An In-Depth Overview of Osteoarthritis

For Physicians


Joseph A. Markenson, MD

Joseph A. Markenson, MD

Attending Physician, Hospital for Special Surgery
Professor of Clinical Medicine, Weill Cornell Medical College
Attending Physician, Department of Medicine, Memorial Sloan-Kettering Cancer Center

  1. Definition
  2. Pathogenesis
  3. Clinical Presentation
  4. Laboratory Findings and Imaging
  5. Differential Diagnosis
  6. Initial Treatment
  7. Long-term Management Issues Including Surgery
  8. Prognosis
  9. When to Refer to a Rheumatologist
I. Definition

Osteoarthritis is a disease of complex etiology that results in loss of normal function due to breakdown of articular cartilage. A consensus definition comes from a workshop held in 1995: "Osteoarthritic diseases are a result of both mechanical and biologic events that destabilize the normal coupling of degradation and synthesis of articular cartilage chondrocytes and extracellular matrix, and subchondral bone. Although they may be initiated by multiple factors, including genetic, developmental, metabolic, and traumatic, osteoarthritic diseases involve all of the tissues of the diarthrodial joint. Ultimately, osteoarthritis diseases are manifested by morphological, biochemical, molecular, and biochemical changes of both cells and matrix which lead to a softening, fibrillation, ulceration, loss of articular cartilage, sclerosis and eburnation of subchondral bone, osteophytes, and subchondral cysts. When clinically evident, osteoarthritis diseases are characterized by joint pain, tenderness, limitation of movement, crepitus, occasional effusion, and variable degrees of inflammation without systemic effects."[1]

Thirty-seven million people in the United States suffer from some form of arthritis. In 1994 the Centers for Disease Control reported that by year 2020, when one out of every two Americans will be over the age of 50, there will be a larger increase in new cases of arthritis than of any other disease in the United States. Among the leading causes of disability, arthritis heads the list; osteoarthritis is the most prevalent form and has the greatest economic impact. Because osteoarthritis (>30% of the population over the age of 65) is much more prevalent than rheumatoid arthritis, the economic impact of osteoarthritis may be 30 times greater than that of rheumatoid arthritis. Osteoarthritis will soon account for more than 30% of office visits. As physicians, our most important contribution will be to limit days lost from work as well as the social and psychological impact of this devastating disease.

II. Pathogenesis

Osteoarthritis is primarily a disease of the articular cartilage. However, subchondral bone, synovium, ligament and supporting neuromuscular apparatus, if damaged will contribute to accelerated cartilage degradation. The components of articular cartilage include type II and other collagens, proteoglycans and chondrocytes. Nutrition of chondrocytes is provided by diffusion from the blood supply of subchondral bone and synovial fluid.

Types III, IV, IX, X and XI collagen make up 10-20% of the total cartilage collagen and maintain the stability of Type II collagen. For example, type IX and XI collagen regulate its fibril diameter. The proteoglycan aggrecan is highly hydrophilic, with low viscosity. Its ability to retain water under conditions of load and release it during unloading imparts to articular cartilage its elastic property, allowing the cartilage to function as a shock absorber in the diarthrodial joint. An abnormality in the structure of these proteins leads to cartilage with poor function and thus to the development of osteoarthritis.

 

Interleukin 1 (IL-1), a cytokine produced by mononuclear cells, synovial lining cells and chondrocytes, stimulates the chondrocyte to produce neutral metalloproteinases (collagenase, stromelysin and gelatinase) which degrade cartilage.[2] Other cytokines stimulate the chondrocyte to secrete tissue inhibitor of metalloproteinase (TIMP). Synthesis of cartilage components depends on growth factors such as insulin-like growth factor 1 (IGF-1) and transforming growth factor ß (TGFß).

Chondrocytes obtained from patients with osteoarthritis produce nitric oxide (NO), prostaglandins, tumor necrosis factor (TNF), IL-6 and IL. Since chondrocytes live in a milieu that is avascular and aneural, these mediators may not produce the classical signs of inflammation, but nevertheless they are involved in degradation of cartilate.[3]

With advancing age, the homeostatic mechanism that maintains the joint, fails. Cells are no longer able to maintain matrix and collagen production, and osteoarthritis develops. What initiates the shift in balance between degradation and repair of cartilage is not known. Trauma causing a microfracture or inflammation causing a slight increase in enzymatic activity may allow the formation of "wear" particles, which are then engulfed by resident macrophages. At some point in time, the production of these "wear" particles overwhelms the ability of the system to eliminate them and they become mediators of inflammation, stimulating the chondrocyte to release degradative enzymes. Molecules from breakdown of collagen and proteoglycan, also taken up by synovial macrophages, cause release of proinflammatory cytokines.[4] Both IL-1 and TNF increase prostaglandin synthesis by synovial cells, leading to further inflammation.

