Osteoarthritis (OA) is a common joint disease, osteoarthritis is characterized by degeneration of the cartilage that lines the joints or by formation of osteophytes (bony outgrowths), leading to pain, stiffness, and occasionally loss of function. Osteoarthritis is the most common form of arthritis.Cervical osteoarthritis is a particular form of osteoarthritis that affects mainly the joints between the cervical vertebrae (the bones in the neck). 

Causes and symptoms

Osteoarthritis is due to inflammation and destruction of the cartilage that occurs at joint surfaces and changes to the bone beneath. This condition is most likely to occur in the weight-bearing joints as well as in any joints that have previously suffered some kind of damage. However, these are not the only causes. Genetic factors may be involved in cases in which osteoarthrtis affects the joints.

Evidence of osteoarthritis can be seen on X-rays of almost everyone over the age of 60; however, not all of these people have symptoms. Factors that lead to the development of osteoarthritis at an earlier age include excessive wear of, or injury to, a joint; congenital deformity or misalignment of the bones in a joint; obesity; or inflammation from another disease such as gout.

Severe osteoarthritis affects about three times as many women as men. Affected joints become enlarged and distorted by osteophytes, which are responsible for the gnarled appearance of arthritic hands. Weakness and shrink-age of surrounding muscles may occur if severe pain prevents the joint from being used regularly.

Treatment

There is no cure for osteoarthritis. Pain can be relieved by analgesics and non-steroidal anti-inflammatory drugs; injection of corticosteroid drugs into an affected joint or of hyaluronic acid into an affected knee may temporarily relieve the symptoms; physiotherapy to improve muscle strength around the affected joints can help to limit the deterioration that otherwise results from joint instability. In overweight people, weight loss often provides relief of symptoms. If the condition is severe, various aids are available that can make coping at home easier. Surgery for osteoarthritis, including arthroplasty and arthrodesis, is only undertaken if the pain and disability are too severe to cope with.

Osteoarthritis in detail - technical

Essentials

Osteoarthritis is the commonest form of arthritis, detectable radiographically in 80% of patients over the age of 55 and accounting for more dependency in walking and stair-climbing than any other disease. In clinical practice it is defined by the presence of joint symptoms (pain, aching, stiffness) plus evidence of structural change (including crepitus on active joint motion, bony enlargement, radiographic changes of joint space narrowing or osteophytes).

Aetiology and pathogenesis

Risk factors include being female, increasing age, obesity, family history of osteoarthritis (particularly for the hand), increased bone density, trauma, and certain occupational exposures (particularly for the knee). Early onset severe osteoarthritis has been linked to an autosomal dominant mutation in the type 2 procollagen gene (COL2A1), and mutations in other genes may also be important. There are many causes of secondary osteoarthritis, including congenital/developmental abnormalities, trauma, and metabolic and endocrine conditions.

Osteoarthritis results from an imbalance in catabolic and anabolic processes that lead to progressive cartilage damage and destruction. Early stages are characterized by increased water content and cartilage swelling, followed by fragmentation. Reparative processes, involving the formation of fibrocartilage in place of hyaline cartilage, may initially lead to joint stabilization, but ultimately contribute to disease progression by exposing subchondral bone to increased forces. Sclerosis and osteophyte formation develop.

Clinical features

Idiopathic osteoarthritis commonly involves the hands, hips, knees, and spine. Mild to moderate pain is the predominant symptom, increasing with joint use and at the end of the day, and generally improved with rest and moderation of activity. Physical examination reveals tenderness to palpation, bony thickening (osteophyte formation), small effusions, and crepitus. Specific joint findings in the hand are bony enlargement of the proximal interphalangeal joints (Bouchard’s nodes) and the distal interphalangeal joints (Heberden’s nodes), and a ‘squared’ appearance of the lateral aspect of the hand owing to involvement of the first carpometacarpal joint.

Radiographic findings include asymmetry, joint space narrowing, subchondral sclerosis, subchondral cysts, and (the hallmark) osteophytes.

