Degenerative Joint Disease

Hip & Knee

Current & Future

Mohamad Hidayat
 Degenerative Joint
Disease/Osteoarthritis(OA).
• OAresults from a complex system of interactingmechanical,
biological, biochemical, molecular and enzymatic feedback loops
• The final common pathway is joint tissue destruction resultingfrom
the failure of cells to maintain a homeostatic balance between
matrix synthesis & degradation
• Osteoarthritis (OA) hasrecently been defined asa‘whole joint’ disease
with pathological changes in all tissues, including articular
cartilage degradation, subchondral bone thickening, osteophyte
formation, synovial inflammation and degeneration of ligaments,
and, in the knee, the menisci.
• In healthy articular cartilage, chondrocytes resist proliferation and
terminal differentiation. By contrast, chondrocytes in OA cartilage
progressively proliferate and develop hypertrophy.
 Cartilage Injury
“from Hippocrates to present ageit is universally
allowed that ulcerated cartilageis a
troublesome thing and that once destroyed,
is not repaired.

?
John Hunter 1743
(John Hunter, (1718-1783), Scottish surgeon/anatomist, founder ofHunterian
School of Medicine inLondon)

3
 Chondrocyte
• Provide the formation (in
growth) and maintenance
(mature tissue) of articular
cartilage
• Metabolically active & are
able to respond to a variety
environmental stimuli:
– Mediators: growth factors,
interleukin, free radicals
– Matrix molecules
– Mechanical loads
– Hydrostatic pressure changes
– Etc.

4
 Extracellular Matrix
• Chondrocytes, create and maintain
collagen and other matrix proteins
• Highly hydrated combination of
proteoglycans & non-collagenous
protein immobilized within a typeII
collagen network
• Major components
– Water, Collagen II, proteoglycans
agregate
• Minor components
– Lipids, phospholipid,proteins,
glycoprotein
• Proteoglycan + water > provide
shear strength, negative ion charged
• Type II Collagen provide tensile
strengh

5
Classification of OA

• Primary (idiopathic)
unidentified causes

• Secondary
precipitating factors

7
 Risk factors for osteoarthritis

Osteoarthritis is defined not as a disease or a single

condition but as a common complex disorder with
multiple risk factors. These risk factors are broadly
divisible into:
– genetic factors (heritability estimates forhand, knee and
hip osteoarthritis are high at 40–60%, though the
responsible genes are largely unknown)
– constitutional factors (for example, ageing, femalesex,
obesity, high bone density)
– biomechanical risk factors (for example, obesity, joint
injury, occupational/recreational usage, reduced muscle
strength, joint laxity, joint malalignment).
 Epidemiology
Approximately 190 Million people are suffering
From osteoarthritis in the world

20 Million of those live in

the USA

68% of 58% of
women older men older
then 65 years then 65 years
have have
osteoarthritis osteoarthritis
NORMAL OSTEOARTHIRTIS

Patella

Femoralcondyles
Tibial plateaus
Subchondralbone
 Biomechanical Stress
(Konsep 2003)
mechanoelectro
ATP↓ chemical signal

Oxidative Stress
Chondrocyte
CHONDROCYTE
(Reperfusion injury?)
Mediator expression
iNOS expression (IL-1,TNF
NO
Reactive oxygen MMPS Enzymes
Species (ROS )
ECM degradation Debris Ag
(PG/Collagen) Autoimmune resp?

OOsSTtEeOoAaRrTtHhRrIiTtiIS Inflammation
s
New Horizon in OA (2010)Leonardo Punzi et.al

ROS
Chondrocyte as central action
Crosstalk between Osteoblast & Chondrocyte
Normal OA
Chondrogenic
Hypertrophic chondrocyte
Chondrocyte
- collagen type II i
- collagen type II h
- aggrecan i
- aggrecan h
- ALP h
- ALP i
- collagen type X h
- collagen type X i
- CBFA1/Runx2 h
- CBFA1/Runx2 i
MAPK, ERK½, p38

Hilal, 1999; Sanchez, 2005; Prasadam, 2010)

Flow of fluid in OA joint &Crosstalk
chondrocyte-osteoblast
 Some Signaling factors in OA chondrocyte
• Signaling factors • Role in OA
• BMP • Stimulation of MMP-13
• FGF • Stimulation of ADAMTS-5
• TGF-β • Stimulation of MMP-13
• Wnt/β catenin • Regulator of Hypertrophic
Chondrocyte
• Induction of Matrix degradation
• Sox9 • Involved in MMP13 expression
• Runx2/3 • Induction in Chondrocyte
hypertrophy
• MMPs/ADAMTS • Key factors in matrix degradation
• Etc.