The effects of eicosanoid over-production, although initially thought to be on detrimental to cartilage metabolism, are now reported in experimental models to reveal a variety of both catabolic and anabolic activities depending on the end products produced (e.g. PGE1 or PGE2) and their interaction with different receptors and signaling pathways. The role of the lipoxygenase pathway in OA is still similarly unclear. Leukotriene B4 (LTB4) as well as leukotriene C4 production was found to be elevated in synovial fluid but not in chondrocytes in OA patients. LTB4 can also induce IL-1B production in synovial cells. The significance of these findings in terms of OA pathogenesis is still uncertain and merits further investigation.[5],[6]

Synovial inflammation (synovitis) is thought to be associated with structural damage and recent evidence links a number of biologic markers with high disease progression and structural damage[7] using molecular markers to monitor osteoarthritis. Elevated levels of cartilage oligomeric protein (COMP), a component of the extracellular matrix of articular cartilage formed by activated synovial cells, correlates possibly with active synovitis. Similarly, some evidence suggests that elevated levels of CRP (c-reactive protein) are predictive of long term radiological damage in knee OA[8] Levels of hyaluronic acid (HA) rise during inflammation.[9]

Expression factors for the proinflammatory gene nuclear factor kb (NF-kb) occur in osteoarthritic synovium, and nitric oxide (NO) is produced in synovial fluid from osteoarthritic joints. NO compromises chondrocyte survival,[10] affects IL-1 induced suppression of glycosaminoglycan and collagen synthesis, mediates IL-1 expression of matrix metalloproteinases and blocks production of IL-1 receptor antagonist (IL-1ra, a natural inhibitor of IL-1). Inhibitors of nitric oxide synthetase diminish arthritis in an animal model. Treatments that block NO or NO synthetase may treat osteoarthritis in the future.

Like other cells in the body "apoptosis" or programmed cell death plays a role in the disease process. Excess production of NO in OA tissues has be demonstrated to cause apoptosis of chondrocytes in vivo and invitro[11]. In addition, another mechanism contributing to chondrocyte apoptosis involves the expression of Fas antigen in a subpopulation of chondrocytes located in the superficial zone of cartilage. For apoptosis to occur these cells would have to come in contact with cells expressing Fas ligand (possibly inflammatory synovial cells).[12]

Osteoarthritis has several risk factors associated with its development, of which age is the greatest.[13]

A rare but exciting risk factor is a point mutation in the gene for type II procollagen in young patients with chondrodysplasia and precocious osteoarthritis, indicating that a genetic defect in assembly of matrix articular collagen is responsible for precocious osteoarthritis. A different point mutation occurs in patients with spondyloepiphyseal dysplasia who also develop premature osteoarthritis.

Epidemiological data suggest a genetic component to idiopathic osteoarthritis. Heberden's nodes (see Figure 8) are autosomally dominantly inherited in women and are associated with primary generalized osteoarthritis, a variant that involves multiple weight bearing joints in patients under the age of 50. In men Heberden's nodes are autosomally recessive. There may be an hormonal component to osteoarthritis, since estrogen replacement therapy confers a protective effect on its development in post-menopausal women.

Trauma is a risk factor for secondary osteoarthritis, especially periarticular injuries of the menisci, cruciate, and collateral ligaments of the knee, as well as fractures that involve the joint. Occupational injuries are less well established as risk factors, but studies report an increased incidence of osteoarthritis among jackhammer operators (wrists, hands and elbows), coal miners (knee), floor layers, construction workers, forestry workers and farmers, cotton pickers (fingers), and farmers (hips).[14],[15],[16] More recently, three more studies have related occupation to hip osteoarthritis.[17],[18],[19] Though a recent report noted an increased incidence of radiological but asymptomatic osteoarthritis in ex-female athletes and in a subgroup of control women engaged in long-term weight-bearing exercise, recreational sports are not associated with osteoarthritis in any age group.[20] Varus-valgus laxity, possibly related to defects in proprioception, may increase the risk of preventable knee osteoarthritis in women.[21]

