SURGICAL ONCOLOGY AND RECONSTRUCTION

1 57
2 58
3 59
4
5
Nasolabial Flap Improves Healing in 60
61
6
7 Medication-Related Osteonecrosis 62
63
8 64
9 of the Jaw 65
10 66
11 Q3 Juliana Lemound, MD, DMD,* Thomas Muecke, MD, DMD,y 67
12 Alexander-Nicolai Zeller, MD,z J€
urgen Lichtenstein, MD, DMD,x 68
13 Andre Eckardt, MD, DMD,k and Nils-Claudius Gellrich, MD, DMD{ 69
14 70
Purpose: Medication-related osteonecrosis of the jaw (MRONJ) is an adverse side effect of antiresorptive
15 71
and antiangiogenic therapeutic agents that is difficult to treat owing to its high relapse rate. The aim of the
16 72
present study was to determine whether patients with MRONJ treated using decortication and a nasolabial
17 73
flap compared with those who underwent decortication with mucoperiosteal flaps have better outcomes
18 74
regarding stable wound closure.
19 75
20 Materials and Methods: Two groups of patients with MRONJ and intraoral exposed bone were evalu- 76
21 ated in a cohort clinical study retrospectively. The primary predictor variable was the treatment group. 77
22 The experimental group used the nasolabial flap for wound closure, and the control group used the mu- 78
23 coperiosteal flap for closure. The outcome variable was successful wound closure defined as a symptom- 79
24 less and closed wound after at least 12 months. Other study variables included factors such as 80
25 perioperative drug holiday, duration of postoperative oral antibiotic administration, and postoperative 81
26 use of nasogastric feeding tubes. Cox proportional hazard regression analysis and Kaplan-Meier curves 82
27 were used to determine the factors independently associated with the dependent variable. The Mann- 83
28 Whitney U test and c2 test were used for analyses regarding group-related data. 84
29 Results: Both groups showed similar demographics. The 16 study patients receiving nasolabial flaps had 85
30 a mean age of 69.9 years, and the 16 control patients receiving mucoperiosteal flaps had a mean age of 86
31 71.8 years. Both groups included 10 women and 6 men. Of the 16 patients in each group, 15 had received 87
32 a bisphosphonate and 1, monoclonal antibody therapy. All evaluated patients underwent combined treat- 88
33 ment, including decortication and intravenous antibiotics. Of the 16 patients receiving nasolabial flaps, 89
34 symptomless intact wound closure was achieved in 68.8%. Of the 16 patients with mucoperiosteal closure, 90
35 18.7% achieved wound closure, with 81.2% developing a relapse of MRONJ, a statistically significant dif- 91
36 ference (P < .001). No statistically significant differences were found between the 2 groups in the demo- 92
37 graphic variables. The mean interval to relapse for the experimental and control groups was 13.6  7.8 and 93
38 8.2  7.9 months, respectively (P = .017). 94
39 95
Conclusions: MRONJ is a complication of antiosteoclastic treatment of mostly oncologic, palliative
40 96
patients, which requires a very methodical approach to surgical treatment. A variety of different methods
41 97
42 98
43 *Consultant, Department of Oral and Maxillofacial Surgery, Conflict of Interest Disclosures: None of the authors have any 99
44 Klinikum Darmstadt, Darmstadt, Germany. relevant financial relationship(s) with a commercial interest. 100
45 yHead, Department of Oral and Maxillofacial Surgery, Malteser Address correspondence and reprint requests to Dr Lemound: 101
46 Klinikum Krefeld-Uerdingen and Duisburg Homberg, Krefeld, Department of Oral and Maxillofacial Surgery, Klinikum Darmstadt, 102
47 Germany. Grafenstrasse 9, Darmstadt 64283, Germany; e-mail: juliana. 103
48 zResident, Department of Oral and Maxillofacial Surgery, lemound@mail.klinikum-darmstadt.de 104
49 Hannover Medical School, Hannover, Germany. Received December 6 2016 105
50 xSpecialist, Clinic of Oral and Maxillofacial Surgery, University Accepted September 29 2017 106
51 Hospital of Schleswig-Holstein, Kiel, Germany. Ó 2017 Published by Elsevier Inc on behalf of the American Association of Oral 107
52 kProfessor and Head, Department of Oral and Maxillofacial and Maxillofacial Surgeons 108
53 Surgery, Hospital Bremerhaven-Reinkenheide, Bremerhaven, 0278-2391/17/31246-6 109
54 Germany. https://doi.org/10.1016/j.joms.2017.09.021
110
55 {Professor and Head, Department of Oral and Maxillofacial 111
56 Surgery, Hannover Medical School, Hannover, Germany. 112