17
DIAGNOSTIC ofOA
• CLINICAL
• RADIOLOGICAL EXAMINATION
• SCINTIGRAFI
• MRI
• LABORATORY TEST
• SYNOVIAL FLUID ANALYSIS
• ARTHROSCOPY
• BIOCHEMICAL ‘MARKERS’
 CLINICAL FEATURES
• SYMPTOMS SIGNS
• Pain • Crepitus
• Stiffness • Restricted movement
• Limping • Tenderness
• Functional impairment • Deformity
• Anxiety,depression • Muscle
wasting/weakness
 Sources of OA jointpain
• Subchondral bone
• Nerve endings in periosteum
• Stretching of ligaments
• Distention of joint capsule
• Inflammation of synovium
• Periarticular muscle spasm

20
 Radiological Presentation
• Joint space narrowing
• Osteophyte formation
• Subchondral sclerosis
• Subchondral cyst formation
• Joint mice/loose bodies
Osteoarthritis
 OA Biomarker
• Need for Biomarker :
1. Identify early OA
2. Identify ‘fastprogressors’
3. Assessment of disease progression
4. Assessment of therapeutic efficacy
 Biomarkers include:
• Proteins and proteins fragment
• Metabolite
• Carbohydrate biomarkers
• Genomic biomarkers (RNA& DNA)
• Cellular biomarkers
• Imaging biomarkers
 Biomarkers OA

Application of biomarkers in the development of drugs intended for the

treatment of osteoarthritis
V.B. Kraus, B. Burnett, J. Coindreau, S.Cottrell, D. Eyre, M. Gendreau, J. Gardiner, P.Garnero, J. Hardin, Y.
Henrotin, D.Heinegård, A. Ko, L.S. Lohmander, G. Matthews, J. Menetski, R. Moskowitz, S. Persiani,A.R.
Poole, J.-C. Rousseau, M. Todman
and OARSIFDAOsteoarthritis Biomarkers Working Group
Osteoarthritis and Cartilage
DOI: 10.1016/j.joca.2010.08.019
BIPED/Biomarker
Common Biomarkers OA
 OA Management
Despite a number of advances in our
knowledge of the disease process in recent years,
treatment for osteoarthritis is still relativelylimited.
There are no currently available pharmacological
agents capable of retarding or preventing the
disease. So effective management of people with
osteoarthritis is predominantly focused on pain
relief, improvement in function and maintenanceof
a certain level of quality of life in these patients.
Algorithm for OAManagement
 Treatment Goals

• Provide adequate pain relief

• Maintain or improve joint mobility
• Minimize functional impairment
• Educate patients/families

Better Quality of Life

 FOLLOWUPSTUDIES

• PATIENT- CENTERED, CLINICAL EVALUATION

JOINT PAIN & DISABILITY,  WOMAC/LEQUESNE INDEX

• MEASUREMENT OF STRUCTURAL CHANGES

RADIOLOGICAL, MRI, ARTHROSCOPY, ULTRASOUND

• MEASUREMENT OF THE DISEASE PROCESS

BONE SCINTIGRAPHY, METABOLIC MARKERS, MRI ?
 Knee OA Prevention

Other

Obesity

Occupational
risk

Knee injury

Arthritis Rheum. 1998, Aug;41(8):1343-55.