Management

Treatment modalities for all forms of osteoarthritis are limited. Weight loss is effective but difficult to achieve and maintain. Physical therapy and exercise have been demonstrated to improve functional outcome and pain scores in clinical trials. Paracetamol (acetaminophen) is superior to placebo but less efficacious than nonsteroidal anti-inflammatory drugs (NSAIDs) in relieving pain. NSAIDs have been a cornerstone of treatment for many years, but recently their use has diminished because of reports of serious cardiovascular adverse effects. Intra-articular corticosteroids may be effective, but injections should be limited to three to four per year in any given joint to minimize the risk of complications.

Physical aids—a joint that is unstable and painful can be made more stable and less painful by appropriate aids. Walking sticks can be very effective; wheelchairs and other appliances may make it possible for patients to maintain their independence.

Surgical intervention—this is generally reserved for patients who have failed conservative management, including analgesics, physiotherapy, and intra-articular injection. Options include synovectomy, repair of meniscal tears, realignment osteotomy, and total joint replacement (the only known ‘cure’ for osteoarthritis).

Other proposed treatments—irrigation of osteoarthritic joints has been used as a method of relieving joint pain, but remains controversial. Intra-articular injections of hyaluronic acid preparations have become popular in recent years, but any effect is likely to be small. Many patients feel that glucosamine salts and chondroitin sulphate improve symptoms, but recent data from large randomized clinical trials do not support these claims.

Introduction

Osteoarthritis is the commonest form of arthritis, detectable radiographically in 80% of patients over the age of 55. Symptomatic osteoarthritis of the knee (pain with radiographic abnormalities) was noted in 6.1% of adults aged 30 and over in the Framingham Study, with comparable frequency in the United Kingdom. Approximately 20.7 million people in the United States of America have physician-diagnosed osteoarthritis, and although some of these may be asymptomatic, many have significant pain and disability, with one study finding that osteoarthritis accounts for 12.3% of all those with limitation of activity. The prevalence of osteoarthritis is likely to increase, paralleling the increase in the absolute and relative number of people who are over 65 years of age. The social impact of this disease is enormous, accounting for more dependency in walking and stair climbing than any other disease. The estimated annual cost associated with osteoarthritis in the United States of America is $15.5 billion in 1994 dollars, which approaches 1% of the gross national product, with more than 50% of the costs due to work loss.

Definition

Osteoarthritis has been defined by the American College of Rheumatology (ACR) as:

a heterogeneous group of conditions that lead to joint symptoms and signs which are associated with defective integrity of articular cartilage, in addition to related changes in the underlying bone at the joint margins.

Source: Altman R, Asch E, Bloch D, et al. (1986) The American College of Rheumatology criteria for the classification and reporting of osteoarthritis of the knee. Arthritis Rheum, 29, 1039–49.

There are alternative definitions, including those based on symptoms, physical findings, and radiographic and arthroscopic findings. The presence of joint symptoms plus evidence of structural change generally defines clinical osteoarthritis, whereas many studies use radiographic assessment alone as the primary means of identifying the condition. Most clinical investigators use the Kellgren and Lawrence scale for grading osteoarthritis of the knee, which defines osteoarthritis on the basis of osteophytes, the presence of which relates well with the presence of knee symptoms. The American College of Rheumatology has developed classification criteria for the presence of osteoarthritis based on the joint involved (Tables 1-3): these are based on clinical criteria alone, clinical and laboratory criteria, and clinical plus radiographic criteria. Initially, only the clinical and radiographic criteria were validated; more recently, Wu and colleagues have validated the clinical classification criteria.

Risk factors and epidemiology

There are many risk factors for the development of osteoarthritis of the knee, including being female, increasing age, obesity, family history, increased bone density, trauma, and certain occupational exposures (Table 4).

Age, sex, and race

Age is the strongest associated risk factor for the development of osteoarthritis in many studies. The National Health and Nutrition Examination Survey found a prevalence of osteoarthritis of only 0.1% in people aged 25 to 34 years, compared with over 80% in those aged 55 to 64 years. This increased incidence occurs in osteoarthritis of the hands, back, hip, and knees.

Sex differences in osteoarthritis are complicated. There is an overall higher prevalence in women, in whom the disease more often involves multiple joints. However, before the age of 50 years there is a higher prevalence and incidence in men, whereas after 50 years the reverse applies, with increasing female predominance as age increases. There is a plateau or decline in both sexes by the age of 80 years. The sex- and age-related differences in prevalence parallel the effect of postmenopausal oestrogen deficiency in increasing the risk of osteoarthritis. Other probable factors that help explain the increase in the incidence and prevalence of osteoarthritis with age include a decreased responsiveness of chondrocytes to growth factors that stimulate repair, an increase in the laxity of ligamentous structures, and a decrease in proprioceptive responses.