The role of quadriceps strengthening exercises on already involved knees was further investigated by Sharma, L et al.[22] Adults with primary knee osteoarthritis were studied prospectively for eighteen months. Baseline quadriceps strength was measured and greater strength was associated with greater risk for progressive tibiofemoral joint space narrowing among adults with malaligned or very lax knees. Although these results do not imply that physical activity in adults with knee osteoarthritis is harmful it does call into question whether maximum quadriceps exercise in patients with malaligned and/or lax knees is protective or actually harmful.

Obesity is associated with preventable osteoarthritis of the knee in women.[23]

Lack of vitamin D predisposes patients with established osteoarthritis of the knee to further progression, and low levels of 25-OH Vitamin D are associated with radiographic progression of hip osteoarthritis.

III. Clinical Presentation

Most clinicians divide osteoarthritis into two basic forms. Primary or idiopathic osteoarthritis refers to the type that occurs without any underlying predisposing factor. Secondary osteoarthritis follows an identifiable predisposing factor, either local or systemic.

Fewer patients have symptomatic disease than is seen on x-ray.

More than 80% of persons over the age of 50 have some radiographic evidence of osteoarthritis. The joints most commonly involved are the distal and proximal interphalangeals of the hand, first carpometacarpal of the wrist, hip, knee and cervical and lumbar spine, in an asymmetrical fashion.

Pain is the most prominent feature and the most common presenting complaint of osteoarthritis. Pain appears upon motion of the affected joint and resolves with rest. Since cartilage has no nerve supply, the pain comes from subchondral bone, synovium, joint capsule, ligaments, and muscle. Passive and active motion of the joint elicits pain, and coarse crepitus on motion may be heard or palpated. Although the sources of pain are well known, the perception of pain depends on the relationship between structural change and peripheral and central pain processing, with input from cultural, gender, and psychological factors.[24] Since the major symptom of osteoarthritis is pain, consideration of all of these issues is important in the treatment plan.

In osteoarthritis, stiffness in the morning typically lasts less than 20 minutes. After being immobile, some patients report a transient stiffness, the so-called "gelling phenomenon," which also lasts no longer than 20 minutes. In contrast, in rheumatoid arthritis, gelling lasts for several hours. Osteoarthritis is not associated with the presence of fever, weight loss, anorexia, severe muscle atrophy, or symmetry of joint involvement.

As the disease progresses decreased range of motion occurs because of joint surface incongruity and because of increased pain with motion. Other reasons for decreased range of motion are muscle spasm and contracture, capsular contracture, and mechanical problems related to osteophytes or loose bodies in the joint. Accumulation of synovial fluid may contribute to pain, decreased range of motion, and distention of the capsule.

Advanced disease is associated with subluxation of the joint and gross deformity. In osteoarthritis, Heberden's nodes are bony enlargements of the distal interphalangeal joints with loss of joint space and osteophyte formation. Small gelatinous cysts (synovial herniations) may also be seen alongside the node. A similar bony enlargement of the proximal interphalangeal joints is called a Bouchard's node.

Heberden's and Bouchard's nodes begin after age 45 and affect women more than men by 10:1. Heredity plays an important role in their development in women. Most are asymptomatic but some at onset are inflamed and painful. Involvement of the first carpometacarpal joint (base of the thumb) limits a patient's ability to open jars or use the wrist. Symptoms in this joint are the only evidence of wrist involvement in osteoarthritis and clearly differentiate it from rheumatoid arthritis, in which the entire wrist is swollen. Often the joint will sublux and give the hand a "squared off" appearance.

The talonavicular and the first metatarsophalangeal joints are the most common joints involved in the feet. In the metatarsophalangeal joint, bunion formation causes pain and widening of the foot. In addition hallux rigidus (rigid great toe) can also occur, limiting motion and causing difficulty in walking. Very often the patient finds he must buy wider shoes to accommodate the deformity.

A rocker bar placed under the first metatarsophalangeal joint is often very effective in decreasing pain. Pain on inversion and eversion motions of the ankle is usually due to degenerative osteoarthritis of the subtalar or talonavicular joint and should be differentiated from the true ankle joint (tibiotalar, plantar and dorsiflexion of the foot) arthritis, which is more likely to be due to traumatic secondary osteoarthritis.

