals only
(degrees)
10 25 metre walking time (sec) 1 Mean Difference (IV, Fixed, 95% CI) Subtotals only
post-injection
11 Knee circumference (mm) 1 Mean Difference (IV, Fixed, 95% CI) Subtotals only
post-injection
12 WOMAC stiffness (2 to 10 2 Mean Difference (IV, Random, 95% CI) Subtotals only
Likert)
post-injection
post-injection
post-injection
13 WOMAC total score (0 to 2 Mean Difference (IV, Fixed, 95% CI) Subtotals only
100 mm VAS; change from
baseline)
post-injection 04]
post-injection 60]
14 Patient global assessment (0 to 1 Mean Difference (IV, Fixed, 95% CI) Subtotals only
100 mm VAS; where 100 is
worst severity)
post-injection
post-injection

post-injection
baseline)
post-injection
post-injection
(number patients rating
treatment as effective or very
effective)
post-injection
17 Physician global assessment (0 1 Mean Difference (IV, Fixed, 95% CI) Subtotals only
to 100 mm VAS; where 100 is
worst severity)
post-injection
post-injection
post-injection
(0 to 100 VAS; change from
baseline)
post-injection
post-injection
19 Synovial fluid effusion volume 1 Mean Difference (IV, Fixed, 95% CI) Subtotals only
(ml)
post-injection
20 Interleukin 6 level in the 1 Mean Difference (IV, Fixed, 95% CI) Subtotals only
synovial fluid (pg/ml)
post-injection 71]
21 Interleukin 8 level in the 1 Mean Difference (IV, Fixed, 95% CI) Subtotals only
synovial fluid (pg/ml)
post-injection
22 Tumor necrosis factor alpha 1 Mean Difference (IV, Fixed, 95% CI) Subtotals only
levels in synovial fluid
post-injection
of efficacy

26 Safety: number of 1 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only
patients withdrawn due to
noncompliance
with reported musculoskeletal
adverse events
general body adverse events
local skin rash
30 Safety: number patients with 3 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only
reported respiratory adverse
events
nervous system adverse events
urinary adverse events
withdrawn due to local adverse
events
Comparison 35. Orthovisc versus betamethasone
No. of No. of
VAS)
post-injection
post-injection
(number of patients good or
very good)
post-injection
events
local adverse events
Comparison 36. Orthovisc versus 6-methylprednisolone acetate
No. of No. of
mm VAS)
post-injection 77]
post-injection 89]
post-injection
post-injection
3 Pain on walking (0-100 mm 1 Mean Difference (IV, Fixed, 95% CI) Subtotals only
VAS)
3.1 1 to 4 weeks post-injection 1 55 Mean Difference (IV, Fixed, 95% CI) -0.40 [-11.46, 10.
66]
post-injection 67]
post-injection 89]
post-injection
post-injection
5 Flexion (active range in degrees) 1 Mean Difference (IV, Fixed, 95% CI) Subtotals only
post-injection
post-injection
withdrawn due to increased
pain
reporting musculoskeletal
adverse events
reporting skin adverse events
reporting gastrointestinal
adverse events
reporting general adverse events
reporting knee pain after
injection
Comparison 37. Orthovisc versus (Orthovisc plus triamcinolone acetonide)
No. of No. of
1 Pain (0-100 mm VAS) 1 Mean Difference (IV, Fixed, 95% CI) Subtotals only
post-injection
post-injection
post-injection 41]
post-injection
post-injection
post-injection
(0-68 Likert)
post-injection
post-injection
post-injection
4 50 foot walking time (seconds) 1 Mean Difference (IV, Fixed, 95% CI) Subtotals only
post-injection
post-injection
post-injection
post-injection
post-injection
post-injection
post-injection
post-injection
6.4 34 weeks post-injection 1 40 Mean Difference (IV, Fixed, 95% CI) 0.80 [0.12, 1.48]
post-injection
Likert)
post-injection
post-injection
post-injection
of efficacy
reporting adverse events (local
reactions)

Comparison 38. Orthovisc versus (Orthovisc plus lidocaine trigger point injection)(1 week post-injection)
No. of No. of
1 Pain at rest (0 to 4 point scale) 1 Mean Difference (IV, Fixed, 95% CI) Subtotals only
2 Pain/restrictions walking (0 to 4 1 Mean Difference (IV, Fixed, 95% CI) Subtotals only
point scale)
3 Pain/restrictions going up or 1 Mean Difference (IV, Fixed, 95% CI) Subtotals only
down stairs (0 to 4 point scale)
Comparison 39. Orthovisc versus physical therapy
No. of No. of
VAS)
32]
post-injection
post-injection
post-injection 91]
2 WOMAC pain 1 Mean Difference (IV, Fixed, 95% CI) Subtotals only
post-injection
post-injection
post-injection
post-injection
post-injection
post-injection
59]
post-injection 42]
post-injection 73]
post-injection
post-injection
post-injection
post-injection 24]
Comparison 40. (Orthovisc + physiotherapy) versus physiotherapy
No. of No. of
1 Activity pain (0-100 mm VAS) 1 Mean Difference (IV, Fixed, 95% CI) Subtotals only
post-injection
VAS)
post-injection
3 Night pain (0-100 mm VAS) 1 Mean Difference (IV, Fixed, 95% CI) Subtotals only
post-injection
4 Lequesne (0-24) 1 Mean Difference (IV, Fixed, 95% CI) Subtotals only
post-injection
5 25 m walk time (sec) 1 Mean Difference (IV, Fixed, 95% CI) Subtotals only
post-injection
6.1 1 to 4 weeks post 1 40 Mean Difference (IV, Fixed, 95% CI) 0.0 [0.0, 0.0]
-injection
post-injection
(number of patients evaluating
treatment as effective or very
effective)
post-injection
post-injection
local reactions
events
post-injection
post-injection
Comparison 41. (Orthovisc + physiotherapy) versus (Hylan G-F 20 + physiotherapy)
No. of No. of
post-injection
Comparison 42. Orthovisc versus hylan G-F 20
No. of No. of
1 WOMAC pain (0-20 or 5-25 3 Std. Mean Difference (IV, Fixed, 95% CI) Subtotals only
Likert)
1.1 1 to 4 weeks post-injection 3 121 Std. Mean Difference (IV, Fixed, 95% CI) 0.07 [-0.29, 0.43]
1.2 5 to 13 weeks 2 81 Std. Mean Difference (IV, Fixed, 95% CI) 0.28 [-0.16, 0.73]
post-injection
post-injection
1.4 37 weeks post-injection 1 40 Std. Mean Difference (IV, Fixed, 95% CI) 0.0 [-0.62, 0.62]
post-injection
VAS)
post-injection
post-injection
post-injection
69]
post-injection 57]
post-injection 08]
post-injection
4 Hospital for Special Surgery 1 Mean Difference (IV, Fixed, 95% CI) Subtotals only
Knee Score
post-injection
post-injection
post-injection
5 Pain during activity (Hospital 1 Mean Difference (IV, Fixed, 95% CI) Subtotals only
for Special Surgery)
post-injection
post-injection
post-injection
6 Pain at rest (Hospital for Special 1 Mean Difference (IV, Fixed, 95% CI) Subtotals only
Surgery)
post-injection
post-injection

post-injection
7 Pain during climbing stairs 1 Mean Difference (IV, Fixed, 95% CI) Subtotals only
(Hospital for Special Surgery)
post-injection
post-injection
post-injection
8 Pain during transfer activity 1 Mean Difference (IV, Fixed, 95% CI) Subtotals only
(Hospital for Special Surgery)
post-injection
post-injection
post-injection
9 WOMAC physical function 3 Std. Mean Difference (IV, Fixed, 95% CI) Subtotals only
(0-68 or 17-85 Likert)
9.1 1 to 4 weeks post-injection 3 121 Std. Mean Difference (IV, Fixed, 95% CI) 0.07 [-0.29, 0.43]
9.2 5 to 13 weeks 2 81 Std. Mean Difference (IV, Fixed, 95% CI) -0.13 [-0.57, 0.31]
post-injection
post-injection
9.4 37 weeks post-injection 1 40 Std. Mean Difference (IV, Fixed, 95% CI) 0.08 [-0.54, 0.70]
post-injection
post-injection 53]
post-injection 93]
post-injection 09]
post-injection 03]
post-injection
post-injection
post-injection
post-injection
12 Walking distance 1 Mean Difference (IV, Fixed, 95% CI) Subtotals only

post-injection
post-injection
post-injection
post-injection
13 Patient global assessment 1 Mean Difference (IV, Fixed, 95% CI) Subtotals only
(0-100 mm VAS where 100 is
worst severity)
post-injection
post-injection
post-injection
(0-100 mm VAS where 100 is
worst severity)
post-injection
post-injection
post-injection
15 WOMAC stiffness (0-8 or 2-10 2 Std. Mean Difference (IV, Fixed, 95% CI) Subtotals only
Likert)
post-injection
post-injection
post-injection
16 Synovial fluid intercellular 1 Mean Difference (IV, Fixed, 95% CI) Subtotals only
adhesion molecule-1 (ICAM-1)
post-injection
17 Synovial fluid vascular 1 Mean Difference (IV, Fixed, 95% CI) Subtotals only
cell adhesion molecule-1
(VCAM-1)
post-injection
of efficacy
local adverse event
noncompliance

Comparison 43. Orthovisc versus Orthovisc
No. of No. of
1 WOMAC total score (0 to 1 Mean Difference (IV, Fixed, 95% CI) Subtotals only
baseline)
post-injection 52]
post-injection 35]
baseline)
post-injection
post-injection
3 Physician global assessment (0 1 Mean Difference (IV, Fixed, 95% CI) Subtotals only
baseline)
post-injection
post-injection
4 WOMAC pain on standing (0 1 Mean Difference (IV, Fixed, 95% CI) Subtotals only
baseline)
post-injection
post-injection
WOMAC pain score
post-injection
post-injection
WOMAC pain score
post-injection
post-injection
WOMAC pain score
post-injection
post-injection
9 Safety: total withdrawals due to 1 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only
lack of efficacy
gastrointestinal adverse events
general body adverse events
infections
musculoskeletal adverse events
nervous system adverse events
respiratory adverse events
skin adverse events
Comparison 44. Replasyn versus placebo
No. of No. of
1 Safety: Number of patients with 1 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only
drug continued
Comparison 45. SLM-10 versus Artz (end of treatment)
No. of No. of
1 Pain in movement (number of 1 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only
patients improved)
2 Pain when resting (number of 1 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only
patients improved)
patients improved)
(number of patients better or
much better)
6 Safety: local adverse events 1 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only
related to study drug resulting
in withdrawals
7 Safety: local adverse events no 1 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only
specific causal relationship to
study drug and continuation in
trial
Comparison 46. Suplasyn versus placebo: 1 week post-injection
No. of No. of
1 Pain after walking (0-10 cm 1 Mean Difference (IV, Fixed, 95% CI) Subtotals only
VAS)
2 WOMAC pain (0-10 cm VAS) 1 Mean Difference (IV, Fixed, 95% CI) Subtotals only
3 Pain at rest (0-10 cm VAS) 1 Mean Difference (IV, Fixed, 95% CI) Subtotals only
4 WOMAC function (0-10 cm 1 Mean Difference (IV, Fixed, 95% CI) Subtotals only
VAS)
5 Walk time (sec) 1 Mean Difference (IV, Fixed, 95% CI) Subtotals only
Comparison 47. Suplasyn versus NSAID: 1 week post-injection
No. of No. of
1 Pain after walking (0-10 cm 1 Mean Difference (IV, Random, 95% CI) Subtotals only
VAS)
VAS)

Comparison 48. (Suplasyn + NSAID) versus NSAID: 1 week post-injection
No. of No. of
1 Pain after walking (0-10 cm 1 Mean Difference (IV, Fixed, 95% CI) Subtotals only
VAS)
VAS)
Comparison 49. Zeel compositum versus Hyalart (end of treatment (5 weeks))
No. of No. of
1 Pain during movement (0-100 1 Mean Difference (IV, Fixed, 95% CI) Subtotals only
mm VAS )
2 Pain during the night (0-100 1 Mean Difference (IV, Fixed, 95% CI) Subtotals only
mm VAS)
3 Patient global: number of 1 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only
patients with noticeable
improvements in symptoms
4 Patient assessment of 1 Mean Difference (IV, Fixed, 95% CI) Subtotals only
improvement (0-100 mm VAS)
5 Patient assessment of tolerance 1 Mean Difference (IV, Fixed, 95% CI) Subtotals only
(0-100 mm VAS)
side effects
withdrawn due to lack of
efficacy
Comparison 50. HA/hylan versus placebo
No. of No. of
1 Pain on weight bearing (0-100 27 Mean Difference (IV, Random, 95% CI) Subtotals only
mm VAS)
post-injection 23]
post-injection
post-injection
2 Pain at rest (0-100 mm VAS) 12 Mean Difference (IV, Random, 95% CI) Subtotals only
3 WOMAC pain 9 Std. Mean Difference (IV, Random, 95% CI) Subtotals only
3.1 1 to 4 weeks post-injection 7 412 Std. Mean Difference (IV, Random, 95% CI) -1.22 [-1.93, -0.52]
3.2 5 to 13 weeks 7 639 Std. Mean Difference (IV, Random, 95% CI) -1.02 [-1.57, -0.47]
post-injection
post-injection
4 WOMAC physical function 9 Std. Mean Difference (IV, Random, 95% CI) Subtotals only
4.1 1 to 4 weeks post-injection 7 412 Std. Mean Difference (IV, Random, 95% CI) -1.02 [-1.62, -0.42]
post-injection
post-injection
post-injection
post-injection
post-injection
6 Patient global assessment 14 Risk Ratio (M-H, Random, 95% CI) Subtotals only
6.1 1 to 4 weeks post-injection 6 594 Risk Ratio (M-H, Random, 95% CI) 1.10 [0.89, 1.36]
(much better/better or
excellent/good)
post-injection (excellent/very
good/good/better/somewhat
better)
6.3 14 to 26 4 552 Risk Ratio (M-H, Random, 95% CI) 1.04 [0.73, 1.47]
(better/somewhat/much)
post-injection (number of
patients rating treatment
effective or very good or good)
post-injection
post-injection

post-injection
post-injection
local adverse reaction and study
drug discontinued
drug continued
discontinued due to adverse
events
post-injection
post-injection
of efficacy
post-injection
post-injection
post-injection
events for injection site pain
post-injection
events local skin rash
post-injection
post-injection
post-injection
with possible study medication
related events
post-injection
18 Safety: number of serious 2 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only
adverse events
post-injection

events probably or possibly
related to treatment
post-injection
post-injection
Comparison 51. HA/hylan versus NSAID
No. of No. of
1 Pain after walking (0-100 mm 2 Mean Difference (IV, Random, 95% CI) Subtotals only
VAS)
1.1 1 to 4 weeks post-injection 2 333 Mean Difference (IV, Random, 95% CI) 3.28 [-6.45, 13.02]
2 Patient general satisfaction wtih 1 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only
treatment (excellent or good vs
satisfactory or bad)
2.1 HA arm versus regular 1 60 Risk Ratio (M-H, Fixed, 95% CI) 0.62 [0.46, 0.84]
dose celecoxib
2.2 HA + low dose celecoxib 1 60 Risk Ratio (M-H, Fixed, 95% CI) 1.03 [0.94, 1.13]
arm versus regular dose
celecoxib
2.3 HA + voluntary dose of 1 60 Risk Ratio (M-H, Fixed, 95% CI) 1.0 [0.91, 1.10]
celecoxib arm versus regular
dose of celecoxib
post-injection
post-injection
4 Safety: number of withdrawals 2 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only
due to inefficacy
Comparison 52. HA/hylan versus Methylprednisolone acetate
No. of No. of
1 Function: range of motion 3 Mean Difference (IV, Fixed, 95% CI) Subtotals only
(active flexion in degrees)
post-injection
Comparison 53. HA versus HA
No. of No. of
1 Pain in movement (number of 2 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only
patients improved)
patients improved)
post-injection
post-injection
post-injection
post-injection

Analysis 1.1. Comparison 1 Adant versus Hyalgan, Outcome 1 Patient global assessment (number of
patients excellent/good).
Review: Viscosupplementation for the treatment of osteoarthritis of the knee
Comparison: 1 Adant versus Hyalgan
Outcome: 1 Patient global assessment (number of patients excellent/good)
Study or subgroup Adant Hyalgan Risk Ratio Weight Risk Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI
1 1 to 4 weeks post-injection
Roman 2000 13/30 7/19 100.0 % 1.18 [ 0.57, 2.41 ]
Subtotal (95% CI) 30 19 100.0 % 1.18 [ 0.57, 2.41 ]

Total events: 13 (Adant), 7 (Hyalgan)
Heterogeneity: not applicable
Test for overall effect: Z = 0.44 (P = 0.66)
Roman 2000 15/30 4/19 100.0 % 2.38 [ 0.93, 6.09 ]
Subtotal (95% CI) 30 19 100.0 % 2.38 [ 0.93, 6.09 ]

Roman 2000 10/30 3/19 100.0 % 2.11 [ 0.67, 6.70 ]
Subtotal (95% CI) 30 19 100.0 % 2.11 [ 0.67, 6.70 ]

0.1 0.2 0.5 1 2 5 10

Favours Hyalgan Favours Adant

Analysis 1.2. Comparison 1 Adant versus Hyalgan, Outcome 2 Safety: number of painful injections.
Comparison: 1 Adant versus Hyalgan
Outcome: 2 Safety: number of painful injections
Study or subgroup Adant Hyalgan Risk Ratio Weight Risk Ratio

Roman 2000 6/30 2/19 100.0 % 1.90 [ 0.43, 8.46 ]
Subtotal (95% CI) 30 19 100.0 % 1.90 [ 0.43, 8.46 ]

0.1 0.2 0.5 1 2 5 10

Favours Adant Favours Hyalgan

Analysis 2.1. Comparison 2 Artz versus placebo, Outcome 1 Pain (100 mm VAS).
Comparison: 2 Artz versus placebo
Outcome: 1 Pain (100 mm VAS)
Mean Mean
Study or subgroup Artzal/Artz Saline/Vehicle Difference Weight Difference
N Mean(SD) N Mean(SD) IV,Fixed,95% CI IV,Fixed,95% CI
Karlsson 2002a (AvP) 90 44 (24.44) 33 44 (30.39) 14.5 % 0.0 [ -11.53, 11.53 ]
Lohmander 1996 96 36.64 (25.49) 93 32.24 (24.81) 37.4 % 4.40 [ -2.77, 11.57 ]
Puhl 1993 95 29.14 (22.6) 100 31.4 (22.4) 48.2 % -2.26 [ -8.58, 4.06 ]
Subtotal (95% CI) 281 226 100.0 % 0.56 [ -3.83, 4.94 ]

Heterogeneity: Chi2 = 1.88, df = 2 (P = 0.39); I2 =0.0%
Karlsson 2002a (AvP) 90 42 (28.07) 33 46 (34.9) 11.8 % -4.00 [ -17.24, 9.24 ]
Lohmander 1996 96 34.69 (27.25) 93 35.23 (25.49) 36.5 % -0.54 [ -8.06, 6.98 ]
Puhl 1993 95 26.5 (22.6) 100 34 (22.4) 51.7 % -7.50 [ -13.82, -1.18 ]
Subtotal (95% CI) 281 226 100.0 % -4.55 [ -9.09, 0.00 ]

Karlsson 2002a (AvP) 90 48 (33.78) 33 44 (33.78) 23.1 % 4.00 [ -9.47, 17.47 ]
Lohmander 1996 96 33.65 (25.74) 93 35.4 (26.06) 76.9 % -1.75 [ -9.14, 5.64 ]
Subtotal (95% CI) 186 126 100.0 % -0.42 [ -6.90, 6.06 ]

Test for subgroup differences: Chi2 = 2.67, df = 2 (P = 0.26), I2 =25%
-10 -5 0 5 10
Favours Artzal/Artz Favours saline/vehic

Analysis 2.2. Comparison 2 Artz versus placebo, Outcome 2 Pain score (0-3).
Outcome: 2 Pain score (0-3)
Mean Mean
Study or subgroup Artz+lactose Vehicle+lactose Difference Weight Difference
1 1 to 4 weeks post -injection

Shichikawa 1983b 48 0.66 (0.56) 50 0.73 (0.5) 100.0 % -0.07 [ -0.28, 0.14 ]
Subtotal (95% CI) 48 50 100.0 % -0.07 [ -0.28, 0.14 ]

Test for subgroup differences: Not applicable
-10 -5 0 5 10
Favours Artz+lactose Favours vehicle+lact
Analysis 2.3. Comparison 2 Artz versus placebo, Outcome 3 WOMAC pain (0-20 Likert).
Outcome: 3 WOMAC pain (0-20 Likert)
Mean Mean
Study or subgroup Artz Saline Difference Weight Difference
Day 2004 108 3.84 (3.27) 115 4.61 (3.14) 100.0 % -0.77 [ -1.61, 0.07 ]
Subtotal (95% CI) 108 115 100.0 % -0.77 [ -1.61, 0.07 ]

-10 -5 0 5 10
Favours Artz Favours Saline

Analysis 2.4. Comparison 2 Artz versus placebo, Outcome 4 WOMAC function (0-68 Likert).
Outcome: 4 WOMAC function (0-68 Likert)
Mean Mean
Day 2004 108 15.37 (11.41) 115 17.81 (10.53) 100.0 % -2.44 [ -5.33, 0.45 ]
Subtotal (95% CI) 108 115 100.0 % -2.44 [ -5.33, 0.45 ]

-10 -5 0 5 10

Analysis 2.5. Comparison 2 Artz versus placebo, Outcome 5 Lequesne Index (0-24).
Outcome: 5 Lequesne Index (0-24)
Mean Mean
Study or subgroup Artzal/Artz Saline/vehicle Difference Weight Difference
Puhl 1993 95 7.19 (3.9) 100 7 (3.5) 100.0 % 0.19 [ -0.85, 1.23 ]
Subtotal (95% CI) 95 100 100.0 % 0.19 [ -0.85, 1.23 ]

Puhl 1993 95 6.43 (3.9) 100 6.79 (3.5) 100.0 % -0.36 [ -1.40, 0.68 ]
Subtotal (95% CI) 95 100 100.0 % -0.36 [ -1.40, 0.68 ]

Karlsson 2002a (AvP) 92 10 (4.96) 66 8.9 (4.77) 37.6 % 1.10 [ -0.43, 2.63 ]
Lohmander 1996 119 7.98 (4.4) 120 7.82 (4.98) 62.4 % 0.16 [ -1.03, 1.35 ]
Subtotal (95% CI) 211 186 100.0 % 0.51 [ -0.43, 1.45 ]

Test for subgroup differences: Chi2 = 1.50, df = 2 (P = 0.47), I2 =0.0%
-10 -5 0 5 10
Favours Artzal/Artz Favours saline/vehic

Analysis 2.6. Comparison 2 Artz versus placebo, Outcome 6 Range of motion.
Outcome: 6 Range of motion
Mean Mean
Study or subgroup Artz+lactose Vehicle+Lactose Difference Weight Difference
Shichikawa 1983b 48 135.65 (14.48) 50 132.6 (13.45) 3.05 [ -2.49, 8.59 ]
-10 -5 0 5 10
Favours Vehicle+lact Favours Artz+lactose
Analysis 2.7. Comparison 2 Artz versus placebo, Outcome 7 Patient global assessment (number of patients
improved).
Outcome: 7 Patient global assessment (number of patients improved)
Study or subgroup Artzal/Artz Saline/vehicle Risk Ratio Weight Risk Ratio

Lohmander 1996 59/96 56/93 36.1 % 1.02 [ 0.81, 1.28 ]
Shichikawa 1983a 87/103 67/105 42.1 % 1.32 [ 1.12, 1.56 ]
Shichikawa 1983b 38/48 35/50 21.8 % 1.13 [ 0.90, 1.43 ]
Subtotal (95% CI) 247 248 100.0 % 1.17 [ 1.04, 1.32 ]

Total events: 184 (Artzal/Artz), 158 (Saline/vehicle)
Heterogeneity: Chi2 = 3.55, df = 2 (P = 0.17); I2 =44%
Lohmander 1996 53/96 51/93 39.6 % 1.01 [ 0.78, 1.30 ]
0.1 0.2 0.5 1 2 5 10

Favours saline/vehic Favours Artz/Artzal
(Continued . . . )

(. . . Continued)
Study or subgroup Artzal/Artz Saline/vehicle Risk Ratio Weight Risk Ratio
Puhl 1993 86/95 81/100 60.4 % 1.12 [ 1.00, 1.25 ]
Subtotal (95% CI) 191 193 100.0 % 1.07 [ 0.95, 1.21 ]

Lohmander 1996 58/96 43/93 100.0 % 1.31 [ 1.00, 1.72 ]
Subtotal (95% CI) 96 93 100.0 % 1.31 [ 1.00, 1.72 ]

0.1 0.2 0.5 1 2 5 10

Favours saline/vehic Favours Artz/Artzal
Analysis 2.8. Comparison 2 Artz versus placebo, Outcome 8 WOMAC stiffness (0-8 Likert).
Outcome: 8 WOMAC stiffness (0-8 Likert)
Mean Mean
Day 2004 108 2.11 (1.42) 115 2.46 (1.44) 100.0 % -0.35 [ -0.73, 0.03 ]
Subtotal (95% CI) 108 115 100.0 % -0.35 [ -0.73, 0.03 ]

-10 -5 0 5 10

Analysis 2.9. Comparison 2 Artz versus placebo, Outcome 9 Number of survivors (patients not requiring
additional treatment for study knee) 45 to 52 weeks post-injection.
Outcome: 9 Number of survivors (patients not requiring additional treatment for study knee) 45 to 52 weeks post-injection
Study or subgroup Artzal Saline Risk Ratio Weight Risk Ratio

Karlsson 2002a (AvP) 39/90 22/66 1.30 [ 0.86, 1.97 ]
0.1 0.2 0.5 1 2 5 10

Favours saline Favours Artzal
Analysis 2.10. Comparison 2 Artz versus placebo, Outcome 10 Number of clinical failures.
Outcome: 10 Number of clinical failures

Karlsson 2002a (AvP) 2/90 7/66 100.0 % 0.21 [ 0.04, 0.98 ]
Subtotal (95% CI) 90 66 100.0 % 0.21 [ 0.04, 0.98 ]

Total events: 2 (Artzal), 7 (Saline)
Karlsson 2002a (AvP) 26/66 26/48 100.0 % 0.73 [ 0.49, 1.08 ]
Subtotal (95% CI) 66 48 100.0 % 0.73 [ 0.49, 1.08 ]

Total events: 26 (Artzal), 26 (Saline)
0.1 0.2 0.5 1 2 5 10

Favours Artzal Favours saline

Analysis 2.11. Comparison 2 Artz versus placebo, Outcome 11 Safety: total withdrawals overall.
Outcome: 11 Safety: total withdrawals overall
Study or subgroup Artz/Artzal Saline/vehicle Risk Ratio Weight Risk Ratio

Shichikawa 1983a 8/111 7/112 58.9 % 1.15 [ 0.43, 3.07 ]
Shichikawa 1983b 4/52 5/55 41.1 % 0.85 [ 0.24, 2.98 ]
Subtotal (95% CI) 163 167 100.0 % 1.03 [ 0.48, 2.22 ]

Total events: 12 (Artz/Artzal), 12 (Saline/vehicle)
Day 2004 19/116 19/124 72.9 % 1.07 [ 0.60, 1.92 ]
Puhl 1993 7/102 7/107 27.1 % 1.05 [ 0.38, 2.89 ]
Subtotal (95% CI) 218 231 100.0 % 1.06 [ 0.64, 1.76 ]

Lohmander 1996 3/120 5/120 100.0 % 0.60 [ 0.15, 2.45 ]
Subtotal (95% CI) 120 120 100.0 % 0.60 [ 0.15, 2.45 ]

0.1 0.2 0.5 1 2 5 10

Favours Artz/Artzal Favours saline/vehic

Analysis 2.12. Comparison 2 Artz versus placebo, Outcome 12 Safety: number of patients reporting
adverse events (45 to 52 weeks post- injection).
Outcome: 12 Safety: number of patients reporting adverse events (45 to 52 weeks post- injection)

Karlsson 2002a (AvP) 55/90 33/66 1.22 [ 0.91, 1.64 ]
0.1 0.2 0.5 1 2 5 10

Favours treatment Favours control
Analysis 2.13. Comparison 2 Artz versus placebo, Outcome 13 Safety: withdrawals due to adverse events.
Outcome: 13 Safety: withdrawals due to adverse events
Study or subgroup Artz/Artzal Saline/Vehicle Risk Ratio Weight Risk Ratio

Shichikawa 1983a 0/110 1/109 38.3 % 0.33 [ 0.01, 8.02 ]
Shichikawa 1983b 0/50 2/53 61.7 % 0.21 [ 0.01, 4.31 ]
Subtotal (95% CI) 160 162 100.0 % 0.26 [ 0.03, 2.28 ]

Total events: 0 (Artz/Artzal), 3 (Saline/Vehicle)
Day 2004 1/108 1/115 100.0 % 1.06 [ 0.07, 16.81 ]
Subtotal (95% CI) 108 115 100.0 % 1.06 [ 0.07, 16.81 ]

0.1 0.2 0.5 1 2 5 10

Favours Artz/Artzal Favours saline/place
(Continued . . . )

(. . . Continued)
Study or subgroup Artz/Artzal Saline/Vehicle Risk Ratio Weight Risk Ratio
Lohmander 1996 2/120 5/120 100.0 % 0.40 [ 0.08, 2.02 ]
Subtotal (95% CI) 120 120 100.0 % 0.40 [ 0.08, 2.02 ]

Karlsson 2002a (AvP) 2/90 2/66 100.0 % 0.73 [ 0.11, 5.07 ]
Subtotal (95% CI) 90 66 100.0 % 0.73 [ 0.11, 5.07 ]

0.1 0.2 0.5 1 2 5 10

Favours Artz/Artzal Favours saline/place
Analysis 2.14. Comparison 2 Artz versus placebo, Outcome 14 Safety: number of patients with local
adverse reaction but study drug continued.
Outcome: 14 Safety: number of patients with local adverse reaction but study drug continued
Study or subgroup Artz Vehicle Risk Ratio Weight Risk Ratio

Shichikawa 1983a 1/110 4/109 0.25 [ 0.03, 2.18 ]
0.1 0.2 0.5 1 2 5 10

Favours Artz Favours vehicle

Analysis 2.15. Comparison 2 Artz versus placebo, Outcome 15 Safety: number of adverse events
probably/possibly related to treatment.
Outcome: 15 Safety: number of adverse events probably/possibly related to treatment
Study or subgroup Artz Saline Risk Ratio Weight Risk Ratio

Day 2004 50/108 31/115 86.0 % 1.72 [ 1.19, 2.47 ]
Puhl 1993 4/102 5/107 14.0 % 0.84 [ 0.23, 3.04 ]
Subtotal (95% CI) 210 222 100.0 % 1.59 [ 1.12, 2.26 ]

Total events: 54 (Artz), 36 (Saline)
Karlsson 2002a (AvP) 2/146 2/78 100.0 % 0.53 [ 0.08, 3.72 ]
Subtotal (95% CI) 146 78 100.0 % 0.53 [ 0.08, 3.72 ]

Total events: 2 (Artz), 2 (Saline)
0.1 0.2 0.5 1 2 5 10

Analysis 2.16. Comparison 2 Artz versus placebo, Outcome 16 Safety: number of serious adverse events
(45 to 52 weeks post-injection).
Outcome: 16 Safety: number of serious adverse events (45 to 52 weeks post-injection)

Karlsson 2002a (AvP) 12/146 11/78 0.58 [ 0.27, 1.26 ]
0.1 0.2 0.5 1 2 5 10

Favours Artzal Favours Saline

Analysis 2.17. Comparison 2 Artz versus placebo, Outcome 17 Safety: total withdrawals overall (knees).
Outcome: 17 Safety: total withdrawals overall (knees)
Study or subgroup Artz Vehicle (Placebo) Risk Ratio Weight Risk Ratio
Wu 1997 6/62 13/54 100.0 % 0.40 [ 0.16, 0.98 ]
Subtotal (95% CI) 62 54 100.0 % 0.40 [ 0.16, 0.98 ]

Total events: 6 (Artz), 13 (Vehicle (Placebo))
Wu 1997 30/62 28/54 100.0 % 0.93 [ 0.65, 1.34 ]
Subtotal (95% CI) 62 54 100.0 % 0.93 [ 0.65, 1.34 ]

Total events: 30 (Artz), 28 (Vehicle (Placebo))
0.1 0.2 0.5 1 2 5 10

Favours Artz Favours Placebo

Analysis 3.1. Comparison 3 Artzal versus Hylan G-F 20 (Also see Hylan G-F 20 versus hyaluronan, NRD-101
versus Artz, SLM-10 versus Artz), Outcome 1 Pain on weight bearing (0-100 mm VAS).
Comparison: 3 Artzal versus Hylan G-F 20 (Also see Hylan G-F 20 versus hyaluronan, NRD-101 versus Artz, SLM-10 versus Artz)
Outcome: 1 Pain on weight bearing (0-100 mm VAS)
Mean Mean
Study or subgroup Artzal Synvisc Difference Weight Difference
Karlsson 2002c (AvS) 90 44 (24.44) 86 45 (25.67) 100.0 % -1.00 [ -8.41, 6.41 ]
Subtotal (95% CI) 90 86 100.0 % -1.00 [ -8.41, 6.41 ]

Karlsson 2002c (AvS) 90 42 (28.07) 86 41 (31.53) 100.0 % 1.00 [ -7.83, 9.83 ]
Subtotal (95% CI) 90 86 100.0 % 1.00 [ -7.83, 9.83 ]

Karlsson 2002c (AvS) 90 48 (33.78) 86 43 (33.78) 100.0 % 5.00 [ -4.98, 14.98 ]
Subtotal (95% CI) 90 86 100.0 % 5.00 [ -4.98, 14.98 ]

-10 -5 0 5 10
Favours Artzal Favours Synvisc

versus Artz, SLM-10 versus Artz), Outcome 2 Lequesne Index (0-24).
Mean Mean
Study or subgroup Artzal Synvisc Difference Weight Difference
Subtotal (95% CI) 0 0 Not estimable
Test for overall effect: not applicable
Karlsson 2002c (AvS) 92 10 (4.96) 88 9 (4.44) 100.0 % 1.00 [ -0.37, 2.37 ]
Subtotal (95% CI) 92 88 100.0 % 1.00 [ -0.37, 2.37 ]

-10 -5 0 5 10

versus Artz, SLM-10 versus Artz), Outcome 3 Number of clinical failures.
Study or subgroup Artzal Synvisc Risk Ratio Weight Risk Ratio

Karlsson 2002c (AvS) 2/90 6/86 100.0 % 0.32 [ 0.07, 1.54 ]
Subtotal (95% CI) 90 86 100.0 % 0.32 [ 0.07, 1.54 ]

Total events: 2 (Artzal), 6 (Synvisc)
Karlsson 2002c (AvS) 26/66 32/70 100.0 % 0.86 [ 0.58, 1.28 ]
Subtotal (95% CI) 66 70 100.0 % 0.86 [ 0.58, 1.28 ]

Total events: 26 (Artzal), 32 (Synvisc)
0.1 0.2 0.5 1 2 5 10

versus Artz, SLM-10 versus Artz), Outcome 4 Number of survivors (patients not requiring additional
treatment for study knee) (45 to 52 weeks post-injectio.
Outcome: 4 Number of survivors (patients not requiring additional treatment for study knee) (45 to 52 weeks post-injectio
Study or subgroup Artzal Synvisc Risk Ratio Weight Risk Ratio

Karlsson 2002c (AvS) 39/90 38/86 0.98 [ 0.70, 1.37 ]
0.1 0.2 0.5 1 2 5 10

Favours Synvisc Favours Artzal

versus Artz, SLM-10 versus Artz), Outcome 5 Safety: number of patients withdrawn due to adverse events (45
to 52 weeks post-injection).
Outcome: 5 Safety: number of patients withdrawn due to adverse events (45 to 52 weeks post-injection)
Study or subgroup Artzal Hylan G-F 20 Risk Ratio Weight Risk Ratio
Karlsson 2002c (AvS) 2/90 1/86 1.91 [ 0.18, 20.69 ]
0.1 0.2 0.5 1 2 5 10

Favours Artzal Favours Hylan G-F 20
versus Artz, SLM-10 versus Artz), Outcome 6 Safety: number of adverse events related to treatment (45 to 52
weeks post- injection).
Outcome: 6 Safety: number of adverse events related to treatment (45 to 52 weeks post- injection)
Karlsson 2002c (AvS) 2/146 1/90 1.23 [ 0.11, 13.40 ]
0.1 0.2 0.5 1 2 5 10


versus Artz, SLM-10 versus Artz), Outcome 7 Safety: number of patients reporting adverse events (45 to 52
weeks post- injection).
Outcome: 7 Safety: number of patients reporting adverse events (45 to 52 weeks post- injection)
Karlsson 2002c (AvS) 55/90 44/86 1.19 [ 0.92, 1.56 ]
0.1 0.2 0.5 1 2 5 10

Analysis 4.1. Comparison 4 BioHy (Arthrease, Euflexxa) versus placebo, Outcome 1 Safety: total
withdrawals overall.
Comparison: 4 BioHy (Arthrease, Euflexxa) versus placebo
Study or subgroup BioHy Saline Risk Ratio Weight Risk Ratio

Tamir 2001 3/25 4/24 100.0 % 0.72 [ 0.18, 2.89 ]
Subtotal (95% CI) 25 24 100.0 % 0.72 [ 0.18, 2.89 ]

Total events: 3 (BioHy), 4 (Saline)
0.1 0.2 0.5 1 2 5 10

Favours BioHy Favours Saline

Analysis 4.2. Comparison 4 BioHy (Arthrease, Euflexxa) versus placebo, Outcome 2 Safety: number of
adverse events for injection site pain.
Comparison: 4 BioHy (Arthrease, Euflexxa) versus placebo
Outcome: 2 Safety: number of adverse events for injection site pain
Study or subgroup BioHy Saline Risk Ratio Weight Risk Ratio

Tamir 2001 18/25 11/24 100.0 % 1.57 [ 0.95, 2.59 ]
Subtotal (95% CI) 25 24 100.0 % 1.57 [ 0.95, 2.59 ]

Total events: 18 (BioHy), 11 (Saline)
0.1 0.2 0.5 1 2 5 10


Analysis 5.1. Comparison 5 BioHy (Arthrease, Euflexxa) versus Hylan G-F 20 (Synvisc), Outcome 1
WOMAC pain (0-100 mm VAS).
Comparison: 5 BioHy (Arthrease, Euflexxa) versus Hylan G-F 20 (Synvisc)
Outcome: 1 WOMAC pain (0-100 mm VAS)
Mean Mean
Study or subgroup Euflexxa Synvisc Difference Weight Difference
Kirchner 2005 160 21.7 (20.24) 161 25.4 (20.3) 100.0 % -3.70 [ -8.13, 0.73 ]
Subtotal (95% CI) 160 161 100.0 % -3.70 [ -8.13, 0.73 ]

Kirchner 2005 160 19.2 (20.24) 161 23 (19.03) 100.0 % -3.80 [ -8.10, 0.50 ]
Subtotal (95% CI) 160 161 100.0 % -3.80 [ -8.10, 0.50 ]

-10 -5 0 5 10
Favours Euflexxa Favours Synvisc

WOMAC physical function (0-100 mm VAS).
Outcome: 2 WOMAC physical function (0-100 mm VAS)
Mean Mean
Kirchner 2005 159 22.3 (20.18) 158 27.4 (20.11) 100.0 % -5.10 [ -9.54, -0.66 ]
Subtotal (95% CI) 159 158 100.0 % -5.10 [ -9.54, -0.66 ]

Kirchner 2005 157 20 (20.05) 158 25.4 (20.11) 100.0 % -5.40 [ -9.83, -0.97 ]
Subtotal (95% CI) 157 158 100.0 % -5.40 [ -9.83, -0.97 ]

-10 -5 0 5 10

WOMAC stiffness (0-100 mm VAS).
Outcome: 3 WOMAC stiffness (0-100 mm VAS)
Mean Mean
Kirchner 2005 159 21.2 (20.18) 158 24.2 (20.11) 100.0 % -3.00 [ -7.44, 1.44 ]
Subtotal (95% CI) 159 158 100.0 % -3.00 [ -7.44, 1.44 ]

Kirchner 2005 157 18.2 (20.05) 158 22 (20.11) 100.0 % -3.80 [ -8.23, 0.63 ]
Subtotal (95% CI) 157 158 100.0 % -3.80 [ -8.23, 0.63 ]

-10 -5 0 5 10

WOMAC pain (number of patients symptom free: VAS score below 20 mm).
Outcome: 4 WOMAC pain (number of patients symptom free: VAS score below 20 mm)
Study or subgroup Euflexxa Synvisc Risk Ratio Weight Risk Ratio

Kirchner 2005 101/160 84/161 100.0 % 1.21 [ 1.00, 1.46 ]
Subtotal (95% CI) 160 161 100.0 % 1.21 [ 1.00, 1.46 ]

Total events: 101 (Euflexxa), 84 (Synvisc)
0.1 0.2 0.5 1 2 5 10

Favours Synvisc Favours Euflexxa
WOMAC function (number of patients symptom free: VAS score below 20 mm).
Outcome: 5 WOMAC function (number of patients symptom free: VAS score below 20 mm)

Kirchner 2005 101/157 75/158 100.0 % 1.36 [ 1.11, 1.66 ]
Subtotal (95% CI) 157 158 100.0 % 1.36 [ 1.11, 1.66 ]

0.1 0.2 0.5 1 2 5 10


Analysis 5.6. Comparison 5 BioHy (Arthrease, Euflexxa) versus Hylan G-F 20 (Synvisc), Outcome 6 Patient
assessment of treatment (number of patients very satisfied or satisfied).
Outcome: 6 Patient assessment of treatment (number of patients very satisfied or satisfied)

Kirchner 2005 127/157 119/158 100.0 % 1.07 [ 0.96, 1.21 ]
Subtotal (95% CI) 157 158 100.0 % 1.07 [ 0.96, 1.21 ]

0.1 0.2 0.5 1 2 5 10


Analysis 5.7. Comparison 5 BioHy (Arthrease, Euflexxa) versus Hylan G-F 20 (Synvisc), Outcome 7 Rescue
medication usage (number of patients using acetaminophen).
Outcome: 7 Rescue medication usage (number of patients using acetaminophen)

Kirchner 2005 65/158 89/156 100.0 % 0.72 [ 0.57, 0.91 ]
Subtotal (95% CI) 158 156 100.0 % 0.72 [ 0.57, 0.91 ]

Kirchner 2005 64/154 91/155 100.0 % 0.71 [ 0.56, 0.89 ]
Subtotal (95% CI) 154 155 100.0 % 0.71 [ 0.56, 0.89 ]

3 During the trial
Kirchner 2005 97/159 118/161 100.0 % 0.83 [ 0.71, 0.97 ]
Subtotal (95% CI) 159 161 100.0 % 0.83 [ 0.71, 0.97 ]

0.1 0.2 0.5 1 2 5 10


Analysis 5.8. Comparison 5 BioHy (Arthrease, Euflexxa) versus Hylan G-F 20 (Synvisc), Outcome 8 Safety:
total withdrawals overall.

Kirchner 2005 4/160 3/161 1.34 [ 0.31, 5.90 ]
0.1 0.2 0.5 1 2 5 10

Analysis 5.9. Comparison 5 BioHy (Arthrease, Euflexxa) versus Hylan G-F 20 (Synvisc), Outcome 9 Safety:
withdrawals due to adverse events.

Kirchner 2005 0/160 1/161 0.34 [ 0.01, 8.17 ]
0.1 0.2 0.5 1 2 5 10


Safety: withdrawals due to lack of efficacy.
Outcome: 10 Safety: withdrawals due to lack of efficacy

Kirchner 2005 0/160 0/161 Not estimable
0.1 0.2 0.5 1 2 5 10

Safety: number of patients with serious adverse events.
Outcome: 11 Safety: number of patients with serious adverse events

Kirchner 2005 3/160 2/161 1.51 [ 0.26, 8.91 ]
0.1 0.2 0.5 1 2 5 10


Safety: number of patients with joint effusion.
Outcome: 12 Safety: number of patients with joint effusion

Kirchner 2005 1/160 13/161 0.08 [ 0.01, 0.58 ]
0.01 0.1 1 10 100

Safety: number of patients reporting adverse events.
Outcome: 13 Safety: number of patients reporting adverse events

Kirchner 2005 54/160 65/161 0.84 [ 0.63, 1.11 ]
0.1 0.2 0.5 1 2 5 10


Analysis 6.1. Comparison 6 Durolane versus placebo, Outcome 1 Responder: reduction in the WOMAC
pain score of at least 40% with an absolute improvement of at least 5 points.
Comparison: 6 Durolane versus placebo
Outcome: 1 Responder: reduction in the WOMAC pain score of at least 40% with an absolute improvement of at least 5 points
Study or subgroup Durolane Saline Risk Ratio Weight Risk Ratio

1 Week 2
Altman 2004 50/172 63/174 100.0 % 0.80 [ 0.59, 1.09 ]
Subtotal (95% CI) 172 174 100.0 % 0.80 [ 0.59, 1.09 ]

Total events: 50 (Durolane), 63 (Saline)
2 Week 6
Altman 2004 63/172 52/174 100.0 % 1.23 [ 0.91, 1.66 ]
Subtotal (95% CI) 172 174 100.0 % 1.23 [ 0.91, 1.66 ]

3 Week 13
Ardic 2001 55/172 61/174 100.0 % 0.91 [ 0.68, 1.23 ]
Subtotal (95% CI) 172 174 100.0 % 0.91 [ 0.68, 1.23 ]

4 Week 26
Altman 2004 50/172 56/174 100.0 % 0.90 [ 0.66, 1.24 ]
Subtotal (95% CI) 172 174 100.0 % 0.90 [ 0.66, 1.24 ]

0.1 0.2 0.5 1 2 5 10

Favours Saline Favours Durolane

Analysis 6.2. Comparison 6 Durolane versus placebo, Outcome 2 Responder: patients only with knee OA,
reduction in WOMAC pain score of at least 40%, abs improvement 5 points.
Outcome: 2 Responder: patients only with knee OA, reduction in WOMAC pain score of at least 40%, abs improvement 5 points

1 Week 2
Altman 2004 36/107 38/109 100.0 % 0.97 [ 0.67, 1.40 ]
Subtotal (95% CI) 107 109 100.0 % 0.97 [ 0.67, 1.40 ]

2 Week 6
Altman 2004 45/107 30/109 100.0 % 1.53 [ 1.05, 2.23 ]
Subtotal (95% CI) 107 109 100.0 % 1.53 [ 1.05, 2.23 ]

3 Week 13
Altman 2004 38/107 36/109 100.0 % 1.08 [ 0.74, 1.56 ]
Subtotal (95% CI) 107 109 100.0 % 1.08 [ 0.74, 1.56 ]

4 Week 26
Altman 2004 33/107 35/109 100.0 % 0.96 [ 0.65, 1.42 ]
Subtotal (95% CI) 107 109 100.0 % 0.96 [ 0.65, 1.42 ]

0.1 0.2 0.5 1 2 5 10

Favours Saline Favours Durolane

Analysis 6.3. Comparison 6 Durolane versus placebo, Outcome 3 WOMAC pain (change from baseline; 0 to
20 Likert).
Outcome: 3 WOMAC pain (change from baseline; 0 to 20 Likert)
Mean Mean
Study or subgroup Durolane Saline Difference Weight Difference
1 Week 2
Altman 2004 172 -2.75 (3.27) 174 -3.49 (3.59) 100.0 % 0.74 [ 0.02, 1.46 ]
Subtotal (95% CI) 172 174 100.0 % 0.74 [ 0.02, 1.46 ]

2 Week 6
Altman 1998 172 -3.15 (3.9) 174 -3.39 (3.81) 100.0 % 0.24 [ -0.57, 1.05 ]
Subtotal (95% CI) 172 174 100.0 % 0.24 [ -0.57, 1.05 ]

3 Week 13
Altman 1998 172 -2.87 (3.97) 174 -3.42 (4.1) 100.0 % 0.55 [ -0.30, 1.40 ]
Subtotal (95% CI) 172 174 100.0 % 0.55 [ -0.30, 1.40 ]

4 Week 26
Altman 1998 172 -2.5 (4) 174 -2.89 (4.17) 100.0 % 0.39 [ -0.47, 1.25 ]
Subtotal (95% CI) 172 174 100.0 % 0.39 [ -0.47, 1.25 ]

-10 -5 0 5 10
Favours Durolane Favours Saline

Analysis 6.4. Comparison 6 Durolane versus placebo, Outcome 4 WOMAC stiffness (change from baseline;
0 to 8 Likert).
Outcome: 4 WOMAC stiffness (change from baseline; 0 to 8 Likert)
Mean Mean
1 Week 2
Altman 2004 172 -0.48 (1.63) 174 -0.99 (1.73) 100.0 % 0.51 [ 0.16, 0.86 ]
Subtotal (95% CI) 172 174 100.0 % 0.51 [ 0.16, 0.86 ]

2 Week 6
Altman 1998 172 -0.87 (1.96) 174 -1.03 (1.39) 100.0 % 0.16 [ -0.20, 0.52 ]
Subtotal (95% CI) 172 174 100.0 % 0.16 [ -0.20, 0.52 ]

3 Week 13
Altman 2004 172 -0.71 (1.87) 174 -1.05 (1.96) 100.0 % 0.34 [ -0.06, 0.74 ]
Subtotal (95% CI) 172 174 100.0 % 0.34 [ -0.06, 0.74 ]

4 Week 26
Altman 2004 172 -0.47 (1.77) 174 -0.82 (1.96) 100.0 % 0.35 [ -0.04, 0.74 ]
Subtotal (95% CI) 172 174 100.0 % 0.35 [ -0.04, 0.74 ]

-10 -5 0 5 10

Analysis 6.5. Comparison 6 Durolane versus placebo, Outcome 5 WOMAC physical function (change from
baseline; 0 to 68 Likert).
Outcome: 5 WOMAC physical function (change from baseline; 0 to 68 Likert)
Mean Mean
1 Week 2
Altman 2004 172 -6.35 (10.48) 174 -8.5 (11.22) 100.0 % 2.15 [ -0.14, 4.44 ]
Subtotal (95% CI) 172 174 100.0 % 2.15 [ -0.14, 4.44 ]

2 Week 6
Altman 2004 172 -7.52 (12.12) 174 -8.52 (12.41) 100.0 % 1.00 [ -1.58, 3.58 ]
Subtotal (95% CI) 172 174 100.0 % 1.00 [ -1.58, 3.58 ]

3 Week 13
Altman 2004 172 -6.98 (12.27) 174 -8.72 (13.39) 100.0 % 1.74 [ -0.97, 4.45 ]
Subtotal (95% CI) 172 174 100.0 % 1.74 [ -0.97, 4.45 ]

4 Week 26
Altman 2004 172 -5.82 (12.16) 174 -7.42 (13.52) 100.0 % 1.60 [ -1.11, 4.31 ]
Subtotal (95% CI) 172 174 100.0 % 1.60 [ -1.11, 4.31 ]

-10 -5 0 5 10

Analysis 6.6. Comparison 6 Durolane versus placebo, Outcome 6 Safety: total withdrawals overall.

Altman 1998 39/173 35/174 1.12 [ 0.75, 1.68 ]
0.1 0.2 0.5 1 2 5 10

Analysis 6.7. Comparison 6 Durolane versus placebo, Outcome 7 Safety: withdrawals due to inefficacy.
Outcome: 7 Safety: withdrawals due to inefficacy

Altman 2004 10/173 6/174 1.68 [ 0.62, 4.51 ]
0.1 0.2 0.5 1 2 5 10


Analysis 6.8. Comparison 6 Durolane versus placebo, Outcome 8 Safety: withdrawals due to adverse events.

Altman 2004 13/173 6/174 2.18 [ 0.85, 5.60 ]
0.1 0.2 0.5 1 2 5 10

Analysis 6.9. Comparison 6 Durolane versus placebo, Outcome 9 Safety: number of patients affected by
device-related adverse events.
Outcome: 9 Safety: number of patients affected by device-related adverse events
Study or subgroup Durolaje Saline Risk Ratio Weight Risk Ratio

Altman 2004 3/173 2/174 1.51 [ 0.26, 8.92 ]
0.1 0.2 0.5 1 2 5 10


Analysis 6.10. Comparison 6 Durolane versus placebo, Outcome 10 Safety: number of patients with adverse
events related to injection only.
Outcome: 10 Safety: number of patients with adverse events related to injection only

Altman 2004 1/173 2/174 0.50 [ 0.05, 5.49 ]
0.1 0.2 0.5 1 2 5 10

Analysis 6.11. Comparison 6 Durolane versus placebo, Outcome 11 Safety: number of patients with non-
serious treatment-related adverse events.
Outcome: 11 Safety: number of patients with non-serious treatment-related adverse events

Altman 2004 22/173 15/174 1.48 [ 0.79, 2.75 ]
0.1 0.2 0.5 1 2 5 10


Analysis 6.12. Comparison 6 Durolane versus placebo, Outcome 12 Safety: number of patients with non-
serious adverse events.
Outcome: 12 Safety: number of patients with non-serious adverse events

Altman 2004 112/173 114/174 0.99 [ 0.85, 1.15 ]
0.1 0.2 0.5 1 2 5 10

Analysis 6.13. Comparison 6 Durolane versus placebo, Outcome 13 Safety: number of patients with treated
unrelated adverse events.
Outcome: 13 Safety: number of patients with treated unrelated adverse events

Altman 2004 101/173 109/174 0.93 [ 0.79, 1.10 ]
0.1 0.2 0.5 1 2 5 10


Analysis 6.14. Comparison 6 Durolane versus placebo, Outcome 14 Safety: number of patients with serious
treatment-unrelated adverse events.
Outcome: 14 Safety: number of patients with serious treatment-unrelated adverse events

Altman 2004 7/173 3/174 2.35 [ 0.62, 8.93 ]
0.1 0.2 0.5 1 2 5 10

Analysis 7.1. Comparison 7 Fermathron versus Hyalart, Outcome 1 Pain (0-100 mm VAS).
Comparison: 7 Fermathron versus Hyalart
Outcome: 1 Pain (0-100 mm VAS)
Mean Mean
Study or subgroup Fermathron Hyalart Difference Weight Difference
McDonald 2000 114 31.3 (19.4) 119 29 (20.6) 100.0 % 2.30 [ -2.84, 7.44 ]
Subtotal (95% CI) 114 119 100.0 % 2.30 [ -2.84, 7.44 ]

2 5 to13 weeks post-injection
McDonald 2000 114 25.4 (19.3) 119 24.6 (22) 100.0 % 0.80 [ -4.51, 6.11 ]
Subtotal (95% CI) 114 119 100.0 % 0.80 [ -4.51, 6.11 ]

-10 -5 0 5 10
Favours Fermathron Favours Hyalart

Analysis 7.2. Comparison 7 Fermathron versus Hyalart, Outcome 2 Lequesne Index (0-24).
Mean Mean
Study or subgroup Fermathron Hyalart Difference Weight Difference
McDonald 2000 114 7.92 (4.09) 119 7.46 (4.08) 100.0 % 0.46 [ -0.59, 1.51 ]
Subtotal (95% CI) 114 119 100.0 % 0.46 [ -0.59, 1.51 ]

McDonald 2000 114 6.91 (4.22) 119 6.36 (3.74) 100.0 % 0.55 [ -0.48, 1.58 ]
Subtotal (95% CI) 114 119 100.0 % 0.55 [ -0.48, 1.58 ]

-10 -5 0 5 10

Analysis 7.3. Comparison 7 Fermathron versus Hyalart, Outcome 3 Patient global assessment (number of
patients much better/better).
Outcome: 3 Patient global assessment (number of patients much better/better)
Study or subgroup Fermathron Hyalart Risk Ratio Weight Risk Ratio

McDonald 2000 87/125 92/127 100.0 % 0.96 [ 0.82, 1.13 ]
Subtotal (95% CI) 125 127 100.0 % 0.96 [ 0.82, 1.13 ]

Total events: 87 (Fermathron), 92 (Hyalart)
0.1 0.2 0.5 1 2 5 10

Favours Hyalart Favours Fermathron
Analysis 7.4. Comparison 7 Fermathron versus Hyalart, Outcome 4 Safety: number of related adverse
events.
Outcome: 4 Safety: number of related adverse events
Study or subgroup Fermathron Hyalart Risk Ratio Weight Risk Ratio

McDonald 2000 24/114 17/119 100.0 % 1.47 [ 0.84, 2.59 ]
Subtotal (95% CI) 114 119 100.0 % 1.47 [ 0.84, 2.59 ]

Total events: 24 (Fermathron), 17 (Hyalart)
0.1 0.2 0.5 1 2 5 10


Analysis 8.1. Comparison 8 Hyalgan versus placebo, Outcome 1 Pain on weight bearing (walking) (0-100
mm VAS).
Comparison: 8 Hyalgan versus placebo
Outcome: 1 Pain on weight bearing (walking) (0-100 mm VAS)
Mean Mean
Study or subgroup Hyalgan Placebo Difference Weight Difference
N Mean(SD) N Mean(SD) IV,Random,95% CI IV,Random,95% CI
Altman 1998 136 25 (24) 149 25 (25) 9.3 % 0.0 [ -5.69, 5.69 ]
Carrabba 1995 20 41.8 (14.4) 10 56.4 (13.5) 7.1 % -14.60 [ -25.08, -4.12 ]
Carrabba 1995a 20 46 (16.5) 10 56.4 (13.5) 6.8 % -10.40 [ -21.46, 0.66 ]
Carrabba 1995b 20 41.8 (14.4) 10 59.7 (14.9) 6.8 % -17.90 [ -29.09, -6.71 ]
Carrabba 1995c 20 46 (16.5) 10 59.7 (14.9) 6.5 % -13.70 [ -25.43, -1.97 ]
Corrado 1995 19 35.4 (28.6) 16 41.6 (25.4) 4.3 % -6.20 [ -24.10, 11.70 ]
Creamer 1994 12 41.12 (0) 12 33.93 (3.12) Not estimable
Dougados 1993 52 34.13 (23.49) 50 35.62 (23.68) 7.7 % -1.49 [ -10.65, 7.67 ]
Henderson 1994 18 28.1 (7.6) 19 38.8 (6.5) 9.8 % -10.70 [ -15.27, -6.13 ]
Henderson 1994a 22 39.8 (7.3) 25 31.3 (6.1) 10.0 % 8.50 [ 4.62, 12.38 ]
Huskisson 1999 45 35.29 (27.83) 48 48.02 (30.42) 6.5 % -12.73 [ -24.57, -0.89 ]
Jubb 2003 205 43.87 (24.05) 200 43.88 (25.36) 9.7 % -0.01 [ -4.83, 4.81 ]
St. J. Dixon 1988 28 50.54 (29.11) 33 64.91 (26.52) 5.6 % -14.37 [ -28.45, -0.29 ]
Tsai 2003 96 22.6 (14.31) 93 23.92 (15) 9.9 % -1.32 [ -5.50, 2.86 ]
Subtotal (95% CI) 713 685 100.0 % -6.20 [ -11.02, -1.38 ]

Heterogeneity: Tau2 = 56.65; Chi2 = 68.99, df = 12 (P<0.00001); I2 =83%
Altman 1998 115 23 (25) 129 24 (26) 13.5 % -1.00 [ -7.40, 5.40 ]
Carrabba 1995 20 42.1 (12.5) 10 59.8 (14.5) 9.9 % -17.70 [ -28.23, -7.17 ]
Carrabba 1995a 20 47.8 (17.7) 10 59.8 (14.5) 8.8 % -12.00 [ -23.87, -0.13 ]
Carrabba 1995b 20 42.1 (12.5) 10 63.2 (13.7) 10.2 % -21.10 [ -31.21, -10.99 ]
Carrabba 1995c 20 47.8 (17.7) 10 63.2 (13.7) 9.1 % -15.40 [ -26.90, -3.90 ]
-100 -50 0 50 100

Favours Hyalgan Favours Placebo
(Continued . . . )

(. . . Continued)
Mean Mean
Corrado 1995 19 29.7 (22.9) 16 43.2 (22.3) 6.8 % -13.50 [ -28.51, 1.51 ]
Creamer 1994 12 41.8 (29.58) 12 41.8 (27.26) 3.8 % 0.0 [ -22.76, 22.76 ]
Huskisson 1999 43 37.4 (32.44) 45 50.18 (30.96) 7.9 % -12.78 [ -26.04, 0.48 ]
Jubb 2003 207 46.51 (26.38) 200 50.2 (25.27) 14.7 % -3.69 [ -8.71, 1.33 ]
Tsai 2003 88 19.32 (14.76) 89 19.78 (14.85) 15.2 % -0.46 [ -4.82, 3.90 ]
Subtotal (95% CI) 564 531 100.0 % -9.04 [ -14.10, -3.98 ]

Heterogeneity: Tau2 = 38.77; Chi2 = 28.31, df = 9 (P = 0.00085); I2 =68%
Altman 1998 105 18 (21) 113 24 (27) 24.3 % -6.00 [ -12.40, 0.40 ]
Huskisson 1999 39 39.44 (27.81) 40 53.68 (29.86) 9.0 % -14.24 [ -26.96, -1.52 ]
Jubb 2003 206 50.06 (25.68) 199 50.14 (25.79) 31.3 % -0.08 [ -5.09, 4.93 ]
Tsai 2003 88 15.57 (13.88) 88 20.68 (15.52) 35.3 % -5.11 [ -9.46, -0.76 ]
Subtotal (95% CI) 438 440 100.0 % -4.57 [ -8.72, -0.42 ]

Dougados 1993 47 28.51 (23.77) 48 29.35 (24.26) 24.7 % -0.84 [ -10.50, 8.82 ]
Jubb 2003 208 47.59 (29.37) 200 50.45 (29.21) 71.2 % -2.86 [ -8.54, 2.82 ]
St. J. Dixon 1988 11 48.45 (28.89) 13 57 (29.46) 4.2 % -8.55 [ -31.96, 14.86 ]
Subtotal (95% CI) 266 261 100.0 % -2.60 [ -7.40, 2.19 ]

Heterogeneity: Tau2 = 0.0; Chi2 = 0.38, df = 2 (P = 0.83); I2 =0.0%
-100 -50 0 50 100


Analysis 8.2. Comparison 8 Hyalgan versus placebo, Outcome 2 Pain spontaneous (0-100 mm VAS).
Outcome: 2 Pain spontaneous (0-100 mm VAS)
Mean Mean
Bragantini 1987 19 17.12 (13.03) 18 46.21 (28.04) 45.8 % -29.09 [ -43.31, -14.87 ]
Grecomoro 1987 20 14.55 (18.78) 16 34.02 (20.72) 54.2 % -19.47 [ -32.54, -6.40 ]
Subtotal (95% CI) 39 34 100.0 % -23.88 [ -33.50, -14.25 ]

Test for overall effect: Z = 4.86 (P < 0.00001)
Bragantini 1987 19 15.59 (8.11) 18 46.95 (30.93) 39.2 % -31.36 [ -46.11, -16.61 ]
Grecomoro 1987 20 20.8 (16.77) 16 35.18 (18.92) 60.8 % -14.38 [ -26.21, -2.55 ]
Subtotal (95% CI) 39 34 100.0 % -21.03 [ -30.26, -11.80 ]

-100 -50 0 50 100


Analysis 8.3. Comparison 8 Hyalgan versus placebo, Outcome 3 Pain at rest (0-100 mm VAS).
Outcome: 3 Pain at rest (0-100 mm VAS)
Mean Mean
Carrabba 1995 20 28.3 (11.6) 10 37.4 (13.7) 10.5 % -9.10 [ -19.00, 0.80 ]
Carrabba 1995a 20 30.3 (14.5) 10 37.4 (13.7) 9.9 % -7.10 [ -17.71, 3.51 ]
Carrabba 1995b 20 28.3 (11.6) 10 40.4 (14.7) 10.1 % -12.10 [ -22.53, -1.67 ]
Carrabba 1995c 20 30.3 (14.5) 10 40.4 (14.7) 9.6 % -10.10 [ -21.21, 1.01 ]
Corrado 1995 19 9.4 (22.2) 16 9.1 (18.8) 7.9 % 0.30 [ -13.28, 13.88 ]
Dougados 1993 52 10.87 (16.94) 48 14.69 (18.7) 13.0 % -3.82 [ -10.83, 3.19 ]
Henderson 1994 18 17.7 (5.6) 19 31.3 (7.2) 15.3 % -13.60 [ -17.74, -9.46 ]
Henderson 1994a 22 25.3 (6.5) 25 24 (6) 15.7 % 1.30 [ -2.29, 4.89 ]
St. J. Dixon 1988 28 20.5 (24.69) 33 22.64 (28.35) 8.0 % -2.14 [ -15.45, 11.17 ]
Subtotal (95% CI) 219 181 100.0 % -6.37 [ -11.57, -1.18 ]

Carrabba 1995 20 29.3 (9.3) 10 39.9 (14.6) 20.8 % -10.60 [ -20.52, -0.68 ]
Carrabba 1995a 20 33 (15.8) 10 39.9 (14.6) 15.7 % -6.90 [ -18.29, 4.49 ]
Carrabba 1995b 20 29.3 (9.3) 10 43.2 (14.8) 20.3 % -13.90 [ -23.94, -3.86 ]
Carrabba 1995c 20 33 (15.8) 10 43.2 (14.8) 15.5 % -10.20 [ -21.69, 1.29 ]
Corrado 1995 19 5.1 (12.3) 16 12.2 (13.4) 27.7 % -7.10 [ -15.68, 1.48 ]
Subtotal (95% CI) 99 56 100.0 % -9.65 [ -14.18, -5.13 ]

Dougados 1993 47 11.87 (20.01) 48 9.65 (15.64) 91.0 % 2.22 [ -5.01, 9.45 ]
St. J. Dixon 1988 14 20.86 (30.68) 11 25.36 (27.78) 9.0 % -4.50 [ -27.47, 18.47 ]
Subtotal (95% CI) 61 59 100.0 % 1.61 [ -5.28, 8.51 ]

-100 -50 0 50 100


Analysis 8.4. Comparison 8 Hyalgan versus placebo, Outcome 4 Pain at night (0-100 mm VAS).
Outcome: 4 Pain at night (0-100 mm VAS)
Mean Mean
Study or subgroup Hyalgan Control Difference Weight Difference
Henderson 1994 18 45.5 (6.7) 19 54.2 (6.2) 48.8 % -8.70 [ -12.87, -4.53 ]
Henderson 1994a 22 60.2 (6.4) 25 60.8 (5.1) 51.2 % -0.60 [ -3.94, 2.74 ]
Subtotal (95% CI) 40 44 100.0 % -4.55 [ -12.49, 3.39 ]

-10 -5 0 5 10
Favours Hyalgan Favours control

Analysis 8.5. Comparison 8 Hyalgan versus placebo, Outcome 5 WOMAC pain (0-100 mm VAS).
Mean Mean
Study or subgroup Hyalgan Saline Difference Weight Difference
Tsai 2003 96 23.21 (14.14) 93 25.88 (15.05) 100.0 % -2.67 [ -6.84, 1.50 ]
Subtotal (95% CI) 96 93 100.0 % -2.67 [ -6.84, 1.50 ]