Racial differences in osteoarthritis of the hip are conflicting, but the higher relative weight of African–American women may predispose them to higher rates of osteoarthritis of the knee. There are few data available for other racial differences in osteoarthritis of the knee among the population of the United States of America.

Genetic factors

Several studies have confirmed that inheritance is a risk factor for osteoarthritis, with conventional twin and nontwin sibling, population, and modern molecular studies implicating genetic factors in the development of the condition. Most cases of osteoarthritis of the hand are inherited; the percentage for osteoarthritis of the knee is smaller, perhaps because this often develops more as a result of repeated mechanical insults. Individuals are at higher risk of developing osteoarthritis if their parents had it, especially if the parental disease was polyarticular or had its onset in middle age or earlier. Inheritance may be more important among women than men. Numerous extended families with high rates of early onset severe osteoarthritis have been characterized in which the condition has been linked to an autosomal dominant mutation in type II procollagen; using linkage analysis, two reports on three unrelated families showed co-inheritance of generalized osteoarthritis with specific alleles of a type II procollagen gene (COL2A1) on chromosome 12. Mutations in genes other than COL2A1 may also be important, such as genes encoding minor collagen types and extracellular matrix protein. The gene for asporin, a matrix protein, appears to be a promising candidate; an allele that increases the number of aspartic acid residues in one portion of the asporin molecule associates with knee osteoarthritis in a Japanese population, and asporin produced from this allele appears to suppress transforming growth factor β (TGFβ)-stimulated synthesis of the major articular cartilage structural proteins, type II collagen and aggrecan, by cultured chondrocytes.

Obesity

Several longitudinal studies suggest that increased weight is a risk factor for the development of osteoarthritis of the knee, and that overweight patients with established osteoarthritis of the knee are at greater risk of developing progressive disease compared with those who are not overweight. The associations between obesity and osteoarthritis of the knee are significantly greater for women than men and are not affected by adjustments for concurrent diseases. Data from the Chingford Study showed that patients in the highest weight tertile had an odds ratio of 6.17 for radiographic osteoarthritis of the knee compared with the lowest weight tertile. For every two-unit increase in body mass index (BMI) (c.5 kg), the odds ratio for radiographic osteoarthritis of the knee increased by 1.36. A follow-up study of incident osteoarthritis of the knee in women with unilateral disease found the tertile with the highest BMI had a relative risk of 4.69 for developing osteoarthritis in the contralateral knee compared with patients in the lowest BMI tertile. There are similar findings for osteoarthritis of the hand and hip, but the association is less robust; a recent study noted a significant association between BMI and total hip arthroplasty for osteoarthritis in a cohort of over 1 million Norwegian men and women. The importance of obesity cannot be understated, as this may be a modifiable risk factor. An obvious possible mechanism for the effect of obesity on osteoarthritis of the knee is increased force across the weight-bearing joint, which induces cartilage breakdown by altered walking mechanics, but obesity may also have effects through metabolic intermediaries.

Oestrogen deficiency

Oestrogen deficiency has been implicated as a risk factor for the development of osteoarthritis, as evidenced by the high incidence of osteoarthritis after the menopause. Several studies suggest that oestrogen replacement therapy reduces the risk of osteoarthritis of the hip and knee. Both the Study of Osteoporotic Fractures and the Framingham Study have reported a strong inverse relationship between oestrogen replacement therapy and osteoarthritis among those taking long-term oestrogen replacement therapy.

Reactive oxygen species

Reactive oxygen species have been implicated in the development of osteoarthritis, and antioxidants may prevent or delay the onset of the condition. In the Framingham Study, those in the lowest tertile of vitamin C intake had a threefold greater risk of progression of osteoarthritis of the knee, joint space loss, and onset of knee pain compared with subjects with a higher intake. However, the effects of β-carotene and vitamin E against disease progression were inconsistent. No effect of serum 25-hydroxyvitamin D was seen on incident osteoarthritis, but among subjects with radiographic osteoarthritis at baseline, those who were in the lowest tertile of serum 25-hydroxyvitamin D had a higher rate of radiographic progression compared with those in the highest tertile. There is conflicting evidence related to the association of specific polymorphisms of vitamin D receptor and oestrogen receptor genes and a predisposition for osteoarthritis; however, no association between these polymorphisms and osteoarthritis was seen in a well-designed case–control study.