1
FLA 5.5.0 DTD
YJOMS58001_proof
1 November 2017
7:02 pm
CE BD
 2 NASOLABIAL FLAP IMPROVES HEALING IN MRONJ Q1

113 have been reported. The use of nasolabial flaps can be considered as a highly reliable option for coverage 169
114 the bone wound with less morbidity than microvascular free flaps and better long-term results compared 170
115 with mucoperiosteal flaps. 171
116 Ó 2017 Published by Elsevier Inc on behalf of the American Association of Oral and Maxillofacial 172
117 Surgeons 173
118 J Oral Maxillofac Surg -:1-9, 2017 174
119 175
120 176
121 Since first being described in 2003,1 bisphosphonate variety of therapy concepts have remained high.22-24 177
122 (BP)-associated osteonecrosis of the jaws has been One part of most therapeutic concepts is close 178
123 identified as one of the most adverse side effects of follow-up. 179
124 BP therapy. The occurrence of medication-related os- The American Association of Oral and Maxillofacial 180
125 teonecrosis of the jaw (MRONJ) has also been Surgeons (AAOMS) proposed conservative therapy, 181
126 described with the use of monoclonal antibodies2,3 including administration of antibiotics and antimicro- 182
127 and tyrosine kinase inhibitors.4,5 bial rinses, as the most suitable for the first stage of 183
128 The effects of BP medication are well understood.6,7 MRONJ. Radical surgical procedures such as block or 184
129 A causal association between the occurrence of MRONJ continuity resections of the mandible are only advised 185
130 and the use of antiangiogenic and antiosteoclastic for the more severe cases and depending on the gen- 186
131 agents has been described, although the exact eral condition of the patient.8 In contrast, surgical ap- 187
132 mechanisms of pathogenesis remain unknown. proaches for early-stage MRONJ have been suggested 188
133 MRONJ is defined by an area of exposed bone persist- by German guidelines. The recommendations include 189
134 ing for more than 8 weeks. By definition, patients must careful, but complete, removal of necrotic bone and 190
135 have been treated with antiosteoclastic or antiangio- well-vascularized, tension-free wound closure, com- 191
136 genic agents without previous craniofacial radiation.8 bined with the administration of intravenous 192
137 Intravenous administration of antiosteoclastic drugs is antibiotics.25 193
138 associated with a high rate of occurrence of MRONJ Sufficient soft tissue covering after decortication is 194
139 of up to 18%. In contrast, oral BP is associated with essential for good long-term results. According to the 195
140 an occurrence rate of MRONJ of 0.2%.9-15 Treatment current algorithms, mucoperiosteal flaps should be 196
141 periods of more than 4 years are associated with an tried first or, in the case of compromised soft tissues, 197
142 increased risk of MRONJ development.16 supported by additional local flaps such as mylohyoid 198
143 Osteonecrosis can develop after invasive dental or or buccal fad pad flaps.26 As the final step, considering 199
144 surgical procedures, mechanical stress, periodontitis, the mostly palliative character of surgical MRONJ treat- 200
145 or denture sore spots. BPs are considered to inhibit os- ment, free flaps should serve as a last resort.27 201
146 teoclasts in their activity and to reduce their half-life The purpose of the present study was to evaluate 202
147 time. By attaching to the bony surface, BPs can inhibit the healing results after the completion of decortica- 203
148 processes of remodelling and bone mineralization.17-19 tion in a MRONJ patient cohort receiving either muco- 204
149 However, remodelling is essential for healing of bony periosteal or nasolabial flaps for soft tissue closure. We 205
150 lesions. Furthermore, the use of BPs is associated hypothesized that nasolabial flaps would offer more 206
151 with adverse effects to fibroblasts and endothelial reliable wound closure with less relapse of bone ne- 207
152 function, prompting a decrease of osseous perfusion crosis. The specific aim of the present study was to es- 208
153 and leading to osteonecrosis and inhibited timate and compare the long-term success during at 209
154 bone healing.20 least 12 months postoperatively for nasolabial and mu- 210
155 Osteonecrosis of the jaw is assumed to have multi- coperiosteal flaps. 211
156 ple etiologies and risk factors. A review by Filleul 212
157 et al21 concluded that 67% of all MRONJ cases devel- Materials and Methods 213
158 oped after tooth extractions, and only 26% occurred 214
159 spontaneously. Furthermore, chemotherapy (55%) STUDY DESIGN AND SAMPLE 215
160 and steroids (32%) had been frequently used in pa- To address the research purpose, we designed and 216
161 tients with MRONJ. In addition, periodontal diseases implemented a cohort clinical study after completion 217
162 (16%), hormonal therapy (9%), smoking (3%), diabetes of follow-up terms. This allowed evaluation of treat- 218
163 (2%), hyperlipidemia (2%), and excessive alcohol con- ment success in the experimental group, composed 219
164 sumption (1%) were considered to be risk factors.21 At of MRONJ patients who had received a nasolabial flap, 220
165 present, no better insights are available regarding their and the control group, composed of MRONJ patients 221
166 role in the pathogenesis MRONJ. To date, no who had received mucoperiosteal flap wound closure. 222
167 consensus has been reached regarding MRONJ The ethics committee of Hannover Medical School 223
168 therapy, because the challenging relapse rates with a approved the present retrospective clinical study 224