Tsai 2003 88 21.48 (14.5) 89 22.97 (14.44) 100.0 % -1.49 [ -5.75, 2.77 ]
Subtotal (95% CI) 88 89 100.0 % -1.49 [ -5.75, 2.77 ]

Tsai 2003 88 16.48 (14.53) 88 22.14 (15.22) 100.0 % -5.66 [ -10.06, -1.26 ]
Subtotal (95% CI) 88 88 100.0 % -5.66 [ -10.06, -1.26 ]

-10 -5 0 5 10
Favours Hyalgan Favours saline

Analysis 8.6. Comparison 8 Hyalgan versus placebo, Outcome 6 Number of joints improved for walking pain.
Outcome: 6 Number of joints improved for walking pain
Study or subgroup Hyalgan Saline Risk Ratio Weight Risk Ratio

1 End of treatment
Bragantini 1987 16/19 9/18 100.0 % 1.68 [ 1.02, 2.78 ]
Subtotal (95% CI) 19 18 100.0 % 1.68 [ 1.02, 2.78 ]

Total events: 16 (Hyalgan), 9 (Saline)
2 1 week post-injection
Grecomoro 1987 16/20 4/18 100.0 % 3.60 [ 1.48, 8.78 ]
Subtotal (95% CI) 20 18 100.0 % 3.60 [ 1.48, 8.78 ]

Bragantini 1987 17/19 7/18 100.0 % 2.30 [ 1.26, 4.19 ]
Subtotal (95% CI) 19 18 100.0 % 2.30 [ 1.26, 4.19 ]

0.1 0.2 0.5 1 2 5 10

Favours Hyalgan Favours Saline

Analysis 8.7. Comparison 8 Hyalgan versus placebo, Outcome 7 Number of joints improved for pain under
load.
Outcome: 7 Number of joints improved for pain under load

1 End of treatment
Bragantini 1987 17/19 6/18 100.0 % 2.68 [ 1.37, 5.25 ]
Subtotal (95% CI) 19 18 100.0 % 2.68 [ 1.37, 5.25 ]

Grecomoro 1987 16/20 4/18 100.0 % 3.60 [ 1.48, 8.78 ]
Subtotal (95% CI) 20 18 100.0 % 3.60 [ 1.48, 8.78 ]

Bragantini 1987 17/19 4/18 100.0 % 4.03 [ 1.67, 9.69 ]
Subtotal (95% CI) 19 18 100.0 % 4.03 [ 1.67, 9.69 ]

0.1 0.2 0.5 1 2 5 10

Favours Saline Favours Hyalgan

Analysis 8.8. Comparison 8 Hyalgan versus placebo, Outcome 8 Number of knee joints without rest pain.
Outcome: 8 Number of knee joints without rest pain
Study or subgroup Hyalgan Placebo Risk Ratio Weight Risk Ratio

Creamer 1994 6/12 5/12 100.0 % 1.20 [ 0.50, 2.88 ]
Subtotal (95% CI) 12 12 100.0 % 1.20 [ 0.50, 2.88 ]

Total events: 6 (Hyalgan), 5 (Placebo)
Creamer 1994 5/12 2/12 100.0 % 2.50 [ 0.60, 10.46 ]
Subtotal (95% CI) 12 12 100.0 % 2.50 [ 0.60, 10.46 ]

0.1 0.2 0.5 1 2 5 10

Favours Placebo Favours Hyalgan

Analysis 8.9. Comparison 8 Hyalgan versus placebo, Outcome 9 Number of knee joints without night pain.
Outcome: 9 Number of knee joints without night pain

Creamer 1994 7/12 5/12 100.0 % 1.40 [ 0.61, 3.19 ]
Subtotal (95% CI) 12 12 100.0 % 1.40 [ 0.61, 3.19 ]

Creamer 1994 7/12 5/12 100.0 % 1.40 [ 0.61, 3.19 ]
Subtotal (95% CI) 12 12 100.0 % 1.40 [ 0.61, 3.19 ]

0.1 0.2 0.5 1 2 5 10

Analysis 8.10. Comparison 8 Hyalgan versus placebo, Outcome 10 Number of joints with improvement in
pain on touch.
Outcome: 10 Number of joints with improvement in pain on touch
Study or subgroup Hyalgan Control Risk Ratio Weight Risk Ratio

Grecomoro 1987 15/20 6/18 2.25 [ 1.12, 4.53 ]
0.1 0.2 0.5 1 2 5 10


Analysis 8.11. Comparison 8 Hyalgan versus placebo, Outcome 11 Number of patients with
moderate/marked pain.
Outcome: 11 Number of patients with moderate/marked pain

Altman 1998 36/105 53/115 100.0 % 0.74 [ 0.53, 1.04 ]
Subtotal (95% CI) 105 115 100.0 % 0.74 [ 0.53, 1.04 ]

Total events: 36 (Hyalgan), 53 (Control)
0.1 0.2 0.5 1 2 5 10


Analysis 8.12. Comparison 8 Hyalgan versus placebo, Outcome 12 Pain (number of patients improved).
Outcome: 12 Pain (number of patients improved)

Jubb 2003 88/208 71/200 100.0 % 1.19 [ 0.93, 1.52 ]
Subtotal (95% CI) 208 200 100.0 % 1.19 [ 0.93, 1.52 ]

2 32 weeks post-injection
Jubb 2003 92/208 65/200 100.0 % 1.36 [ 1.06, 1.75 ]
Subtotal (95% CI) 208 200 100.0 % 1.36 [ 1.06, 1.75 ]

0.1 0.2 0.5 1 2 5 10


Analysis 8.13. Comparison 8 Hyalgan versus placebo, Outcome 13 WOMAC function (0-100 mm VAS).
Outcome: 13 WOMAC function (0-100 mm VAS)
Mean Mean
Study or subgroup Hyalgan Saline Difference Weight Difference
Tsai 2003 96 26.91 (14.89) 93 28.21 (14.71) 100.0 % -1.30 [ -5.52, 2.92 ]
Subtotal (95% CI) 96 93 100.0 % -1.30 [ -5.52, 2.92 ]

Tsai 2003 88 24.25 (14.65) 89 25.31 (14.63) 100.0 % -1.06 [ -5.37, 3.25 ]
Subtotal (95% CI) 88 89 100.0 % -1.06 [ -5.37, 3.25 ]

Tsai 2003 88 20.85 (14.42) 88 24.9 (14.89) 100.0 % -4.05 [ -8.38, 0.28 ]
Subtotal (95% CI) 88 88 100.0 % -4.05 [ -8.38, 0.28 ]

-10 -5 0 5 10
Favours Hyalgan Favours saline

Analysis 8.14. Comparison 8 Hyalgan versus placebo, Outcome 14 Lequesne Index (0-24).
Mean Mean
Carrabba 1995 20 11.5 (3) 10 13.4 (3.4) 11.9 % -1.90 [ -4.38, 0.58 ]
Carrabba 1995a 20 11.6 (3.7) 10 13.4 (3.4) 10.4 % -1.80 [ -4.46, 0.86 ]
Carrabba 1995b 20 11.5 (3) 10 14.1 (3.5) 11.4 % -2.60 [ -5.14, -0.06 ]
Carrabba 1995c 20 11.6 (3.7) 10 14.1 (3.5) 10.0 % -2.50 [ -5.21, 0.21 ]
Dougados 1993 49 8.53 (3.81) 50 8.78 (3.59) 34.5 % -0.25 [ -1.71, 1.21 ]
Huskisson 1999 40 10 (4.6) 41 12.1 (3.8) 21.7 % -2.10 [ -3.94, -0.26 ]
Subtotal (95% CI) 169 131 100.0 % -1.50 [ -2.36, -0.65 ]

Carrabba 1995 20 11.6 (2.6) 10 13.9 (3.5) 19.1 % -2.30 [ -4.75, 0.15 ]
Carrabba 1995a 20 12 (4.3) 10 13.9 (3.5) 13.9 % -1.90 [ -4.77, 0.97 ]
Carrabba 1995b 20 11.6 (2.6) 10 14.4 (3.2) 21.9 % -2.80 [ -5.09, -0.51 ]
Carrabba 1995c 20 12 (4.3) 10 14.4 (3.2) 15.3 % -2.40 [ -5.14, 0.34 ]
Huskisson 1999 40 10.2 (4.8) 41 12.4 (4.2) 29.7 % -2.20 [ -4.17, -0.23 ]
Subtotal (95% CI) 120 81 100.0 % -2.34 [ -3.41, -1.27 ]

Huskisson 1999 40 11.2 (4.4) 41 12.6 (4.8) 100.0 % -1.40 [ -3.40, 0.60 ]
Subtotal (95% CI) 40 41 100.0 % -1.40 [ -3.40, 0.60 ]

Dougados 1993 47 7.06 (4.09) 47 8.17 (3.76) 100.0 % -1.11 [ -2.70, 0.48 ]
Subtotal (95% CI) 47 47 100.0 % -1.11 [ -2.70, 0.48 ]

-10 -5 0 5 10

Analysis 8.15. Comparison 8 Hyalgan versus placebo, Outcome 15 Flexion (degrees).
Outcome: 15 Flexion (degrees)
Mean Mean
Corrado 1995 19 123.5 (10.2) 16 120 (12.4) 100.0 % 3.50 [ -4.11, 11.11 ]
Subtotal (95% CI) 19 16 100.0 % 3.50 [ -4.11, 11.11 ]

Corrado 1995 19 125.5 (9.9) 16 117.9 (11.4) 100.0 % 7.60 [ 0.46, 14.74 ]
Subtotal (95% CI) 19 16 100.0 % 7.60 [ 0.46, 14.74 ]

-10 -5 0 5 10
Favours Control Favours Hyalgan

Analysis 8.16. Comparison 8 Hyalgan versus placebo, Outcome 16 Synovial fluid volume (ml).
Outcome: 16 Synovial fluid volume (ml)
Mean Mean
Corrado 1995 21 14.1 (24.1) 19 11.4 (12.3) 5.5 % 2.70 [ -9.00, 14.40 ]
Creamer 1994 12 6.05 (4.16) 12 6.52 (4.65) 60.0 % -0.47 [ -4.00, 3.06 ]
Dougados 1993 49 6.1 (11.08) 46 7.9 (12) 34.5 % -1.80 [ -6.45, 2.85 ]
Subtotal (95% CI) 82 77 100.0 % -0.76 [ -3.49, 1.98 ]

Corrado 1995 21 2.3 (6.2) 19 10.4 (13.7) 29.1 % -8.10 [ -14.81, -1.39 ]
Creamer 1994 12 5.67 (4.15) 12 6.42 (6.37) 70.9 % -0.75 [ -5.05, 3.55 ]
Subtotal (95% CI) 33 31 100.0 % -2.89 [ -6.51, 0.73 ]

-10 -5 0 5 10

Analysis 8.17. Comparison 8 Hyalgan versus placebo, Outcome 17 Joint space width (mm).
Outcome: 17 Joint space width (mm)
Mean Mean
1 45 to 52 weeks post-injection (after three courses of treatment)

Jubb 2001a 136 4.8 (1.7) 137 4.4 (1.4) 100.0 % 0.40 [ 0.03, 0.77 ]
Subtotal (95% CI) 136 137 100.0 % 0.40 [ 0.03, 0.77 ]

-10 -5 0 5 10
Favours placebo Favours Hyalgan

Analysis 8.18. Comparison 8 Hyalgan versus placebo, Outcome 18 Patient global assessment (number of
patients improved).

1 1 to 4 weeks post-injection (number of patients improved (much better/better or excellent/good))

Corrado 1995 13/19 4/16 20.3 % 2.74 [ 1.11, 6.74 ]
Creamer 1994 7/12 8/12 37.5 % 0.88 [ 0.47, 1.63 ]
Formiguera Sala 1995 12/20 9/20 42.2 % 1.33 [ 0.73, 2.44 ]
Subtotal (95% CI) 51 48 100.0 % 1.45 [ 0.97, 2.15 ]

2 5 to 13 weeks post-injection (number of patients improved (excellent/very good/good/better/somewhat better)
Corrado 1995 15/19 4/16 38.3 % 3.16 [ 1.31, 7.61 ]
Formiguera Sala 1995 14/20 7/20 61.7 % 2.00 [ 1.03, 3.88 ]
Subtotal (95% CI) 39 36 100.0 % 2.44 [ 1.43, 4.16 ]

3 14 to 26 weeks post-injection (number of patients improved (better/somewhat/much; excellent/fair)
Henderson 1994 23/40 27/44 28.6 % 0.94 [ 0.66, 1.34 ]
Huskisson 1999 30/40 19/41 20.9 % 1.62 [ 1.11, 2.35 ]
Lin 2004 58/100 45/98 50.5 % 1.26 [ 0.96, 1.66 ]
Subtotal (95% CI) 180 183 100.0 % 1.24 [ 1.03, 1.50 ]

4 45 to 52 weeks post-injection (number of patients rating treatment effective)
Dougados 1993 31/47 27/48 100.0 % 1.17 [ 0.85, 1.62 ]
Subtotal (95% CI) 47 48 100.0 % 1.17 [ 0.85, 1.62 ]

0.1 0.2 0.5 1 2 5 10

Favours control Favours Hyalgan

Analysis 8.19. Comparison 8 Hyalgan versus placebo, Outcome 19 Patient global assessment (number of
joints fairly good/good/very good).
Outcome: 19 Patient global assessment (number of joints fairly good/good/very good)

Bragantini 1987 17/19 6/18 60.6 % 2.68 [ 1.37, 5.25 ]
Creamer 1994 5/12 4/12 39.4 % 1.25 [ 0.44, 3.55 ]
Subtotal (95% CI) 31 30 100.0 % 2.12 [ 1.22, 3.70 ]

0.1 0.2 0.5 1 2 5 10


Analysis 8.20. Comparison 8 Hyalgan versus placebo, Outcome 20 Safety: total withdrawals overall.

Carrabba 1995 0/20 0/20 Not estimable
Carrabba 1995a 0/20 0/20 Not estimable
Carrabba 1995b 0/20 0/20 Not estimable
Carrabba 1995c 0/20 0/20 Not estimable
Corrado 1995 2/21 3/19 100.0 % 0.60 [ 0.11, 3.23 ]
Subtotal (95% CI) 101 99 100.0 % 0.60 [ 0.11, 3.23 ]

Altman 1998 59/164 53/168 58.1 % 1.14 [ 0.84, 1.54 ]
Henderson 1994 18/45 17/46 18.6 % 1.08 [ 0.64, 1.82 ]
Huskisson 1999 10/50 9/50 10.0 % 1.11 [ 0.49, 2.50 ]
Lin 2004 12/100 12/100 13.3 % 1.00 [ 0.47, 2.12 ]
Subtotal (95% CI) 359 364 100.0 % 1.11 [ 0.87, 1.41 ]

Dougados 1993 8/55 7/55 13.1 % 1.14 [ 0.45, 2.93 ]
Jubb 2003 48/208 41/200 78.0 % 1.13 [ 0.78, 1.63 ]
St. J. Dixon 1988 5/30 5/33 8.9 % 1.10 [ 0.35, 3.43 ]
Subtotal (95% CI) 293 288 100.0 % 1.13 [ 0.81, 1.56 ]

0.1 0.2 0.5 1 2 5 10


Analysis 8.21. Comparison 8 Hyalgan versus placebo, Outcome 21 Safety: withdrawals due to lack of
efficacy.

1 During treatment phase

Dougados 1993 1/55 1/55 100.0 % 1.00 [ 0.06, 15.59 ]
Subtotal (95% CI) 55 55 100.0 % 1.00 [ 0.06, 15.59 ]

Altman 1998 17/164 16/168 56.8 % 1.09 [ 0.57, 2.08 ]
Huskisson 1999 2/50 8/50 28.8 % 0.25 [ 0.06, 1.12 ]
Lin 2004 3/100 4/100 14.4 % 0.75 [ 0.17, 3.27 ]
Subtotal (95% CI) 314 318 100.0 % 0.80 [ 0.47, 1.36 ]

0.1 0.2 0.5 1 2 5 10

Favours Hyalgan Favours placebo

Analysis 8.22. Comparison 8 Hyalgan versus placebo, Outcome 22 Safety: withdrawals due to painful
injection.
Outcome: 22 Safety: withdrawals due to painful injection

1 During treatment phase

Dougados 1993 2/55 1/55 100.0 % 2.00 [ 0.19, 21.42 ]
Subtotal (95% CI) 55 55 100.0 % 2.00 [ 0.19, 21.42 ]

0.1 0.2 0.5 1 2 5 10

Analysis 8.23. Comparison 8 Hyalgan versus placebo, Outcome 23 Safety: number of patients with local
adverse reaction and study drug discontinued.
Outcome: 23 Safety: number of patients with local adverse reaction and study drug discontinued

Altman 1998 6/164 1/168 6.15 [ 0.75, 50.50 ]
Dougados 1993 2/55 1/55 2.00 [ 0.19, 21.42 ]
Henderson 1994 5/45 0/46 11.24 [ 0.64, 197.51 ]
Jubb 2003 5/208 3/200 1.60 [ 0.39, 6.62 ]
0.01 0.1 1 10 100



Bunyaratavej 2001 0/24 0/25 Not estimable
Carrabba 1995 1/20 0/20 3.00 [ 0.13, 69.52 ]
Carrabba 1995a 1/20 0/20 3.00 [ 0.13, 69.52 ]
Carrabba 1995b 0/20 1/20 0.33 [ 0.01, 7.72 ]
Henderson 1994 21/45 10/44 2.05 [ 1.10, 3.85 ]
Jubb 2003 75/208 55/200 1.31 [ 0.98, 1.75 ]
0.1 0.2 0.5 1 2 5 10

Analysis 8.25. Comparison 8 Hyalgan versus placebo, Outcome 25 Safety: number of patients discontinued
due to adverse events.
Outcome: 25 Safety: number of patients discontinued due to adverse events

Huskisson 1999 2/50 1/50 2.00 [ 0.19, 21.36 ]
Jubb 2003 15/208 6/200 2.40 [ 0.95, 6.07 ]
0.1 0.2 0.5 1 2 5 10


Analysis 8.26. Comparison 8 Hyalgan versus placebo, Outcome 26 Safety: number of patients with serious
or severe adverse events.
Outcome: 26 Safety: number of patients with serious or severe adverse events

Huskisson 1999 2/50 1/50 33.3 % 2.00 [ 0.19, 21.36 ]
Lin 2004 3/100 2/100 66.7 % 1.50 [ 0.26, 8.79 ]
Subtotal (95% CI) 150 150 100.0 % 1.67 [ 0.41, 6.85 ]

Dougados 1993 0/55 0/55 Not estimable
Jubb 2003 27/208 14/200 100.0 % 1.85 [ 1.00, 3.43 ]
Subtotal (95% CI) 263 255 100.0 % 1.85 [ 1.00, 3.43 ]

0.1 0.2 0.5 1 2 5 10


Analysis 8.27. Comparison 8 Hyalgan versus placebo, Outcome 27 Safety: number of knee joints with local
adverse reaction.
Outcome: 27 Safety: number of knee joints with local adverse reaction

Bragantini 1987 2/19 0/18 4.75 [ 0.24, 92.65 ]
Creamer 1994 3/12 2/12 1.50 [ 0.30, 7.43 ]
0.1 0.2 0.5 1 2 5 10

Analysis 8.28. Comparison 8 Hyalgan versus placebo, Outcome 28 Safety: number of patients with injection
site pain or painful intra-articular injection.
Outcome: 28 Safety: number of patients with injection site pain or painful intra-articular injection

Altman 1998 38/164 22/168 1.77 [ 1.10, 2.86 ]
Dougados 1993 18/55 18/55 1.00 [ 0.59, 1.71 ]
Formiguera Sala 1995 3/20 3/20 1.00 [ 0.23, 4.37 ]
0.1 0.2 0.5 1 2 5 10


joint pain or swelling.
Outcome: 29 Safety: number of patients with local joint pain or swelling

Altman 1998 21/164 22/168 100.0 % 0.98 [ 0.56, 1.71 ]
Subtotal (95% CI) 164 168 100.0 % 0.98 [ 0.56, 1.71 ]

0.1 0.2 0.5 1 2 5 10

skin rash or ecchymosis.
Outcome: 30 Safety: number of patients with local skin rash or ecchymosis

Altman 1998 23/164 26/168 100.0 % 0.91 [ 0.54, 1.52 ]
Subtotal (95% CI) 164 168 100.0 % 0.91 [ 0.54, 1.52 ]

0.1 0.2 0.5 1 2 5 10


Analysis 8.31. Comparison 8 Hyalgan versus placebo, Outcome 31 Safety: number of patients with
gastrointestinal complaints.
Outcome: 31 Safety: number of patients with gastrointestinal complaints

Altman 1998 48/164 59/168 100.0 % 0.83 [ 0.61, 1.14 ]
Subtotal (95% CI) 164 168 100.0 % 0.83 [ 0.61, 1.14 ]

0.1 0.2 0.5 1 2 5 10

Analysis 8.32. Comparison 8 Hyalgan versus placebo, Outcome 32 Safety: number of patients with pruritis
(local).
Outcome: 32 Safety: number of patients with pruritis (local)

Altman 1998 12/164 7/168 100.0 % 1.76 [ 0.71, 4.35 ]
Subtotal (95% CI) 164 168 100.0 % 1.76 [ 0.71, 4.35 ]

0.1 0.2 0.5 1 2 5 10


Analysis 8.33. Comparison 8 Hyalgan versus placebo, Outcome 33 Safety: number of patients with
treatment related adverse events.
Outcome: 33 Safety: number of patients with treatment related adverse events

Formiguera Sala 1995 0/20 0/20 Not estimable

Henderson 1994 21/45 10/44 95.3 % 2.05 [ 1.10, 3.85 ]
Huskisson 1999 2/50 0/50 4.7 % 5.00 [ 0.25, 101.58 ]
Subtotal (95% CI) 119 119 100.0 % 2.19 [ 1.18, 4.07 ]

St. J. Dixon 1988 3/30 0/33 100.0 % 7.68 [ 0.41, 142.77 ]
Subtotal (95% CI) 30 33 100.0 % 7.68 [ 0.41, 142.77 ]

0.1 0.2 0.5 1 2 5 10


Analysis 8.34. Comparison 8 Hyalgan versus placebo, Outcome 34 Safety: number of patients reporting
adverse events.

Huskisson 1999 17/50 14/30 100.0 % 0.73 [ 0.42, 1.25 ]
Subtotal (95% CI) 50 30 100.0 % 0.73 [ 0.42, 1.25 ]

0.1 0.2 0.5 1 2 5 10

Analysis 8.35. Comparison 8 Hyalgan versus placebo, Outcome 35 Number of patients with
none/slight/mild pain.
Outcome: 35 Number of patients with none/slight/mild pain

Altman 1998 69/105 62/115 100.0 % 1.22 [ 0.98, 1.52 ]
Subtotal (95% CI) 105 115 100.0 % 1.22 [ 0.98, 1.52 ]

0.1 0.2 0.5 1 2 5 10


Analysis 8.36. Comparison 8 Hyalgan versus placebo, Outcome 36 Joint space width (mm) (after three
courses of treatment and stratified subgroups).
Outcome: 36 Joint space width (mm) (after three courses of treatment and stratified subgroups)
Mean Mean
Study or subgroup Treatment Control Difference Weight Difference
Jubb 2001b 76 5.8 (1.4) 63 5.4 (1) 48.7 % 0.40 [ 0.00, 0.80 ]
Jubb 2001c 60 3.5 (1.1) 74 3.6 (1.2) 51.3 % -0.10 [ -0.49, 0.29 ]
Subtotal (95% CI) 136 137 100.0 % 0.14 [ -0.14, 0.42 ]

-10 -5 0 5 10
Favours control Favours Hyalgan

Analysis 9.1. Comparison 9 Hyalgan versus arthroscopy, Outcome 1 Pain (0-10 cm VAS).
Comparison: 9 Hyalgan versus arthroscopy
Outcome: 1 Pain (0-10 cm VAS)
Mean Mean
Study or subgroup Hyalgan Arthroscopy Difference Weight Difference
1 Pre-trial
Forster 2003 18 7.6 (1.7) 15 7.5 (2.5) 100.0 % 0.10 [ -1.39, 1.59 ]
Subtotal (95% CI) 18 15 100.0 % 0.10 [ -1.39, 1.59 ]

Forster 2003 17 6.6 (2.4) 13 5.4 (3.2) 100.0 % 1.20 [ -0.88, 3.28 ]
Subtotal (95% CI) 17 13 100.0 % 1.20 [ -0.88, 3.28 ]

Forster 2003 16 6 (3.4) 15 6 (3.7) 100.0 % 0.0 [ -2.51, 2.51 ]
Subtotal (95% CI) 16 15 100.0 % 0.0 [ -2.51, 2.51 ]

Forster 2003 13 5.3 (3.4) 15 6.2 (3.5) 100.0 % -0.90 [ -3.46, 1.66 ]
Subtotal (95% CI) 13 15 100.0 % -0.90 [ -3.46, 1.66 ]

Forster 2003 11 5.7 (2.7) 14 5.7 (3.6) 100.0 % 0.0 [ -2.47, 2.47 ]
Subtotal (95% CI) 11 14 100.0 % 0.0 [ -2.47, 2.47 ]

-10 -5 0 5 10
Favours Hyalgan Favours Arthroscopy

Analysis 9.2. Comparison 9 Hyalgan versus arthroscopy, Outcome 2 Knee Society Function scale.
Outcome: 2 Knee Society Function scale
Mean Mean
1 Pre-trial
Forster 2003 18 64.4 (24.5) 15 42 (22.7) 100.0 % 22.40 [ 6.27, 38.53 ]
Subtotal (95% CI) 18 15 100.0 % 22.40 [ 6.27, 38.53 ]

Forster 2003 17 66.5 (28.5) 13 49.6 (34.7) 100.0 % 16.90 [ -6.32, 40.12 ]
Subtotal (95% CI) 17 13 100.0 % 16.90 [ -6.32, 40.12 ]

Forster 2003 16 67.5 (30.8) 15 51.3 (33.5) 100.0 % 16.20 [ -6.50, 38.90 ]
Subtotal (95% CI) 16 15 100.0 % 16.20 [ -6.50, 38.90 ]

Forster 2003 13 73.5 (27.9) 15 50 (31) 100.0 % 23.50 [ 1.68, 45.32 ]
Subtotal (95% CI) 13 15 100.0 % 23.50 [ 1.68, 45.32 ]

Forster 2003 11 75 (32.8) 14 51.1 (31.2) 100.0 % 23.90 [ -1.45, 49.25 ]
Subtotal (95% CI) 11 14 100.0 % 23.90 [ -1.45, 49.25 ]

-100 -50 0 50 100

Favours Arthroscopy Favours Hyalgan

Analysis 9.3. Comparison 9 Hyalgan versus arthroscopy, Outcome 3 Lequesne Index (0-24).
Mean Mean
1 Pre-trial
Forster 2003 18 11.4 (4.9) 15 13.3 (3.7) 100.0 % -1.90 [ -4.84, 1.04 ]
Subtotal (95% CI) 18 15 100.0 % -1.90 [ -4.84, 1.04 ]

Forster 2003 17 11.1 (5.7) 13 10.5 (6.2) 100.0 % 0.60 [ -3.72, 4.92 ]
Subtotal (95% CI) 17 13 100.0 % 0.60 [ -3.72, 4.92 ]

Forster 2003 16 10.9 (6.6) 15 11.5 (5.9) 100.0 % -0.60 [ -5.00, 3.80 ]
Subtotal (95% CI) 16 15 100.0 % -0.60 [ -5.00, 3.80 ]

Forster 2003 13 8.7 (6.4) 15 11.7 (5.9) 100.0 % -3.00 [ -7.58, 1.58 ]
Subtotal (95% CI) 13 15 100.0 % -3.00 [ -7.58, 1.58 ]

Forster 2003 11 8.3 (6.5) 14 11.2 (6.7) 100.0 % -2.90 [ -8.10, 2.30 ]
Subtotal (95% CI) 11 14 100.0 % -2.90 [ -8.10, 2.30 ]

-10 -5 0 5 10

Analysis 9.4. Comparison 9 Hyalgan versus arthroscopy, Outcome 4 Clinical outcome (number of patients
requiring further intervention).
Outcome: 4 Clinical outcome (number of patients requiring further intervention)
Study or subgroup Hyalgan Arthroscopy Risk Ratio Weight Risk Ratio

Forster 2003 7/17 3/15 100.0 % 2.06 [ 0.64, 6.57 ]
Subtotal (95% CI) 17 15 100.0 % 2.06 [ 0.64, 6.57 ]

Total events: 7 (Hyalgan), 3 (Arthroscopy)
0.1 0.2 0.5 1 2 5 10

Analysis 9.5. Comparison 9 Hyalgan versus arthroscopy, Outcome 5 Safety: total withdrawals overall.

Forster 2003 2/19 4/19 100.0 % 0.50 [ 0.10, 2.41 ]
Subtotal (95% CI) 19 19 100.0 % 0.50 [ 0.10, 2.41 ]

Total events: 2 (Hyalgan), 4 (Arthroscopy)
0.1 0.2 0.5 1 2 5 10


Analysis 9.6. Comparison 9 Hyalgan versus arthroscopy, Outcome 6 Safety: number of patients with pain at
injection site.
Outcome: 6 Safety: number of patients with pain at injection site

Forster 2003 2/19 0/19 5.00 [ 0.26, 97.70 ]
0.1 0.2 0.5 1 2 5 10

Analysis 10.1. Comparison 10 Hyalgan versus NSAID, Outcome 1 Pain after 50 foot walk (0-100 mm VAS).
Comparison: 10 Hyalgan versus NSAID
Outcome: 1 Pain after 50 foot walk (0-100 mm VAS)
Mean Mean
Study or subgroup Hyalgan Naproxen Difference Weight Difference
Altman 1998 136 25 (24) 143 25 (27) 100.0 % 0.0 [ -5.99, 5.99 ]
Subtotal (95% CI) 136 143 100.0 % 0.0 [ -5.99, 5.99 ]

Altman 1998 115 23 (25) 125 21 (25) 100.0 % 2.00 [ -4.33, 8.33 ]
Subtotal (95% CI) 115 125 100.0 % 2.00 [ -4.33, 8.33 ]

Altman 1998 105 18 (21) 111 21 (25) 100.0 % -3.00 [ -9.15, 3.15 ]
-10 -5 0 5 10
Favours Hyalgan Favours Naproxen
(Continued . . . )

(. . . Continued)
Mean Mean
Study or subgroup Hyalgan Naproxen Difference Weight Difference
Subtotal (95% CI) 105 111 100.0 % -3.00 [ -9.15, 3.15 ]
-10 -5 0 5 10
Analysis 10.2. Comparison 10 Hyalgan versus NSAID, Outcome 2 Number of patients with moderate or
marked pain.
Outcome: 2 Number of patients with moderate or marked pain
Study or subgroup Hyalgan Naproxen Risk Ratio Weight Risk Ratio

Altman 1998 36/105 43/113 100.0 % 0.90 [ 0.63, 1.28 ]
Subtotal (95% CI) 105 113 100.0 % 0.90 [ 0.63, 1.28 ]

Total events: 36 (Hyalgan), 43 (Naproxen)
0.1 0.2 0.5 1 2 5 10


Analysis 10.3. Comparison 10 Hyalgan versus NSAID, Outcome 3 Number of patients with none/slight/mild
pain.
Outcome: 3 Number of patients with none/slight/mild pain

Altman 1998 69/105 70/113 100.0 % 1.06 [ 0.87, 1.30 ]
Subtotal (95% CI) 105 113 100.0 % 1.06 [ 0.87, 1.30 ]

0.1 0.2 0.5 1 2 5 10

Analysis 10.4. Comparison 10 Hyalgan versus NSAID, Outcome 4 Safety: total withdrawals overall.

Altman 1998 59/164 50/163 100.0 % 1.17 [ 0.86, 1.60 ]
Subtotal (95% CI) 164 163 100.0 % 1.17 [ 0.86, 1.60 ]

0.1 0.2 0.5 1 2 5 10


Analysis 10.5. Comparison 10 Hyalgan versus NSAID, Outcome 5 Safety: withdrawals due to lack of efficacy.

Altman 1998 17/164 10/163 100.0 % 1.69 [ 0.80, 3.58 ]
Subtotal (95% CI) 164 163 100.0 % 1.69 [ 0.80, 3.58 ]

0.1 0.2 0.5 1 2 5 10

Analysis 10.6. Comparison 10 Hyalgan versus NSAID, Outcome 6 Safety: number of patients withdrawn
due to gastrointestinal events.
Outcome: 6 Safety: number of patients withdrawn due to gastrointestinal events

Altman 1998 4/164 14/163 100.0 % 0.28 [ 0.10, 0.84 ]
Subtotal (95% CI) 164 163 100.0 % 0.28 [ 0.10, 0.84 ]

0.1 0.2 0.5 1 2 5 10


Analysis 10.7. Comparison 10 Hyalgan versus NSAID, Outcome 7 Safety: number of patients withdrawn
due to injection site pain.
Outcome: 7 Safety: number of patients withdrawn due to injection site pain

Altman 1998 6/164 1/163 100.0 % 5.96 [ 0.73, 48.99 ]
Subtotal (95% CI) 164 163 100.0 % 5.96 [ 0.73, 48.99 ]

0.1 0.2 0.5 1 2 5 10

Analysis 10.8. Comparison 10 Hyalgan versus NSAID, Outcome 8 Safety: number of patients with injection
site pain.
Outcome: 8 Safety: number of patients with injection site pain

Altman 1998 38/164 14/163 100.0 % 2.70 [ 1.52, 4.79 ]
Subtotal (95% CI) 164 163 100.0 % 2.70 [ 1.52, 4.79 ]

0.1 0.2 0.5 1 2 5 10


Analysis 10.9. Comparison 10 Hyalgan versus NSAID, Outcome 9 Safety: number of patients with local
joint pain or swelling.
Outcome: 9 Safety: number of patients with local joint pain or swelling

Altman 1998 21/164 10/163 100.0 % 2.09 [ 1.01, 4.29 ]
Subtotal (95% CI) 164 163 100.0 % 2.09 [ 1.01, 4.29 ]

0.1 0.2 0.5 1 2 5 10

Analysis 10.10. Comparison 10 Hyalgan versus NSAID, Outcome 10 Safety: number of patients with local
skin rash.
Outcome: 10 Safety: number of patients with local skin rash

Altman 1998 23/164 29/163 100.0 % 0.79 [ 0.48, 1.30 ]
Subtotal (95% CI) 164 163 100.0 % 0.79 [ 0.48, 1.30 ]

0.1 0.2 0.5 1 2 5 10


Analysis 10.11. Comparison 10 Hyalgan versus NSAID, Outcome 11 Safety: number of patients with

Altman 1998 48/164 68/163 100.0 % 0.70 [ 0.52, 0.95 ]
Subtotal (95% CI) 164 163 100.0 % 0.70 [ 0.52, 0.95 ]

0.1 0.2 0.5 1 2 5 10

Analysis 10.12. Comparison 10 Hyalgan versus NSAID, Outcome 12 Safety: number of patients with
pruritis (local).
Outcome: 12 Safety: number of patients with pruritis (local)

Altman 1998 12/164 7/163 100.0 % 1.70 [ 0.69, 4.22 ]
Subtotal (95% CI) 164 163 100.0 % 1.70 [ 0.69, 4.22 ]

0.1 0.2 0.5 1 2 5 10


Analysis 11.1. Comparison 11 Hyalgan versus methylprednisolone acetate, Outcome 1 Spontaneous pain
intensity (0-100 mm VAS).
Comparison: 11 Hyalgan versus methylprednisolone acetate
Outcome: 1 Spontaneous pain intensity (0-100 mm VAS)
Mean Mean
Study or subgroup Hyalgan MPA Difference Weight Difference
Leardini 1987 20 13 (19.68) 20 9.6 (16.99) 19.3 % 3.40 [ -7.99, 14.79 ]
Leardini 1991 20 10.73 (17.22) 20 20.83 (14) 26.5 % -10.10 [ -19.83, -0.37 ]
Pietrogrande 1991 45 20 (16.44) 45 25.32 (16.44) 54.3 % -5.32 [ -12.11, 1.47 ]
Subtotal (95% CI) 85 85 100.0 % -4.90 [ -9.91, 0.10 ]

Leardini 1987 20 11.2 (20.57) 20 9.1 (21.02) 15.5 % 2.10 [ -10.79, 14.99 ]
Leardini 1991 20 9.48 (15.83) 20 23.33 (14.89) 28.5 % -13.85 [ -23.37, -4.33 ]
Pietrogrande 1991 45 19.71 (16.44) 45 27.05 (16.44) 56.0 % -7.34 [ -14.13, -0.55 ]
Subtotal (95% CI) 85 85 100.0 % -7.73 [ -12.81, -2.64 ]

Leardini 1987 15 20.3 (25.56) 17 17.8 (24.74) 100.0 % 2.50 [ -14.98, 19.98 ]
Subtotal (95% CI) 15 17 100.0 % 2.50 [ -14.98, 19.98 ]

-100 -50 0 50 100

Favours Hyalgan Favours MPA

Analysis 11.2. Comparison 11 Hyalgan versus methylprednisolone acetate, Outcome 2 Number of joints
with moderate or severe walking pain.
Outcome: 2 Number of joints with moderate or severe walking pain
Study or subgroup Hyalgan MPA Risk Ratio Weight Risk Ratio

Leardini 1987 11/20 9/20 100.0 % 1.22 [ 0.65, 2.29 ]
Subtotal (95% CI) 20 20 100.0 % 1.22 [ 0.65, 2.29 ]

Total events: 11 (Hyalgan), 9 (MPA)
Leardini 1987 8/20 10/20 100.0 % 0.80 [ 0.40, 1.60 ]
Subtotal (95% CI) 20 20 100.0 % 0.80 [ 0.40, 1.60 ]

Leardini 1987 11/15 12/17 100.0 % 1.04 [ 0.67, 1.60 ]
Subtotal (95% CI) 15 17 100.0 % 1.04 [ 0.67, 1.60 ]

0.1 0.2 0.5 1 2 5 10


Analysis 11.3. Comparison 11 Hyalgan versus methylprednisolone acetate, Outcome 3 Number of patients
with moderate or severe pain under load.
Outcome: 3 Number of patients with moderate or severe pain under load

Leardini 1991 14/20 19/20 51.4 % 0.74 [ 0.54, 1.00 ]
Pietrogrande 1991 21/45 18/45 48.6 % 1.17 [ 0.73, 1.88 ]
Subtotal (95% CI) 65 65 100.0 % 0.95 [ 0.71, 1.27 ]

Leardini 1991 13/20 20/20 47.4 % 0.66 [ 0.48, 0.91 ]
Pietrogrande 1991 13/44 23/45 52.6 % 0.58 [ 0.34, 0.99 ]
Subtotal (95% CI) 64 65 100.0 % 0.62 [ 0.45, 0.85 ]

0.1 0.2 0.5 1 2 5 10


Analysis 11.4. Comparison 11 Hyalgan versus methylprednisolone acetate, Outcome 4 Number of joints
with moderate or severe pain under load.
Outcome: 4 Number of joints with moderate or severe pain under load

Leardini 1987 8/20 8/20 100.0 % 1.00 [ 0.47, 2.14 ]
Subtotal (95% CI) 20 20 100.0 % 1.00 [ 0.47, 2.14 ]

Leardini 1987 6/20 7/20 100.0 % 0.86 [ 0.35, 2.10 ]
Subtotal (95% CI) 20 20 100.0 % 0.86 [ 0.35, 2.10 ]

Leardini 1987 8/15 11/17 100.0 % 0.82 [ 0.46, 1.49 ]
Subtotal (95% CI) 15 17 100.0 % 0.82 [ 0.46, 1.49 ]

0.1 0.2 0.5 1 2 5 10


with at least moderate or greater night pain.
Outcome: 5 Number of patients with at least moderate or greater night pain

Leardini 1991 1/20 4/20 80.0 % 0.25 [ 0.03, 2.05 ]
Pietrogrande 1991 5/45 1/45 20.0 % 5.00 [ 0.61, 41.11 ]
Subtotal (95% CI) 65 65 100.0 % 1.20 [ 0.38, 3.80 ]

Leardini 1991 0/20 4/20 64.5 % 0.11 [ 0.01, 1.94 ]
Pietrogrande 1991 0/44 2/45 35.5 % 0.20 [ 0.01, 4.14 ]
Subtotal (95% CI) 64 65 100.0 % 0.14 [ 0.02, 1.13 ]

0.1 0.2 0.5 1 2 5 10


with moderate or greater rest pain.
Outcome: 6 Number of patients with moderate or greater rest pain

Leardini 1991 6/20 12/20 63.2 % 0.50 [ 0.23, 1.07 ]
Pietrogrande 1991 7/45 7/45 36.8 % 1.00 [ 0.38, 2.62 ]
Subtotal (95% CI) 65 65 100.0 % 0.68 [ 0.38, 1.24 ]

Leardini 1991 6/20 15/20 83.5 % 0.40 [ 0.20, 0.82 ]
Pietrogrande 1991 1/44 3/45 16.5 % 0.34 [ 0.04, 3.15 ]
Subtotal (95% CI) 64 65 100.0 % 0.39 [ 0.19, 0.78 ]

0.1 0.2 0.5 1 2 5 10


Analysis 11.7. Comparison 11 Hyalgan versus methylprednisolone acetate, Outcome 7 Function: range of
motion (flexion in degrees).
Outcome: 7 Function: range of motion (flexion in degrees)
Mean Mean
Study or subgroup Hyalgan MPA Difference Weight Difference
Leardini 1987 20 113.4 (12.97) 20 112.4 (15.21) 35.4 % 1.00 [ -7.76, 9.76 ]
Pietrogrande 1991 45 121.38 (15.7) 45 112.75 (15.7) 64.6 % 8.63 [ 2.14, 15.12 ]
Subtotal (95% CI) 65 65 100.0 % 5.93 [ 0.71, 11.14 ]

Leardini 1987 20 116.7 (12.52) 20 114.3 (11.18) 43.7 % 2.40 [ -4.96, 9.76 ]
Pietrogrande 1991 45 121.1 (16.03) 45 113.35 (15.36) 56.3 % 7.75 [ 1.26, 14.24 ]
Subtotal (95% CI) 65 65 100.0 % 5.41 [ 0.54, 10.28 ]

Leardini 1987 15 109.6 (22.85) 17 108.1 (18.14) 100.0 % 1.50 [ -12.92, 15.92 ]
Subtotal (95% CI) 15 17 100.0 % 1.50 [ -12.92, 15.92 ]

-10 -5 0 5 10
Favours MPA Favours Hyalgan

Analysis 11.8. Comparison 11 Hyalgan versus methylprednisolone acetate, Outcome 8 Patient global
(number of patients very good or good, excellent or /good).
Outcome: 8 Patient global (number of patients very good or good, excellent or /good)

Frizziero 2002 21/46 32/37 54.2 % 0.53 [ 0.38, 0.74 ]
Leardini 1991 11/20 9/20 13.7 % 1.22 [ 0.65, 2.29 ]
Pietrogrande 1991 32/45 21/45 32.1 % 1.52 [ 1.06, 2.19 ]
Subtotal (95% CI) 111 102 100.0 % 0.94 [ 0.75, 1.18 ]

Leardini 1991 10/20 7/20 31.8 % 1.43 [ 0.68, 3.00 ]
Pietrogrande 1991 31/45 15/45 68.2 % 2.07 [ 1.31, 3.27 ]
Subtotal (95% CI) 65 65 100.0 % 1.86 [ 1.26, 2.75 ]

Frizziero 2002 30/38 24/32 100.0 % 1.05 [ 0.81, 1.36 ]
Subtotal (95% CI) 38 32 100.0 % 1.05 [ 0.81, 1.36 ]

0.1 0.2 0.5 1 2 5 10

Favours MPA Favours Hyalgan

Analysis 11.9. Comparison 11 Hyalgan versus methylprednisolone acetate, Outcome 9 Safety: total

Frizziero 2002 6/52 10/47 100.0 % 0.54 [ 0.21, 1.38 ]
Subtotal (95% CI) 52 47 100.0 % 0.54 [ 0.21, 1.38 ]

Leardini 1991 0/20 0/20 Not estimable
Pietrogrande 1991 1/45 0/45 100.0 % 3.00 [ 0.13, 71.74 ]
Subtotal (95% CI) 65 65 100.0 % 3.00 [ 0.13, 71.74 ]

Frizziero 2002 10/52 5/47 100.0 % 1.81 [ 0.67, 4.91 ]
Subtotal (95% CI) 52 47 100.0 % 1.81 [ 0.67, 4.91 ]

Leardini 1987 5/20 3/20 100.0 % 1.67 [ 0.46, 6.06 ]
Subtotal (95% CI) 20 20 100.0 % 1.67 [ 0.46, 6.06 ]

0.1 0.2 0.5 1 2 5 10


Analysis 11.10. Comparison 11 Hyalgan versus methylprednisolone acetate, Outcome 10 Safety: number of
patients withdrawn due to lack of efficacy.
Outcome: 10 Safety: number of patients withdrawn due to lack of efficacy

Pietrogrande 1991 1/45 0/45 100.0 % 3.00 [ 0.13, 71.74 ]
Subtotal (95% CI) 45 45 100.0 % 3.00 [ 0.13, 71.74 ]

0.1 0.2 0.5 1 2 5 10

patients withdrawn due to adverse events.
Outcome: 11 Safety: number of patients withdrawn due to adverse events

1 After first injection

Frizziero 2002 0/52 1/47 100.0 % 0.30 [ 0.01, 7.24 ]
Subtotal (95% CI) 52 47 100.0 % 0.30 [ 0.01, 7.24 ]

0.1 0.2 0.5 1 2 5 10


patients with local or systemic reactions.
Outcome: 12 Safety: number of patients with local or systemic reactions

Leardini 1991 0/20 0/20 Not estimable
Pietrogrande 1991 1/45 0/45 100.0 % 3.00 [ 0.13, 71.74 ]
Subtotal (95% CI) 65 65 100.0 % 3.00 [ 0.13, 71.74 ]

0.1 0.2 0.5 1 2 5 10

joints with local reactions but continued in trial.
Outcome: 13 Safety: number of joints with local reactions but continued in trial

Leardini 1987 4/20 3/20 100.0 % 1.33 [ 0.34, 5.21 ]
Subtotal (95% CI) 20 20 100.0 % 1.33 [ 0.34, 5.21 ]

0.1 0.2 0.5 1 2 5 10


Analysis 12.1. Comparison 12 Hyalgan versus triamcinolone hexacetonide, Outcome 1 Pain on nominated
activity (0-100 mm VAS).
Comparison: 12 Hyalgan versus triamcinolone hexacetonide
Outcome: 1 Pain on nominated activity (0-100 mm VAS)
Mean Mean
Study or subgroup Hyalgan Triamcinolone Difference Weight Difference
1 End of treatment (week 4)

Jones 1995 29 56.5 (33.93) 27 56.7 (31.7) 100.0 % -0.20 [ -17.39, 16.99 ]
Subtotal (95% CI) 29 27 100.0 % -0.20 [ -17.39, 16.99 ]

Jones 1995 12 44.3 (24.94) 8 54.3 (24.04) 100.0 % -10.00 [ -31.83, 11.83 ]
Subtotal (95% CI) 12 8 100.0 % -10.00 [ -31.83, 11.83 ]

-100 -50 0 50 100

Favours Hyalgan Favours Triamcinolon

Analysis 12.2. Comparison 12 Hyalgan versus triamcinolone hexacetonide, Outcome 2 Pain at rest (0-100
mm VAS).
Mean Mean

Jones 1995 29 39.9 (34.47) 27 40.6 (32.22) 100.0 % -0.70 [ -18.17, 16.77 ]
Subtotal (95% CI) 29 27 100.0 % -0.70 [ -18.17, 16.77 ]

Jones 1995 12 28.2 (24.94) 8 48.6 (27.15) 100.0 % -20.40 [ -43.92, 3.12 ]
Subtotal (95% CI) 12 8 100.0 % -20.40 [ -43.92, 3.12 ]

-100 -50 0 50 100


Analysis 12.3. Comparison 12 Hyalgan versus triamcinolone hexacetonide, Outcome 3 Pain at night (0-100
mm VAS).
Mean Mean

Jones 1995 29 35.9 (31.77) 27 43 (33.77) 100.0 % -7.10 [ -24.30, 10.10 ]
Subtotal (95% CI) 29 27 100.0 % -7.10 [ -24.30, 10.10 ]

Jones 1995 12 15.4 (15.24) 8 36.1 (21.21) 100.0 % -20.70 [ -37.74, -3.66 ]
Subtotal (95% CI) 12 8 100.0 % -20.70 [ -37.74, -3.66 ]

-100 -50 0 50 100


Analysis 12.4. Comparison 12 Hyalgan versus triamcinolone hexacetonide, Outcome 4 Safety: total
Study or subgroup Hyalgan Triamcinolone Risk Ratio Weight Risk Ratio


Jones 1995 3/32 4/31 100.0 % 0.73 [ 0.18, 2.99 ]
Subtotal (95% CI) 32 31 100.0 % 0.73 [ 0.18, 2.99 ]

Total events: 3 (Hyalgan), 4 (Triamcinolone)
Jones 1995 19/32 23/31 100.0 % 0.80 [ 0.56, 1.14 ]
Subtotal (95% CI) 32 31 100.0 % 0.80 [ 0.56, 1.14 ]

0.1 0.2 0.5 1 2 5 10


Analysis 12.5. Comparison 12 Hyalgan versus triamcinolone hexacetonide, Outcome 5 Safety: wIthdrawals
due to lack efficacy.
Outcome: 5 Safety: wIthdrawals due to lack efficacy


Jones 1995 2/32 0/31 100.0 % 4.85 [ 0.24, 97.11 ]
Subtotal (95% CI) 32 31 100.0 % 4.85 [ 0.24, 97.11 ]

2 14 to 26 week post-injection
Jones 1995 12/32 13/31 100.0 % 0.89 [ 0.49, 1.65 ]
Subtotal (95% CI) 32 31 100.0 % 0.89 [ 0.49, 1.65 ]

0.1 0.2 0.5 1 2 5 10

Favours Hyalgan Favours triamcinolon

Analysis 12.6. Comparison 12 Hyalgan versus triamcinolone hexacetonide, Outcome 6 Safety: wIthdrawals
due to adverse events.
Outcome: 6 Safety: wIthdrawals due to adverse events


Jones 1995 1/32 1/31 100.0 % 0.97 [ 0.06, 14.82 ]
Subtotal (95% CI) 32 31 100.0 % 0.97 [ 0.06, 14.82 ]

Jones 1995 4/32 5/31 100.0 % 0.78 [ 0.23, 2.62 ]
Subtotal (95% CI) 32 31 100.0 % 0.78 [ 0.23, 2.62 ]

0.1 0.2 0.5 1 2 5 10

Favours Hyalgan Favours triamcinolon

Analysis 13.1. Comparison 13 Hyalgan versus mucopolysaccharide polysulfuric acid ester, Outcome 1 Pain
(0-30) change.
Comparison: 13 Hyalgan versus mucopolysaccharide polysulfuric acid ester
Outcome: 1 Pain (0-30) change
Mean Mean
Study or subgroup Hyalgan MucoPolySulf Difference Weight Difference
1 End of treatment at week 6

Graf 1993 33 5.5 (6.2) 26 1.5 (5.6) 100.0 % 4.00 [ 0.98, 7.02 ]
Subtotal (95% CI) 33 26 100.0 % 4.00 [ 0.98, 7.02 ]

-10 -5 0 5 10
Favours MucoPolySulf Favours Hyalgan
Analysis 13.2. Comparison 13 Hyalgan versus mucopolysaccharide polysulfuric acid ester, Outcome 2
Function (0-30) change.
Outcome: 2 Function (0-30) change
Mean Mean

Graf 1993 33 1.1 (5.8) 26 0.5 (4.2) 100.0 % 0.60 [ -1.95, 3.15 ]
Subtotal (95% CI) 33 26 100.0 % 0.60 [ -1.95, 3.15 ]

-10 -5 0 5 10

Range of motion (0-10) change.
Outcome: 3 Range of motion (0-10) change
Mean Mean

Graf 1993 33 0.3 (0.9) 26 0 (0.5) 100.0 % 0.30 [ -0.06, 0.66 ]
Subtotal (95% CI) 33 26 100.0 % 0.30 [ -0.06, 0.66 ]

-10 -5 0 5 10

Analysis 13.4. Comparison 13 Hyalgan versus mucopolysaccharide polysulfuric acid ester, Outcome 4 Total
Larson rating score (0-77) change.
Outcome: 4 Total Larson rating score (0-77) change
Mean Mean

Graf 1993 33 8.4 (10.3) 26 2.5 (7.7) 100.0 % 5.90 [ 1.31, 10.49 ]
Subtotal (95% CI) 33 26 100.0 % 5.90 [ 1.31, 10.49 ]

-10 -5 0 5 10
Patient global (number of patients symptom free or markedly improved).
Outcome: 5 Patient global (number of patients symptom free or markedly improved)
Study or subgroup Hyalgan MucoPolysulf Risk Ratio Weight Risk Ratio

Graf 1993 25/33 11/24 100.0 % 1.65 [ 1.03, 2.66 ]
Subtotal (95% CI) 33 24 100.0 % 1.65 [ 1.03, 2.66 ]

Total events: 25 (Hyalgan), 11 (MucoPolysulf)
0.1 0.2 0.5 1 2 5 10


Safety: total withdrawals overall.
Study or subgroup Hyalgan MucoPolySulf Risk Ratio Weight Risk Ratio

Graf 1993 1/33 2/27 100.0 % 0.41 [ 0.04, 4.27 ]
Subtotal (95% CI) 33 27 100.0 % 0.41 [ 0.04, 4.27 ]

Total events: 1 (Hyalgan), 2 (MucoPolySulf)
0.1 0.2 0.5 1 2 5 10

Favours Hyalgan Favours MucoPolySulf

Safety: adverse events due to study medication.
Outcome: 7 Safety: adverse events due to study medication
Study or subgroup Hyalgan MucoPolySulf Risk Ratio Weight Risk Ratio

Graf 1993 6/33 2/27 100.0 % 2.45 [ 0.54, 11.19 ]
Subtotal (95% CI) 33 27 100.0 % 2.45 [ 0.54, 11.19 ]

Total events: 6 (Hyalgan), 2 (MucoPolySulf)
0.1 0.2 0.5 1 2 5 10

Favours Hyalgan Favours MucoPolySulf

Analysis 14.1. Comparison 14 (Hyalgan plus exercise plus ultrasound) versus control warmup exercise,
Outcome 1 Pain (0-10 cm VAS).
Comparison: 14 (Hyalgan plus exercise plus ultrasound) versus control warmup exercise
Mean Mean
Study or subgroup EX+US+HA Control warmup EX Difference Weight Difference
1 End of treatment
Huang 2005 34 2.5 (1.6) 32 4.9 (1.2) 100.0 % -2.40 [ -3.08, -1.72 ]
Subtotal (95% CI) 34 32 100.0 % -2.40 [ -3.08, -1.72 ]

2 One-year follow-up
Huang 2005 32 2 (1.3) 28 6.6 (1.5) 100.0 % -4.60 [ -5.32, -3.88 ]
Subtotal (95% CI) 32 28 100.0 % -4.60 [ -5.32, -3.88 ]

-10 -5 0 5 10
Favours EX+US+HA Favours control EX

Outcome 2 Lequesne Index (0-26).
Mean Mean
1 End of treatment
Huang 2005 34 4 (0.7) 32 6.9 (1.3) 100.0 % -2.90 [ -3.41, -2.39 ]
Subtotal (95% CI) 34 32 100.0 % -2.90 [ -3.41, -2.39 ]

Huang 2005 32 2.5 (1.6) 28 8.1 (1.5) 100.0 % -5.60 [ -6.38, -4.82 ]
Subtotal (95% CI) 32 28 100.0 % -5.60 [ -6.38, -4.82 ]

-10 -5 0 5 10

Outcome 3 Range of motion (degrees).
Outcome: 3 Range of motion (degrees)
Mean Mean
1 End of treatment
Huang 2005 34 120 (13) 32 98 (10) 100.0 % 22.00 [ 16.42, 27.58 ]
Subtotal (95% CI) 34 32 100.0 % 22.00 [ 16.42, 27.58 ]

Huang 2005 32 124 (18) 28 98 (17) 100.0 % 26.00 [ 17.14, 34.86 ]
Subtotal (95% CI) 32 28 100.0 % 26.00 [ 17.14, 34.86 ]

-100 -50 0 50 100

Favours Control EX Favours EX+US+HA

Outcome 4 Ambulation speed (metres per minute).
Outcome: 4 Ambulation speed (metres per minute)
Mean Mean
1 End of treatment
Huang 2005 34 95.6 (2.7) 32 75.8 (3.9) 100.0 % 19.80 [ 18.17, 21.43 ]
Subtotal (95% CI) 34 32 100.0 % 19.80 [ 18.17, 21.43 ]

Huang 2005 32 99.3 (6.8) 28 70.1 (5.1) 100.0 % 29.20 [ 26.18, 32.22 ]
Subtotal (95% CI) 32 28 100.0 % 29.20 [ 26.18, 32.22 ]

-100 -50 0 50 100

Favours control EX Favours EX+US+HA

Outcome 5 Safety: total withdrawals overall.
Study or subgroup EX+US+HA Control warmup EX Risk Ratio Weight Risk Ratio
1 During treatment
Huang 2005 1/35 3/35 100.0 % 0.33 [ 0.04, 3.05 ]
Subtotal (95% CI) 35 35 100.0 % 0.33 [ 0.04, 3.05 ]

Total events: 1 (EX+US+HA), 3 (Control warmup EX)
2 Overall
Huang 2005 3/35 7/35 100.0 % 0.43 [ 0.12, 1.52 ]
Subtotal (95% CI) 35 35 100.0 % 0.43 [ 0.12, 1.52 ]

Total events: 3 (EX+US+HA), 7 (Control warmup EX)
0.1 0.2 0.5 1 2 5 10


Analysis 15.1. Comparison 15 (Hyalgan plus exercise plus ultrasound) versus exercise, Outcome 1 Pain (0-
10 cm VAS).
Comparison: 15 (Hyalgan plus exercise plus ultrasound) versus exercise
Mean Mean
Study or subgroup EX+US+HA Exercise Difference Weight Difference
1 End of treatment
Huang 2005 34 2.5 (1.6) 30 4.1 (0.6) 100.0 % -1.60 [ -2.18, -1.02 ]
Subtotal (95% CI) 34 30 100.0 % -1.60 [ -2.18, -1.02 ]

Huang 2005 32 2 (1.3) 26 3.9 (1.4) 100.0 % -1.90 [ -2.60, -1.20 ]
Subtotal (95% CI) 32 26 100.0 % -1.90 [ -2.60, -1.20 ]

-10 -5 0 5 10
Favours EX+US+HA Favours Exercise

Analysis 15.2. Comparison 15 (Hyalgan plus exercise plus ultrasound) versus exercise, Outcome 2 Lequesne
Index (0-26).
Mean Mean
1 End of treatment
Huang 2005 34 4 (0.7) 30 6.1 (0.9) 100.0 % -2.10 [ -2.50, -1.70 ]
Subtotal (95% CI) 34 30 100.0 % -2.10 [ -2.50, -1.70 ]

Huang 2005 32 2.5 (1.6) 26 5.8 (1.8) 100.0 % -3.30 [ -4.19, -2.41 ]
Subtotal (95% CI) 32 26 100.0 % -3.30 [ -4.19, -2.41 ]

-10 -5 0 5 10

Analysis 15.3. Comparison 15 (Hyalgan plus exercise plus ultrasound) versus exercise, Outcome 3 Range of
motion (degrees).
Mean Mean
1 End of treatment
Huang 2005 34 120 (13) 30 108 (17) 100.0 % 12.00 [ 4.51, 19.49 ]
Subtotal (95% CI) 34 30 100.0 % 12.00 [ 4.51, 19.49 ]

Huang 2005 32 124 (18) 26 110 (14) 100.0 % 14.00 [ 5.76, 22.24 ]
Subtotal (95% CI) 32 26 100.0 % 14.00 [ 5.76, 22.24 ]

-100 -50 0 50 100

Favours Exercise Favours EX+US+HA

Analysis 15.4. Comparison 15 (Hyalgan plus exercise plus ultrasound) versus exercise, Outcome 4
Ambulation speed (metres per minute).
Mean Mean
1 End of treatment
Huang 2005 34 95.6 (2.7) 30 82.9 (5.3) 100.0 % 12.70 [ 10.60, 14.80 ]
Subtotal (95% CI) 34 30 100.0 % 12.70 [ 10.60, 14.80 ]

Huang 2005 32 99.3 (6.8) 26 85.3 (6.5) 100.0 % 14.00 [ 10.57, 17.43 ]
Subtotal (95% CI) 32 26 100.0 % 14.00 [ 10.57, 17.43 ]

-100 -50 0 50 100

Favours Exercise Favours EX+US+HA

Analysis 15.5. Comparison 15 (Hyalgan plus exercise plus ultrasound) versus exercise, Outcome 5 Safety:
Study or subgroup EX+US+HA Exercise Risk Ratio Weight Risk Ratio

1 During treatment
Huang 2005 1/35 5/35 100.0 % 0.20 [ 0.02, 1.63 ]
Subtotal (95% CI) 35 35 100.0 % 0.20 [ 0.02, 1.63 ]

Total events: 1 (EX+US+HA), 5 (Exercise)
2 Overall
Huang 2005 3/35 9/35 100.0 % 0.33 [ 0.10, 1.13 ]
Subtotal (95% CI) 35 35 100.0 % 0.33 [ 0.10, 1.13 ]

Total events: 3 (EX+US+HA), 9 (Exercise)
0.1 0.2 0.5 1 2 5 10


Analysis 16.1. Comparison 16 (Hyalgan plus exercise plus ultrasound) versus (exercise plus ultrasound),
Outcome 1 Pain (0-10 cm VAS).
Comparison: 16 (Hyalgan plus exercise plus ultrasound) versus (exercise plus ultrasound)
Mean Mean
Study or subgroup EX+US+HA EX+US Difference Weight Difference
1 End of treatment
Huang 2005 34 2.5 (1.6) 32 3 (1.8) 100.0 % -0.50 [ -1.32, 0.32 ]
Subtotal (95% CI) 34 32 100.0 % -0.50 [ -1.32, 0.32 ]

Huang 2005 32 2 (1.3) 29 2.6 (1.5) 100.0 % -0.60 [ -1.31, 0.11 ]
Subtotal (95% CI) 32 29 100.0 % -0.60 [ -1.31, 0.11 ]

-10 -5 0 5 10
Favours EX+US+HA Favours EX+US

Outcome 2 Lequesne Index (0-26).
Mean Mean
1 End of treatment
Huang 2005 34 4 (0.7) 32 4.4 (1.1) 100.0 % -0.40 [ -0.85, 0.05 ]
Subtotal (95% CI) 34 32 100.0 % -0.40 [ -0.85, 0.05 ]

Huang 2005 32 2.5 (1.6) 29 3.3 (1.5) 100.0 % -0.80 [ -1.58, -0.02 ]
Subtotal (95% CI) 32 29 100.0 % -0.80 [ -1.58, -0.02 ]

-10 -5 0 5 10
Favours EX+US+HA Favours EX+US

Outcome 3 Range of motion (degrees).
Mean Mean
1 End of treatment
Huang 2005 34 120 (13) 32 114 (15) 100.0 % 6.00 [ -0.79, 12.79 ]
Subtotal (95% CI) 34 32 100.0 % 6.00 [ -0.79, 12.79 ]

Huang 2005 32 124 (18) 29 118 (14) 100.0 % 6.00 [ -2.05, 14.05 ]
Subtotal (95% CI) 32 29 100.0 % 6.00 [ -2.05, 14.05 ]

-100 -50 0 50 100

Favours EX+US Favours EX+US+HA

Outcome 4 Ambulation speed (metres per minute).
Mean Mean
1 End of treatment
Huang 2005 34 95.6 (2.7) 32 90.2 (3.1) 100.0 % 5.40 [ 3.99, 6.81 ]
Subtotal (95% CI) 34 32 100.0 % 5.40 [ 3.99, 6.81 ]

Huang 2005 32 99.3 (6.8) 29 94.3 (6.8) 100.0 % 5.00 [ 1.58, 8.42 ]
Subtotal (95% CI) 32 29 100.0 % 5.00 [ 1.58, 8.42 ]

-100 -50 0 50 100

Favours EX+US Favours EX+US+HA

Study or subgroup EX+US+HA EX+US Risk Ratio Weight Risk Ratio

1 During treatment
Huang 2005 1/35 3/35 100.0 % 0.33 [ 0.04, 3.05 ]
Subtotal (95% CI) 35 35 100.0 % 0.33 [ 0.04, 3.05 ]

Total events: 1 (EX+US+HA), 3 (EX+US)
2 Overall
Huang 2005 3/35 6/35 100.0 % 0.50 [ 0.14, 1.84 ]
Subtotal (95% CI) 35 35 100.0 % 0.50 [ 0.14, 1.84 ]

Total events: 3 (EX+US+HA), 6 (EX+US)
0.1 0.2 0.5 1 2 5 10

Favours EX+US+HA FavoursEX+US

Analysis 17.1. Comparison 17 Hyalgan versus conventional therapy (three courses of treatment), Outcome
1 Pain overall (0-100 mm VAS).
Comparison: 17 Hyalgan versus conventional therapy (three courses of treatment)
Outcome: 1 Pain overall (0-100 mm VAS)
Mean Mean
Study or subgroup Hyalgan Convent Care Difference Weight Difference
Listrat 1997 19 32.4 (25.5) 17 46.8 (27.7) 100.0 % -14.40 [ -31.86, 3.06 ]
Subtotal (95% CI) 19 17 100.0 % -14.40 [ -31.86, 3.06 ]

-100 -50 0 50 100

Favours Hyalgan Favours convent care
2 Lequesne Index (0-24).
Mean Mean
Listrat 1997 19 7.2 (4.8) 17 8.1 (4.1) 100.0 % -0.90 [ -3.81, 2.01 ]
Subtotal (95% CI) 19 17 100.0 % -0.90 [ -3.81, 2.01 ]

-10 -5 0 5 10
Favours Hyalgan Favours Convent Care

3 Joint space width (mm).
Outcome: 3 Joint space width (mm)
Mean Mean
Study or subgroup Hyalgan Conventional care Difference Weight Difference
Listrat 1997 19 4 (1.8) 17 2.9 (1.6) 100.0 % 1.10 [ -0.01, 2.21 ]
Subtotal (95% CI) 19 17 100.0 % 1.10 [ -0.01, 2.21 ]

-10 -5 0 5 10
Favours Convent care Favours Hyalgan

4 Quality of life (AIMS: total of 12 items).
Outcome: 4 Quality of life (AIMS: total of 12 items)
Mean Mean
Study or subgroup Hyalgan Conventional care Difference Weight Difference
Listrat 1997 19 2.2 (1.3) 17 2.4 (1.1) 100.0 % -0.20 [ -0.98, 0.58 ]
Subtotal (95% CI) 19 17 100.0 % -0.20 [ -0.98, 0.58 ]