Hip osteoarthritis is more common in men, is usually unilateral, and causes a characteristic painful (antalgic) gait. Very often hip pain is referred to the knee. In hip disease, the following motions are impaired, in order of frequency: internal rotation in flexion, internal rotation in extension, flexion, external rotation in flexion, external rotation in extension, and extension.

Knee osteoarthritis is common. Unlike rheumatoid arthritis, osteoarthritis is of usually limited to a single (patellofemoral, medial, or lateral) compartment of the knee and is not symmetrical. The effusions are less inflammatory in osteoarthritis than in rheumatoid arthritis. Loss of lateral compartment joint space causes genu valgus or "knock knee". Loss of medial compartment space leads to genu varus or a "bow legs". In patellofemoral involvement the patient complains of anterior pain usually going up (more than down) stairs.

IV. Laboratory Findings and Imaging

The laboratory evaluation in osteoarthritis is important for the lack of positive findings associated with the disease. Routine tests such as blood count, urinalysis, sedimentation rate (ESR), biochemistries, and specialized tests such as rheumatoid factor, antinuclear antibody, and thyroid function tests are normal but useful to exclude other disease. However, the elderly have a high incidence of rheumatoid factor, antinuclear antibody, and elevated ESR without obvious illness. The history and clinical presentation are the most important elements of diagnosing a specific type of arthritis. The laboratory helps support, rule out, or subclassify a clinical diagnosis.

Synovial fluid analysis should be done on joints with large effusions. In osteoarthritis aspiration should demonstrate clear fluid with a cell count of less than 10,000 WBC/mm3 (higher than this suggests inflammatory arthritis or infection) with normal protein and glucose, good viscosity, and a negative polarized light microscopic examination for crystals. (When aspirating any joint, use aseptic technique, wear gloves, and send a specimen from every aspiration of joint fluid for culture and sensitivity regardless of the working diagnosis.)

Measurement of degradation components of cartilage of cartilage and matrix in serum, urine or joint fluid has attracted much recent interest, since finding evidence of early cartilage breakdown might lead to earlier diagnosis and intervention. One can measure constituents of the extracellular matrix, (proteoglycans [aggrecan], collagen, and non-collagenous proteins), degradative proteolytic enzymes, cytokines, and nitric oxide. Measurement of these products in joint fluid offers an advantage in that the concentration will be higher and demonstration of their presence more specific than in serum. However, assessment of biologic markers is still experimental.[25],[26]

X-ray evaluation is the "gold standard" in the diagnosis of osteoarthritis.

X-rays of the knee and hip should always be obtained weight bearing. For the knee, it is helpful to obtain a lateral and Merchant view to evaluate the patellofemoral joint. In addition one should do a standing semi-flexed view of the knee to approximate the normal anatomic standing position (Buckland-Wright)

Joint space narrowing is a non-specific finding that results from degeneration and disappearance of the articular cartilage for any cause. Increased bone density due to subchondral bony sclerosis and marginal osteophyte formation is more specific for osteoarthritis. Osteophytes are a late sign. Bone cysts are seen as periarticular translucent areas. Bone scans may be useful to rule out fracture due to metabolic, traumatic, or metastatic causes; mild increased activity at the involved joints is commonly seen in osteoarthritis. Bone scan coupled with radio-labeled bone-seeking diphosphonates may predict subsequent radiographic progression. Nuclear magnetic resonance imaging (MRI) is extremely helpful in the spine and has almost replaced computerized tomography (CT) scanning and myelography in defining disc disease, tumors, and spinal stenosis.

X-ray changes in osteoarthritis occur slowly and the possible value of MRI in the future would be in allowing investigators to demonstrate a change in the progression of the disease with medication in a shorter period of time. Methodologies are now being developed and validated to look at surrogate markers such as Global Cartilage Volume loss. Correlations with x-ray joint space narrowing in patients with osteoarthritis are being defined and related to fast and slow progressors. In preliminary data by Jean-Pierre Pelletier, it appears as if medial meniscal extrusion (but a not a simple tear of the medial meniscus) is associated with significant cartilage volume loss at 2 years.

