At the molecular bases

1. OSTEOARTHRITIS (OA)
Dr. Yusuph Mwalunu
Resident Orthopedics and Tramatology

2. TABLE OF CONTENTS
 Introduction
 Epidemiology
 Risk factors and Aetiology
 Pathophysiology
 Clinical presentation
 Investigations
 Treatments
 Prognosis
 References

3. INTRODUCTION
 Osteoarthritis (OA) was formerly considered to be simply a
degenerative "wear and tear" process and therefore often
misnamed as degenerative joint disease.
 The pathogenesis of OA is much more complex than just wear
and tear and the term “osteoarthritis,” where “-itis” is indicative
of an inflammatory process, is correct

4. EPIDEMIOLOGY

5. RISK FACTORS
Multiple risk factors have been linked to the pathogenesis of OA, including
 Age
 Joint injury
 Obesity
 Genetics
 Anatomical factors including joint shape and alignment
 Gender.

6. AETIOLOGY
1. AGE
The aging changes within the joint that contribute to OA can be divided into aging
of the extracellular matrix and cellular aging.
Matrix changes
 Thinning of the articular cartilage with age, reduced hydration, and an
accumulation of proteins containing Advanced Glycation End-products (AGEs).
 AGEs cause increased crosslinking of collagen, resulting in altered
biomechanical properties characterized by increased "brittleness“
 AGEs are best known for their role in diabetes, where their production is
facilitated by chronic elevations in glucose (e.g. HBA1c, which is glycosylated
haemoglobin).

7.  In cartilage, AGEs can form and accumulate independent of blood glucose
levels.
 1st The most likely explanation is the very long half-life of matrix proteins in
cartilage, particularly type II collagen, which has a half-life calculated at over
100 years.
 2nd The low turnover rate in cartilage allows for a very slow accumulation of
AGEs that are not removed as they would be in tissues that have a higher
turnover of their matrix such as bone.
 3rd Another age-related matrix change seen in cartilage, as well as the meniscus,
is abnormal calcification referred to as "chondrocalcinosis."

8. Chondrocalcinosis
 Is most commonly results from the accumulation of calcium pyrophosphate
dihydrate (CPP) crystals, although basic calcium phosphate and hydroxyapatite
crystals may also play a role.
 Chondrocalcinosis is associated with episodes of acute crystal-induced mono- or
oligoarticular arthritis or pseudogout that is most commonly due to CPPD
crystals.
 It is thought, although still debated, that chondrocalcinosis could contribute to the
development of OA.
 Chondrocalcinosis is often seen in joints which also have radiographic evidence
of OA; abnormal calcification could alter the mechanical properties of joint
tissues, and crystal-induced inflammation that results from activation of the
innate immune system in joint tissues could contribute to OA by stimulating
production of proinflammatory mediators.

9. Cellular changes
 There are a host of cellular changes that can link aging and OA.
 These include mitochondrial dysfunction related to oxidative stress and
mitochondrial DNA damage
 Reduced responsiveness to anabolic growth factor stimulation including insulin-like
growth factor (IGF)-1 and transforming growth factor (TGF)-beta
 Cell senescence that results in the senescence-associated secretory phenotype
 And a reduction in the process called autophagy which is a protective mechanism
responsible for the degradation and removal of damaged cellular constituents.
These cellular changes contribute to an imbalance between anabolic activity mediated
by growth factors that is necessary to produce and repair damaged matrix and
catabolic activity mediated by proinflammatory mediators and proteases that promote
joint tissue.

10. 2. JOINT INJURY
 OA that develops after injury to a joint is commonly called
posttraumatic OA. The pathologic changes are often evident
within 10 years after injury, with the time of onset influenced in
part by the age of the individual at the time of injury
 OA can develop after injuries that result in
ligament and/or meniscal tears, or after injuries such as
fractures that involve the joint
 Tears incite acute inflammation with joint swelling that is
particularly severe when a major ligament, such as the anterior
cruciate ligament (ACL), is torn.

11.  The risk of developing OA after an ACL tear is the same whether
the ligament is repaired or not
 This suggests that either the mechanics of the joint are not
completely restored after ACL reconstruction or that the acute
inflammation that occurs with the tear puts the OA process in
motion and it is not stopped by reconstruction of the ligament.
 The latter is supported by studies demonstrating that markers of
collagen and proteoglycan degradation are present acutely after
injury and sustained over time.
 Host of inflammatory mediators, including tumour necrosis factor
(TNF)-alpha (elevated sixfold) and interleukin (IL)-6 (elevated
1000-fold), are present shortly after injury.