Local biomechanical factors

Local biomechanical factors such as caused by hip dislocation, congenital dysplasia, trauma or repetitive joint use are risk factors for osteoarthritis. In animal models, a change in biomechanics that occurs after injury leads to increased shear stress on local areas of cartilage, possibly causing osteoarthritis. In humans, traumatic injury to joints is a common cause of osteoarthritis, and Kellgren and Lawrence found that a history of previous trauma could be elicited in about 40% of men and 20% of women aged 55 to 64 years with osteoarthritis of the knee. In the Framingham Study, men with a history of major trauma to the knee had a fivefold increased risk of osteoarthritis of the knee, and women with a similar history had a greater than threefold increased risk. Trauma that causes damage to a cruciate ligament and/or a meniscus has been associated with subsequent development of osteoarthritis of the knee, perhaps through concurrent damage to articular cartilage. With regard to repetitive use, occupations that require kneeling and squatting are associated with a higher prevalence of osteoarthritis of the knee, but heavy physical work is less consistently associated. The level of physical activity increases the risk of developing osteoarthritis. In the Framingham Study, physical activity (generally consisting of walking and gardening in this population) was found to correlate directly with the risk of developing radiographic osteoarthritis of the knee in elderly subjects followed for 8 years. Those with high levels of these activities had a threefold increase in the risk of osteoarthritis compared with sedentary controls. Elite athletes have higher rates of incidence of osteoarthritis of weight-bearing joints compared with controls, probably because athletic activities often involve both increased risk of injury and repetitive use.

Quadriceps weakness has been associated with radiographic osteoarthritis of the knee. Muscular strength may be required to stabilize the knee, distribute force, or lessen the effect of an impact load, and maintenance of muscular strength may be important in decreasing the incidence of osteoarthritis of the knee and its progression and disability due to established disease. Proprioceptive sensation, which declines with age, is impaired in elderly patients with osteoarthritis of the knee, suggesting that poor proprioception may contribute to functional impairment in these patients.

Protective factors

The incidence of osteoarthritis is lower in the setting of osteoporosis: bone density in patients with osteoarthritis is greater than in age-matched controls, even at sites distant from the affected joints. Most studies linking osteoarthritis with high bone density are cross-sectional. Although osteoarthritis and high bone density are both linked to obesity, the association of osteoarthritis with high bone density is independent of BMI. It has been suggested that osteophyte formation rather than cartilage loss is linked to high bone density, which suggests the presence of a circulating bone growth factor in those with osteophytes; possibilities include insulin-like growth factor type 1 (IGF-1), platelet-derived growth factor (PDGF), fibroblast growth factor (FGF), TGFβ, and colony-stimulating factor (CSF).

Pathogenesis and pathological features

The pathogenesis of osteoarthritis remains controversial. Once thought of as a normal consequence of ageing, the complex nature of this disease is only now being understood. Current theories suggest that osteoarthritis results from an imbalance in catabolic and anabolic processes that lead to progressive cartilage damage and destruction. Increased catabolism may be the result of acute injuries such as an acute meniscal tear or of chronic microtraumatic events. Initially, anabolic processes such as proteoglycan synthesis maintain balance with catabolic processes, and damage to cartilage is repaired. However, with time and age, anabolic processes decline and progressive cartilage damage ensues.

Histological changes in osteoarthritis are complex. Early stages are characterized by increased water content and cartilage swelling, and this swollen cartilage is believed to be more susceptible to injury and may lead to fragmentation of the articular surface. Fragmented cartilage is less able to withstand biomechanical insults, resulting in further deterioration. Chondrocytes become activated and proinflammatory cytokines such as interleukin 1 (IL-1) and tumour necrosis factor α (TNFα) are synthesized. These cytokines increase the synthesis of degradative proteases such as collagenase, gelatinase, and stromelysin. As cartilage destruction progresses, proteoglycan content becomes reduced and it becomes thinned and fragmented.