FLA 5.5.0 DTD
YJOMS58001_proof
1 November 2017
7:02 pm
CE BD

 LEMOUND ET AL 3

225 (approval no. 3447-2016), which was performed in VARIABLES 281

226 accordance with the guidelines of the Declaration The predictor variable was treatment type: decorti- 282
227 of Helsinki. cation and nasolabial flap versus decortication and mu- 283
228 The subjects were recruited from 2009 to 2015. Sur- coperiosteal flap. The outcome variable was ‘‘wound 284
229 gical treatment was performed if the patient reported healing’’ defined as the recurrence of exposed bone 285
230 pain and/or neurologic deficits of the inferior alveolar at the operated site during at least 12 months of 286
231 nerve, the maxillary sinus was exposed, progression follow-up after surgery (Table 1). 287
232 with higher disease stage was observed, or nonheal- Demographic data such as patient age and gender 288
233 ing exposed bone was present in mandible or maxilla were collected (Table 1). Furthermore, the type of 289
234 for longer than 8 weeks without any change in the antiresorptive agent and administration, drug holiday 290
235 stage of disease. All surgical procedures were per- and duration, and reason for antiresorptive therapy un- 291
236 formed according to the same surgical protocol. The til the occurrence of MRONJ were recorded. The time 292
237 patients were evaluated preoperatively and investi- of exposure to BPs was defined in months from the 293
238 gated at least twice with an endpoint after at least initial infusion until the occurrence of MRONJ. The 294
239 12 months. The criteria for MRONJ included current BP was discontinued in terms of a ‘‘drug holiday’’ if 295
240 or previous treatment with BPs, exposed necrotic this was in the best interest of the patient in relation 296
241 bone in the maxillofacial region that had persisted to symptoms and disease progression of their original 297
242 for more than 8 weeks, and no history of radiation pathology based on the practice of the oncologist. 298
243 therapy to the jaws.28,29 The exclusion criteria were The collected data also included the stage and site of 299
244 inadequate information or the presence of MRONJ and type of surgical defect closure after decor- 300
245 confounding variables (eg, corticosteroids in the tication. Staging of MRONJ was determined using the 301
246 medication, history of radiation, metastases within patient’s clinical stage according to the classification 302
247 the gingiva or jaws). of Ruggiero et al.8 303
248 304
249 305
250 306
251 Table 1. DISTRIBUTION OF DEMOGRAPHIC DATA AND OTHER CO-VARIABLES STRATIFIED BY GROUP (N = 32) 307
252 308
253 Surgical Treatment Group 309
254 Control Group Experimental Group 310
255 (Decortication and (Decortication and 311
256 Variable Mucoperiosteal Flap; n = 16) Nasolabial Flap; n = 16) P Value 312
257 313
258 Age (yr) 69.6  11.3 71.8  9.9 .696 314
259 Gender 1.0 315
260 Female 10 (62.5) 10 (62.5) 316
261 Male 6 (37.5) 6 (37.5) 317
262 Antiresorptive agent 1.0 318
263 Bisphosphonate 15 (93.8) 15 (93.8) 319
Monoclonal antibody 1 (6.2) 1 (6.2)
264 320
Drug holiday 1.0
265 Yes 6 (37.5) 6 (37.5)
321
266 No 10 (62.5) 10 (62.5) 322
267 Duration of antiresorptive 34.8  24.2 54.8  55.8 .47 323
268 therapy until MRONJ (mo) 324
269 Site of MRONJ .067 325
270 Maxilla 8 (50) 13 (81.3) 326
271 Mandible 8 (50) 3 (18.7) 327
272 Stage of MRONJ <.001* 328
273 I 10 (62.5) 0 (0) 329
274 II 3 (18.75) 5 (31.3) 330
III 3 (18.75) 11 (68.7)
275 331
Duration until MRONJ relapse (mo) 8.2  7.9 13.6  7.8 .017*
276 332
277 Data presented as mean  standard deviation or n (%). 333
278 Abbreviation: MRONJ, medication-related osteonecrosis of the jaw. 334
279 * ---. Q2 335
280 Lemound et al. Nasolabial Flap Improves Healing in MRONJ. J Oral Maxillofac Surg 2017. 336

FLA 5.5.0 DTD
YJOMS58001_proof
1 November 2017
7:02 pm
CE BD

 4 NASOLABIAL FLAP IMPROVES HEALING IN MRONJ

337 DATA COLLECTION METHODS 393

338 In addition to the clinical examination, a radiologic 394
339 evaluation was performed, which included orthopan- 395
340 tomography and 3-dimensional imaging such as 396
341 computed tomography and cone-beam computed to- 397
342 mography to detect the areas affected by MRONJ. 398
343 The clinical data were completed with further 399
344 information from the patient medical records 400
345 and classified. 401
346 402

print & web 4C=FPO

347 SURGICAL TREATMENT 403
348 404
Surgery was performed 2 weeks after the last dose of
349 405
BP (if not discontinued), which was begun again no
350 406
sooner than 2 weeks after surgery. This did not seem
351 407
to cause any disturbances in wound healing. Biopsy FIGURE 1. Cranially pedicled nasolabial flap.
352 408
of the bone was routinely performed in all cases to
353 Lemound et al. Nasolabial Flap Improves Healing in MRONJ. J Oral 409
confirm the diagnosis and exclude metastatic disease. Maxillofac Surg 2017.
354 410
Antiseptic mouth rinses with hexetidine were per-
355 411
formed 3 times daily, with additional rinsing per-
356 (IBM Corp, Armonk, NY) was used for statistical anal- 412
formed at least once daily by the surgical staff.
357 ysis. Measurements of group-specific differences were 413
The therapeutic regimens for all patients included
358
early antibiotic treatment starting 1 day before sur- compared using the Mann-Whitney U test and c2 test, 414
359 as appropriate. Cox proportional hazard regression 415
gery. Administration of intravenous antibiotics was
360 models were used to determine the factors indepen- 416
continued for 5 days after surgery. The treatment of
361 dently associated with the dependent variable—the 417
patients with MRONJ included decortication. Wound
362 418
closure was performed without tension on the local
363 419
mucoperiosteal or nasolabial flap. Interrupted su-
364 420
tures were used with resorbable suture material
365 421
(Vicryl 3-0; Ethicon, Norderstedt, Germany). The
366 422
wounds were checked daily for signs of infection,
367 423
wound breakdown, and disease recurrence. Further-
368 424
more, oral antibiotics were given until complete
369 425
wound consolidation had occurred. Standard
370 426
follow-up examinations were performed 3 months
371 427
after discharge.
372 428
373 429
SURGICAL TECHNIQUE
374 430
375 Mucoperiosteal flaps were used as described in the 431
376 published data by local cutting of the gingiva and peri- 432
377 osteal slitting, followed by tension-free sutures.30 The 433
378 nasolabial flap was used as described previously,31 434
379 either caudally or cranially pedicled as an axial pattern 435
380 flap (Figs 1, 2). Both jaws could be covered using this 436
381 flap (Figs 3, 4). To ensure flap perfusion, a sufficiently 437
382 large soft tissue tunnel intraorally was constructed to 438
383 avoid pedicle compression. Within the area of 439
384 tunneling, the epithelium was removed during 440
reconstruction or in a second step combined with
print & web 4C=FPO

385 441
386 surgical wound revision. 442
387 443
388 STATISTICAL ANALYSIS 444
389 Descriptive statistics for quantitative variables are 445
390 presented as the mean  standard deviation. If appro- FIGURE 2. Caudally pedicled nasolabial flap. 446
391 priate, the median and range were also computed. The Lemound et al. Nasolabial Flap Improves Healing in MRONJ. J Oral 447
392 Statistical Package for the Social Sciences, version 23 Maxillofac Surg 2017. 448