MRI otherwise offers little benefit in the evaluation of primary osteoarthritis but may also be helpful in identifying avascular necrosis, pigmented villonodular synovitis, and internal derangement of the knee. In sports injuries MRI changes correlate with changes seen at arthroscopy.

V. Differential Diagnosis

The key to differentiating among the various rheumatic diseases is first to divide the diseases into inflammatory and non-inflammatory categories. Patients in the former category have swelling and systemic symptoms, such as morning stiffness and fatigue, and may have extraarticular features such as olecranon nodules. Next, determine whether the illness is symmetric or asymmetric, and whether its onset is gradual or acute. Lastly, define its course as progressive or episodic, with flares and remissions. Osteoarthritis is asymmetric, unassociated with extraarticular or systemic features, and has a gradual onset. Careful correlation of the clinical, laboratory and x-ray findings is important.

Rheumatoid Arthritis

Rheumatoid arthritis is the illness that many clinicians confuse with osteoarthritis. Rheumatoid factor is not diagnostic of rheumatoid arthritis. In contrast to the inflammatory conditions (polymyalgia rheumatica, rheumatoid arthritis, psoriatic arthritis, etc.), anemia is not a feature of osteoarthritis. In rheumatoid arthritis a symmetrical pattern of joint involvement is almost always seen, while osteoarthritis is usually a disease of asymmetry affecting the large joints and spine. Osteoarthritis affects the first carpometacarpal joint but rarely (unless secondary to trauma) the other joints of the wrists, while rheumatoid arthritis affects the wrists in a symmetrical fashion. In osteoarthritis the distal interphalangeal joints are involved in an asymmetric manner, whereas in rheumatoid arthritis these joints are spared and the metacarpophalangeal joints are symmetrically involved. Although in osteoarthritis any one hand joint may become inflamed and show and erosion (erosive osteoarthritis), in rheumatoid arthritis most joints become eroded in a more or less symmetric fashion. Occasionally rheumatoid and osteoarthritis coexist. (Any joint that is damaged by one form of arthritis may eventually develop secondary osteoarthritis.) The x-ray features are quite distinct, with rheumatoid arthritis having osteopenia and erosive disease in contradistinction to osteoarthritis in which osteophytes and subchondral sclerosis occur.

Lumbosacral Radicular Pain

In examining the hip, it is important to determine whether motion of the hip causes the patient's pain, particularly pain referred to the knee. To differentiate hip pain from lumbosacral radicular pain, note that hip pain does not radiate below the knee into the calf, but radicular pain does. If the source is lumbosacral-radicular, active motion of the hip in flexion does not reproduce the patient's pain. Because both sources of pain can exist simultaneously it is important to determine which is the predominant complaint. A careful neurologic exam combined with electromyography will be of some help. Although some physicians inject the hip with lidocaine to determine the origin of pain, I have found this technique to be of little help.

Trochanteric Bursitis

Another cause of pain about the hip is trochanteric bursitis. This patient complains of lateral hip pain, but has good (gentle) passive range of motion. In contrast to pain truly originating from the hip, tenderness is localized over the greater trochanter on the lateral aspect of the leg and not in the groin. In this case injecting the bursa with lidocaine and corticosteroid often gives excellent relief.

VI. Initial Treatment

Before starting therapy, the physician must do a complete evaluation, including a medication history, medical history, and physical exam. Many patients with osteoarthritis are elderly, have co-morbid medical conditions, and take medications that may interact with those prescribed for osteoarthritis. In addition, when the physician does a complete evaluation, other conditions (such as cancer or thyroid disease) that may cause joint pain can be identified and treated properly.

Treatment is aimed at control of pain by decreasing inflammation in the joint, adjuvant control with analgesics, and physical and occupational therapy modalities.[27]

Non-Pharmacological Treatment

All too often, patients who receive a diagnosis of arthritis envision themselves in a wheelchair. The physician's first duty after diagnosis is education. A straightforward discussion of prognosis is always helpful, and the patient should encourage the physician to provide it. Disease-specific pamphlets, are available from the local chapter of the Arthritis Foundation. A list of pamphlets can also be obtained from the headquarters of the Arthritis Foundation, located in Atlanta, by calling 1-800-283-7800.