12. OBESITY
 Body weight is a risk factor for OA not only in weight bearing joints including the knee
and hip, but also in the hand.
 Excess weight will certainly produce increased load on the joint, but there is growing
evidence for a metabolic contribution to OA.
 This would explain the association of obesity with hand OA and why not all overweight
and obese individuals develop knee or hip OA
 Macrophages within adipose tissue are a source of proinflammatory cytokines, including
IL-6 and TNF-alpha, and adipocytes produce adipokines such as leptin.
 The cytokines associated with obesity may promote a low-grade, systemic,
proinflammatory state that could contribute to the development of OA, while leptin has
been proposed to have direct effects on joint tissues that promote the development of OA
 . Metabolic OA related to obesity may also involve altered lipid metabolism and increased
activity of peroxisome proliferator-activated receptor (PPAR)-delta.

13. 4.ANATOMICAL FACTORS
 Joint shape, particularly of the hip, can influence the development of OA.
 Congenital acetabular dysplasia is associated with premature hip OA that often
requires joint replacement.
 An important anatomic factor related to knee OA is lower-extremity alignment.
 Individuals who have a varus alignment (bow-legged) are at increased risk of medial
tibial-femoral OA, while those with a valgus alignment (knocked-knee) are at risk for
lateral tibial-femoral OA.
 The relationship of anatomic factors to OA is best explained by altered joint
mechanics as the initiating cause for OA.
 Altered mechanics that place excessive and abnormal loads on joint tissue cells
activate mechanotransduction pathways that result in increased production of
inflammatory mediators and proteolytic enzymes.

14. 5 GENETICS
 Heredity forms of OA due to certain rare mutations in collagen types
II, IX, or XI, which are structural collagens found in articular
cartilage, result in premature OA that can begin as early as
adolescence, resulting in a severe destructive form of arthritis that
affects multiple joints.
 Because the vitreous of the eye also contains these collagen types,
some patients also have eye disease. These mutations are causes of
Stickler syndrome which affects 1 in 7500 to 9000 newborns
 Less severe forms of OA also have a genetic component which, from
twin studies, has been estimated to explain approximately 40 percent
of the risk for OA

15.  Several risk loci have been discovered by genome wide-association
studies with perhaps the most consistent association being found for
polymorphisms in the gene that codes for growth and differentiation
factor (GDF)-5, which is a bone morphogenetic family member that
plays a role in joint development
 Mutations in GDF-5 are thought to predispose to OA due to altered
joint shape.
 Genetic studies have found that individual genes provide a very slight
increase in the risk for OA suggesting that either multiple genes are
needed for a more substantial OA risk or that environmental
factors and/or epigenetics are important.

16. 6 GENDER
 OA of the hands and knees is more common in women than men,
while hip OA is equally prevalent.
 The strong association of OA with age could explain why OA is more
common in the postmenopausal years, although there is some
evidence that loss of oestrogen could be a contributing factor

17. PATHOPHYSIOLOGY OF OA
The pathophysiology of OA involve 4 types of tissue around the
joints
1. Articular Cartilage
2. Bone
3. Synovium
4. Soft tissue
There are a variety of factors that play an important role in the
pathogenesis of OA, including
1. Biomechanical factors
2. Proinflammatory mediators
3. Proteases.

18. Inflammatory mediators
Mediator In synovial fluid
 IL-6
 Macrophage Chemotactic Protein (MCP)-1
 Interferon-Induced Protein (IP)-10
 Monokine Induced by Interferon (MIG)
NB
Early studies focused on the role of the cytokine IL-1 which was initially named "catabolin"
due to its ability to stimulate cartilage catabolic activity resulting in matrix degradation. The
role of IL-1 in OA has been questioned because the levels found in OA joints (in
the pg/mL range) are much lower than the levels required to cause cartilage
degradation (ng/mL range). Other cytokines are present in OA synovial fluid at much
greater levels than IL-1 or TNF-alpha