Osteoarthritis Cartilage. 2009; Sep 2.
 Patient education
Self-management programs
Weight loss (if overweight or obese)
Aerobic exercise programs
Physical therapy
Muscle-strengthening exercises
Assistive devices for ambulation
Patellar taping
Appropriate footwear
Medial-wedged insoles (for genu valgum)
Bracing Pharmacologic intervention
Occupational therapy Surgical
Joint protection and energy conservation intervention
Assistive devices for activities of dailyliving

Therapeutic Advances in Musculoskeletal Diseases 1: 35-47

 Surgery

NSAID

Analgesic (Acetaminophen)

Education
Physical & Occupational therapy
Weight control, Exercises, Orthotics
 Guideline Xclinical practice
• Numerous recent guidelines with substantive merit.
• OARSI. Osteoarthritis & Cartilage. 2008; 16:137-162
• EULAR.Annals of the Rheumatic Diseases64:669-681
• AAOS. JAm Acad Orthop Surg. 2009 17: 591-600.
• Little relation between clinical practice and
management practices recommended in guidelines.
• Great need for dissemination, translation and quality
indicators.
 Non surgical management
• Physical alter joint loading • Pharmacologic & Nutritional
– Patient education – Oral medication
– Activity modification • Analgesics
• Antiinflammatory agent
– Weight loss
– Intraarticular injection
– Assist device
• Hyaluronan
– Bracing • Corticosteroid
– Canes & walking sticks • PRP?
– Impact absorbing shoes – Oral DMOAD
• Diacerein/Strontium ranelate/ avocado
• Physical therapy : soybean/MSM/Doxycycline
– Muscles exercise/strengthening /Glucosamine/chondroitin S
– Aerobic/ROM – Biphosphonat
– Thermal/diathermy/TENS – Herbal (rose hip)
– Acupunture – Antioxidan
• Occupational therapy
 Effect of Exercises
• Intermittent compression stimulates cell bio-
synthesis
• Cartilage mechanically adapts to loads
• Activity levels above certain threshold maybe
destructive
• Immobilization causes cartilage atrophy
 Pharmacotherapy
• Simple Analgesic
– Acetaminophen,Tramadol, Opioids
– Adjunctive analgesic, gabapentin, pregabalin, tricyclic
antidepressants
• NSAID
– Selective/non selective COX2 inhibitor
• Intraarticular injections
– HA/Corticosteroid/PRP?
• Nutraceutical/Sysadoa/SMOAD
– Glucosamine/chondroitin sulfate, diacerein, Avocado S,etc.
• Others
– MMPs inhibitors
 Hyaluronan Joint Fluid Therapy
– Joint Fluid Therapy is a
treatment to help treat the
pain of osteoarthritis of the
knee.
– It provides long-lasting relief
from arthritis pain for many
patients.
– Joint Fluid Therapy involves
injecting a substance called
hyaluronic acid into the knee.
– This substance is similar to
the fluid that occursnaturally
in the knee – synovial fluid –
which helps to lubricate the
knee, reducing friction and
protecting from pain.
 Hyaluronan functions in NormalJoint
(molecular weight, 350 – 500kDa)
• Stabilize joint function
– Lubrication at low shear
– Increased friction at high shear
• Mechanical barrier
– Viscoelastic properties, shock absorber
• Physical barrier of synovial cavity for PMN
• Anti inflammatory
• Analgesic, coat pain receptors
• Modulate synovial cell behavior,
– e.g. stimulates HAsynthesis, reduces gaps between synovial cells etc.
• Modulates Chondrocyte behavior
– Increases PG synthesis/TIMP, reduces NO>chondrocyteapoptosis ↓
Mechanism action of HA I.A. injection in OA

• Unknown
• Although often labelled as viscosupplementation, the longest
resident time ranging from 5 – 30 days. Beyond that it is no
longer present and cannot provide biomechanical property
• If benefit is achieved beyond the the resident time, the
benefit must be from some other action and not by it’s
biomechanical properties
• HA binding the CD44 receptor in many tissue, participate in
leucocytes recruitment > activating various inflammatory
cells, unless the HA at molecular weight above 300kDa.
Some commercially available HA and their
molecular weights