Reparative processes may initially lead to joint stabilization, but ultimately contribute to progression of the disease. Fibrocartilage may be synthesized in response to loss of the more durable hyaline cartilage, temporarily improving joint mechanics and protecting the subchondral bone. However, fibrocartilage is less able to withstand mechanical loading, exposing the subchondral bone to increased force relative to that when covered by hyaline cartilage. Subchondral bony changes, such as sclerosis and osteophyte formation, develop.

The gross pathological findings of osteoarthritis include cartilage loss and reactive bone formation. Cartilage loss occurs primarily in areas of joint loading and may be related to repetitive mechanical insults. Cartilage loss may be best visualized arthroscopically, when findings include cartilage softening, fibrillation, and thinning. Areas of complete cartilage loss may be seen. More commonly, the clinician will recognize these findings as radiographic joint space narrowing. Similarly, bony changes may be seen on pathological specimens or arthroscopically, including osteophyte projections and subchondral bone visualized through denuded cartilage. The classic radiographic bony changes include osteophyte formation and subchondral bony sclerosis and cysts.

The pathological abnormalities of osteoarthritis can also extend to juxta-articular bone marrow. Recent MRI studies have demonstrated bone marrow abnormalities that correlate with the presence of relatively increased bone mineral density, although the significance of this finding from the perspective of pathogenesis is uncertain.

Clinical features

Precise definition of clinical osteoarthritis has remained elusive, as radiographic findings and symptoms may diverge. In addition, osteoarthritis may be categorized by the joint area involved or as being idiopathic or secondary to other disorders. An essential element to diagnosis of osteoarthritis is the correct attribution of symptoms to the affected joint. Initial evaluation of soft tissue abnormalities such as bursitis, tendinitis, and ligamentous strain should be performed. In addition, consideration of neurological or underlying bone abnormalities should be entertained when appropriate.

A thorough history and physical examination should be performed to evaluate for secondary forms of osteoarthritis. These include developmental, mechanical, or biochemical abnormalities known to increase the risk for osteoarthritis (Table 5). These forms tend to present earlier in life (e.g. congenital hip abnormality), in atypical joints (e.g. calcium hydroxyapatite), or as more inflammatory in nature (e.g. calcium pyrophosphate deposition disease).

Idiopathic osteoarthritis may occur localized to one body area or as a more generalized disease. Common areas of involvement include the hands, hips, knees, and spine. Less commonly, osteoarthritis involves the shoulders, wrists, ankles, feet, and jaw.

Pain is the predominant symptom of osteoarthritis, usually mild to moderate in nature and increasing with joint use and at the end of the day. Pain is generally improved with rest and moderation of activity. Severe disease may cause pain at rest or at night. The source of pain may be the underlying bone, the joint capsule, or surrounding structures. Cartilage is avascular and without nerves and not itself a source of pain.

Stiffness may occur but is generally limited to less than 30 min in duration (gelling phenomenon). It is typical in the morning or after any prolonged rest (theatre sign). Effusions may occur, but warmth and soft tissue swelling is rare and suggests another diagnosis.

Physical examination reveals tenderness to palpation, bony thickening (osteophyte formation), small effusions, and crepitus. Specific joint findings also occur. Typical in the hand are bony enlargement of the proximal interphalangeal joints (Bouchard’s nodes) and the distal interphalangeal joints (Heberden’s nodes). The first carpometacarpal joint may be involved, causing a ‘squared’ appearance of the lateral aspect of the hand (in anatomical position). Involvement of the foot yields bunions, and of the knee pronounced valgus and varus deformities, Baker’s cyst, or locking, suggesting meniscal damage. Early hip findings include limited internal and external rotation. Back findings include pain: true osteoarthritis occurs at the apophyseal joints; degenerative disc disease and diffuse idiopathic skeletal hyperostosis are distinct entities.

In an effort to standardize the diagnosis of osteoarthritis, the American College of Rheumatology formed a subcommittee to define osteoarthritis of the knee, hip, and hand. Clinical, laboratory, and radiographic findings were evaluated by an expert panel and statistical analysis to yield classification criteria with acceptable sensitivity and specificity values. These instruments should be used with caution in individual patients but provide a framework for analysis (see Tables 1-3).

Common clinical mimics of osteoarthritis include rheumatoid arthritis, calcium pyrophosphate deposition disease, and infectious monoarticular arthritis.

