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Tufts OpenCourseware
Author: Grace Lo
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1. Introduction

Osteoarthritis (OA) is the world’s most common joint disorder, affecting more than 10% of people aged over 65 years. It is strongly related to increasing age and is more common in women than men. The radiographic features of the disease can affect almost any joint in the body and are most frequently seen in the hands, knees, great toe and spine. Radiographic OA is frequently attended by pain and disability, and, partly because it is so common, may account for more disability in the population than any other disease.

OA is variable in its patterns of joint involvement and in its pathologic manifestations within each joint. Many investigators consider OA to be the final common pathway for a large number of different joint disorders. Thus, each joint may need to be treated separately for definitional purposes and for risk factor studies. Certain exposures may be risk factors for OA in some joints but not others. For example, joint injury is an important risk factor for knee disease but is not strongly implicated in OA of the hip joint. On the other hand, congenital dislocation of the hip and slipped capital epiphyses may lead to premature OA of the hip.

Many individuals with radiologic features of OA may be asymptomatic, especially those with mild disease. Furthermore, progression of disease severity, measured by radiologic appearances, is also quite variable - indeed a large percent remain unchanged over long periods of time.

2. Pathology

Focal cartilage damage is the central feature of OA. This may range in severity from minor surface roughening to complete cartilage erosion. The process is generally non-inflammatory and is often described as being ‘degenerative’ or due to ‘wear and tear’. The cartilage damage is usually accompanied by some form of ‘reaction’ in the surrounding bone. Osteophytes are an early bony response to cartilage damage. These consist of outgrowths of bone from the peripheral margin of the joint. They may confer some protection to an osteoarthritic joint by reducing instability. The trabeculae in the bone adjacent to an area of osteoarthritic cartilage become thickened, and are susceptible to microscopic fracturing. This gives rise to the appearance of ‘subchondral sclerosis’ on a radiograph. In severe disease, particularly where full thickness cartilage damage has occurred, circumscribed areas of bony necrosis may develop in the subchondral bone. These may be filled with marrow fat, or with synovial fluid which has tracked from the joint space through the cartilage defect into the subchondral bone. They give rise to the radiographic appearance of ‘cysts’. Ultimately the subchondral bone itself may be eroded, or may collapse. In some cases a low-level synovitis develops due to the presence of crystal or other cartilaginous ‘detritus’, which may contribute to damage in the joint.

Biochemically, cartilage consists of a network of collagen fibrils (predominantly type II) which constrain an interlocking mesh of proteoglycans that resist compressive forces through their affinity for water. The tissue is relatively avascular and acellular. Turnover in healthy cartilage is slow and represents a balance between collagen and proteoglycan synthesis and degradation by enzymes such as metalloproteinases. In early OA, the chondrocytes (cartilage cells) proliferate and become metabolically active. These hypertrophic chondrocytes express vitamin D receptors and produce cytokines (e.g. IL-1, TNF-á), degradative enzymes (e.g. metalloproteinases) and other growth factors. Proteoglycan production is increased in early OA, but falls sharply at a later stage when the chondrocyte ‘fails’. In cartilage, the protein sector of proteoglycan is 250kDa in MW. This core protein constitutes only 5 – 10% of the total mass, the rest is carbohydrate. The proteoglycan complexes attach along hyaluronic acid strands (HA). HA is a polymer of in which the repeating unit is a disaccharide made up of D-glucuronic acid and N-acetyl-D-glucosamine. The binding site on the proteoglycan has a high affinity for long HA strands.

3. Osteoarthritis Risk Factors

3.1. Obesity

The relationship between obesity and knee OA is the strongest association known for any rheumatic disease. Importantly, people who lose weight also reduced their risk of developing the disease. Because of the frequency of both obesity and knee OA in the developed world, promoting weight loss in this population could have considerable impact in terms of reducing the societal burden of knee OA.

The association of obesity with other forms of OA is less clear. Some studies have demonstrated an up to two-fold increase in both hand and hip OA in subjects with high body mass index, but these findings have not always been replicated.

3.2. Occupational Factors

Increased rates of certain site-specific forms of OA have been reported in a number of occupational groups. Kellgren and Lawrence, in pioneering studies of arthritis epidemiology in the 1950’s found excess rates of knee and lumbar spine OA among miners compared with other manual workers and with office workers. Other studies have found increased rates of hand and knee OA in dockers and shipyard laborers, finger joint OA in cotton and mill workers, elbow and wrist OA in pneumatic drill operators, hip OA in farmers and knee OA in carpet-layers. Two studies have shown that individuals who have occupations involving knee-bending activities or who report frequent knee-bending as part of daily life have increased rates of knee OA. Indeed there is evidence of an interaction between knee-bending activities and carrying heavy loads suggesting that the two factors may be multiplicative in risk.