-10 -5 0 5 10
5 Arthroscopy overall assessment (0-100 mm VAS).
Outcome: 5 Arthroscopy overall assessment (0-100 mm VAS)
Mean Mean
Listrat 1997 19 47 (26.6) 17 69.3 (28.9) 100.0 % -22.30 [ -40.52, -4.08 ]
Subtotal (95% CI) 19 17 100.0 % -22.30 [ -40.52, -4.08 ]

-100 -50 0 50 100


6 SFA scoring (0-100 mm VAS).
Outcome: 6 SFA scoring (0-100 mm VAS)
Mean Mean
Listrat 1997 19 29.8 (18.5) 17 48 (21.2) 100.0 % -18.20 [ -31.27, -5.13 ]
Subtotal (95% CI) 19 17 100.0 % -18.20 [ -31.27, -5.13 ]

-100 -50 0 50 100


7 Safety: total withdrawals.
Outcome: 7 Safety: total withdrawals
Study or subgroup Hyalgan Conventional Care Risk Ratio Weight Risk Ratio
Listrat 1997 1/20 2/19 100.0 % 0.48 [ 0.05, 4.82 ]
Subtotal (95% CI) 20 19 100.0 % 0.48 [ 0.05, 4.82 ]

Total events: 1 (Hyalgan), 2 (Conventional Care)
0.1 0.2 0.5 1 2 5 10

Analysis 18.1. Comparison 18 Hyalgan versus Hylan G-F 20, Outcome 1 Safety: number of patients with
local reaction (acute inflammation and pain).
Comparison: 18 Hyalgan versus Hylan G-F 20
Outcome: 1 Safety: number of patients with local reaction (acute inflammation and pain)
Study or subgroup Hyalgan Hylan G-F 20 Risk Ratio Weight Risk Ratio
Brown 2003 0/25 6/29 0.09 [ 0.01, 1.50 ]
0.1 0.2 0.5 1 2 5 10

Favours Hyalgan Favours Hylan G-F 20

Analysis 19.1. Comparison 19 Hyalgan versus Hyalgan, Outcome 1 Patient global (number of patients
assessing response as satisfactory).
Comparison: 19 Hyalgan versus Hyalgan
Outcome: 1 Patient global (number of patients assessing response as satisfactory)
Study or subgroup Hyalgan 5-inj Hyalgan 3-inj Risk Ratio Weight Risk Ratio
Karras 2001 49/73 68/86 100.0 % 0.85 [ 0.70, 1.03 ]
Subtotal (95% CI) 73 86 100.0 % 0.85 [ 0.70, 1.03 ]

Total events: 49 (Hyalgan 5-inj), 68 (Hyalgan 3-inj)
0.1 0.2 0.5 1 2 5 10

Favours Hyalgan 5inj Favours Hyalgan 3inj

Analysis 20.1. Comparison 20 Hylan G-F 20 versus placebo, Outcome 1 Pain on weight bearing (0-100 mm
VAS).
Comparison: 20 Hylan G-F 20 versus placebo
Mean Mean
Study or subgroup Hylan G-F 20 Placebo Difference Weight Difference
Karlsson 2002b (SvP) 86 45 (25.67) 33 44 (30.39) 16.5 % 1.00 [ -10.70, 12.70 ]
Moreland 1993 46 47 (27.13) 48 51 (27.71) 17.2 % -4.00 [ -15.09, 7.09 ]
Scale 1994a (2 inj) 23 32 (23.98) 24 47 (24.5) 14.4 % -15.00 [ -28.86, -1.14 ]
Scale 1994b (3 inj) 15 22 (19.36) 15 44 (19.36) 14.4 % -22.00 [ -35.86, -8.14 ]
Wobig 1998 57 31 (22.65) 60 53 (23.24) 20.2 % -22.00 [ -30.32, -13.68 ]
Wobig 1999c (NEhyl) 38 40 (24.66) 36 53 (24) 17.2 % -13.00 [ -24.09, -1.91 ]
Subtotal (95% CI) 265 216 100.0 % -12.54 [ -20.39, -4.69 ]

Karlsson 2002b (SvP) 86 41 (31.53) 33 46 (34.9) 19.1 % -5.00 [ -18.65, 8.65 ]
Scale 1994a (2 inj) 23 27 (23.98) 24 53 (24.5) 19.0 % -26.00 [ -39.86, -12.14 ]
Scale 1994b (3 inj) 15 11 (19.36) 15 43 (19.36) 19.0 % -32.00 [ -45.86, -18.14 ]
Wobig 1998 57 23 (22.65) 60 60 (23.24) 22.2 % -37.00 [ -45.32, -28.68 ]
Wobig 1999c (NEhyl) 37 32 (24.33) 35 43 (23.66) 20.7 % -11.00 [ -22.09, 0.09 ]
Subtotal (95% CI) 218 167 100.0 % -22.46 [ -35.24, -9.68 ]

Karlsson 2002b (SvP) 86 43 (33.78) 33 44 (33.78) 25.5 % -1.00 [ -14.56, 12.56 ]
Scale 1994a (2 inj) 15 18 (23.24) 21 57 (22.91) 24.1 % -39.00 [ -54.31, -23.69 ]
Scale 1994b (3 inj) 15 22 (23.24) 15 45 (23.24) 23.0 % -23.00 [ -39.63, -6.37 ]
Wobig 1998 56 35 (29.93) 60 56 (30.98) 27.4 % -21.00 [ -32.09, -9.91 ]
Subtotal (95% CI) 172 129 100.0 % -20.70 [ -35.56, -5.83 ]

-100 -50 0 50 100

Favours Hylan G-F 20 Favours Placebo

Analysis 20.2. Comparison 20 Hylan G-F 20 versus placebo, Outcome 2 Pain walking (0-100 mm VAS).
Outcome: 2 Pain walking (0-100 mm VAS)
Mean Mean
Cubukcu 2004 20 46.66 (9.66) 10 50.8 (5.72) 83.8 % -4.14 [ -9.66, 1.38 ]
Moreland 1993 46 57 (27.13) 48 60 (34.64) 16.2 % -3.00 [ -15.55, 9.55 ]
Subtotal (95% CI) 66 58 100.0 % -3.96 [ -9.01, 1.10 ]

Cubukcu 2004 20 40 (9.08) 10 53.8 (7.12) 100.0 % -13.80 [ -19.74, -7.86 ]
Subtotal (95% CI) 20 10 100.0 % -13.80 [ -19.74, -7.86 ]

-100 -50 0 50 100


Analysis 20.3. Comparison 20 Hylan G-F 20 versus placebo, Outcome 3 WOMAC pain.
Outcome: 3 WOMAC pain
Std. Std.
Mean Mean
Study or subgroup Hylan G-F 20 Saline/Arthro Difference Weight Difference
Cubukcu 2004 20 11.4 (1.83) 10 14.1 (1.52) 48.0 % -1.51 [ -2.38, -0.65 ]
Kotevoglu 2005 21 10 (3.3) 9 13.5 (3.4) 52.0 % -1.02 [ -1.85, -0.19 ]
Subtotal (95% CI) 41 19 100.0 % -1.26 [ -1.86, -0.66 ]

Cubukcu 2004 20 9.36 (1.52) 10 14.6 (1.77) 8.2 % -3.18 [ -4.33, -2.03 ]
Dickson 2001 53 26 (29.12) 57 34 (22.65) 76.8 % -0.31 [ -0.68, 0.07 ]
Kotevoglu 2005 21 10 (3) 9 14 (3.2) 14.9 % -1.27 [ -2.13, -0.42 ]
Subtotal (95% CI) 94 76 100.0 % -0.69 [ -1.02, -0.36 ]

Heterogeneity: Chi2 = 23.79, df = 2 (P<0.00001); I2 =92%
Kotevoglu 2005 21 10 (2.5) 9 13 (3.1) 100.0 % -1.09 [ -1.92, -0.25 ]
Subtotal (95% CI) 21 9 100.0 % -1.09 [ -1.92, -0.25 ]

-10 -5 0 5 10
Favours Hylan G-F 20 Favours Saline/arthr

Analysis 20.4. Comparison 20 Hylan G-F 20 versus placebo, Outcome 4 Pain at night (0-100 mm VAS).
Mean Mean
Cubukcu 2004 20 27.33 (7.69) 10 37 (9.49) 33.4 % -9.67 [ -16.45, -2.89 ]
Moreland 1993 46 36 (33.91) 48 45 (34.64) 8.0 % -9.00 [ -22.86, 4.86 ]
Scale 1994a (2 inj) 23 18 (23.98) 24 23 (24.5) 8.0 % -5.00 [ -18.86, 8.86 ]
Scale 1994b (3 inj) 14 7 (14.97) 15 17 (15.49) 12.5 % -10.00 [ -21.09, 1.09 ]
Wobig 1998 57 15 (22.65) 60 26 (23.24) 22.2 % -11.00 [ -19.32, -2.68 ]
Wobig 1999c (NEhyl) 38 12 (18.49) 36 12 (24) 16.0 % 0.0 [ -9.80, 9.80 ]
Subtotal (95% CI) 198 193 100.0 % -8.03 [ -11.95, -4.12 ]

Cubukcu 2004 20 22.66 (9.3) 10 44 (10.31) 29.2 % -21.34 [ -28.92, -13.76 ]
Scale 1994a (2 inj) 23 16 (23.98) 24 26 (24.5) 8.7 % -10.00 [ -23.86, 3.86 ]
Scale 1994b (3 inj) 14 2 (11.22) 15 15 (11.62) 24.2 % -13.00 [ -21.31, -4.69 ]
Wobig 1998 57 12 (22.65) 60 30 (23.24) 24.2 % -18.00 [ -26.32, -9.68 ]
Wobig 1999c (NEhyl) 37 13 (24.33) 35 12 (23.66) 13.6 % 1.00 [ -10.09, 12.09 ]
Subtotal (95% CI) 151 144 100.0 % -14.47 [ -18.57, -10.38 ]

Scale 1994a (2 inj) 15 10 (23.24) 21 32 (22.91) 15.9 % -22.00 [ -37.31, -6.69 ]
Scale 1994b (3 inj) 15 3 (15.49) 15 16 (15.49) 30.3 % -13.00 [ -24.09, -1.91 ]
Wobig 1998 56 16 (22.45) 60 34 (23.24) 53.8 % -18.00 [ -26.32, -9.68 ]
Subtotal (95% CI) 86 96 100.0 % -17.12 [ -23.22, -11.02 ]

-100 -50 0 50 100


Analysis 20.5. Comparison 20 Hylan G-F 20 versus placebo, Outcome 5 Pain at rest (0-100 mm VAS).
Mean Mean
Cubukcu 2004 20 29 (7.83) 10 39 (5.66) 88.9 % -10.00 [ -14.91, -5.09 ]
Moreland 1993 46 39 (33.91) 48 44 (34.64) 11.1 % -5.00 [ -18.86, 8.86 ]
Subtotal (95% CI) 66 58 100.0 % -9.44 [ -14.07, -4.82 ]

Cubukcu 2004 20 22.33 (6.98) 10 41 (5.66) 100.0 % -18.67 [ -23.32, -14.02 ]
Subtotal (95% CI) 20 10 100.0 % -18.67 [ -23.32, -14.02 ]

-100 -50 0 50 100


Analysis 20.6. Comparison 20 Hylan G-F 20 versus placebo, Outcome 6 Pain overall (0-100 mm VAS).
Mean Mean
Moreland 1993 46 55 (27.13) 48 57 (27.71) 100.0 % -2.00 [ -13.09, 9.09 ]
Subtotal (95% CI) 46 48 100.0 % -2.00 [ -13.09, 9.09 ]

-10 -5 0 5 10

Analysis 20.7. Comparison 20 Hylan G-F 20 versus placebo, Outcome 7 WOMAC physical function.
Outcome: 7 WOMAC physical function
Mean Mean
Study or subgroup Hylan G-F 20 Saline/Arthro Difference Weight Difference
Cubukcu 2004 20 40.9 (4.96) 10 46.5 (5.12) 84.2 % -5.60 [ -9.45, -1.75 ]
Kotevoglu 2005 21 31 (9.4) 9 46 (12.1) 15.8 % -15.00 [ -23.87, -6.13 ]
Subtotal (95% CI) 41 19 100.0 % -7.09 [ -10.62, -3.56 ]

Cubukcu 2004 20 35.9 (4.65) 10 47.4 (5.31) 66.2 % -11.50 [ -15.37, -7.63 ]
Dickson 2001 53 38 (21.84) 57 47 (15.1) 19.9 % -9.00 [ -16.07, -1.93 ]
Kotevoglu 2005 21 30 (9.2) 9 48 (11.4) 14.0 % -18.00 [ -26.42, -9.58 ]
Subtotal (95% CI) 94 76 100.0 % -11.91 [ -15.06, -8.76 ]

Kotevoglu 2005 21 31 (10.5) 9 48 (13.5) 100.0 % -17.00 [ -26.90, -7.10 ]
Subtotal (95% CI) 21 9 100.0 % -17.00 [ -26.90, -7.10 ]

-100 -50 0 50 100

Favours Hylan G-F 20 Favours saline/arthr

Analysis 20.8. Comparison 20 Hylan G-F 20 versus placebo, Outcome 8 Lequesne Index (0-24).
Mean Mean
Study or subgroup Hylan G-F 20 Saline Difference Weight Difference
Dickson 2001 53 10.9 (3.64) 57 12.5 (3.77) 100.0 % -1.60 [ -2.98, -0.22 ]
Subtotal (95% CI) 53 57 100.0 % -1.60 [ -2.98, -0.22 ]

Karlsson 2002b (SvP) 88 9 (4.44) 66 8.9 (4.77) 100.0 % 0.10 [ -1.38, 1.58 ]
Subtotal (95% CI) 88 66 100.0 % 0.10 [ -1.38, 1.58 ]

-10 -5 0 5 10
Favours Hylan G-F 20 Favours saline

Analysis 20.9. Comparison 20 Hylan G-F 20 versus placebo, Outcome 9 Function: improvment in most
painful knee movement (0-100 mm VAS).
Outcome: 9 Function: improvment in most painful knee movement (0-100 mm VAS)
Mean Mean
Scale 1994a (2 inj) 22 56 (28.14) 24 36 (24.5) 21.1 % 20.00 [ 4.69, 35.31 ]
Scale 1994b (3 inj) 15 71 (27.11) 15 41 (27.11) 13.1 % 30.00 [ 10.60, 49.40 ]
Wobig 1998 57 60 (30.2) 60 38 (30.98) 40.1 % 22.00 [ 10.91, 33.09 ]
Wobig 1999c (NEhyl) 38 45 (30.82) 36 36 (30) 25.7 % 9.00 [ -4.86, 22.86 ]
Subtotal (95% CI) 132 135 100.0 % 19.29 [ 12.26, 26.31 ]

Scale 1994a (2 inj) 22 65 (28.14) 23 31 (28.77) 18.1 % 34.00 [ 17.37, 50.63 ]
Scale 1994b (3 inj) 15 88 (23.24) 15 38 (27.11) 15.3 % 50.00 [ 31.93, 68.07 ]
Wobig 1998 57 74 (30.2) 59 37 (30.72) 40.6 % 37.00 [ 25.91, 48.09 ]
Wobig 1999c (NEhyl) 37 62 (30.41) 35 45 (29.58) 26.0 % 17.00 [ 3.14, 30.86 ]
Subtotal (95% CI) 131 132 100.0 % 33.25 [ 26.18, 40.31 ]

-100 -50 0 50 100

Favours Placebo Favours Hylan G-F 20

Analysis 20.10. Comparison 20 Hylan G-F 20 versus placebo, Outcome 10 15 metre walking time.
Outcome: 10 15 metre walking time
Mean Mean
Cubukcu 2004 20 17.4 (2.37) 10 16.6 (1.55) 100.0 % 0.80 [ -0.61, 2.21 ]
Subtotal (95% CI) 20 10 100.0 % 0.80 [ -0.61, 2.21 ]

Cubukcu 2004 20 16.13 (2.46) 10 17 (2.02) 100.0 % -0.87 [ -2.52, 0.78 ]
Subtotal (95% CI) 20 10 100.0 % -0.87 [ -2.52, 0.78 ]

-10 -5 0 5 10
Favours Hylan G-F 20 Favours Saline

Analysis 20.11. Comparison 20 Hylan G-F 20 versus placebo, Outcome 11 WOMAC stiffness (2 to 10 Likert).
Outcome: 11 WOMAC stiffness (2 to 10 Likert)
Mean Mean
Cubukcu 2004 20 4.2 (1.03) 10 5 (1.14) 59.4 % -0.80 [ -1.64, 0.04 ]
Kotevoglu 2005 21 4 (1.3) 9 5.5 (1.3) 40.6 % -1.50 [ -2.52, -0.48 ]
Subtotal (95% CI) 41 19 100.0 % -1.08 [ -1.73, -0.44 ]

Cubukcu 2004 20 3.5 (1.07) 10 5.1 (1.52) 56.8 % -1.60 [ -2.65, -0.55 ]
Kotevoglu 2005 21 4 (1.1) 9 5 (1.7) 43.2 % -1.00 [ -2.21, 0.21 ]
Subtotal (95% CI) 41 19 100.0 % -1.34 [ -2.13, -0.55 ]

Kotevoglu 2005 21 4 (1) 18 5 (1.7) 100.0 % -1.00 [ -1.89, -0.11 ]
Subtotal (95% CI) 21 18 100.0 % -1.00 [ -1.89, -0.11 ]

-10 -5 0 5 10
Favours Hylan G-F 20 Favours saline

Analysis 20.12. Comparison 20 Hylan G-F 20 versus placebo, Outcome 12 Patient global assessment (0-100
mm VAS; where 100 is worst severity).
Outcome: 12 Patient global assessment (0-100 mm VAS; where 100 is worst severity)
Mean Mean
Kotevoglu 2005 21 50 (13.5) 9 70 (18.1) 100.0 % -20.00 [ -33.16, -6.84 ]
Subtotal (95% CI) 21 9 100.0 % -20.00 [ -33.16, -6.84 ]

Kotevoglu 2005 21 50 (12.1) 9 70 (14.1) 100.0 % -20.00 [ -30.57, -9.43 ]
Subtotal (95% CI) 21 9 100.0 % -20.00 [ -30.57, -9.43 ]

3 14 to 26 weeks post injection
Kotevoglu 2005 21 70 (16.1) 9 70 (16.3) 100.0 % 0.0 [ -12.68, 12.68 ]
Subtotal (95% CI) 21 9 100.0 % 0.0 [ -12.68, 12.68 ]

-100 -50 0 50 100


Analysis 20.13. Comparison 20 Hylan G-F 20 versus placebo, Outcome 13 Patient global assessment
(number of patients good or very good) 5 to 13 weeks post-injection.
Outcome: 13 Patient global assessment (number of patients good or very good) 5 to 13 weeks post-injection
Arthro+dummy
Study or subgroup Hylan G-F 20 caps Risk Ratio Weight Risk Ratio
Dickson 2001 29/42 23/48 1.44 [ 1.01, 2.06 ]
0.1 0.2 0.5 1 2 5 10

Favours Arthro+caps Favours Hylan G-F 20
Analysis 20.14. Comparison 20 Hylan G-F 20 versus placebo, Outcome 14 Patient global evaluation of
efficacy due to treatment.
Outcome: 14 Patient global evaluation of efficacy due to treatment
Std. Std.
Mean Mean
Cubukcu 2004 20 2.6 (0.49) 10 2.3 (0.66) 9.4 % 0.53 [ -0.24, 1.30 ]
Scale 1994a (2 inj) 23 61 (28.77) 24 39 (29.39) 15.9 % 0.74 [ 0.15, 1.34 ]
Scale 1994b (3 inj) 15 79 (23.24) 15 51 (23.24) 9.1 % 1.17 [ 0.39, 1.96 ]
Wobig 1998 57 71 (30.2) 60 45 (30.98) 39.0 % 0.84 [ 0.47, 1.22 ]
Wobig 1999c (NEhyl) 38 53 (30.82) 36 42 (31) 26.5 % 0.35 [ -0.11, 0.81 ]
Subtotal (95% CI) 153 145 100.0 % 0.70 [ 0.46, 0.93 ]

-100 -50 0 50 100

(Continued . . . )

(. . .Continued)
Std. Std.
Mean Mean
Cubukcu 2004 20 3.6 (0.54) 10 1.8 (0.41) 4.5 % 3.49 [ 2.28, 4.70 ]
Scale 1994a (2 inj) 23 66 (28.77) 24 34 (29.39) 17.4 % 1.08 [ 0.47, 1.70 ]
Scale 1994b (3 inj) 15 91 (23.24) 15 43 (23.24) 8.2 % 2.01 [ 1.11, 2.91 ]
Wobig 1998 57 82 (30.2) 59 40 (30.72) 40.2 % 1.37 [ 0.96, 1.78 ]
Wobig 1999c (NEhyl) 37 67 (30.41) 35 50 (29.58) 29.7 % 0.56 [ 0.09, 1.03 ]
Subtotal (95% CI) 152 143 100.0 % 1.23 [ 0.97, 1.48 ]

-100 -50 0 50 100


Analysis 20.15. Comparison 20 Hylan G-F 20 versus placebo, Outcome 15 Physician global assessment (0-
100 mm VAS; where 100 is worst severity).
Outcome: 15 Physician global assessment (0-100 mm VAS; where 100 is worst severity)
Mean Mean
Kotevoglu 2005 21 50 (21.1) 9 70 (23.2) 100.0 % -20.00 [ -37.64, -2.36 ]
Subtotal (95% CI) 21 9 100.0 % -20.00 [ -37.64, -2.36 ]

Kotevoglu 2005 21 50 (18.4) 9 70 (21.5) 100.0 % -20.00 [ -36.10, -3.90 ]
Subtotal (95% CI) 21 9 100.0 % -20.00 [ -36.10, -3.90 ]

3 14 to 26 weeks post injection
Kotevoglu 2005 21 60 (18.1) 9 70 (22.1) 100.0 % -10.00 [ -26.38, 6.38 ]
Subtotal (95% CI) 21 9 100.0 % -10.00 [ -26.38, 6.38 ]

-100 -50 0 50 100


Analysis 20.16. Comparison 20 Hylan G-F 20 versus placebo, Outcome 16 Number of survivors (patients
not requiring additional treatment for study knee).
Outcome: 16 Number of survivors (patients not requiring additional treatment for study knee)
Study or subgroup Hylan G-F 20 Saline Risk Ratio Weight Risk Ratio
Karlsson 2002b (SvP) 38/86 22/66 100.0 % 1.33 [ 0.87, 2.01 ]
Subtotal (95% CI) 86 66 100.0 % 1.33 [ 0.87, 2.01 ]

Total events: 38 (Hylan G-F 20), 22 (Saline)
0.1 0.2 0.5 1 2 5 10

Favours saline Favours Hylan G-F 20

Analysis 20.17. Comparison 20 Hylan G-F 20 versus placebo, Outcome 17 Number of clinical failures.
Karlsson 2002b (SvP) 6/86 7/66 100.0 % 0.66 [ 0.23, 1.87 ]
Subtotal (95% CI) 86 66 100.0 % 0.66 [ 0.23, 1.87 ]

Karlsson 2002b (SvP) 32/70 26/48 100.0 % 0.84 [ 0.59, 1.22 ]
Subtotal (95% CI) 70 48 100.0 % 0.84 [ 0.59, 1.22 ]

0.1 0.2 0.5 1 2 5 10


Analysis 20.18. Comparison 20 Hylan G-F 20 versus placebo, Outcome 18 Need for paracetamol (pill count).
Outcome: 18 Need for paracetamol (pill count)
Mean Mean
Cubukcu 2004 20 0 (0) 10 0.1 (0.51) Not estimable

Cubukcu 2004 20 0 (0) 10 0.7 (0.47) Not estimable

Test for subgroup differences: Chi2 = 0.0, df = -1 (P = 0.0), I2 =0.0%
-10 -5 0 5 10

Analysis 20.19. Comparison 20 Hylan G-F 20 versus placebo, Outcome 19 Safety: total withdrawals overall.
Study or subgroup Hylan G-F 20 Placebo Risk Ratio Weight Risk Ratio
Moreland 1993 2/46 3/48 100.0 % 0.70 [ 0.12, 3.97 ]
Subtotal (95% CI) 46 48 100.0 % 0.70 [ 0.12, 3.97 ]

Total events: 2 (Hylan G-F 20), 3 (Placebo)
Cubukcu 2004 0/20 0/10 Not estimable
Dickson 2001 10/53 8/57 83.6 % 1.34 [ 0.57, 3.15 ]
Wobig 1998 1/57 0/60 5.3 % 3.16 [ 0.13, 75.90 ]
Wobig 1999c (NEhyl) 1/37 1/35 11.1 % 0.95 [ 0.06, 14.55 ]
Subtotal (95% CI) 167 162 100.0 % 1.40 [ 0.64, 3.06 ]

Kotevoglu 2005 5/26 8/26 100.0 % 0.63 [ 0.24, 1.66 ]
Subtotal (95% CI) 26 26 100.0 % 0.63 [ 0.24, 1.66 ]

0.1 0.2 0.5 1 2 5 10


Analysis 20.20. Comparison 20 Hylan G-F 20 versus placebo, Outcome 20 Safety: number of patients
withdrawn due to noncomplinance.
Outcome: 20 Safety: number of patients withdrawn due to noncomplinance
Kotevoglu 2005 1/26 2/26 0.50 [ 0.05, 5.18 ]
0.1 0.2 0.5 1 2 5 10

Analysis 20.21. Comparison 20 Hylan G-F 20 versus placebo, Outcome 21 Safety: number of patients with
local reaction.
Outcome: 21 Safety: number of patients with local reaction
M- M-
H,Random,95% H,Random,95%
n/N n/N CI CI
Dickson 2001 7/50 4/54 1.89 [ 0.59, 6.07 ]
Kotevoglu 2005 1/26 0/26 3.00 [ 0.13, 70.42 ]
Moreland 1993 14/46 0/48 30.23 [ 1.86, 492.56 ]
Wobig 1998 0/57 2/60 0.21 [ 0.01, 4.29 ]
Wobig 1999c (NEhyl) 2/37 2/35 0.95 [ 0.14, 6.35 ]
0.1 0.2 0.5 1 2 5 10


local adverse reactions but study drug continued.
Outcome: 22 Safety: number of patients with local adverse reactions but study drug continued
Scale 1994b (3 inj) 1/15 0/15 100.0 % 3.00 [ 0.13, 68.26 ]
Subtotal (95% CI) 15 15 100.0 % 3.00 [ 0.13, 68.26 ]

0.1 0.2 0.5 1 2 5 10

one or more probable or possible related systemic adverse events.
Outcome: 23 Safety: number of patients with one or more probable or possible related systemic adverse events
Dickson 2001 11/50 6/54 100.0 % 1.98 [ 0.79, 4.96 ]
Subtotal (95% CI) 50 54 100.0 % 1.98 [ 0.79, 4.96 ]

0.1 0.2 0.5 1 2 5 10


Analysis 20.24. Comparison 20 Hylan G-F 20 versus placebo, Outcome 24 Safety: number of patients
reporting systemic reactions.
Outcome: 24 Safety: number of patients reporting systemic reactions
Study or subgroup Hylan G-F 20 Control Risk Ratio Weight Risk Ratio
Wobig 1998 3/57 0/60 100.0 % 7.36 [ 0.39, 139.44 ]
Wobig 1999c (NEhyl) 0/37 0/35 Not estimable
Subtotal (95% CI) 114 105 100.0 % 7.36 [ 0.39, 139.44 ]

Total events: 3 (Hylan G-F 20), 0 (Control)
0.1 0.2 0.5 1 2 5 10


Analysis 21.1. Comparison 21 Hylan G-F 20 versus NSAID, Outcome 1 Pain on motion (0-100 mm VAS).
Comparison: 21 Hylan G-F 20 versus NSAID
Outcome: 1 Pain on motion (0-100 mm VAS)
Mean Mean
Study or subgroup Hylan G-F 20 NSAID Difference Weight Difference
Adams 1995 25 38 (20) 32 44 (22.63) 100.0 % -6.00 [ -17.09, 5.09 ]
Subtotal (95% CI) 25 32 100.0 % -6.00 [ -17.09, 5.09 ]

Adams 1995 27 40 (25.98) 31 52 (22.27) 100.0 % -12.00 [ -24.55, 0.55 ]
Subtotal (95% CI) 27 31 100.0 % -12.00 [ -24.55, 0.55 ]

-100 -50 0 50 100

Favours Hylan G-F 20 Favours NSAID

Analysis 21.2. Comparison 21 Hylan G-F 20 versus NSAID, Outcome 2 WOMAC pain (0-100 mm VAS).
Mean Mean
Dickson 2001 53 26 (29.12) 55 38 (29.66) 100.0 % -12.00 [ -23.09, -0.91 ]
Subtotal (95% CI) 53 55 100.0 % -12.00 [ -23.09, -0.91 ]

-100 -50 0 50 100


Analysis 21.3. Comparison 21 Hylan G-F 20 versus NSAID, Outcome 3 Pain at rest (0-100 mm VAS).
Mean Mean
Adams 1995 25 17 (20) 32 20 (22.63) 100.0 % -3.00 [ -14.09, 8.09 ]
Subtotal (95% CI) 25 32 100.0 % -3.00 [ -14.09, 8.09 ]

Adams 1995 27 25 (15.59) 31 28 (22.27) 100.0 % -3.00 [ -12.80, 6.80 ]
Subtotal (95% CI) 27 31 100.0 % -3.00 [ -12.80, 6.80 ]

-10 -5 0 5 10

Analysis 21.4. Comparison 21 Hylan G-F 20 versus NSAID, Outcome 4 Pain at night (0-100 mm VAS).
Mean Mean
Adams 1995 25 14 (25) 32 21 (22.63) 100.0 % -7.00 [ -19.55, 5.55 ]
Subtotal (95% CI) 25 32 100.0 % -7.00 [ -19.55, 5.55 ]

Adams 1995 27 25 (25.98) 31 28 (22.27) 100.0 % -3.00 [ -15.55, 9.55 ]
Subtotal (95% CI) 27 31 100.0 % -3.00 [ -15.55, 9.55 ]

-10 -5 0 5 10

Analysis 21.5. Comparison 21 Hylan G-F 20 versus NSAID, Outcome 5 Pain overall (0-100 mm VAS).
Mean Mean
Adams 1995 25 38 (25) 32 43 (28.28) 100.0 % -5.00 [ -18.86, 8.86 ]
Subtotal (95% CI) 25 32 100.0 % -5.00 [ -18.86, 8.86 ]

Adams 1995 27 47 (20.78) 31 52 (22.27) 100.0 % -5.00 [ -16.09, 6.09 ]
Subtotal (95% CI) 27 31 100.0 % -5.00 [ -16.09, 6.09 ]

-10 -5 0 5 10

Analysis 21.6. Comparison 21 Hylan G-F 20 versus NSAID, Outcome 6 WOMAC function (0-100 mm VAS).
Mean Mean
Dickson 2001 53 38 (21.84) 55 42 (14.83) 100.0 % -4.00 [ -11.07, 3.07 ]
Subtotal (95% CI) 53 55 100.0 % -4.00 [ -11.07, 3.07 ]

-10 -5 0 5 10
Analysis 21.7. Comparison 21 Hylan G-F 20 versus NSAID, Outcome 7 Lequesne Index (0-24).
Mean Mean
Dickson 2001 53 10.9 (3.64) 55 11.9 (3.71) 100.0 % -1.00 [ -2.39, 0.39 ]
Subtotal (95% CI) 53 55 100.0 % -1.00 [ -2.39, 0.39 ]

-10 -5 0 5 10

Analysis 21.8. Comparison 21 Hylan G-F 20 versus NSAID, Outcome 8 Patient overall assessment of
treatment (number of patients excellent, very good, good).
Outcome: 8 Patient overall assessment of treatment (number of patients excellent, very good, good)
Study or subgroup Hylan G-F 20 NSAID Risk Ratio Weight Risk Ratio
1 5 to 13 weeks post-injection (numbe of patients very good or good)

Dickson 2001 29/42 35/42 100.0 % 0.83 [ 0.65, 1.06 ]
Subtotal (95% CI) 42 42 100.0 % 0.83 [ 0.65, 1.06 ]

Total events: 29 (Hylan G-F 20), 35 (NSAID)
2 14 to 26 weeks post-injection (number of patients excellent/very good/good)
Adams 1995 17/27 12/31 100.0 % 1.63 [ 0.96, 2.76 ]
Subtotal (95% CI) 27 31 100.0 % 1.63 [ 0.96, 2.76 ]

0.1 0.2 0.5 1 2 5 10

Favours NSAID Favours Hylan G-F 20

Analysis 21.9. Comparison 21 Hylan G-F 20 versus NSAID, Outcome 9 Safety: total withdrawals overall.
Dickson 2001 10/53 13/55 100.0 % 0.80 [ 0.38, 1.66 ]
Subtotal (95% CI) 53 55 100.0 % 0.80 [ 0.38, 1.66 ]

Adams 1995 4/31 3/34 100.0 % 1.46 [ 0.36, 6.02 ]
Subtotal (95% CI) 31 34 100.0 % 1.46 [ 0.36, 6.02 ]

0.1 0.2 0.5 1 2 5 10


Analysis 21.10. Comparison 21 Hylan G-F 20 versus NSAID, Outcome 10 Safety: number of patients with
local reactions.
Outcome: 10 Safety: number of patients with local reactions
Dickson 2001 7/50 4/52 100.0 % 1.82 [ 0.57, 5.84 ]
Subtotal (95% CI) 50 52 100.0 % 1.82 [ 0.57, 5.84 ]

0.1 0.2 0.5 1 2 5 10

Analysis 21.11. Comparison 21 Hylan G-F 20 versus NSAID, Outcome 11 Safety: number of patients with
probable or possible related systemic adverse events.
Outcome: 11 Safety: number of patients with probable or possible related systemic adverse events
Dickson 2001 11/50 25/52 100.0 % 0.46 [ 0.25, 0.83 ]
Subtotal (95% CI) 50 52 100.0 % 0.46 [ 0.25, 0.83 ]

0.1 0.2 0.5 1 2 5 10


Analysis 21.12. Comparison 21 Hylan G-F 20 versus NSAID, Outcome 12 Safety: withdrawals due to
adverse events.
Adams 1995 1/31 0/34 100.0 % 3.28 [ 0.14, 77.69 ]
Subtotal (95% CI) 31 34 100.0 % 3.28 [ 0.14, 77.69 ]

0.1 0.2 0.5 1 2 5 10


Analysis 22.1. Comparison 22 (Hylan G-F 20 + NSAID + arthrocentesis) versus (NSAID + arthrocentesis),
Outcome 1 Pain on motion (0-100 mm VAS).
Comparison: 22 (Hylan G-F 20 + NSAID + arthrocentesis) versus (NSAID + arthrocentesis)
Outcome: 1 Pain on motion (0-100 mm VAS)
Hylan G- Mean Mean

Study or subgroup F20+NSAID+AR NSAID+ARTHRO Difference Weight Difference
Adams 1995 32 34 (22.63) 32 44 (22.63) 100.0 % -10.00 [ -21.09, 1.09 ]
Subtotal (95% CI) 32 32 100.0 % -10.00 [ -21.09, 1.09 ]

Adams 1995 32 37 (22.63) 31 52 (22.27) 100.0 % -15.00 [ -26.09, -3.91 ]
Subtotal (95% CI) 32 31 100.0 % -15.00 [ -26.09, -3.91 ]

-100 -50 0 50 100

Favours HYLAN+NSAID Favours NSAID

Outcome 2 Pain at rest (0-100 mm VAS).
Hylan Mean Mean

Study or subgroup GF20+NSAID+ART NSAID+ARTHRO Difference Weight Difference
Adams 1995 32 14 (22.63) 32 20 (22.63) 100.0 % -6.00 [ -17.09, 5.09 ]
Subtotal (95% CI) 32 32 100.0 % -6.00 [ -17.09, 5.09 ]

Adams 1995 32 11 (16.97) 31 22 (16.7) 100.0 % -11.00 [ -19.31, -2.69 ]
Subtotal (95% CI) 32 31 100.0 % -11.00 [ -19.31, -2.69 ]

-100 -50 0 50 100

Favours HYLAN+NSAID Favours NSAID+AR

Outcome 3 Pain at night (0-100 mm VAS).
Hylan G- Mean Mean

Adams 1995 32 10 (22.63) 32 21 (22.63) 100.0 % -11.00 [ -22.09, 0.09 ]
Subtotal (95% CI) 32 32 100.0 % -11.00 [ -22.09, 0.09 ]

Adams 1995 32 9 (22.63) 31 28 (22.27) 100.0 % -19.00 [ -30.09, -7.91 ]
Subtotal (95% CI) 32 31 100.0 % -19.00 [ -30.09, -7.91 ]

-100 -50 0 50 100

Favours Hylan+NSAID Favours NSAID

Outcome 4 Pain overall (0-100 mm VAS).
Hylan G- Mean Mean

Adams 1995 32 31 (22.63) 32 43 (28.28) 100.0 % -12.00 [ -24.55, 0.55 ]
Subtotal (95% CI) 32 32 100.0 % -12.00 [ -24.55, 0.55 ]

Adams 1995 32 37 (22.63) 31 52 (22.27) 100.0 % -15.00 [ -26.09, -3.91 ]
Subtotal (95% CI) 32 31 100.0 % -15.00 [ -26.09, -3.91 ]

-100 -50 0 50 100


Outcome 5 Patient overall assessment of treatment (number of patients excellent, very good, or good).
Outcome: 5 Patient overall assessment of treatment (number of patients excellent, very good, or good)
Study or subgroup Hylan+NSAID+ARTHRO

NSAID+ARTHRO Risk Ratio Weight Risk Ratio
Adams 1995 17/27 18/32 100.0 % 1.12 [ 0.73, 1.70 ]
Subtotal (95% CI) 27 32 100.0 % 1.12 [ 0.73, 1.70 ]

Total events: 17 (Hylan+NSAID+ARTHRO), 18 (NSAID+ARTHRO)
0.1 0.2 0.5 1 2 5 10

Favours NSAID+ARTHRO Favours Hylan+NSAID
Study or subgroup Hylan+NSAID+ARTHRO

NSAID+ARTHRO Risk Ratio Weight Risk Ratio
Adams 1995 5/37 3/34 100.0 % 1.53 [ 0.40, 5.93 ]
Subtotal (95% CI) 37 34 100.0 % 1.53 [ 0.40, 5.93 ]

Total events: 5 (Hylan+NSAID+ARTHRO), 3 (NSAID+ARTHRO)
0.1 0.2 0.5 1 2 5 10

Favours GF+NSAID+AR Favours NSAID+AR

Analysis 23.1. Comparison 23 Hylan G-F 20 versus betamethasone, Outcome 1 Safety: total withdrawals
overall.
Comparison: 23 Hylan G-F 20 versus betamethasone
Study or subgroup Hylan G-F 20 Betamethasone Risk Ratio Weight Risk Ratio
Leopold 2003 14/50 9/50 1.56 [ 0.74, 3.26 ]
0.1 0.2 0.5 1 2 5 10

Favours Hylan G-F 20 Favours betamethason
Analysis 23.2. Comparison 23 Hylan G-F 20 versus betamethasone, Outcome 2 Safety: wIthdrawals due to
lack of efficacy.
Outcome: 2 Safety: wIthdrawals due to lack of efficacy
Leopold 2003 12/50 8/50 1.50 [ 0.67, 3.35 ]
0.1 0.2 0.5 1 2 5 10


Analysis 23.3. Comparison 23 Hylan G-F 20 versus betamethasone, Outcome 3 Safety: wIthdrawals due to
acute local reaction.
Outcome: 3 Safety: wIthdrawals due to acute local reaction
Leopold 2003 1/38 0/42 3.31 [ 0.14, 78.84 ]
0.1 0.2 0.5 1 2 5 10

Analysis 24.1. Comparison 24 Hylan G-F 20 versus triamcinolone hexacetonide, Outcome 1 WOMAC pain
walking on a flat surface (Question 1: 0-4 Likert).
Comparison: 24 Hylan G-F 20 versus triamcinolone hexacetonide
Outcome: 1 WOMAC pain walking on a flat surface (Question 1: 0-4 Likert)
Triamcinolone Mean Mean

Study or subgroup Hylan G-F 20 hexace Difference Weight Difference
Caborn 2004 113 1.2 (0.85) 102 1.6 (1.01) 100.0 % -0.40 [ -0.65, -0.15 ]
Subtotal (95% CI) 113 102 100.0 % -0.40 [ -0.65, -0.15 ]

Caborn 2004 113 1.4 (1.06) 102 1.8 (1.01) 100.0 % -0.40 [ -0.68, -0.12 ]
Subtotal (95% CI) 113 102 100.0 % -0.40 [ -0.68, -0.12 ]

-10 -5 0 5 10
Favours Hylan G-F 20 Favours TH

Analysis 24.2. Comparison 24 Hylan G-F 20 versus triamcinolone hexacetonide, Outcome 2 WOMAC
physical function subscale (0-68 Likert).
Outcome: 2 WOMAC physical function subscale (0-68 Likert)

Caborn 2004 113 23.5 (13.18) 102 28.5 (15.45) 100.0 % -5.00 [ -8.86, -1.14 ]
Subtotal (95% CI) 113 102 100.0 % -5.00 [ -8.86, -1.14 ]

Caborn 2004 113 25.5 (14.46) 102 30.7 (14.64) 100.0 % -5.20 [ -9.10, -1.30 ]
Subtotal (95% CI) 113 102 100.0 % -5.20 [ -9.10, -1.30 ]

-10 -5 0 5 10

Analysis 24.3. Comparison 24 Hylan G-F 20 versus triamcinolone hexacetonide, Outcome 3 WOMAC total
score (0-96 Likert).
Outcome: 3 WOMAC total score (0-96 Likert)

Caborn 2004 113 32.7 (18.28) 102 40.1 (21.31) 100.0 % -7.40 [ -12.74, -2.06 ]
Subtotal (95% CI) 113 102 100.0 % -7.40 [ -12.74, -2.06 ]

Caborn 2004 113 35.6 (20.3) 102 42.9 (20.5) 100.0 % -7.30 [ -12.76, -1.84 ]
Subtotal (95% CI) 113 102 100.0 % -7.30 [ -12.76, -1.84 ]

-10 -5 0 5 10

Analysis 24.4. Comparison 24 Hylan G-F 20 versus triamcinolone hexacetonide, Outcome 4 Patient global
overall assessment (0-100 mm VAS).
Outcome: 4 Patient global overall assessment (0-100 mm VAS)

Caborn 2004 113 36.7 (24.98) 102 50.1 (24.54) 100.0 % -13.40 [ -20.03, -6.77 ]
Subtotal (95% CI) 113 102 100.0 % -13.40 [ -20.03, -6.77 ]

Caborn 2004 113 40.3 (26.79) 102 55.4 (26.06) 100.0 % -15.10 [ -22.17, -8.03 ]
Subtotal (95% CI) 113 102 100.0 % -15.10 [ -22.17, -8.03 ]

-100 -50 0 50 100


Analysis 24.5. Comparison 24 Hylan G-F 20 versus triamcinolone hexacetonide, Outcome 5 Number of
responders (greater than or equal to one category on WOMAC pain Q1).
Outcome: 5 Number of responders (greater than or equal to one category on WOMAC pain Q1)
Triamcinolone
Study or subgroup Hylan G-F 20 hexace Risk Ratio Weight Risk Ratio
Caborn 2004 71/113 53/102 100.0 % 1.21 [ 0.96, 1.53 ]
Subtotal (95% CI) 113 102 100.0 % 1.21 [ 0.96, 1.53 ]

Total events: 71 (Hylan G-F 20), 53 (Triamcinolone hexace)
Caborn 2004 67/113 42/102 100.0 % 1.44 [ 1.09, 1.90 ]
Subtotal (95% CI) 113 102 100.0 % 1.44 [ 1.09, 1.90 ]

Caborn 2004 48/113 30/102 100.0 % 1.44 [ 1.00, 2.09 ]
Subtotal (95% CI) 113 102 100.0 % 1.44 [ 1.00, 2.09 ]

0.1 0.2 0.5 1 2 5 10

Favours TH Favours Hylan G-F 20

Analysis 24.6. Comparison 24 Hylan G-F 20 versus triamcinolone hexacetonide, Outcome 6 Analgesic
usage.
Outcome: 6 Analgesic usage
Triamcinolone
1 From week 0 to prior to week 12

Caborn 2004 111/113 99/102 100.0 % 1.01 [ 0.97, 1.06 ]
Subtotal (95% CI) 113 102 100.0 % 1.01 [ 0.97, 1.06 ]

2 From week 12 prior to week 26
Caborn 2004 44/83 44/70 100.0 % 0.84 [ 0.64, 1.11 ]
Subtotal (95% CI) 83 70 100.0 % 0.84 [ 0.64, 1.11 ]

0.1 0.2 0.5 1 2 5 10

Analysis 24.7. Comparison 24 Hylan G-F 20 versus triamcinolone hexacetonide, Outcome 7 Safety: total
Triamcinolone
Caborn 2004 30/113 35/103 0.78 [ 0.52, 1.17 ]
0.1 0.2 0.5 1 2 5 10


Analysis 24.8. Comparison 24 Hylan G-F 20 versus triamcinolone hexacetonide, Outcome 8 Safety:
withdrawals due to adverse event.
Outcome: 8 Safety: withdrawals due to adverse event
Triamcinolone
Caborn 2004 11/113 10/103 1.00 [ 0.44, 2.26 ]
0.1 0.2 0.5 1 2 5 10

Analysis 24.9. Comparison 24 Hylan G-F 20 versus triamcinolone hexacetonide, Outcome 9 Safety:
withdrawals due to lack of efficacy.
Triamcinolone
Caborn 2004 0/113 15/102 0.03 [ 0.00, 0.48 ]
0.01 0.1 1 10 100


Analysis 25.1. Comparison 25 Hylan G-F 20 versus physical therapy, Outcome 1 Spontaneous pain (0-100
mm VAS).
Comparison: 25 Hylan G-F 20 versus physical therapy
Outcome: 1 Spontaneous pain (0-100 mm VAS)
Mean Mean
Study or subgroup Synvisc Phys therapy Difference Weight Difference
Atamaz 2005 20 64 (18.4) 20 43.5 (14.6) 100.0 % 20.50 [ 10.21, 30.79 ]
Subtotal (95% CI) 20 20 100.0 % 20.50 [ 10.21, 30.79 ]

Atamaz 2005 20 45.5 (18.2) 20 49.5 (15.5) 100.0 % -4.00 [ -14.48, 6.48 ]
Subtotal (95% CI) 20 20 100.0 % -4.00 [ -14.48, 6.48 ]

Atamaz 2005 20 50.7 (18.3) 20 48.5 (15.2) 100.0 % 2.20 [ -8.23, 12.63 ]
Subtotal (95% CI) 20 20 100.0 % 2.20 [ -8.23, 12.63 ]

Atamaz 2005 20 51.7 (15.4) 20 50.7 (17.3) 100.0 % 1.00 [ -9.15, 11.15 ]
Subtotal (95% CI) 20 20 100.0 % 1.00 [ -9.15, 11.15 ]

Atamaz 2005 20 49 (13.3) 20 59.5 (21.2) 100.0 % -10.50 [ -21.47, 0.47 ]
Subtotal (95% CI) 20 20 100.0 % -10.50 [ -21.47, 0.47 ]

-100 -50 0 50 100

Favours Synvisc Favours phys therapy

Analysis 25.2. Comparison 25 Hylan G-F 20 versus physical therapy, Outcome 2 WOMAC pain.
Mean Mean
Atamaz 2005 20 8.3 (3.4) 20 11.3 (2.5) 100.0 % -3.00 [ -4.85, -1.15 ]
Subtotal (95% CI) 20 20 100.0 % -3.00 [ -4.85, -1.15 ]

Atamaz 2005 20 8.7 (3.8) 20 11.8 (2.6) 100.0 % -3.10 [ -5.12, -1.08 ]
Subtotal (95% CI) 20 20 100.0 % -3.10 [ -5.12, -1.08 ]

Atamaz 2005 20 10.4 (4.9) 20 11.3 (2.6) 100.0 % -0.90 [ -3.33, 1.53 ]
Subtotal (95% CI) 20 20 100.0 % -0.90 [ -3.33, 1.53 ]

Atamaz 2005 20 10.4 (2.6) 20 12.3 (3.2) 100.0 % -1.90 [ -3.71, -0.09 ]
Subtotal (95% CI) 20 20 100.0 % -1.90 [ -3.71, -0.09 ]

Atamaz 2005 20 10.2 (2.9) 20 15.5 (4.1) 100.0 % -5.30 [ -7.50, -3.10 ]
Subtotal (95% CI) 20 20 100.0 % -5.30 [ -7.50, -3.10 ]

-10 -5 0 5 10
Favours Synvisc Favours phys therapy

Analysis 25.3. Comparison 25 Hylan G-F 20 versus physical therapy, Outcome 3 WOMAC physical function.
Mean Mean
Study or subgroup Synvisc Phys Therapy Difference Weight Difference
Atamaz 2005 20 40.1 (15.7) 20 37.6 (12.7) 100.0 % 2.50 [ -6.35, 11.35 ]
Subtotal (95% CI) 20 20 100.0 % 2.50 [ -6.35, 11.35 ]

Atamaz 2005 20 41.7 (14) 20 38.9 (13.6) 100.0 % 2.80 [ -5.75, 11.35 ]
Subtotal (95% CI) 20 20 100.0 % 2.80 [ -5.75, 11.35 ]

Atamaz 2005 20 41.9 (14.6) 20 41.9 (15.4) 100.0 % 0.0 [ -9.30, 9.30 ]
Subtotal (95% CI) 20 20 100.0 % 0.0 [ -9.30, 9.30 ]

Atamaz 2005 20 38.6 (11.5) 20 38.2 (12) 100.0 % 0.40 [ -6.88, 7.68 ]
Subtotal (95% CI) 20 20 100.0 % 0.40 [ -6.88, 7.68 ]

Atamaz 2005 20 38.9 (11.7) 20 38.2 (12.6) 100.0 % 0.70 [ -6.84, 8.24 ]
Subtotal (95% CI) 20 20 100.0 % 0.70 [ -6.84, 8.24 ]

-10 -5 0 5 10
Favours Synvisc Favours Phys Therapy

Analysis 25.4. Comparison 25 Hylan G-F 20 versus physical therapy, Outcome 4 SF-36 pain.
Outcome: 4 SF-36 pain
Mean Mean
Atamaz 2005 20 59.4 (20.9) 20 59.1 (15.8) 100.0 % 0.30 [ -11.18, 11.78 ]
Subtotal (95% CI) 20 20 100.0 % 0.30 [ -11.18, 11.78 ]

Atamaz 2005 20 58.8 (21.9) 20 56.2 (17.5) 100.0 % 2.60 [ -9.69, 14.89 ]
Subtotal (95% CI) 20 20 100.0 % 2.60 [ -9.69, 14.89 ]

Atamaz 2005 20 55.7 (27.2) 20 54.6 (18.1) 100.0 % 1.10 [ -13.22, 15.42 ]
Subtotal (95% CI) 20 20 100.0 % 1.10 [ -13.22, 15.42 ]

Atamaz 2005 20 43.8 (14.5) 20 51.3 (16.4) 100.0 % -7.50 [ -17.09, 2.09 ]
Subtotal (95% CI) 20 20 100.0 % -7.50 [ -17.09, 2.09 ]

Atamaz 2005 20 46.7 (19.1) 20 50.2 (18.6) 100.0 % -3.50 [ -15.18, 8.18 ]
Subtotal (95% CI) 20 20 100.0 % -3.50 [ -15.18, 8.18 ]

-10 -5 0 5 10
Favours Phys therapy Favours Synvisc

Analysis 25.5. Comparison 25 Hylan G-F 20 versus physical therapy, Outcome 5 SF-36 physical functioning.
Outcome: 5 SF-36 physical functioning
Mean Mean
Study or subgroup Synvisc Phys Therapy Difference Weight Difference
Atamaz 2005 20 57.2 (26.7) 20 53.7 (23.2) 100.0 % 3.50 [ -12.00, 19.00 ]
Subtotal (95% CI) 20 20 100.0 % 3.50 [ -12.00, 19.00 ]

Atamaz 2005 20 61.7 (17.7) 20 53.5 (22.9) 100.0 % 8.20 [ -4.48, 20.88 ]
Subtotal (95% CI) 20 20 100.0 % 8.20 [ -4.48, 20.88 ]

Atamaz 2005 20 55.7 (28.3) 20 54 (20.6) 100.0 % 1.70 [ -13.64, 17.04 ]
Subtotal (95% CI) 20 20 100.0 % 1.70 [ -13.64, 17.04 ]

Atamaz 2005 20 45 (21.4) 20 49.2 (20.8) 100.0 % -4.20 [ -17.28, 8.88 ]
Subtotal (95% CI) 20 20 100.0 % -4.20 [ -17.28, 8.88 ]

Atamaz 2005 20 54 (25.9) 20 53 (22.7) 100.0 % 1.00 [ -14.09, 16.09 ]
Subtotal (95% CI) 20 20 100.0 % 1.00 [ -14.09, 16.09 ]

-10 -5 0 5 10
Favours Phys therapy Favours Synvisc

Analysis 26.1. Comparison 26 (Hylan G-F 20 + physiotherapy) versus physiotherapy, Outcome 1 Lequesne
Index (0-24).
Comparison: 26 (Hylan G-F 20 + physiotherapy) versus physiotherapy
Mean Mean
Study or subgroup Hylan G-F 20+PT PT Difference Weight Difference
1 End of treatment
Bayramoglu 2003 12 8.6 (2.2) 9 9.3 (3.4) 100.0 % -0.70 [ -3.25, 1.85 ]
Subtotal (95% CI) 12 9 100.0 % -0.70 [ -3.25, 1.85 ]

Bayramoglu 2003 12 8.6 (2.5) 9 9.4 (4.3) 100.0 % -0.80 [ -3.95, 2.35 ]
Subtotal (95% CI) 12 9 100.0 % -0.80 [ -3.95, 2.35 ]

-10 -5 0 5 10
Favours HylanGF20+PT Favours PT

Analysis 26.2. Comparison 26 (Hylan G-F 20 + physiotherapy) versus physiotherapy, Outcome 2 Safety:
total withdrawls overall.
Outcome: 2 Safety: total withdrawls overall
Study or subgroup Hylan G-F 20+PT PT Risk Ratio Weight Risk Ratio
Bayramoglu 2003 3/15 6/15 100.0 % 0.50 [ 0.15, 1.64 ]
Subtotal (95% CI) 15 15 100.0 % 0.50 [ 0.15, 1.64 ]

Total events: 3 (Hylan G-F 20+PT), 6 (PT)
0.1 0.2 0.5 1 2 5 10

Analysis 26.3. Comparison 26 (Hylan G-F 20 + physiotherapy) versus physiotherapy, Outcome 3 Safety:
number of patients with adverse events.
Outcome: 3 Safety: number of patients with adverse events
Study or subgroup Hylan G-F 20+PT PT Risk Ratio Weight Risk Ratio
1 End of treatment
Bayramoglu 2003 0/12 0/9 Not estimable

Total events: 0 (Hylan G-F 20+PT), 0 (PT)
0.1 0.2 0.5 1 2 5 10


Analysis 27.1. Comparison 27 Hylan G-F 20 versus progressive knee exercises, Outcome 1 Pain during
activity.
Comparison: 27 Hylan G-F 20 versus progressive knee exercises
Outcome: 1 Pain during activity
Mean Mean
Study or subgroup Hylan G-F 20 Exercise Difference Weight Difference
Karatosun 2005 52 10.8 (4) 53 8.9 (4.9) 100.0 % 1.90 [ 0.19, 3.61 ]
Subtotal (95% CI) 52 53 100.0 % 1.90 [ 0.19, 3.61 ]

Karatosun 2005 52 10.8 (3.8) 53 9.1 (4.2) 100.0 % 1.70 [ 0.17, 3.23 ]
Subtotal (95% CI) 52 53 100.0 % 1.70 [ 0.17, 3.23 ]

Karatosun 2005 52 11.1 (3.9) 53 8.6 (4.7) 100.0 % 2.50 [ 0.85, 4.15 ]
Subtotal (95% CI) 52 53 100.0 % 2.50 [ 0.85, 4.15 ]

Karatosun 2005 46 8.5 (4.4) 53 10.2 (4.3) 100.0 % -1.70 [ -3.42, 0.02 ]
Subtotal (95% CI) 46 53 100.0 % -1.70 [ -3.42, 0.02 ]

Karatay 2005 31 12.9 (3.4) 53 12.1 (3.1) 100.0 % 0.80 [ -0.66, 2.26 ]
Subtotal (95% CI) 31 53 100.0 % 0.80 [ -0.66, 2.26 ]

-10 -5 0 5 10
Favours Exercise Favours Hylan G-F 20

Analysis 27.2. Comparison 27 Hylan G-F 20 versus progressive knee exercises, Outcome 2 Pain at rest.
Outcome: 2 Pain at rest
Mean Mean
Karatosun 2005 52 13.1 (3.1) 53 12.2 (3.9) 100.0 % 0.90 [ -0.45, 2.25 ]
Subtotal (95% CI) 52 53 100.0 % 0.90 [ -0.45, 2.25 ]

Karatosun 2005 52 12.7 (3.1) 53 12.7 (3.4) 100.0 % 0.0 [ -1.24, 1.24 ]
Subtotal (95% CI) 52 53 100.0 % 0.0 [ -1.24, 1.24 ]

Karatosun 2005 52 12.8 (2.9) 53 12.4 (4.1) 100.0 % 0.40 [ -0.96, 1.76 ]
Subtotal (95% CI) 52 53 100.0 % 0.40 [ -0.96, 1.76 ]

Karatosun 2005 46 11.7 (3.7) 53 12.9 (3.4) 100.0 % -1.20 [ -2.61, 0.21 ]
Subtotal (95% CI) 46 53 100.0 % -1.20 [ -2.61, 0.21 ]

Karatosun 2005 31 13.7 (2.5) 53 13.2 (3) 100.0 % 0.50 [ -0.69, 1.69 ]
Subtotal (95% CI) 31 53 100.0 % 0.50 [ -0.69, 1.69 ]

-10 -5 0 5 10

climbing stairs.
Outcome: 3 Pain during climbing stairs
Mean Mean
Karatosun 2005 52 3.2 (1.4) 53 3 (1.4) 100.0 % 0.20 [ -0.34, 0.74 ]
Subtotal (95% CI) 52 53 100.0 % 0.20 [ -0.34, 0.74 ]

Karatosun 2005 52 3.3 (1.4) 53 3.2 (1.4) 100.0 % 0.10 [ -0.44, 0.64 ]
Subtotal (95% CI) 52 53 100.0 % 0.10 [ -0.44, 0.64 ]

Karatosun 2005 52 3.2 (1.4) 53 3.2 (1.4) 100.0 % 0.0 [ -0.54, 0.54 ]
Subtotal (95% CI) 52 53 100.0 % 0.0 [ -0.54, 0.54 ]

Karatosun 2005 46 3.1 (1.4) 53 3.2 (1.4) 100.0 % -0.10 [ -0.65, 0.45 ]
Subtotal (95% CI) 46 53 100.0 % -0.10 [ -0.65, 0.45 ]

Karatosun 2005 31 3.9 (1.4) 53 3.7 (1.4) 100.0 % 0.20 [ -0.42, 0.82 ]
Subtotal (95% CI) 31 53 100.0 % 0.20 [ -0.42, 0.82 ]

-10 -5 0 5 10

transfer activity.
Outcome: 4 Pain during transfer activity
Mean Mean
Karatosun 2005 52 4 (1.4) 53 4.3 (1.2) 100.0 % -0.30 [ -0.80, 0.20 ]
Subtotal (95% CI) 52 53 100.0 % -0.30 [ -0.80, 0.20 ]

Karatosun 2005 52 4.2 (1.3) 53 4.4 (1.1) 100.0 % -0.20 [ -0.66, 0.26 ]
Subtotal (95% CI) 52 53 100.0 % -0.20 [ -0.66, 0.26 ]

Karatosun 2005 52 4.3 (1.2) 53 4.3 (1.2) 100.0 % 0.0 [ -0.46, 0.46 ]
Subtotal (95% CI) 52 53 100.0 % 0.0 [ -0.46, 0.46 ]

Karatosun 2005 46 4.1 (1.3) 53 4.6 (0.9) 100.0 % -0.50 [ -0.95, -0.05 ]
Subtotal (95% CI) 46 53 100.0 % -0.50 [ -0.95, -0.05 ]

Karatosun 2005 31 4.1 (1.3) 53 4.2 (1.3) 100.0 % -0.10 [ -0.68, 0.48 ]
Subtotal (95% CI) 31 53 100.0 % -0.10 [ -0.68, 0.48 ]

-10 -5 0 5 10

Analysis 27.5. Comparison 27 Hylan G-F 20 versus progressive knee exercises, Outcome 5 Walking distance.
Outcome: 5 Walking distance
Mean Mean
Karatosun 2005 52 10.2 (2) 53 9.3 (2.6) 100.0 % 0.90 [ 0.01, 1.79 ]
Subtotal (95% CI) 52 53 100.0 % 0.90 [ 0.01, 1.79 ]

Karatosun 2005 52 10.5 (1.5) 53 10.1 (2.3) 100.0 % 0.40 [ -0.34, 1.14 ]
Subtotal (95% CI) 52 53 100.0 % 0.40 [ -0.34, 1.14 ]

Karatosun 2005 52 10.4 (1.9) 53 9.7 (2.8) 100.0 % 0.70 [ -0.21, 1.61 ]
Subtotal (95% CI) 52 53 100.0 % 0.70 [ -0.21, 1.61 ]

Karatosun 2005 46 9.6 (2.7) 53 9.9 (2.4) 100.0 % -0.30 [ -1.31, 0.71 ]
Subtotal (95% CI) 46 53 100.0 % -0.30 [ -1.31, 0.71 ]

Karatosun 2005 31 10.4 (2.8) 53 10.3 (2.1) 100.0 % 0.10 [ -1.04, 1.24 ]
Subtotal (95% CI) 31 53 100.0 % 0.10 [ -1.04, 1.24 ]

-10 -5 0 5 10

Analysis 27.6. Comparison 27 Hylan G-F 20 versus progressive knee exercises, Outcome 6 Range of motion
(degrees).
Mean Mean
Karatosun 2005 52 116.3 (12.1) 53 117.1 (9.9) 100.0 % -0.80 [ -5.03, 3.43 ]
Subtotal (95% CI) 52 53 100.0 % -0.80 [ -5.03, 3.43 ]

Karatosun 2005 52 117.1 (11.8) 53 117.9 (9.1) 100.0 % -0.80 [ -4.84, 3.24 ]
Subtotal (95% CI) 52 53 100.0 % -0.80 [ -4.84, 3.24 ]

Karatosun 2005 52 117.8 (10.9) 53 117.8 (9.1) 100.0 % 0.0 [ -3.84, 3.84 ]
Subtotal (95% CI) 52 53 100.0 % 0.0 [ -3.84, 3.84 ]

Karatosun 2005 46 117.2 (10.8) 53 117.8 (9.1) 100.0 % -0.60 [ -4.57, 3.37 ]
Subtotal (95% CI) 46 53 100.0 % -0.60 [ -4.57, 3.37 ]

Karatosun 2005 31 118.6 (11.5) 53 117.9 (9.2) 100.0 % 0.70 [ -4.05, 5.45 ]
Subtotal (95% CI) 31 53 100.0 % 0.70 [ -4.05, 5.45 ]

-10 -5 0 5 10

Analysis 27.7. Comparison 27 Hylan G-F 20 versus progressive knee exercises, Outcome 7 Hospital for
Special Surgery Knee Score (100 points).
Outcome: 7 Hospital for Special Surgery Knee Score (100 points)
Mean Mean
Karatosun 2005 52 81.3 (10.8) 53 79.8 (13.1) 100.0 % 1.50 [ -3.09, 6.09 ]
Subtotal (95% CI) 52 53 100.0 % 1.50 [ -3.09, 6.09 ]

Karatosun 2005 52 82.2 (10) 53 81.52 (11.8) 100.0 % 0.68 [ -3.50, 4.86 ]
Subtotal (95% CI) 52 53 100.0 % 0.68 [ -3.50, 4.86 ]

Karatosun 2005 52 82.7 (9.8) 53 80 (13.4) 100.0 % 2.70 [ -1.78, 7.18 ]
Subtotal (95% CI) 52 53 100.0 % 2.70 [ -1.78, 7.18 ]

Karatosun 2005 46 78.8 (12.3) 53 82.76 (13) 100.0 % -3.96 [ -8.95, 1.03 ]
Subtotal (95% CI) 46 53 100.0 % -3.96 [ -8.95, 1.03 ]

Karatosun 2005 31 88.8 (11.1) 53 88.3 (9.1) 100.0 % 0.50 [ -4.11, 5.11 ]
Subtotal (95% CI) 31 53 100.0 % 0.50 [ -4.11, 5.11 ]

-10 -5 0 5 10

Analysis 27.8. Comparison 27 Hylan G-F 20 versus progressive knee exercises, Outcome 8 Safety: total
Study or subgroup Hylan G-F 20 Exercise Risk Ratio Weight Risk Ratio
Karatosun 2005 21/52 0/53 43.81 [ 2.72, 704.87 ]
0.01 0.1 1 10 100

Favours Hylan G-F 20 Favours Exercise
Analysis 28.1. Comparison 28 Hylan G-F 20 versus appropriate care, Outcome 1 WOMAC pain (0-20
Likert).
Comparison: 28 Hylan G-F 20 versus appropriate care
Mean Mean
Study or subgroup Synvisc+AC Appro Care Difference Weight Difference
Raynauld 2002 127 6.94 (3.97) 127 10.1 (4.24) 100.0 % -3.16 [ -4.17, -2.15 ]
Subtotal (95% CI) 127 127 100.0 % -3.16 [ -4.17, -2.15 ]

-10 -5 0 5 10
Favours Synvisc Favours Appro Care

Analysis 28.2. Comparison 28 Hylan G-F 20 versus appropriate care, Outcome 2 WOMAC pain (0-100 mm
VAS).
Mean Mean
Study or subgroup Hylan G-F 20 Convent Care Difference Weight Difference
Kahan 2003a 251 25.4 (19.6) 246 38.1 (22.5) 100.0 % -12.70 [ -16.41, -8.99 ]
Subtotal (95% CI) 251 246 100.0 % -12.70 [ -16.41, -8.99 ]

-100 -50 0 50 100

Favours Hylan G-F 20 Favours Convent Care
Analysis 28.3. Comparison 28 Hylan G-F 20 versus appropriate care, Outcome 3 Pain on walking (0-100
mm VAS).
Outcome: 3 Pain on walking (0-100 mm VAS)
Mean Mean
Kahan 2003a 253 23.8 (21.3) 253 35.9 (24) 100.0 % -12.10 [ -16.05, -8.15 ]
Subtotal (95% CI) 253 253 100.0 % -12.10 [ -16.05, -8.15 ]