• Durolane 1000 kDa

• Euflexxa 2400 – 3600kDa
• Hyalgan 500 – 730 kDa
• Hylan G-F 20(Synvisc) 5000 – 6000kDa
• Orthovisc 1000 – 2900kDa
• Sinovial 800 – 1200 kDa
• Suplasyn 500 – 730 kDa
 Platelet Rich Plasma (PRP)
• Promising new Tx of number Orthopaedic
condition
• Clinical studies have shown conflicting result
• The molecular mechanism→ generallyunknown
• Platelet contain ofvariable growth factor &
cytokines
• Few quality clinical studies to date→
– Further laboratory & clin.Studies more needed
– level 1 long term outcome areneeded
 Platelet-Rich Plasma in KneeOA
– Kon et al 2010 and Filardo et al 2011 , series n=115
• Three 5ml PRP;improved at 6 and 12 mos
– Sampson et al 2010 seriesn=14
• PRPat 0/4/8 wks; pain reduction out to 52 weeks in majority
– Wang-Saegusa et al 2011 seriesn=261
• PRPat 0/2/4 wks; improved pain/fxn/QOL to 6 mos w/oAdvEfx
– Sanchez et al. 2008 case/cont
• PGRFvs Hyaluronic acid (HA), weekly x3
• At 5 weeks, 33% decrease pain w/ PRGF,10% w/ HA
– Spakova et al 2012 case/cont, n=120
• PRPvs HA, weekly x3; At 3 & 6 mo, PRPbetterWOMAC/VAS
– Kon & Mendelbaum etal 2011 case/cont n=150
• LMW HA vs HMW-HA vs PRPat weekly x3
• PRPbetter than HA at 6mo
• Age > 50 and severe OA: PRP= LMW-HA
• Age<50 with cartilage lesions, and mild OA: PRPbest
– Li & Zhang et al, 2011 RCTn=30
• PRPvs HA at 0/3/6 weeks; PRPmore effective at 6mo
 Surgical Indication
• When nonoperative treatment of OAof the knee
failed to alleviate pain and knee function
compromised, → surgical intervention is
warranted.
• The timing of and recommendation for the most
appropriate surgical procedure require great skill,
and cooperation between patient & physician

Brian JC, Osteoarthritis, Diagnosis &

Medical/Surgical Management 4th ed, 2007
 Prior Surgery consider:

• Clinical assesment
– Womac
– SF36
– Lequesne
• Radiological assesment
– Kellgren- Lawrence
• MRI
• Co-morbid/ obesity/etc.
 Prior Surgical Treatment
• Consider the riks and benefit
• Select Op. Tx based on manyfactors
• No absolute contraindication for Hip/KneeOA,
indication depend on clinical judgement
• Relative contraindication e.g.
– Active infection, poor motor control,neuropathic
joint, mark inadequate bone stock, etc.
 Aim of Surgical Intervention
• Improving current symptoms
– Lavage & Joint debridement
• Preventing the risk structural
progression
– Cartilage resurfacing (ACI,MACI,Mosaic)
– Osteotomy, (valgus,varus, derotational)
• Improving the symptoms/function
related to an advanceddisease
– Joint replacement→ uni/total
– Arthrodesis
 AAOSClinical Practice Guideline 2009
Tx. of Symptomatic OA of the Knee(Nonarthroplasty)

Recommendations:
1. Self management programs
2. Regular contacts
3. To lose weight ( minimum 5%) for BMI>25
4. Low impact aerobic fitness exercise
5. ROM/flexibility exercise
6. Quadriceps exercise
7. Patellar taping > short term relief pain
 AAOSClinical Practice Guideline 2009
Tx. of Symptomatic OA of the Knee(Nonarthroplasty)

8. No lateral heel wedges for medial compartmentKnee OA

9. Bracing valgus directing force for medial compartmentknee
OA> limited evidence ofeffectiveness
10. Idem for lateral compartment
11. Acupunture > limited evidence of effectiveness
12. No prescription for glucosamine/chondroitin
13. Analgesic: acetaminophen or NSAID
14. Avoid Gastric comorbid: acetaminophen (not>4g/day), topical
NSAIDs, non selective oral NSAIDs plus gastroprotective
agent, or COX2inhibitors
 AAOSClinical Practice Guideline 2009
Tx. of Symptomatic OA of the Knee(Nonarthroplasty)

15. I.A. corticosteroid can be used for short term pain relief
16. I.A hyaluronic acid either well/not recommended with mild to
moderate symptomatic OAof the knee
17. Needle lavage not be used for patients with symptomatic OA
of the knee.
18. Arthroscopic debridement & lavage is notrecommended with
a primary Dx of symptomatic OAof the knee
19. Arthroscopic partial meniscectomy or loose body removalis
an option in sympt OAof the knee
 AAOSClinical Practice Guideline 2009
Tx. of Symptomatic OA of the Knee(Nonarthroplasty)