FLA 5.5.0 DTD
YJOMS58001_proof
1 November 2017
7:02 pm
CE BD

 LEMOUND ET AL 5

449 patients. The patient demographic data are presented 505

450 in Table 1. All the patients completed the study 506
451 12 months postoperatively. The mean age of all pa- 507
452 tients was 70.7  10.5 years. In the control group (mu- 508
453 coperiosteal flaps after decortication), the mean age 509
454 was 69.6  11.3 years and was 71.8  9.9 years in 510
455 the experimental group (nasolabial flaps after decorti- 511
456 cation). The mean duration of antiresorptive therapy 512
457 was 44.8  43.5 months until the diagnosis of MRONJ. 513
458 In the control group, the mean duration was 514
print & web 4C=FPO

459 34.8  24.2 months, and in the experimental group, 515

460 it was 54.8  55.8 months. In the case of MRONJ 516
461 relapse, the mean time after surgery for all patients 517
462 was 10.9  8.2 months. In the control group, the 518
463 mean time was 8.2  7.9 months compared with 519
FIGURE 3. Covering defects in the maxilla using a nasolabial flap.
464 13.6  7.8 months in the experimental group. The in- 520
465 Lemound et al. Nasolabial Flap Improves Healing in MRONJ. J Oral terval until relapse for patients with treatment failure, 521
Maxillofac Surg 2017.
466 shown as exposed bone only, was 5.7  4.2 months in 522
467 the control group and 6.0  5.7 months in the exper- 523
468 recurrence of BP-related osteonecrosis of the imental group (Fig 5). 524
469 jaw (BRONJ). 525
470 The covariates in this model were the treatment- COMPARISON OF GROUPS 526
471 dependent variables, including the extent of necrosis, The groups were different in terms of stage of 527
472 location, and surgical group (mucoperiosteal flap vs MRONJ, with higher stages (P < .001) and a longer 528
473 nasolabial flap), type and duration of BP treatment, period until MRONJ relapse (P = .017) in the experi- 529
474 and drug holiday. The 95% confidence intervals for mental group (Table 1). Variables such as age, gender, 530
475 the estimated odds ratios, approximating the relative type of antiresorptive agent and administration, drug 531
476 risks are also given. The P values are 2-sided and sub- holiday, duration of antiresorptive therapy until the 532
477 ject to a significance level of .05. The Kaplan-Meier occurrence of MRONJ, and the site of MRONJ did 533
478 method was used to plot the outcome curves for not differ between the 2 groups (Table 2). The success 534
479 each putative binary prognostic factor. of treatment was significantly greater in the experi- 535
480 mental group (P = .005; Table 3). 536
481 Results 537
482 538
483 From 2009 and 2015, 32 patients were included in 539
484 the present study. The 2 groups each included 16 540
485 541
486 542
487 543
488 544
489 545
490 546
491 547
492 548
493 549
494 550
print & web 4C=FPO

495 551
496 552
print & web 4C=FPO

497 553
498 554
499 555
500 FIGURE 5. Overall relapse curves for patients treated in the control 556
group versus the experimental group showing a significant influence
501 FIGURE 4. Covering defects in the mandible using a nasolabial on the time to relapse on univariate analysis using the log-rank test
557
502 flap. (P = .004). 558
503 Lemound et al. Nasolabial Flap Improves Healing in MRONJ. J Oral Lemound et al. Nasolabial Flap Improves Healing in MRONJ. J Oral 559
504 Maxillofac Surg 2017. Maxillofac Surg 2017. 560