3.3. Injury

Joint injury with anatomic disruption of soft-tissue structures is a major risk factor for the subsequent development of OA, especially at the knee joint. Several studies have found an association between reported knee injury and knee OA. The substantially increased rate of knee OA found among runners and soccer players also seems to be accountable to injuries rather than the sports themselves, while physical activities with less risk of injury, such as recreational running, increase the risk of symptomatic OA only slightly, if at all. Studies of individuals with cruciate or collateral ligament laxity, or meniscal damage, support the notion that unstable or damaged knees are prone to premature OA. A substantial number of individuals undergoing meniscectomy will develop knee OA in the long-term.

3.4. Muscle Function

Wasting of the thigh muscles has been recognized to be a prominent feature of knee OA since its earliest descriptions. Exercises designed to strengthen the quadriceps muscle, which stabilizes and may protect the knee joint, are a traditional component of therapy for knee OA. In fact, muscle weakness is the major determinant of functional limitation in OA.

3.5. Genetic Factors

Early studies suggested familial aggregation of certain patterns of OA such as Heberden nodes and generalized radiographic disease. Studies of twins also suggest that a large proportion of the variance in the OA score is attributable to genetic factors. Individuals with certain inherited defects of connective tissue such as congenital epiphyseal dysplasia and Ehlers-Danlos syndrome are susceptible to premature generalized OA. Recent studies of families with an atypical form of primary generalized OA has found associations with specific polymorphisms of the gene for type II procollagen. However, these are uncommon forms of OA.

3.6. Estrogen Withdrawal

The female preponderance of OA, and descriptions of ‘perimenopausal OA’ - a syndrome of pain and stiffness in the hand joints followed by the appearance of Heberden nodes - have engendered speculation that sex hormones may be implicated in the development of OA. Studies investigating endocrine effects have produced conflicting results. Hysterectomy was shown to be associated with OA in one study, but other studies have shown no association with this, or other endocrine variables. Recent investigations of estrogen replacement therapy have found a protective effect in relation to the prevalence of knee and hip OA, and this remains to be substantiated.

3.7. Osteoarthritis and Diet

There is enormous public interest in the relationship between diet and arthritis. In contrast, there has been relatively little focus in traditional scientific studies on the relationship between nutritional factors (other than obesity) and OA. However, there are many mechanisms by which certain micronutrients can be hypothesized to influence OA processes:

  • Antioxidant effects
  • Effects on collagen metabolism
  • Effects on chondrocyte metabolism
  • Effects on bone
  • Anti-inflammatory effects

A prospective study of participants in the Framingham Study cohort suggested that vitamin C, and possibly vitamin E, may reduce the risk of progression of radiographic knee OA. Two independent epidemiologic studies have also demonstrated an inverse association of vitamin D status with risk for OA. Both of these studies used a prospective design and included relatively robust measures of vitamin D. The studies were also concordant for the observation that individuals with the lowest risk had 25-hydroxyvitamin D levels >30 ng/ml. On the other hand, one VA hospital-based prospective study of knee OA progression found no such effects.

Table 1. Risk factors for radiographic knee OA and possible preventive measures
Risk factor Preventive strategy
Definite BMI >25 Kg/m2 optimize BMI
knee injury avoid injuries
meniscectomy correct instability
knee bending optimize occupational
heavy loads ergonomics
family history (genetics) (risk stratification)
Possible biomechanical factors orthotics?
muscle weakness muscle strengthening?
diet vitamins C, D?
estrogen withdrawal estrogen replacement?

4. Determinants of Functional Limitation in OA

Muscle weakness is a long established correlate of functional limitation in individuals with OA, particularly knee OA. Other physiological factors related to impaired function include restricted range of motion and aerobic deconditioning. The impact of OA is greater among those who have comorbidities. Psychological factors such as self-efficacy, depression, anxiety, and pain coping skills, are predictors of both pain and disability among individuals with knee OA.

5. Clinical Manifestations

Pain in OA is caused through diverse mechanisms, including subchondral/intraosseous lesions, raised intraosseous pressure, raised intra-articular pressure, capsular distension, ligamentous strain, synovial inflammation, muscle dysfunction, and alteration in the architecture of the osteoarthritic joint. Pain is worse with weight bearing or joint use, and relieved by rest.

Stiffness is a sensation of joint ‘gelling’ prominent after periods of inactivity especially sleeping. In OA this typically lasts 30 minutes or less, relieved by activity, warmth etc.