19. Mediators produced by Articular chondrocytes of meniscal cells
 IL-7, IL-8, IL-15, IL-17, IL-18
 Oncostatin M (OSM)
 Growth-related oncogene (GRO)-alpha
 Chemokine (C-C-motif) ligand 19 (CCL19)
 Macrophage inflammatory protein (MIP)-1beta
 TGF-alpha
 Other inflammatory mediators include the alarmins (S100
proteins) and the damage-associated molecular patterns (DAMPs)

20.  There is growing evidence that OA is associated with activation
of the innate immune response that can be initiated by tissue
damage
 The mediators found in the OA joint are similar to those found in
a chronic non-healing wound.
 The articular cartilage does not exhibit an adequate repair
response, perhaps because it is avascular, and so once sufficient
matrix damage has occurred it is not reversible.
 Fragments of matrix proteins, including fibronectin, cartilage
oligomeric protein (COMP), fibromodulin, proteoglycans, and
collagen are released from the damage matrix.

21.  These matrix fragments stimulate the innate immune response and further promote the
upregulation of degradative pathways through activation of toll-like receptors and
integrins and further promote the upregulation of degradative pathways through
activation of toll-like receptors and integrins.
 These mediators promote synovitis by attracting macrophages into the joint and
promote matrix degradation by stimulating the expression of various proteases
Medication targets
 Studies have also provided evidence for complement activation in OA joints.
 Inhibition of complement activation by gene deletion or pharmacologic
modulation was found to protect mice from surgically induced OA
 Data from genetically modified mice have shown inconsistent protection from
surgically induced OA in IL-1beta knockouts while IL-6 knockouts were
protected from injury-induced OA but not age-associated OA, which was worse
than the controls

22. Proteases
 The destruction of joint tissues in OA is mediated by a variety of
proteases including
1. Several Matrix Metalloproteinases (MMPs)
2. Cysteine Proteinases including Cathepsin K
3. Serine proteinases
Proteases involved in OA is concentrated on those that mediate
degradation of cartilage extracellular matrix proteins

23.  Aggrecan is the large proteoglycan that provides much of the resiliency of
cartilage. It is degraded, starting in the early stages of OA, by members of
the ADAMTS (A Disintegrin and Metalloproteinase
with Thrombospondin Motifs) family referred to as aggrecanases
(ADAMTS-4 and -5)
 Type II collagen, the most abundant collagen in cartilage, is responsible for
the tensile strength of cartilage and is degraded by collagenases, which, like
aggrecanases, are MMPs. MMP-13 is thought to be the major collagenase
responsible for cartilage degradation in OA.
 Once significant collagen degradation has occurred, it is felt that repair of
the damaged matrix is not possible and progression of matrix loss is likely

24. Medications Targets
 Tissue inhibitors of metalloproteinases (TIMPs) are endogenous inhibitors
found in joint tissues and synovial fluid that may serve as an alternative to
synthetic small molecule inhibitors.
 MMPs are produced as pro-forms that require proteolytic cleavage to be
activated. Serine proteases, including HtrA1 and activated protein C, can serve
this role and therefore could also serve as therapeutic targets in OA. Cathepsin
K is a cysteine proteinase that is expressed by osteoclasts that can degrade
type I collagen in bone but also may degrade type II collagen in cartilage.

25.  ARTICULAR CARTILAGE
The earliest pathologic changes in OA are commonly seen at the surface of
the articular cartilage with fibrillation in focal regions that experience
maximal loading
The cartilage initially swells as the collagen network loosens allowing the
hydrophilic proteoglycans to attract water and expand
The quotient chondrocytes start to proliferate (to a modest degree) and form
clusters, likely in response to loss of matrix.
At least a portion of the cells undergo a phenotypic switch to a hypertrophic
chondrocyte which is similar to the cells found in the hypertrophic zone of
the growth plate that produce type X collagen and matrix metalloproteinase
(MMP)-13

26. As OA progresses, extensive matrix degradation and loss occurs due to the continued production
of proteases driven by proinflammatory cytokines and fragments of matrix proteins that feedback
and stimulate chondrocytes in an autocrine and paracrine manner to produce more cytokines and
proteases
Cartilage has limited capacity to repair, and once collagen is degraded and lost, it is not replaced
to a measurable degree
As significant matrix damage occurs, chondrocyte death can be seen, resulting in areas of matrix
devoid of cells