-100 -50 0 50 100

Favours Hylan G-F 20 Favours Convent care

Analysis 28.4. Comparison 28 Hylan G-F 20 versus appropriate care, Outcome 4 WOMAC function (0-68
Likert).
Outcome: 4 WOMAC function (0-68 Likert)
Mean Mean
Study or subgroup Synvisc+AC Appro Care Difference Weight Difference
Raynauld 2002 124 24.26 (12.95) 107 33.87 (13.88) 100.0 % -9.61 [ -13.09, -6.13 ]
Subtotal (95% CI) 124 107 100.0 % -9.61 [ -13.09, -6.13 ]

-10 -5 0 5 10
Favours Synvisc Favours Appro Care

Analysis 28.5. Comparison 28 Hylan G-F 20 versus appropriate care, Outcome 5 WOMAC function (0-100
mm VAS).
Mean Mean
Kahan 2003a 251 27.1 (20.7) 247 40.3 (22.7) 100.0 % -13.20 [ -17.02, -9.38 ]
Subtotal (95% CI) 251 247 100.0 % -13.20 [ -17.02, -9.38 ]

-100 -50 0 50 100

Analysis 28.6. Comparison 28 Hylan G-F 20 versus appropriate care, Outcome 6 Lequesne Index (0-24).
Mean Mean
Kahan 2003a 253 7.5 (4.4) 253 9.7 (4.5) 100.0 % -2.20 [ -2.98, -1.42 ]
Subtotal (95% CI) 253 253 100.0 % -2.20 [ -2.98, -1.42 ]

-10 -5 0 5 10

Analysis 28.7. Comparison 28 Hylan G-F 20 versus appropriate care, Outcome 7 WOMAC total score (0-
100 mm VAS).
Outcome: 7 WOMAC total score (0-100 mm VAS)
Mean Mean
Kahan 2003a 250 26.5 (20) 245 39.7 (22.1) 100.0 % -13.20 [ -16.92, -9.48 ]
Subtotal (95% CI) 250 245 100.0 % -13.20 [ -16.92, -9.48 ]

-100 -50 0 50 100

Analysis 28.8. Comparison 28 Hylan G-F 20 versus appropriate care, Outcome 8 Patient global assessment
(number of patients improved in study knee).
Outcome: 8 Patient global assessment (number of patients improved in study knee)
Study or subgroup Synvisc+AC Appro Care Risk Ratio Weight Risk Ratio
Raynauld 2002 93/127 35/128 2.68 [ 1.98, 3.62 ]
0.1 0.2 0.5 1 2 5 10

Favours Appro Care Favours Synvisc+AC

Analysis 28.9. Comparison 28 Hylan G-F 20 versus appropriate care, Outcome 9 Patient global evaluation
of effectiveness (good or satisfactory).
Outcome: 9 Patient global evaluation of effectiveness (good or satisfactory)
Study or subgroup Hylan G-F 20 Convent care Risk Ratio Weight Risk Ratio
Kahan 2003a 186/253 129/253 100.0 % 1.44 [ 1.25, 1.66 ]
Subtotal (95% CI) 253 253 100.0 % 1.44 [ 1.25, 1.66 ]

Total events: 186 (Hylan G-F 20), 129 (Convent care)
0.1 0.2 0.5 1 2 5 10

Favours Convent care Favours Hylan G-F20
Analysis 28.10. Comparison 28 Hylan G-F 20 versus appropriate care, Outcome 10 Number of responders
(20% decrease in pain on walking).
Outcome: 10 Number of responders (20% decrease in pain on walking)
Kahan 2003a 223/253 172/253 100.0 % 1.30 [ 1.18, 1.43 ]
Subtotal (95% CI) 253 253 100.0 % 1.30 [ 1.18, 1.43 ]

Total events: 223 (Hylan G-F 20), 172 (Convent care)
0.1 0.2 0.5 1 2 5 10

Favours Convent care Favours Hylan G-F 20

Analysis 28.11. Comparison 28 Hylan G-F 20 versus appropriate care, Outcome 11 Safety: total
M- M-
n/N n/N CI CI
Kahan 2003a 13/258 25/260 0.52 [ 0.27, 1.00 ]
Raynauld 2002 3/127 21/128 0.14 [ 0.04, 0.47 ]
0.1 0.2 0.5 1 2 5 10

Favours Hylan G-F 20 Favours convent care
Analysis 28.12. Comparison 28 Hylan G-F 20 versus appropriate care, Outcome 12 Safety: wIthdrawals due
to lack of effectiveness.
Outcome: 12 Safety: wIthdrawals due to lack of effectiveness
Kahan 2003a 6/253 17/253 0.35 [ 0.14, 0.88 ]
0.1 0.2 0.5 1 2 5 10


Analysis 28.13. Comparison 28 Hylan G-F 20 versus appropriate care, Outcome 13 Safety: wIthdrawals due
to adverse events.
Outcome: 13 Safety: wIthdrawals due to adverse events
Kahan 2003a 2/253 1/253 2.00 [ 0.18, 21.92 ]
0.1 0.2 0.5 1 2 5 10

Analysis 28.14. Comparison 28 Hylan G-F 20 versus appropriate care, Outcome 14 Safety: number of
patients reporting mild, moderate or severe side effects at month 12.
Outcome: 14 Safety: number of patients reporting mild, moderate or severe side effects at month 12
Study or subgroup Hylan G-F 20 +AC AC Risk Ratio Weight Risk Ratio
Raynauld 2002 64/124 73/107 0.76 [ 0.61, 0.94 ]
0.1 0.2 0.5 1 2 5 10

Favours HylanGF20+AC Favours AC

Analysis 28.15. Comparison 28 Hylan G-F 20 versus appropriate care, Outcome 15 Safety: total number of
patients reporting side effects from baseline.
Outcome: 15 Safety: total number of patients reporting side effects from baseline
Appro/Convent
Study or subgroup Hylan G-F 20 Care Risk Ratio Weight Risk Ratio
M- M-
n/N n/N CI CI
Kahan 2003a 114/258 83/260 1.38 [ 1.11, 1.73 ]
Raynauld 2002 48/127 76/128 0.64 [ 0.49, 0.83 ]
0.1 0.2 0.5 1 2 5 10

Favours hylanGF20 Favours Appro/ConCar
Analysis 28.16. Comparison 28 Hylan G-F 20 versus appropriate care, Outcome 16 Safety: number of
patients with gastrointestinal adverse events.
Outcome: 16 Safety: number of patients with gastrointestinal adverse events
Study or subgroup Hylan G-F 20 AC/CC Risk Ratio Weight Risk Ratio
Kahan 2003a 9/258 31/260 0.29 [ 0.14, 0.60 ]
Raynauld 2002 15/127 32/128 0.47 [ 0.27, 0.83 ]
0.1 0.2 0.5 1 2 5 10

Favours hylanGF20 Favours AC/CC

Analysis 29.1. Comparison 29 Hylan G-F 20 versus gaseous oxygen, Outcome 1 Pain under load (0-100 mm
VAS).
Comparison: 29 Hylan G-F 20 versus gaseous oxygen
Outcome: 1 Pain under load (0-100 mm VAS)
Mean Mean
Study or subgroup Hylan G-F 20 Oxygen Difference Weight Difference
1 End of treatment
Auerbach 2002 56 41.57 (30.62) 53 32.43 (29.93) 100.0 % 9.14 [ -2.23, 20.51 ]
Subtotal (95% CI) 56 53 100.0 % 9.14 [ -2.23, 20.51 ]

Auerbach 2002 56 43 (29.56) 53 30.17 (28.33) 100.0 % 12.83 [ 1.96, 23.70 ]
Subtotal (95% CI) 56 53 100.0 % 12.83 [ 1.96, 23.70 ]

Auerbach 2002 56 40.87 (29.41) 53 32.85 (28.82) 100.0 % 8.02 [ -2.91, 18.95 ]
Subtotal (95% CI) 56 53 100.0 % 8.02 [ -2.91, 18.95 ]

Auerbach 2002 56 35.23 (27.87) 53 28.71 (26.89) 100.0 % 6.52 [ -3.76, 16.80 ]
Subtotal (95% CI) 56 53 100.0 % 6.52 [ -3.76, 16.80 ]

-100 -50 0 50 100

Favours Hylan G-F 20 Favours Oxygen

Analysis 29.2. Comparison 29 Hylan G-F 20 versus gaseous oxygen, Outcome 2 Pain at rest (0-100 mm
VAS).
Mean Mean
1 End of treatment
Auerbach 2002 56 18.33 (24.8) 53 16.92 (24.42) 100.0 % 1.41 [ -7.83, 10.65 ]
Subtotal (95% CI) 56 53 100.0 % 1.41 [ -7.83, 10.65 ]

Auerbach 2002 56 21.33 (29.18) 53 14.43 (23.95) 100.0 % 6.90 [ -3.10, 16.90 ]
Subtotal (95% CI) 56 53 100.0 % 6.90 [ -3.10, 16.90 ]

Auerbach 2002 56 20.38 (30.8) 53 17.44 (27.9) 100.0 % 2.94 [ -8.08, 13.96 ]
Subtotal (95% CI) 56 53 100.0 % 2.94 [ -8.08, 13.96 ]

Auerbach 2002 56 14.52 (24.11) 53 14.43 (24.47) 100.0 % 0.09 [ -9.04, 9.22 ]
Subtotal (95% CI) 56 53 100.0 % 0.09 [ -9.04, 9.22 ]

-10 -5 0 5 10

Analysis 29.3. Comparison 29 Hylan G-F 20 versus gaseous oxygen, Outcome 3 WOMAC pain (0-20 Likert).
Mean Mean
1 End of treatment
Auerbach 2002 56 5.3 (3.7) 53 4 (4) 100.0 % 1.30 [ -0.15, 2.75 ]
Subtotal (95% CI) 56 53 100.0 % 1.30 [ -0.15, 2.75 ]

Auerbach 2002 56 5.7 (4.2) 53 4.3 (3.8) 100.0 % 1.40 [ -0.10, 2.90 ]
Subtotal (95% CI) 56 53 100.0 % 1.40 [ -0.10, 2.90 ]

Auerbach 2002 56 4.6 (4.8) 53 4 (3.9) 100.0 % 0.60 [ -1.04, 2.24 ]
Subtotal (95% CI) 56 53 100.0 % 0.60 [ -1.04, 2.24 ]

Auerbach 2002 56 4.5 (4.2) 53 3.7 (3.9) 100.0 % 0.80 [ -0.72, 2.32 ]
Subtotal (95% CI) 56 53 100.0 % 0.80 [ -0.72, 2.32 ]

-10 -5 0 5 10

Analysis 29.4. Comparison 29 Hylan G-F 20 versus gaseous oxygen, Outcome 4 WOMAC physical function
(0-68 Likert).
Outcome: 4 WOMAC physical function (0-68 Likert)
Mean Mean
1 End of treatment
Auerbach 2002 56 17.7 (13.5) 53 14.4 (13.8) 100.0 % 3.30 [ -1.83, 8.43 ]
Subtotal (95% CI) 56 53 100.0 % 3.30 [ -1.83, 8.43 ]

Auerbach 2002 56 16.6 (13.2) 53 13.8 (13.9) 100.0 % 2.80 [ -2.29, 7.89 ]
Subtotal (95% CI) 56 53 100.0 % 2.80 [ -2.29, 7.89 ]

Auerbach 2002 56 16.7 (16.3) 53 12.6 (13.5) 100.0 % 4.10 [ -1.51, 9.71 ]
Subtotal (95% CI) 56 53 100.0 % 4.10 [ -1.51, 9.71 ]

Auerbach 2002 56 15.1 (15.8) 53 11.1 (14.2) 100.0 % 4.00 [ -1.63, 9.63 ]
Subtotal (95% CI) 56 53 100.0 % 4.00 [ -1.63, 9.63 ]

-10 -5 0 5 10

Analysis 29.5. Comparison 29 Hylan G-F 20 versus gaseous oxygen, Outcome 5 WOMAC stiffness (0-8
Likert).
Mean Mean
1 End of treatment
Auerbach 2002 56 2.2 (1.8) 53 2 (2.1) 100.0 % 0.20 [ -0.54, 0.94 ]
Subtotal (95% CI) 56 53 100.0 % 0.20 [ -0.54, 0.94 ]

Auerbach 2002 56 2.3 (1.8) 53 1.8 (1.8) 100.0 % 0.50 [ -0.18, 1.18 ]
Subtotal (95% CI) 56 53 100.0 % 0.50 [ -0.18, 1.18 ]

Auerbach 2002 56 2.6 (2) 53 1.7 (1.8) 100.0 % 0.90 [ 0.19, 1.61 ]
Subtotal (95% CI) 56 53 100.0 % 0.90 [ 0.19, 1.61 ]

Auerbach 2002 56 2.2 (1.9) 53 1.7 (2.1) 100.0 % 0.50 [ -0.25, 1.25 ]
Subtotal (95% CI) 56 53 100.0 % 0.50 [ -0.25, 1.25 ]

-10 -5 0 5 10

Analysis 29.6. Comparison 29 Hylan G-F 20 versus gaseous oxygen, Outcome 6 Safety: total number of
withdrawals.
Outcome: 6 Safety: total number of withdrawals
Study or subgroup Hylan G-F 20 Oxygen Risk Ratio Weight Risk Ratio
Auerbach 2002 3/56 2/53 1.42 [ 0.25, 8.16 ]
0.1 0.2 0.5 1 2 5 10

Analysis 29.7. Comparison 29 Hylan G-F 20 versus gaseous oxygen, Outcome 7 Safety: number of patients
having total knee replacements.
Outcome: 7 Safety: number of patients having total knee replacements
Study or subgroup Hylan G-F 20 Oxygen Risk Ratio Weight Risk Ratio
Auerbach 2002 3/56 1/53 2.84 [ 0.30, 26.45 ]
0.1 0.2 0.5 1 2 5 10


Analysis 30.1. Comparison 30 Hylan G-F 20 versus hyaluronan (Also see Artzal, BioHy (Arthrease),
Hyalgan and Orthovisc versus Hylan G-F 20), Outcome 1 Pain on weight bearing (0-100 mm VAS).
Comparison: 30 Hylan G-F 20 versus hyaluronan (Also see Artzal, BioHy (Arthrease), Hyalgan and Orthovisc versus Hylan G-F 20)
Mean Mean
Study or subgroup Hylan G-F 20 HA Difference Weight Difference
Karlsson 2002c (AvS) 86 45 (25.67) 90 44 (24.4) 52.8 % 1.00 [ -6.41, 8.41 ]
Wobig 1999a (Healon) 38 40 (24.66) 39 48 (24.98) 23.6 % -8.00 [ -19.09, 3.09 ]
Wobig 1999b (Artz) 38 40 (24.66) 35 43 (23.66) 23.6 % -3.00 [ -14.09, 8.09 ]
Subtotal (95% CI) 162 164 100.0 % -2.06 [ -7.45, 3.32 ]

Karlsson 2002c (AvS) 86 41 (31.53) 90 42 (28.07) 44.1 % -1.00 [ -9.83, 7.83 ]
Wobig 1999a (Healon) 37 32 (24.33) 37 38 (24.33) 28.0 % -6.00 [ -17.09, 5.09 ]
Wobig 1999b (Artz) 37 32 (24.33) 35 48 (23.66) 28.0 % -16.00 [ -27.09, -4.91 ]
Subtotal (95% CI) 160 162 100.0 % -6.59 [ -12.46, -0.73 ]

Karlsson 2002c (AvS) 86 43 (33.78) 90 48 (33.78) 100.0 % -5.00 [ -14.98, 4.98 ]
Subtotal (95% CI) 86 90 100.0 % -5.00 [ -14.98, 4.98 ]

-100 -50 0 50 100

Favours Hylan G-F 20 Favours HA

Hyalgan and Orthovisc versus Hylan G-F 20), Outcome 2 Pain at night (0-100 mm VAS).
Mean Mean
Wobig 1999a (Healon) 38 12 (18.49) 39 22 (18.73) 58.1 % -10.00 [ -18.31, -1.69 ]
Wobig 1999b (Artz) 38 12 (18.49) 35 15 (23.66) 41.9 % -3.00 [ -12.80, 6.80 ]
Subtotal (95% CI) 76 74 100.0 % -7.07 [ -13.41, -0.73 ]

Wobig 1999a (Healon) 37 13 (24.33) 37 16 (24.33) 50.0 % -3.00 [ -14.09, 8.09 ]
Wobig 1999b (Artz) 37 13 (24.33) 35 17 (23.66) 50.0 % -4.00 [ -15.09, 7.09 ]
Subtotal (95% CI) 74 72 100.0 % -3.50 [ -11.34, 4.34 ]

-100 -50 0 50 100


Analysis 30.3. Comparison 30 Hylan G-F 20 versus hyaluronan (Also see Artzal, BioHy (Arthrease), Hyalgan
and Orthovisc versus Hylan G-F 20), Outcome 3 Function: improvement in knee movement (0-100 mm VAS).
Outcome: 3 Function: improvement in knee movement (0-100 mm VAS)
Mean Mean
Wobig 1999a (Healon) 38 45 (30.82) 39 45 (31.22) 50.0 % 0.0 [ -13.86, 13.86 ]
Wobig 1999b (Artz) 38 45 (30.82) 35 46 (29.58) 50.0 % -1.00 [ -14.86, 12.86 ]
Subtotal (95% CI) 76 74 100.0 % -0.50 [ -10.30, 9.30 ]

Wobig 1999a (Healon) 37 62 (30.41) 37 54 (30.41) 50.0 % 8.00 [ -5.86, 21.86 ]
Wobig 1999b (Artz) 37 62 (30.41) 35 45 (29.58) 50.0 % 17.00 [ 3.14, 30.86 ]
Subtotal (95% CI) 74 72 100.0 % 12.50 [ 2.70, 22.30 ]

-100 -50 0 50 100

Favours HA Favours Hylan G-F 20

Hyalgan and Orthovisc versus Hylan G-F 20), Outcome 4 Patient global evaluation of treatment efficacy
(improvement: 0-100 mm VAS).
Outcome: 4 Patient global evaluation of treatment efficacy (improvement: 0-100 mm VAS)
Mean Mean
Wobig 1999a (Healon) 38 53 (30.82) 39 54 (31.22) 50.0 % -1.00 [ -14.86, 12.86 ]
Wobig 1999b (Artz) 38 53 (30.82) 35 48 (29.58) 50.0 % 5.00 [ -8.86, 18.86 ]
Subtotal (95% CI) 76 74 100.0 % 2.00 [ -7.80, 11.80 ]

Wobig 1999a (Healon) 37 67 (30.41) 37 64 (30.41) 50.0 % 3.00 [ -10.86, 16.86 ]
Wobig 1999b (Artz) 37 67 (30.41) 35 51 (29.58) 50.0 % 16.00 [ 2.14, 29.86 ]
Subtotal (95% CI) 74 72 100.0 % 9.50 [ -0.30, 19.30 ]

-100 -50 0 50 100

Favours HA Favours Hylan G-F 20

Hyalgan and Orthovisc versus Hylan G-F 20), Outcome 5 Safety: total withdrawals overall.
Study or subgroup Hylan G-F 20 HA Risk Ratio Weight Risk Ratio

Wobig 1999a (Healon) 1/37 2/37 79.6 % 0.50 [ 0.05, 5.28 ]
Wobig 1999b (Artz) 1/37 0/35 20.4 % 2.84 [ 0.12, 67.53 ]
Subtotal (95% CI) 74 72 100.0 % 0.98 [ 0.17, 5.55 ]

Total events: 2 (Hylan G-F 20), 2 (HA)
0.1 0.2 0.5 1 2 5 10

Hyalgan and Orthovisc versus Hylan G-F 20), Outcome 6 Safety: number of patients with local reactions.
Study or subgroup Hylan G-F 20 HA Risk Ratio Weight Risk Ratio

Wobig 1999b (Artz) 2/37 1/35 67.3 % 1.89 [ 0.18, 19.95 ]
Wobig 1999c (NEhyl) 2/37 0/37 32.7 % 5.00 [ 0.25, 100.72 ]
Subtotal (95% CI) 74 72 100.0 % 2.91 [ 0.47, 17.86 ]

Total events: 4 (Hylan G-F 20), 1 (HA)
0.1 0.2 0.5 1 2 5 10


Analysis 31.1. Comparison 31 NRD-101 (Suvenyl) versus placebo (saline plus oral placebo), Outcome 1 Pain
(0-100 mm VAS) change between baseline and 45 to 52 weeks post-injection.
Comparison: 31 NRD-101 (Suvenyl) versus placebo (saline plus oral placebo)
Outcome: 1 Pain (0-100 mm VAS) change between baseline and 45 to 52 weeks post-injection
Mean Mean
Study or subgroup NRD-101 Saline+oral placebo Difference Weight Difference
Pham 2004 131 -33.5 (28.5) 43 -34.5 (27.4) 1.00 [ -8.53, 10.53 ]
-10 -5 0 5 10
Favours NRD-101 Favours saline+PL po

Analysis 31.2. Comparison 31 NRD-101 (Suvenyl) versus placebo (saline plus oral placebo), Outcome 2
Lequesne Index (0-100 modified scale) change between baseline and 45 to 52 weeks post-injection.
Outcome: 2 Lequesne Index (0-100 modified scale) change between baseline and 45 to 52 weeks post-injection
Mean Mean
Pham 2004 131 -20 (16.5) 43 -18.9 (16.9) -1.10 [ -6.89, 4.69 ]
-10 -5 0 5 10
Patient global assessment (0-100 mm VAS) change between baseline and 45 to 52 weeks post-injection.
Outcome: 3 Patient global assessment (0-100 mm VAS) change between baseline and 45 to 52 weeks post-injection
Mean Mean
Pham 2004 131 -29.7 (26.9) 43 -31.1 (31.7) 1.40 [ -9.14, 11.94 ]
-10 -5 0 5 10

Percentage of painful days (0-100 mm VAS) change between baseline and 45 to 52 weeks post-injection.
Outcome: 4 Percentage of painful days (0-100 mm VAS) change between baseline and 45 to 52 weeks post-injection
Mean Mean
Pham 2004 131 -43.5 (40.3) 43 -46.6 (37.2) 3.10 [ -9.99, 16.19 ]
-100 -50 0 50 100

Patient assessment of treatment efficacy (no. of patients rating very good or good versus mod, bad or very bad.
Outcome: 5 Patient assessment of treatment efficacy (no. of patients rating very good or good versus mod, bad or very bad
Study or subgroup NRD-101 Saline+oral placebo Risk Ratio Weight Risk Ratio
Pham 2004 86/120 57/75 0.94 [ 0.80, 1.12 ]
0.1 0.2 0.5 1 2 5 10


Joint space width (percentage of progressors: joint space narrowing greater than 0.5 mm).
Outcome: 6 Joint space width (percentage of progressors: joint space narrowing greater than 0.5 mm)
Study or subgroup NRD 101 Saline+oral placebo Risk Ratio Weight Risk Ratio
Pham 2003 23/131 17/85 0.88 [ 0.50, 1.54 ]
0.1 0.2 0.5 1 2 5 10

Pham 2004 9/131 5/85 1.17 [ 0.41, 3.37 ]
0.1 0.2 0.5 1 2 5 10


Safety: withdrawals due to inefficacy.
Pham 2004 1/131 2/85 0.32 [ 0.03, 3.52 ]
0.1 0.2 0.5 1 2 5 10

Safety: number of withdrawals due to adverse events.
Outcome: 9 Safety: number of withdrawals due to adverse events
Pham 2004 4/131 2/85 1.30 [ 0.24, 6.93 ]
0.1 0.2 0.5 1 2 5 10


Safety: number of patients reporting knee pain during or after IA injection.
Outcome: 10 Safety: number of patients reporting knee pain during or after IA injection
Pham 2004 31/131 16/85 1.26 [ 0.73, 2.15 ]
0.1 0.2 0.5 1 2 5 10

Safety: number of patients reporting diarrhoea.
Outcome: 11 Safety: number of patients reporting diarrhoea
Pham 2004 12/131 7/85 1.11 [ 0.46, 2.71 ]
0.1 0.2 0.5 1 2 5 10


Analysis 32.1. Comparison 32 NRD-101 (Suvenyl) versus Diacerein, Outcome 1 Pain (0-100 mm VAS)
change between baseline and 45 to 52 weeks post-injection.
Comparison: 32 NRD-101 (Suvenyl) versus Diacerein
Outcome: 1 Pain (0-100 mm VAS) change between baseline and 45 to 52 weeks post-injection
Mean Mean
Study or subgroup NRD-101 Diacerein Difference Weight Difference
Pham 2004 131 -33.5 (28.5) 85 -33.9 (25.7) 0.40 [ -6.93, 7.73 ]
-10 -5 0 5 10
Favours NRD-101 Favours Diacerein
Analysis 32.2. Comparison 32 NRD-101 (Suvenyl) versus Diacerein, Outcome 2 Lequesne Index (0-100
modified scale) change between baseline and 45 to 52 weeks post-injection.
Outcome: 2 Lequesne Index (0-100 modified scale) change between baseline and 45 to 52 weeks post-injection
Mean Mean
Pham 2004 131 -20 (16.5) 85 -18.8 (14.7) -1.20 [ -5.41, 3.01 ]
-10 -5 0 5 10

Analysis 32.3. Comparison 32 NRD-101 (Suvenyl) versus Diacerein, Outcome 3 Patient global assessment
Outcome: 3 Patient global assessment (0-100 mm VAS) change between baseline and 45 to 52 weeks post-injection
Mean Mean
Pham 2004 131 -29.7 (26.9) 85 -32.8 (24) 3.10 [ -3.77, 9.97 ]
-10 -5 0 5 10
Analysis 32.4. Comparison 32 NRD-101 (Suvenyl) versus Diacerein, Outcome 4 Percentage of painful days
Outcome: 4 Percentage of painful days (0-100 mm VAS) change between baseline and 45 to 52 weeks post-injection
Mean Mean
Pham 2004 131 -43.5 (40.3) 85 -45.6 (37.8) 2.10 [ -8.49, 12.69 ]
-10 -5 0 5 10

Analysis 32.5. Comparison 32 NRD-101 (Suvenyl) versus Diacerein, Outcome 5 Patient assessment of
treatment efficacy (no. of patients rating very good or good versus mod, bad or very bad.
Outcome: 5 Patient assessment of treatment efficacy (no. of patients rating very good or good versus mod, bad or very bad
Study or subgroup NRD-101 Diacerein Risk Ratio Weight Risk Ratio

Pham 2004 86/120 49/75 1.10 [ 0.90, 1.34 ]
0.1 0.2 0.5 1 2 5 10

Analysis 32.6. Comparison 32 NRD-101 (Suvenyl) versus Diacerein, Outcome 6 Joint space width
(percentage progressors: joint space narrowing greater than 0.5 mm).
Outcome: 6 Joint space width (percentage progressors: joint space narrowing greater than 0.5 mm)
Study or subgroup NRD 101 Diacerein Risk Ratio Weight Risk Ratio
Pham 2003 23/131 16/85 0.93 [ 0.52, 1.66 ]
0.1 0.2 0.5 1 2 5 10


Analysis 32.7. Comparison 32 NRD-101 (Suvenyl) versus Diacerein, Outcome 7 Safety: total withdrawals
overall.

Pham 2004 9/131 5/85 1.17 [ 0.41, 3.37 ]
0.1 0.2 0.5 1 2 5 10

Analysis 32.8. Comparison 32 NRD-101 (Suvenyl) versus Diacerein, Outcome 8 Safety: withdrawals due to
inefficacy.

Pham 2004 1/131 1/85 0.65 [ 0.04, 10.23 ]
0.1 0.2 0.5 1 2 5 10


Analysis 32.9. Comparison 32 NRD-101 (Suvenyl) versus Diacerein, Outcome 9 Safety: number of
withdrawlals due to adverse events.
Outcome: 9 Safety: number of withdrawlals due to adverse events

Pham 2004 4/131 2/85 1.30 [ 0.24, 6.93 ]
0.1 0.2 0.5 1 2 5 10

patients reporting knee pain during or after IA injection.
Outcome: 10 Safety: number of patients reporting knee pain during or after IA injection

Pham 2004 31/131 8/85 2.51 [ 1.21, 5.21 ]
0.1 0.2 0.5 1 2 5 10


patients reporting diarrhoea.
Outcome: 11 Safety: number of patients reporting diarrhoea

Pham 2004 12/131 35/85 0.22 [ 0.12, 0.40 ]
0.1 0.2 0.5 1 2 5 10

Analysis 33.1. Comparison 33 NRD-101 (Suvenyl) versus Artz (end of treatment), Outcome 1 Spontaneous
pain (number of patients improved).
Comparison: 33 NRD-101 (Suvenyl) versus Artz (end of treatment)
Outcome: 1 Spontaneous pain (number of patients improved)
Study or subgroup NRD-101 Artz Risk Ratio Weight Risk Ratio

Yamamoto 1994 48/67 43/70 1.17 [ 0.92, 1.48 ]
0.1 0.2 0.5 1 2 5 10

Favours Artz Favours NRD-101

Analysis 33.2. Comparison 33 NRD-101 (Suvenyl) versus Artz (end of treatment), Outcome 2 Pain during
the night (number of patients improved).
Outcome: 2 Pain during the night (number of patients improved)

Yamamoto 1994 39/54 39/53 0.98 [ 0.78, 1.24 ]
0.1 0.2 0.5 1 2 5 10

Analysis 33.3. Comparison 33 NRD-101 (Suvenyl) versus Artz (end of treatment), Outcome 3 Pressure pain
(number of patients improved).
Outcome: 3 Pressure pain (number of patients improved)

Yamamoto 1994 60/94 48/84 1.12 [ 0.88, 1.42 ]
0.1 0.2 0.5 1 2 5 10


Analysis 33.4. Comparison 33 NRD-101 (Suvenyl) versus Artz (end of treatment), Outcome 4 Passive
movement pain (number of patients improved).
Outcome: 4 Passive movement pain (number of patients improved)

Yamamoto 1994 31/53 57/86 0.88 [ 0.67, 1.16 ]
0.1 0.2 0.5 1 2 5 10

flexion (degrees).
Outcome: 5 Passive flexion (degrees)
Mean Mean
Study or subgroup NRD-101 Artz Difference Weight Difference
Yamamoto 1994 95 137.1 (11.6) 86 136.1 (13.8) 1.00 [ -2.73, 4.73 ]
-10 -5 0 5 10

extension (degrees).
Outcome: 6 Passive extension (degrees)
Mean Mean
Study or subgroup NRD-101 Artz Difference Weight Difference
Yamamoto 1994 95 4 (5.3) 86 4.2 (5.6) -0.20 [ -1.79, 1.39 ]
-10 -5 0 5 10
Analysis 33.7. Comparison 33 NRD-101 (Suvenyl) versus Artz (end of treatment), Outcome 7 Patient
global assessment.
Outcome: 7 Patient global assessment

Yamamoto 1994 50/81 43/72 1.03 [ 0.80, 1.33 ]
0.1 0.2 0.5 1 2 5 10

Favours NRD-101 Favours Artz

Analysis 33.8. Comparison 33 NRD-101 (Suvenyl) versus Artz (end of treatment), Outcome 8 Safety: total

Yamamoto 1994 6/100 15/101 0.40 [ 0.16, 1.00 ]
0.1 0.2 0.5 1 2 5 10

Analysis 33.9. Comparison 33 NRD-101 (Suvenyl) versus Artz (end of treatment), Outcome 9 Safety:
number of adverse events.
Outcome: 9 Safety: number of adverse events

Yamamoto 1994 2/100 3/99 0.66 [ 0.11, 3.87 ]
0.1 0.2 0.5 1 2 5 10


Analysis 34.1. Comparison 34 Orthovisc versus placebo, Outcome 1 WOMAC pain (5 to 25 Likert).
Comparison: 34 Orthovisc versus placebo
Outcome: 1 WOMAC pain (5 to 25 Likert)
Mean Mean
Study or subgroup Orthovisc Saline Difference Weight Difference
Hizmetli 1999 20 10.2 (3.9) 20 17.7 (4.8) 2.8 % -7.50 [ -10.21, -4.79 ]
Kotevoglu 2005 20 9.5 (3.1) 9 13.5 (3.4) 3.0 % -4.00 [ -6.60, -1.40 ]
Sezgin 2005 22 8.9 (0.7) 19 11.1 (0.8) 94.3 % -2.20 [ -2.66, -1.74 ]
Subtotal (95% CI) 62 48 100.0 % -2.40 [ -2.85, -1.95 ]

Hizmetli 1999 20 11.75 (3.1) 20 17.7 (3.1) 62.3 % -5.95 [ -7.87, -4.03 ]
Kotevoglu 2005 20 9.5 (3) 9 14 (3.2) 37.7 % -4.50 [ -6.97, -2.03 ]
Subtotal (95% CI) 40 29 100.0 % -5.40 [ -6.92, -3.89 ]

Hizmetli 1999 20 12.8 (3) 20 18.4 (2.9) 62.6 % -5.60 [ -7.43, -3.77 ]
Kotevoglu 2005 20 10 (2.8) 9 13 (3.1) 37.4 % -3.00 [ -5.37, -0.63 ]
Subtotal (95% CI) 40 29 100.0 % -4.63 [ -6.08, -3.18 ]

Hizmetli 1999 20 13.8 (2.4) 20 19.1 (3.1) 100.0 % -5.30 [ -7.02, -3.58 ]
Subtotal (95% CI) 20 20 100.0 % -5.30 [ -7.02, -3.58 ]

-10 -5 0 5 10
Favours Orthovisc Favours saline

Analysis 34.2. Comparison 34 Orthovisc versus placebo, Outcome 2 WOMAC pain (number of patients
who improved).
Outcome: 2 WOMAC pain (number of patients who improved)
Study or subgroup Orthovisc Saline Risk Ratio Weight Risk Ratio

Brandt 2001 61/66 60/69 1.06 [ 0.95, 1.19 ]
0.1 0.2 0.5 1 2 5 10

Analysis 34.3. Comparison 34 Orthovisc versus placebo, Outcome 3 WOMAC pain (number of patients
who achieved greater than 5 unit improvement (relative to baseline score)).
Outcome: 3 WOMAC pain (number of patients who achieved greater than 5 unit improvement (relative to baseline score))

Brandt 2001 38/66 28/69 100.0 % 1.42 [ 1.00, 2.02 ]
Subtotal (95% CI) 66 69 100.0 % 1.42 [ 1.00, 2.02 ]

Total events: 38 (Orthovisc), 28 (Saline)
0.1 0.2 0.5 1 2 5 10


Analysis 34.4. Comparison 34 Orthovisc versus placebo, Outcome 4 Number of patients with a 20%
improvement from baseline in WOMAC pain score.
Outcome: 4 Number of patients with a 20% improvement from baseline in WOMAC pain score
Study or subgroup Orthovisc 3 or 4 inj Arthrocentesis Risk Ratio Weight Risk Ratio
M- M-
n/N n/N CI CI
Neustadt 2005a -3inj 61/90 67/100 46.7 % 1.01 [ 0.83, 1.23 ]
Neustadt 2005b-4inj 89/104 67/100 53.3 % 1.28 [ 1.09, 1.50 ]
Subtotal (95% CI) 194 200 100.0 % 1.15 [ 0.91, 1.44 ]

Total events: 150 (Orthovisc 3 or 4 inj), 134 (Arthrocentesis)
Neustadt 2005a -3inj 59/90 62/100 46.5 % 1.06 [ 0.85, 1.31 ]
Neustadt 2005b-4inj 72/104 62/100 53.5 % 1.12 [ 0.91, 1.36 ]
Subtotal (95% CI) 194 200 100.0 % 1.09 [ 0.94, 1.26 ]

0.1 0.2 0.5 1 2 5 10

Favours Arthrocentes Favours Ortho 3/4inj

Neustadt 2005a -3inj 49/90 47/100 48.2 % 1.16 [ 0.87, 1.53 ]
Neustadt 2005b-4inj 70/104 47/100 51.8 % 1.43 [ 1.12, 1.83 ]
Subtotal (95% CI) 194 200 100.0 % 1.30 [ 1.08, 1.57 ]

Neustadt 2005a -3inj 45/90 45/100 48.2 % 1.11 [ 0.82, 1.50 ]
Neustadt 2005b-4inj 62/104 45/100 51.8 % 1.32 [ 1.01, 1.73 ]
Subtotal (95% CI) 194 200 100.0 % 1.22 [ 1.00, 1.49 ]

0.1 0.2 0.5 1 2 5 10


Neustadt 2005a -3inj 42/90 43/100 48.2 % 1.09 [ 0.79, 1.49 ]
Neustadt 2005b-4inj 60/104 43/100 51.8 % 1.34 [ 1.01, 1.77 ]
Subtotal (95% CI) 194 200 100.0 % 1.22 [ 0.99, 1.50 ]

Neustadt 2005a -3inj 38/90 39/100 48.2 % 1.08 [ 0.77, 1.53 ]
Neustadt 2005b-4inj 55/104 39/100 51.8 % 1.36 [ 1.00, 1.84 ]
Subtotal (95% CI) 194 200 100.0 % 1.22 [ 0.97, 1.54 ]

0.1 0.2 0.5 1 2 5 10


Analysis 34.7. Comparison 34 Orthovisc versus placebo, Outcome 7 WOMAC pain on standing (0 to 100
mm VAS; change from baseline).
Outcome: 7 WOMAC pain on standing (0 to 100 mm VAS; change from baseline)
Mean Mean
Study or subgroup Orthovisc 3 or 4 inj Arthrocentesis Difference Weight Difference
Neustadt 2005a -3inj 90 -25.4 (29.6) 50 -26.4 (28.1) 49.3 % 1.00 [ -8.90, 10.90 ]
Neustadt 2005b-4inj 104 -32.9 (30.6) 50 -26.4 (28.1) 50.7 % -6.50 [ -16.26, 3.26 ]
Subtotal (95% CI) 194 100 100.0 % -2.80 [ -9.76, 4.15 ]

Neustadt 2005a -3inj 90 -25.5 (30.2) 50 -24.6 (29.9) 49.4 % -0.90 [ -11.27, 9.47 ]
Neustadt 2005b-4inj 104 -29.5 (31.4) 50 -24.6 (29.9) 50.6 % -4.90 [ -15.15, 5.35 ]
Subtotal (95% CI) 194 100 100.0 % -2.92 [ -10.22, 4.37 ]

-100 -50 0 50 100

Favours Ortho 3/4inj Favours Arthrocentes

Analysis 34.8. Comparison 34 Orthovisc versus placebo, Outcome 8 WOMAC physical function (17 to 85
Likert).
Outcome: 8 WOMAC physical function (17 to 85 Likert)
Mean Mean
Hizmetli 1999 20 39.85 (11) 20 52.1 (16.2) 3.6 % -12.25 [ -20.83, -3.67 ]
Kotevoglu 2005 20 33 (10.1) 9 46 (12.1) 3.3 % -13.00 [ -22.06, -3.94 ]
Sezgin 2005 22 32.2 (2.6) 19 39 (2.9) 93.1 % -6.80 [ -8.50, -5.10 ]
Subtotal (95% CI) 62 48 100.0 % -7.20 [ -8.84, -5.56 ]

Hizmetli 1999 20 41.35 (10.4) 20 51.5 (13.8) 57.2 % -10.15 [ -17.72, -2.58 ]
Kotevoglu 2005 20 31.5 (10.5) 9 48 (11.4) 42.8 % -16.50 [ -25.25, -7.75 ]
Subtotal (95% CI) 40 29 100.0 % -12.87 [ -18.60, -7.14 ]

Hizmetli 1999 20 43.2 (10.5) 20 52.5 (14.1) 62.4 % -9.30 [ -17.00, -1.60 ]
Kotevoglu 2005 20 34.5 (10.4) 9 48 (13.5) 37.6 % -13.50 [ -23.43, -3.57 ]
Subtotal (95% CI) 40 29 100.0 % -10.88 [ -16.97, -4.79 ]

Hizmetli 1999 20 45.8 (11.1) 20 52.9 (15.4) 100.0 % -7.10 [ -15.42, 1.22 ]
Subtotal (95% CI) 20 20 100.0 % -7.10 [ -15.42, 1.22 ]

-100 -50 0 50 100


Analysis 34.9. Comparison 34 Orthovisc versus placebo, Outcome 9 Range of motion: flexion (degrees).
Outcome: 9 Range of motion: flexion (degrees)
Mean Mean
Sezgin 2005 22 125.2 (3) 19 121.2 (3.4) 100.0 % 4.00 [ 2.02, 5.98 ]
Subtotal (95% CI) 22 19 100.0 % 4.00 [ 2.02, 5.98 ]

-10 -5 0 5 10
Favours Saline Favours Orthovisc
Analysis 34.10. Comparison 34 Orthovisc versus placebo, Outcome 10 25 metre walking time (sec).
Outcome: 10 25 metre walking time (sec)
Mean Mean
Sezgin 2005 22 26.4 (1.2) 19 26 (1.4) 100.0 % 0.40 [ -0.40, 1.20 ]
Subtotal (95% CI) 22 19 100.0 % 0.40 [ -0.40, 1.20 ]

-10 -5 0 5 10

Analysis 34.11. Comparison 34 Orthovisc versus placebo, Outcome 11 Knee circumference (mm).
Outcome: 11 Knee circumference (mm)
Mean Mean
Sezgin 2005 22 40 (0.7) 19 40.3 (0.7) 100.0 % -0.30 [ -0.73, 0.13 ]
Subtotal (95% CI) 22 19 100.0 % -0.30 [ -0.73, 0.13 ]

-10 -5 0 5 10

Analysis 34.12. Comparison 34 Orthovisc versus placebo, Outcome 12 WOMAC stiffness (2 to 10 Likert).
Outcome: 12 WOMAC stiffness (2 to 10 Likert)
Mean Mean
Kotevoglu 2005 20 3.5 (1.3) 9 5.5 (1.3) 46.7 % -2.00 [ -3.02, -0.98 ]
Sezgin 2005 22 3.4 (0.3) 19 3.4 (0.3) 53.3 % 0.0 [ -0.18, 0.18 ]
Subtotal (95% CI) 42 28 100.0 % -0.93 [ -2.89, 1.02 ]

Kotevoglu 2005 20 3.5 (1.7) 9 5 (1.7) 100.0 % -1.50 [ -2.84, -0.16 ]
Subtotal (95% CI) 20 9 100.0 % -1.50 [ -2.84, -0.16 ]

Kotevoglu 2005 20 3.5 (1.1) 9 5 (1.7) 100.0 % -1.50 [ -2.71, -0.29 ]
Subtotal (95% CI) 20 9 100.0 % -1.50 [ -2.71, -0.29 ]

-10 -5 0 5 10
Favours Orthovisc Favours Saline

Analysis 34.13. Comparison 34 Orthovisc versus placebo, Outcome 13 WOMAC total score (0 to 100 mm
VAS; change from baseline).
Outcome: 13 WOMAC total score (0 to 100 mm VAS; change from baseline)
Mean Mean
Neustadt 2005a -3inj 107 -121.1 (123.2) 57 -125.8 (117.6) 48.8 % 4.70 [ -33.73, 43.13 ]
Neustadt 2005b-4inj 115 -145.5 (119.1) 57 -125.8 (117.6) 51.2 % -19.70 [ -57.19, 17.79 ]
Subtotal (95% CI) 222 114 100.0 % -7.80 [ -34.64, 19.04 ]

Neustadt 2005a -3inj 107 -108.4 (124.6) 57 -111.8 (117) 49.2 % 3.40 [ -35.07, 41.87 ]
Neustadt 2005b-4inj 115 -123.7 (123.4) 57 -111.8 (117) 50.8 % -11.90 [ -49.73, 25.93 ]
Subtotal (95% CI) 222 114 100.0 % -4.38 [ -31.35, 22.60 ]

-100 -50 0 50 100

Favours Ortho 3/4inj Favours arthrocente

Analysis 34.14. Comparison 34 Orthovisc versus placebo, Outcome 14 Patient global assessment (0 to 100
mm VAS; where 100 is worst severity).
Outcome: 14 Patient global assessment (0 to 100 mm VAS; where 100 is worst severity)
Mean Mean
Kotevoglu 2005 20 50 (13.5) 9 70 (18.1) 100.0 % -20.00 [ -33.22, -6.78 ]
Subtotal (95% CI) 20 9 100.0 % -20.00 [ -33.22, -6.78 ]

Kotevoglu 2005 20 50 (12.1) 9 70 (14.1) 100.0 % -20.00 [ -30.63, -9.37 ]
Subtotal (95% CI) 20 9 100.0 % -20.00 [ -30.63, -9.37 ]

Kotevoglu 2005 20 70 (16.1) 9 70 (16.3) 100.0 % 0.0 [ -12.77, 12.77 ]
Subtotal (95% CI) 20 9 100.0 % 0.0 [ -12.77, 12.77 ]

-100 -50 0 50 100


Analysis 34.15. Comparison 34 Orthovisc versus placebo, Outcome 15 Patient global assessment (0 to 100
Outcome: 15 Patient global assessment (0 to 100 mm VAS; change from baseline)
Mean Mean
Neustadt 2005a -3inj 107 -27.5 (30) 57 -28.2 (27) 48.7 % 0.70 [ -8.32, 9.72 ]
Neustadt 2005b-4inj 115 -36.3 (29.1) 57 -28.2 (27) 51.3 % -8.10 [ -16.90, 0.70 ]
Subtotal (95% CI) 222 114 100.0 % -3.81 [ -10.11, 2.49 ]

Neustadt 2005a -3inj 107 -26.1 (30.6) 57 -26.2 (27.5) 48.4 % 0.10 [ -9.10, 9.30 ]
Neustadt 2005b-4inj 115 -33.4 (29.1) 57 -26.2 (27.5) 51.6 % -7.20 [ -16.10, 1.70 ]
Subtotal (95% CI) 222 114 100.0 % -3.67 [ -10.07, 2.73 ]

-100 -50 0 50 100

Favours Ortho 3/4inj Favours arthrocentes

Analysis 34.16. Comparison 34 Orthovisc versus placebo, Outcome 16 Patient global assessment (number
patients rating treatment as effective or very effective).
Outcome: 16 Patient global assessment (number patients rating treatment as effective or very effective)

Guler 1996 11/15 5/15 100.0 % 2.20 [ 1.01, 4.79 ]
Subtotal (95% CI) 15 15 100.0 % 2.20 [ 1.01, 4.79 ]

Total events: 11 (Orthovisc), 5 (Saline)
0.1 0.2 0.5 1 2 5 10

Favours saline Favours Orthovisc

Analysis 34.17. Comparison 34 Orthovisc versus placebo, Outcome 17 Physician global assessment (0 to
100 mm VAS; where 100 is worst severity).
Outcome: 17 Physician global assessment (0 to 100 mm VAS; where 100 is worst severity)
Mean Mean
Kotevoglu 2005 20 70 (20.5) 9 70 (23.2) 100.0 % 0.0 [ -17.62, 17.62 ]
Subtotal (95% CI) 20 9 100.0 % 0.0 [ -17.62, 17.62 ]

Kotevoglu 2005 20 70 (20.5) 9 70 (21.5) 100.0 % 0.0 [ -16.67, 16.67 ]
Subtotal (95% CI) 20 9 100.0 % 0.0 [ -16.67, 16.67 ]

Kotevoglu 2005 20 60 (18.2) 9 70 (22.1) 100.0 % -10.00 [ -26.50, 6.50 ]
Subtotal (95% CI) 20 9 100.0 % -10.00 [ -26.50, 6.50 ]

-100 -50 0 50 100


Analysis 34.18. Comparison 34 Orthovisc versus placebo, Outcome 18 Physician global assessment (0 to
100 VAS; change from baseline).
Outcome: 18 Physician global assessment (0 to 100 VAS; change from baseline)
Mean Mean
Neustadt 2005a -3inj 107 -23 (23.2) 57 -20 (23.4) 49.2 % -3.00 [ -10.50, 4.50 ]
Neustadt 2005b-4inj 115 -25.4 (22.9) 57 -20 (23.4) 50.8 % -5.40 [ -12.78, 1.98 ]
Subtotal (95% CI) 222 114 100.0 % -4.22 [ -9.48, 1.04 ]

Neustadt 2005a -3inj 107 -18.3 (26.3) 57 -16 (21.8) 47.6 % -2.30 [ -9.84, 5.24 ]
Neustadt 2005b-4inj 115 -21.7 (24.2) 57 -16 (21.8) 52.4 % -5.70 [ -12.88, 1.48 ]
Subtotal (95% CI) 222 114 100.0 % -4.08 [ -9.28, 1.12 ]

-100 -50 0 50 100

Favours Ortho 3/4inj Favours arthrocentes

Analysis 34.19. Comparison 34 Orthovisc versus placebo, Outcome 19 Synovial fluid effusion volume (ml).
Outcome: 19 Synovial fluid effusion volume (ml)
Mean Mean
Sezgin 2005 22 7.6 (2.6) 19 11.6 (2.8) 100.0 % -4.00 [ -5.66, -2.34 ]
Subtotal (95% CI) 22 19 100.0 % -4.00 [ -5.66, -2.34 ]

-10 -5 0 5 10
Analysis 34.20. Comparison 34 Orthovisc versus placebo, Outcome 20 Interleukin 6 level in the synovial
fluid (pg/ml).
Outcome: 20 Interleukin 6 level in the synovial fluid (pg/ml)
Mean Mean
Sezgin 2005 22 22.3 (3.4) 19 34.2 (3.7) 100.0 % -11.90 [ -14.09, -9.71 ]
Subtotal (95% CI) 22 19 100.0 % -11.90 [ -14.09, -9.71 ]

-100 -50 0 50 100


Analysis 34.21. Comparison 34 Orthovisc versus placebo, Outcome 21 Interleukin 8 level in the synovial
fluid (pg/ml).
Outcome: 21 Interleukin 8 level in the synovial fluid (pg/ml)
Mean Mean
Sezgin 2005 22 17 (2.8) 21 21.8 (3) 100.0 % -4.80 [ -6.54, -3.06 ]
Subtotal (95% CI) 22 21 100.0 % -4.80 [ -6.54, -3.06 ]

-10 -5 0 5 10
Analysis 34.22. Comparison 34 Orthovisc versus placebo, Outcome 22 Tumor necrosis factor alpha levels in
synovial fluid.
Outcome: 22 Tumor necrosis factor alpha levels in synovial fluid
Mean Mean
Sezgin 2005 22 58.7 (19.1) 19 68 (20.6) 100.0 % -9.30 [ -21.53, 2.93 ]
Subtotal (95% CI) 22 19 100.0 % -9.30 [ -21.53, 2.93 ]

-10 -5 0 5 10

Analysis 34.23. Comparison 34 Orthovisc versus placebo, Outcome 23 Safety: total withdrawals overall.
Study or subgroup Orthovisc Saline/arthrocentesi Risk Ratio Weight Risk Ratio

Brandt 2001 23/114 28/112 0.81 [ 0.50, 1.31 ]
Kotevoglu 2005 6/26 8/26 0.75 [ 0.30, 1.86 ]
Neustadt 2005a -3inj 44/120 35/124 1.30 [ 0.90, 1.87 ]
Neustadt 2005b-4inj 35/128 35/124 0.97 [ 0.65, 1.44 ]
Sezgin 2005 0/22 0/19 Not estimable
0.1 0.2 0.5 1 2 5 10

Favours Orthovisc Favours saline/arthr

Analysis 34.24. Comparison 34 Orthovisc versus placebo, Outcome 24 Safety: withdrawals due to lack of
efficacy.
Study or subgroup Orthovisc Saline/Arthrocentesi Risk Ratio Weight Risk Ratio

Brandt 2001 13/114 15/112 0.85 [ 0.42, 1.71 ]
Neustadt 2005a -3inj 8/119 15/123 0.55 [ 0.24, 1.25 ]
Neustadt 2005b-4inj 9/128 15/123 0.58 [ 0.26, 1.27 ]
0.1 0.2 0.5 1 2 5 10

Favours Orthovisc Favours Saline/Arthr
Analysis 34.25. Comparison 34 Orthovisc versus placebo, Outcome 25 Safety: number of patients with

Brandt 2001 9/114 11/112 0.80 [ 0.35, 1.86 ]
0.1 0.2 0.5 1 2 5 10


Analysis 34.26. Comparison 34 Orthovisc versus placebo, Outcome 26 Safety: number of patients
withdrawn due to noncompliance.
Outcome: 26 Safety: number of patients withdrawn due to noncompliance

Kotevoglu 2005 1/26 2/26 0.50 [ 0.05, 5.18 ]
0.1 0.2 0.5 1 2 5 10

reported musculoskeletal adverse events.
Outcome: 27 Safety: number of patients with reported musculoskeletal adverse events
Study or subgroup Orthovisc Saline/Arthro Risk Ratio Weight Risk Ratio

Brandt 2001 34/114 39/112 0.86 [ 0.59, 1.25 ]
Neustadt 2005a -3inj 23/119 21/123 1.13 [ 0.66, 1.93 ]
Neustadt 2005b-4inj 35/128 21/123 1.60 [ 0.99, 2.59 ]
0.1 0.2 0.5 1 2 5 10


general body adverse events.
Outcome: 28 Safety: number of patients with general body adverse events

Brandt 2001 21/114 23/112 0.90 [ 0.53, 1.53 ]
Neustadt 2005a -3inj 13/119 9/123 1.49 [ 0.66, 3.36 ]
Neustadt 2005b-4inj 8/128 9/123 0.85 [ 0.34, 2.14 ]
0.1 0.2 0.5 1 2 5 10

Analysis 34.29. Comparison 34 Orthovisc versus placebo, Outcome 29 Safety: number of patients with local
skin rash.
Outcome: 29 Safety: number of patients with local skin rash

Brandt 2001 5/114 6/112 0.82 [ 0.26, 2.61 ]
Neustadt 2005a -3inj 1/119 4/123 0.26 [ 0.03, 2.28 ]
Neustadt 2005b-4inj 3/128 4/123 0.72 [ 0.16, 3.15 ]
0.1 0.2 0.5 1 2 5 10


Analysis 34.30. Comparison 34 Orthovisc versus placebo, Outcome 30 Safety: number patients with
Outcome: 30 Safety: number patients with gastrointestinal complaints

Brandt 2001 11/114 16/112 0.68 [ 0.33, 1.39 ]
Neustadt 2005a -3inj 11/119 10/123 1.14 [ 0.50, 2.58 ]
Neustadt 2005b-4inj 10/128 10/123 0.96 [ 0.41, 2.23 ]
0.1 0.2 0.5 1 2 5 10

reported respiratory adverse events.
Outcome: 31 Safety: number of patients with reported respiratory adverse events

Brandt 2001 26/114 18/112 1.42 [ 0.83, 2.44 ]
Neustadt 2005a -3inj 4/119 5/123 0.83 [ 0.23, 3.01 ]
Neustadt 2005b-4inj 5/128 5/123 0.96 [ 0.29, 3.24 ]
0.1 0.2 0.5 1 2 5 10


nervous system adverse events.
Outcome: 32 Safety: number of patients with nervous system adverse events

Brandt 2001 15/114 16/112 0.92 [ 0.48, 1.77 ]
Neustadt 2005a -3inj 18/119 26/123 0.72 [ 0.41, 1.23 ]
Neustadt 2005b-4inj 20/128 26/123 0.74 [ 0.44, 1.25 ]
0.1 0.2 0.5 1 2 5 10

urinary adverse events.
Outcome: 33 Safety: number of patients with urinary adverse events

Brandt 2001 6/114 9/112 0.65 [ 0.24, 1.78 ]
0.1 0.2 0.5 1 2 5 10


Analysis 34.34. Comparison 34 Orthovisc versus placebo, Outcome 34 Safety: number of patients
withdrawn due to local adverse events.
Outcome: 34 Safety: number of patients withdrawn due to local adverse events

Kotevoglu 2005 1/26 0/26 3.00 [ 0.13, 70.42 ]
0.1 0.2 0.5 1 2 5 10

Analysis 35.1. Comparison 35 Orthovisc versus betamethasone, Outcome 1 WOMAC function (0-100 mm
VAS).
Comparison: 35 Orthovisc versus betamethasone
Mean Mean
Study or subgroup Orthovisc Betamethasone Difference Weight Difference
Tekeoglu 1998 20 34.3 (8.8) 20 31.3 (8.6) 100.0 % 3.00 [ -2.39, 8.39 ]
Subtotal (95% CI) 20 20 100.0 % 3.00 [ -2.39, 8.39 ]

Tekeoglu 1998 20 30.9 (8.7) 20 39.9 (7.9) 100.0 % -9.00 [ -14.15, -3.85 ]
Subtotal (95% CI) 20 20 100.0 % -9.00 [ -14.15, -3.85 ]

-10 -5 0 5 10
Favours Orthovisc Favours Betamethason

Analysis 35.2. Comparison 35 Orthovisc versus betamethasone, Outcome 2 Flexion (degrees).
Mean Mean
Study or subgroup Orthovisc Betamethasone Difference Weight Difference
Tekeoglu 1998 20 117.3 (19.2) 20 122.2 (11.4) 100.0 % -4.90 [ -14.69, 4.89 ]
Subtotal (95% CI) 20 20 100.0 % -4.90 [ -14.69, 4.89 ]

Tekeoglu 1998 20 121.2 (16.3) 20 128.25 (10.2) 100.0 % -7.05 [ -15.48, 1.38 ]
Subtotal (95% CI) 20 20 100.0 % -7.05 [ -15.48, 1.38 ]

-10 -5 0 5 10
Favours Betamethason Favours Orthovisc

Analysis 35.3. Comparison 35 Orthovisc versus betamethasone, Outcome 3 Patient global assessment
(number of patients good or very good).
Outcome: 3 Patient global assessment (number of patients good or very good)
Study or subgroup Orthovisc Betamethasone Risk Ratio Weight Risk Ratio

Tekeoglu 1998 10/20 12/20 100.0 % 0.83 [ 0.47, 1.47 ]
Subtotal (95% CI) 20 20 100.0 % 0.83 [ 0.47, 1.47 ]

Total events: 10 (Orthovisc), 12 (Betamethasone)
Tekeoglu 1998 15/20 8/20 100.0 % 1.88 [ 1.04, 3.39 ]
Subtotal (95% CI) 20 20 100.0 % 1.88 [ 1.04, 3.39 ]

Total events: 15 (Orthovisc), 8 (Betamethasone)
0.1 0.2 0.5 1 2 5 10

Favours Betamethason Favours Orthovisc
Analysis 35.4. Comparison 35 Orthovisc versus betamethasone, Outcome 4 Safety: total withdrawals
overall.

Tekeoglu 1998 0/20 0/20 Not estimable
0.1 0.2 0.5 1 2 5 10


Analysis 35.5. Comparison 35 Orthovisc versus betamethasone, Outcome 5 Safety: number of patients
withdrawn due to adverse events.

0.1 0.2 0.5 1 2 5 10

with local adverse events.
Outcome: 6 Safety: number of patients with local adverse events

0.1 0.2 0.5 1 2 5 10

Favours Orthovisc Favours betamethason

with systemic adverse events.
Outcome: 7 Safety: number of patients with systemic adverse events

0.1 0.2 0.5 1 2 5 10

Analysis 36.1. Comparison 36 Orthovisc versus 6-methylprednisolone acetate, Outcome 1 Pain on weight
bearing (0-100 mm VAS).
Comparison: 36 Orthovisc versus 6-methylprednisolone acetate
Mean Mean
Study or subgroup Orthovisc 6-MPA Difference Weight Difference
Tascioglu 2003 28 31.83 (21.57) 27 26.8 (15.83) 100.0 % 5.03 [ -4.94, 15.00 ]
Subtotal (95% CI) 28 27 100.0 % 5.03 [ -4.94, 15.00 ]

Tascioglu 2003 28 22.86 (17.05) 27 38.5 (16.53) 100.0 % -15.64 [ -24.51, -6.77 ]
Subtotal (95% CI) 28 27 100.0 % -15.64 [ -24.51, -6.77 ]

Tascioglu 2003 28 40.96 (23.15) 27 56.36 (16.1) 100.0 % -15.40 [ -25.91, -4.89 ]
-100 -50 0 50 100

Favours Orthovisc Favours 6-MPA
(Continued . . . )

(. . . Continued)
Mean Mean
Subtotal (95% CI) 28 27 100.0 % -15.40 [ -25.91, -4.89 ]
-100 -50 0 50 100

Analysis 36.2. Comparison 36 Orthovisc versus 6-methylprednisolone acetate, Outcome 2 Pain at rest (0-
100 mm VAS).
Mean Mean
Tascioglu 2003 28 11.83 (11.47) 27 8.3 (9.76) 100.0 % 3.53 [ -2.09, 9.15 ]
Subtotal (95% CI) 28 27 100.0 % 3.53 [ -2.09, 9.15 ]

Tascioglu 2003 28 12 (10.15) 27 19.7 (11.72) 100.0 % -7.70 [ -13.50, -1.90 ]
Subtotal (95% CI) 28 27 100.0 % -7.70 [ -13.50, -1.90 ]

Tascioglu 2003 28 23.56 (10.11) 27 26.46 (14.3) 100.0 % -2.90 [ -9.47, 3.67 ]
Subtotal (95% CI) 28 27 100.0 % -2.90 [ -9.47, 3.67 ]

-10 -5 0 5 10

Analysis 36.3. Comparison 36 Orthovisc versus 6-methylprednisolone acetate, Outcome 3 Pain on walking
(0-100 mm VAS).
Outcome: 3 Pain on walking (0-100 mm VAS)
Mean Mean
Tascioglu 2003 28 37.6 (25) 27 38 (16.01) 100.0 % -0.40 [ -11.46, 10.66 ]
Subtotal (95% CI) 28 27 100.0 % -0.40 [ -11.46, 10.66 ]

Tascioglu 2003 28 32.03 (22.15) 27 50.46 (18.46) 100.0 % -18.43 [ -29.19, -7.67 ]
Subtotal (95% CI) 28 27 100.0 % -18.43 [ -29.19, -7.67 ]

Tascioglu 2003 28 51.16 (20.81) 27 66.06 (20.83) 100.0 % -14.90 [ -25.91, -3.89 ]
Subtotal (95% CI) 28 27 100.0 % -14.90 [ -25.91, -3.89 ]

-100 -50 0 50 100


Analysis 36.4. Comparison 36 Orthovisc versus 6-methylprednisolone acetate, Outcome 4 Lequesne Index
(0-24).
Mean Mean
Tascioglu 2003 28 7.86 (1.47) 27 7.96 (1.58) 100.0 % -0.10 [ -0.91, 0.71 ]
Subtotal (95% CI) 28 27 100.0 % -0.10 [ -0.91, 0.71 ]

Tascioglu 2003 28 7.66 (1.6) 27 9.06 (1.13) 100.0 % -1.40 [ -2.13, -0.67 ]
Subtotal (95% CI) 28 27 100.0 % -1.40 [ -2.13, -0.67 ]

Tascioglu 2003 28 8.46 (2.04) 27 9.6 (1.83) 100.0 % -1.14 [ -2.16, -0.12 ]
Subtotal (95% CI) 28 27 100.0 % -1.14 [ -2.16, -0.12 ]

-10 -5 0 5 10

Analysis 36.5. Comparison 36 Orthovisc versus 6-methylprednisolone acetate, Outcome 5 Flexion (active
range in degrees).
Outcome: 5 Flexion (active range in degrees)
Mean Mean
Tascioglu 2003 28 116.36 (7.79) 27 114.2 (9.98) 100.0 % 2.16 [ -2.58, 6.90 ]
Subtotal (95% CI) 28 27 100.0 % 2.16 [ -2.58, 6.90 ]

Tascioglu 2003 28 115.76 (7.72) 27 113.4 (8.1) 100.0 % 2.36 [ -1.82, 6.54 ]
Subtotal (95% CI) 28 27 100.0 % 2.36 [ -1.82, 6.54 ]

Tascioglu 2003 28 114.6 (8.19) 27 109.6 (9.91) 100.0 % 5.00 [ 0.19, 9.81 ]
Subtotal (95% CI) 28 27 100.0 % 5.00 [ 0.19, 9.81 ]

-10 -5 0 5 10
Favours 6-MPA Favours Orthovisc

Analysis 36.6. Comparison 36 Orthovisc versus 6-methylprednisolone acetate, Outcome 6 Safety: total
Study or subgroup Orthovisc 6-MPA Risk Ratio Weight Risk Ratio

Tascioglu 2003 2/30 3/30 0.67 [ 0.12, 3.71 ]
0.1 0.2 0.5 1 2 5 10

Analysis 36.7. Comparison 36 Orthovisc versus 6-methylprednisolone acetate, Outcome 7 Safety: number
of patients withdrawn due to increased pain.
Outcome: 7 Safety: number of patients withdrawn due to increased pain

Tascioglu 2003 1/30 1/30 1.00 [ 0.07, 15.26 ]
0.1 0.2 0.5 1 2 5 10


of patients reporting musculoskeletal adverse events.
Outcome: 8 Safety: number of patients reporting musculoskeletal adverse events

Tascioglu 2003 7/28 5/27 1.35 [ 0.49, 3.74 ]
0.1 0.2 0.5 1 2 5 10

of patients reporting skin adverse events.
Outcome: 9 Safety: number of patients reporting skin adverse events

Tascioglu 2003 2/28 1/27 1.93 [ 0.19, 20.05 ]
0.1 0.2 0.5 1 2 5 10


Analysis 36.10. Comparison 36 Orthovisc versus 6-methylprednisolone acetate, Outcome 10 Safety:
number of patients reporting gastrointestinal adverse events.
Outcome: 10 Safety: number of patients reporting gastrointestinal adverse events

Tascioglu 2003 3/28 2/27 1.45 [ 0.26, 7.99 ]
0.1 0.2 0.5 1 2 5 10


number of patients reporting general adverse events.
Outcome: 11 Safety: number of patients reporting general adverse events

Tascioglu 2003 4/28 5/27 0.77 [ 0.23, 2.57 ]
0.1 0.2 0.5 1 2 5 10


number of patients reporting knee pain after injection.
Outcome: 12 Safety: number of patients reporting knee pain after injection

Tascioglu 2003 6/28 5/27 1.16 [ 0.40, 3.35 ]
0.1 0.2 0.5 1 2 5 10

Analysis 37.1. Comparison 37 Orthovisc versus (Orthovisc plus triamcinolone acetonide), Outcome 1 Pain
(0-100 mm VAS).
Comparison: 37 Orthovisc versus (Orthovisc plus triamcinolone acetonide)
Outcome: 1 Pain (0-100 mm VAS)
Mean Mean
Study or subgroup Orthovisc OR+TA Difference Weight Difference
Ozturk 2005 24 53.5 (14.1) 16 40.5 (14.9) 100.0 % 13.00 [ 3.77, 22.23 ]
Subtotal (95% CI) 24 16 100.0 % 13.00 [ 3.77, 22.23 ]

Ozturk 2005 24 51.4 (14) 16 53.4 (15.3) 100.0 % -2.00 [ -11.36, 7.36 ]
Subtotal (95% CI) 24 16 100.0 % -2.00 [ -11.36, 7.36 ]

Ozturk 2005 24 54.8 (13.3) 16 49.8 (14.8) 100.0 % 5.00 [ -3.99, 13.99 ]
-100 -50 0 50 100

Favours Orthovisc Favours OR+TA
(Continued . . . )

(. . . Continued)
Mean Mean
Subtotal (95% CI) 24 16 100.0 % 5.00 [ -3.99, 13.99 ]
Ozturk 2005 24 61.5 (19.5) 16 59.5 (14.7) 100.0 % 2.00 [ -8.62, 12.62 ]
Subtotal (95% CI) 24 16 100.0 % 2.00 [ -8.62, 12.62 ]

Ozturk 2005 24 61.5 (19.8) 16 62.1 (15.6) 100.0 % -0.60 [ -11.61, 10.41 ]
Subtotal (95% CI) 24 16 100.0 % -0.60 [ -11.61, 10.41 ]

-100 -50 0 50 100


Analysis 37.2. Comparison 37 Orthovisc versus (Orthovisc plus triamcinolone acetonide), Outcome 2
WOMAC pain (0-20 Likert).
Mean Mean
Study or subgroup Orthovisc Orthovisc+TA Difference Weight Difference
Ozturk 2005 24 12.6 (4.1) 16 11.8 (3.7) 100.0 % 0.80 [ -1.64, 3.24 ]
Subtotal (95% CI) 24 16 100.0 % 0.80 [ -1.64, 3.24 ]

Ozturk 2005 24 13.1 (4.2) 16 14.2 (3.6) 100.0 % -1.10 [ -3.54, 1.34 ]
Subtotal (95% CI) 24 16 100.0 % -1.10 [ -3.54, 1.34 ]

Ozturk 2005 24 12.4 (3.4) 16 13.6 (5.3) 100.0 % -1.20 [ -4.13, 1.73 ]
Subtotal (95% CI) 24 16 100.0 % -1.20 [ -4.13, 1.73 ]

Ozturk 2005 24 13.3 (4.2) 16 13.4 (4.8) 100.0 % -0.10 [ -2.99, 2.79 ]
Subtotal (95% CI) 24 16 100.0 % -0.10 [ -2.99, 2.79 ]

Ozturk 2005 24 13.5 (4) 16 13.4 (5.5) 100.0 % 0.10 [ -3.03, 3.23 ]
Subtotal (95% CI) 24 16 100.0 % 0.10 [ -3.03, 3.23 ]

-10 -5 0 5 10

WOMAC physical function (0-68 Likert).
Outcome: 3 WOMAC physical function (0-68 Likert)
Mean Mean
Ozturk 2005 24 45.6 (13.3) 16 40.6 (13.3) 100.0 % 5.00 [ -3.41, 13.41 ]
Subtotal (95% CI) 24 16 100.0 % 5.00 [ -3.41, 13.41 ]

Ozturk 2005 24 47.3 (11) 16 40.5 (12.2) 100.0 % 6.80 [ -0.62, 14.22 ]
Subtotal (95% CI) 24 16 100.0 % 6.80 [ -0.62, 14.22 ]

Ozturk 2005 24 44.9 (10.9) 16 39.6 (11.9) 100.0 % 5.30 [ -1.98, 12.58 ]
Subtotal (95% CI) 24 16 100.0 % 5.30 [ -1.98, 12.58 ]

Ozturk 2005 24 44 (10.4) 16 39.7 (8.9) 100.0 % 4.30 [ -1.73, 10.33 ]
Subtotal (95% CI) 24 16 100.0 % 4.30 [ -1.73, 10.33 ]

Ozturk 2005 24 46 (11.3) 16 42.9 (12) 100.0 % 3.10 [ -4.32, 10.52 ]
Subtotal (95% CI) 24 16 100.0 % 3.10 [ -4.32, 10.52 ]

-10 -5 0 5 10

Analysis 37.4. Comparison 37 Orthovisc versus (Orthovisc plus triamcinolone acetonide), Outcome 4 50
foot walking time (seconds).
Outcome: 4 50 foot walking time (seconds)
Mean Mean
Ozturk 2005 24 22.3 (7) 16 22.2 (3) 100.0 % 0.10 [ -3.06, 3.26 ]
Subtotal (95% CI) 24 16 100.0 % 0.10 [ -3.06, 3.26 ]

Ozturk 2005 24 21.9 (7.6) 16 21.7 (2.9) 100.0 % 0.20 [ -3.16, 3.56 ]
Subtotal (95% CI) 24 16 100.0 % 0.20 [ -3.16, 3.56 ]

Ozturk 2005 24 22.3 (7) 16 22.5 (2.8) 100.0 % -0.20 [ -3.32, 2.92 ]
Subtotal (95% CI) 24 16 100.0 % -0.20 [ -3.32, 2.92 ]

Ozturk 2005 24 22.4 (2.3) 16 23.4 (3.5) 100.0 % -1.00 [ -2.95, 0.95 ]
Subtotal (95% CI) 24 16 100.0 % -1.00 [ -2.95, 0.95 ]

Ozturk 2005 24 22.4 (7.2) 16 22.6 (3.3) 100.0 % -0.20 [ -3.50, 3.10 ]
Subtotal (95% CI) 24 16 100.0 % -0.20 [ -3.50, 3.10 ]

-10 -5 0 5 10

Range of motion (degrees).
Mean Mean
Ozturk 2005 24 115.9 (13.7) 16 118.9 (10.6) 100.0 % -3.00 [ -10.55, 4.55 ]
Subtotal (95% CI) 24 16 100.0 % -3.00 [ -10.55, 4.55 ]

Ozturk 2005 24 115 (12.5) 16 119.9 (10.3) 100.0 % -4.90 [ -12.00, 2.20 ]
Subtotal (95% CI) 24 16 100.0 % -4.90 [ -12.00, 2.20 ]

Ozturk 2005 24 114.7 (13.4) 16 118.9 (10.6) 100.0 % -4.20 [ -11.66, 3.26 ]
Subtotal (95% CI) 24 16 100.0 % -4.20 [ -11.66, 3.26 ]

Ozturk 2005 24 113.5 (15.1) 16 117.8 (11.4) 100.0 % -4.30 [ -12.53, 3.93 ]
Subtotal (95% CI) 24 16 100.0 % -4.30 [ -12.53, 3.93 ]

Ozturk 2005 24 113.7 (15.6) 16 118.2 (10.2) 100.0 % -4.50 [ -12.50, 3.50 ]
Subtotal (95% CI) 24 16 100.0 % -4.50 [ -12.50, 3.50 ]

-10 -5 0 5 10
Favours OR+TA Favours Orthovisc

WOMAC stiffness (0-8 Likert).
Mean Mean
Ozturk 2005 24 3.9 (1.4) 16 3.1 (1.1) 100.0 % 0.80 [ 0.02, 1.58 ]
Subtotal (95% CI) 24 16 100.0 % 0.80 [ 0.02, 1.58 ]

Ozturk 2005 24 3.5 (1) 16 3.3 (1.4) 100.0 % 0.20 [ -0.59, 0.99 ]
Subtotal (95% CI) 24 16 100.0 % 0.20 [ -0.59, 0.99 ]

Ozturk 2005 24 3.6 (1) 16 3.2 (1) 100.0 % 0.40 [ -0.23, 1.03 ]
Subtotal (95% CI) 24 16 100.0 % 0.40 [ -0.23, 1.03 ]

Ozturk 2005 24 3.9 (1.3) 16 3.1 (0.9) 100.0 % 0.80 [ 0.12, 1.48 ]
Subtotal (95% CI) 24 16 100.0 % 0.80 [ 0.12, 1.48 ]

Ozturk 2005 24 3.9 (1.4) 16 3.1 (1) 100.0 % 0.80 [ 0.06, 1.54 ]
Subtotal (95% CI) 24 16 100.0 % 0.80 [ 0.06, 1.54 ]

-10 -5 0 5 10

WOMAC total score (0-96 Likert).
Outcome: 7 WOMAC total score (0-96 Likert)
Mean Mean
Ozturk 2005 24 62.3 (15.8) 16 55.5 (16.1) 100.0 % 6.80 [ -3.31, 16.91 ]
Subtotal (95% CI) 24 16 100.0 % 6.80 [ -3.31, 16.91 ]

Ozturk 2005 24 63.9 (14.2) 16 58 (15.5) 100.0 % 5.90 [ -3.58, 15.38 ]
Subtotal (95% CI) 24 16 100.0 % 5.90 [ -3.58, 15.38 ]

Ozturk 2005 24 60.9 (12.7) 16 56.4 (16) 100.0 % 4.50 [ -4.84, 13.84 ]
Subtotal (95% CI) 24 16 100.0 % 4.50 [ -4.84, 13.84 ]

Ozturk 2005 24 61.2 (13.3) 16 56.3 (11.9) 100.0 % 4.90 [ -2.99, 12.79 ]
Subtotal (95% CI) 24 16 100.0 % 4.90 [ -2.99, 12.79 ]

Ozturk 2005 24 63.4 (13.9) 16 59.5 (14.8) 100.0 % 3.90 [ -5.24, 13.04 ]
Subtotal (95% CI) 24 16 100.0 % 3.90 [ -5.24, 13.04 ]

-10 -5 0 5 10

Study or subgroup Orthovisc OR+TA Risk Ratio Weight Risk Ratio

Ozturk 2005 1/24 8/23 0.12 [ 0.02, 0.88 ]
0.1 0.2 0.5 1 2 5 10

Safety: withdrawals due to lack of efficacy.