FLA 5.5.0 DTD
YJOMS58001_proof
1 November 2017
7:02 pm
CE BD

 6 NASOLABIAL FLAP IMPROVES HEALING IN MRONJ

561 Table 2. STATISTICAL RESULTS REGARDING RELATION Table 4. REGRESSION MODEL OF PRIMARY PREDICA-
617
562 BETWEEN ALL STUDY VARIABLES VERSUS PRIMARY TOR VARIABLE, TYPE OF SURGICAL TREATMENT 618
563 OUTCOME VARIABLE (MRONJ RELAPSE; N = 32) VERSUS PRIMARY OUTCOME VARIABLE, ADJUSTED 619
FOR COFOUNDERS OR EFFECTS MODIFIERS (N = 32)
564 620
Hazard
565 Hazard 621
Variable Ratio 95% CI P Value
566 Variable Ratio 95% CI P Value 622
567 Age 1.04 0.97-1.12 .25
623
568 Gender 0.5 0.11-2.21 .36 Age 1.06 0.27-1.06 .27 624
569 Type of antiresorptive 0.98 0.57-1.7 .94 Gender 0.6 0.13-2.23 .38 625
570 treatment Administration of 0.96 0.18-5.19 .96 626
571 Drug holiday 0.27 0.06-1.32 .11 antiresorptive treatment 627
572 Duration of antiresorptive 1.01 0.99-1.02 .43 Drug holiday 0.08 0.05-1.31 .08 628
573 therapy until MRONJ Duration of antiresorptive 1.03 0.98-1.03 .55 629
574 Site of MRONJ 0.63 0.14-2.81 .54 therapy until MRONJ 630
Stage of MRONJ 1.49 0.4-3.43 .35 Site of MRONJ 2.49 0.2-30.51 .48
575 631
Type of surgical treatment 9.53 1.85-49.2 .007* Stage of MRONJ 0.23 0.02-2.29 .21
576 Type of surgical treatment 24.64 1.74-348.59 .018*
632
577 Abbreviations: CI, confidence interval; MRONJ, medication- 633
578 related osteonecrosis of the jaw. Abbreviations: CI, confidence interval; MRONJ, medication- 634
579 * P < .05. related osteonecrosis of the jaw. 635
* P < .05.
580 Lemound et al. Nasolabial Flap Improves Healing in MRONJ. J Oral 636
Maxillofac Surg 2017. Lemound et al. Nasolabial Flap Improves Healing in MRONJ. J Oral
581 Maxillofac Surg 2017.
637
582 638
583 MULTIVARIATE ANALYSES 639
584 The results of adjusted regression analyses are pre- Inhibition of endothelial cell function32 and 640
585 sented in Table 4. Only the type of surgical treatment reduced bone perfusion have been demonstrated as 641
586 after completion of decortication was found to hold side effects of treatment with BPs.33 In the present 642
587 a significant value on the relapse of MRONJ. None of study, we were able to evaluate that an additional local 643
588 the other variables were significantly associated flap such as the nasolabial flap, which is easy to raise, 644
589 with relapse. showed significant effects on the postoperative 645
590 course. This was demonstrated by comparison with 646
591 Discussion the control group and in the logistic regression ana- 647
592 lyses. The inclusion of another well-vascularized tissue 648
593 Insufficient mucosal perfusion might be one of the above the decorticated bone, in addition to the 649
594 crucial causes of MRONJ. Whether the associated tensionless wound closure, improved the healing 650
595 drugs are antiangiogenic or antiresorptive seems rates. This is similar to the use of the mylohyoid muscle 651
596 to have no significant effect, although evidence or the buccal fat pad flap in each jaw. 652
597 and insight into the pathophysiologic processes After decortication, sufficient and tension-free 653
598 are lacking. wound closure is essential for stable postoperative re- 654
599 sults. The surgeon must decide whether an additional 655
600 local flap is necessary to achieve tensionless wound 656
Table 3. BIVARIATE STATISTICAL ANALYSES EXAM-
601 INING RELATION BETWEEN PRIMARY PREDICATOR
closure. No doubt exists that radical treatment, fol- 657
602 VARIABLE, SURGICAL TREATMENT VERSUS PRIMARY lowed by free flap surgery, should be reserved for 658
603 OUTCOME VARIABLE (N = 32) symptomatic patients with MRONJ at an advanced 659
604 stage and a good prognosis. Therefore, the role of local 660
Control Group
605 flaps is unclear but should be considered. The reduced 661
(Decortication and Experimental Group
606 Treatment Mucoperiosteal (Decortication and
perfusion of bone-covering tissues and the bone itself 662
607 Success Flap; n = 16) Nasolabial Flap; n = 16) should be carefully evaluated during surgery. The local 663
608 gingiva of higher grade osteonecrosis is both clinically 664
609 Yes 3 (18.8) 11 (68.7) and histologically inadequate for stable wound 665
610 No 13 (81.2) 5 (31.3) closure,34 indicating the need for additional healthy 666
611 tissue using local flaps. 667
Data presented as n (%).
612 Relapse and disease progression are frequently 668
Hazard ratio, 9.53 and 95% confidence interval, 1.85 to
613 49.2 (P = .007 [statistically significant at P < .05]) for surgical observed in the follow-up period shortly after surgery 669
614 treatment type. and after more than 6 months. Current guidelines have 670
615 Lemound et al. Nasolabial Flap Improves Healing in MRONJ. J Oral recommended surgical decortication for infected 671
616 Maxillofac Surg 2017. MRONJ, including tension-free wound closure and 672