Hand osteoarthritis may be confused with rheumatoid arthritis, as both cause pain and visible swelling. Less commonly hip or knee arthritis may present as diagnostic challenges. Hand osteoarthritis typically involves the proximal interphalangeal and the distal interphalangeal joints; the ‘swelling’ is not true swelling but hard, bony thickening due to osteophyte formation; and stiffness is limited. By contrast, rheumatoid arthritis typically involves the proximal interphalangeal, metacarpophalangeal, and carpal joints, sparing the distal interphalangeals. True swelling occurs and is soft with palpation. Multiple joints are involved, symptoms of systemic inflammation occur, and rheumatoid factor is usually positive. In rheumatoid arthritis radiographs demonstrate symmetric joint space narrowing, bony erosions, minimal sclerosis, and minimal osteophyte formation.

Calcium pyrophosphate deposition disease is difficult to differentiate from idiopathic osteoarthritis because the two may coexist. Typical distributions for this disease include the knees, wrist, shoulder, and metacarpophalangeals. Patients may have more prolonged stiffness and pain, and swelling may occur. Radiographs with evidence of chondrocalcinosis strongly suggest calcium pyrophosphate deposition disease, but the presence of crystals on arthrocentesis is the gold standard for diagnosis.

Infectious monoarthritis can occasionally mimic osteoarthritis. The distinction is more difficult with subacute infections, such as fungal or mycobacterial infections. If there is clinical suspicion, radiographs and arthrocentesis should be performed.

Investigation

Laboratory tests, if performed, reveal normal sedimentation rates and noninflammatory synovial fluid. Radiographic findings include asymmetry, joint space narrowing, subchondral sclerosis, subchondral cysts, and (the hallmark) osteophytes.

Treatment

Treatment modalities for all forms of osteoarthritis, listed in Table 6, remain limited. Traditional therapies include analgesics, NSAIDs, intra-articular corticosteroid injections, intra-articular hyaluronic acid injections, topical agents, tidal lavage, arthroscopic irrigation, and total joint replacement. With the exception of joint replacement, none of these therapies address the underlying problem of cartilage damage. Newer therapies include weight loss and exercise, both of which have been difficult to maintain over long periods of time. Emerging therapies such as tetracycline, cytokine modulators, and inhibitors of metalloproteinases may potentially alter the progression of osteoarthritis. Nutrition supplements such as glucosamine, chondroitin sulphate, soybean, and avocado products have been reported to provide better long-term analgesia than NSAIDs, and some of these agents may alter the progression of osteoarthritis and repair cartilage damage.

Weight loss

Weight loss, although effective, is difficult to achieve and maintain, but a weight loss of 4.5 kg (10 lb) over 10 years may decrease the risk of developing contralateral knee osteoarthritis by 50%. Studies demonstrating improvement in disease outcome are more controversial. However, given potential benefits in osteoarthritis as well as the additional health benefits of a normal BMI, obese patients should be encouraged to lose weight.

Exercise and psychosocial support

Physical therapy and exercise are advocated in osteoarthritis for a variety of reasons. Improvements in flexibility and muscle strength may decrease joint loading, preventing further damage, and they have been demonstrated to improve functional outcome and pain scores in clinical trials. In addition, they provide a sense of self-determination, an adjunct for weight loss, improve depressive symptoms, and decrease patient disability. Obstacles include expense and the lack of motivation to continue exercising after a programme has been completed.

The role of psychosocial support may be significant. Telephone helplines providing contact and education have been demonstrated to improve pain and functional status. Education and support improve feelings of frustration, minimize dependency, and improve coping mechanisms.

Simple analgesics

A recent meta-analysis of 10 randomized clinical trials found that paracetamol (acetaminophen) is superior to placebo but less efficacious than NSAIDs in relieving pain due to osteoarthritis, but the lower relative risk of complications has favoured the use of this drug over NSAIDs, especially in older populations. Typical daily doses of paracetamol are 4 g (3 g in elderly patients), but this drug may be associated with liver problems and interactions with other drugs such as warfarin. Narcotic analgesics are generally avoided because of potential complications, including constipation, sedation, addiction, and impairment of balance.