Ozturk 2005 1/24 0/23 2.88 [ 0.12, 67.29 ]
0.1 0.2 0.5 1 2 5 10


Safety: number of patients reporting adverse events (local reactions).
Outcome: 10 Safety: number of patients reporting adverse events (local reactions)

Ozturk 2005 2/24 1/23 1.92 [ 0.19, 19.73 ]
0.1 0.2 0.5 1 2 5 10

Analysis 38.1. Comparison 38 Orthovisc versus (Orthovisc plus lidocaine trigger point injection)(1 week
post-injection), Outcome 1 Pain at rest (0 to 4 point scale).
Comparison: 38 Orthovisc versus (Orthovisc plus lidocaine trigger point injection)(1 week post-injection)
Outcome: 1 Pain at rest (0 to 4 point scale)
Mean Mean
Study or subgroup Orthovisc+lido Orthovisc Difference Weight Difference
Yentur 2003 17 0.52 (0.7) 16 2.25 (0.7) -1.73 [ -2.21, -1.25 ]
-10 -5 0 5 10
Favours Ortho+lidoca Favours lido

post-injection), Outcome 2 Pain/restrictions walking (0 to 4 point scale).
Outcome: 2 Pain/restrictions walking (0 to 4 point scale)
Mean Mean
Study or subgroup Orthovisc+lidocaine Orthovisc Difference Weight Difference
Yentur 2003 17 0.88 (0.6) 16 2 (0.8) -1.12 [ -1.60, -0.64 ]
-4 -2 0 2 4
Favours Ortho+lidoca Favours Orthovisc
post-injection), Outcome 3 Pain/restrictions going up or down stairs (0 to 4 point scale).
Outcome: 3 Pain/restrictions going up or down stairs (0 to 4 point scale)
Mean Mean
Study or subgroup Ortho+lidocaine Orthovisc Difference Weight Difference
Yentur 2003 17 0.88 (0.6) 16 2.37 (0.8) -1.49 [ -1.97, -1.01 ]
-4 -2 0 2 4

post-injection), Outcome 4 Range of motion (degrees).
Mean Mean
Study or subgroup Orthovisc+lidocaine Orthovisc Difference Weight Difference
Yentur 2003 17 124.4 (15) 16 116.8 (13) 7.60 [ -1.96, 17.16 ]
-100 -50 0 50 100

Favours Orthovisc Favours Ortho+lido
post-injection), Outcome 5 Safety: total withdrawals overall.
Study or subgroup Orthovisc+lidocaine Orthovisc Risk Ratio Weight Risk Ratio

Yentur 2003 0/17 1/17 0.33 [ 0.01, 7.65 ]
0.1 0.2 0.5 1 2 5 10


Analysis 39.1. Comparison 39 Orthovisc versus physical therapy, Outcome 1 Spontaneous pain (0-100 mm
VAS).
Comparison: 39 Orthovisc versus physical therapy
Mean Mean
Study or subgroup Orthovisc Physical therapy Difference Weight Difference
Atamaz 2005 20 42.9 (20.2) 20 43.5 (14.6) 100.0 % -0.60 [ -11.52, 10.32 ]
Subtotal (95% CI) 20 20 100.0 % -0.60 [ -11.52, 10.32 ]

Atamaz 2005 20 58.4 (20.6) 20 49.5 (15.5) 100.0 % 8.90 [ -2.40, 20.20 ]
Subtotal (95% CI) 20 20 100.0 % 8.90 [ -2.40, 20.20 ]

Atamaz 2005 20 66.2 (28.1) 20 48.5 (15.2) 100.0 % 17.70 [ 3.70, 31.70 ]
Subtotal (95% CI) 20 20 100.0 % 17.70 [ 3.70, 31.70 ]

Atamaz 2005 20 52.2 (23.1) 20 50.7 (17.3) 100.0 % 1.50 [ -11.15, 14.15 ]
Subtotal (95% CI) 20 20 100.0 % 1.50 [ -11.15, 14.15 ]

Atamaz 2005 20 56.7 (23) 20 59.5 (21.2) 100.0 % -2.80 [ -16.51, 10.91 ]
Subtotal (95% CI) 20 20 100.0 % -2.80 [ -16.51, 10.91 ]

-100 -50 0 50 100

Favours Orthovisc Favours therapy

Analysis 39.2. Comparison 39 Orthovisc versus physical therapy, Outcome 2 WOMAC pain.
Mean Mean
Study or subgroup Orthovisc Physical Therapy Difference Weight Difference
Atamaz 2005 20 9.3 (2.7) 20 11.3 (2.5) 100.0 % -2.00 [ -3.61, -0.39 ]
Subtotal (95% CI) 20 20 100.0 % -2.00 [ -3.61, -0.39 ]

Atamaz 2005 20 11.2 (2.4) 20 11.8 (2.6) 100.0 % -0.60 [ -2.15, 0.95 ]
Subtotal (95% CI) 20 20 100.0 % -0.60 [ -2.15, 0.95 ]

Atamaz 2005 20 11.9 (5.1) 20 11.3 (2.6) 100.0 % 0.60 [ -1.91, 3.11 ]
Subtotal (95% CI) 20 20 100.0 % 0.60 [ -1.91, 3.11 ]

Atamaz 2005 20 10.4 (3.8) 20 12.3 (3.2) 100.0 % -1.90 [ -4.08, 0.28 ]
Subtotal (95% CI) 20 20 100.0 % -1.90 [ -4.08, 0.28 ]

Atamaz 2005 20 11.2 (3.5) 20 15.5 (4.1) 100.0 % -4.30 [ -6.66, -1.94 ]
Subtotal (95% CI) 20 20 100.0 % -4.30 [ -6.66, -1.94 ]

-10 -5 0 5 10
Favours Orthovisc Favours physical the

Analysis 39.3. Comparison 39 Orthovisc versus physical therapy, Outcome 3 WOMAC physical function.
Mean Mean
Study or subgroup Orthovisc Physical Therapy Difference Weight Difference
Atamaz 2005 20 35.2 (11.5) 20 37.6 (12.7) 100.0 % -2.40 [ -9.91, 5.11 ]
Subtotal (95% CI) 20 20 100.0 % -2.40 [ -9.91, 5.11 ]

Atamaz 2005 20 36.2 (11.8) 20 38.9 (13.6) 100.0 % -2.70 [ -10.59, 5.19 ]
Subtotal (95% CI) 20 20 100.0 % -2.70 [ -10.59, 5.19 ]

Atamaz 2005 20 41.8 (13.3) 20 41.9 (15.4) 100.0 % -0.10 [ -9.02, 8.82 ]
Subtotal (95% CI) 20 20 100.0 % -0.10 [ -9.02, 8.82 ]

Atamaz 2005 20 39.6 (11.8) 20 38.2 (12) 100.0 % 1.40 [ -5.98, 8.78 ]
Subtotal (95% CI) 20 20 100.0 % 1.40 [ -5.98, 8.78 ]

Atamaz 2005 20 37.6 (13.6) 20 38.2 (12.6) 100.0 % -0.60 [ -8.73, 7.53 ]
Subtotal (95% CI) 20 20 100.0 % -0.60 [ -8.73, 7.53 ]

-10 -5 0 5 10
Favours Orthovisc Favours phys therapy

Analysis 39.4. Comparison 39 Orthovisc versus physical therapy, Outcome 4 SF-36 pain.
Mean Mean
Study or subgroup Orthovisc Phys therapy Difference Weight Difference
Atamaz 2005 20 47.5 (22.9) 20 59.1 (15.8) 100.0 % -11.60 [ -23.79, 0.59 ]
Subtotal (95% CI) 20 20 100.0 % -11.60 [ -23.79, 0.59 ]

Atamaz 2005 20 28 (17.3) 20 56.2 (17.5) 100.0 % -28.20 [ -38.98, -17.42 ]
Subtotal (95% CI) 20 20 100.0 % -28.20 [ -38.98, -17.42 ]

Atamaz 2005 20 35.9 (23.4) 20 54.6 (18.1) 100.0 % -18.70 [ -31.67, -5.73 ]
Subtotal (95% CI) 20 20 100.0 % -18.70 [ -31.67, -5.73 ]

Atamaz 2005 20 45.3 (15.1) 20 51.3 (16.4) 100.0 % -6.00 [ -15.77, 3.77 ]
Subtotal (95% CI) 20 20 100.0 % -6.00 [ -15.77, 3.77 ]

Atamaz 2005 20 37.7 (21.7) 20 50.2 (18.6) 100.0 % -12.50 [ -25.03, 0.03 ]
Subtotal (95% CI) 20 20 100.0 % -12.50 [ -25.03, 0.03 ]

-100 -50 0 50 100

Favours Phys therapy Favours Orthovisc

Analysis 39.5. Comparison 39 Orthovisc versus physical therapy, Outcome 5 SF-36 physical functioning.
Mean Mean
Study or subgroup Orthovisc Phys Therapy Difference Weight Difference
Atamaz 2005 20 54.2 (15.5) 20 53.7 (23.2) 100.0 % 0.50 [ -11.73, 12.73 ]
Subtotal (95% CI) 20 20 100.0 % 0.50 [ -11.73, 12.73 ]

Atamaz 2005 20 41.5 (11.6) 20 53.5 (22.9) 100.0 % -12.00 [ -23.25, -0.75 ]
Subtotal (95% CI) 20 20 100.0 % -12.00 [ -23.25, -0.75 ]

Atamaz 2005 20 44.5 (24.1) 20 54 (20.6) 100.0 % -9.50 [ -23.39, 4.39 ]
Subtotal (95% CI) 20 20 100.0 % -9.50 [ -23.39, 4.39 ]

Atamaz 2005 20 49.2 (16) 20 49.2 (20.8) 100.0 % 0.0 [ -11.50, 11.50 ]
Subtotal (95% CI) 20 20 100.0 % 0.0 [ -11.50, 11.50 ]

Atamaz 2005 20 31 (14.3) 20 53 (22.7) 100.0 % -22.00 [ -33.76, -10.24 ]
Subtotal (95% CI) 20 20 100.0 % -22.00 [ -33.76, -10.24 ]

-100 -50 0 50 100

Favours Phys Therapy Favours Orthovisc

Analysis 40.1. Comparison 40 (Orthovisc + physiotherapy) versus physiotherapy, Outcome 1 Activity pain
(0-100 mm VAS).
Comparison: 40 (Orthovisc + physiotherapy) versus physiotherapy
Outcome: 1 Activity pain (0-100 mm VAS)
Mean Mean
Study or subgroup Orthovisc+PT PT Difference Weight Difference
Kalay 1997 20 12.5 (9.3) 20 14.2 (8.5) 100.0 % -1.70 [ -7.22, 3.82 ]
Subtotal (95% CI) 20 20 100.0 % -1.70 [ -7.22, 3.82 ]

Kalay 1997 20 6.1 (8.2) 20 12.6 (9.3) 100.0 % -6.50 [ -11.93, -1.07 ]
Subtotal (95% CI) 20 20 100.0 % -6.50 [ -11.93, -1.07 ]

-10 -5 0 5 10
Favours Orthovisc+PT Favours PT

Analysis 40.2. Comparison 40 (Orthovisc + physiotherapy) versus physiotherapy, Outcome 2 Spontaneous
pain (0-100 mm VAS).
Mean Mean
Kalay 1997 20 5.8 (5.8) 20 5.4 (5.9) 100.0 % 0.40 [ -3.23, 4.03 ]
Subtotal (95% CI) 20 20 100.0 % 0.40 [ -3.23, 4.03 ]

Kalay 1997 20 1.7 (4.1) 20 5.8 (6.4) 100.0 % -4.10 [ -7.43, -0.77 ]
Subtotal (95% CI) 20 20 100.0 % -4.10 [ -7.43, -0.77 ]

-10 -5 0 5 10

Analysis 40.3. Comparison 40 (Orthovisc + physiotherapy) versus physiotherapy, Outcome 3 Night pain (0-
100 mm VAS).
Outcome: 3 Night pain (0-100 mm VAS)
Mean Mean
Kalay 1997 20 5.4 (6.9) 20 5.6 (6.5) 100.0 % -0.20 [ -4.35, 3.95 ]
Subtotal (95% CI) 20 20 100.0 % -0.20 [ -4.35, 3.95 ]

Kalay 1997 20 1.6 (4) 20 4.9 (7) 100.0 % -3.30 [ -6.83, 0.23 ]
Subtotal (95% CI) 20 20 100.0 % -3.30 [ -6.83, 0.23 ]

-10 -5 0 5 10

Analysis 40.4. Comparison 40 (Orthovisc + physiotherapy) versus physiotherapy, Outcome 4 Lequesne (0-
24).
Outcome: 4 Lequesne (0-24)
Mean Mean
1 End of treatment
Bayramoglu 2003 16 9.1 (3.4) 9 9.3 (3.4) 100.0 % -0.20 [ -2.98, 2.58 ]
Subtotal (95% CI) 16 9 100.0 % -0.20 [ -2.98, 2.58 ]

Bayramoglu 2003 16 7.6 (3.7) 9 9.4 (4.3) 100.0 % -1.80 [ -5.14, 1.54 ]
Subtotal (95% CI) 16 9 100.0 % -1.80 [ -5.14, 1.54 ]

-10 -5 0 5 10

Analysis 40.5. Comparison 40 (Orthovisc + physiotherapy) versus physiotherapy, Outcome 5 25 m walk
time (sec).
Outcome: 5 25 m walk time (sec)
Mean Mean
Kalay 1997 20 15.3 (3.39) 20 14.55 (2.48) 100.0 % 0.75 [ -1.09, 2.59 ]
Subtotal (95% CI) 20 20 100.0 % 0.75 [ -1.09, 2.59 ]

Kalay 1997 20 13.25 (2.79) 20 14.4 (2.64) 100.0 % -1.15 [ -2.83, 0.53 ]
Subtotal (95% CI) 20 20 100.0 % -1.15 [ -2.83, 0.53 ]

-10 -5 0 5 10

Analysis 40.6. Comparison 40 (Orthovisc + physiotherapy) versus physiotherapy, Outcome 6 Flexion
(degrees).
Mean Mean

Kalay 1997 20 130 (0) 20 129.75 (1.12) Not estimable

Kalay 1997 20 130 (0) 20 129.75 (1.12) Not estimable

Test for subgroup differences: Chi2 = 0.0, df = -1 (P = 0.0), I2 =0.0%
-10 -5 0 5 10

Analysis 40.7. Comparison 40 (Orthovisc + physiotherapy) versus physiotherapy, Outcome 7 Patient global
assessment (number of patients evaluating treatment as effective or very effective).
Outcome: 7 Patient global assessment (number of patients evaluating treatment as effective or very effective)
Study or subgroup Orthovisc+PT PT Risk Ratio Weight Risk Ratio

Kalay 1997 19/20 12/20 100.0 % 1.58 [ 1.09, 2.30 ]
Subtotal (95% CI) 20 20 100.0 % 1.58 [ 1.09, 2.30 ]

Total events: 19 (Orthovisc+PT), 12 (PT)
0.1 0.2 0.5 1 2 5 10

Favours PT Favours ORTHOVISC+PT
Analysis 40.8. Comparison 40 (Orthovisc + physiotherapy) versus physiotherapy, Outcome 8 Safety: total
Study or subgroup HA+PT PT Risk Ratio Weight Risk Ratio

Bayramoglu 2003 0/16 6/15 100.0 % 0.07 [ 0.00, 1.18 ]
Kalay 1997 0/20 0/20 Not estimable
Subtotal (95% CI) 36 35 100.0 % 0.07 [ 0.00, 1.18 ]

Total events: 0 (HA+PT), 6 (PT)
0.1 0.2 0.5 1 2 5 10

Favours HA+PT Favours PT

Analysis 40.9. Comparison 40 (Orthovisc + physiotherapy) versus physiotherapy, Outcome 9 Safety:
number of patients with local reactions.

1 End of treatment

Kalay 1997 2/20 0/20 100.0 % 5.00 [ 0.26, 98.00 ]
Subtotal (95% CI) 20 20 100.0 % 5.00 [ 0.26, 98.00 ]

0.1 0.2 0.5 1 2 5 10


number of patients withdrawn due to adverse events.

1 End of treatment


0.1 0.2 0.5 1 2 5 10


number of patients with systemic adverse events.
Outcome: 11 Safety: number of patients with systemic adverse events

1 End of treatment


0.1 0.2 0.5 1 2 5 10


Analysis 41.1. Comparison 41 (Orthovisc + physiotherapy) versus (Hylan G-F 20 + physiotherapy), Outcome
1 Lequesne Index (0-24).
Comparison: 41 (Orthovisc + physiotherapy) versus (Hylan G-F 20 + physiotherapy)
Mean Mean
Study or subgroup Orthovisc+PT Hylan G-F 20 + PT Difference Weight Difference
1 End of treatment
Bayramoglu 2003 16 9.1 (3.4) 12 8.6 (2.2) 100.0 % 0.50 [ -1.58, 2.58 ]
Subtotal (95% CI) 16 12 100.0 % 0.50 [ -1.58, 2.58 ]

Bayramoglu 2003 16 7.6 (3.7) 12 8.6 (2.5) 100.0 % -1.00 [ -3.30, 1.30 ]
Subtotal (95% CI) 16 12 100.0 % -1.00 [ -3.30, 1.30 ]

-10 -5 0 5 10
Favours Orthovisc+PT Favours G-F20+PT

Analysis 42.1. Comparison 42 Orthovisc versus hylan G-F 20, Outcome 1 WOMAC pain (0-20 or 5-25
Likert).
Comparison: 42 Orthovisc versus hylan G-F 20
Outcome: 1 WOMAC pain (0-20 or 5-25 Likert)
Std. Std.
Mean Mean
Study or subgroup Orthovisc Hylan G-F 20 Difference Weight Difference
Atamaz 2005 20 9.3 (2.7) 20 8.3 (3.4) 32.8 % 0.32 [ -0.30, 0.94 ]
Karatay 2004 20 6.4 (4.1) 20 6.2 (3.6) 33.2 % 0.05 [ -0.57, 0.67 ]
Kotevoglu 2005 20 9.5 (3.1) 21 10 (3.3) 34.0 % -0.15 [ -0.77, 0.46 ]
Subtotal (95% CI) 60 61 100.0 % 0.07 [ -0.29, 0.43 ]

Atamaz 2005 20 11.2 (2.4) 20 8.7 (3.8) 47.5 % 0.77 [ 0.13, 1.42 ]
Kotevoglu 2005 20 9.5 (3) 21 10 (3) 52.5 % -0.16 [ -0.78, 0.45 ]
Subtotal (95% CI) 40 41 100.0 % 0.28 [ -0.16, 0.73 ]

Atamaz 2005 20 11.9 (5.1) 20 10.4 (4.9) 49.1 % 0.29 [ -0.33, 0.92 ]
Kotevoglu 2005 20 10 (2.8) 21 10 (2.5) 50.9 % 0.0 [ -0.61, 0.61 ]
Subtotal (95% CI) 40 41 100.0 % 0.14 [ -0.29, 0.58 ]

Atamaz 2005 20 10.4 (3.8) 20 10.4 (2.6) 100.0 % 0.0 [ -0.62, 0.62 ]
Subtotal (95% CI) 20 20 100.0 % 0.0 [ -0.62, 0.62 ]

Atamaz 2005 20 11.2 (3.5) 20 10.2 (2.9) 100.0 % 0.30 [ -0.32, 0.93 ]
Subtotal (95% CI) 20 20 100.0 % 0.30 [ -0.32, 0.93 ]

-10 -5 0 5 10
Favours Orthovisc Favours Hylan G-F 20

Analysis 42.2. Comparison 42 Orthovisc versus hylan G-F 20, Outcome 2 Spontaneous pain (0-100 mm
VAS).
Mean Mean
Study or subgroup Orthovisc Synvisc Difference Weight Difference
Atamaz 2005 20 42.9 (20.2) 20 64 (18.4) 100.0 % -21.10 [ -33.08, -9.12 ]
Subtotal (95% CI) 20 20 100.0 % -21.10 [ -33.08, -9.12 ]

Atamaz 2005 20 58.4 (20.6) 20 45.5 (18.2) 100.0 % 12.90 [ 0.85, 24.95 ]
Subtotal (95% CI) 20 20 100.0 % 12.90 [ 0.85, 24.95 ]

Atamaz 2005 20 66.2 (28.1) 20 50.7 (18.3) 100.0 % 15.50 [ 0.80, 30.20 ]
Subtotal (95% CI) 20 20 100.0 % 15.50 [ 0.80, 30.20 ]

Atamaz 2005 20 52.2 (23.1) 20 51.7 (15.4) 100.0 % 0.50 [ -11.67, 12.67 ]
Subtotal (95% CI) 20 20 100.0 % 0.50 [ -11.67, 12.67 ]

Atamaz 2005 20 56.7 (23) 20 49 (13.3) 100.0 % 7.70 [ -3.94, 19.34 ]
Subtotal (95% CI) 20 20 100.0 % 7.70 [ -3.94, 19.34 ]

-100 -50 0 50 100

Favours Orthovisc Favours Synvisc

Analysis 42.3. Comparison 42 Orthovisc versus hylan G-F 20, Outcome 3 SF-36 pain.
Mean Mean
Atamaz 2005 20 47.5 (22.9) 20 59.4 (20.9) 100.0 % -11.90 [ -25.49, 1.69 ]
Subtotal (95% CI) 20 20 100.0 % -11.90 [ -25.49, 1.69 ]

Atamaz 2005 20 28 (17.3) 20 58.8 (21.9) 100.0 % -30.80 [ -43.03, -18.57 ]
Subtotal (95% CI) 20 20 100.0 % -30.80 [ -43.03, -18.57 ]

Atamaz 2005 20 35.9 (23.4) 20 55.7 (27.2) 100.0 % -19.80 [ -35.52, -4.08 ]
Subtotal (95% CI) 20 20 100.0 % -19.80 [ -35.52, -4.08 ]

Atamaz 2005 20 45.3 (15.1) 20 43.8 (14.5) 100.0 % 1.50 [ -7.67, 10.67 ]
Subtotal (95% CI) 20 20 100.0 % 1.50 [ -7.67, 10.67 ]

Atamaz 2005 20 37.7 (21.7) 20 46.7 (19.1) 100.0 % -9.00 [ -21.67, 3.67 ]
Subtotal (95% CI) 20 20 100.0 % -9.00 [ -21.67, 3.67 ]

-100 -50 0 50 100

Favours Synvisc Favours Orthovisc

Analysis 42.4. Comparison 42 Orthovisc versus hylan G-F 20, Outcome 4 Hospital for Special Surgery Knee
Score.
Outcome: 4 Hospital for Special Surgery Knee Score
Mean Mean
Karatosun 2005a 39 86.5 (9.5) 40 86.7 (7.8) 100.0 % -0.20 [ -4.04, 3.64 ]
Subtotal (95% CI) 39 40 100.0 % -0.20 [ -4.04, 3.64 ]

Karatosun 2005a 39 87.3 (9.9) 34 86.3 (7.7) 100.0 % 1.00 [ -3.04, 5.04 ]
Subtotal (95% CI) 39 34 100.0 % 1.00 [ -3.04, 5.04 ]

Karatosun 2005a 37 84.7 (10.3) 34 85.7 (9.7) 100.0 % -1.00 [ -5.65, 3.65 ]
Subtotal (95% CI) 37 34 100.0 % -1.00 [ -5.65, 3.65 ]

Karatosun 2005a 30 86.6 (10.6) 32 86.7 (13) 100.0 % -0.10 [ -5.99, 5.79 ]
Subtotal (95% CI) 30 32 100.0 % -0.10 [ -5.99, 5.79 ]

-10 -5 0 5 10
Favours Hylan G-F 20 Favours Orthovisc

Analysis 42.5. Comparison 42 Orthovisc versus hylan G-F 20, Outcome 5 Pain during activity (Hospital for
Special Surgery).
Outcome: 5 Pain during activity (Hospital for Special Surgery)
Mean Mean
Karatosun 2005a 39 11.2 (4.3) 40 11.2 (3.4) 100.0 % 0.0 [ -1.71, 1.71 ]
Subtotal (95% CI) 39 40 100.0 % 0.0 [ -1.71, 1.71 ]

Karatosun 2005a 39 11.3 (4.3) 34 10.3 (3.5) 100.0 % 1.00 [ -0.79, 2.79 ]
Subtotal (95% CI) 39 34 100.0 % 1.00 [ -0.79, 2.79 ]

Karatosun 2005a 37 10.5 (4.7) 34 10.6 (3.8) 100.0 % -0.10 [ -2.08, 1.88 ]
Subtotal (95% CI) 37 34 100.0 % -0.10 [ -2.08, 1.88 ]

Karatosun 2005a 30 10.8 (4.8) 32 11.1 (5.6) 100.0 % -0.30 [ -2.89, 2.29 ]
Subtotal (95% CI) 30 32 100.0 % -0.30 [ -2.89, 2.29 ]

-10 -5 0 5 10

Analysis 42.6. Comparison 42 Orthovisc versus hylan G-F 20, Outcome 6 Pain at rest (Hospital for Special
Surgery).
Outcome: 6 Pain at rest (Hospital for Special Surgery)
Mean Mean
Karatosun 2005a 39 14.1 (2.1) 40 13 (2.8) 100.0 % 1.10 [ 0.01, 2.19 ]
Subtotal (95% CI) 39 40 100.0 % 1.10 [ 0.01, 2.19 ]

Karatosun 2005a 39 13.4 (3.1) 34 13.2 (2.8) 100.0 % 0.20 [ -1.15, 1.55 ]
Subtotal (95% CI) 39 34 100.0 % 0.20 [ -1.15, 1.55 ]

Karatosun 2005a 37 13.2 (3.5) 34 13.5 (2.7) 100.0 % -0.30 [ -1.75, 1.15 ]
Subtotal (95% CI) 37 34 100.0 % -0.30 [ -1.75, 1.15 ]

Karatosun 2005a 30 13.4 (3) 32 13.1 (4.1) 100.0 % 0.30 [ -1.48, 2.08 ]
Subtotal (95% CI) 30 32 100.0 % 0.30 [ -1.48, 2.08 ]

-10 -5 0 5 10

Analysis 42.7. Comparison 42 Orthovisc versus hylan G-F 20, Outcome 7 Pain during climbing stairs
(Hospital for Special Surgery).
Outcome: 7 Pain during climbing stairs (Hospital for Special Surgery)
Mean Mean
Karatosun 2005a 39 3.5 (1.5) 40 3.5 (1.5) 100.0 % 0.0 [ -0.66, 0.66 ]
Subtotal (95% CI) 39 40 100.0 % 0.0 [ -0.66, 0.66 ]

Karatosun 2005a 39 3.5 (1.5) 34 3.6 (1.5) 100.0 % -0.10 [ -0.79, 0.59 ]
Subtotal (95% CI) 39 34 100.0 % -0.10 [ -0.79, 0.59 ]

Karatosun 2005a 37 3 (1.4) 34 3.1 (1.4) 100.0 % -0.10 [ -0.75, 0.55 ]
Subtotal (95% CI) 37 34 100.0 % -0.10 [ -0.75, 0.55 ]

Karatosun 2005a 30 3 (1.4) 32 3.4 (1.4) 100.0 % -0.40 [ -1.10, 0.30 ]
Subtotal (95% CI) 30 32 100.0 % -0.40 [ -1.10, 0.30 ]

-10 -5 0 5 10

Analysis 42.8. Comparison 42 Orthovisc versus hylan G-F 20, Outcome 8 Pain during transfer activity
(Hospital for Special Surgery).
Outcome: 8 Pain during transfer activity (Hospital for Special Surgery)
Mean Mean
Karatosun 2005a 39 4 (1.4) 40 4.2 (1.3) 100.0 % -0.20 [ -0.80, 0.40 ]
Subtotal (95% CI) 39 40 100.0 % -0.20 [ -0.80, 0.40 ]

Karatosun 2005a 39 4.5 (1.1) 34 4.1 (1.3) 100.0 % 0.40 [ -0.16, 0.96 ]
Subtotal (95% CI) 39 34 100.0 % 0.40 [ -0.16, 0.96 ]

Karatosun 2005a 37 3.9 (1.4) 34 3.8 (1.4) 100.0 % 0.10 [ -0.55, 0.75 ]
Subtotal (95% CI) 37 34 100.0 % 0.10 [ -0.55, 0.75 ]

Karatosun 2005a 30 4.3 (1.3) 32 4.1 (1.4) 100.0 % 0.20 [ -0.47, 0.87 ]
Subtotal (95% CI) 30 32 100.0 % 0.20 [ -0.47, 0.87 ]

-10 -5 0 5 10

Analysis 42.9. Comparison 42 Orthovisc versus hylan G-F 20, Outcome 9 WOMAC physical function (0-68
or 17-85 Likert).
Outcome: 9 WOMAC physical function (0-68 or 17-85 Likert)
Std. Std.
Mean Mean
Atamaz 2005 20 35.2 (11.5) 20 40.1 (15.7) 32.9 % -0.35 [ -0.97, 0.28 ]
Karatay 2004 20 27.8 (10) 20 24.3 (9.9) 32.9 % 0.34 [ -0.28, 0.97 ]
Kotevoglu 2005 20 33 (10.1) 21 31 (9.4) 34.1 % 0.20 [ -0.41, 0.82 ]
Subtotal (95% CI) 60 61 100.0 % 0.07 [ -0.29, 0.43 ]

Atamaz 2005 20 36.2 (11.8) 20 41.7 (14) 48.9 % -0.42 [ -1.04, 0.21 ]
Kotevoglu 2005 20 31.5 (10.5) 21 30 (9.2) 51.1 % 0.15 [ -0.46, 0.76 ]
Subtotal (95% CI) 40 41 100.0 % -0.13 [ -0.57, 0.31 ]

Atamaz 2005 20 41.8 (13.3) 20 41.9 (14.6) 49.8 % -0.01 [ -0.63, 0.61 ]
Kotevoglu 2005 20 34.5 (10.4) 21 31 (10.5) 50.2 % 0.33 [ -0.29, 0.95 ]
Subtotal (95% CI) 40 41 100.0 % 0.16 [ -0.28, 0.60 ]

Atamaz 2005 20 39.6 (11.8) 20 38.6 (11.5) 100.0 % 0.08 [ -0.54, 0.70 ]
Subtotal (95% CI) 20 20 100.0 % 0.08 [ -0.54, 0.70 ]

Atamaz 2005 20 37.6 (13.6) 20 38.9 (11.7) 100.0 % -0.10 [ -0.72, 0.52 ]
Subtotal (95% CI) 20 20 100.0 % -0.10 [ -0.72, 0.52 ]

-10 -5 0 5 10

Analysis 42.10. Comparison 42 Orthovisc versus hylan G-F 20, Outcome 10 SF-36 physical functioning.
Mean Mean
Atamaz 2005 20 54.2 (15.5) 20 57.2 (26.7) 100.0 % -3.00 [ -16.53, 10.53 ]
Subtotal (95% CI) 20 20 100.0 % -3.00 [ -16.53, 10.53 ]

Atamaz 2005 20 41.5 (11.6) 20 61.7 (17.7) 100.0 % -20.20 [ -29.47, -10.93 ]
Subtotal (95% CI) 20 20 100.0 % -20.20 [ -29.47, -10.93 ]

Atamaz 2005 20 44.5 (24.1) 20 55.7 (28.3) 100.0 % -11.20 [ -27.49, 5.09 ]
Subtotal (95% CI) 20 20 100.0 % -11.20 [ -27.49, 5.09 ]

Atamaz 2005 20 49.2 (16) 20 45 (21.4) 100.0 % 4.20 [ -7.51, 15.91 ]
Subtotal (95% CI) 20 20 100.0 % 4.20 [ -7.51, 15.91 ]

Atamaz 2005 20 31 (14.3) 20 54 (25.9) 100.0 % -23.00 [ -35.97, -10.03 ]
Subtotal (95% CI) 20 20 100.0 % -23.00 [ -35.97, -10.03 ]

-100 -50 0 50 100

Favours Synvisc Favours Orthovisc

Analysis 42.11. Comparison 42 Orthovisc versus hylan G-F 20, Outcome 11 Range of motion (degrees).
Mean Mean
Karatosun 2005a 39 123 (8.8) 40 120.6 (13.8) 100.0 % 2.40 [ -2.69, 7.49 ]
Subtotal (95% CI) 39 40 100.0 % 2.40 [ -2.69, 7.49 ]

Karatosun 2005a 39 121.9 (10.6) 34 121 (5.3) 100.0 % 0.90 [ -2.87, 4.67 ]
Subtotal (95% CI) 39 34 100.0 % 0.90 [ -2.87, 4.67 ]

Karatosun 2005a 37 118 (10.9) 34 119.8 (9.2) 100.0 % -1.80 [ -6.48, 2.88 ]
Subtotal (95% CI) 37 34 100.0 % -1.80 [ -6.48, 2.88 ]

Karatosun 2005a 30 122 (11.4) 32 121.3 (9.4) 100.0 % 0.70 [ -4.52, 5.92 ]
Subtotal (95% CI) 30 32 100.0 % 0.70 [ -4.52, 5.92 ]

-10 -5 0 5 10

Analysis 42.12. Comparison 42 Orthovisc versus hylan G-F 20, Outcome 12 Walking distance.
Outcome: 12 Walking distance
Mean Mean
Karatosun 2005a 39 8.7 (3.2) 40 9.9 (2.6) 100.0 % -1.20 [ -2.49, 0.09 ]
Subtotal (95% CI) 39 40 100.0 % -1.20 [ -2.49, 0.09 ]

Karatosun 2005a 39 9.2 (3.2) 34 10.1 (2) 100.0 % -0.90 [ -2.11, 0.31 ]
Subtotal (95% CI) 39 34 100.0 % -0.90 [ -2.11, 0.31 ]

Karatosun 2005a 37 9.1 (2.8) 34 10 (2.2) 100.0 % -0.90 [ -2.07, 0.27 ]
Subtotal (95% CI) 37 34 100.0 % -0.90 [ -2.07, 0.27 ]

Karatosun 2005a 30 9.6 (2.4) 32 10.2 (2.9) 100.0 % -0.60 [ -1.92, 0.72 ]
Subtotal (95% CI) 30 32 100.0 % -0.60 [ -1.92, 0.72 ]

-10 -5 0 5 10

Analysis 42.13. Comparison 42 Orthovisc versus hylan G-F 20, Outcome 13 Patient global assessment (0-
100 mm VAS where 100 is worst severity).
Outcome: 13 Patient global assessment (0-100 mm VAS where 100 is worst severity)
Mean Mean
Kotevoglu 2005 20 50 (13.5) 21 50 (13.5) 100.0 % 0.0 [ -8.27, 8.27 ]
Subtotal (95% CI) 20 21 100.0 % 0.0 [ -8.27, 8.27 ]

Kotevoglu 2005 20 50 (12.1) 21 50 (12.1) 100.0 % 0.0 [ -7.41, 7.41 ]
Subtotal (95% CI) 20 21 100.0 % 0.0 [ -7.41, 7.41 ]

Kotevoglu 2005 20 70 (16.1) 21 70 (16.1) 100.0 % 0.0 [ -9.86, 9.86 ]
Subtotal (95% CI) 20 21 100.0 % 0.0 [ -9.86, 9.86 ]

-100 -50 0 50 100


Analysis 42.14. Comparison 42 Orthovisc versus hylan G-F 20, Outcome 14 Physician global assessment (0-
100 mm VAS where 100 is worst severity).
Outcome: 14 Physician global assessment (0-100 mm VAS where 100 is worst severity)
Mean Mean
Kotevoglu 2005 20 70 (20.5) 21 50 (21.1) 100.0 % 20.00 [ 7.27, 32.73 ]
Subtotal (95% CI) 20 21 100.0 % 20.00 [ 7.27, 32.73 ]

Kotevoglu 2005 20 70 (20.5) 21 50 (18.4) 100.0 % 20.00 [ 8.06, 31.94 ]
Subtotal (95% CI) 20 21 100.0 % 20.00 [ 8.06, 31.94 ]

Kotevoglu 2005 20 60 (18.2) 21 60 (18.1) 100.0 % 0.0 [ -11.12, 11.12 ]
Subtotal (95% CI) 20 21 100.0 % 0.0 [ -11.12, 11.12 ]

-100 -50 0 50 100


Analysis 42.15. Comparison 42 Orthovisc versus hylan G-F 20, Outcome 15 WOMAC stiffness (0-8 or 2-10
Likert).
Outcome: 15 WOMAC stiffness (0-8 or 2-10 Likert)
Std. Std.
Mean Mean
Karatay 2004 20 3.2 (1.8) 20 2.6 (1.3) 49.4 % 0.37 [ -0.25, 1.00 ]
Kotevoglu 2005 20 3.5 (1.3) 21 4 (1.3) 50.6 % -0.38 [ -1.00, 0.24 ]
Subtotal (95% CI) 40 41 100.0 % -0.01 [ -0.45, 0.43 ]

Kotevoglu 2005 20 3.5 (1.7) 21 4 (1.1) 100.0 % -0.34 [ -0.96, 0.27 ]
Subtotal (95% CI) 20 21 100.0 % -0.34 [ -0.96, 0.27 ]

Kotevoglu 2005 20 3.5 (1.1) 21 4 (1) 100.0 % -0.47 [ -1.09, 0.15 ]
Subtotal (95% CI) 20 21 100.0 % -0.47 [ -1.09, 0.15 ]

-10 -5 0 5 10

Analysis 42.16. Comparison 42 Orthovisc versus hylan G-F 20, Outcome 16 Synovial fluid intercellular
adhesion molecule-1 (ICAM-1).
Outcome: 16 Synovial fluid intercellular adhesion molecule-1 (ICAM-1)
Mean Mean
Karatay 2004 20 12 (7.5) 20 12.6 (8.8) 100.0 % -0.60 [ -5.67, 4.47 ]
Subtotal (95% CI) 20 20 100.0 % -0.60 [ -5.67, 4.47 ]

-10 -5 0 5 10
Analysis 42.17. Comparison 42 Orthovisc versus hylan G-F 20, Outcome 17 Synovial fluid vascular cell
adhesion molecule-1 (VCAM-1).
Outcome: 17 Synovial fluid vascular cell adhesion molecule-1 (VCAM-1)
Mean Mean
Karatay 2004 20 31.6 (12.8) 20 34.6 (10.4) 100.0 % -3.00 [ -10.23, 4.23 ]
Subtotal (95% CI) 20 20 100.0 % -3.00 [ -10.23, 4.23 ]

-10 -5 0 5 10

Analysis 42.18. Comparison 42 Orthovisc versus hylan G-F 20, Outcome 18 Safety: total withdrawals overall.
Study or subgroup Orthovisc Hylan G-F 20 Risk Ratio Weight Risk Ratio
Karatosun 2005a 16/46 14/46 1.14 [ 0.63, 2.06 ]
Kotevoglu 2005 6/26 5/26 1.20 [ 0.42, 3.45 ]
0.1 0.2 0.5 1 2 5 10

Analysis 42.19. Comparison 42 Orthovisc versus hylan G-F 20, Outcome 19 Safety: withdrawals due to lack
of efficacy.
Karatosun 2005a 5/46 4/46 1.25 [ 0.36, 4.36 ]
0.1 0.2 0.5 1 2 5 10


Analysis 42.20. Comparison 42 Orthovisc versus hylan G-F 20, Outcome 20 Safety: number of patients with
local adverse event.
Outcome: 20 Safety: number of patients with local adverse event
Atamaz 2005 3/20 1/20 3.00 [ 0.34, 26.45 ]
Kotevoglu 2005 1/26 1/26 1.00 [ 0.07, 15.15 ]
0.1 0.2 0.5 1 2 5 10

Analysis 42.21. Comparison 42 Orthovisc versus hylan G-F 20, Outcome 21 Safety: withdrawals due to
noncompliance.
Outcome: 21 Safety: withdrawals due to noncompliance
Kotevoglu 2005 1/26 1/26 1.00 [ 0.07, 15.15 ]
0.1 0.2 0.5 1 2 5 10


Analysis 43.1. Comparison 43 Orthovisc versus Orthovisc, Outcome 1 WOMAC total score (0 to 100 mm
VAS; change from baseline).
Comparison: 43 Orthovisc versus Orthovisc
Outcome: 1 WOMAC total score (0 to 100 mm VAS; change from baseline)
Mean Mean
Study or subgroup Orthovisc 4 injectio Ortho 3 inj + 1 arth Difference Weight Difference
Neustadt 2005a -3inj 115 -145.5 (119.1) 107 -121.1 (123.2) 100.0 % -24.40 [ -56.32, 7.52 ]
Subtotal (95% CI) 115 107 100.0 % -24.40 [ -56.32, 7.52 ]

Neustadt 2005a -3inj 115 -123.7 (123.4) 107 -108.4 (124.6) 100.0 % -15.30 [ -47.95, 17.35 ]
Subtotal (95% CI) 115 107 100.0 % -15.30 [ -47.95, 17.35 ]

-100 -50 0 50 100

Favours Ortho 4 inj Favours Orth3inj1art

Analysis 43.2. Comparison 43 Orthovisc versus Orthovisc, Outcome 2 Patient global assessment (0 to 100
Outcome: 2 Patient global assessment (0 to 100 mm VAS; change from baseline)
Mean Mean
Study or subgroup Orthovisc 4 inj Ortho3inj+1arthrocen Difference Weight Difference
Neustadt 2005a -3inj 115 -36.3 (29.1) 107 -27.5 (30.2) 100.0 % -8.80 [ -16.61, -0.99 ]
Subtotal (95% CI) 115 107 100.0 % -8.80 [ -16.61, -0.99 ]

Neustadt 2005a -3inj 115 -33.4 (29.1) 107 -26.1 (30.6) 100.0 % -7.30 [ -15.17, 0.57 ]
Subtotal (95% CI) 115 107 100.0 % -7.30 [ -15.17, 0.57 ]

-100 -50 0 50 100


Analysis 43.3. Comparison 43 Orthovisc versus Orthovisc, Outcome 3 Physician global assessment (0 to
100 mm VAS; change from baseline).
Outcome: 3 Physician global assessment (0 to 100 mm VAS; change from baseline)
Mean Mean
Neustadt 2005a -3inj 115 -25.4 (22.9) 107 -23 (23.2) 100.0 % -2.40 [ -8.47, 3.67 ]
Subtotal (95% CI) 115 107 100.0 % -2.40 [ -8.47, 3.67 ]

Neustadt 2005a -3inj 115 -21.7 (24.2) 107 -18.3 (26.3) 100.0 % -3.40 [ -10.06, 3.26 ]
Subtotal (95% CI) 115 107 100.0 % -3.40 [ -10.06, 3.26 ]

-10 -5 0 5 10

Analysis 43.4. Comparison 43 Orthovisc versus Orthovisc, Outcome 4 WOMAC pain on standing (0 to 100
Outcome: 4 WOMAC pain on standing (0 to 100 mm VAS; change from baseline)
Mean Mean
Neustadt 2005a -3inj 104 -32.9 (30.6) 90 -25.4 (29.6) 100.0 % -7.50 [ -15.98, 0.98 ]
Subtotal (95% CI) 104 90 100.0 % -7.50 [ -15.98, 0.98 ]

Neustadt 2005a -3inj 104 -29.5 (31.4) 90 -25.5 (30.2) 100.0 % -4.00 [ -12.68, 4.68 ]
Subtotal (95% CI) 104 90 100.0 % -4.00 [ -12.68, 4.68 ]

-100 -50 0 50 100


Analysis 43.5. Comparison 43 Orthovisc versus Orthovisc, Outcome 5 Number of patients with a 20%
Study or subgroup Orthovisc 4 inj Ortho3inj+1arthrocen Risk Ratio Weight Risk Ratio
Neustadt 2005a -3inj 89/104 61/90 100.0 % 1.26 [ 1.07, 1.49 ]
Subtotal (95% CI) 104 90 100.0 % 1.26 [ 1.07, 1.49 ]

Total events: 89 (Orthovisc 4 inj), 61 (Ortho3inj+1arthrocen)
Neustadt 2005a -3inj 72/104 59/90 100.0 % 1.06 [ 0.87, 1.29 ]
Subtotal (95% CI) 104 90 100.0 % 1.06 [ 0.87, 1.29 ]

0.1 0.2 0.5 1 2 5 10

Favours Ortho3in1art Favours Ortho 4 inj

Ortho
Study or subgroup Orthovisc 4 inj 3inj+1arthroce Risk Ratio Weight Risk Ratio
Neustadt 2005a -3inj 70/104 49/90 100.0 % 1.24 [ 0.98, 1.56 ]
Subtotal (95% CI) 104 90 100.0 % 1.24 [ 0.98, 1.56 ]

Total events: 70 (Orthovisc 4 inj), 49 (Ortho 3inj+1arthroce)
Neustadt 2005a -3inj 62/104 45/90 100.0 % 1.19 [ 0.92, 1.55 ]
Subtotal (95% CI) 104 90 100.0 % 1.19 [ 0.92, 1.55 ]

Total events: 62 (Orthovisc 4 inj), 45 (Ortho 3inj+1arthroce)
0.1 0.2 0.5 1 2 5 10

Favours Ortho3in1art Favours Orth 4 inj

Study or subgroup Orthovisc 4 inj Ortho3inj+1arthrocen Risk Ratio Weight Risk Ratio
Neustadt 2005a -3inj 60/104 42/90 100.0 % 1.24 [ 0.94, 1.63 ]
Subtotal (95% CI) 104 90 100.0 % 1.24 [ 0.94, 1.63 ]

Neustadt 2005a -3inj 55/104 38/90 100.0 % 1.25 [ 0.93, 1.69 ]
Subtotal (95% CI) 104 90 100.0 % 1.25 [ 0.93, 1.69 ]

0.1 0.2 0.5 1 2 5 10

Favours Ortho3in1art Favours Ortho 4 inj
Analysis 43.8. Comparison 43 Orthovisc versus Orthovisc, Outcome 8 Safety: total withdrawals overall.
Orthovisc
Study or subgroup Orthovisc 4-injectio 3inj+1arth Risk Ratio Weight Risk Ratio
Neustadt 2005a -3inj 35/128 44/120 0.75 [ 0.52, 1.08 ]
0.1 0.2 0.5 1 2 5 10

Favours Ortho 4inj Favours Ortho3inj1ar

Analysis 43.9. Comparison 43 Orthovisc versus Orthovisc, Outcome 9 Safety: total withdrawals due to lack
of efficacy.
Outcome: 9 Safety: total withdrawals due to lack of efficacy
Ortho
Study or subgroup Orthovisc 4 injectio 3inj+1arthroce Risk Ratio Weight Risk Ratio
Neustadt 2005a -3inj 9/128 8/120 1.05 [ 0.42, 2.64 ]
0.1 0.2 0.5 1 2 5 10

Analysis 43.10. Comparison 43 Orthovisc versus Orthovisc, Outcome 10 Safety: number of patients
reporting adverse events.
Study or subgroup Orthovisc 4 injectio Ortho 3 inj+1arthro Risk Ratio Weight Risk Ratio
Neustadt 2005a -3inj 75/128 61/120 1.15 [ 0.92, 1.45 ]
0.1 0.2 0.5 1 2 5 10

Favours Ortho 4 inj Favours Orth3in+1art

Analysis 43.11. Comparison 43 Orthovisc versus Orthovisc, Outcome 11 Safety: number of patients with
gastrointestinal adverse events.
Outcome: 11 Safety: number of patients with gastrointestinal adverse events
Study or subgroup Orthovisc 4 injectio Ortho3inj+Arthro1inj Risk Ratio Weight Risk Ratio
Neustadt 2005a -3inj 10/128 11/119 0.85 [ 0.37, 1.92 ]
0.1 0.2 0.5 1 2 5 10

Favours Ortho 4 inj Favours Or3inAr1inj
general body adverse events.
Outcome: 12 Safety: number of patients with general body adverse events
Study or subgroup Orthovisc 4 injectio Ortho3injArthro1inj Risk Ratio Weight Risk Ratio
Neustadt 2005a -3inj 8/128 13/119 0.57 [ 0.25, 1.33 ]
0.1 0.2 0.5 1 2 5 10

Favours Ortho4inj Favours Or3injAr1inj

infections.
Outcome: 13 Safety: number of patients with infections
Study or subgroup Orthovisc 4 injectio Orho3injArthro1inj Risk Ratio Weight Risk Ratio
Neustadt 2005a -3inj 27/128 22/119 1.14 [ 0.69, 1.89 ]
0.1 0.2 0.5 1 2 5 10

Favours Ortho 4inj Favours Or3injAr1inj
musculoskeletal adverse events.
Outcome: 14 Safety: number of patients with musculoskeletal adverse events
Neustadt 2005a -3inj 35/128 23/119 1.41 [ 0.89, 2.25 ]
0.1 0.2 0.5 1 2 5 10

Favours Ortho 4 inje Favours Ortho3injAr1

nervous system adverse events.
Outcome: 15 Safety: number of patients with nervous system adverse events
Neustadt 2005a -3inj 20/128 18/119 1.03 [ 0.58, 1.86 ]
0.1 0.2 0.5 1 2 5 10

Favours Ortho4inj Favours Ortho3inAr1i
respiratory adverse events.
Outcome: 16 Safety: number of patients with respiratory adverse events
Study or subgroup Orthovisc 4injection Ortho3injArthro1inj Risk Ratio Weight Risk Ratio
Neustadt 2005a -3inj 5/128 4/119 1.16 [ 0.32, 4.23 ]
0.1 0.2 0.5 1 2 5 10

Favours Ortho4inj Favours Orth3injAr1i

skin adverse events.
Outcome: 17 Safety: number of patients with skin adverse events
Neustadt 2005a -3inj 3/128 1/119 2.79 [ 0.29, 26.45 ]
0.1 0.2 0.5 1 2 5 10

Favours Ortho 4inj Favours Orth3injAr1i
Analysis 44.1. Comparison 44 Replasyn versus placebo, Outcome 1 Safety: Number of patients with local
Comparison: 44 Replasyn versus placebo
Outcome: 1 Safety: Number of patients with local adverse reaction but study drug continued
Study or subgroup Replasyn Placebo Risk Ratio Weight Risk Ratio

Cohen 1994 3/19 6/20 0.53 [ 0.15, 1.81 ]
0.1 0.2 0.5 1 2 5 10

Favours Replasyn Favours control

Analysis 45.1. Comparison 45 SLM-10 versus Artz (end of treatment), Outcome 1 Pain in movement
Comparison: 45 SLM-10 versus Artz (end of treatment)
Outcome: 1 Pain in movement (number of patients improved)
Study or subgroup SLM-10 Artz Risk Ratio Weight Risk Ratio

Kawabata 1993 59/82 60/74 0.89 [ 0.75, 1.06 ]
0.1 0.2 0.5 1 2 5 10

Favours Artz Favours SLM-10
Analysis 45.2. Comparison 45 SLM-10 versus Artz (end of treatment), Outcome 2 Pain when resting
Outcome: 2 Pain when resting (number of patients improved)

Kawabata 1993 33/39 33/41 1.05 [ 0.86, 1.29 ]
0.1 0.2 0.5 1 2 5 10


Analysis 45.3. Comparison 45 SLM-10 versus Artz (end of treatment), Outcome 3 Pressure pain (number
of patients improved).

Kawabata 1993 48/75 54/66 0.78 [ 0.64, 0.96 ]
0.1 0.2 0.5 1 2 5 10

Analysis 45.4. Comparison 45 SLM-10 versus Artz (end of treatment), Outcome 4 Patient global
assessment (number of patients better or much better).
Outcome: 4 Patient global assessment (number of patients better or much better)

Kawabata 1993 56/82 53/74 0.95 [ 0.78, 1.17 ]
0.1 0.2 0.5 1 2 5 10


Analysis 45.5. Comparison 45 SLM-10 versus Artz (end of treatment), Outcome 5 Safety: total withdrawals
overall.