FLA 5.5.0 DTD
YJOMS58001_proof
1 November 2017
7:02 pm
CE BD

 LEMOUND ET AL 7

673 the simultaneous administration of intravenous antibi- rate of 90% after 18 months, on average.53 These re- 729
674 otics.25 In some patients in poor condition owing to sults were confirmed in a further study.26 Both studies 730
675 the underlying disease, stage reduction is also an op- showed the effect and role of additional healthy tissue 731
676 tion to provide patients with a higher quality of life on wound healing and the postoperative condition of 732
677 without experiencing pain. Considering the life ex- the wound. Even if the mucosa does not heal, the un- 733
678 pectancy of these patients, extensive bone resection derlying flap, either muscular or fat flaps, can heal and 734
679 and complex reconstructive procedures are not real- provide coverage of the decorticated bone. In the pre- 735
680 istic or even an option owing to the high complication sent study, the mucosa was not closed, although the 736
681 rate of such procedures. These complications can also skin portion of the nasolabial flap healed uneventfully. 737
682 lead to functional impairment and poor postoperative In cases of mucosal tissues close to the area of MRONJ, 738
683 esthetic results.21,35 Therefore, the surgical procedure the mucosa will be less stable compared with healthy 739
684 chosen and extent of radical resection should be mucosa after tooth extraction or skin used as a local 740
685 always a balance of interests. flap. Therefore, it is important that the nasolabial 741
686 After additional drugs with antiangiogenic and anti- flap ‘‘fits’’ into the defect and is partly larger in size to 742
687 osteoclastic activity were introduced, it was observed provide sufficient tissue over the decorticated bone. 743
688 that adverse effects similar to those BP-associated os- The 16 presented cases in the experimental group 744
689 teonecrosis occurred in patients treated with these of the present study had a success rate of 68.8% using 745
690 substances. A recent randomized study by Smith nasolabial flaps. The control group with local gingiva 746
691 et al36 found a 5% probability of the occurrence of os- flaps achieved favorable results in 18.7% of cases. 747
692 teonecrosis in 1,432 patients treated with the mono- The follow-up period was 15 to 17 months. Similar re- 748
693 clonal antibody denosumab. In contrast, including ported studies have suggested that nasolabial flaps can 749
694 less recent data, a meta-analysis from 2014 only found be successfully used for different types of defects, 750
695 a MRONJ rate of 1.9% within a very similar collective.3 independently of the resected entity.56 751
696 Individual cases of MRONJ were also found in patients In the presented collective, the use of the nasolabial 752
697 receiving treatment with bevacizumab.2 Recent re- flap in the maxilla predominated. This was because the 753
698 ports have described MRONJ cases associated with mylohyoid muscle was often used to close mandibular 754
699 tyrosine kinase inhibitors such as sunitinib5,37 and defects to avoid an extraoral donor site. However, 755
700 carbozanitinib.4 considering only the maxilla lesions in the control 756
701 Considering the increasing number of substances group revealed that a relapse of MRONJ occurred in 757
702 being held responsible for MRONJ, the AAOMS recom- all cases. The healing rate of mandibular lesions in 758
703 mended a change in nomenclature in 2014.8 Accord- the control group was 37.5%. Nasolabial flaps can be 759
704 ingly, a change from BRONJ (‘‘BP-related harvested using a comparatively simple method with 760
705 osteonecrosis of the jaw’’) to MRONJ (‘‘medication- either a cranial or a caudal pedicle. Thus, they offer a 761
706 related osteonecrosis of the jaw’’) was proposed. broad range of possible uses such as wound coverage 762
707 The current version of the AAOMS guidelines for in the anterior and posterior regions of the maxilla and 763
708 MRONJ treatment recommends conservative treat- mandible. The esthetic results can be described as 764
709 ment for stage I and II disease.8 Surgical treatment, excellent and usually lead to almost invisible scars hid- 765
710 especially in the past, was used in a rather reserved den in the nasolabial crease. Thus, the nasolabial flap is 766
711 manner. The conservative treatment of 4,019 MRONJ very versatile and helpful, especially for older patients 767
712 patients only led to sufficient long-term results in with increased skin at this site. 768
713 23% of the patients.14 Another study reported a 53% Administration of oral antibiotics after dismissal did 769
714 success rate within a group of 30 conservatively not have major effects on the cure rates in the present 770
715 treated MRONJ patients.23 In contrast, radical surgical study or the analyses. Furthermore, no significant 771
716 wound revision, including marginal or segment resec- benefit was found for enteral nutrition using feeding 772
717 tions, resulted in healing rates of 86 versus 46% within tubes. Nevertheless, both could be adequate support- 773
718 the conservatively treated control group.38 In a cohort ive measures in surgical MRONJ treatment, especially 774
719 study of 347 BRONJ-affected patients, an improvement for patients with a compromised wound. The low 775
720 in BRONJ stage was observed in 49% of patients long-term success rate in the control group clearly 776
721 treated with local debridement and 68% of those highlight the importance of wound closure using unaf- 777
722 treated with resection.39 Although some investigators fected tissue. The surgical use of multiple layers of tis- 778
723 strongly doubt the success of surgical proced- sue such as mylohyoid muscle or the Bichat cheek fat 779
724 ures,11,19,40-42 reported success rates of up to 91.6% pad appears to be a key factor influencing the long- 780
725 emphasize the importance of surgical MRONJ term results of surgical MRONJ treatment. 781
726 treatment.38,43-55 In conclusion, to date, no international uniform 782
727 Within a study using mylohyoid muscle flaps for guidelines regarding MRONJ treatment exist. Never- 783
728 wound closure, we were able to report a success theless, the results of our retrospective study have 784