27.  BONE
Thickening of the subchondral bone (bone sclerosis) occurs due to increased production
of collagen that is improperly mineralized.
Osteophytes (bony spurs) form at the joint margins, often at the insertion site of tendons
or ligaments.
In more advanced disease, bone cysts occur but bone erosions are not typically seen.
Erosive OA that most commonly noted in the distal joints of the hands (distal
interphalangeals and proximal interphalangeals) and is associated with centrally located
erosions that differ in location from the marginal erosions seen in rheumatoid arthritis
(RA) and gout.
Bone marrow lesions, evident on MRI, can be seen most commonly in areas with
overlying cartilage loss and where mechanical loads are greatest.
Pathologically, these focal lesions consist of microstructural damage to bone accompanied
by localized necrosis and fibrosis

28.  SYNOVIUM
Most people with symptomatic OA will exhibit some degree of synovial
inflammation (synovitis) and/or synovial hypertrophy during the course of OA.
Unlike RA and other forms of so-called inflammatory arthritis, synovitis is not
thought to be the initiating factor in primary OA.
Synovitis contributes to pain and disease progression including cartilage
destruction, mediated by the production of proinflammatory factors and
proteins referred to as damage-associated molecular patterns (DAMPs),
including the alarmins.
Secondary OA can be seen in joints previously affected by inflammatory
arthritis, although the pathology is somewhat different from that of primary OA
due to the prior effects of a more striking inflammatory component that causes
more extensive joint destruction including bone erosions.

29.  SOFT TISSUES
In addition to the cartilage, soft-tissue components of the joint, including
ligaments, the joint capsule, and, in the knee, the menisci, are commonly affected
by OA.
These tissues exhibit disruption of their extracellular matrix and loss of cells.
Thickening of the joint capsule along with osteophytes contribute to the
enlargement observed in OA joints.
In older adults with established OA, it is quite common to find tears in ligaments
and the meniscus, which, without a history of prior joint injury, are most likely
degenerative in nature.
In addition to the effects of meniscal tears on joint mechanics, studies have shown
that torn menisci can be a source of inflammatory mediators in the joint.
Periarticular muscles and nerves are also affected by OA resulting in weakness and
pain

30. CLINICAL PRESENTATION
 Pain in OA is worse with joint use (usage-related pain) and relieved by rest. It is
often the most frequent symptom and generally progresses through three stages
Stage 1 – Predictable, sharp pain usually brought on by a mechanical insult that
eventually limits high-impact activities with relatively modest effect on function.
Stage 2 – Pain becomes more constant and starts to affect daily activities. There
may be unpredictable episodes of stiffness.
Stage 3 – Constant dull/aching pain punctuated by episodes of often unpredictable,
intense, exhausting pain which results in severe limitations in function.
 However, not all patients go through such distinct stages, and pain progression
may be arrested at any stage.

31.  Pain is generally worse in the late afternoon and early evening but can also
be worse in the morning soon after waking up
 There may also be night pain in severe OA which can interfere with sleep.
In some people, the pain has a burning (neuropathic) quality, is widespread
around the joint, and is associated with paraesthesia, such features also
suggest comorbid fibromyalgia
 Painful periarticular soft-tissue lesions may coexist, especially with large-
joint OA
 Periarticular soft-tissue lesions cause localized pain away from the joint
line, whereas OA-related pain more commonly is most severe over the
joint line, except for proximal joints like the hip or the shoulder that may
have the maximal pain distal to the originating joint.

32. Patient characteristic
Age of onset >40
Symptoms
• Pain
• Stiffness
• Swelling
• Constitutional symptoms
• Affect one or few joints at a time
• Gradual onset with low progression
• Intermittent
• Increase with activities and relieved by rest
• Night pain in severe disease
• Short-lived (<30 minutes) and early morning-
or inactivity-related
• Some present with nodal OA and deformity
• Absent

33. Appearance
•Swelling (bony overgrowth ± fluid/synovial
hypertrophy)
•Attitude
•Deformity
•Muscle wasting (global - all muscles acting
over the joint)
Palpation
•Absence of warmth
•Swelling (effusion if present is usually small
and cool)
•Joint line tenderness
•Periarticular tenderness (especially knee, hip)
Range of motion
•Crepitus (knee, thumb bases)
•Reduced range of movement
•Weak local muscles

34. Diagnosis
Clinical diagnosis Peripheral joint OA may be diagnosed
confidently on clinical grounds alone if the following are present:
 Persistent usage-related joint pain in one or few joints
 Age ≥45 years
 Morning stiffness ≤30 minutes