20. Realignment osteotomy is an option in active patientswith

symptomatic unicompartmental OAof the knee.
21. Osteotomy of the tibial tubercle with isolated symptomatic
patellofemoral OAeither well/not recommended
22. Using a free-floating interpositional device for patients with
symptomatic unicompartmental OAof the knee is not
recommended.
 Arthroscopic Intervention

• Meniscectomy
• Removing loose bodies

Cambell’s Operative Orthopaedics. 11th ed. 2007. Mosby

 Cartilage resurfacing
• A number of options exist :
• • Arthroscopic or
• laser debridement
• • Steadman pick
• technique
• (microfracture)
• • ‘eplacement, bone
• grafting and
• pinning
• • Mosaic plasty
• • Osteochondral
• transplant
• – auto\allograft
• • Periosteal
• transplant
• • Cartilage cell
• transplant
• • Artificial implants
Knee OA → ValgusHigh Tibial osteotomy,
Varus supracondylar femoral osteotomy
 Total knee replacement

Degenerative knee Cuts Implant components Implanted

Knee OA → TK‘/TKA
Total Knee Prosthesis
Coxarthrosis→Total Hip
replacement
Knee Arthrodesis

Cambell’s Operative Orthopaedics. 11th ed. 2007. Mosby

Future Perspective for Treatment
• Old Concept
– Boring degenerative disease
– Advance disease solved by surgical treatment
• New concept
– Understand mechanism of destruction
– Find targets for treatment > by molecular pathway

62
Future DMOAD: Potential Targets?
• Growth factor,
– TGFẞhasdual pathway,normal protective, but mayinduce degradative enzyme
• Enzyme (MMPs),
– blocking MMP 9/13
• Cytokines,
– enhance Il-6, IL-10, blocking Il-1
• Inhibit Receptors such as RAGE,DDR, SAC
• Nitric oxide synthase inhibitor
• Adipokines > leptin inhibitor
• Activation pathway such as Wnt, blocking Frzb
• Recombinant Lubricin > IA supplementation
• Biopolymer IAsupplementation
• Blocking syndecan 4 > decrease aggrecanase
• TD-198946 > target Runx1> induce chondrogenesis , without promoting
chondrocyte hypertrophy.

63
Gene Therapy
Gene/cDNA needed to be transfered
• Growth factors
– TGFb, FGF,IGF-1, EGF,BMP etc
• Spec. ECM
– Collagen type II, Tesnacin, COMP
• Transcription factors for chondrogenesis
– SOX9, Sox 6, LSOX5
• Secreted protein IHH, SHH
– Regulating hypertrophic chondrocyte
• Antiinflammatory agent
– IL-1RA, IL-4, IL-10, sTNFαetc.
• Antiapoptosis agent
– Bcl-2, iNOS
• TD-198946 (thienoindazole) > regulation Runx1 expression
• KGN(Kartogenin), blocks interaction CBFβ& FLNA.
 Stem cell Treatment
• Stem cells have properties that may make
them particularly useful in treating
osteoarthritis. Not only can adult stem cells
differentiate into cartilage, bone, and other
tissues, but stem cells themselves regulate
immune response and inflammation, and may
regulate both fibrosis and cell response to
oxidative stress. Stem cells also produce
factors that promote nervegrowth.
Future Treatment Options

• Minimally Invasive without the dailydose of

drugs
• We are almost there!
 Related Stem cell Tx
Marcel Karperien, 2013

• Injecting biomaterial/ liquid plaster (scaffold)

containing autologous SCand chondrocyte
into affected cartilage damage
• This ‘injectable plaster’ fills up the space where
the cartilage has been lost, creatingan
environment in which the damaged cartilage
can repair itself. After a while – once the
cartilage defect has been repaired – thebody
breaks down the biomaterial automatically.
 Endogenous stem cell
(Blanco F.J., Ruiz-Romero, 2013)

• Localisation for MSChave been identified in OAjoint:

– Articular cartilage
– Synovial tissue
– Synovial fluid
– MSClike property > superficial & middle zones chondrocyte
• Higher MSCs marker have been found in synovium, synovial
fluid, superficial zone
• Drugs, to modulate transcription factor Runx1 activitysuch
as TD-198946 & Kartogenin (KGN), enhance endogenous
MSCto induce chondrogenesis & inhibit hypertrophic
chondrocyte, stopped the degeneration of articular
cartilage.
 Localisation of mesenchymal cells, the chondrogenesis process in the joint and targets for a
new DMOAD: Three locations for MSC have been identified in the OA joint.