Kawabata 1993 3/87 10/85 0.29 [ 0.08, 1.03 ]
0.1 0.2 0.5 1 2 5 10

Analysis 45.6. Comparison 45 SLM-10 versus Artz (end of treatment), Outcome 6 Safety: local adverse
events related to study drug resulting in withdrawals.
Outcome: 6 Safety: local adverse events related to study drug resulting in withdrawals

Kawabata 1993 1/85 2/79 0.46 [ 0.04, 5.03 ]
0.1 0.2 0.5 1 2 5 10

Favours SLM-10 Favours Artz

Analysis 45.7. Comparison 45 SLM-10 versus Artz (end of treatment), Outcome 7 Safety: local adverse
events no specific causal relationship to study drug and continuation in trial.
Outcome: 7 Safety: local adverse events no specific causal relationship to study drug and continuation in trial

Kawabata 1993 1/85 1/79 0.93 [ 0.06, 14.61 ]
0.1 0.2 0.5 1 2 5 10

Favours SLM-10 Favours Artz
Analysis 46.1. Comparison 46 Suplasyn versus placebo: 1 week post-injection, Outcome 1 Pain after walking
(0-10 cm VAS).
Comparison: 46 Suplasyn versus placebo: 1 week post-injection
Outcome: 1 Pain after walking (0-10 cm VAS)
Mean Mean
Study or subgroup Suplasyn Saline+Lactose Difference Weight Difference
Petrella 2002 25 2.89 (1.72) 28 3.56 (1.77) -0.67 [ -1.61, 0.27 ]
-10 -5 0 5 10
Favours Suplasyn Favours Saline+lacto

Analysis 46.2. Comparison 46 Suplasyn versus placebo: 1 week post-injection, Outcome 2 WOMAC pain (0-
10 cm VAS).
Outcome: 2 WOMAC pain (0-10 cm VAS)
Mean Mean
Petrella 2002 25 2.42 (2.34) 28 3.19 (2.81) -0.77 [ -2.16, 0.62 ]
-10 -5 0 5 10
Favours Suplasyn Favours saline+lacto
Analysis 46.3. Comparison 46 Suplasyn versus placebo: 1 week post-injection, Outcome 3 Pain at rest (0-10
cm VAS).
Outcome: 3 Pain at rest (0-10 cm VAS)
Mean Mean
Petrella 2002 25 2.6 (1.64) 28 1.77 (1.3) 0.83 [ 0.03, 1.63 ]
-10 -5 0 5 10

Analysis 46.4. Comparison 46 Suplasyn versus placebo: 1 week post-injection, Outcome 4 WOMAC
function (0-10 cm VAS).
Outcome: 4 WOMAC function (0-10 cm VAS)
Mean Mean
Petrella 2002 25 2.45 (2.23) 28 3.73 (2.99) -1.28 [ -2.69, 0.13 ]
-10 -5 0 5 10
Analysis 46.5. Comparison 46 Suplasyn versus placebo: 1 week post-injection, Outcome 5 Walk time (sec).
Outcome: 5 Walk time (sec)
Mean Mean
Petrella 2002 25 74.21 (17.43) 28 71.07 (16.46) 3.14 [ -6.02, 12.30 ]
-10 -5 0 5 10

Analysis 46.6. Comparison 46 Suplasyn versus placebo: 1 week post-injection, Outcome 6 Safety: total
Study or subgroup Suplasyn Saline+Lactose Risk Ratio Weight Risk Ratio

Petrella 2002 5/30 2/30 2.50 [ 0.53, 11.89 ]
0.1 0.2 0.5 1 2 5 10

Analysis 47.1. Comparison 47 Suplasyn versus NSAID: 1 week post-injection, Outcome 1 Pain after walking
(0-10 cm VAS).
Comparison: 47 Suplasyn versus NSAID: 1 week post-injection
Mean Mean
Study or subgroup Suplasyn NSAID Difference Weight Difference
Petrella 2002 25 2.89 (2.72) 29 1.81 (2.72) 1.08 [ -0.37, 2.53 ]
-100 -50 0 50 100

Favours Suplasyn Favours NSAID

Analysis 47.2. Comparison 47 Suplasyn versus NSAID: 1 week post-injection, Outcome 2 WOMAC pain (0-
10 cm VAS).
Mean Mean
Petrella 2002 25 2.42 (2.34) 29 2.86 (2.75) -0.44 [ -1.80, 0.92 ]
-10 -5 0 5 10
Analysis 47.3. Comparison 47 Suplasyn versus NSAID: 1 week post-injection, Outcome 3 Pain at rest (0-10
cm VAS).
Mean Mean
Petrella 2002 25 2.6 (2.64) 29 1.58 (2.34) 1.02 [ -0.32, 2.36 ]
-10 -5 0 5 10

Analysis 47.4. Comparison 47 Suplasyn versus NSAID: 1 week post-injection, Outcome 4 WOMAC function
(0-10 cm VAS).
Mean Mean
Petrella 2002 25 2.45 (2.23) 29 2.76 (2.61) -0.31 [ -1.60, 0.98 ]
-10 -5 0 5 10
Analysis 47.5. Comparison 47 Suplasyn versus NSAID: 1 week post-injection, Outcome 5 Walk time (sec).
Mean Mean
Petrella 2002 25 74.21 (17.43) 29 75.7 (15.63) -1.49 [ -10.38, 7.40 ]
-10 -5 0 5 10

Analysis 47.6. Comparison 47 Suplasyn versus NSAID: 1 week post-injection, Outcome 6 Safety: total
Study or subgroup Suplasyn NSAID Risk Ratio Weight Risk Ratio

Petrella 2002 5/30 1/30 5.00 [ 0.62, 40.28 ]
0.1 0.2 0.5 1 2 5 10

Analysis 48.1. Comparison 48 (Suplasyn + NSAID) versus NSAID: 1 week post-injection, Outcome 1 Pain
after walking (0-10 cm VAS).
Comparison: 48 (Suplasyn + NSAID) versus NSAID: 1 week post-injection
Mean Mean
Study or subgroup SUPLASYN+NSAID NSAID Difference Weight Difference
Petrella 2002 26 2.05 (2.32) 29 1.81 (2.72) 0.24 [ -1.09, 1.57 ]
-10 -5 0 5 10
Favours Suplasyn+NSA Favours NSAID

Analysis 48.2. Comparison 48 (Suplasyn + NSAID) versus NSAID: 1 week post-injection, Outcome 2
WOMAC pain (0-10 cm VAS).
Mean Mean
Study or subgroup Suplasyn+NSAID NSAID Difference Weight Difference
Petrella 2002 26 2.59 (2.59) 29 2.86 (2.75) -0.27 [ -1.68, 1.14 ]
-10 -5 0 5 10
Analysis 48.3. Comparison 48 (Suplasyn + NSAID) versus NSAID: 1 week post-injection, Outcome 3 Pain at
rest (0-10 cm VAS).
Mean Mean
Petrella 2002 26 1.56 (2.34) 29 1.58 (2.34) -0.02 [ -1.26, 1.22 ]
-10 -5 0 5 10

Analysis 48.4. Comparison 48 (Suplasyn + NSAID) versus NSAID: 1 week post-injection, Outcome 4
WOMAC function (0-10 cm VAS).
Mean Mean
Petrella 2002 26 2.73 (2.64) 29 2.76 (2.61) -0.03 [ -1.42, 1.36 ]
-10 -5 0 5 10
Analysis 48.5. Comparison 48 (Suplasyn + NSAID) versus NSAID: 1 week post-injection, Outcome 5 Walk
time (sec).
Mean Mean
Petrella 2002 26 72.22 (17) 29 75.7 (15.63) -3.48 [ -12.14, 5.18 ]
-10 -5 0 5 10

Analysis 48.6. Comparison 48 (Suplasyn + NSAID) versus NSAID: 1 week post-injection, Outcome 6 Safety:
Study or subgroup Suplasyn+NSAID NSAID Risk Ratio Weight Risk Ratio

Petrella 2002 4/30 1/30 4.00 [ 0.47, 33.73 ]
0.1 0.2 0.5 1 2 5 10

Analysis 49.1. Comparison 49 Zeel compositum versus Hyalart (end of treatment (5 weeks)), Outcome 1
Pain during movement (0-100 mm VAS ).
Comparison: 49 Zeel compositum versus Hyalart (end of treatment (5 weeks))
Outcome: 1 Pain during movement (0-100 mm VAS )
Mean Mean
Study or subgroup Zeel Hyalart Difference Weight Difference
Nahler 1998 54 31 (23.25) 54 26 (19.75) 5.00 [ -3.14, 13.14 ]
-10 -5 0 5 10
Favours Zeel Favours Hyalart

Pain during the night (0-100 mm VAS).
Outcome: 2 Pain during the night (0-100 mm VAS)
Mean Mean
Nahler 1998 54 9 (23.75) 54 7 (19.25) 2.00 [ -6.15, 10.15 ]
-10 -5 0 5 10
Patient global: number of patients with noticeable improvements in symptoms.
Outcome: 3 Patient global: number of patients with noticeable improvements in symptoms
Study or subgroup Zeel Hyalart Risk Ratio Weight Risk Ratio

Nahler 1998 48/55 53/57 0.94 [ 0.83, 1.06 ]
0.1 0.2 0.5 1 2 5 10

Favours Hyalart Favours Zeel

Patient assessment of improvement (0-100 mm VAS).
Outcome: 4 Patient assessment of improvement (0-100 mm VAS)
Mean Mean
Nahler 1998 55 59 (24.25) 57 63 (25) -4.00 [ -13.12, 5.12 ]
-10 -5 0 5 10
Patient assessment of tolerance (0-100 mm VAS).
Outcome: 5 Patient assessment of tolerance (0-100 mm VAS)
Mean Mean
Nahler 1998 55 94 (21.75) 57 97 (16) -3.00 [ -10.09, 4.09 ]
-10 -5 0 5 10

Safety: number of patients with side effects.
Outcome: 6 Safety: number of patients with side effects

Nahler 1998 6/57 13/57 0.46 [ 0.19, 1.13 ]
0.1 0.2 0.5 1 2 5 10

Safety: number of patients withdrawn due to lack of efficacy.
Outcome: 7 Safety: number of patients withdrawn due to lack of efficacy

Nahler 1998 2/57 1/57 2.00 [ 0.19, 21.44 ]
0.1 0.2 0.5 1 2 5 10


Analysis 50.1. Comparison 50 HA/hylan versus placebo, Outcome 1 Pain on weight bearing (0-100 mm
VAS).
Comparison: 50 HA/hylan versus placebo
Mean Mean
Study or subgroup HA Placebo Difference Weight Difference
Altman 1998 136 25 (24) 149 25 (25) 4.8 % 0.0 [ -5.69, 5.69 ]
Bragantini 1987 19 17.12 (13.03) 18 46.21 (28.04) 2.9 % -29.09 [ -43.31, -14.87 ]
Carrabba 1995 20 41.8 (14.4) 10 56.4 (13.5) 3.7 % -14.60 [ -25.08, -4.12 ]
Carrabba 1995a 20 46 (16.5) 10 56.4 (13.5) 3.6 % -10.40 [ -21.46, 0.66 ]
Carrabba 1995b 20 41.8 (14.4) 10 59.7 (14.9) 3.6 % -17.90 [ -29.09, -6.71 ]
Carrabba 1995c 20 46 (16.5) 10 59.7 (14.9) 3.4 % -13.70 [ -25.43, -1.97 ]
Corrado 1995 19 35.4 (28.6) 16 41.6 (25.4) 2.3 % -6.20 [ -24.10, 11.70 ]
Creamer 1994 12 41.12 (0) 12 33.93 (3.12) Not estimable
Cubukcu 2004 20 46.66 (9.66) 10 50.8 (5.72) 4.8 % -4.14 [ -9.66, 1.38 ]
Dougados 1993 52 34.13 (23.49) 50 35.62 (23.68) 4.0 % -1.49 [ -10.65, 7.67 ]
Grecomoro 1987 20 14.55 (18.78) 16 34.02 (20.72) 3.2 % -19.47 [ -32.54, -6.40 ]
Henderson 1994 18 28.1 (7.6) 19 38.8 (6.5) 5.0 % -10.70 [ -15.27, -6.13 ]
Henderson 1994a 22 39.8 (7.3) 25 31.3 (6.1) 5.1 % 8.50 [ 4.62, 12.38 ]
Huskisson 1999 45 35.29 (27.83) 48 48.02 (30.42) 3.4 % -12.73 [ -24.57, -0.89 ]
Jubb 2003 205 43.87 (24.05) 200 43.88 (25.36) 4.9 % -0.01 [ -4.83, 4.81 ]
Karlsson 2002a (AvP) 90 44 (24.44) 33 44 (30.39) 3.5 % 0.0 [ -11.53, 11.53 ]
Karlsson 2002b (SvP) 86 45 (25.67) 33 44 (30.39) 3.4 % 1.00 [ -10.70, 12.70 ]
Lohmander 1996 96 36.64 (25.49) 93 32.24 (24.81) 4.5 % 4.40 [ -2.77, 11.57 ]
Moreland 1993 46 47 (27.13) 48 51 (27.71) 3.6 % -4.00 [ -15.09, 7.09 ]
Petrella 2002 25 28.9 (17.2) 28 35.6 (17.7) 4.0 % -6.70 [ -16.10, 2.70 ]
Puhl 1993 95 29.14 (22.6) 100 31.4 (22.4) 4.6 % -2.26 [ -8.58, 4.06 ]
Scale 1994a (2 inj) 23 32 (23.98) 24 47 (24.5) 3.0 % -15.00 [ -28.86, -1.14 ]
Scale 1994b (3 inj) 15 22 (19.36) 15 44 (19.36) 3.0 % -22.00 [ -35.86, -8.14 ]
-100 -50 0 50 100

Favours HA Favours Placebo
(Continued . . . )

(. . . Continued)
Mean Mean
St. J. Dixon 1988 28 50.54 (29.11) 33 64.91 (26.52) 3.0 % -14.37 [ -28.45, -0.29 ]
Tsai 2003 96 22.6 (14.31) 93 23.92 (15) 5.0 % -1.32 [ -5.50, 2.86 ]
Wobig 1998 57 31 (22.65) 60 53 (23.24) 4.2 % -22.00 [ -30.32, -13.68 ]
Wobig 1999c (NEhyl) 38 40 (24.66) 36 53 (24) 3.6 % -13.00 [ -24.09, -1.91 ]
Subtotal (95% CI) 1343 1199 100.0 % -7.70 [ -11.29, -4.10 ]

Altman 1998 115 23 (25) 129 24 (26) 5.7 % -1.00 [ -7.40, 5.40 ]
Bragantini 1987 19 15.59 (8.11) 18 46.95 (30.93) 4.0 % -31.36 [ -46.11, -16.61 ]
Carrabba 1995 20 42.1 (12.5) 10 59.8 (14.5) 4.9 % -17.70 [ -28.23, -7.17 ]
Carrabba 1995a 20 47.8 (17.7) 10 59.8 (14.5) 4.6 % -12.00 [ -23.87, -0.13 ]
Carrabba 1995b 20 42.1 (12.5) 10 63.2 (13.7) 5.0 % -21.10 [ -31.21, -10.99 ]
Carrabba 1995c 20 47.8 (17.7) 10 63.2 (13.7) 4.7 % -15.40 [ -26.90, -3.90 ]
Corrado 1995 19 29.7 (22.9) 16 43.2 (22.3) 3.9 % -13.50 [ -28.51, 1.51 ]
Creamer 1994 12 41.8 (29.58) 12 41.8 (27.26) 2.6 % 0.0 [ -22.76, 22.76 ]
Cubukcu 2004 20 40 (9.08) 10 53.8 (7.12) 5.8 % -13.80 [ -19.74, -7.86 ]
Grecomoro 1987 20 20.8 (16.77) 16 35.18 (18.92) 4.6 % -14.38 [ -26.21, -2.55 ]
Huskisson 1999 43 37.4 (32.44) 45 50.18 (30.96) 4.3 % -12.78 [ -26.04, 0.48 ]
Jubb 2003 207 46.51 (26.38) 200 50.2 (25.27) 6.0 % -3.69 [ -8.71, 1.33 ]
Karlsson 2002a (AvP) 90 42 (28.07) 33 46 (34.9) 4.3 % -4.00 [ -17.24, 9.24 ]
Karlsson 2002b (SvP) 86 41 (31.53) 33 46 (34.9) 4.2 % -5.00 [ -18.65, 8.65 ]
Lohmander 1996 96 34.69 (27.25) 93 35.23 (25.49) 5.5 % -0.54 [ -8.06, 6.98 ]
Puhl 1993 95 26.5 (22.6) 100 34 (22.4) 5.7 % -7.50 [ -13.82, -1.18 ]
Scale 1994a (2 inj) 23 27 (23.98) 24 53 (24.5) 4.1 % -26.00 [ -39.86, -12.14 ]
Scale 1994b (3 inj) 15 11 (19.36) 15 43 (19.36) 4.1 % -32.00 [ -45.86, -18.14 ]
Tsai 2003 88 19.32 (14.76) 89 19.78 (14.85) 6.1 % -0.46 [ -4.82, 3.90 ]
Wobig 1998 57 23 (22.65) 60 60 (23.24) 5.3 % -37.00 [ -45.32, -28.68 ]
Wobig 1999c (NEhyl) 37 32 (24.33) 35 43 (23.66) 4.7 % -11.00 [ -22.09, 0.09 ]
Subtotal (95% CI) 1122 968 100.0 % -13.00 [ -17.77, -8.23 ]

-100 -50 0 50 100

(Continued . . . )

(. . . Continued)
Mean Mean
Altman 1998 105 18 (21) 113 24 (27) 12.5 % -6.00 [ -12.40, 0.40 ]
Huskisson 1999 39 39.44 (27.81) 40 53.68 (29.86) 8.6 % -14.24 [ -26.96, -1.52 ]
Jubb 2003 206 50.06 (25.68) 199 50.14 (25.79) 13.3 % -0.08 [ -5.09, 4.93 ]
Karlsson 2002a (AvP) 90 48 (33.78) 33 44 (33.78) 8.2 % 4.00 [ -9.47, 17.47 ]
Karlsson 2002b (SvP) 86 43 (33.78) 33 44 (33.78) 8.2 % -1.00 [ -14.56, 12.56 ]
Lohmander 1996 96 33.65 (25.74) 93 35.4 (26.06) 11.9 % -1.75 [ -9.14, 5.64 ]
Scale 1994a (2 inj) 15 18 (23.24) 21 57 (22.91) 7.3 % -39.00 [ -54.31, -23.69 ]
Scale 1994b (3 inj) 15 22 (23.24) 15 45 (23.24) 6.7 % -23.00 [ -39.63, -6.37 ]
Tsai 2003 88 15.57 (13.88) 88 20.68 (15.52) 13.7 % -5.11 [ -9.46, -0.76 ]
Wobig 1998 56 35 (29.93) 60 56 (30.98) 9.6 % -21.00 [ -32.09, -9.91 ]
Subtotal (95% CI) 796 695 100.0 % -9.04 [ -14.83, -3.24 ]

Dougados 1993 47 28.51 (23.77) 48 29.35 (24.26) 24.7 % -0.84 [ -10.50, 8.82 ]
Jubb 2003 208 47.59 (29.37) 200 50.45 (29.21) 71.2 % -2.86 [ -8.54, 2.82 ]
St. J. Dixon 1988 11 48.45 (28.89) 13 57 (29.46) 4.2 % -8.55 [ -31.96, 14.86 ]
Subtotal (95% CI) 266 261 100.0 % -2.60 [ -7.40, 2.19 ]

-100 -50 0 50 100


Analysis 50.2. Comparison 50 HA/hylan versus placebo, Outcome 2 Pain at rest (0-100 mm VAS).
Mean Mean
Carrabba 1995 20 28.3 (11.6) 10 37.4 (13.7) 7.8 % -9.10 [ -19.00, 0.80 ]
Carrabba 1995a 20 30.3 (14.5) 10 37.4 (13.7) 7.4 % -7.10 [ -17.71, 3.51 ]
Carrabba 1995b 20 28.3 (11.6) 10 40.4 (14.7) 7.5 % -12.10 [ -22.53, -1.67 ]
Carrabba 1995c 20 30.3 (14.5) 10 40.4 (14.7) 7.1 % -10.10 [ -21.21, 1.01 ]
Corrado 1995 19 9.4 (22.2) 16 9.1 (18.8) 5.9 % 0.30 [ -13.28, 13.88 ]
Cubukcu 2004 20 29 (7.83) 10 39 (5.66) 10.9 % -10.00 [ -14.91, -5.09 ]
Dougados 1993 52 10.87 (16.94) 48 14.69 (18.7) 9.6 % -3.82 [ -10.83, 3.19 ]
Henderson 1994 18 17.7 (5.6) 19 31.3 (7.2) 11.3 % -13.60 [ -17.74, -9.46 ]
Henderson 1994a 22 25.3 (6.5) 25 24 (6) 11.6 % 1.30 [ -2.29, 4.89 ]
Moreland 1993 46 39 (33.91) 48 44 (34.64) 5.8 % -5.00 [ -18.86, 8.86 ]
Petrella 2002 25 26 (16.4) 28 17.7 (13) 9.0 % 8.30 [ 0.27, 16.33 ]
St. J. Dixon 1988 28 20.5 (24.69) 33 22.64 (28.35) 6.0 % -2.14 [ -15.45, 11.17 ]
Subtotal (95% CI) 310 267 100.0 % -5.37 [ -9.90, -0.85 ]

-100 -50 0 50 100


Analysis 50.3. Comparison 50 HA/hylan versus placebo, Outcome 3 WOMAC pain.
Std. Std.
Mean Mean
Cubukcu 2004 20 11.4 (1.83) 10 14.1 (1.52) 13.5 % -1.51 [ -2.38, -0.65 ]
Hizmetli 1999 20 10.2 (3.1) 20 17.7 (4.8) 14.2 % -1.82 [ -2.57, -1.07 ]
Kotevoglu 2002 21 10 (3.3) 9 13.5 (3.4) 13.7 % -1.02 [ -1.85, -0.19 ]
Kotevoglu 2005 20 9.5 (3.1) 9 13.5 (3.4) 13.5 % -1.22 [ -2.07, -0.36 ]
Petrella 2002 25 24.2 (24.3) 28 31.9 (28.1) 15.4 % -0.29 [ -0.83, 0.25 ]
Sezgin 2005 22 8.9 (0.7) 19 11.1 (0.8) 13.3 % -2.88 [ -3.78, -1.99 ]
Tsai 2003 96 23.21 (14.14) 93 25.88 (15.05) 16.4 % -0.18 [ -0.47, 0.10 ]
Subtotal (95% CI) 224 188 100.0 % -1.22 [ -1.93, -0.52 ]

Cubukcu 2004 20 9.36 (1.52) 10 14.6 (1.77) 10.1 % -3.18 [ -4.33, -2.03 ]
Day 2004 108 3.84 (3.27) 115 4.61 (3.14) 17.4 % -0.24 [ -0.50, 0.02 ]
Dickson 2001 53 26 (29.12) 57 34 (22.65) 16.7 % -0.31 [ -0.68, 0.07 ]
Hizmetli 1999 20 11.8 (3.1) 20 17.7 (3.1) 13.5 % -1.87 [ -2.62, -1.11 ]
Kotevoglu 2002 21 10 (3) 9 14 (3.2) 12.6 % -1.27 [ -2.13, -0.42 ]
Kotevoglu 2005 20 9.5 (3) 9 14 (3.2) 12.4 % -1.43 [ -2.31, -0.55 ]
Tsai 2003 88 21.48 (14.5) 89 22.97 (14.44) 17.3 % -0.10 [ -0.40, 0.19 ]
Subtotal (95% CI) 330 309 100.0 % -1.02 [ -1.57, -0.47 ]

Hizmetli 1999 20 12.8 (3) 20 18.4 (2.9) 24.0 % -1.86 [ -2.61, -1.11 ]
Kotevoglu 2002 21 10 (2.5) 9 13 (3.1) 22.6 % -1.09 [ -1.92, -0.25 ]
Kotevoglu 2005 20 10 (2.8) 9 13 (3.1) 22.6 % -1.01 [ -1.84, -0.17 ]
Tsai 2003 88 16.48 (14.53) 88 22.14 (15.22) 30.8 % -0.38 [ -0.68, -0.08 ]
-10 -5 0 5 10
(Continued . . . )

(. . .Continued)
Std. Std.
Mean Mean
Subtotal (95% CI) 149 126 100.0 % -1.04 [ -1.75, -0.32 ]
-10 -5 0 5 10
Analysis 50.4. Comparison 50 HA/hylan versus placebo, Outcome 4 WOMAC physical function.
Std. Std.
Mean Mean
Cubukcu 2004 20 40.9 (4.96) 10 46.5 (5.12) 13.4 % -1.09 [ -1.90, -0.27 ]
Hizmetli 1999 20 39.85 (11) 20 52.1 (16.2) 14.7 % -0.87 [ -1.52, -0.22 ]
Kotevoglu 2002 21 31 (9.4) 9 46 (12.1) 12.9 % -1.42 [ -2.30, -0.55 ]
Kotevoglu 2005 20 33 (10.1) 9 46 (12.1) 13.1 % -1.18 [ -2.03, -0.33 ]
Petrella 2002 25 24.5 (22.3) 28 37.3 (29.9) 15.5 % -0.47 [ -1.02, 0.07 ]
Sezgin 2005 22 32.2 (2.6) 19 39 (2.9) 13.3 % -2.43 [ -3.26, -1.60 ]
Tsai 2003 96 26.91 (14.89) 93 28.21 (14.71) 17.1 % -0.09 [ -0.37, 0.20 ]
Subtotal (95% CI) 224 188 100.0 % -1.02 [ -1.62, -0.42 ]

Cubukcu 2004 20 35.9 (4.65) 10 47.4 (5.31) 10.3 % -2.30 [ -3.28, -1.31 ]
Day 2004 108 15.37 (11.41) 115 17.81 (10.53) 18.3 % -0.22 [ -0.49, 0.04 ]
-100 -50 0 50 100

(Continued . . . )

(. . .Continued)
Std. Std.
Mean Mean
Dickson 2001 53 38 (21.84) 57 47 (15.1) 17.2 % -0.48 [ -0.86, -0.10 ]
Hizmetli 1999 20 41.35 (10.4) 20 51.5 (13.8) 14.0 % -0.81 [ -1.46, -0.17 ]
Kotevoglu 2002 21 30 (9.2) 9 48 (11.4) 11.0 % -1.77 [ -2.69, -0.86 ]
Kotevoglu 2005 20 31.5 (10.5) 9 48 (11.4) 11.3 % -1.49 [ -2.38, -0.60 ]
Tsai 2003 88 24.25 (14.65) 89 25.31 (14.63) 18.0 % -0.07 [ -0.37, 0.22 ]
Subtotal (95% CI) 330 309 100.0 % -0.85 [ -1.31, -0.39 ]

Hizmetli 1999 20 43.2 (10.5) 20 51.5 (13.8) 25.6 % -0.66 [ -1.30, -0.03 ]
Kotevoglu 2002 21 31 (10.5) 9 48 (13.5) 19.9 % -1.45 [ -2.32, -0.57 ]
Kotevoglu 2005 20 34.5 (9) 9 48 (13.5) 20.2 % -1.25 [ -2.10, -0.39 ]
Tsai 2003 88 20.85 (14.42) 88 24.9 (14.89) 34.3 % -0.28 [ -0.57, 0.02 ]
Subtotal (95% CI) 149 126 100.0 % -0.80 [ -1.37, -0.24 ]

-100 -50 0 50 100


Analysis 50.5. Comparison 50 HA/hylan versus placebo, Outcome 5 Lequesne Index (0-24).
Mean Mean
Carrabba 1995 20 11.5 (3) 10 13.4 (3.4) 7.1 % -1.90 [ -4.38, 0.58 ]
Carrabba 1995a 20 11.6 (3.7) 10 13.4 (3.4) 6.2 % -1.80 [ -4.46, 0.86 ]
Carrabba 1995b 20 11.5 (3) 10 14.1 (3.5) 6.8 % -2.60 [ -5.14, -0.06 ]
Carrabba 1995c 20 11.6 (3.7) 10 14.1 (3.5) 6.0 % -2.50 [ -5.21, 0.21 ]
Dougados 1993 49 8.53 (3.81) 50 8.78 (3.59) 20.6 % -0.25 [ -1.71, 1.21 ]
Huskisson 1999 40 10 (4.6) 41 12.1 (3.8) 12.9 % -2.10 [ -3.94, -0.26 ]
Puhl 1993 95 7.19 (3.9) 100 7 (3.5) 40.4 % 0.19 [ -0.85, 1.23 ]
Subtotal (95% CI) 264 231 100.0 % -0.82 [ -1.48, -0.16 ]

Carrabba 1995 20 11.6 (2.6) 10 13.9 (3.5) 7.2 % -2.30 [ -4.75, 0.15 ]
Carrabba 1995a 20 12 (4.3) 10 13.9 (3.5) 5.2 % -1.90 [ -4.77, 0.97 ]
Carrabba 1995b 20 11.6 (2.6) 10 14.4 (3.2) 8.3 % -2.80 [ -5.09, -0.51 ]
Carrabba 1995c 20 12 (4.3) 10 14.4 (3.2) 5.8 % -2.40 [ -5.14, 0.34 ]
Dickson 2001 53 10.9 (3.64) 57 12.5 (3.77) 22.5 % -1.60 [ -2.98, -0.22 ]
Huskisson 1999 40 10.2 (4.8) 41 12.4 (4.2) 11.2 % -2.20 [ -4.17, -0.23 ]
Puhl 1993 95 6.43 (3.9) 100 6.79 (3.5) 39.8 % -0.36 [ -1.40, 0.68 ]
Subtotal (95% CI) 268 238 100.0 % -1.38 [ -2.04, -0.73 ]

Huskisson 1999 40 11.2 (4.4) 41 12.6 (4.8) 16.5 % -1.40 [ -3.40, 0.60 ]
Karlsson 2002a (AvP) 92 10 (4.96) 33 8.9 (4.77) 18.0 % 1.10 [ -0.82, 3.02 ]
Karlsson 2002b (SvP) 88 9 (4.44) 33 8.9 (4.77) 18.9 % 0.10 [ -1.77, 1.97 ]
Lohmander 1996 119 7.98 (4.4) 120 7.82 (4.98) 46.7 % 0.16 [ -1.03, 1.35 ]
Subtotal (95% CI) 339 227 100.0 % 0.06 [ -0.75, 0.87 ]
-10 -5 0 5 10
(Continued . . . )

(. . . Continued)
Mean Mean
Dougados 1993 47 7.06 (4.09) 47 8.17 (3.76) 100.0 % -1.11 [ -2.70, 0.48 ]
Subtotal (95% CI) 47 47 100.0 % -1.11 [ -2.70, 0.48 ]

-10 -5 0 5 10
Analysis 50.6. Comparison 50 HA/hylan versus placebo, Outcome 6 Patient global assessment (number of
patients improved).
Study or subgroup HA Placebo Risk Ratio Weight Risk Ratio

M- M-
n/N n/N CI CI
1 1 to 4 weeks post-injection (much better/better or excellent/good)
Corrado 1995 6/19 12/16 7.0 % 0.42 [ 0.20, 0.86 ]
Creamer 1994 5/12 4/12 3.7 % 1.25 [ 0.44, 3.55 ]
Formiguera Sala 1995 12/20 9/20 9.3 % 1.33 [ 0.73, 2.44 ]
Lohmander 1996 59/96 56/93 25.4 % 1.02 [ 0.81, 1.28 ]
Shichikawa 1983a 87/103 67/105 29.4 % 1.32 [ 1.12, 1.56 ]
Shichikawa 1983b 38/48 35/50 25.1 % 1.13 [ 0.90, 1.43 ]
Subtotal (95% CI) 298 296 100.0 % 1.10 [ 0.89, 1.36 ]

Total events: 207 (HA), 183 (Placebo)
0.1 0.2 0.5 1 2 5 10

Favours Placebo Favours HA
(Continued . . . )

(. . . Continued)
M- M-
n/N n/N CI CI
2 5 to 13 weeks post-injection (excellent/very good/good/better/somewhat better)
Corrado 1995 14/19 12/16 17.1 % 0.98 [ 0.67, 1.45 ]
Dickson 2001 13/42 25/48 12.2 % 0.59 [ 0.35, 1.01 ]
Formiguera Sala 1995 14/20 7/20 8.9 % 2.00 [ 1.03, 3.88 ]
Guler 1996 11/15 5/15 6.9 % 2.20 [ 1.01, 4.79 ]
Lohmander 1996 53/96 51/93 23.7 % 1.01 [ 0.78, 1.30 ]
Puhl 1993 86/95 81/100 31.2 % 1.12 [ 1.00, 1.25 ]
Subtotal (95% CI) 287 292 100.0 % 1.09 [ 0.87, 1.37 ]

3 14 to 26 weeks post-injection (better/somewhat/much)
Henderson 1994 17/40 17/44 20.6 % 1.10 [ 0.66, 1.85 ]
Huskisson 1999 10/40 22/41 17.6 % 0.47 [ 0.25, 0.86 ]
Lin 2004 58/100 45/98 30.9 % 1.26 [ 0.96, 1.66 ]
Lohmander 1996 58/96 43/93 30.8 % 1.31 [ 1.00, 1.72 ]
Subtotal (95% CI) 276 276 100.0 % 1.04 [ 0.73, 1.47 ]

4 45 to 52 weeks post-injection (number of patients rating treatment effective or very good or good)
Dougados 1993 31/47 27/48 30.1 % 1.17 [ 0.85, 1.62 ]
Pham 2004 86/120 57/75 69.9 % 0.94 [ 0.80, 1.12 ]
Subtotal (95% CI) 167 123 100.0 % 1.01 [ 0.82, 1.23 ]

0.1 0.2 0.5 1 2 5 10


Analysis 50.7. Comparison 50 HA/hylan versus placebo, Outcome 7 Flexion (degrees).
Mean Mean
Corrado 1995 19 123.5 (10.2) 16 120 (12.4) 5.6 % 3.50 [ -4.11, 11.11 ]
Sezgin 2005 22 125.2 (3) 19 121.2 (3.4) 83.7 % 4.00 [ 2.02, 5.98 ]
Shichikawa 1983b 48 135.65 (14.48) 50 132.6 (13.45) 10.7 % 3.05 [ -2.49, 8.59 ]
Subtotal (95% CI) 89 85 100.0 % 3.87 [ 2.06, 5.68 ]

Corrado 1995 19 125.5 (9.9) 16 117.9 (11.4) 100.0 % 7.60 [ 0.46, 14.74 ]
Subtotal (95% CI) 19 16 100.0 % 7.60 [ 0.46, 14.74 ]

-10 -5 0 5 10

Analysis 50.8. Comparison 50 HA/hylan versus placebo, Outcome 8 Safety: total withdrawals overall.

Moreland 1993 2/46 3/48 17.5 % 0.70 [ 0.12, 3.97 ]
Petrella 2002 5/30 2/30 11.9 % 2.50 [ 0.53, 11.89 ]
Shichikawa 1983a 8/111 7/112 41.6 % 1.15 [ 0.43, 3.07 ]
Shichikawa 1983b 4/52 5/55 29.0 % 0.85 [ 0.24, 2.98 ]
Subtotal (95% CI) 261 264 100.0 % 1.14 [ 0.61, 2.15 ]

Carrabba 1995 0/20 0/20 Not estimable
Corrado 1995 2/21 3/19 8.4 % 0.60 [ 0.11, 3.23 ]
Day 2004 19/116 19/124 48.9 % 1.07 [ 0.60, 1.92 ]
Dickson 2001 10/53 8/57 20.5 % 1.34 [ 0.57, 3.15 ]
Puhl 1993 7/102 7/107 18.2 % 1.05 [ 0.38, 2.89 ]
Wobig 1998 1/57 0/60 1.3 % 3.16 [ 0.13, 75.90 ]
Wobig 1999c (NEhyl) 1/37 1/35 2.7 % 0.95 [ 0.06, 14.55 ]
Subtotal (95% CI) 426 432 100.0 % 1.11 [ 0.73, 1.67 ]

Altman 1998 59/164 53/168 31.5 % 1.14 [ 0.84, 1.54 ]
Altman 2004 39/173 35/174 21.0 % 1.12 [ 0.75, 1.68 ]
Brandt 2001 23/114 28/112 17.0 % 0.81 [ 0.50, 1.31 ]
Henderson 1994 18/45 17/46 10.1 % 1.08 [ 0.64, 1.82 ]
Huskisson 1999 10/50 9/50 5.4 % 1.11 [ 0.49, 2.50 ]
0.1 0.2 0.5 1 2 5 10

(Continued . . . )

(. . . Continued)
Kotevoglu 2002 5/26 8/26 4.8 % 0.63 [ 0.24, 1.66 ]
Kotevoglu 2005 6/26 8/26 4.8 % 0.75 [ 0.30, 1.86 ]
Lohmander 1996 3/120 5/120 3.0 % 0.60 [ 0.15, 2.45 ]
Tamir 2001 3/25 4/24 2.5 % 0.72 [ 0.18, 2.89 ]
Subtotal (95% CI) 743 746 100.0 % 1.00 [ 0.83, 1.20 ]

Dougados 1993 8/55 7/55 39.3 % 1.14 [ 0.45, 2.93 ]
Pham 2004 9/131 5/85 34.0 % 1.17 [ 0.41, 3.37 ]
St. J. Dixon 1988 5/30 5/33 26.7 % 1.10 [ 0.35, 3.43 ]
Subtotal (95% CI) 216 173 100.0 % 1.14 [ 0.63, 2.08 ]

0.1 0.2 0.5 1 2 5 10


Analysis 50.9. Comparison 50 HA/hylan versus placebo, Outcome 9 Safety: number of patients with local
adverse reaction and study drug discontinued.
Outcome: 9 Safety: number of patients with local adverse reaction and study drug discontinued
Study or subgroup Artz Placebo Risk Ratio Weight Risk Ratio

Dougados 1993 2/55 1/55 2.00 [ 0.19, 21.42 ]
Henderson 1994 5/45 0/46 11.24 [ 0.64, 197.51 ]
Shichikawa 1983a 0/110 1/109 0.33 [ 0.01, 8.02 ]
Shichikawa 1983b 0/50 2/53 0.21 [ 0.01, 4.31 ]
0.1 0.2 0.5 1 2 5 10

Analysis 50.10. Comparison 50 HA/hylan versus placebo, Outcome 10 Safety: number of patients with local

Carrabba 1995 1/20 0/20 3.00 [ 0.13, 69.52 ]
Scale 1994b (3 inj) 1/15 0/15 3.00 [ 0.13, 68.26 ]
Shichikawa 1983a 1/110 4/109 0.25 [ 0.03, 2.18 ]
0.1 0.2 0.5 1 2 5 10


Analysis 50.11. Comparison 50 HA/hylan versus placebo, Outcome 11 Safety: number of patients
discontinued due to adverse events.
Outcome: 11 Safety: number of patients discontinued due to adverse events
Study or subgroup HA Control Risk Ratio Weight Risk Ratio

Altman 2004 13/173 6/174 49.9 % 2.18 [ 0.85, 5.60 ]
Huskisson 1999 2/50 1/50 8.3 % 2.00 [ 0.19, 21.36 ]
Lohmander 1996 2/120 5/120 41.7 % 0.40 [ 0.08, 2.02 ]
Subtotal (95% CI) 343 344 100.0 % 1.42 [ 0.69, 2.93 ]

Total events: 17 (HA), 12 (Control)
Pham 2004 4/131 2/85 100.0 % 1.30 [ 0.24, 6.93 ]
Subtotal (95% CI) 131 85 100.0 % 1.30 [ 0.24, 6.93 ]

0.1 0.2 0.5 1 2 5 10

Favours HA Favours control

Analysis 50.12. Comparison 50 HA/hylan versus placebo, Outcome 12 Safety: withdrawals due to lack of
efficacy.


Altman 1998 17/164 16/168 35.2 % 1.09 [ 0.57, 2.08 ]
Altman 2004 10/173 6/174 13.3 % 1.68 [ 0.62, 4.51 ]
Brandt 2001 13/114 15/112 33.7 % 0.85 [ 0.42, 1.71 ]
Huskisson 1999 2/50 8/50 17.8 % 0.25 [ 0.06, 1.12 ]
Subtotal (95% CI) 501 504 100.0 % 0.94 [ 0.63, 1.40 ]

Pham 2004 1/131 2/85 100.0 % 0.32 [ 0.03, 3.52 ]
Subtotal (95% CI) 131 85 100.0 % 0.32 [ 0.03, 3.52 ]

0.1 0.2 0.5 1 2 5 10


Analysis 50.13. Comparison 50 HA/hylan versus placebo, Outcome 13 Safety: number of adverse events for
injection site pain.
Outcome: 13 Safety: number of adverse events for injection site pain

Altman 1998 38/164 22/168 65.9 % 1.77 [ 1.10, 2.86 ]
Tamir 2001 18/25 11/24 34.1 % 1.57 [ 0.95, 2.59 ]
Subtotal (95% CI) 189 192 100.0 % 1.70 [ 1.19, 2.44 ]

0.1 0.2 0.5 1 2 5 10

Analysis 50.14. Comparison 50 HA/hylan versus placebo, Outcome 14 Safety: number of adverse events
local skin rash.
Outcome: 14 Safety: number of adverse events local skin rash

Altman 1998 23/164 26/168 80.9 % 0.91 [ 0.54, 1.52 ]
Brandt 2001 5/114 6/112 19.1 % 0.82 [ 0.26, 2.61 ]
Subtotal (95% CI) 278 280 100.0 % 0.89 [ 0.55, 1.43 ]

0.1 0.2 0.5 1 2 5 10


Analysis 50.15. Comparison 50 HA/hylan versus placebo, Outcome 15 Safety: number of patients with

Altman 1998 48/164 26/168 61.4 % 1.89 [ 1.24, 2.90 ]
Brandt 2001 11/114 16/112 38.6 % 0.68 [ 0.33, 1.39 ]
Subtotal (95% CI) 278 280 100.0 % 1.42 [ 0.99, 2.03 ]

0.1 0.2 0.5 1 2 5 10



Brandt 2001 9/114 11/112 51.1 % 0.80 [ 0.35, 1.86 ]
Henderson 1994 21/45 10/44 46.6 % 2.05 [ 1.10, 3.85 ]
Huskisson 1999 2/50 0/50 2.3 % 5.00 [ 0.25, 101.58 ]
Subtotal (95% CI) 233 231 100.0 % 1.48 [ 0.91, 2.41 ]

0.1 0.2 0.5 1 2 5 10


possible study medication related events.
Outcome: 17 Safety: number of patients with possible study medication related events

St. J. Dixon 1988 3/30 0/33 100.0 % 7.68 [ 0.41, 142.77 ]
Subtotal (95% CI) 30 33 100.0 % 7.68 [ 0.41, 142.77 ]

0.1 0.2 0.5 1 2 5 10

Analysis 50.18. Comparison 50 HA/hylan versus placebo, Outcome 18 Safety: number of serious adverse
events.
Outcome: 18 Safety: number of serious adverse events

Karlsson 2002a (AvP) 12/146 11/78 54.9 % 0.58 [ 0.27, 1.26 ]
Karlsson 2002b (SvP) 8/90 11/78 45.1 % 0.63 [ 0.27, 1.49 ]
Subtotal (95% CI) 236 156 100.0 % 0.60 [ 0.34, 1.07 ]

0.1 0.2 0.5 1 2 5 10


Analysis 50.19. Comparison 50 HA/hylan versus placebo, Outcome 19 Safety: number of adverse events
probably or possibly related to treatment.
Outcome: 19 Safety: number of adverse events probably or possibly related to treatment

Karlsson 2002a (AvP) 2/146 2/78 54.9 % 0.53 [ 0.08, 3.72 ]
Karlsson 2002b (SvP) 1/90 2/78 45.1 % 0.43 [ 0.04, 4.69 ]
Subtotal (95% CI) 236 156 100.0 % 0.49 [ 0.11, 2.20 ]

0.1 0.2 0.5 1 2 5 10


Analysis 50.20. Comparison 50 HA/hylan versus placebo, Outcome 20 Safety: number of patients reporting
adverse events.

Karlsson 2002a (AvP) 55/90 33/66 50.5 % 1.22 [ 0.91, 1.64 ]
Karlsson 2002b (SvP) 44/86 33/66 49.5 % 1.02 [ 0.74, 1.41 ]
Subtotal (95% CI) 176 132 100.0 % 1.12 [ 0.91, 1.39 ]

0.1 0.2 0.5 1 2 5 10

Analysis 51.1. Comparison 51 HA/hylan versus NSAID, Outcome 1 Pain after walking (0-100 mm VAS).
Comparison: 51 HA/hylan versus NSAID
Outcome: 1 Pain after walking (0-100 mm VAS)
Mean Mean
Altman 1998 136 25 (24) 143 25 (27) 69.6 % 0.0 [ -5.99, 5.99 ]
Petrella 2002 25 28.9 (27.2) 29 18.1 (27.2) 30.4 % 10.80 [ -3.75, 25.35 ]
Subtotal (95% CI) 161 172 100.0 % 3.28 [ -6.45, 13.02 ]

-100 -50 0 50 100


Analysis 51.2. Comparison 51 HA/hylan versus NSAID, Outcome 2 Patient general satisfaction wtih
treatment (excellent or good vs satisfactory or bad).
Outcome: 2 Patient general satisfaction wtih treatment (excellent or good vs satisfactory or bad)
Study or subgroup Hyaluronic acid Celecoxib Risk Ratio Weight Risk Ratio
1 HA arm versus regular dose celecoxib

Wu 2004 18/30 29/30 100.0 % 0.62 [ 0.46, 0.84 ]
Subtotal (95% CI) 30 30 100.0 % 0.62 [ 0.46, 0.84 ]

Total events: 18 (Hyaluronic acid), 29 (Celecoxib)
2 HA + low dose celecoxib arm versus regular dose celecoxib
Wu 2004 30/30 29/30 100.0 % 1.03 [ 0.94, 1.13 ]
Subtotal (95% CI) 30 30 100.0 % 1.03 [ 0.94, 1.13 ]

3 HA + voluntary dose of celecoxib arm versus regular dose of celecoxib
Wu 2004 29/30 29/30 100.0 % 1.00 [ 0.91, 1.10 ]
Subtotal (95% CI) 30 30 100.0 % 1.00 [ 0.91, 1.10 ]

0.1 0.2 0.5 1 2 5 10

Favours celecoxib Favours HA

Analysis 51.3. Comparison 51 HA/hylan versus NSAID, Outcome 3 Safety: total withdrawals overall.

Adams 1995 4/31 3/34 5.4 % 1.46 [ 0.36, 6.02 ]
Altman 1998 59/164 50/163 94.6 % 1.17 [ 0.86, 1.60 ]
Subtotal (95% CI) 195 197 100.0 % 1.19 [ 0.88, 1.61 ]

Pham 2004 9/131 5/85 100.0 % 1.17 [ 0.41, 3.37 ]
Subtotal (95% CI) 131 85 100.0 % 1.17 [ 0.41, 3.37 ]

0.1 0.2 0.5 1 2 5 10


Analysis 51.4. Comparison 51 HA/hylan versus NSAID, Outcome 4 Safety: number of withdrawals due to
inefficacy.
Outcome: 4 Safety: number of withdrawals due to inefficacy
Study or subgroup Hyaluronic acid Celecoxib regular Risk Ratio Weight Risk Ratio
Pham 2004 1/131 1/85 0.65 [ 0.04, 10.23 ]
Wu 2004 7/30 0/30 15.00 [ 0.89, 251.42 ]
0.01 0.1 1 10 100

Favours HA Favours Celecoxib
Analysis 52.1. Comparison 52 HA/hylan versus Methylprednisolone acetate, Outcome 1 Function: range of
motion (active flexion in degrees).
Comparison: 52 HA/hylan versus Methylprednisolone acetate
Outcome: 1 Function: range of motion (active flexion in degrees)
Mean Mean
Leardini 1987 20 113.4 (12.97) 20 112.4 (15.21) 16.0 % 1.00 [ -7.76, 9.76 ]
Pietrogrande 1991 45 121.38 (15.7) 45 112.75 (15.7) 29.2 % 8.63 [ 2.14, 15.12 ]
Tascioglu 2003 28 116.36 (7.79) 27 114.2 (9.98) 54.7 % 2.16 [ -2.58, 6.90 ]
Subtotal (95% CI) 93 92 100.0 % 3.87 [ 0.36, 7.37 ]

Leardini 1987 20 116.7 (12.52) 20 114.3 (11.18) 18.6 % 2.40 [ -4.96, 9.76 ]
-10 -5 0 5 10
(Continued . . . )

(. . . Continued)
Mean Mean
Pietrogrande 1991 45 121.1 (16.03) 45 113.35 (15.36) 23.9 % 7.75 [ 1.26, 14.24 ]
Tascioglu 2003 28 115.76 (7.72) 27 113.4 (8.1) 57.5 % 2.36 [ -1.82, 6.54 ]
Subtotal (95% CI) 93 92 100.0 % 3.66 [ 0.48, 6.83 ]

-10 -5 0 5 10
Analysis 53.1. Comparison 53 HA versus HA, Outcome 1 Pain in movement (number of patients improved).
Comparison: 53 HA versus HA
Outcome: 1 Pain in movement (number of patients improved)
SLM-10
and NRD
Study or subgroup 101 Artz Risk Ratio Weight Risk Ratio
Kawabata 1993 59/82 60/74 59.2 % 0.89 [ 0.75, 1.06 ]
Yamamoto 1994 31/53 57/86 40.8 % 0.88 [ 0.67, 1.16 ]
Subtotal (95% CI) 135 160 100.0 % 0.89 [ 0.76, 1.03 ]

Total events: 90 (SLM-10 and NRD 101), 117 (Artz)
0.1 0.2 0.5 1 2 5 10

Favours Artz Favours NRD101/SLM10

Analysis 53.2. Comparison 53 HA versus HA, Outcome 2 Pressure pain (number of patients improved).
NRD 101
AND
Kawabata 1993 48/75 54/66 53.1 % 0.78 [ 0.64, 0.96 ]
Yamamoto 1994 60/94 48/84 46.9 % 1.12 [ 0.88, 1.42 ]
Subtotal (95% CI) 169 150 100.0 % 0.94 [ 0.80, 1.10 ]

Total events: 108 (NRD 101 AND SLM-10), 102 (Artz)
0.1 0.2 0.5 1 2 5 10

Favours Artz Favours NRD101/SLM10

Analysis 53.3. Comparison 53 HA versus HA, Outcome 3 Lequesne Index (0-24).
Mean Mean
Study or subgroup HA HA Difference Weight Difference
McDonald 2000 114 7.92 (4.09) 119 7.46 (4.08) 100.0 % 0.46 [ -0.59, 1.51 ]
Subtotal (95% CI) 114 119 100.0 % 0.46 [ -0.59, 1.51 ]

Bayramoglu 2003 16 7.6 (3.7) 12 8.6 (2.5) 16.6 % -1.00 [ -3.30, 1.30 ]
McDonald 2000 114 6.91 (4.22) 119 6.36 (3.74) 83.4 % 0.55 [ -0.48, 1.58 ]
Subtotal (95% CI) 130 131 100.0 % 0.29 [ -0.64, 1.23 ]

-10 -5 0 5 10
Favours HA Favours HA

Analysis 53.4. Comparison 53 HA versus HA, Outcome 4 Patient global assessment.
Outcome: 4 Patient global assessment
Study or subgroup HA HA Risk Ratio Weight Risk Ratio

Kawabata 1993 56/82 53/74 48.1 % 0.95 [ 0.78, 1.17 ]
Roman 2000 17/30 12/19 12.7 % 0.90 [ 0.56, 1.43 ]
Yamamoto 1994 50/81 43/72 39.3 % 1.03 [ 0.80, 1.33 ]
Subtotal (95% CI) 193 165 100.0 % 0.98 [ 0.84, 1.14 ]

Total events: 123 (HA), 108 (HA)
McDonald 2000 87/125 92/127 83.2 % 0.96 [ 0.82, 1.13 ]
Roman 2000 15/30 15/19 16.8 % 0.63 [ 0.41, 0.97 ]
Subtotal (95% CI) 155 146 100.0 % 0.91 [ 0.78, 1.05 ]

Roman 2000 10/30 3/19 100.0 % 2.11 [ 0.67, 6.70 ]
Subtotal (95% CI) 30 19 100.0 % 2.11 [ 0.67, 6.70 ]

Karras 2001 49/73 68/86 100.0 % 0.85 [ 0.70, 1.03 ]
Subtotal (95% CI) 73 86 100.0 % 0.85 [ 0.70, 1.03 ]

0.1 0.2 0.5 1 2 5 10

Favours HA Favours HA

ADDITIONAL TABLES
Table 1. Discrepancies between RevMan analysis and published reports
Product Study ID Outcome mea- p value Analysis popu- Statistical test Description
sure lation
Adant Roman 2000 Patient global as- P (paper): <0.05, ITT chi-square of At three months
sessment R (report):0.07 95% CI P reports signifi-
cance, 50% ver-
sus 21.1%
Painful injection P:<0.001, R:0.4 ITT chi-square of 8 of

95% CI 49=16.3% Total
population, 6 of
30=20% Adant,
and 2 of 19=
10.5% Hyalgan.
Appears an error
in P as they re-
port 8 of 49=
20% Total pop-
ulation and 16.
3% Adant
BioHy Thompson 2002 Patient global P:0.03, R:0.5 ITT Wilcoxon’s two- P reports signifi-
(Euflexxa) (subjective) sample test cance comparing
assessment number
of patients very
satisfied between
groups. R com-
pares very satis-
fied and satisfied
versus slightly
satisfied and dis-
satisfied
Euflexxa Kirchner 2005 WOMAC P: ns, R: 0.02 ITT one-way P reports no sta-
OA Index physi- ANOVA (GLM) tistically sig-
cal function sub- nificant between
scale group difference
whereas RevMan
detected a statis-
tically significant
be-
tween group dif-
ference both at 1
to 4 and 5 to 13
weeks postinjec-
tion

Table 1. Discrepancies between RevMan analysis and published reports (Continued)
Euflexxa Kirchner 2005 Number of pa- P: 0.038, R: 0.05 ITT Cochran-Man- P reports signifi-
tients symptom- tel-Haenszel test cance. R no sta-
free (WOMAC tistically signifi-
pain) cant difference
Euflexxa Kirchner 2005 Number of pa- P: 0.03, R: 0.23 ITT Wilcoxon’s two- P reports signifi-
tients as- sample test cance whereas R
sessing the treat- detects
ment as ’very sat- no difference but
isfied’ (P) or ’very this may be at-
satisfied or satis- tributable to the
fied’ (R) categories which
were compared
Euflexxa Kirchner 2005 Number of pa- P: 0.013, R: 0.02 ITT Cochran-Man- Both P and R re-
tients tel-Haenszel test port signifi-
requiring rescue cance, but P val-
medication dur- ues differ.
ing trial
Durolane Altman 2004 WOMAC OA P: ns; R:0.04 ITT Wilcoxon P reports no sta-
Index pain sub- rank sum test tistically signifi-
scale for change from cant be-
baseline tween-group dif-
ference while R
detected a sta-
tistically signifi-
cant difference at
week 2 in favour
of saline
Altman 2004 WOMAC P:s; R: ns ITT Wilcoxon P reports a statis-

OA Index stiff- rank sum test tically significant
ness subscale for change from be-
baseline tween-group dif-
ference at week
26 while R de-
tected no statis-
tically significant
between-group
difference
Altman 2004 WOMAC P:s; R:ns ITT Wilcoxon P reports a statis-

OA Index physi- rank sum test tically significant
cal function sub- for change from between-
scale baseline group difference
at week 2 while R
detected no sta-

tistically signifi-
cant between-
group difference
Suplasyn Petrella 2002 Pain relief P:HA=NSAID ITT within-group re- P concludes
peated ANOVA HA=NSAID for
resting pain re-
lief. R finds no
difference
Pain with physi- HA>PL ITT within-group re- P concludes HA

cal activity peated ANOVA may be supe-
rior to PL alone/
NSAID alone. R
no difference
Pain at rest PL>HA P value ITT within-group re- P does not report
0.04 peated ANOVA between-group
comparisons. R
found difference
in favour of PL
Functional per- HA>PL ITT within-group re- P concludes HA

formance peated ANOVA may be supe-
rior to PL alone/
NSAID alone. R
finds no differ-
ence
Orthovisc Brandt 2001 WOMAC pain P:0.04, R:0.05 Effectiveness Wilcoxon rank P concludes
categoric sum tests HA>PL. R RR
improvement of 58% versus
40% no signifi-
cant difference
Six month pain P:ns, R:0.008 ITT one-way P: no significant

on walking ANOVA differ-
ence, R: signifi-
cant difference in
favour of Ortho-
visc
Six month P:ns, R:0.03 ITT one-way P: no significant

Lequesne Index ANOVA differ-
ence, R: signifi-
cant difference in
favour of Ortho-
visc

Six month flex- P:ns, R:0.04 ITT one-way P: no significant

ion ANOVA differ-
ence, R: signifi-
cant difference in
favour of Ortho-
visc
Kalay 1997 Activity P:0.0303, R:0.5 ITT Mann-Whitney P: significant dif-

pain 21st day (1 U test ference in favour
to 4 weeks) of OR+PT,
R: no significant
difference
Night pain 56th P:0.0284, R:0. ITT Mann-Whitney P: significant dif-

day (5 to 13 07 U test ference in favour
weeks) of OR+PT,
R: no significant
difference
Walk time 21st P:0.0049, R: 0.4 ITT Mann-Whitney P: significant dif-

day (1 to 4weeks) U test ference in favour
of OR+PT,
R: no significant
difference
Walk time 56th P:0.0001, R:0.2 ITT Mann-Whitney P: significant dif-

day (5 to 13 U test ference in favour
weeks) of OR+PT,
R: no significant
difference
Hylan G-F 20 Dickson 2001 WOMAC pain P:0.04, R:0.11 ITT re- P: significant dif-
(5 to 13 weeks) peated measures ference in favour
ANOVA cor- of Hylan G-F 20
rected for statis- compared to PL,
tically significant R: no significant
covariates difference
WOMAC func- P:0.05, R:0.01 ITT repeated mea- P: 0.05 which

tion (5 to 13 sures ANOVA we would clas-
weeks) sify as not signif-
icant; Hylan G-F
20 > PL
Lequesne Index P:0.17, R:0.02 ITT repeated mea- P: no

(5 to 13 weeks) sures ANOVA significnt differ-
ence, R: signif-
icant difference
in favour of Hy-

lan G-F 20 com-

pared to PL
Adams 1995 Pain at rest (5 to P:0.05, R:0.6 ITT ANOVA P: Hylan G-F
13 weeks) 20 > NSAID,
R: no significant
difference
Hyalgan Dougados 1993 Lequesne Index P:0.046,R:0.17 One-sided Stu- P: Hyalgectin >
(45 to 52 weeks) dent’s t-test PL, R: no signif-
icant difference
Hyalgan Tsai 2003 WOMAC func- P:0.0038, R:0. ITT ANOVA P: Hyalgan > PL,
tion (14 to 26 07 R: no significant
weeks) difference
Hyalgan Jubb 2003 Joint space width P:ns,R:0.03 ITT t-test P: No significant
(week 52) difference in to-
tal popula-
tion, but signifi-
cant difference in
>=4.6 mm sub-
group; R: dif-
ference in total
population but
not in the 2 sub-
groups
Hylan G-F 20 Auerbach 2002 Pain under load P:0.001, R:0.2 ITT Wilcoxon test P: Hylan G-F 20
(45 to 52 weeks) > O2;
R: no significant
difference
WOMAC pain P:0.003, R:0.3 ITT Wilcoxon test P: Hylan G-F 20

(45 to 52 weeks) > O2;
R: no significant
difference
WOMAC func- P:0.001, R:0.16 ITT Wilcoxon test P: Hylan G-F 20

tion (45 to 52 > O2;
weeks) R: no significant
difference
Artz Day 2004 WOMAC pain P:0.045, R:0.07 ITT Repeated mea- P: Artz > PL;
(5 to 13 weeks) sures ANCOVA R: no significant
difference
WOMAC stiff- P:0.024, R:0.07 ITT Repeated mea- P: Artz > PL;
ness (5 to 13 sures ANCOVA R: no significant
weeks) difference

Artz Puhl 1993 Lequesne Index P:0.043, R:0.7 ITT Simultaneous t- P: Artz > PL;
(1 to 4 weeks) tests, MANOVA R: no significant
[t6] difference
Lequesne Index P:0.0053, R: 0.5 ITT Simultaneous t- P: Artz > PL;

(5 to 13 weeks) tests, MANOVA R: no significant
[t14] difference
Hyalgan Jubb 2003 Pain (number of P:0.04, R:0.16 ITT Chi-square P: HA > PL;
pa- R: no significant
tients improved) difference
(5-13 wk)
Hyalgan Forster 2003 Knee P: ns, R:0.03 ITT Mann-Whitney P: no significant

Society Score (six difference; R:
months) HA>Arthroscopy
Hyalgan Jones 1995 Pain at rest (week P:significant; R: Not reported in P: significant dif-
29) 0.09 publication. ference in favour
of HA versus TH
(Table III) but
with ITT, LOCF
no sta-
tistically signifi-
cant difference.
R: based on Ta-
ble III, no signif-
icant difference
Pain on P:significant, R: Not reported in P: significant dif-

nominated activ- 0.4 publication. ference in favour
ity (week 29) of HA versus TH
(Table III) but
with ITT, LOCF
no sta-
tistically signifi-
cant difference.
R: based on Ta-
ble III, no signif-
icant difference
Hyalgan Listrat 1997 AIMS (45 to 52 P:0.047, R:0.6 ITT ANCOVA P: HA > conven-
weeks) tional care;
R: no significant
difference

Table 2. Clinical benefit table: Adant. Patient global assessment
Study Time Treatment Outcome No. of pts No. of pts Risk (%) Risk NNT
improved difference
Roman 1-4 wk E: Adant Number of 13 30 43 6 16.7

2000 patients ex-
cellent/good
C: Hyalgan 7 19 37
5-13 wk E: Adant Number of 15 30 50 29 3.5

patients ex-
cellent/good
C: Hyalgan 4 19 21
14-26 wk E: Adant Number of 10 30 33 17 5.9

patients ex-
cellent/good
C: Hyalgan 3 19 16
Table 3. Clinical benefit table: Adant. Safety
Outcome Event rate Event rate Relative risk Abs risk diff NNH (95% #/100 Adant #/100 Hyal-
Hyalgan Adant 95%CI 95% CI CI) with AE gan withAE
Painful injec- 10.5% 2/19 20% 6/30 190% (43 to 9% (-10% to 11 20 11

tion 846%) 29%)
Table 4. Clinical benefit table: Artz versus placebo. Dichotomous outcome measures
Study Time Treatment Outcome No. No. of pts Risk (%) Risk difference NNT
improved
Lohmander 1-4 wk E: Artzal Number of 59 96 61 1 100

1996 patients im-
proved
C: Saline 56 93 60
Shichikawa 1-4 wk E: Artz Number of 87 103 84 20 5

1983a patients im-
proved
C: Vehicle 67 105 64

Table 4. Clinical benefit table: Artz versus placebo. Dichotomous outcome measures (Continued)
Shichikawa 1-4 wk E: Artz Number of 38 48 79 9 11

1983b patients im-
proved
C: Vehicle 35 50 70
Lohmander 5-13 wk E: Artzal Number of 53 96 55 0 0

1996 patients im-
proved
C: Saline 51 93 55
Puhl 1993 5-13 wk E: Artz Number of 86 95 91 10 10

patients im-
proved
C: Vehicle 81 100 81
Lohmander 14-26 wk E: Artzal Number of 58 96 60 14 7.1

1996 patients im-
proved
C: Saline 43 93 46
Karlsson 14-26 wk E: Artzal Num- 2 90 2 -9 11

2002a ber of clinical
failures
C: Saline 7 66 11
Karlsson 45-52 wk E: Artzal Num- 26 66 39 -15 6.7

2002a ber of clinical
failures
C: Saline 26 48 54
Karlsson 14-26 wk E: Artzal Number of 39 90 43 10 10

2002a survivors
C: Saline 22 66 33
Table 5. Clinical benefit table: Artz versus placebo. Continuous outcome measures
Study Time Treatment Outcome N of Pts Baseline End of Study Absolute Relative Dif-
Mean Mean Benefit ference
Lohmander 1-4 wk E: Artzal Pain (0-100 96 49.76 36.64 2.48 (W) 5.2% (W)
1996 mm VAS)

Table 5. Clinical benefit table: Artz versus placebo. Continuous outcome measures (Continued)
C: Saline 93 47.84 32.24
Lohmander 5-13 wk E: Artzal Pain (0-100 96 49.76 34.69 -2.46 (I) -5.1% (I)
1996 mm VAS)
C: Saline 93 47.84 35.23
Lohmander 14-26 wk E: Artzal Pain (0-100 96 49.76 33.65 -3.67 (I) -7.7% (I)
1996 mm VAS)
C: Saline 93 47.84 35.40
Lohmander 1-4 wk E: Artzal Activity level 96 62.98 43.69 4.77 (W) 7.4% (W)
1996 (0-100 mm
VAS)
C: Saline 93 64.71 40.65
Lohmander 5-13 wk E: Artzal Activity level 96 62.98 45.17 4.71 (W) 7.3% (W)
1996 (0-100 mm
VAS)
C: Saline 93 64.71 42.19
Lohmander 14-26 wk E: Artzal Activity level 96 62.98 41.67 -0.68 (I) -1.1% (I)
1996 (0-100 mm
VAS)
C: Saline 93 64.71 44.08
Lohmander 14-26 wk E: Artzal Lequesne (0- 120 9.89 7.98 -0.17 (I) -1.8% (I)
1996 24)
C: Saline 120 9.56 7.82
Lohmander 1-4 wk E: Artzal Knee func- 96 53.76 38.00 2.17 (W) 4.1% (W)
1996 tion (0-100
mm VAS)
C: Saline 93 53.02 35.09
Lohmander 5-13 wk E: Artzal Knee func- 96 53.76 42.34 4.09 (W) 7.7% (W)
1996 tion (0-100
mm VAS)
C: Saline 93 53.02 37.51

Lohmander 14-26 wk E: Artzal Knee func- 96 53.76 38.27 -2.3 (I) -4.3% (I)
1996 tion (0-100
mm VAS)
C: Saline 93 53.02 39.83
Karlsson 1-4 wk E: Artzal Pain on 92 64 44 1.0 (W) 1.5% (W)

2002a weight bear-
ing (0-100
mm VAS)
C: Saline 66 65 44
Karlsson 5-13 wk E: Artzal Pain on 92 64 42 -3 (I) -4.6% (I)

2002a weight bear-
ing (0-100
mm VAS)
C: Saline 66 65 46
Karlsson 14-26 wk E: Artzal Pain on 92 64 48 5 (W) 7.7% (W)

2002a weight bear-
ing (0-100
mm VAS)
C: Saline 66 65 44
Karlsson 5-13 wk E: Artzal WOMAC 92 48.7 34.7 4.2 (W) 8.6% (W)
2002a (0-100 mm
VAS)
C: Saline 66 48.9 30.7
2002a (0-100 mm
VAS)
C: Saline 66 48.9 32.1
Karlsson 14-26 wk E: Artzal Lequesne In- 92 13.9 10.0 0.8 (W) 5.9% (W)
2002a dex (0-24)
C: Saline 66 13.6 8.9
Puhl 1993 1-4 wk E: Artz Pain (0-100 95 54.10 29.14 -4.96 (I) -9.6% (I)
mm VAS)
C: Vehicle 100 51.40 31.40

Puhl 1993 5-13 wk E: Artz Pain (0-100 95 54.10 26.50 -10.2 (I) -19.8 (I)
mm VAS)
C: Vehicle 100 51.40 34.00
Puhl 1993 1-4 wk E: Artz Lequesne In- 95 10.4 7.19 -0.81 (I) -8.6% (I)
dex (0-24)
C: Vehicle 100 9.4 7.00
Puhl 1993 5-13 wk E: Artz Lequesne In- 95 10.4 6.43 -1.36 (I) -14.5% (I)
dex (0-24)
C: Vehicle 100 9.4 6.79
Shichikawa 1-4 wk E: Artz Pain (0-3) 52 1.03 0.66 0.02 (W) 1.8% (W)
1983b
C: Vehicle 55 1.12 0.73
Shichikawa 1-4 wk E: Artz Range of 52 133.4 135.65 -1.75 (W) -1.4% (W)
1983b motion (flex-
ion degrees)
C: Vehicle 55 128.6 132.60
Day 2004 5-13 wk E: Artz WOMAC 116 7.96 3.84 -0.05 (I) -0.6% (I)
pain (0-20
Likert)
C: Saline 124 8.68 4.61
Day 2004 E: Artz WOMAC 116 28.07 11.41 4.06 (W) 13% (W)
function (0-
68 Likert)
C: Saline 124 31.25 10.53
Day 2004 E: Artz WOMAC 116 3.70 1.42 0.07 (W) 1.8% (W)
stiffness (0-
8)
C: Saline 124 3.79 1.44

Table 6. Clinical benefit table. Artz versus Hylan G-F 20. Dichotomous outcome measure
Study Time Treatment Outcome No. No. of pts Risk (%) Risk NNT
improved difference
Karlsson 14-26 wk E: Artzal Number of 2 90 2 -5 20

2002c clinical fail-
ures
C: Hylan G- 6 86 7
F 20
Karlsson 14-26 wk E: Artzal Number of 39 90 43 -1 100

2002c survivors
C: Hylan G- 38 86 44
F 20
Karlsson 45-52 wk E: Artzal Number of 26 66 39 -7 14.3

2002c clinical fail-
ures
C: Hylan G- 32 70 46
F 20
Table 7. Clinical benefit table: Artz versus Hylan G-F 20. Continuous outcome measure
Karlsson 1-4 wk E: Artzal Pain on 92 64 44 -2 (I) -3.2% (I)

2002c weight bear-
ing (0-100
mm VAS)
C: Hylan G- 88 63 45
F 20
Karlsson 5-13 wk E: Artzal Pain on 92 64 42 0 0%

2002c weight bear-
ing (0-100
mm VAS)
C: Hylan G- 88 63 41
F 20
Karlsson 14-26 wk E: Artzal Pain on 92 64 48 4 (W) 6.3% (W)

2002c weight bear-
ing (0-100
mm VAS)

Table 7. Clinical benefit table: Artz versus Hylan G-F 20. Continuous outcome measure (Continued)
C: Hylan G- 88 63 43
F 20
2002c (0-100 mm
VAS)
C: Hylan G- 88 48.7 31.7

F 20
2002c (0-100 mm
VAS)
C: Hylan G- 88 48.7 31.9

F 20
Karlsson 14-26 wk E: Artzal Lequesne In- 92 13.9 10.0 0.5 (W) 3.7% (W)
2002c dex (0-24)
C: Hylan G- 88 13.4 9.0

F 20
Table 8. Clinical benefit table: Euflexxa (Arthrease, BioHy, Nuflexxa) versus placebo
Outcome Event rate PL Event rate TR RR (95% CI) AR difference NNH (95% No. pt taking No. pt taking
group group (95%CI CI) BioHy PL
Painful injec- 11/24 (45.8 18/25 (72. 157% (95% -26% (0% 4 72 46
tion %) 0%) to 259%) to53%)
Table 9. Clinical benefit table: Euflexxa (Arthrease, BioHy) versus Hylan G-F 20
Thompson 1-4 wk E: BioHy WOMAC 160 49.20 21.70 -1.00 (I) -1.9% (I)
2002 (Arthrease) pain (0-100
mm VAS)
C: Hylan G- 161 51.90 25.40

F 20
Thompson 5-13 wk E: BioHy WOMAC 160 49.20 19.20 -1.10 (I) -2.1% (I)
2002 (Arthrease) pain (0-100
mm VAS)

Table 9. Clinical benefit table: Euflexxa (Arthrease, BioHy) versus Hylan G-F 20 (Continued)
C: Hylan G- 161 51.90 23.00

F 20
Kirchner 1-4 wk E: Euflexxa WOMAC 160 47.0 22.3 -1.30 (I) -2.6% (I)
2005 phys-
ical function
(0-100 mm
VAS)
C: Hylan G- 161 50.8 27.4

F 20
Kirchner 5-13 wk E: Euflexxa WOMAC 157 47.0 20.0 -1.60 (I) -3.1% (I)
2005 phys-
ical function
(0-100 mm
VAS)
C: Hylan G- 158 50.8 25.4

F 20
Kirchner 1-4 wk E: Euflexxa WOMAC 160 43.2 21.2 1.6 (W) 3.3% (W)
2005 stiffness
(0-100 mm
VAS)
C: Hylan G- 161 47.8 24.2

F 20
Kirchner 5-13 wk E: Euflexxa WOMAC 157 43.2 18.2 0.8 (W) 1.7% (W)
2005 stiffness
(0-100 mm
VAS)
C: Hylan G- 158 47.8 22.0

F 20
Table 10. Clinical benefit table: Euflexxa (BioHy, Arthrease) versus Hylan G-F 20. Safety
Outcome Event rate in Event rate in RR (95% CI) AR difference NNH No. pts tak- No. pts tak-
BioHy Hylan (95%CI (95%CI) ing BioHy ing Hylan
Total with- 2.5% 4/160 1.9% 3/161 134% (31 to 1% (-3% to 3 2

drawals overall 590%) 4%)
Withdrawals 0% 0/160 0.6% 1/161 34% (1 to -1% (-2% to 0 1

due to adverse 817%) 1%)
events

Table 10. Clinical benefit table: Euflexxa (BioHy, Arthrease) versus Hylan G-F 20. Safety (Continued)
Withdrawals 0% 0/160 0% 0/161 0% 0% (-1% to 0 0 0

due to lack of 1%)
efficacy
Number of 1.9% 3/160 1.2% 2/161 151% (26 to 1% (-2% to 2 1

patients with 891%) 3%)
serious adverse
events
Joint effusion 0.6% 1/160 8% 13/161 8% (1 to 58%) -7% (-12% to 14 (13-30) 8 8