35. When to consider additional testing — Appropriate imaging and
laboratory investigations should be carried out in:
 Younger individuals with joint symptoms/signs of OA
 Presence of atypical symptoms and signs such as an unusual site
of involvement, symptoms and signs of joint inflammation,
marked rest and/or night pain, and rapidly progressive pain
 Presence of weight loss or constitutional symptoms
 Those with knee pain and true "locking," which suggests
additional mechanical derangement

36. Differential Diagnosis
 Rheumatoid arthritis
 Psoriatic arthritis
 Crystalline arthritis
 Hemochromatosis
 Infectious arthritis

37. Investigations
 X-ray
 MRI
 USS

38. Radiography
Conventional radiography is the most widely used imaging modality in OA
and allows for detection of characteristic features of OA including
 Marginal osteophytes,
 Joint space narrowing
 Subchondral sclerosis
 Bone cysts
Radiographs can also be used to measure joint space narrowing, which is
sometimes used as a surrogate measure of cartilage loss. However,
radiographic changes in OA are insensitive, particularly with early disease,
and often correlate poorly with symptoms
Also, radiographic OA is a common incidental finding in older people.

40. Magnetic resonance imaging
Magnetic resonance imaging (MRI) is not necessary for most patients
with symptoms suggestive of OA and/or typical radiographic features.
However, MRI can identify OA at earlier stages of disease before
radiographic changes become apparent. These changes include
 Cartilage defect
 Bone marrow lesions.
 Effusion
 Synovitis
 ligaments.

42. Ultrasonography
 Ultrasonography is another imaging modality that can identify OA-associated
structural changes and is useful for detecting synovial inflammation, effusion,
and osteophytosis.
 Limitations of ultrasound include that it is operator-dependent and cannot be
used to assess deeper articular structures and subchondral bone.

43. Other investigations
 Synovial fluid
 Synovial fluid from OA joints is usually non-inflammatory or
mildly inflammatory with less than 2000 white
blood cells/mm3, predominantly mononuclear cells. Inflammatory
effusion in OA may occur in the presence of calcium
pyrophosphate crystal.
 In RA number of leukocytes are more than 2000 cell/mm3

44. Additional laboratory testing may include
 erythrocyte sedimentation rate (ESR)
 C-reactive protein (CRP).
Inflammatory markers are normal in OA and may be useful in
excluding other diagnoses.
 In patients with hand arthralgia and a mix of inflammatory and
mechanical joint symptoms
 rheumatoid factor (RF) and anti-cyclic citrullinated peptide (CCP)
antibodies may be checked to evaluate for possible of rheumatoid
arthritis (RA)

45. GENERALIZED OA
 American College of Rheumatology (ACR) and the European
League of Rheumatology (EULAR) suggests that generalized OA
is present if there is OA at the spinal or hand joints, respectively,
and in at least two other joint regions
 It is characterized by slow accumulation of multiple joint
involvement over several years. Symptoms usually commence in
the hands around middle age and subsequently affect the knees
and other joints over the next few decades.

46.  The clinical marker for generalized OA is the presence of
multiple Heberden's nodes, which are posterolateral hard
swellings of the DIP joints
 Heberden's nodes are often accompanied by less well-defined
posterolateral swellings of the proximal interphalangeal (PIP)
joints referred to as Bouchard's nodes
 Generalized OA may occur in the absence of nodes, so called
non-nodal generalized OA, which is more common in men
(compared with nodal generalized OA, which is more common in
women)

47.  Generalized OA implies a polyarticular subset of OA typically
involving
 distal interphalangeal (DIP) joints
 thumb bases (first CMC joints and trapezioscaphoid joints)
 first MTP joints
 lower cervical
 lumbar facet joints
 knees, and hips

48. CHARACTERISTICS OF SPECIFIC JOINT
INVOLVEMENT
KNEE
 Most common affect and most common cause of disability in above 50 age
world
 Patellofemolal joint or medial tibiofemoral joint are most common site
 Isolated lateral tibiofemoral joint is very rare
 Usually bilaterally but one joint can be severely than another
 Does not cause posterior knee pain unless it associated with Baker’s cyst
 Knee effusion is common
 It may associate with quadriceps wasting, weakness and hip abductor
weakness