Physical and occupational therapy includes exercise and physical modalities (hydrocollator, ultrasound, paraffin wax, ice packs, and splints and braces). On the first visit I ask a trained physical or occupational therapist to instruct the patient on the proper use of these modalities. Exercise, including supervised fitness walking, maintains range of motion and integrity of the supporting muscles. Quadriceps strengthening exercises reduces pain and improves function in patients with osteoarthritis of the knee.[28]

The patient lies on his back with the affected leg straight and the ankle dorsiflexed to 90°, then tightens the quadriceps by pushing the back of the knee against the bed and holding it for ten seconds. This maneuver is repeated ten times twice daily.

In addition the patient, lying flat on the back, raises the affected leg (knee straight) ten inches off the bed and holds that position for ten seconds, also repeating this maneuver ten times twice daily.

Swimming, where one kicks from the hips with the legs straight is another form of quadriceps strengthening. Exercise that causes more pain to the affected joint should be discontinued. Although weight loss has been proven to be beneficial in osteoarthritis of the knee only in women, a weight loss program is essential for overall general health in overweight patients.

Diet

There is no specific diet that is efficacious in the treatment of arthritis. Nevertheless, it is important to maintain good nutrition with high calcium intake, especially in women, along with a program that keeps weight down and cholesterol under 200mg/dl.

Acupuncture

Acupuncture is founded on naturalistic theories that are compatible with Confucianism and Taoism, and it use for relieving pain is increasing with more physicians being trained in its practice. There are some uncontrolled trials in osteoarthritis of the knee and low back pain demonstrating benefit. In addition, there is a multicenter trial under the auspices of the National Institutes of Health now in progress.[29]

Pharmacological Treatment

The American College of Rheumatology Guidelines for the Diagnosis and Treatment of Osteoarthritis of the Hip and Knee suggests that drug therapy should begin with simple analgesics such as acetaminophen.[30] These guidelines were derived from data which demonstrated that the first available non-steroidal anti-inflammatory drugs (NSAIDs), which are non-specific cyclooxygenase inhibitors, were costly in terms of side effects (gastric ulcerations, perforations and hemorrhages) and had no higher benefit than that afforded by acetaminophen. The discovery and release of cyclooxygenase-2 (COX-2) specific NSAIDs, with their superior safety profiles, allows clinicians to return to the use of anti-inflammatory medication as the first step in drug management of osteoarthritis.

Professor John Vane won the Nobel Prize for elucidating the mechanism of action of aspirin. It, and other NSAIDs, block the enzyme cyclooxygenase, which converts arachidonic acid to prostaglandin. Prostaglandins are short-lived substances that act as local hormones (autocoids), of which prostaglandin E2 is the principal one active in inflammation. NSAIDs represent the most widely prescribed class of drugs in the world and are second only to antihypertensives in being prescribed for long periods of time in any one patient. Side effects involving the gastrointestinal, renal and hematopoietic systems have limited their usefulness.

A second cyclooxygenase enzyme (COX-2) system has been described. Inhibition of COX-2 confers anti-inflammatory effects without inhibiting the (COX-1 generated) prostaglandins that are important for normal function of the stomach and platelets. Celecoxib (Celebrex) 200mg/day, and rofecoxib (Vioxx) 12.5-25mg/day (Vioxx was voluntarily withdrawn by Merck from the market as of 9/30/04-see next paragraph), represent the first generation of specific COX-2 inhibitors approved for the treatment of osteoarthritis, followed by Valdecoxib (Bextra), a second generation COX-2. Two large studies recently attempted to document superior gastrointestinal safety of the COX-2 agents, but fell short of proving the point without a doubt because of methodological problems.[31],[32] However, most physicians, based on these results, coupled with several prelaunch safety and efficacy studies with these agents, believe in their GI safety.