Mechanical symptoms like buckling (the joint gives way) and a sensation of instability are common. Bony swelling due to osteophytes and spurs can be palpated.

Bony swelling around the distal interphalangeal joints results in the appearance known as Heberden’s nodes; around the proximal interphalangeal joints results in the appearance known as Bouchard’s nodes.

Soft tissue swelling can be caused by joint effusions (accumulation of synovial fluid), synovitis, and changes within the connective tissue.

Tenderness at joint lines may be present.

Crepitus is common, a “crunchy” sensation appreciated upon palpation of any given joint while ranging that joint, occurring secondary to irregularity of the cartilaginous surfaces.

The focality of cartilage damage in OA leads to deformity and malalignment, and range of joint motion becomes limited. Flexion contractures can follow, due to joint immobility in the presence of pain.

6. Diagnostic Approach

The assessment of a patient with OA focuses on two issues (i) confirmation of the diagnosis, and (ii) exclusion of other conditions which might be causing the current symptoms. For example, common causes of knee pain are presented in Table 2.

Table 2. Common Causes Of Knee Pain that can mimic OA
  • Ligament strains
  • Meniscal disorders
  • Bursitis (anserine, patellar)
  • Tendonitis (quadriceps, hamstring)
  • Iliotibial band syndrome
  • Synovial plicae
  • Chondromalacia patellae
  • Referred pain (hip, lumbar spine)
  • Pseudogout
  • Gout
  • Regional chronic pain disorder
  • Spontaneous osteonecrosis of the knee (SONK)

A history and physical examination may provide sufficient evaluation to establish a diagnosis of OA; however, certain features may indicate the need for further tests. Pain which is very severe, of abrupt onset, or occurring at rest, may indicate other serious pathologies such as spontaneous osteonecrosis of the knee or tibial plateau collapse. Pain in the groin may suggest that the primary lesion resides in the hip joint. Other articular symptoms may suggest a systemic polyarthropathy. Also, effusions should be aspirated as part of any diagnostic assessment. The characteristics of synovial fluid offer valuable insights into the underlying disorder (Table 3). In the proper setting, screening blood tests are instrumental in evaluating for systemic inflammatory arthropathies.

Radiographs can confirm and localize OA. More specialized imaging modalities such as scintigraphy and MRI should be reserved for situations were other pathologies are suspected such as traumatic meniscal tears, algodystrophy, spontaneous osteonecrosis of the knee, pigmented villonodular synovitis.

Table 3. Diagnostically Useful Features Of Synovial Fluid
Feature Pathologic correlate
White cell count
low (<2,000 WBC/mm3) osteoarthritis
high (>5,000 WBC/mm3) inflammatory joint disease, sepsis
monosodium urate (negatively birefringent) gout
calcium pyrophosphate dehydrate (CPPD) (positively birefringent) pseudogout
Red cell count
high hemarthrosis
pseudogout pigmented
villonodular synovitis
Bacterial/fungal culture
septic joint

7. Treatment

The American College of Rheumatology has recently reviewed and promulgated therapeutic guidelines for the medical management of knee and hip OA.

  • Exercise
  • Non-pharmacologic treatments such as education and orthotics (e.g. canes, braces, splints)
  • Acetaminophen (safe and inexpensive)
  • Non-steroidal anti-inflammatory agents (can cause side effects, especially in older persons)
  • Joint aspiration, and injection of corticosteroids (particularly when inflammation evident).
  • Arthroplasty, other surgery
  • Other therapeutic approaches widely used that require further evaluation, include viscosupplementation (intra-articular hyaluronic acid), glucosamine/chondroitin, diacerein
  • Alternative therapies like acupuncture, transcutaneous nerve stimulation, and pulsed electromagnetic field therapy are possible treatments

8. Experimental Therapies in Development

In addition to tissue inhibitors of matrix metalloproteinases (MMPs), other chondoprotective agents are being explored as possible new therapies for OA. For a long time, the primary focus in OA therapies was symptoms. In recent years, more effort has been directed at identifying Disease Modifying OsteoArthritis Drugs (DMOADS), treatments whose mechanism of action is directed at the inhibition of catabolic processes or stimulation of anabolic processes in the OA joint. Doxycyline, an antibiotic with anti-inflammatory effects, inhibits gelatinase, an MMP that degrades type XI collagen, and as a result is being explored as a possible DMOAD. There is also research directed at enhancing chondrogenesis with cartilage transplants and cytokine therapy. Cartilage transplants are now being attempted on patients with isolated and focal traumatically-induced cartilage defects. The efficacy of these treatments is still unclear.