Non steroidal anti-inflammatory drugs (NSAIDs)

NSAIDs have been a cornerstone of osteoarthritis treatment for many years, but recently their use has diminished as a treatment for osteoarthritis because of reports of serious cardiovascular adverse effects. The selective cyclooxygenase-2 (COX-2) inhibitors (e.g. celecoxib and etoricoxib), which appear to be similarly efficacious to the traditional nonselective NSAIDs for the relief of pain associated with osteoarthritis but with less associated gastroduodenal toxicity and antiplatelet effects compared with nonselective NSAIDs, were the first NSAIDs reported to be associated with increased risks of cardiovascular adverse events. These reports led to the withdrawal of two agents, rofecoxib and valdecoxib, from the market, and subsequent claims of serious cardiovascular adverse events with nonselective NSAIDs has led to mandated warnings of the potential of cardiovascular effects with all NSAIDs, including nonselective and COX-2 inhibitors. Besides their association with peptic ulcer disease and antiplatelet effects, nonselective NSAIDs less commonly cause rash, hepatic dysfunction, and central nervous system effects.

Corticosteroids

Intra-articular corticosteroids may be effective in decreasing joint pain associated with osteoarthritis. Dosage varies depending on patient body size, comorbidity, and the joint involved. They have multiple side effects, including risk of infection, bleeding, and (possibly) cartilage damage. To minimize the risk of complications, injections should be limited to three to four per year in any given joint.

Hyaluronic acid

The use of hyaluronic acid preparations (e.g. Hyalgan, Synvisc) has become popular in recent years. These agents are reported to increase viscosity of synovial fluid by replacing depleted hyaluronic acid (which occurs in osteoarthritis), and one meta-analysis concluded that hyaluronic acid injections were superior to intra-articular saline injections, but the effect was relatively small. A subsequent meta-analysis noted statistically significant improvements in rest pain between 2 and 6 weeks after hyaluronic acid injections compared with placebo injections. In a trial comparing hyaluronic acid to NSAIDs, there were similar effects in those receiving injections and those receiving naproxen, but a reanalysis of the data using an intention-to-treat basis suggested that there were no differences between the hyaluronic acid and placebo groups at either 12 or 26 weeks of treatment.

Joint lavage

Irrigation of osteoarthritic joints has been proposed as a method of relieving joint pain by removing debris or inflammatory cytokines, but remains controversial. Livesley compared arthroscopic irrigation with physiotherapy and found that the arthroscopic group experienced significant improvement in pain that was sustained over 12 months. Ike and colleagues compared medical management plus joint lavage without arthroscopy with medical management alone in a multicentre, randomized prospective study: significant improvements in pain and stiffness occurred in the group receiving irrigation. Ravaud and colleagues evaluated the efficacy of joint lavage and intra-articular steroid injection in osteoarthritis of the knee. Patients who underwent joint lavage had improved significantly at 6 months; those given only corticosteroids had early improvement but no long-term benefit. Kalunian and colleagues studied the effectiveness of visually guided arthroscopic irrigation in early osteoarthritis of the knee unresponsive to conservative management. Patients received 3 litre or minimal (<250 ml) arthroscopic irrigation, the former having an effect on pain as measured on two rating scales. In a hypothesis-generating post-hoc analysis of the effect of positively birefringent intra-articular crystals, patients with and without intra-articular crystals had statistically significant improvements in pain assessments at 12 months; patients with crystals had statistically greater improvements in pain. Moseley et al. conducted a randomized, placebo-controlled, double-blind trial comparing arthroscopic debridement, arthroscopic lavage, and placebo surgery as treatment modalities for osteoarthritis of the knee. Placebo surgery consisted of skin incisions and simulated debridement without insertion of an arthroscope. At no point did either of the intervention groups report less pain or better function than the placebo group, but this study did not examine the effects of associated crystals or inflammation on outcome.

Surgery

Surgical intervention is generally reserved for patients who have failed conservative management, including analgesics, physiotherapy, and intra-articular injection. Prescribed treatments include synovectomy, repair of meniscal tears, realignment osteotomy, and total joint replacement. Total joint replacement removes the affected structure and is the only known ‘cure’ for osteoarthritis to date, providing marked pain relief and functional improvement.