Blanco F J , and Ruiz-Romero C Ann Rheum Dis

2013;72:631-634

©2013 by BMJ Publishing Group Ltd and European League Against Rheumatism
 Conclusion
• During the past decade there have been significant developments in the
scientific understanding of OA. Aided by advances in imaging technology,
we have come to appreciate that OAis a disease of the 'whole joint',
which involves a complex series of molecular changes at the cell, matrix,
and tissue levels and complex interactions between the tissues that make
up the joint.
• We are beginning to understand better themechanisms by which genetic,
mechanical, and metabolic risk factors initiate and perpetuate the
biochemical changes that lead to progressive failure of the joint. We are
also gaining a better appreciation of the processes of aging and
senescence that underlie diseasemechanisms.
• These discoveries have opened opportunities for the identification of
targets for therapeutic intervention, which hopefully will lead to effective
therapies that reduce the symptoms and slow the progression of OA.
Masa bakti di Bagian Ilmu Bedah FKUB/RSSA, &
Lahirnya Ortopedi di Malang
• 1 april 1968, lulus FKUnair, menjadi staf dosen bagian ilmu bedahSTKM dan
ditempatkan sebagai dokterpembantu dibagian bedah RSSoepraoen/RST
• Sept 1972, s/d Juni 1974 ditugaskan belajar Ortopedi oleh dr. Syamsul Ma’arif direktur
RSSoepraoen, di Kobeuniversity
• Th ‘74-‘76 dipindahkan ke ‘“UD ‘Saiful Anwar’, sebagai ‘residen’ bedah umum
• Maret ‘76 s/d Okt ‘78 meneruskan pendidikan ahli bedah umum FKUI → ahli BU
• Nov ‘78 s/d Nov ’80 pendidikan ahli bedah ortopedi FKUI → SpBO
• Januari 1981 sebagai staf pengajar di bagian Ilmu Bedah FKUB/RSSAdan memulai
pelayanan ortopedi di Malang.
• Penambahan staf spesialis seksi Ortopedi & Traumatologi:
– Dr.‘espati “D ‘89, dr.Tjuk ‘ ‘92, dr. Edi Mustamsir ‘97, dr. Istan I ‘03, dr. Thomas‘06 , dr. “aifullah A‘08, dr. Persi ‘10, dr. Panji ‘10,
dr.Agung ‘13, dr. Krishna ‘13.
• Th 2007, Seksi Ortopedi  SMFortopedi
• Januari 2008, pembukaan pendidikan program studi FKUB, meluluskan 10 ahli SpOT:
– Dr. Agung, dr. Hendra, dr. Aji, dr. Aris, dr. Krishna, dr. Sagala, dr. Dian Kalista, dr. Indo Rizki, dr. Gde Chandra,
dr. Donny
 Hikmah selama 45 th sbgdokter
• Rintangan dan kegagalan meningkatkan daya juang seseorang
• Belajar dari pengalaman keberhasilan seseorang yang diidolakan,
membentuk idealisme diri
• Belajar tekun untuk menjadi ahli bedah ortopedidalam kurun waktu 13
tahun, setelah dokter.
• Menjalankan kegiatan demi kegiatan secara alami, bak air mengalir
dengan berusaha tanpa adanya friksi dengan lingkungan sekitar
• Pengaruh orang terdekat sangat mempengaruhi dalam menjalankan
profesi dan karier.
• Menjadi profesional, berpegang teguh kepada kompetensi danetika
kedokteran
• Merintis ortopedi di Malang dengan semangatkebersamaan.
• Menanamkan daya juang kepada para yunior untuk menjadi “Man onthe
top” melebihi para seniornya, bagaikan gelombang ombak sungai
Tiangkang, yang akan menerjang gelombang ombak didepannya.
Terima kasih atas perhatiannya