FLA 5.5.0 DTD
YJOMS58001_proof
1 November 2017
7:02 pm
CE BD

 8 NASOLABIAL FLAP IMPROVES HEALING IN MRONJ

785 clearly shown that surgical treatment, including decor- 17. Ruggiero SL: Bisphosphonate-related osteonecrosis of the jaw 841
(BRONJ): Initial discovery and subsequent development. J
786 tication and wound closure using nasolabial flaps, 842
Oral Maxillofac Surg 67:13, 2009
787 dramatically improves the long-term results compared 18. Reid IR: Osteonecrosis of the jaw: Who gets it, and why? Bone 843
788 with decortication and local mucoperiosteal flap 44:4, 2009 844
19. Marx RE, Sawatari Y, Fortin M, Broumand V: Bisphosphonate-
789 use only. induced exposed bone (osteonecrosis/osteopetrosis) of the
845
790 Considering the high variability in the healing pro- jaws: Risk factors, recognition, prevention, and treatment. J 846
791 cesses of MRONJ, interdisciplinary cooperation among Oral Maxillofac Surg 63:1567, 2005 847
20. Scheper MA, Badros A, Chaisuparat R, et al: Effect of zoledronic
792 the general practitioner, oncologist, craniomaxillofa- acid on oral fibroblasts and epithelial cells: A potential mecha-
848
793 cial surgeon, and patient is crucial for successful treat- nism of bisphosphonate-associated osteonecrosis. Br J Haematol 849
794 ment. MRONJ has high demands on patient education, 144:667, 2009 850
21. Filleul O, Crompot E, Saussez S: Bisphosphonate-induced osteo-
795 and regular screening for signs of osteonecrosis should necrosis of the jaw: A review of 2,400 patient cases. J Cancer Res
851
796 be offered to all patients receiving antiresorptive or Clin Oncol 136:1117, 2010 852
797 antiangiogenic therapy. 22. Fantasia JE: Bisphosphonates—What the dentist needs to know: 853
Practical considerations. J Oral Maxillofac Surg 67:53, 2009
798 23. Van den Wyngaert T, Claeys T, Huizing MT, et al: Initial experi-
854
799 References ence with conservative treatment in cancer patients with osteo- 855
800 necrosis of the jaw (ONJ) and predictors of outcome. Ann Oncol 856
1. Marx RE: Pamidronate (Aredia) and zoledronate (Zometa) 20:331, 2009
801 857
induced avascular necrosis of the jaws: A growing epidemic. J 24. Scoletta M, Arduino PG, Dalmasso P, et al: Treatment outcomes
802 Oral Maxillofac Surg 61:1115, 2003 in patients with bisphosphonate-related osteonecrosis of the 858
803 2. Santos-Silva AR, Belizario Rosa GA, Castro Junior G, et al: Osteo- jaws: A prospective study. Oral Surg Oral Med Oral Pathol Oral 859
necrosis of the mandible associated with bevacizumab therapy. Radiol Endod 110:46, 2010
804 25. Gr€otz KA, Piesold J-U, Al-Nawas B: Bisphosphonat-assoziierte
860
Oral Surg Oral Med Oral Pathol Oral Radiol 115:e32, 2013
805 3. Qi WX, Tang LN, He AN, et al: Risk of osteonecrosis of the jaw Kiefernekrose (BP-ONJ) und andere Medikamenten-assoziierte 861
806 in cancer patients receiving denosumab: A meta-analysis of Kiefernekrosen. AWMF online AWMF-Register No. 007/091; 862
seven randomized controlled trials. Int J Clin Oncol 19:403, 2012
807 26. Muecke T, Koerdt S, Jung M, et al: The role of mylohyoid flap in
863
2014
808 4. Marino R, Orlandi F, Arecco F, et al: Osteonecrosis of the jaw in a the treatment of bisphosphonate related osteonecrosis of the 864
809 patient receiving cabozantinib. Aust Dent J 60:528, 2015 jaws. J Craniomaxillofac Surg 44:369, 2016 865
5. Fleissig Y, Regev E, Lehman H: Sunitinib related osteonecrosis of 27. Mucke T, Jung M, Koerdt S, et al: Free flap reconstruction for
810 patients with bisphosphonate related osteonecrosis of the
866
jaw: A case report. Oral Surg Oral Med Oral Pathol Oral Radiol
811 113:e1, 2012 jaws after mandibulectomy. J Craniomaxillofac Surg 44:142, 867
812 6. Weitzman R, Sauter N, Eriksen EF, et al: Critical review: Updated 2016 868
recommendations for the prevention, diagnosis, and treatment 28. Advisory Task Force on Bisphosphonate-Related Osteonecrosis
813 of the Jaws, American Association of Oral and Maxillofacial Sur-
869
of osteonecrosis of the jaw in cancer patients—May 2006. Crit
814 Rev Oncol Hematol 62:148, 2007 geons. American Association of Oral and Maxillofacial Surgeons 870
815 7. Vasikaran SD: Bisphosphonates: An overview with special refer- position paper on bisphosphonate-related osteonecrosis of the 871
ence to alendronate. Ann Clin Biochem 38:608, 2001 jaws. J Oral Maxillofac Surg 65:369, 2007
816 29. Ruggiero SL, Mehrotra B, Rosenberg TJ, Engroff SL: Osteonecro-
872
8. Ruggiero SL, Dodson TB, Fantasia J, et al: American Association
817 of Oral and Maxillofacial Surgeons: American Association of Oral sis of the jaws associated with the use of bisphosphonates: A re- 873
818 and Maxillofacial Surgeons position paper on medication-related view of 63 cases. J Oral Maxillofac Surg 62:527, 2004 874
osteonecrosis of the jaw—2014 Update. J Oral Maxillofac Surg 30. von Wowern N: Closure of oroantral fistula with buccal flap: Re-
819 hrmann versus Moczar. Int J Oral Surg 11:156, 1982
875
72:1938, 2014
820 9. Badros A, Terpos E, Katodritou E, et al: Natural history of osteo- 31. Maria L, Konstantinos V, Ioannis D, et al: Nasolabial pedicled 876
821 necrosis of the jaw in patients with multiple myeloma. J Clin On- compared with island flaps for intraoral reconstruction of onco- 877
col 26:5904, 2008 logical defects: Complications, recovery of sensitivity, and
822 assessment of quality of life. Br J Oral Maxillofac Surg 54:746,
878
10. Bamias A, Kastritis E, Bamia C, et al: Osteonecrosis of the jaw in
823 cancer after treatment with bisphosphonates: Incidence and 2016 879
824 risk factors. J Clin Oncol 23:8580, 2005 32. Kapitola J, Zak J, Justova V, Lacinova Z: Effect of pamidronate on 880
11. Boonyapakorn T, Schirmer I, Reichart PA, et al: Bisphosphonate- bone blood flow and serum levels of IGF-I in sham-operated and
825 881
induced osteonecrosis of the jaws: Prospective study of 80 oophorectomized female rats. Sb Lek 103:455, 2002
826 patients with multiple myeloma and other malignancies. Oral 33. Fournier P, Boissier S, Filleur S, et al: Bisphosphonates inhibit 882
827 Oncol 44:857, 2008 angiogenesis in vitro and testosterone-stimulated vascular re- 883
12. Durie BG, Katz M, Crowley J: Osteonecrosis of the jaw and bi- growth in the ventral prostate in castrated rats. Cancer Res 62:
828 6538, 2002
884
sphosphonates. N Engl J Med 353:99, 2005
829 13. Mavrokokki T, Cheng A, Stein B, Goss A: Nature and frequency of 34. Lorenzo SD, Trapassi A, Corradino B, Cordova A: Histology of the 885
830 bisphosphonate-associated osteonecrosis of the jaws in oral mucosa in patients with BRONJ at III stage: A microscopic 886
Australia. J Oral Maxillofac Surg 65:415, 2007 study proves the unsuitability of local mucosal flaps. J Clin
831 Med Res 5:22, 2013
887
14. Hoff AO, Toth BB, Altundag K, et al: Frequency and risk factors
832 associated with osteonecrosis of the jaw in cancer patients 35. Lachmann S, Reinert S, Hoefert S: Thema mit großer Praxisrele- 888
833 treated with intravenous bisphosphonates. J Bone Miner Res vanz. T€ ubinger Bisphosphonat-Symposium. ZM Online; 2012 889
23:826, 2008 36. Smith MR, Saad F, Oudard S, et al: Denosumab and bone
834 metastasis-free survival in men with nonmetastatic castration-
890
15. Walter C, Al-Nawas B, Frickhofen N, et al: Prevalence of bi-
835 sphosphonate associated osteonecrosis of the jaws in multiple resistant prostate cancer: Exploratory analyses by baseline 891
836 myeloma patients. Head Face Med 6:11, 2010 prostate-specific antigen doubling time. J Clin Oncol 31:3800, 892
16. Lo JC, O’Ryan FS, Gordon NP, et al: Predicting Risk of Osteonec- 2013
837 37. Hoefert S, Eufinger H: Sunitinib may raise the risk of
893
rosis of the Jaw with Oral Bisphosphonate Exposure (PROBE) In-
838 vestigators: Prevalence of osteonecrosis of the jaw in patients bisphosphonate-related osteonecrosis of the jaw: Presentation 894
839 with oral bisphosphonate exposure. J Oral Maxillofac Surg 68: of three cases. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 895
243, 2010 110:463, 2010
840 896