Aids and appliances

A joint that is unstable and painful can be made more stable and less painful by appropriate aids. Wheelchairs and other appliances may make it possible for a patient to maintain their independence. Walking sticks can be very effective, and for a painful hip or knee should be held in the contralateral hand to transfer weight from the affected joint. If the main problem is instability, the stick should be held in the hand that inspires most confidence. Splinting to correct instability, correction of valgus or varus deformity at the knee or ankle, use of a rocker sole to ease hallux rigidus pain, or a heel raise if the legs are of unequal length, can all allow significant reduction of symptoms, as can the simple recommendation of shoes with good shock-absorbing soles. These simple and apparently mundane issues should not be ignored by the physician.

Other therapies

Glucosamine and chondroitin sulphate

Many patients with osteoarthritis feel that glucosamine salts and chondroitin sulphate improve symptoms; however, recent data from large randomized clinical trials do not support these claims, and there is little data to suggest that these supplements repair cartilage damage.

Glucosamine, an aminomonosaccharide, is present in almost all human tissues, but particularly in articular cartilage, where it is an intermediate substrate in the synthesis of glycosaminoglycan and proteoglycans. Exogenous glucosamine salts significantly enhance chondrocyte synthesis of glycosaminoglycans, collagen, and DNA. Both glucosamine hydrochloride and glucosamine sulphate are rapidly absorbed after oral administration and are not toxic, even at high oral doses. Chondroitin sulphate is a long-chain polymer of a repeating disaccharide. It is the predominant glycosaminoglycan found in articular cartilage and differs from glucosamine in that it stimulates glycosaminoglycan and proteoglycan synthesis by both extracellular and intracellular mechanisms, whereas glucosamine utilizes only intracellular mechanisms. By virtue of its long chains, chondroitin sulphate competitively inhibits enzymes that degrade proteoglycans, and this may be its mechanism of action, with increased availability of substrates for formation of articular matrix another possibility. It is 70% absorbed after oral ingestion, with affinity for synovial fluid and articular cartilage.

A meta-analysis of 20 controlled trials of glucosamine sulphate, which included 2570 patients with osteoarthritis, was reported in 2005. When results of all these trials were considered, a significant improvement with glucosamine sulphate was noted; however, when the analysis of efficacy was restricted to the eight studies that were adequately blinded, there was no significant benefit of glucosamine for pain or function. In a large, multicentre study that compared glucosamine hydrochloride, chondroitin sulphate, the combination of the two supplements, celecoxib, and placebo, glucosamine hydrochloride either used alone or in combination with chondroitin sulphate was not more effective in relieving pain or improving function than placebo. In this study, there were no significant differences in pain relief in those receiving chondroitin sulphate alone compared to the placebo group. In an exploratory subgroup analysis, a possible benefit of the combination of glucosamine hydrochloride and chondroitin sulphate was suggested for patients with osteoarthritis of the knee who had moderate to severe pain.

Tetracyclines, IL-1 antagonists, and collagenase inhibitors

Tetracyclines have been demonstrated to inactivate matrix metalloproteinases, such as collagenase, stromolysin, and gelatinase. Dog models using doxycycline reduce the incidence of osteoarthritis. In a large, multicentre study in which obese women with symptomatic and radiographically apparent unilateral knee osteoarthritis were treated with either doxycycline or placebo for 30 months, the rate of joint space narrowing was significantly less in those treated with doxycycline compared with the placebo group, but there were no significant differences between the two groups in reduction of knee pain.

Other agents demonstrating efficacy in osteoarthritis include use of diacerein and avocado/soybean extracts. Diacerein is an oral agent with analgesic properties, hypothesized to have an effect in osteoarthritis by inhibiting synthesis and activity of IL-1 and demonstrating cartilage preservation in an animal model. Human studies have demonstrated improvements in pain and function in hip osteoarthritis, as well as an NSAID-sparing effect. Similarly, avocado and soybean unsaponifiables are believed to exert their effects through IL-1. Clinical studies have demonstrated an NSAID-sparing effect and improvement in functional index and pain.

Cipemastat (Ro 32-335, Trocade) is an orally active collagenase inhibitor that has demonstrated chondroprotection by radiographic criteria in a mouse osteoarthritis model. Bay 129 566 is a stromelysin-1 (MMP-3) inhibitor that demonstrated efficacy in both dog and guinea pig menisectomy models. Further studies of these compounds are needed. Future strategies for chondroprotection include manipulation of tumour necrosis factor, nitrous oxide, and insulin-like growth factor.

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