-3%)
Number of pts 34% 54/160 40% 65/161 84% (63 to -7% (-17% to 16 (ns) 40 40
reporting ad- 111%) 4%)
verse events
Table 11. Clinical benefit table: Durolane. Continuous outcome measures
Altman 1-4 wk E: Durolane WOMAC 172 9.90 6.75 0.24 (W) 2.3% (W)
2004 pain (0-20)
C: Saline 174 10.42 7.03
2004 function (0-
68)
C: Saline 174 32.16 23.64
2004 stiffness (0-
8)
C: Saline 174 4.30 3.27
2004 pain (0-20)
C: Saline 174 10.42 7.00
2004 function (0-
68)
C: Saline 174 32.16 23.44

Table 11. Clinical benefit table: Durolane. Continuous outcome measures (Continued)
2004 stiffness (0-
8)
C: Saline 174 4.30 3.25
2004 pain (0-20)
C: Saline 174 10.42 7.53
2004 function (0-
68)
C: Saline 174 32.16 24.74
2004 stiffness (0-
8)
C: Saline 174 4.30 3.48
Table 12. Clinical benefit table. Durolane. Dichotomous outcome measures
improved difference
Altman 1-4 wk E: Durolane Responder: 63 172 37 7 14

2004 reduction
in WOMAC
pain score of
at least
40% with an
absolute im-
provement
of at least 5
points
C: Saline 52 174 30

2004 reduction
in WOMAC
pain score of
at least
40% with an
absolute im-

Table 12. Clinical benefit table. Durolane. Dichotomous outcome measures (Continued)
provement
of at least 5
points
C: Saline 61 174 35

2004 reduction
in WOMAC
pain score of
at least
40% with an
absolute im-
provement
of at least 5
points
C: Saline 56 174 32

2004 patients only
with
knee OA, re-
duction
in WOMAC
pain score of
at least
40% with an
absolute im-
provement
of at least 5
points
C: Saline 30 109 28

2004 patients only
with
knee OA, re-
duction
in WOMAC
pain score of
at least
40% with an
absolute im-
provement
of at least 5
points

Table 12. Clinical benefit table. Durolane. Dichotomous outcome measures (Continued)
C: Saline 36 109 33

2004 patients only
with
knee OA, re-
duction
in WOMAC
pain score of
at least
40% with an
absolute im-
provement
of at least 5
points
C: Saline 35 109 32
Table 13. Clinical benefit table. Durolane. Safety
Outcome Event rate Event rate RR (95% CI) AR diff (95% NNH (95% No. pts tak- No. pts tak-
Durolane Saline CI) CI) ing Durol ing Salin
Total with- 39 35 1.12 (0.75,1. 0.02 (-0.06,0. 173 174

drawals overall 68) 11)
With- 10 6 1.68 (0.62,4. 0.02 (-0.02,0. 173 174

drawals due to 51) 07)
inefficacy
Withdrawals 13 6 2.18 (0.85,5. 0.04 (-0.01,0. 173 174

due to adverse 60) 09)
events
Num- 3 2 1.51 (0.26,8. 0.01 (-0.02,0. 173 174

ber of patients 92) 03)
affected by de-
vice-related
adverse events
Number of 1 2 0.50 (0.05,5. -0.01 (-0.03, 173 174

patients with 49) 0.01)
injection only
adverse events
Num- 22 15 1.48 (0.79,2. 0.04 (-0.02,0. 173 174

ber of patients 75) 11)
with non-seri-

Table 13. Clinical benefit table. Durolane. Safety (Continued)
ous treatment-
related adverse
events
Num- 112 114 0.99 (0.85,1. -0.01 (-0.11, 173 174

ber of patients 15) 0.09)
with non-se-
rious adverse
events
Number of 101 109 0.93 (0.79,1. -0.04 (-0.15, 173 174

patients with 10) 0.06)
treated unre-
lated adverse
events
Number of 7 3 2.35(0.62,8. 0.02 (-0.01,0. 173 174

patientts with 93) 06)
seri-
ous treatment-
unrelated ad-
verse events
Table 14. Clinical benefit table: Fermathron. Continuous outcome measures
McDonald 1-4 wk E: Fermath- Lequesne In- 114 11.21 7.92 0.37 (W) 3.3% (W)
2000 ron dex (0-24)
C: Hyalart 119 11.12 7.46
McDonald 5-13 wk E: Fermath- Lequesne In- 114 11.21 6.91 0.46 (W) 4.1% (W)
2000 ron dex (0-24)
C: Hyalart 119 11.12 6.36
McDonald 1-4 wk E: Fermath- Pain (0-100 114 56.2 31.3 3.3 (W) 5.8% (W)
2000 ron mm VAS)
C: Hyalart 119 57.2 29.0
McDonald 5-13 wk E: Fermath- Pain (0-100 114 56.2 25.4 1.8 (W) 3.1% (W)
2000 ron mm VAS)
C: Hyalart 119 57.2 24.6

Table 15. Clinical benefit table: Fermathron. Dichotomous outcome measures
improved difference
McDonald 5-13 wk E: Fermath- Num- 87 125 70 2 50

2000 ron ber of pa-
tients much
better/better
C: Hyalart 92 127 72
Table 16. Clinical benefit table: Hyalgan versus placebo. Continuous outcome measures (1)
Study Time Treatment Outcome N of Pts Baseline End of Absolute Relative Dif-
(scale) Mean Study Mean Benefit ference
Carrabba 1-4 wk E: Hyalgan Pain on 20 63.3 41.8 -13.5 (I) -21% (I)
1995 (5) move-
ment (0-100
mm VAS)
C: Saline 20 64.4 56.4
Carrabba 1-4 wk E: Hyalgan Pain on 20 64.2 46.0 -10.2 (I) -15.8% (I)
1995a (3) move-
ment (0-100
mm VAS)
C: Saline 20 64.4 56.4
1995b (5) move-
ment (0-100
mm VAS)
C: Arthro- 20 64.5 59.7

centesis
1995c (3) move-
ment (0-100
mm VAS)
C: Arthro- 20 64.5 59.7

centesis
Corrado 1-4 wk E: Hyalgan Pain on 19 71.2 35.4 -18.5 (I) -31.4% (I)
1995 move-
ment (0-100
mm VAS)

Table 16. Clinical benefit table: Hyalgan versus placebo. Continuous outcome measures (1) (Continued)
C: Saline 16 58.9 41.6
Creamer 1-4 wk E: Hyalgan Pain use re- 12 52.58 41.12 8.99 (W) 16.5% (W)
1994 lated (0-100
mm VAS)
C: Saline 12 54.38 33.93
Henderson 1-4 wk E: Hyalgan Pain 18 43.7 28.1 -1.4 (I) -2.3% (I)
1994 active move-
ment (0-100
mm VAS)
C: Saline 19 53.0 38.8
Henderson 1-4 wk E: Hyalgan Pain 22 48.5 39.8 9.3 (W) 18.9% (W)
1994a active move-
ment (0-100
mm VAS)
C: Saline 25 49.3 31.3
Huskisson 1-4 wk E: Hyalgan Pain walk- 45 67.20 35.29 -15.41 (I) -23.88% (I)
1999 ing (0-100
mm VAS)
C: Saline 48 64.52 48.02
Jubb 2003 1-4 wk E: Hyalgan Pain 208 56.95 43.87 -1.8 (I) -3.3% (I)
on walking
(0-100 mm
VAS)
C: Saline 200 55.15 43.88
Tsai 2003 1-4 wk E: Hyalgan Pain on 50 100 47.85 22.60 -4.0 (I) -8.9% (I)
foot walk (0-
100 mm
VAS)
C: Saline 98 45.15 23.92
1995 (5) move-
ment (0-100
mm VAS)
C: Saline 20 64.4 59.80

1995a (3) move-
ment (0-100
mm VAS)
C: Saline 20 64.4 59.80
1995b (5) move-
ment (0-100
mm VAS)
C: Arthro- 20 64.5 63.20

centesis
1995c (3) move-
ment (0-100
mm VAS)
C: Arthro- 20 64.5 63.20

centesis
Corrado 5-13 wk E: Hyalgan Pain on 19 71.2 29.70 -25.8 (I) -43.8% (I)
1995 move-
ment (0-100
mm VAS)
C: Saline 16 58.9 43.20
Creamer 5-13 wk E: Hyalgan Pain use re- 12 52.58 41.80 1.80 (W) 3.3% (W)
1994 lated (0-100
mm VAS)
C: Saline 12 54.38 41.80
1999 ing (0-100
mm VAS)
C: Saline 45 64.52 50.18
on walking
(0-100 mm
VAS)
C: Saline 200 55.15 50.20

foot walk (0-
100 mm
VAS)
C: Saline 98 45.15 19.78
1999 ing (0-100
mm VAS)
C: Saline 40 64.52 53.68
on walking
(0-100 mm
VAS)
C: Saline 200 55.15 50.14
foot walk (0-
100 mm
VAS)
C: Saline 98 45.15 20.68
(RC) on walking
(0-100 mm
VAS)
C: Saline 200 55.15 50.45
Bragantini 1-4 wk E: Hyalgan Pain sponta- 19 47.74 17.12 -29.5 (I) -62.5% (I)
1987 neous
(0-100 mm
VAS)
C: Saline 18 47.29 46.21
Grecomoro 1-4 wk E: Hyalgan Pain inten- 20 50.71 14.55 -22.9 (I) -48.3% (I)
1987 sity (0-100
mm VAS)
C: Phos- 18 47.32 34.02

phate buffer

Bragantini 5-13 wk E: Hyalgan Pain sponta- 19 47.74 15.59 -31.8 (I) -67.3% (I)
1987 neous
(0-100 mm
VAS)
C: Saline 18 47.29 46.95
Grecomoro 5-13 wk E: Hyalgan Pain inten- 20 50.71 20.80 -17.8 (I) -37.6% (I)
1987 sity (0-100
mm VAS)
C: Phos- 18 47.32 35.18

phate buffer
Tsai 2003 1-4 wk E: Hyalgan WOMAC 100 45.73 23.21 -3.31 (I) -7.3% (I)
pain (0-100
mm VAS)
C: Saline 98 45.09 25.88
pain (0-100
mm VAS)
C: Saline 98 45.09 22.97
pain (0-100
mm VAS)
C: Saline 98 45.09 22.14
function (0-
100 mm
VAS)
C: Saline 98 45.01 28.21
function (0-
100 mm
VAS)
C: Saline 98 45.01 25.31
function (0-
100 mm

VAS)
C: Saline 98 45.01 24.90
Carrabba 1-4 wk E: Hyalgan Lequesne 20 15.1 11.5 -2.5 (I) -17.2% (I)
1995 (5) Index (0-24)
C: Saline 20 14.5 13.4
1995a (3) Index (0-24)
C: Saline 20 14.5 13.4
1995b (5) Index (0-24)
C: Arthro- 20 14.3 14.1

centesis
1995c (3) Index (0-24)
C: Arthro- 20 14.3 14.1

centesis
Dougados 1-4 wk E: Hyalectin Lequesne 49 11.71 8.53 -1.02 (I) -9.32% (I)
1993 Index (0-24)
C: Saline 50 10.94 8.78
Huskisson 1-4 wk E: Hyalgan Lequesne 40 13.4 10.0 -1.5 (I) -10.7% (I)
1999 Index (0-24)
C: Saline 41 14.0 12.1
Carrabba 5-13 wk E: Hyalgan Lequesne 20 15.1 11.6 -2.9 (I) -20% (I)
1995 (5) Index (0-24)
C: Saline 20 14.5 13.9
1995a (3) Index (0-24)
C: Saline 20 14.5 13.9
1995b (5) Index (0-24)

C: Arthro- 20 14.3 14.4

centesis
Carrabba 5-13 wk E: Hyalgan Lequesne 20 14.9 12.0 -3.0 (I) -21% (I)
1995c (3) Index (0-24)
C: Arthro- 20 14.3 14.4

centesis
1999 Index (0-24)
C: Saline 41 14.0 12.4
1999 Index (0-24)
C: Saline 41 14.0 12.6
Dougados 45-52 wk E: Hyalectin Lequesne 47 11.71 7.06 -1.88 (I) -17.18% (I)
1993 Index (0-24)
C: Saline 47 10.94 8.17
Table 17. Clinical benefit table: Hyalgan versus placebo. Continuous outcome measures (2)
Altman 1-4 wk E: Hyalgan Pain after 163 54 25 1 (W) 1.8% (W)

1998 walking 50
feet (0-100
mm VAS)
C: Saline 167 55 25
Altman 5-13 wk E: Hyalgan Pain after 163 54 23 0 0

1998 walking 50
feet (0-100
mm VAS)
C: Saline 167 55 24
Altman 14-26 wk E: Hyalgan Pain after 163 54 18 -2 (I) -3.6% (I)

1998 walking 50
feet (0-100
mm VAS)

C: Saline 167 55 21
Dougados 1-4 wk E: Hyalectin Pain on 52 67.85 34.13 -7.52 (I) -12.16% (I)
1993 move-
ment (0-100
mm VAS)
C: Saline 50 61.82 35.62
Dougados 45-52 wk E: Hyalectin Pain on 47 67.85 28.51 -6.87(I) -11.11% (I)

1993 move-
ment (0-100
mm VAS)
C: Saline 48 61.82 29.35
Carrabba 1-4 wk E: Hyalgan Pain at rest 20 43.6 28.3 -7.1 (I) -15.6% (I)
1995 (5) (0-100 mm
VAS)
C: Saline 20 45.6 37.4
1995a (3) (0-100 mm
VAS)
C: Saline 20 45.6 37.4
1995b (5) (0-100 mm
VAS)
C: Arthro- 20 43.3 40.4

centesis
1995c (3) (0-100 mm
VAS)
C: Arthro- 20 43.3 40.4

centesis
Corrado 1-4 wk E: Hyalgan Pain at rest 19 22.5 9.4 -8.5 (I) -62% (I)
1995 (0-100 mm
VAS)
C: Saline 16 13.7 9.1

Dougados 1-4 wk E: Hyalectin Pain at rest 52 31.44 10.87 -7.72 (I) -28.03% (I)
1993 (0-100 mm
VAS)
C: Saline 48 27.54 14.69
Henderson 1-4 wk E: Hyalgan Pain at rest 18 20.8 17.7 -4.1 (I) -13.5% (I)
1994 (0-100 mm
VAS)
C: Saline 19 30.3 31.3
Henderson 1-4 wk E: Hyalgan Pain at rest 22 25.2 25.3 15 (W) 38.5% (W)
1994a (0-100 mm
VAS)
C: Saline 25 38.9 24.0
1995 (5) (0-100 mm
VAS)
C: Saline 20 45.6 39.9
Carrabba 5-13 wk E: Hyalgan Pain at rest 20 44.7 33.0 -6 (I) -13.2% (I)
1995a (3) (0-100 mm
VAS)
C: Saline 20 45.6 39.9
1995b (5) (0-100 mm
VAS)
C: Arthro- 20 43.3 43.2

centesis
1995c (3) (0-100 mm
VAS)
C: Arthro- 20 43.3 43.2

centesis
Corrado 5-13 wk E: Hyalgan Pain at rest 19 22.5 5.1 -15.9 (I) -116.1% (I)
1995 (0-100 mm
VAS)
C: Saline 16 13.7 12.2

Dougados 45-52 wk E: Hyalectin Pain at rest 47 31.44 11.87 -1.68 (I) -6.10% (I)
1993 (0-100 mm
VAS)
C: Saline 48 27.54 9.65
Henderson 1-4 wk E: Hyalgan Pain at night 18 69.6 45.50 -10.3 (I) -15.1% (I)
1994 (0-100 mm
VAS)
C: Saline 19 68.0 54.20
Henderson 1-4 wk E: Hyalgan Pain at night 22 68.3 60.20 4.4 (W) 6% (W)
1994a (0-100 mm
VAS)
C: Saline 25 73.3 60.80
Corrado 1-4 wk E: Hyalgan Flexion (de- 19 114.7 123.5 2.1 (I) 1.9% (I)
1995 grees)
C: Saline 16 113.3 120.0
Corrado 5-13 wk E: Hyalgan Flexion (de- 19 114.7 125.5 6.2 (I) 5.5% (I)
1995 grees)
C: Saline 16 113.3 117.9
Corrado 1-4 wk E: Hyalgan Synovial 21 20.3 14.10 -2.3 (I) -15% (I)
1995 fluid volume
(ml)
C: Saline 19 15.3 11.40
Dougados 1-4 wk E: Hyalectin Synovial 55 18.5 6.10 -6.4 (I) -46% (I)
1993 fluid volume
(ml)
C: Saline 55 13.9 7.90
Corrado 5-13 wk E: Hyalgan Synovial 21 20.3 2.30 -13.1 (I) -85.6% (I)
1995 fluid volume
(ml)
C: Saline 19 15.3 10.40
Jubb 2001a 45-52 wk E: Hyalgan Joint space 136 4.9 4.80 0 0

width (mm)

C: Saline 137 4.5 4.40
Jubb 2001b 45-52 wk E: Hyalgan Joint space 76 5.9 5.80 0.4 (I) 6.8% (I)
width (mm)
C: Saline 63 5.9 5.40
Jubb 2001c 45-52 wk E: Hyalgan Joint space 60 3.5 3.50 -0.2 (W) -5.9% (W)
width (mm)
C: Saline 74 3.4 3.60
St. J. Dixon 1-4 wk E: Hyalgan Pain on 28 66.52 50.54 -14.13 (I) -21.17% (I)
1988 move-
ment (0-100
mm VAS)
C: Vehicle 33 66.76 64.91
St. J. Dixon 45-52 wk E: Hyalgan Pain on 11 66.52 48.45 -8.31(I) -12.45% (I)
1988 (repeat) move-
ment (0-100
mm VAS)
C: Vehicle 13 66.76 57.00
St. J. Dixon 1-4 wk E: Hyalgan Pain at rest 29 30.86 20.50 -11.61 (I) -54.28% (I)
1988 (0-100 mm
VAS)
C: Vehicle 33 21.39 22.64
St. J. Dixon 45-52 wk E: Hyalgan Pain at rest 11 30.86 25.36 -4.97 (I) -23.24% (I)
1988 (repeat) (0-100 mm
VAS)
C: Vehicle 14 21.39 20.86
Table 18. Clinical benefit table: Hyalgan versus placebo. Dichotomous outcome measures
Study Time Treatment Outcome No. No. of pts Risk (%) Risk Differ- NNT
group improved ence
Creamer 1-4 wk T: Hyalgan Number of 7 12 58 16 6.3

1994 joints with-
out night
pain

Table 18. Clinical benefit table: Hyalgan versus placebo. Dichotomous outcome measures (Continued)
C: Saline 5 12 42

1994 joints with-
out night
pain
C: Saline 5 12 42

1994 joints with-
out rest pain
C: Saline 5 12 42
Creamer 5-13 wk T: Hyalgan Number of 5 12 42 25 4

1994 joints with-
out rest pain
C: Saline 2 12 17
Grecomoro 1 wk T: Hyalgan Number of 16 20 80 58 1.7

1987 joints with
improve-
ment in pain
under load/
walking
C: Phos- 4 18 22
phate buffer
Grecomoro 1 wk T: Hyalgan Num- 15 20 75 42 2.4

1987 ber of joints
with im-
provement
on pain on
touch
C: Phos- 6 18 33
phate buffer
Altman 14-26 wk T: Hyalgan Number of 36 105 34 -12 -8.3

1998 patients
with moder-
ate/marked
pain
C: Saline 53 115 46

Corrado 1-4 wk T: Hyalgan Pa- 6 19 32 -43 -2.3

1995 tient global
assessment
(number of
patients im-
proved)
C: Saline 12 16 75
Creamer 1-4 wk T: Hyalgan Pa- 5 12 42 9 11.1

1994 tient global
assessment
(number of
patients im-
proved)
C: Saline 4 12 33
Formiguera 1-4 wk T: Hyalgan Pa- 8 20 40 -15 -6.7

Sala 1995 tient global
assessment
(number of
patients im-
proved)
C: Saline 11 20 55
Corrado 5-13 wk T: Hyalgan Pa- 14 19 74 -1 -10

1995 tient global
assessment
(number of
patients im-
proved)
C: Saline 12 16 75
Formiguera 5-13 wk T: Hyalgan Pa- 6 20 30 -35 -2.9

Sala 1995 tient global
assessment
(number of
patients im-
proved)
C: Saline 13 20 65
Henderson 14-26 wk T: Hyalgan Pa- 17 40 43 4 25

1994 tient global
assessment
(number of

patients im-
proved)
C: Saline 17 44 39
Huskisson 14-26 wk T: Hyalgan Pa- 10 40 25 -32 -3.1

1999 tient global
assessment
(number of
patients im-
proved)
C: Saline 22 41 57
Dougados 45-52 wk T: Hyalectin Number of 31 47 66 -10 -10

1993 patients rat-
ing treat-
ment effec-
tive
C: Saline 27 48 56
Bragantini 5-13 wk T: Hyalgan Number of 2 19 11 -56 -1.8

1987 joints fairly
good, good,
very good
C: Saline 12 18 67

1994 joints fairly
good, good,
very good
C: Saline 4 12 33
Jubb 2003 5-13 wk T: Hyalgan Pain (num- 88 208 42 6 16.7

ber of
patients im-
proved)
C: Saline 71 200 36
Jubb 2003 32 wk T: Hyalgan Pain (num- 92 208 44 11 9.1

ber of
patients im-
proved)
C: Saline 65 200 33

Bragantini End of treat- T: Hyalgan Num- 16 19 84 34 2.9

1987 ment ber of joints
improved in
walking
pain
C: Saline 9 18 50
Bragantini 5-13 wk T: Hyalgan Num- 17 19 89 50 2

1987 ber of joints
improved in
walking
pain
C: Saline 7 18 39
Grecomoro 1 wk T: Hyalgan Num- 16 20 80 58 1.7

1987 ber of joints
improved in
walking
pain
C: Phos- 4 18 22
phate buffer
Bragantini End of treat- T: Hyalgan Number of 6 18 33 -56 -1.8

1987 ment joints with
improve-
ment in pain
under load
C: Saline 17 19 89
Bragantini 5-13 wk T: Hyalgan Number of 4 18 22 -67 -1.5

1987 joints with
improve-
ment in pain
under load
C: Saline 17 19 89
Table 19. Clinical benefit table: Hyalgan versus arthroscopy. Continuous outcome measures
Study TIme Treatment Outcome N of Pts Baseline End of Study Absolute Relative Dif-
(scale) Mean Mean Benefit ference
Forster 2003 1 wk T: Hyalgan Pain (0-10 18 7.6 6.6 1.0 (W) 13.4% (W)
cm VAS)

Table 19. Clinical benefit table: Hyalgan versus arthroscopy. Continuous outcome measures (Continued)
C: 15 7.5 5.4
Arthroscopy
Forster 2003 5-13 wk T: Hyalgan Pain (0-10 18 7.6 6.0 -0.1 (I) -1.5% (I)
cm VAS)
C: 15 7.5 6.0
Arthroscopy
cm VAS)
C: 15 7.5 6.2
Arthroscopy
cm VAS)
C: 15 7.5 5.7
Arthroscopy
Forster 2003 1 wk T: Hyalgan Knee Society 18 64.4 66.5 -5.6 (W) -13.3% (W)
Function
Scale
C: 15 42.0 49.6
Arthroscopy
Forster 2003 5-13 wk T: Hyalgan Knee Society 18 64.4 67.5 6.3 (W) 14.9% (W)
Function
Scale
C: 15 42.0 51.3
Arthroscopy
Forster 2003 14-26 wk T: Hyalgan Knee Society 18 64.4 73.5 1.0 (I) 2.4% (I)
Function
Scale
C: 15 42.0 50.0
Arthroscopy
Forster 2003 45-52 wk T: Hyalgan Knee Society 18 64.4 75.0 1.5 (I) 3.5% (I)
Function
Scale
C: 15 42.0 51.1
Arthroscopy

Table 19. Clinical benefit table: Hyalgan versus arthroscopy. Continuous outcome measures (Continued)
Forster 2003 1 wk T: Hyalgan Lequesne In- 18 11.4 11.1 2.4 (W) 18.1% (W)
dex (0-24)
C: 15 13.3 10.5
Arthroscopy
Forster 2003 5-13 wk T: Hyalgan Lequesne In- 18 11.4 10.9 1.3 (W) 9.8% (W)
dex (0-24)
C: 15 13.3 11.5
Arthroscopy
Forster 2003 14-26 wk T: Hyalgan Lequesne In- 18 11.4 8.7 -1.2 (I) -8.6% (I)
dex (0-24)
C: 15 13.3 11.7
Arthroscopy
Forster 2003 45-52 wk T: Hyalgan Lequesne In- 18 11.4 8.3 -1.1 (I) -7.9% (I)
dex (0-24)
C: 15 13.3 11.2
Arthroscopy
Table 20. Clinical benefit table: Hyalgan versus corticosteroids and other IA therapy. Dic
group improved Difference
Leardini 1-4 wk T: Hyalgan Num- 8 20 40 0

1987 ber of joints
with moder-
ate/se-
vere pain un-
der load
C: MPA 8 20 40
Leardini 1-4 wk T: Hyalgan Number of 14 20 70 25 4

1991 patients with
moderate/
severe pain
under load
C: MPA 19 20 95

Table 20. Clinical benefit table: Hyalgan versus corticosteroids and other IA therapy. Dic (Continued)
Pietro- 1-4 wk T: Hyalgan Number of 21 45 47 7 14.3

grande 1991 patients with
moderate/
severe pain
under load
C: MPA 18 45 40
Leardini 5-13 wk T: Hyalgan Num- 6 20 30 5 20

1987 ber of joints
with moder-
ate/se-
vere pain un-
der load
C: MPA 7 20 35
Leardini 5-13 wk T: Hyalgan Number of 13 20 65 35 2.9

1991 patients with
moderate/
severe pain
under load
C: MPA 20 20 100
Pietro- 5-13 wk T: Hyalgan Number of 13 44 30 21 4.8

moderate/
severe pain
under load
C: MPA 23 45 51
Leardini 45-52 wk T: Hyalgan Num- 8 15 53 12 8.3

1987 ber of joints
with moder-
ate/se-
vere pain un-
der load
C: MPA 11 17 65

1987 ber of joints
with moder-
ate/severe
walking pain
C: MPA 9 20 45


1987 ber of joints
with moder-
ate/severe
walking pain
C: MPA 10 20 50

1987 ber of joints
with moder-
ate/severe
walking pain
C: MPA 12 17 71
Leardini 1-4 wk T: Hyalgan Num- 1 20 5 15 6.7

1991 ber of pa-
tients with at
least moder-
ate or greater
night pain
C: MPA 4 20 20
Pietro- 1-4 wk T: Hyalgan Num- 5 45 11 9 11.1

grande 1991 ber of pa-
tients with at
least moder-
ate or greater
night pain
C: MPA 1 45 2

1991 ber of pa-
tients with at
least moder-
ate or greater
night pain
C: MPA 4 20 20
Pietro- 5-13 wk T: Hyalgan Num- 0 44 0

grande 1991 ber of pa-
tients with at
least moder-
ate or greater
night pain

C: MPA 2 45 4 4 25

1991 patients with
moder-
ate or greater
rest pain
C: MPA 12 20 60
Pietro- 1-4 wk T: Hyalgan Number of 7 45 16 0 0

moder-
ate or greater
rest pain
C: MPA 7 45 16

1991 patients with
moder-
ate or greater
rest pain
C: MPA 15 20 75
Pietro- 5-13 wk T: Hyalgan Number of 1 44 2 5 20

moder-
ate or greater
rest pain
C: MPA 3 45 7
Frizziero 1-4 wk T: Hyalgan Pa- 21 46 46 -40 2.5

2002 tient global
(number of
patients very
good/good)
C: MPA 32 37 86
Leardini 1-4 wk T: Hyalgan Pa- 11 20 55 10 10

1991 tient global
(number of
patients very
good/good)
C: MPA 9 20 45

Pietro- 1-4 wk T: Hyalgan Pa- 32 45 71 24 4.2

grande 1991 tient global
(number of
patients very
good/good)
C:MPA 21 45 47
Leardini 5-13 wk T: Hyalgan Pa- 10 20 50 15 6.7

1991 tient global
(number of
patients very
good/good)
C: MPA 7 20 35
Pietro- 5-13 wk T: Hyalgan Pa- 31 45 69 36 2.8

grande 1991 tient global
(numbe of
patients very
good/good)
C: MPA 15 45 33
Frizziero 14-26 wk T: Hyalgan Pa- 30 38 79 4 25

2002 tient global
(number of
patients very
good/good)
C: MPA 24 32 75
Graf 14-26 wk T: Hyalgan Patient 25 33 76 30 3.3

1993 (other global (num-
ia therapy) ber of pa-
tients symp-
tom free/
markedly
improved)
C: Mu- 11 24 46
copolysac-
charide poly-
sulfuric acid
ester

Table 21. Clinical benefit table: Hyalgan vs corticosteroids and other IA therapy. Continu
Leardini 1-4 wk T: Hyalgan Pain inten- 20 41.30 13.00 -4.5 (I) -13.5% (I)
1987 sity (0-100
mm VAS)
C: MPA 20 33.40 9.60
1991 sity (0-100
mm VAS)
C: MPA 20 43.54 20.83
Pietro- 1-4 wk T: Hyalgan Pain inten- 45 64.89 20.00 -5.3 (I) -8.2% (I)
grande 1991 sity (0-100
mm VAS)
C: MPA 45 64.89 25.32
1987 sity (0-100
mm VAS)
C: MPA 20 33.40 9.10
1991 sity (0-100
mm VAS)
C: MPA 20 43.54 23.33
Pietro- 5-13 wk T: Hyalgan Pain inten- 45 64.89 19.71 -7.3 (I) -11.3% (I)
grande 1991 sity (0-100
mm VAS)
C: MPA 45 64.89 27.05
1987 sity (0-100
mm VAS)
C: MPA 17 33.40 17.80
Leardini 1-4 wk T: Hyalgan Range of 20 108.40 113.40 -3.2 (W) -3.1% (W)
1987 mo-
tion (flexion
in degrees)

Table 21. Clinical benefit table: Hyalgan vs corticosteroids and other IA therapy. Continu (Continued)
C: MPA 20 104.20 112.40
Pietro- 1-4 wk T: Hyalgan Range of 45 114.13 121.38 3.3 (I) 3% (I)

grande 1991 mo-
tion (flexion
in degrees)
C: MPA 45 108.81 112.75
1987 mo-
tion (flexion
in degrees)
C: MPA 20 104.20 114.30
Pietro- 5-13 wk T: Hyalgan Range of 45 114.13 121.10 2.4 (I) 2.2% (I)
grande 1991 mo-
tion (flexion
in degrees)
C: MPA 45 108.81 113.35
1987 mo-
tion (flexion
in degrees)
C: MPA 17 104.20 108.10
Jones 1995 End of treat- T: Hyalgan Pain on 32 77.2 56.5 -1.6 (I) -2.1% (I)
ment nominated
ac-
tivity (0-100
mm VAS)
C: Triamci- 31 75.8 56.7

nolone hex-
acetonide
Jones 1995 End of treat- T: Hyalgan Pain at rest 32 53.2 39.9 1.4 (W) 2.5% (W)
ment (0-100 mm
VAS)
C: Triamci- 31 55.3 40.6

nolone hex-
acetonide

Jones 1995 End of treat- T: Hyalgan Pain at night 32 57.8 35.9 -2.7 (I) -4.3% (I)
ment (0-100 mm
VAS)
C: Triamci- 31 62.2 43.0

nolone hex-
acetonide
Jones 1995 14-26 wk T: Hyalgan Pain on 12 77.2 44.3 -11.4 (I) -15.0% (I)
nominated
ac-
tivity (0-100
mm VAS)
C: Triamci- 8 75.8 54.3

nolone hex-
acetonide
Jones 1995 14-26 wk T: Hyalgan Pain at rest 12 53.2 28.2 -18.3 (I) -33.1% (I)
(0-100 mm
VAS)
C: Triamci- 8 55.3 48.6

nolone hex-
acetonide
Jones 1995 14-26 wk T: Hyalgan Pain at night 12 57.8 15.4 -16.3 (I) -26.2% (I)
(0-100 mm
VAS)
C: Triamci- 8 62.2 36.1

nolone hex-
acetonide
Graf End of treat- T: Hyalgan Pain (0-30) 33 14.1 19.6 4 (I) 24.7% (I)
1993 (other ment
ia therapy)
C: MPAE 27 16.2 17.7
Graf End of treat- T: Hyalgan Larson func- 33 18.0 19.1 0.6 (I) 3.6% (I)
1993 (other ment tion (0-30)
ia therapy)
C: MPAE 27 16.9 17.4
Graf End of treat- T: Hyalgan Larson total 33 45.7 54.1 5.9 (I) 12.7% (I)
1993 (other ment (0-77)
ia therapy)

C: MPAE 27 46.6 49.1
Graf End of treat- T: Hyalgan Range of 33 8.8 9.1 0.3 (I) 3.5% (I)
1993 (other ment motion (0-
ia therapy) 10)
C: MPAE 27 8.7 8.7
Table 22. Clinical benefit table: Hyalgan versus NSAID. Dichotomous outcome measures
group improved Difference
Altman 14-26 wk T: Hyalgan Number of 69 105 66 4% 25

1998 patients with
moderate/
marked pain
C: Naproxen 70 113 62
Table 23. Clinical benefit table: Hyalgan versus NSAID. Continuous outcome measures
Altman 1-4 wk E: Hyalgan Pain after 50 163 54 25 0 0

1998 foot walk (0-
100 mm
VAS)
Altman 5-13 wk E: Hyalgan Pain after 50 115 54 23 2 (W) 3.7% (W)

1998 foot walk (0-
100 mm
VAS)
Altman 14-26 wk E: Hyalgan Pain after 50 105 54 18 -3 (I) -5.6% (I)

1998 foot walk (0-
100 mm
VAS)

Table 24. Clinical benefit table: Hyalgan versus conventional care. Continuous outcome mea
Listrat 1997 45-52 wk E: Hyalgan Pain overall 19 49.2 32.4 -11.5 (I) -22.1% (I)
(0-100 mm
VAS)
C: Conven- 17 52.1 46.8

tional ther-
apy
Listrat 1997 45-52 wk E: Hyalgan Lequesne In- 19 8.9 7.2 -0.4 (I) -4.3% (I)
dex (0-24)
C: Conven- 17 9.4 8.1

tional ther-
apy
Listrat 1997 45-52 wk E: Hyalgan Joint space 19 4.5 4.0 0.1 (I) 2.9% (I)
width (mm)
C: Conven- 17 3.5 2.9

tional ther-
apy
Listrat 1997 45-52 wk E: Hyalgan Arthroscopy 19 41.8 47.0 -11.5 (I) -21.9% (I)
assess-
ment (0-100
mm VAS)
C: Conven- 17 52.6 69.3

tional ther-
apy
Listrat 1997 45-52 wk E: Hyalgan SFA scoring 19 26.1 29.8 -5.3 (I) -13.6% (I)
system
(0-100 mm
VAS)
C: Conven- 17 39.0 48.0

tional ther-
apy
Listrat 1997 45-52 wk E: Hyalgan Quality of 19 2.6 2.2 -0.6 (I) -27.3% (I)
life (AIMS:
12 item to-
tal)

Table 24. Clinical benefit table: Hyalgan versus conventional care. Continuous outcome mea (Continued)
C: Conven- 17 2.2 2.4

tional ther-
apy
Table 25. Clinical benefit table: Hyalgan+exercise+ultrasound versus exercise+ultrasound.
Mean Study Mean Benefit ference
Huang 2005 End of treat- E: Hyal- Pain (0-10 34 5.6 2.5 -2.5 (I) -45.5% (I)
ment gan+exercise+ultrasound
cm VAS)
C: Exer- 32 5.5 4.9

cise+ultrasound
Huang 2005 52 wk E: Hyal- Pain (0-10 32 5.6 2.0 -4.7 (I) -85.5% (I)
gan+exercise+ultrasound
cm VAS)
C: Exer- 28 5.5 6.6

cise+ultrasound
Huang 2005 End of treat- E: Hyal- Lequesne 34 7.5 4.0 -3.0 (I) -40.5% (I)
Index (0-26)
C: Exer- 32 7.4 6.9

cise+ultrasound
Huang 2005 52 wk E: Hyal- Lequesne 32 7.5 2.5 -5.7 (I) -77.0% (I)
gan+Exercise+ultrasound
Index (0-26)
C: Exer- 28 7.4 8.1

cise+ultrasound
Huang 2005 End of treat- E: Hyal- Range of 34 103 120 23 (I) 22.1% (I)
motion (de-
grees)
C: Exer- 32 104 98
cise+ultrasound
Huang 2005 52 wk E: Hyal- Range of 32 103 124 27 (I) 26.0% (I)

motion (de-
grees)
C: Exer- 28 104 98
cise+ultrasound

Table 25. Clinical benefit table: Hyalgan+exercise+ultrasound versus exercise+ultrasound. (Continued)
Huang 2005 End of treat- E: Hyal- Ambu- 34 72.4 95.6 27.7 (I) 38.8% (I)
lation speed
(metres per
minute)
C: Exer- 32 71.3 75.8

cise+ultrasound
Huang 2005 52 wk E: Hyal- Ambu- 32 72.4 99.3 28.1 (I) 39.4 (I)
lation speed
(metres per
minute)
C: Exer- 28 71.3 70.1

cise+ultrasound
Table 26. Clinical benefit table: Hyalgan plus exercise plus ultrasound versus exercise
cm VAS)
C: Exercise 30 5.3 4.1
cm VAS)
Index (0-26)
Index (0-26)
motion (de-
grees)
C: Exercise 30 103 108

Table 26. Clinical benefit table: Hyalgan plus exercise plus ultrasound versus exercise (Continued)

motion (de-
grees)
C: Exercise 26 103 110
lation speed
(metres per
minute)
C: Exercise 30 72.6 82.9
Huang 2005 52 wk E: Hyal- Ambu- 32 72.4 99.3 14.2 (I) 19.6% (I)
lation speed
(metres per
minute)
C: Exercise 26 72.6 85.3
Table 27. Clinical benefit table: Hyalgan plus exercise plus ultrasound versus control exe
cm VAS)
C: Warmup 32 5.4 4.9

exercises
cm VAS)
C: Warmup 28 5.4 6.6

exercises
Index (0-26)
C: Warmup 32 7.4 6.9

exercises
Index (0-26)
C: Warmup 28 7.4 8.1

exercises
Table 27. Clinical benefit table: Hyalgan plus exercise plus ultrasound versus control exe (Continued)
motion (de-
grees)
C: Warmup 32 101 98
exercises

motion (de-
grees)
C: Warmup 28 101 98
exercises
lation speed
(metres per
minute)
C: Warmup 32 73.9 75.8

exercises
Huang 2005 52 wk E: Hyal- Ambu- 32 72.4 99.3 30.7 (I) 41.5% (I)
lation speed
(metres per
minute)
C: Warmup 28 73.9 70.1

exercises
Table 28. Clinical benefit table: Hylan G-F 20 versus placebo. Continuous outcome measures
group (scale) Mean Mean Benefit ference
Scale 1994a 5-13 wk E: Hylan G- Weight bear- 25 61 27 -20 (I) -29.9% (I)
F 20 ing pain (0-
100 mm
VAS)
C: Saline 25 67 53
Scale 1994a 5-13 wk E: Hylan G- Pain at night 25 29 16 -13 (I) -50.0% (I)
F 20 (0-100 mm
VAS)
C: Saline 25 26 26

Table 28. Clinical benefit table: Hylan G-F 20 versus placebo. Continuous outcome measures (Continued)
Scale 1994b 5-13 wk E: Hylan G- Weight bear- 15 65 11 -27 (I) -38.6% (I)
F 20 ing pain (0-
100 mm
VAS)
C: Saline 15 70 43
Scale 1994b 5-13 wk E: Hylan G- Pain at night 15 30 2 -10 (I) -30.3% (I)
F 20 (0-100 mm
VAS)
C: Saline 15 33 15
Wobig 1998 5-13 wk E: Hylan G- Weight bear- 57 70 23 -32 (I) -42.7% (I)
F 20 ing pain (0-
100 mm
VAS)
C: Saline 60 75 60
Wobig 1998 5-13 wk E: Hylan G- Pain at night 57 41 12 -13 (I) -28.3% (I)
F 20 (0-100 mm
VAS)
C: Saline 60 46 30

F 20 ing pain (0-
100 mm
VAS)
C: Nonelas- 36 80 43
to-
viscous Hy-
lan G-F 20
Wobig 1999 5-13 wk E: Hylan G- Pain at night 38 26 13 2 (W) 7.4% (W)

F 20 (0-100 mm
VAS)
C: Nonelas- 36 27 12
to-
viscous Hy-
lan G-F 20
Moreland 1-4 wk E: Hylan GF Pain on mo- 46 69 47 -3 (I) -4.3% (I)

1993 20 tion (0-100
mm VAS)

C: Arthro- 48 70 51
centesis
Moreland 1-4 wk E: Hylan G- Pain at night 46 60 36 6 (W) 8% (W)

1993 F 20 (0-100 mm
VAS)
C: Arthro- 48 75 45
centesis
Moreland 1-4 wk E: Hylan GF Pain at rest 46 61 39 -2 (I) -3.1% (I)

1993 20 (0-100 mm
VAS)
C: Arthro- 48 64 44
centesis
Moreland 1-4 wk E: Hylan G- Pain walking 46 79 57 -2 (I) -2.5% (I)

1993 F 20 (0-100 mm
VAS)
C: Arthro- 48 80 60
centesis
Moreland 1-4 wk E: Hylan GF Pain overall 46 78 55 -2 (I) -2.6% (I)

1993 20 (0-100 mm
VAS)
C: Arthro- 48 78 57
centesis
Dickson 5-13 wk E: Hylan G- WOMAC 53 59 26 -9 (I) -15.5% (I)

2001 F 20 pain (0-100
mm VAS)
C: 57 58 34
Arthrocente-
sis + Placebo
capsules

2001 F 20 function (0-
100 VAS)
C: 57 56 47
Arthrocente-
sis + Placebo
capsules

Dickson 5-13 wk E: Hylan G- Lequesne In- 53 13.9 10.9 -1 (I) -6.9% (I)
2001 F 20 dex (0-24)
C: 57 14.5 12.5
Arthrocente-
sis + Placebo
capsules
Karlsson 1-4 wk E: Hylan G- Pain on 88 63 45 3.0 (W) 4.6% (W)

2002b F 20 weight bear-
ing (0-100
mm VAS)
C: Saline 66 65 44
Karlsson 5-13 wk E: Hylan G- Pain on 88 63 41 -3.0 (I) -4.6% (I)

ing (0-100
mm VAS)
C: Saline 66 65 46
Karlsson 14-26 wk E: Hylan G- Pain on 88 63 43 1.0 (W) 1.5% (W)

ing (0-100
mm VAS)
C: Saline 66 65 44
Karlsson 5-13 wk E: Hylan G- WOMAC 88 48.7 31.7 1.2 (W) 2.5% (W)
2002b F 20 (0-100 mm
VAS)
C: Saline 66 48.9 30.7
Karlsson 14-26 wk E: Hylan G- WOMAC 88 48.7 31.9 -1.0 (I) -2.0% (I)
2002b F 20 (0-100 mm
VAS)
C: Saline 66 48.9 33.1
Karlsson 14-26 wk E: Hylan G- Lequesne In- 88 13.4 9.0 0.3 (W) 2.2% (W)
2002b F 20 dex (0-24)
C: Saline 66 13.6 8.9
Scale 1994a 14-26 wk E: Hylan G- Pain on 15 61 18 -33 (I) -49.3 (I)

F 20 weight bear-
ing (0-100

mm VAS)
C: Saline 21 67 57
Scale 1994a 14-26 wk E: Hylan G- Pain at night 15 29 10 -25 (I) -96.2 (I)
F 20 (0-100 mm
VAS)
C: Saline 21 26 32
Scale 1994b 14-26 wk E: Hylan G- Pain on 15 65 22 -18 (I) -25.7 (I)

F 20 weight bear-
ing (0-100
mm VAS)
C: Saline 15 70 45
Scale 1994b 14-26 wk E: Hylan G- Pain at night 15 30 3 -10 (I) -30.3 (I)
F 20 (0-100 mm
VAS)
C: Saline 15 33 16
Wobig 1998 14-26 wk E: Hylan G- Pain on 56 70 35 -16 (I) -21.3 (I)

F 20 weight bear-
ing (0-100
mm VAS)
C: Saline 60 75 56
F 20 (0-100 mm
VAS)
C: Saline 60 46 34
Scale 1994a 1-4 wk E: Hylan G- Weight bear- 25 61 32 -9 (I) -13.4% (I)

F 20 ing pain (0-
100 mm
VAS)
C: Saline 25 67 47
Scale 1994a 1-4 wk E: Hylan G- Pain at night 25 29 18 -8 (I) -30.8% (I)

F 20 (0-100 mm
VAS)
C: Saline 25 26 23

Scale 1994b 1-4 wk E: Hylan G- Weight bear- 15 65 22 -17 (I) -24.3% (I)
F 20 ing pain (0-
100 mm
VAS)
C: Saline 15 70 44
Scale 1994b 1-4 wk E: Hylan G- Pain at night 15 30 7 -7 (I) -21.2% (I)

F 20 (0-100 mm
VAS)
C: Saline 15 33 17
F 20 ing pain (0-
100 mm
VAS)
C: Saline 60 75 53

F 20 (0-100 mm
VAS)
C: Saline 60 46 26

F 20 ing pain (0-
100 mm
VAS)
C: Saline 36 80 53

F 20 (0-100 mm
VAS)
C: Saline 36 27 12
Cubukcu 1-4 wk E: Hylan G- Pain at night 20 45 27

2004 F 20 (0-100 mm
VAS)
C: Saline 10 54 37
Cubukcu 5-13 wk E: Hylan G- Pain at night 20 45 23

2004 F 20 (0-100 mm
VAS)

C: Saline 10 54 44
Cubukcu 1-4 wk E: Hylan G- Pain at rest 20 47 29

2004 F 20 (0-100 mm
VAS)
C: Saline 10 51 39
Cubukcu 5-13 wk E: Hylan G- Pain at rest 20 47 22

2004 F 20 (0-100 mm
VAS)
C: Saline 10 51 41
Cubukcu 1-4 wk E: Hylan G- Pain walking 20 71 47

2004 F 20 (0-100 mm
VAS)
C: Saline 10 67 51
Cubukcu 5-13 wk E: Hylan G- Pain walking 20 71 40

2004 F 20 (0-100 mm
VAS)
C: Saline 10 67 54
Cubukcu 1-4 wk E: Hylan G- Need for 20 1.0 0.0

2004 F 20 paracetamol
(pill count)
C: Saline 10 0.9 0.1
Cubukcu 5-13 wk E: Hylan G- Need for 20 1.0 0.0

2004 F 20 paracetamol
(pill count)
C: Saline 10 0.9 0.7
Cubukcu 1-4 wk E: Hylan G- WOMAC 20 16 11

2004 F 20 pain (5-25)
C: Saline 10 18 14

2004 F 20 pain (5-25)
C: Saline 10 18 15


2004 F 20 function
(17-85)
C: Saline 10 48 47

2004 F 20 function
(17-85)
C: Saline 10 48 47
Table 29. Clinical benefit table: Hylan G-F 20. Patient global assessment
Study Time Treat group Outcome No. No.of pts. Risk (% oc- Risk Differ- NNT
improved currence) ence
Dickson 5-13 wk E: Hylan G- Number of 29 42 69 21 4.8

2001 F 20 patients very
good/good
C: Arthro- 23 48 48
centesis
Dickson 5-13 wk E: Hylan G- Number of 29 42 69 14 7.1

2001 F 20 patients very
good/good
C: 35 42 83
Diclofenac +
arthrocente-
sis
Adams 1995 14-26 wk E: Hylan G- Number of 17 27 63 24 4.2

F 20 patients rat-
ing treat-
ment ex-
cellent, very
good, good
C: NSAID + 12 31 39
arthrocente-
sis
Adams 1995 14-26 wk E: Hylan G- Number of 17 27 63 7 14.3

F 20 + patients rat-
NSAID ing treat-
ment ex-

Table 29. Clinical benefit table: Hylan G-F 20. Patient global assessment (Continued)
cellent, very
good, good
C: NSAID + 18 32 56
arthrocente-
sis
Raynauld 45-52 wk E: Hylan G- Number of 93 127 73 46 2.2

2002 F patients
20 + Appro- improved in
priate Care study knee
C: Appropri- 35 128 27
ate care
Table 30. Clinical benefit table. Hylan G-F 20. Continuous outcome measures
Cubukcu 1-4 wk E: Hylan G- WOMAC 20 6 4 -1 (I) -16.7% (I)

2004 F 20 stiffness (2-
10)
C: Saline 10 6 5
Cubukcu 5-13 wk E: Hylan G- WOMAC 20 6 4 -1 (I) -16.7% (I)

2004 F 20 stiffness (2-
10)
C: Saline 10 6 5
Cubukcu 1-4 wk E: Hylan G- 15 m walk- 20 21 17 -3 (I) -16.72% (I)

2004 F 20 ing time
C: Saline 10 18 17
Cubukcu 5-13 wk E: Hylan G- 15 m walk- 20 21 16 -4 (I) -22.2% (I)

2004 F 20 ing time
C: Saline 10 18 17
Karatosun 1-4 wk E: Hylan G- Pain during 52 4.0 10.8 2.4 (I) 53.3% (I)
2005 F 20 activity

Table 30. Clinical benefit table. Hylan G-F 20. Continuous outcome measures (Continued)
2005 F 20 activity
2005 F 20 activity
Karatosun 45-52 wk E: Hylan G- Pain during 46 4.0 8.5 -1.2 (W) -26.7% (W)
2005 F 20 activity
C: Exercise 53 4.5 10.2
Karatosun 74 wk E: Hylan G- Pain during 31 4.0 12.9 1.3 (I) 28.9% (I)
2005 F 20 activity
C: Exercise 53 4.5 12.1
Karatosun 1-4 wk E: Hylan G- Pain at rest 52 7.8 13.1 2.1 (I) 23.1% (I)
2005 F 20
C: Exercise 53 9.1 12.2
2005 F 20
C: Exercise 53 9.1 12.7
2005 F 20
C: Exercise 53 9.1 12.4
2005 F 20
C: Exercise 53 9.1 12.9
Karatosun 74 wk E: Hylan G- Pain at rest 31 7.8 13.7 1.8 (I) 19.8% (I)
2005 F 20
C: Exercise 53 9.1 13.2
Karatosun 1-4 wk E: Hylan G- Pain dur- 52 2.5 3.2 0.2 (I) 8% (I)
2005 F 20 ing climbing
stairs

Karatosun 5-13 wk E: Hylan G- Pain dur- 52 2.5 3.3 0.1 (I) 4% (I)
stairs
Karatosun 14-26 wk E: Hylan G- Pain dur- 52 2.5 3.2 0 0%

stairs
Karatosun 45-52 wk E: Hylan G- Pain dur- 46 2.5 3.1 -0.1 (W) -4% (W)
stairs
Karatosun 74 wk E: Hylan G- Pain dur- 31 2.5 3.9 0.2 (I) 8% (I)

stairs
2005 F 20 transfer ac-
tivity
Karatosun 5-13 wk E: Hylan G- Pain during 52 2.9 4.2 0 0%

tivity
tivity
tivity

Karatosun 74 wk E: Hylan G- Pain during 31 2.9 4.1 0.1 (I) 3.2% (I)
tivity
Karatosun 1-4 wk E: Hylan G- Walkiing 52 8.1 10.2 0.7 (I) 8.9% (I)
2005 F 20 distance
Karatosun 5-13 wk E: Hylan G- Walking dis- 52 8.1 10.5 0.2 (I) 2.5% (I)
2005 F 20 tance
C: Exercise 53 7.9 10.1
Karatosun 14-26 wk E: Hylan G- Walking dis- 52 8.1 10.4 0.5 (I) 6.3% (I)
2005 F 20 tance
Karatosun 45-52 wk E: Hylan G- Walking dis- 46 8.1 9.6 -0.5 (W) -6.3% (W)
2005 F 20 tance
Karatosun 74 wk E: Hylan G- Walking dis- 31 8.1 10.4 -0.1 (W) -1.3% (W)
2005 F 20 tance
C: Exercise 53 7.9 10.3
Karatosun 1-4 wk E: Hylan G- Range of 52 113.2 116.3 0.4 (I) 0.3% (I)
2005 F 20 motion
C: Exercise 53 114.4 117.1
2005 F 20 motion
C: Exercise 53 114.4 117.9
2005 F 20 motion
C: Exercise 53 114.4 117.8
2005 F 20 motion
C: Exercise 53 114.4 117.8

Karatosun 74 wk E: Hylan G- Range of 31 113.2 118.6 1.9 (I) 1.7% (I)

2005 F 20 motion
C: Exercise 53 114.4 117.9
Karatosun 1-4 wk E: Hylan G- Total Hospi- 52 62.6 81.3 4.3 (I) 6.6% (I)
2005 F 20 tal for Spe-
cial Surgery
Knee Score
C: Exercise 53 65.4 79.8
cial Surgery
Knee Score
C: Exercise 53 65.4 81.52
cial Surgery
Knee Score
C: Exercise 53 65.4 80.0
Karatosun 45-52 wk E: Hylan G- Total Hospi- 46 62.6 78.8 -1.16 (W) -1.8% (W)
cial Surgery
Knee Score
C: Exercise 53 65.4 82.76
Karatosun 74 wk E: Hylan G- Total Hospi- 31 62.6 88.8 3.3 (I) 5.0 (I)
cial Surgery
Knee Score
C: Exercise 53 65.4 88.3
Table 31. Clinical benefit table: Hylan G-F 20. Continuous outcome measures
Atamaz 1-4 wk E: Hylan G- WOMAC 20 12.4 8.3 -1.2 (I) -8.5% (I)
2005 F 20 pain (Likert)

Table 31. Clinical benefit table: Hylan G-F 20. Continuous outcome measures (Continued)
C: Physical 40 14.2 11.3

Therapy
C: Physical 40 14.2 11.8

Therapy
Atamaz 14-26 wk E: Hylan G- WOMAC 20 12.4 10.4 0.9 (W) 6.3% (W)
C: Physical 40 14.2 11.3

Therapy
Atamaz 37 wk E: Hylan G- WOMAC 20 12.4 10.4 -0.1 (I) -0.7% (I)

C: Physical 40 14.2 12.3

Therapy
C: Physical 40 14. 15.5

Therapy
Atamaz 1-4 wk E: Hylan G- Spontaneous 20 85.0 64.0 29.0 (W) 31.0% (W)
2005 F 20 pain (0-100
mm VAS)
C: Physical 40 93.5 43.5

Therapy
2005 F 20 pain (0-100
mm VAS)
C: Physical 40 93.5 49.5

Therapy
2005 F 20 pain (0-100
mm VAS)
C: Physical 40 93.5 48.5

Therap

Atamaz 37 wk E: Hylan G- Spontaneous 20 85.0 51.7 9.5 (W) 10.2% (W)

2005 F 20 pain (0-100
mm VAS)
C: Physical 40 93.5 50.7

Therapy
Atamaz 45-52 wk E: Hylan G- Spontaneous 20 85.0 49.0 -2 (I) -2.1% (I)

2005 F 20 pain (0-100
mm VAS)
C: Physical 40 93.5 59.5

Therapy
Atamaz 1-4 wk E: Hylan G- SF-36 pain 20 25.6 59.4 4.3 (I) 14.5% (I)
2005 F 20
C: Physical 40 29.6 59.1

Therapy
2005 F 20
C: Physical 40 29.6 56.2

Therapy
2005 F 20
C: Physical 40 29.6 54.6

Therapy
Atamaz 37 wk E: Hylan G- SF-36 pain 20 25.6 43.8 -3.5 (W) -11.8% (W)
2005 F 20
C: Physical 40 29.6 51.3

Therapy
2005 F 20
C: Physical 40 29.6 50.2

Therapy
2005 F 20 phys-
ical function
(Likert)

C: Physical 40 49.9 37.6

Therapy
2005 F 20 physical
function
C: Physical 40 49.9 38.9

Therapy
2005 F 20 physical
function
C: Physical 40 49.9 41.9

Therapy

2005 F 20 physical
function
C: Physical 40 49.9 38.2

Therapy
2005 F 20 physical
function
C: Physical 40 49.9 38.2

Therapy
Atamaz 1-4 wk E: Hylan G- SF-36 physi- 20 35.5 57.2 -0.3 (W) -0.9% (W)
2005 F 20 cal function-
ing
C: Physical 40 31.7 53.7

Therapy
Atamaz 5-13 wk E: Hylan G- SF-36 physi- 20 35.5 61.7 4.4 (I) 13.9% (I)
ing
C: Physical 40 31.7 53.5

Therapy
ing

C: Physical 40 31.7 54.0

Therapy
Atamaz 37 wk E: Hylan G- SF-36 physi- 20 35.5 45.0 -8.0 (W) -25.2% (W)
ing
C: Physical 40 31.7 49.2

Therapy
ing
C: Physical 40 31.7 53.0

Therapy
Table 32. Clinical benefit table: Hylan G-F 20 versus triamcinolone hexacetonide. Continuo
Study Time Treatment Outcome N of Pts Baseline End of Study Absolute Relative
group (scale) Mean Benefit Benefit
Caborn 5-13 wk E: Hylan G- WOMAC 113 2.12 1.20 -0.37 (I) -17.2% (I)
2004 F 20 - pain walk-
ing on a flat
surface (0-4
Likert)
C: Triamci- 102 2.15 1.60

nolone hex-
acetonide
2004 F 20 - pain walk-
ing on a flat
surface (0-4
Likert)
C: Triamci- 102 2.15 1.80

nolone hex-
acetonide
2004 F 20 phys-
ical function
(0-68 Likert)

Table 32. Clinical benefit table: Hylan G-F 20 versus triamcinolone hexacetonide. Continuo (Continued)
C: Triamci- 102 37.90 28.50

nolone hex-
acetonide
2004 F 20 phys-
ical function
(0-68 Likert)
C: Triamci- 102 37.90 30.70

nolone hex-
acetonide
2004 F 20 total score
(0-96 Likert)
C: Triamci- 102 53.10 40.10

nolone hex-
acetonide
2004 F 20 total score
(0-96)
C: Triamci- 102 53.10 42.90

nolone hex-
acetonide
Caborn 5-13 wk E: Hylan G- Patient 113 68.40 36.70 -14.50 (I) -21.5% (I)
2004 F 20 global assess-
ment (0-100
mm VAS)
C: Triamci- 102 67.30 50.10

nolone hex-
acetonide
Caborn 14-26 wk E: Hylan G- Patient 113 68.40 40.30 -16.20 (I) -24.1% (I)
2004 F 20 global assess-
ment (0-100
mm VAS)
C: Triamci- 102 67.30 55.40

nolone hex-
acetonide

Table 33. Clinical benefit table: Hylan G-F 20 versus NSAID. Continuous outcome measures
Study TIme Treatment Outcome N of pts Baseline End of Study Absolute Relative Dif-
Adams 1995 14-26 wk E: Hylan G- Pain on mo- 29 61 40 -10 (I) -15.9% (I)
F 20 tion (0-100
mm VAS)
C: NSAID 33 63 52
Adams 1995 14-26 wk E: Hylan G- Pain at night 29 35 25 -4 (I) -11.7% (I)

F 20 (0-100 mm
VAS)
C: NSAID 33 34 28
Adams 1995 14-26 wk E: Hylan G- Pain at rest 29 36 25 -4 (I) -13.8% (I)

F 20 (0-100 mm
VAS)
C: NSAID 33 29 22
Adams 1995 14-26 wk E: Hylan G- Pain overall 29 62 47 -5 (I) -8.1% (I)

F 20 (0-100 mm
VAS)
C: NSAID 33 62 52

2001 F 20 pain (0-100
mm VAS)
C: 55 61 38
Diclofenac

2001 F 20 function (0-
100 mm
VAS)
C: 55 56 42
Diclofenac
Dickson 5-13 wk E: Hylan G- Lequesne In- 53 13.9 10.9 -1 (I) -7.2% (I)
2001 F 20 dex (0-24)
C: 55 13.9 11.9
Diclofenac

Table 33. Clinical benefit table: Hylan G-F 20 versus NSAID. Continuous outcome measures (Continued)
Adams 1995 5-13 wk E: Hylan G- Pain on mo- 34 60 34 -7 (I) -11.1% (I)

F 20 + tion (0-100
NSAID mm VAS)
C: NSAID 33 63 44
Adams 1995 5-13 wk E: Hylan GF Pain at night 34 20 10 3 (W) 8.8% (W)

20 + NSAID (0-100 mm
VAS)
C: NSAID 33 34 21

F 20 + (0-100 mm
NSAID VAS)
C: NSAID 33 29 20

F 20 + (0-100 mm
NSAID VAS)
C: NSAID 33 62 43
Adams 1995 14-26 wk E: Hylan G- Pain on mo- 32 60 37 -12 (I) -19% (I)
F 20 + tion (0-100
NSAID mm VAS)
C: NSAID 31 63 52
Adams 1995 14-26 wk E: Hylan G- Pain at night 32 20 9 -5 (I) -14.7% (I)

F 20 + (0-100 mm
NSAID VAS)
C: NSAID 31 34 28

F 20 + (0-100 mm
NSAID VAS)
C: NSAID 31 29 22
F 20 + (0-100 mm
NSAID VAS)
C: NSAID 31 62 52

Table 34. Clinical benefit table: Hylan G-F 20 versus appropriate care. Continuous outcome
Raynauld 45-52 wk E: Hylan G- WOMAC 127 11.35 6.94 -2.57 (I) -21.5% (I)
2002 F pain (0-20
20 + appro- Likert)
priate care
C: Appropri- 127 11.94 10.10

ate care
Raynauld 45-52 wk E: Hylan G- WOMAC 127 39.54 24.26 -8.95 (I) -22.3% (I)
2002 F function (0-
20 + appro- 68 Likert)
priate care
C: Appropri- 127 40.20 33.87

ate care
Raynauld 45-52 wk E: Hylan G- SF-36 Func- 127 28.33 33.24 5.31 (I) 18.8% (I)
2002 F tion
20 + appro-
priate care
C: Appropri- 126 28.18 27.78

ate care
Raynauld 45-52 wk E: Hylan G- SF-36 Men- 127 51.74 55.29 0.81 (I) 1.6% (I)
2002 F tal
20 + appro-
priate care
C: Appropri- 126 49.91 52.65

ate care
Kahan 36 wk E: Hylan G- WOMAC 251 50.00 25.40 -12.4 (I) -24.7% (I)
2003a F pain (0-100
20 + appro- mm VAS)
priate care
C: Appropri- 246 50.30 38.10

ate care
Kahan 36 wk E: Hylan G- Pain 253 61.10 23.80 -12.9 (I) -21.4% (I)
2003a F on walking
20 + appro- (0-100 mm
priate care VAS)

Table 34. Clinical benefit table: Hylan G-F 20 versus appropriate care. Continuous outcome (Continued)
C: Appropri- 253 60.30 35.90

ate care
2003a F function (0-
20 + appro- 100 mm
priate care VAS)
C: Appropri- 247 47.40 40.30

ate care
2003a F stiffness
20 + appro- (0-100 mm
priate care VAS)
C: Appropri- 246 44.90 37.20

ate care
2003a F total (0-100
20 + appro- mm VAS)
priate care
C: Appropri- 245 47.90 39.70

ate care
Kahan 36 wk E: Hylan G- Lequesne In- 253 11.10 7.50 -2 (I) -17.7% (I)
2003a F dex (0-24)
20 + appro-
priate care
C: Appropri- 253 11.30 9.70

ate care
Table 35. Clinical benefit table: Hylan G-F 20 versus appropriate care. Dichotomous outcom
Study Time Treatment Outcome No. No. of pts. Risk (%) Risk NNT
improved difference
Raynauld 45-52 wk E: Hylan G- Pa- 93 127 73 46 2

2002 F tient global
20 + appro- (Number of
priate care patients
improved in
study knee)

Table 35. Clinical benefit table: Hylan G-F 20 versus appropriate care. Dichotomous outcom (Continued)
C: Appropri- 35 128 27
ate care
Kahan 36 wk E: Hylan G- Pa- 186 253 74 23 4.3

2003a F tient global
20 + appro- (Number of
priate care patients rat-
ing effective-
ness good or
satisfactory)
C: Appropri- 129 253 51

ate care
Kahan 36 wk E: Hylan G- Number of 223 253 88 20 5

2003a F responders
20 + appro- (20%
priate care decrease
in pain on
walking)
C: Appropri- 172 253 68

ate care
Table 36. Clinical benefit table: Hylan G-F20 versus hyaluronan.Continuous outcome measure

F 20 ing pain (0-
100 mm
VAS)
C: Artz 35 72 43

F 20 (0-100 mm
VAS)
C: Artz 35 30 15
F 20 ing pain (0-
100 mm
VAS)
C: Artz 35 72 48

Table 36. Clinical benefit table: Hylan G-F20 versus hyaluronan.Continuous outcome measure (Continued)
Wobig 1999 5-13 wk E: Hylan G- Pain at night 38 26 13 0 0%

F 20 (0-100 mm
VAS)
C: Artz 35 30 17

F 20 ing pain (0-
100 mm
VAS)
C: Healon 39 71 48

F 20 (0-100 mm
VAS)
C: Healon 39 35 22

F 20 ing pain (0-
100 mm
VAS)
C: Healon 39 71 38

F 20 (0-100 mm
VAS)
C: Healon 39 35 16
Atamaz 1-4 wk E: Hylan G- WOMAC 20 12.4 8.3 0 0

C: Orthovisc 20 13.4 9.3
Atamaz 36 wk E: Hylan G- WOMAC 20 12.4 10.4 1.0 (W) 7.5% (W)


Atamaz 45-52 wk E: Hylan G- WOMAC 20 12.4 10.2 0 0

2005 F 20 pain (0-100
mm VAS)
Atamaz 5-13 wk E: Hylan G- Spontaneous 20 85.0 50.7 -22.4 (I) -31.9% (I)
2005 F 20 pain (0-100
mm VAS)
2005 F 20 pain (0-100
mm VAS)
Atamaz 36 wk E: Hylan G- Spontaneous 20 85.0 51.7 -15.2 (I) -21.6% (I)

2005 F 20 pain (0-100
mm VAS)
2005 F 20 pain (0-100
mm VAS)
2005 F 20
2005 F 20
2005 F 20

Atamaz 36 wk E: Hylan G- SF-36 pain 20 25.6 43.8 9.3 (I) 25.5% (I)
2005 F 20
2005 F 20
2005 F 20 function
(Likert)
2005 F 20 function
(Likert)
2005 F 20 function
(Likert)

2005 F 20 function
(Likert)
2005 F 20 function
(Likert)
Atamaz 1-4 wk E: Hylan G- SF-36 physi- 20 35.5 57.2 12.0 (I) 27.0 (I)
ing

ing
ing
Atamaz 36 wk E: Hylan G- SF-36 physi- 20 35.5 45.0 4.8 (I) 10.8 (I)
ing
ing
Table 37. Clinical benefit table: NRD-101 (Suvenyl) versus placebo. Continuous outcome mea
Pham 2004 1-4 wk E: NRD- Pain (0-100 131 61.7