FLA 5.5.0 DTD
YJOMS58001_proof
1 November 2017
7:02 pm
CE BD

 LEMOUND ET AL 9

897 38. Abu-Id MH, Warnke PH, Gottschalk J, et al: ‘ Bis-phossy jaws’’— bisphosphonate-related osteonecrosis of the jaws. J Cancer 929
High and low risk factors for bisphosphonate-induced osteonec- Res Clin Oncol 137:907, 2011
898 930
rosis of the jaw. J Craniomaxillofac Surg 36:95, 2008 48. Stockmann P, Vairaktaris E, Wehrhan F, et al: Osteotomy and pri-
899 39. Graziani F, Vescovi P, Campisi G, et al: Resective surgical mary wound closure in bisphosphonate-associated osteonecro- 931
900 approach shows a high performance in the management of sis of the jaw: A prospective clinical study with 12 months 932
advanced cases of bisphosphonate-related osteonecrosis of the follow-up. Support Care Cancer 18:449, 2010
901 jaws: A retrospective survey of 347 cases. J Oral Maxillofac 49. Pautke C, Bauer F, Tischer T, et al: Fluorescence-guided bone
933
902 Surg 70:2501, 2012 resection in bisphosphonate-associated osteonecrosis of the 934
903 40. Woo SB, Hellstein JW, Kalmar JR: Narrative [corrected] review: jaws. J Oral Maxillofac Surg 67:471, 2009 935
Bisphosphonates and osteonecrosis of the jaws. Ann Intern 50. Rotaru H, Kim MK, Kim SG, Park YW: Pedicled buccal fat pad
904 Med 144:753, 2006 flap as a reliable surgical strategy for the treatment of
936
905 41. Migliorati CA, Schubert MM, Peterson DE, Seneda LM: Bi- medication-related osteonecrosis of the jaw. J Oral Maxillofac 937
906 sphosphonate-associated osteonecrosis of mandibular and Surg 73:437, 2015 938
maxillary bone: An emerging oral complication of supportive 51. Diego R, D’Orto O, Pagani D, et al: Bisphosphonate-associated
907 cancer therapy. Cancer 104:83, 2005 osteonecrosis of the jaws: A therapeutic dilemma. Oral Surg
939
908 42. Montebugnoli L, Felicetti L, Gissi DB, et al: Bisphosphonate-asso- Oral Med Oral Pathol Oral Radiol Endod 103:e1, 2007 940
909 ciated osteonecrosis can be controlled by nonsurgical manage- 52. Eckardt AM, Lemound J, Lindhorst D, et al: Surgical manage- 941
ment. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 104: ment of bisphosphonate-related osteonecrosis of the jaw in
910 473, 2007 oncologic patients: A challenging problem. Anticancer Res 31:
942
911 43. Stanton DC, Balasanian E: Outcome of surgical management of 2313, 2011 943
912 bisphosphonate-related osteonecrosis of the jaws: Review of 53. Lemound J, Eckardt A, Kokemuller H, et al: Bisphosphonate- 944
33 surgical cases. J Oral Maxillofac Surg 67:943, 2009 associated osteonecrosis of the mandible: Reliable soft tissue
913 945
44. Alons K, Kuijpers SC, de Jong E, van Merkesteyn JP: Treating reconstruction using a local myofascial flap. Clin Oral Investig
914 low- and medium-potency bisphosphonate-related osteonecro- 16:1143, 2012 946
915 sis of the jaws with a protocol for the treatment of chronic sup- 54. Lopes RN, Rabelo GD, Rocha AC, et al: Surgical therapy for 947
purative osteomyelitis: Report of 7 cases. Oral Surg Oral Med bisphosphonate-related osteonecrosis of the jaw: Six-year expe-
916 Oral Pathol Oral Radiol Endod 107:e1, 2009 rience of a single institution. J Oral Maxillofac Surg 73:1288,
948
917 45. Carlson ER, Basile JD: The role of surgical resection in the man- 2015 949
918 agement of bisphosphonate-related osteonecrosis of the jaws. J 55. Voss PJ, Joshi Oshero J, Kovalova-Muller A, et al: Surgical treat- 950
Oral Maxillofac Surg 67:85, 2009 ment of bisphosphonate-associated osteonecrosis of the jaw:
919 46. Wilde F, Heufelder M, Winter K, et al: The role of surgical ther- Technical report and follow up of 21 patients. J Craniomaxillo-
951
920 apy in the management of intravenous bisphosphonates- fac Surg 40:719, 2012 952
921 related osteonecrosis of the jaw. Oral Surg Oral Med Oral Pathol 56. Eckardt AM, Kokemuller H, Tavassol F, Gellrich NC: Recon- 953
Oral Radiol Endod 111:153, 2011 struction of oral mucosal defects using the nasolabial flap:
922 47. Mucke T, Koschinski J, Deppe H, et al: Outcome of treatment Clinical experience with 22 patients. Head Neck Oncol 3:28,
954
923 and parameters influencing recurrence in patients with 2011 955
924 956
925 957
926 958
927 959
928 960

FLA 5.5.0 DTD
YJOMS58001_proof
1 November 2017
7:02 pm
CE BD