50. HIP
 Unlike knee OA, hip OA is frequently unilateral
 Pain due to hip OA is usually felt deep in the anterior groin but may
involve the anteromedial or upper lateral thigh and occasionally the
buttocks
 Internal rotation with the hip flexed is frequently the earliest, and most
affected movement
 The typical end-stage deformity of hip OA is external rotation, adduction,
and fixed flexion
 Muscle wasting, deformities, and moderate to large joint effusions with
“non-inflammatory" (viscous, occasionally haemorrhagic, low cell count)
synovial fluid are common in rapidly progressive large-joint OA

52. FACET JOINT
 Usually coexists with intervertebral disc degeneration, often
loosely termed "spondylosis.“
 It is difficult to isolate symptoms specifically to facet joint OA
 Leads to localized lumbar pain which may radiate unilaterally or
bilaterally to the buttocks, groin, and thighs, typically ending
above the knees
 Symptoms are worse in the morning and during periods of
activity and are increased by stress, exercise, lumbar spine
extension, rotary motions, and when standing or sitting.
 Similarly, cervical facet joint OA may present with ipsilateral
neck pain, which does not radiate beyond the shoulder and is
aggravated by neck rotation or lateral flexion.

53. HANDS
 Symptoms are usually bilateral, and joint involvement is usually
approximately symmetrical
 Typical symptoms affect just one or a few joints at a time
 Target sites, distal interphalangeal (DIP) joints, thumb bases,
proximal interphalangeal (PIP) joints, and second and third
metacarpophalangeal (MCP) joints
 Individuals without pain may still report an "aching" or stiffness in
the hands
 No correlation between clinical symptoms and radiographic
progression

55. Nodal osteoarthritis
Heberden’s and Bouchard's nodes
 Affected people are frequently women, often with a remarkable
familial predisposition
 It involved interphalangeal joints
 Local examination. firm-hard bony swellings on the posterolateral
aspect of the interphalangeal joints, interphalangeal joints may show
restriction in movement and lateral deviation

57. Thumb-base OA
 older postmenopausal women
 Involve first carpometacarpal and/or scaphotrapeziotrapezoid
 have localized deep thenar, radial wrist, or thumb-base pain,
exacerbated on joint use
 Activities that involve pinching (opposition of the thumb to a finger)
are generally most painful
 Radial subluxation and adduction at the thumb base, giving it a
swollen "squared" appearance
 Localized tenderness may be present and passive thumb circumduction
may be painful

59. Erosive osteoarthritis
 Are uncommon and particularly aggressive subset of hand OA
 It presents with a subacute or insidious onset of pain, stiffness, soft-tissue
swelling, and sometimes paresthesiae affecting multiple interphalangeal
joints
 Compared with nodal hand OA, pain, tenderness, and inflammation (warmth,
soft-tissue swelling, sometimes erythema) are more marked and prolonged
 Erosive OA targets just interphalangeal joints (the DIP joints more frequently
than PIP joints) and usually spares the thumb bases and MCP joints
 Erosive OA is not associated with generalized OA
 Rarely, there may be an opera glass deformity, and
Heberden's and/or Bouchard's nodes may coexist

61. First metatarsophalangeal joint
 First metatarsophalangeal (MTP) joint OA is usually bilateral
 Symptomatic leads to localized big-toe pain on standing and during ambulation
(especially during the "toe-off" stage of gait)
 Bony enlargement of the first MTP joint is a common finding
 Hallux valgus deformity (when the distal end of big toe points towards the midline
of the foot)
 Hallux rigidus (or restricted flexion, and extension at the first MTP joint), and cross-
over toes are common deformities
 Bony enlargement at the first MTP joint and hallux valgus frequently lead to the
development of a complicating bursa with additional fibrous tissue reaction on the
medial aspect of the first MTP joint ("bunion")
 OA also commonly targets the talonavicular joint in the midfoot (aggravated by pes
planus) and also the subtalar and tibiotalar joints in the hindfoot.

63. OVERVIEW OF TREATMENT
 Non-pharmacological
1. Exercise
2. 10% weight loss
3. Walking aids

64.  Pharmacological treatment
1. Topical and oral NSADs with precautions of GI, CVS and Renal
complications
2. Duloxetine for NSAID contraindications
3. Capsaicin
Surgery
Joint replacement

65. References
 https://uptodatefree.ir/topic.htm?path=pathogenesis-of-osteoarthritis