101 mm VAS)
C: Placebo 85 59.1
Pham 2004 14-26 wk E: NRD- Pain (0-100 131 61.7

101 mm VAS)
C: Placebo 85 59.1
Pham 2004 45-52 wk E: NRD- Pain (0-100 131 61.7 28.2 1.0 (W) 1.7% (W)
101 mm VAS)
C: Placebo 85 59.1 24.6
Pham 2004 1-4 wk E: NRD- Lequesne In- 131 11.1

101 dex (0-24)
C: Placebo 85 10.5

Table 37. Clinical benefit table: NRD-101 (Suvenyl) versus placebo. Continuous outcome mea (Continued)

101 dex (0-24)
C: Placebo 85 10.5

101 dex (0-24)
C: Placebo 85 10.5
Pham 2004 1-4 wk E: NRD- Patient 131 59.7

101 global assess-
ment (0-100
mm VAS)
C: Placebo 85 57.3

101 global assess-
ment
C: Placebo 85 57.3
Pham 2004 45-52 wk E: NRD- Patient 131 59.7 30.0 1.4 (W) 2.4% (W)
101 global assess-
ment (0-100
mm VAS)
C: Placebo 85 57.3 26.2
Pham 2004 1-4 wk E: NRD- Percentage 131 85.5

101 of painful
days dur-
ing the pre-
vious month
(0-100 mm
VAS)
C: Placebo 85 82.6

101 of painful
days dur-
ing the pre-
vious month
(0-100 mm
VAS)
C: Placebo 85 82.6

Table 37. Clinical benefit table: NRD-101 (Suvenyl) versus placebo. Continuous outcome mea (Continued)
Pham 2004 45-52 wk E: NRD- Percentage 131 85.5 42.0 3.1 (W) 3.8% (W)
101 of painful
days dur-
ing the pre-
vious month
(0-100 mm
VAS)
C: Placebo 85 82.6 36.0
Table 38. Clinical benefit table: NRD-101 (Suvenyl) versus placebo. Dichotomous outcome me
improved difference
Pham 2004 45-52 wk E: NRD- Patient as- 86 120 72 4 25

101 sessment of
treatment ef-
fi-
cacy (no. pts
rating very
good or good
versus mod-
erate, bad or
very ad)
C: Placebo 57 75 76
(saline + oral
placebo)
Pham 2004 45-52 wk E: NRD- Joint 23 131 18 2 50

101 space width
(percent-
age of pro-
gressors:
joint space
narrowing
greater than
0.5 mm)
C: Placebo 17 85 20
(saline plus
oral placebo)

Table 39. Clinical benefit table: NRD-101 (Suvenyl) versus Diacerein. Continuous outcome m
Pham 2004 1-4 wk E: NRD- Pain (0-100 131 61.7

101 mm VAS)
C: Diacerein 85 59.6
Pham 2004 14-26 wk E: NRD- Pain (0-100 131 61.7

101 mm VAS)
Pham 2004 45-52 wk E: NRD- Pain (0-100 131 61.7 28.2 0.4 (W) 0.7% (W)
101 mm VAS)
C: Diacerein 85 59.6 25.7

101 dex (0-24)

101 dex (0-24)

101 dex (0-24)

101 global assess-
ment (0-100
mm VAS)

101 global assess-
ment (0-100
mm VAS)

Table 39. Clinical benefit table: NRD-101 (Suvenyl) versus Diacerein. Continuous outcome m (Continued)
Pham 2004 45-52 wk E: NRD- Patient 131 59.7 30.0 3.1 (W) 5.4% (W)
101 global assess-
ment

101 of painful
days dur-
ing the pre-
vious month
(0-100 mm
VAS)

101 of painful
days durign
the pre-
vious month
(0-100 mm
VAS)
Pham 2004 45-52 wk E: NRD- Percentage 131 85.5 42.0 2.1 (W) 2.5% (W)
101 of painful
days dur-
ing the pre-
vious month
(0-100 mm
VAS)
Table 40. Clinical benefit table: NRD-101 (Suvenyl) versus Diacerein. Dichotomous outcome
improved difference
Pham 2004 45-52 wk E: NRD- Patient as- 86 120 72 7 14

101 sessment of
treatment ef-
fi-
cacy (no. pts
rating very
good or good

Table 40. Clinical benefit table: NRD-101 (Suvenyl) versus Diacerein. Dichotomous outcome (Continued)
versus mod-
erate, bad or
very bad)
C: Diacerein 49 75 65
Pham 2004 45-52 wk E: NRD- Joint space 23 131 18 1 100

101 width (per-
centage pro-
gressors:
joint space
narrowing
greater than
0.5 mm)
C: Diacerein 16 85 19
Table 41. Clinical benefit table: NRD-101 (Suvenyl) versus Artz. Dichotomous outcome measu
Study TIme Treatment Outcome No. No. of pts. Risk (%) Risk NNT
improved difference
Yamamoto 1-4 wk E: NRD-101 Spon- 48 67 72 11 9.1

1994 taneous pain
(number of
patients im-
proved)
C: Artz 43 70 61
Yamamoto 1-4 wk E: NRD-101 Pain during 39 54 72 -2 50

1994 night (num-
ber of
patients im-
proved)
C: Artz 39 53 74
Yamamoto 1-4 wk E: NRD-101 Pressure pain 60 94 64 7 14.3

1994 (number of
patients im-
proved)
C: Artz 48 84 57
Yamamoto 1-4 wk E: NRD-101 Passive 31 53 58 -8 12.5

1994 movement
pain

Table 41. Clinical benefit table: NRD-101 (Suvenyl) versus Artz. Dichotomous outcome measu (Continued)
(number of
patients im-
proved)
C: Artz 57 86 66
Yamamoto 1-4 wk E: NRD-101 Num- 50 81 62 2 50

1994 ber of pa-
tients good/
very good
C: Artz 43 72 60
Table 42. Clinical benefit table: NRD-101 (Suvenyl) versus Artz. Continuous outcome measur
Study Time Treatment Outcome N of Pts Baseline End of Study Absolute Relative Ben-
Mean Mean Benefit efit
Yamamoto 1-4 wk E: NRD-101 Passive flex- 95 132.30 137.10 1.4 (I) 1.1% (I)
1994 ion (degrees)
C: Artz 86 132.70 136.10
Yamamoto 1-4 wk E: NRD-101 Passive ex- 95 4.8 4.0 0.2 (I) 3.8% (I)
1994 tension (de-
grees)
C: Artz 86 5.2 4.2
Table 43. Clinical benefit table: Orthovisc. Continuous outcome measures (1)
Bayramoglu End of treat- E: Orthovisc Lequesene 16 12.4 9.1 -1.00 (I) -8.6% (I)
2003 ment + PT Index (0-24)
C: PT 15 11.6 9.3
Bayramoglu End of treat- E: Orthovisc Lequesne 16 12.4 9.1 0.9 (W) 7.0% (W)
2003 ment + PT Index (0-24)
C: Hylan G- 15 12.8 8.6

F 20 + PT
Bayramoglu 5-13 wk E: Orthovisc Lequesene 16 12.4 7.6 -2.6 (I) -22.4% (I)
2003 + PT Index (0-24)

Table 43. Clinical benefit table: Orthovisc. Continuous outcome measures (1) (Continued)
C: PT 15 11.6 9.4
Bayramoglu 5-13 wk E: Orthovisc Lequesne 16 12.4 7.6 -0.6 (I) -4.7% (I)
2003 + PT Index (0-24)
C: Hylan G- 15 12.8 8.6

F 20 + PT
Tascioglu 1-4 wk E: Orthovisc Pain on 28 54.26 31.83 3.87 (W) 7.3% (W)
2003 weight bear-
ing (0-100
mm VAS)
C: 6-MPA 27 53.10 26.80
Tascioglu 1-4 wk E: Orthovisc Pain at rest 28 30.43 11.83 3.00 (W) 10.0% (W)
2003 (0-100 mm
VAS)
C: 6-MPA 27 29.90 8.30
Tascioglu 1-4 wk E: Orthovisc Pain 28 67.60 37.60 1.00 (W) 1.5% (W)
2003 on walking
(0-100 mm
VAS)
C: 6-MPA 27 69.00 38.00
Tascioglu 1-4 wk E: Orthovisc Lequesne 28 10.23 7.86 -0.47 (I) -4.8% (I)
2003 Index (0-24)
C: 6-MPA 27 9.86 7.96
Tascioglu 1-4 wk E: Orthovisc Flexion (de- 28 108.70 116.36 1.52 (I) 1.4% (I)
2003 grees)
C: 6-MPA 27 108.06 114.20
Tascioglu 5-13 wk E: Orthovisc Pain on 28 54.26 22.86 -16.80 (I) -31.6% (I)
2003 weight bear-
ing (0-100
mm VAS)
C: 6-MPA 27 53.10 38.50
Tascioglu 5-13 wk E: Orthovisc Pain at rest 28 30.43 12.00 -8.23 (I) -27.5% (I)
2003 (0-100 mm
VAS)

C: 6-MPA 27 29.90 19.70
Tascioglu 5-13 wk E: Orthovisc Pain 28 67.60 32.03 -17.03 (I) -24.7% (I)
2003 on walking
(0-100 mm
VAS)
C: 6-MPA 27 69.00 50.46
2003 Index (0-24)
C: 6-MPA 27 9.86 9.06
2003 grees)
C: 6-MPA 27 108.06 113.40
Tascioglu 14-26 wk E: Orthovisc Pain on 28 54.26 40.96 -16.56 (I) -31.2% (I)
2003 weight bear-
ing (0-100
mm VAS)
C: 6-MPA 27 53.10 56.36
Tascioglu 14-26 wk E: Orthovisc Pain at rest 28 30.43 23.56 -3.43 (I) -11.5% (I)
2003 (0-100 mm
VAS)
C: 6-MPA 27 29.90 26.46
Tascioglu 14-26 wk E: Orthovisc Pain 28 67.60 51.16 -13.50 (I) -19.6% (I)
2003 on walking
(0-100 mm
VAS)
C: 6-MPA 27 69.00 66.06
2003 Index (0-24)
C: 6-MPA 27 9.86 9.60
2003 grees)
C: 6-MPA 27 108.06 109.60

Hizmetli 1-4 wk E: Orthovisc WOMAC 20 17.75 10.20 -7.80 (I) -44.6% (I)
1999 pain (5-25
Likert)
C: Saline 20 17.45 17.70
1999 pain (5-25
Likert)
C: Saline 20 17.45 17.70
1999 pain (5-25
Likert)
C: Saline 20 17.45 18.40
Hizmetli 45-52 wk E: Orthovisc WOMAC 20 17.75 13.80 -5.60 (I) -32% (I)
1999 pain (5-25
Likert)
C: Saline 20 17.45 19.10
1999 function
(17-85 Lik-
ert)
C: Saline 20 52.00 52.10
Hizmetli 5-13 wk E: Orthovisc WOMAC 20 53.15 41.35 -11.30 (I) -21.7 (I)
1999 function
(17-85 Lik-
ert)
C: Saline 20 52.00 51.50
1999 function
(17-85 Lik-
ert)
C: Saline 20 52.00 52.50
1999 function
(17-85 Lik-
ert)

C: Saline 20 52.00 52.90
Tekeoglu 1-4 wk E: Orthovisc WOMAC 20 45.50 34.30 3.10 (W) 6.8% (W)
1998 function
(17-85 Lik-
ert)
C: 20 45.60 31.30
Betametha-
sone
Tekeoglu 5-13 wk E: Orthovisc WOMAC 20 45.50 30.90 -8.90 (I) -19.5% (I)
1998 function
(17-85 Lik-
ert)
C: 20 45.60 39.90
Betametha-
sone
Tekeoglu 1-4 wk E: Orthovisc Maximum 20 110.50 117.30 0.60 (I) 0.5% (I)
1998 flexion (de-
grees)
C: Be- 20 116.00 122.20

tamethsone
Tekeoglu 5-13 wk E: Orthovisc Maximum 20 110.50 121.20 -1.55 (W) -1.3% (W)
1998 flexion (de-
grees)
C: 20 116.00 128.25
Betametha-
sone
Kalay 1997 1-4 wk E: Orthovisc Activity pain 20 46.8 12.50 -11.4 (I) -30.7% (I)
+ PT (0-100 mm
VAS)
C: PT 20 37.1 14.20
Kalay 1997 1-4 wk E: Orthovisc Spon- 20 26.1 5.80 -3.6 (W) -16.3% (W)
+ PT taneous pain
(0-100 mm
VAS)
C: PT 20 22.1 5.40

Kalay 1997 1-4 wk E: Orthovisc Night pain 20 24.3 5.40 -2.8 (I) -12.9% (I)
+ PT (0-100 mm
VAS)
C: PT 20 21.7 5.60
Kalay 1997 1-4 wk E: Orthovisc 25 m walk 20 22.4 15.30 -3.10 (I) -16.7% (I)
+ PT time (sec)
C: PT 20 18.6 14.60
Kalay 1997 1-4 wk E: Orthovisc Flexion (de- 20 126.00 130.00 2.70 (I) 2.1% (I)
+ PT grees)
C: PT 20 128.50 129.80
Kalay 1997 5-13 wk E: Orthovisc Activity pain 20 46.8 6.10 -16.2 (I) -43.7% (I)
+ PT (0-100 mm
VAS)
C: PT 20 37.1 12.60
Kalay 1997 5-13 wk E: Orthovisc Spon- 20 26.1 1.70 -8.1 (I) -16.3% (I)
+ PT taneous pain
(0-100 mm
VAS)
C: PT 20 22.1 5.80
Kalay 1997 5-13 wk E: Orthovisc Night pain 20 24.3 1.60 -5.9 (I) -27.2% (I)
+ PT (0-100 mm
VAS)
C: PT 20 21.7 4.90
Kalay 1997 5-13 wk E: Orthovisc 25 m walk 20 22.4 13.30 -4.90 (I) -26.3% (I)
+ PT time (sec)
C: PT 20 18.6 14.40
Kalay 1997 5-13 wk E: Orthovisc Flexion (de- 20 126.00 130.00 2.70 (I) 2.1% (I)
+ PT grees)
C: PT 20 128.50 129.80
Karatay 1-4 wk E: Orthovisc WOMAC 20 11.2 6.4 -0.8 (I) -7.4% (I)
2004 pain (0-20
Likert)

C: Hylan G- 20 10.8 6.2

F 20
2004 function (0-
68 Likert)
C: Hylan G- 20 31.9 7.5

F 20
2004 stiffness (0-8
Likert)
C: Hylan G- 20 3.6 1.8

F 20
Karatay 1-4 wk E: Orthovisc SF intercel- 20 19.2 11.1 -0.3 (I) -1.7% (I)
2004 lu-
lar adhesion
molecule-1
(ICAM-1)
C: Hylan G- 20 17.8 10.0

F 20
Karatay 1-4 wk E: Orthovisc SF vascu- 20 40.5 14.2 1.3 (W) 3.4% (W)
2004 lar cell adhe-
sion
molecule-1
(VCAM)
C: Hylan G- 20 37.8 10.2

F 20
Sezgin 2005 1-4 wk E: Orthovisc WOMAC 22 18.9 8.9 -3.9 (I) -22.7% (I)
pain (5-25
LIkert)
C: Saline 19 17.2 11.1
stiffness (2-

10 Likert)
C: Saline 19 4.5 3.4
phys-
ical function
(17-85 Lik-
ert)
C: Saline 19 50.0 39.0
Sezgin 2005 1-4 wk E: Orthovisc Flexion (de- 22 95.9 125.2 16.5 (I) 15.2% (I)
grees)
C: Saline 19 108.4 121.2
Sezgin 2005 1-4 wk E: Orthovisc 25 metre 22 43.1 26.4 -11.2 (I) -35.6% (I)
walking time
(sec)
C: Saline 19 31.5 26.0
Sezgin 2005 1-4 wk E: Orthovisc Knee cirum- 22 41.5 40.0 -0.5 (I) -1.2% (I)
ference (cm)
C: Saline 19 41.3 40.3
Sezgin 2005 1-4 wk E: Orthovisc Syn- 22 19.0 7.6 -4.5 (I) -24.3% (I)
ovial fluid ef-
fusion
volume (ml)
C: Saline 19 18.5 11.6
Sezgin 2005 1-4 wk E: Orthovisc Interleukin 6 22 42.8 22.3 -3.0 (I) -5.8% (I)
level in syn-
ovial fluid
(pg/ml)
C: Saline 19 51.7 34.2
Sezgin 2005 1-4 wk E: Orthovisc Interleukin 8 22 20.6 17.0 -7.5 (I) -41.9% (I)
level in syn-
ovial fluid
(pg/ml)
C: Saline 19 17.9 21.8

Sezgin 2005 1-4 wk E: Orthovisc Tu- 22 77.0 58.7 -5.5 (I) -6.8% (I)
mor necrosis
factor alpha
levels in syn-
ovial fluid
(pg/ml)
C: Saline 19 80.8 68.0
Neustadt 5-13 wk E: Orthovisc WOMAC

2005a (4 pain (0-500
injections) mm VAS)
C: Arthro-
centesis

2005a (3 pain (0-500
injections) mm VAS)
C: Arthro-
centesis

2005a (4 pain (0-500
injections) mm VAS)
C: Arthro-
centesis

2005a (3 pain (0-500
injections) mm VAS)
C: Arthro-
centesis
Neustadt 5-13 wk E: Orthovisc Pain

2005a (4 on standing
injections) (0-100 mm
VAS)
C: Arthro-
centesis

VAS)

C: Arthro-
centesis

VAS)
C: Arthro-
centesis

VAS)
C: Arthro-
centesis
Neustadt 5-13 wk E: Orthovisc Patient

2005a (4 global score
VAS)
C: Arthro-
centesis

VAS)
C: Arthro-
centesis

VAS)
C: Arthro-
centesis

VAS)

C: Arthro-
centesis
Neustadt 5-13 wk E: Orthovisc Investi-

2005a (4 gator global
injections) score (0-100
mm VAS)
C: Arthro-
centesis

mm VAS)
C: Arthro-
centesis

mm VAS)
C: Arthro-
centesis

mm VAS)
C: Arthro-
centesis
Yentur 2003 1 wk E: Ortho- Pain at rest 17 2.90 0.52 -2.07 (I) -80.9% (I)
visc+lidocaine (0-4 point
scale)
Yentur 2003 1 wk E: Ortho- Pain/ 17 2.35 0.88 -1.10 (I) -46.4% (I)
visc+lidocaine restrictions
walking (0-4
point scale)

Yentur 2003 1 wk E: Ortho- Pain/restric- 17 2.60 0.88 -1.47 (I) -56.1% (I)
visc+lidocaine tions going
up or down
stairs (0-4
point scale)
Yentur 2003 1 wk E: Ortho- Range of 17 103.8 124.4 21.2 (I) 18.2% (I)
visc+lidocaine motion (de-
grees)
C: Orthovisc 16 116.2 116.8
Karatosun 1-4 wk E: Orthovisc Hos- 39 67.7 86.5 2.2 (I) 3.1% (I)
2005a pital for Spe-
cial Surgery
Knee Score
C: Hylan G- 40 70.1 86.7

F 20
cial Surgery
Knee Score
C: Hylan G- 34 70.1 86.3

F 20
cial Surgery
Knee Score
C: Hylan G- 34 70.1 85.7

F 20
2005 pital for Spe-
cial Surgery
Knee Score
C: Hylan G- 32 70.1 86.7

F 20
Karatosun 1-4 wk E: Orthovisc Pain 39 4.4 11.2 0.8 (I) 15.4% (I)
2005a during activ-
ity (HSSKS)

C: Hylan G- 40 5.2 11.2

F 20
2005a during activ-
ity (HSSKS)
C: Hylan G- 34 5.2 10.3

F 20
2005a during activ-
ity (HSSKS)
C: Hylan G- 34 5.2 10.6

F 20
2005a during activ-
ity (HSSKS)
C: Hylan G- 32 5.2 11.1

F 20
Karatosun 1-4 wk E: Orthovisc Pain at rest 39 9.1 14.1 0.1 (I) 1.2% (I)
2005a (HSSKS)
C: Hylan G- 40 8.1 13.0

F 20
Karatosun 5-13 wk E: Orthovisc Pain at rest 39 9.1 13.4 -0.8 (W) -9.9% (W)
2005a (HSSKS)
C: Hylan G- 34 8.1 13.2

F 20
Karatosun 14-26 wk E: Orthovisc Pain at rest 37 9.1 13.2 -1.3 (W) -16.0% W)
2005a (HSSKS)
C: Hylan G- 34 8.1 13.5

F 20
Karatosun 45-52 wk E: Orthovisc Pain at rest 30 9.1 13.4 -0.7 (W) -8.6% (W)
2005a (HSSKS)
C: Hylan G- 32 8.1 13.1

F 20

Karatosun 1-4 wk E: Orthovisc Pain dur- 39 2.1 3.5 0 0%

2005a ing climbing
stairs
(HSSKS)
C: Hylan G- 40 2.1 3.5

F 20
Karatosun 5-13 wk E: Orthovisc Pain dur- 39 2.1 3.5 -0.1 (W) -4.8% (W)
2005a ing climbing
stairs
(HSSKS)
C: Hylan G- 34 2.1 3.6

F 20
2005a ing climbing
stairs
(HSSKS)
C: Hylan G- 34 2.1 3.1

F 20
2005a ing climbing
stairs
(HSSKS)
C: Hylan G- 32 2.1 3.4

F 20
Karatosun 1-4 wk E: Orthovisc Pain during 39 2.5 4.0 -1.1 (W) -42.3% (W)
2005a transfer ac-
tivity
C: Hylan G- 40 2.6 4.2

F0
Karatosun 5-13 wk E: Orthovisc Pain during 39 2.5 4.5 0.5 (I) 19.25 (I)
2005a transfer ac-
tivity

C: Hylan G- 34 2.6 4.1

F 20
Karatosun 14-26 wj E: Orthovisc Pain during 37 2.5 3.9 0.2 (I) 7.7% (I)
2005a transfer ac-
tivity
C: Hylan G- 34 2.6 3.8

F 20
Karatosun 45-52 wk E: Orthovisc Pain during 30 2.5 4.3 0.3 (I) 11.5% (I)
2005a transfer ac-
tivity
C: Hylan G- 32 2.6 4.1

F 20
Karatosun 1-4 wk E: Orthovisc Walking dis- 39 5.4 8.7 1.7 (I) 20.5% (I)
2005a tance
C: Hylan G- 40 8.3 9.9

F 20
2005a tance
C: Hylan G- 34 8.3 10.1

F 20
2005a tance
C: Hylan G- 34 8.3 10.0

F 20
2005a tance
C: Hylan G- 32 8.3 10.2

F 20
Karatosun 1-4 wk E: Orthovisc Range of 39 113.0 123.0 3.8 (I) 3.3% (I)
2005a motion
C: Hylan G- 40 114.4 120.6

F 20
2005a motion

C: Hylan G- 34 114.4 121.0

F 20
Karatosun 14-26 wk E: Orthovisc Range of 37 113.0 118.0 -0.4 (W) -0.3% (W)
2005a motion
C: Hylan G- 34 114.4 119.8

F 20
2005a motion
C: Hylan G- 32 114.4 121.3

F 20
Atamaz 1-4 wk E: Orthovisc WOMAC 20 13.4 9.3 0 0%

2005 pain (Likert)
C: Hylan G- 20 12.4 8.3

F 20
Atamaz 5-13 wk E: Orthovisc WOMAC 20 13.4 11.2 1.5 (W) 12.1% (W)
2005 pain (Likert)
C: Hylan G- 20 12.4 8.7

F 20
2005 pain (Likert)
C: Hylan G- 20 12.4 10.4

F 20
Atamaz 36 wk E: Orthovisc WOMAC 20 13.4 10.4 -1.0 (I) 8.1% (I)

2005 pain (Likert)
C: Hylan G- 20 12.4 10.4

F 20
Atamaz 45-52 wk E: Orthovisc WOMAC 20 13.4 11.2 0 0%

2005 pain (Likert)
C: Hylan G- 20 12.4 10.2

F 20
Atamaz 1-4 wk E: Orthovisc Spontaneous 20 70.3 42.9 -6.4 (I) -7.5% (I)
2005 pain (0-100
mm VAS)

C: Hylan G- 20 85.0 64.0

F 20
Atamaz 5-13 wk E: Orthovisc Spontaneous 20 70.3 58.4 27.6 (W) 32.5% (W)
2005 pain (0-100
mm VAS)
C: Hylan G- 20 85.0 45.5

F 20
2005 pain (0-100
mm VAS)
C: Hylan G- 20 85.0 50.7

F 20
Atamaz 36 wk E: Orthovisc Spontaneous 20 70.3 52.2 15.2 (W) 17.9% (W)

2005 pain (0-100
mm VAS)
C: Hylan G- 20 85.0 51.7

F 20
2005 pain (0-100
mm VAS)
C: Hylan G- 20 85.0 49.0

F 20
Atamaz 1-4 wk E: Orthovisc SF-36 pain 20 36.4 47.5 -22.7 (W) -88.7% (W)
2005
C: Hylan G- 20 25.6 59.4

F 20
Atamaz 5-13 wk E: Orthovisc SF-36 pain 20 36.4 28.0 24.8 (W) 96.9% (W)
2005
C: Hylan G- 20 25.6 58.8

F 20
2005
C: Hylan G- 20 25.6 55.7

F 20

Atamaz 36 wk E: Orthovisc SF-36 pain 20 36.4 45.3 9.3 (W) 36.3% (W)
2005
C: Hylan G- 20 25.6 43.8

F 20
2005
C: Hylan G- 20 25.6 46.7

F 20
2005 physical
function
C: Hylan G- 20 58.3 40.1

F 20
2005 physical
function
C: Hylan G- 20 58.3 41.7

F 20
2005 physical
function
C: Hylan G- 20 58.3 41.9

F 20
Atamaz 36 wk E: Orthovisc WOMAC 20 41.5 39.6 17.8 (W) 30.5% (W)

2005 physical
function
C: Hylan G- 20 58.3 38.6

F 20
2005 physical
function
C: Hylan G- 20 58.3 38.9

F 20
Atamaz 1-4 wk E: Orthovisc SF-36 physi- 20 44.5 54.2 -12.0 (W) -33.8% (W)
2005 cal function-
ing

C: Hylan G- 20 35.5 57.2

F 20
2005 cal function-
ing
C: Hylan G- 20 35.5 61.7

F 20
2005 cal
functionin
C: Hylan G- 20 35.5 55.7

F 20
Atamaz 36 wk E: Orthovisc SF-36 physi- 20 44.5 49.2 -4.8 (W) -13.5% (W)
2005 cal function-
ing
C: Hylan G- 20 35.5 45.0

F 20
2005 cal function-
ing
C: Hylan G- 20 35.5 54.0

F 20
Atamaz 1-4 wk E: Orthovisc WOMAC 20 13.4 9.3 -1.2 (I) -8.5% (I)
2005 pain (Likert)
C: Physical 40 14.2 11.3

therapy
2005 pain (Likert)
C: Physical 40 14.2 11.8

therapy
2005 pain (Likert)
C: Physical 40 14.2 11.3

therapy

Atamaz 36 wk E: Orthovisc WOMAC 20 13.4 10.4 -1.1 (I) -7.7% (I)

2005 pain (Likert)
C: Physical 40 14.2 12.3

therapy
Atamaz 45-52 wk E: Orthovisc WOMAC 20 13.4 11.2 -3.5 (I) -24.6% (I)
2005 pain (Likert)
C: Physical 40 14.2 15.5

therapy
Atamaz 1-4 wk E: Orthovisc Spontaneous 20 70.3 42.9 -6.4 (I) -7.5% (I)
2005 pain (0-100
mm VAS)
C: Physical 40 93.5 43.5

therapy
2005 pain (0-100
mm VAS)
C: Physical 40 93.5 49.5

therapy
2005 pain (0-100
mm VAS)
C: Physical 40 93.5 48.5

therapy
Atamaz 36 wk E: Orthovisc Spontaneous 20 70.3 52.2 15.2 (W) 17.9% (W)

2005 pain (0-100
mm VAS)
C: Physical 40 93.5 50.7

therapy
2005 pain (0-100
mm VAS)
C: Physical 40 93.5 59.5

therapy

2005
C: Physical 40 29.6 59.1

therapy
2005
C: Physical 40 29.6 56.2

therapy
2005
C: Physical 40 29.6 54.6

therapy
Atamaz 36 wk E: Orthovisc SF-36 pain 20 36.4 45.3 -12.8 (W) -43.2% (W)
2005
C: Physical 40 29.6 51.3

therapy
2005
C: Physical 40 46.7 50.2

therapy
2005 physical
function
C: Physical 40 49.9 37.6

therapy
2005 physical
function
C: Physical 40 49.9 38.9

therapy
Atamaz 14-26 wk E: Orthovisc WOMAC 20 41.5 41.8 7.7 (W) 15.% (W)
2005 physical
function
C: Physical 40 49.9 41.9

therapy
Atamaz 36 wk E: Orthovisc WOMAC 20 41.5 39.6 9.8 (W) 19.6% (W)

2005 physical
function
C: Physical 40 49.9 38.2

therapy
2005 physical
function
C: Physical 40 49.9 38.2

therapy
2005 cal function-
ing
C: Physical 40 31.7 53.7

therapy
2005 cal function-
ing
C: Physical 40 31.7 53.5

therapy
Atamaz 14-26 wk E: Orthovisc SF-36 physi- 20 44.5 44.5 -22.3 (W) -70.3% (WO
2005 cal function-
ing
C: Physical 40 31.7 54.0

therapy
Atamaz 36 wk E: Orthovisc SF-36 physi- 20 44.5 49.2 -12.8 (W) -40.4% (W)
2005 cal function-
ing
C: Physical 40 31.7 49.2

therapy
2005 cal function-
ing

C: Physical 40 31.7 53.0

therapy
Ozturk 1-4 wk E: Orthovisc Pain (0-100 24 66.7 53.5 18.9 (W) -26.0% (W)
2005 mm VAS)
C: Ortho- 16 72.6 40.5

visc+triamcinolone
acetonide
Ozturk 1-4 wk E: Orthovisc WOMAC 24 4.1 3.9 0.8 (W) -19.5% (W)
2005 OA Index
stiffness sub-
scale
C: Ortho- 16 4.1 3.1

visc+triamcinolone
acetonide
2005 OA Index
stiffness sub-
scale
C: Ortho- 16 4.1 3.1

visc+triamcinolone
acetonide
2005 OA Index
stiffness sub-
scale
C: Ortho- 16 4.1 3.1

visc+triamcinolone
acetonide
Table 47. Clinical benefit table: Orthovisc. Dichotomous outcome measures
Study Time Treatment Outcome No. No. of pts. Risk (%) Risk NNT
improved difference
Brandt 2001 14-26 wk E: Orthovisc WOMAC 61 66 92 5 20

pain (num-
ber of
patients im-
proved)

Table 47. Clinical benefit table: Orthovisc. Dichotomous outcome measures (Continued)
C: Saline 60 69 87
Brandt 2001 14-26 wk E: Orthovisc WOMAC 38 66 58 17 5.9

pain greater
than 5 unit
improve-
ment
C: Saline 28 69 41
Tekeoglu 1-4 wk E: Orthovisc Patient 10 20 50 -10 10

1998 global (num-
ber of pa-
tients good/
very good)
C: Be- 12 20 60
tamethasone
Tekeoglu 5-13 wk E: Orthovisc Patient 15 20 75 35 2.9

1998 global (num-
ber of pa-
tients good/
very good)
C: Be- 8 20 40
tamethasone
Kalay 1997 5-13 wk E: Orthovisc Number of 19 20 95 35 2.9

+ PT patients rat-
ing treat-
ment effec-
tive/very ef-
fective
C: PT 12 20 60
Guler 1996 5-13 wk E: Orthovisc Number of 11 15 73 40 2.5

patients rat-
ing treat-
ment effec-
tive/very ef-
fective
C: Saline 5 15 33

Table 48. Clinical benefit table: SLM-10 versus Artz. Dichotomous outcome measures
Study Time Treatment Outcome No. No. of pts Risk (%) Risk difference NNT
improved
Kawabata 1-4 wk E: SLM-10 Pain in move- 59 82 72 -9 11.1

1993 ment (num-
ber of
patients im-
proved)
C: Artz 60 74 81
Kawabata 1-4 wk E: SLM-10 Pain when 33 93 85 5 20

1993 resting (num-
ber of
patietns im-
proved)
C: Artz 33 41 80
Kawabata 1-4 wk E: SLM-10 Pressure pain 48 75 64 -18 5.6

1993 (number of
patients im-
proved)
C: Artz 54 66 82
Kawabata 1-4 wk E: SLM-10 Number of 56 82 68 -4 25

1993 pa-
tients better/
much better
C: Artz 53 74 72
Table 49. Clinical benefit table: Suplasyn. Continuous outcome measures
Petrella 1-4 wk E: Su- WOMAC 30 3.32 2.42 -0.47 (I) -13% (I)
2002 plasyn+lactose pain (0-10
cm)
C: 30 3.62 3.19
Saline+lactose
C: 30 4.22 2.86 0.46 (W) 11% (W)

Saline+NSAID

Table 49. Clinical benefit table: Suplasyn. Continuous outcome measures (Continued)
C: Su- 30 3.65 2.59 0.16 (W) 4% (W)

plasyn+NSAID
2002 plasyn+lactose function (0-
10 cm)
C: 30 4.72 3.73
Saline+lactose
C: 30 4.32 2.76 -0.09 (I) -2% (I)

Saline+NSAID
C: Su- 30 3.90 2.73 -0.48 (I) -12% (I)

plasyn+NSAID
2002 plasyn+lactose stiffness (0-
10 cm)
C: 30 5.12 5.00
Saline+lactose
C: 30 5.14 2.80 0.69 (W) 13% (W)

Saline+NSAID
C: Su- 30 4.82 2.71 0.46 (W) 10% (W)

plasyn+NSAID
Petrella 1-4 wk E: Su- Rest pain (0- 30 3.29 2.60 0.84 (W) 25% (W)
2002 plasyn+lactose 10 cm)
C: 30 3.30 1.77
Saline+lactose
C: Saline + 30 3.34 1.58 1.07 (W) 32% (W)

NSAID
C: Su- 30 3.60 1.56 1.35 (W) 38% (W)

plasyn+NSAID
Petrella 1-4 wk E: Su- Self-paced 30 3.94 2.89 -1.08 (I) -31% (I)
2002 plasyn+lactose walk pain (0-
10 cm)
C: 30 3.53 3.56
Saline+lactose

Table 49. Clinical benefit table: Suplasyn. Continuous outcome measures (Continued)
C: 30 3.78 1.81 0.92 (W) 24% (W)

Saline+NSAID
C: Su- 30 3.84 2.05 0.74 (W) 19% (W)

plasyn+NSAID
Petrella 1-4 wk E: Su- Walk time 30 77.23 74.21 -3.53 (I) -5% (I)
2002 plasyn+lactose (sec)
C: 30 70.56 71.07
Saline+lactose
C: 30 77.64 75.70 -1.08 (I) -1% (I)

Saline+NSAID
C: Su- 30 78.81 72.22 3.57 (W) 5% (W)

plasyn+NSAID
Table 50. Clinical benefit table: Zeel versus Hyalgan. Continuous outcome measures
Nahler 1998 1-4 wk T: Zeel Pain 57 67 31 1 (W) 1.6% (W)

during move-
ment (0-100
mm VAS)
C: Hyalgan 57 63 26
Nahler 1998 1-4 wk T: Zeel Pain at night 57 33 9 4 (W) 11.4% (W)

(0-100 mm
VAS)
C: Hyalgan 57 35 7
Table 51. Trials that utilised repeat courses of treatment
Study ID Product
Jubb 2003 Hyalgan
Karras 2001 Hyalgan
Listrat 1997 Hyalgan

Table 51. Trials that utilised repeat courses of treatment (Continued)
St. J. Dixon 1988 Hyalgan
Groppa 2001 Hylan G-F 20 (Synvisc)
Leopold 2003 Hylan G-F 20 (Synvisc)
Raynauld 2002 Hylan G-F 20 (Synvisc)
Pham 2004 NRD-101 (Suvenyl)
Hizmetli 1999 Orthovisc
Ozturk 2005 Orthovisc
Atamaz 2006 Hylan G-F 20 and Orthovisc
Table 52. Effect size based on Standardised Mean Difference - Part I
Product Comparison Outcome 1-4 wk 5-13 wk 14-26 wk 45-52 wk
Artz, Artzal Placebo Pain (VAS) 0.02 (-0.16,0. -0.19 (-0.37,-0. 0.00 (-0.24,0.
20) P value 0.8 01) P value 0.04 23) P value 1
Pain (0-3) -0.14 (-0.54,0.

26) P value 0.5
WOMAC pain -0.24 (-0.50,0.

(Likert) 02) P value 0.07
WOMAC func- -0.22 (-0.49,0.

tion (Likert) 04) P value 0.10
WOMAC stiff- -0.24 (-0.51,0.

ness (Likert) 02) P value 0.07
Lequesne Index 0.06 (-0.23,0. -0.11 (-0.39,0. 0.11 (-0.09,0.

(0-24) 34) P value 0.7 17) P value 0.5 31) P value 0.3
Range of motion 0.22 (-0.18,0.

(degrees) 61) P value 0.3
Hylan G-F 20 Pain weight -0.04 (-0.34,0. 0.03 (-0.26,0. 0.15 (-0.15,0.
bearing (VAS) 26) P value 0.8 33) P value 0.8 44) P value 0.3
Lequesne Index 0.21 (-0.08,0.

(0-24) 50) P value 0.16

Table 52. Effect size based on Standardised Mean Difference - Part I (Continued)
BioHy Hylan G-F 20 WOMAC pain -0.18 (-0.40,0. -0.19 (-0.41,0.

(Arthrease) (VAS) 04) P value 0.10 03) P value 0.08
Fermathron Hyalart Pain (VAS) 0.11 (-0.14,0. 0.04 (-0.22,0.

37) P value 0.4 30) P value 0.8
Lequesne Index 0.11 (-0.14,0. 0.14 (-0.12,0.

(0-24) 37) P value 0.4 39) P value 0.3
Hyalgan Placebo Pain weight -0.32 (-0.58,-0. -0.41 (-0.66,-0. -0.22 (-0.43,-0. -0.07 (-0.24,0.
bearing (VAS) 05) P value 0.02 16) P value 0. 02) P value 0.03 10) P value 0.4
001
Pain sponta- -1.14 (-1.64,-0. -1.07 (-1.56,-0.

neous (VAS) 64) P value 0. 57) P value 0.
00001 00003
Pain at rest -0.49 (-0.88,-0. -0.72 (-1.06,-0. 0.07 (-0.29,0.

(VAS) 10) P value 0.01 38) P value 0. 43) P value 0.7
00004
Pain at night -0.69 (-1.88,0.

(VAS) 50) P value 0.3
WOMAC pain -0.18 (-0.47,0. -0.10 (-0.40,0. -0.38 (-0.68,-0.

(VAS) 10) P value 0.2 19) P value 0.5 08) P value 0.01
WOMAC func- -0.09 (=0.37,0. -0.07 (-0.37,0. -0.28 (-0.57,0.

tion (VAS) 20) P value 0.5 22) P value 0.6 02) P value 0.07
Lequesne Index -0.39 (-0.63,-0. -0.60 (-0.89,-0. -0.30 (-0.74,0. -0.28 (-0.69,0.
(0-24) 16) P value 0. 31) P value 0. 14) P value 0.18 13) P value 0.18
0010 00006
Flexion (degrees) 0.30 (-0.37,0. 0.70 (0.01,1.39)

97) P value 0.4 P value 0.05
Synovial fluid -0.07 (-0.39,0. -0.51 (-1.02,-0.

volume (ml) 24) P value 0.6 01) P value 0.04
Joint space 0.26 (0.02,0.49)

width (total pop- P value 0.04
ulation)
Joint space width 0.12 (-0.28,0.

(subgroups) 52) P value 0.6
Arthroscopy Pain (VAS) 0.42 (-0.31,1. 0.00 (-0.70,0. -0.25 (-1.00,0. 0.00 (-0.79,0.
15) P value 0.3 70) P value 1 49) P value 0.5 79) P value 1

Knee Society 0.53 (-0.21,1. 0.49 (-0.23,1. 0.77 (0.00,1.54) 0.72 (-0.10,1.
Function Scale 26) P value 0.16 21) P value 0.18 P value 0.05 54) P value 0.08
Lequesne Index 0.53 (-0.21,1. 0.49 (-0.23,1. 0.77 (0.00,1.54) 0.72 (-0.10,1.
(0-24) 26) P value 0.16 21) P value 0.18 P value 0.05 54) P value 0.08
NSAID Pain after 50 foot 0.00 (-0.23,0. 0.08 (-0.17,0. -0.13 (-0.40,0.
walk (VAS) 23) P value 1 33) P value 0.5 14) P value 0.3
Methylpred- Spon- -0.27 (-0.58,0. -0.41 (-0.90,0. 0.10 (-0.60,0.

nisolone acetate taneous pain in- 03) P value 0.08 08) P value 0.10 79) P value 0.8
tensity (VAS)
Range of motion 0.39 (0.05,0.74) 0.40 (0.05,0.75) 0.07 (-0.62,0.

(degrees) P value 0.03 P value 0.02 77) P value 0.8
Triamcinolone Pain on -0.01 (-0. -0.39 (-1.29,0.

hexacetonide nominated activ- 53,0.52) P value 52) P value 0.4
ity (VAS) 1 (end of treat-
ment)
Pain at rest -0.02 (-0. -0.76 (-1.69,0.

(VAS) 54,0.50) P value 18) P value 0.11
0.9 (end of treat-
ment)
Pain at night -0.21 (-0. -1.11 (-2.09,-0.

(VAS) 74,0.31) P value 14) P value 0.03
0.4 (end of treat-
ment)
Mucopolysac- Pain (0-30) 0.66 (0.14,1.19)

charide polysul- P value 0.01 (end
furic acid ester of treatment)
Function (0-30) 0.11 (-0.

40,0.63) P value
0.7 (end of treat-
ment)
Range of motion 0.39 (-0.13,

(0-10) 0.91) P value 0.
14 (end of treat-
ment)
Total Larson rat- 0.63 (0.10,1.16)

ing score (0-77) P value 0.02 (end
of treatment)

Appropriate care Pain overall -0.53 (-1.20,0.

Lequesne Index -0.20 (-0.85,0.

(0-24) 46) P value 0.6
Joint space width 0.63 (-0.04,1.

(mm) 30) P value 0.07
Quality of life: -0.16 (-0.82,0.

AIMS 49) P value 0.6
Arthroscopy -0.79 (-1.47,-0.

overall score 10) P value 0.02
(VAS)
SFA score (VAS) -0.90 (-1.59,-0.

21) P value 0.01
Hylan G-F 20 Placebo Pain weight -0.51 (-0.87,-0. -0.94 (-1.57,-0. -0.77 (-1.38,-0.
bearing (VAS) 15) P value 0. 31) P value 0. 15) P value 0.01
006 003
Pain at night -0.30 (-0.50,-0. -0.52 (-1.00,-0. -0.82 (-1.12,-0.

(VAS) 09) P value 0. 05) P value 0.03 51) p<0.00001
005
WOMAC pain -0.31 (-0.68,0.

Pain at rest -0.14 (-0.55,0.

Pain overall -0.07 (-0.48,0.

Lequesne Index 0.02 (-0.30,0.

(0-24) 34) P value 0.9
WOMAC func- -0.43 (-0.81,-0.

tion (VAS) 05) P value 0.03
Function: 0.63 (0.39,0.88) 1.29 (0.97,1.60)

improvement p<0.00001 p<0.00001
(VAS)
Patient 0.72 (0.47,0.96) 1.19 (0.66,1.71)

global: treatment p<0.00001 P value 0.00001
efficacy (VAS)

NSAID Pain on motion -0.27 (-0.80,0. -0.49 (-1.02,0.

(VAS) 25) P value 0.3 03) P value 0.07
Pain at rest -0.14 (-0.66,0. -0.15 (-0.67,0.

Pain at night -0.29 (-0.82,0. -0.12 (-0.64,0.

Pain overall -0.18 (-0.71,0. -0.23 (-0.75,0.

WOMAC pain -0.41 (-0.79,-0.

WOMAC func- -0.21 (-0.59,0.

Lequesne Index -0.27 (-0.65,0.

(0-24) 11) P value 0.16
Hylan G-F 20 + NSAID Pain on motion -0.44 (-0.93,0. -0.66 (-1.17,-0.

NSAID (VAS) 06) P value 0.08 15) P value 0.01
Pain at rest -0.44 (-0.93,0. -0.66 (-1.17,-0.

Pain at night -0.48 (-0.98,0. -0.84 (-1.35,-0.

(VAS) 02) P value 0.06 32) P value 0.
002
Pain overall -0.46 (-0.96,0. -0.66 (-1.17,-0.

Hylan G-F 20 Triamcinolone WOMAC pain -0.43 (-0.70,-0. -0.38 (-0.65,-0.

hexacetonide Q1 (Likert) 16) P value 0. 11) P value 0.
002 005
WOMAC func- -0.35 (-0.62,-0. -0.36 (-0.63,-0.

tion (Likert) 08) P value 0.01 09) P value 0.
010
WOMAC total -0.37 (-0.64,-0. -0.36 (-0.63,-0.

score (Likert) 10) P value 0. 09) P value 0.
007 010
Patient global -0.54 (-0.81,-0. -0.57 (-0.84,-0.

(VAS) 27) P value 0. 30) P value 0.
0001 00004

Hylan G-F 20 + Physiotherapy Lequesne Index -0.24 (-1.11, -0.23 (-1.10,0.

PT (PT) (0-24) 0.63) P value0. 64) P value 0.6
6 (end of treat-
ment)
Hylan G-F 20 Appropriate care WOMAC pain -0.77 (-1.02,-0.

(Likert) 51) p<0.00001
WOMAC func- -0.72 (-0.98,-0.

tion (Likert) 45) p<0.00001
WOMAC pain -0.60 (-0.78,-0.

(VAS) 42) p<0.00001
(36 wk)
Pain walking -0.53 (-0.71,-0.

(VAS) 36) p<0.00001
(36 wk)
WOMAC func- -0.61 (-0.79,-0.

tion (VAS) 43) p<0.00001
(36 wk)
Lequesne Index -0.49 (-0.67,-0.

(0-24) 32) p<0.00001
(36 wk)
WOMAC total -0.63 (-0.81,-0.

(VAS) 45) p<0.00001
(36 wk)
Gaseous oxygen Pain under load 0.30 (-0.08, 0.44 (0.06,0.82) 0.27 (-0.10,0. 0.24 (-0.14,0.
(VAS) 0.68) P value 0. P value 0.02 65) P value 0.16 61) P value 0.2
12 (end of treat-
ment)
Pain at rest 0.06 (-0. 0.26 (-0.12,0. 0.10 (-0.28,0. 0.00 (-0.37,0.
(VAS) 32,0.43) P value 63) P value 0.18 48) P value 0.6 38) P value 1
0.8 (end of treat-
ment)
WOMAC pain 0.34 (-0.04, 0.35 (-0.03,0. 0.14 (-0.24,0. 0.20 (-0.18,0.
(Likert) 0.71) P value 0. 73) P value 0.07 51) P value 0.5 57) P value 0.3
08 (end of treat-
ment)
WOMAC func- 0.24 (-0. 0.21 (-0.17,0. 0.27 (-0.11,0. 0.26 (-0.11,0.
tion (Likert) 14,0.62) P value 58) P value 0.3 65) P value 0.16 64) P value 0.17

0.2 (end of treat-

ment)
WOMAC stiff- 0.10 (-0. 0.28 (-0.10,0. 0.47 (0.09,0.85) 0.25 (-0.13,0.
ness (Likert) 27,0.48) P value 65) P value 0.15 P value 0.02 63) P value 0.2
0.6 (end of treat-
ment)
Hyaluronan Pain weight -0.08 (-0.30,0. -0.28 (-0.64,0. -0.15 (-0.44,0.

bearing (VAS) 14) P value 0.5 09) P value 0.13 15) P value 0.3
Pain at night -0.34 (-0.06,-0. -0.14 (-0.47,0.

Function: -0.02 (-0.34,0. 0.41 (0.08,0.73)

improvement 30) P value 0.9 P value 0.02
(VAS)
Patient global 0.06 (-0.26,0. 0.31 (-0.02,0.

(treatment effi- 38) P value 0.7 63) P value 0.07
cacy) (VAS)
NRD-101 Artz Flexion (end of 0.08 (-0.21,0.

treatment) 37) P value 0.6
Extension (end -0.04 (-0.33,0.

of treatment) 26) P value 0.8
Orthovisc Placebo WOMAC pain -1.68 (-2.41,-0. -1.88 (-2.64,-1. -1.86 (-2.61,-1. -1.87 (-2.63,-1.
(Likert) 95) p<0.00001 12) p<0.00001 11) p<0.00001 12) p<0.00001
WOMAC func- -0.87 (-1.46,-0. -0.81 (-1.46,-0. -0.73 (-1.38,-0. -0.52 (-1.15,-0.
tion (Likert) 17) P value 0. 17) P value 0.01 09) P value 0.03 11) P value 0.11
009
Betamethasone WOMAC func- 0.34 (-0.29,0. -1.06 (-1.73,-0.

tion (VAS) 96) P value 0.3 40) P value 0.
002
Flexion (degrees) -0.30 (-0.93,0. -0.51 (-1.14,0.

32) P value 0.3 12) P value 0.11
6-MPA Pain weight 0.26 (-0.27,0. -0.92 (-1.48,-0. -0.76 (-1.31,-0.

bearing (VAS) 79) P value 0.3 36) P value 0. 21) P value 0.
001 007
Pain at rest 0.33 (-0.21,0. -0.69 (-1.24,-0. -0.23 (-0.76,0.


Pain on walking -0.02 (-0.55,0. -0.89 (-1.45,-0. -0.71 (-1.25,-0.

(VAS) 51) P value 0.9 33) P value 0. 16) P value 0.01
002
Lequesne Index -0.06 (-0.59,0. -0.99 (-1.56,-0. -0.58 (-1.12,-0.

(0-24) 46) P value 0.8 43) P value 0. 04) P value 0.04
0005
Flexion (degrees) 0.24 (-0.29,0. 0.29 (-0.24,0. 0.54 (0.00,1.08)

77) P value 0.4 83) P value 0.3 P value 0.05
Orthovisc + PT Physiotherapy Activity pain -0.19 (-0.81,0. -0.73 (-1.37,-0.

(PT) (VAS) 43) P value 0.6 08) P value 0.03
Spontaneous 0.07 (-0.55,0. -0.75 (-1.39,-0.

pain (VAS) 69) P value 0.8 10) P value 0.02
Night pain -0.03 (-0.65,0. -0.57 (-1.20,0.

Lequesne Index -0.06 (-0.87,0. -0.44 (-1.27,0.

(0-24) 76) P value 0.9 38) P value 0.3
25 m walk time 0.25 (-0.37,0. -0.41 (-1.04,0.

87) P value 0.4 21) P value 0.19
Table 53. Effect size based on Standardised Mean Difference - Part II
Orthovisc+PT Hylan G-F Lequesne Index 0.16 (-0. -0.30 (-1.05,0.

20+PT (0-24) 59,0.91) P value 45) P value 0.4
0.7 (End of treat-
ment)
Suplasyn Placebo Pain after walk- -0.38 (-0.92,0.

ing (VAS) 17) P value 0.17
WOMAC pain -0.29 (-0.83,0.

Pain at rest 0.56 (0.01,1.11)

(VAS) P value 0.05
WOMAC func- -0.47 (-1.02,0.


Table 53. Effect size based on Standardised Mean Difference - Part II (Continued)
Walk time (sec) 0.18 (-0.36,0.

72) P value 0.5
NSAID Pain after walk- 0.39 (-0.15,0.

ing (VAS) 93) P value 0.16
WOMAC pain -0.17 (-0.70,0.

Pain at rest 0.40 (-0.14,0.

WOMAC func- -0.13 (-0.66,0.

Walk time (sec) -0.09 (-0.62,0.

45) P value 0.7
Su- NSAID Pain after walk- 0.09 (-0.44,0.

plasyn+NSAID ing (VAS) 62) P value 0.7
WOMAC pain -0.10 (-0.63,0.

Pain at rest -0.01 (-0.54,0.

(VAS) 52) P value 1
WOMAC func- -0.01 (-0.54,0.

tion (VAS) 52) P value 1
Walk time (sec) -0.21 (-0.74,0.

32) P value 0.4
Zeel Hyalart Pain during 0.23 (-0.

movement 15,0.61) P value
(VAS) 0.2 (end of treat-
ment)
Pain during 0.09 (-0.

night (VAS) 29,0.47) P value
0.6 (end of treat-
ment)
Pa- -0.16 (-0.

tient assessment 53,0.21) P value
of improvement 0.4 (end of treat-
(VAS) ment)

Table 53. Effect size based on Standardised Mean Difference - Part II (Continued)
Patient as- -0.16 (-0.

sessment of tol- 53,0.21) P value
erance (VAS) 0.4 (end of treat-
ment)
HA/Hylan Placebo Pain weight -0.37 (-0.55,-0. -0.33 (-0.55,-0. -0.33 (-0.55,-0. -0.09 (-0.27,0.
(Pooled) bearing (VAS) 19) P < 0.0001 11) P value 0. 11) P value 0. 08) P value 0.3
004 004
Pain at rest -0.27 (-0.65,0.

WOMAC pain -0.21 (-0.46,0. -0.23 (-0.46,0. -0.38 (-0.68,-0.

WOMAC func- -0.17 (-0.42,0. -0.75 (-1.12,-0.

tion (VAS) 08) P value 0.19 38) P value 0.
00008
Lequesne Index -0.21 (-0.39,-0. -0.36 (-0.54,-0. 0.01 (-0.16,0. -0.28 (-0.69,0.
(0-24) 03) P value 0.02 18) P < 0.0001 19) P value 0.9 13) P value 0.18
Flexion (degrees) 0.24 (-0.10,0. 0.70 (0.01,1.39)

58) P value 0.17 P value 0.05
Table 54. Effect size based on Standardised Mean Difference - Part III
NASHA Saline WOMAC pain

(Durolane) (Likert: 0-20)
WOMAC stiff-
ness (Likert: 0-8)
WOMAC physi-
cal function
(Likert: 0-68)
Patient global as-

sessment (Likert:
1-5)
SF-
36 physical com-
ponet summary (
)

Table 54. Effect size based on Standardised Mean Difference - Part III (Continued)
SF-36
mental compo-
nent summary ( )
NRD-101 (Su- Placebo Pain (0-100 mm

venyl) VAS)
Lequesne Index
(0-24)
Patient global as-

sessment (0-100
mm VAS)
Percentage
of painful days
during the pre-
vious month (0-
100 mm VAS)
NRD-101 (Su- Diacerein Pain (0-100 mm

venyl) VAS)
Lequesne Index
(0-24)
Patient global as-

sessment (0-100
mm VAS)
Percentage
of painful days
during the pre-
vious month (0-
100 mm VAS)
Hyal- Exer- Pain (0-10 cm

cise+ultrasound VAS)
Lequesne Index
(0-26)
Range of motion
(degrees)
Ambu-
lation speed (me-
tres/minute)

Mean
peak torque at
60 degrees per
second (flexion/
concentric)
Mean
peak torque at
180 degrees per
second (flexion/
concentric)
Hyal- Exercise Pain (0-10 cm

gan+exercise+ultrasound VAS)
Lequesne Index
(0-26)
Range of motion
(degrees)
Ambu-
lation speed (me-
tres/minute)
Mean
peak torque at
60 degrees per
second (flexion/
concentric)
Mean
peak torque at
180 degrees per
second (flexion/
concentric)
Hyal- Control warmup Pain (0-10 cm)

exercises
Lequesne Index
(0-26)
Range of motion
(degrees)
Ambu-
lation speed (me-

tres/minute)
Mean
peak torque at
60 degrees per
second (flexion/
concentric)
Mean
peak torque at
180 degrees per
second (flexion/
concentric)
Hylan G-F 20 Exercise Hospital for Spe-

programme cial Surgery
Knee Score


APPENDICES
Appendix 1. Search strategy

1 osteoarthritis.tw,sh.
2 knee joint/
3 knee.tw,sh.
4 1 and (2 or 3)
5 osteoarthritis, knee/
6 4 or 5
7 hyaluronic.sh,tw,rn.
8 hyaluronan.tw.
9 sodium hyaluronate.tw.
10 (hylan or healonid).tw.
11 (hyalgan or hylectin or hyalflex).tw.
12 (hylartil or replasyn or suplasyn).tw.
13 (polyreumin or polireumin).tw.
14 nrd 101.tw
15 (artz or artzal).tw.
16 slm 10.tw.
17 (neovisc or orthovisc).tw.
18 adant.tw.
19 etapharm.tw.
20 or/7-19
21 6 and 20
22 clinical trial.pt.
23 randomized controlled trial.pt.
24 tu.fs.
25 dt.fs.
26 random$.tw.
27 (double adj blind$).tw.
28 placebo$.tw.
29 (single adj blind$).tw.
30 random allocation.tw.
31 or/22-30
32 21 and 31
33 meta-analysis.pt,sh.
34 (meta-anal: or metaanal:).tw.
35 (quantitativ: review: or quantitativ: overv
36 (methodologic: review: or methodologic: ove
37 (systematic: review: or systematic: overvie
38 review.pt. and medline.tw.
39 or/33-38
40 21 and 39
41 32 or 40
42 limit 41 to human
FEEDBACK
New feedback, 21 September 2014
Summary
Date of Submission: 21-Sep-2014
Name: Jos Verbeek
Email Address: jos.verbeek@ttl.fi
Affiliation: Finnish Institute of Occupational Health
Role: senior researcher
Comment: I promised a friend to find out about Hyalgan proposed by a doctor for his osteoarthritic knee. I would like to give my
friend an estimate of the reduction in pain that he could expect from the injections. I was impressed by the conclusion of the review:
overall, these analyses strongly support the evidence for efficacy of Hyalgan.
It took me several hours to find my way through the 673 pages of the review where the text lacks links to the analyses. I was surprised
to find the data not being in concordance with the strong conclusions. At three months follow-up, in ten trials, the median pain level
on weight bearing was 43 out of 100 in the control group and the pooled mean difference 6.2. This means that the pain level decreased
with 15% as a result of the injections. At one year follow-up there is no significant difference anymore.
Given that the review is sponsored by the pharmaceutical industry producing the very product and that there are two more recent
reviews, as mentioned by Hilda Bastian in her comment in Pubmed commons (see altmetrics), with conclusions opposite to this review,
I strongly believe that the authors’ conclusions are wrong and that they should amend their conclusions or that this review should be
retracted.
Based on the data presented above, my friend thought that it would be wise not to take these injections, and I fully agree.
I agree with the conflict of interest statement below:
I certify that I have no affiliations with or involvement in any organization or entity with a financial interest in the subject matter of
my feedback.
Reply
Dear Jos,
Thank you for this feedback. We have a new author team working on an update of this review and have shared this feedback with
them. The updated review is expected by December 2015.
We appreciate you taking the time to send us these comments.
Thanks and best wishes,

Lara Maxwell, Cochrane Musculoskeletal Group, Co-Managing Editor
Contributors
Lara Maxwell, Cochrane Musculoskeletal Group, Co-Managing Editor, on behalf of the CMSG co-ordinating editors
WHAT’S NEW
Last assessed as up-to-date: 20 February 2006.
Date Event Description
6 November 2014 Amended Updated with Feedback and editorial response
6 November 2014 Feedback has been incorporated Updated with Feedback and editorial response

HISTORY
Protocol first published: Issue 2, 1998
Review first published: Issue 2, 2005
Date Event Description
10 November 2008 Amended Converted to new review format.

CMSG ID: A018-R
CONTRIBUTIONS OF AUTHORS
NB filed the protocol for the review with The Cochrane Collaboration. JC coordinated the review under NB’s supervision. JC searched
the literature and extracted data. NB and JC performed the methodological review. JC entered and analysed the data. VR checked data
extraction. GAW provided statistical and methodological support. TG provided statistical support. NB is the guarantor for the review.
For the update, JC completed data extraction and NB verified data extraction. NB and JC performed the methodological review. VR
provided methodological support. GAW provided statistical and methodological support. TG provided statistical support. NB is the
guarantor for the review.
DECLARATIONS OF INTEREST
The original review was externally supported by Genzyme Biosurgery [formerly Biomatrix, Inc] and Wyeth-Ayerst as an unrestricted
educational grant. Finances supported research staff to research this treatment area for all products, not just that manufactured by
Genzyme BioSurgery [formerly Biomatrix, Inc]. The interpretation of the results are those of the reviewers who retain the right to
publish.
Dr. Nicholas Bellamy and Dr. Robert Bourne participated in the Raynauld (Raynauld 2002) trial. Dr. Bellamy was a co-investigator on
the Steering Committee of the Raynauld (Raynauld 2002) trial, and previously provided consulting services to Biomatrix and Genzyme
Inc.
Dr. Bourne was a clinical investigator in the Raynauld (Raynauld 2002) trial.
Product-based analyses were circulated to each respective manufacturer prior to finalisation of the original review to permit any factual
errors to be addressed. Comments were received from some but not all manufacturers.
SOURCES OF SUPPORT
Internal sources
• Centre of National Research on Disability and Rehabilitation Medicine (CONROD), Australia.

External sources
• No sources of support supplied
NOTES
This update was required as the Cochrane Funding Arbitration Panel ruled that the original review contravened the ”current“ sponsorship
policy. In order to have the review reinstated into the Cochrane Library, the review was updated using no commercial sources of support
and the electronic literature search was updated (Medline). The financial support for the original review is now disclosed in the ”conflict
of interest“ statement.
This update includes 16 ”new“ RCT: Altman 2004, Atamaz (accepted for publication), Cubukcu 2005, Huang 2005, Karatay 2004,
Karatosun 2005, Karatosun 2005a, Kirchner 2006, Kotevoglu 2005, Neustadt 2005, Ozturk 2005, Pham 2004, Rejaili 2005, Sezgin
2005, Wu 2004, and Yentur 2003.
In the original review, only limited information was included for three of the ”new“ RCT based on the following abstracts: Ardic 2001
(Cubukcu 2005), Pham 2003 (Pham 2004), and Thompson 2002 (Kirchner 2006).
INDEX TERMS
Medical Subject Headings (MeSH)

Hyaluronic Acid [administration & dosage; ∗ analogs & derivatives; ∗ therapeutic use]; Injections, Intra-Articular; Osteoarthritis, Knee
[∗ drug therapy]; Randomized Controlled Trials as Topic
MeSH check words

Humans


Viscosupplementation

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Cochrane Database of Systematic Reviews

Viscosupplementation for the treatment of osteoarthritis of

Bellamy N, Campbell J, Welch V, Gee TL, Bourne R, Wells GA

Bellamy N, Campbell J, Welch V, Gee TL, Bourne R, Wells GA.

Viscosupplementation for the treatment of osteoarthritis of the knee (Review)

Viscosupplementation for the treatment of osteoarthritis of the knee (Review) iii

Viscosupplementation for the treatment of osteoarthritis of the knee (Review) iv

Viscosupplementation for the treatment of osteoarthritis of the knee (Review) v

Viscosupplementation for the treatment of osteoarthritis of the knee (Review) ix

Viscosupplementation for the treatment of osteoarthritis of the knee (Review) xii

Viscosupplementation for the treatment of osteoarthritis of the knee (Review) xiii

Viscosupplementation for the treatment of osteoarthritis of the knee (Review) xiv

Viscosupplementation for the treatment of osteoarthritis of the knee (Review) xvi

Viscosupplementation for the treatment of osteoarthritis of

Editorial group: Cochrane Musculoskeletal Group.

PLAIN LANGUAGE SUMMARY

Viscosupplementation for the treatment of osteoarthritis of the knee (Review) 2

Viscosupplementation as treatment for knee OA has been the

Viscosupplementation for the treatment of osteoarthritis of the knee (Review) 3

Viscosupplementation for the treatment of osteoarthritis of the knee (Review) 4

Viscosupplementation for the treatment of osteoarthritis of the knee (Review) 5

Viscosupplementation for the treatment of osteoarthritis of the knee (Review) 6

Viscosupplementation for the treatment of osteoarthritis of the knee (Review) 7

Viscosupplementation for the treatment of osteoarthritis of the knee (Review) 8

Viscosupplementation for the treatment of osteoarthritis of the knee (Review) 9

Viscosupplementation for the treatment of osteoarthritis of the knee (Review) 10

Viscosupplementation for the treatment of osteoarthritis of the knee (Review) 11

Viscosupplementation for the treatment of osteoarthritis of the knee (Review) 12

Viscosupplementation for the treatment of osteoarthritis of the knee (Review) 13

Viscosupplementation for the treatment of osteoarthritis of the knee (Review) 14

Viscosupplementation for the treatment of osteoarthritis of the knee (Review) 15

Viscosupplementation for the treatment of osteoarthritis of the knee (Review) 16

Viscosupplementation for the treatment of osteoarthritis of the knee (Review) 17

Viscosupplementation for the treatment of osteoarthritis of the knee (Review) 18

Viscosupplementation for the treatment of osteoarthritis of the knee (Review) 19

Viscosupplementation for the treatment of osteoarthritis of the knee (Review) 20

Viscosupplementation for the treatment of osteoarthritis of the knee (Review) 21

Viscosupplementation for the treatment of osteoarthritis of the knee (Review) 22

Viscosupplementation for the treatment of osteoarthritis of the knee (Review) 23

Viscosupplementation for the treatment of osteoarthritis of the knee (Review) 24

Viscosupplementation for the treatment of osteoarthritis of the knee (Review) 25

Viscosupplementation for the treatment of osteoarthritis of the knee (Review) 26

Viscosupplementation for the treatment of osteoarthritis of the knee (Review) 27

Viscosupplementation for the treatment of osteoarthritis of the knee (Review) 28

Viscosupplementation for the treatment of osteoarthritis of the knee (Review) 29

Viscosupplementation for the treatment of osteoarthritis of the knee (Review) 30

Viscosupplementation for the treatment of osteoarthritis of the knee (Review) 31

Viscosupplementation for the treatment of osteoarthritis of the knee (Review) 32

Viscosupplementation for the treatment of osteoarthritis of the knee (Review) 33

Viscosupplementation for the treatment of osteoarthritis of the knee (Review) 34

Viscosupplementation for the treatment of osteoarthritis of the knee (Review) 35

Viscosupplementation for the treatment of osteoarthritis of the knee (Review) 36

Viscosupplementation for the treatment of osteoarthritis of the knee (Review) 37

Viscosupplementation for the treatment of osteoarthritis of the knee (Review) 38

Viscosupplementation for the treatment of osteoarthritis of the knee (Review) 39

Viscosupplementation for the treatment of osteoarthritis of the knee (Review) 40

Viscosupplementation for the treatment of osteoarthritis of the knee (Review) 41

Viscosupplementation for the treatment of osteoarthritis of the knee (Review) 42

Viscosupplementation for the treatment of osteoarthritis of the knee (Review) 43

HA products differ in their origin, method of production, molec-

Viscosupplementation for the treatment of osteoarthritis of the knee (Review) 44

Viscosupplementation for the treatment of osteoarthritis of the knee (Review) 45

Viscosupplementation for the treatment of osteoarthritis of the knee (Review) 46

Viscosupplementation for the treatment of osteoarthritis of the knee (Review) 47