The incidence of stroke, myocardial infarction, edema, hypertension and gastrointestal events with or without concomitant use of aspirin have been under continuous review by the FDA since the launch of the COX-2 inhibitors. Merck, Inc., on 9/30/04, voluntarily withdrew Vioxx from the marketplace. Their decision was based on a recent double blind 3 year study (APPROVe trial) of 2600 patients who were treated with 25mg of Vioxx to prevent colonic polyps. In this cohort, after 18 months of taking the medication there were close to 50% more cardiovascular events(stroke and myocardial infarct) than in the placebo group. In actuallity there were 25 confirmed caridiovascular events in 3351 patient years of exposure on placebo(0.75events per 100 patient years) and 45 cardiovascular events in 3041 patients years of exposure on Vioxx(1.48 events per 100 patient years). This represents a relative risk of 1.98 with 95%CI (1.201-3.192) (p=0.0071). In a further subgroup analysis the relative risk was the same whether or not the patients took concomittant aspirin. Mortality was similar and low -- 5 death with Vioxx and 5 taking placebo. Although the number of patients involved was small compared to those treated (approx 70 out of 2600) and occurred after 18 months of treatment, the company still felt obligated to withdraw the drug from the market (a responsible act based on the data). Since the numbers are small, what impact this may for have on any individual patient taking Vioxx is unknown but probably small. Vioxx has a different chemical structure and metabolic breakdown products than the other COX-2 inhibitors on the market. These are valdecoxib (Bextra), celecoxib (Celebrex) and the COX-2 selective meloxicam (Mobic). As such, the increase in cardiovascular events should not be interpreted as a "class effect" of COX-2 inhibitors. Meloxicam, valdecoxib and celcoxib have not been demonstrated in any clinical trials to have an increased incidence of stroke or myocardial infarct. A recently published safety trial of lumiracoxib (Prexige), another COX-2 inhibitor in development, likewise failed to demonstrate any increase in stroke or myocardial infarct (Farkouh,M.E. et al Lancet 364675-683,2004).

Two recent publications from observational data bases in the Canadian health care system comprising over 1.5 million patients over the age of 65 demonstrated the improved GI safety of Vioxx and Celebrex over non selective NSAIDS.[33],[34] The real question of whether a cox-2 inhibitor plus low dose aspirin (in those who need to take aspirin for cardiovascular protection) is safer than traditional NSAIDs and low dose aspirin has only been approached but not fully answered. A meta-analysis of short trials of celecoxib by Deeks et al[35] demonstrated that the GI safety of celecoxib plus low dose aspirin was less than celecoxicib alone but much safer than traditional NSAID plus celecoxicib. A recent state of the art report by Fitzgerald et al address the relevance of this question and gives us some guidelines to follow. A COX-2 inhibitor in development (lumiracoxib) will present data from an >18,000 prospectively studied safety database that will hopefully shed more light on this important issue.

Meloxicam (Mobic) is a newer non-steroidal anti-inflammatory agent with a safety profile documented to be similar to that of the specific COX-2 inhibitors. Initial drug therapy of osteoarthritis with NSAIDs is now again possible. However, not all patients benefit from these drugs and some develop side effects, including nausea, diarrhea, and edema. COX-2 inhibitors do not affect platelet function and may, carefully, be used in anticoagulated patients. Like non-selective inhibitors, selective COX-2 inhibitors may cause water retention (edema). Whether they also affect renal function in normal patients is still unknown.

If COX-2 inhibitors are ineffective or have to be discontinued because of side effects then therapy can begin with simple analgesics. In addition, analgesics are excellent adjuvant therapy for patients on NSAIDs who have breakthrough pain. NSAIDs will generally work in three weeks and need not be continued if ineffective. A well-controlled trial of diclofenac plus misoprostol versus acetaminophen in patients with osteoarthritis of the hip or knee by Pincus et al[36] - plus an accompanying editorial by Felson[37] - appears to once again validate the superiority of NSAIDS over simple analgesics in the treatment of osteoarthritis.

We recommend monitoring patients on NSAIDs with baseline then three to four-monthly CBC, platelet count, biochemistries, (liver function and renal tests) and urinalysis.

Corticosteroids, either parental or oral, have no role in the treatment of osteoarthritis. However, injection with intra-articular steroids for a particularly painful joint is, at times, helpful. Use aseptic technique, aspirate the joint and send some fluid for culture and sensitivity; then inject either methylprednisolone acetate 40 mg/ml or triamcinolone hexacetonide 20 mg/ml into the joint. These preparations should be combined with 1 cc of lidocaine in large joints such as the knee, shoulder, and ankle. For the wrist one uses one-half this amount, and for small joints of the hand one should use a tuberculin syringe with a mixture of 0.1 cc lidocaine and 0.1 cc of methylprednisolone acetate 40mg/ml. Do not inject any one joint more than four times per year. Each injection should result in at least three months of relief. Pain relief lasting less than 2-3 months should be considered a failure and not repeated.

Viscosupplementation, a therapy proven useful in animals, has been developed to treat patients with long standing painful osteoarthritis who might not be appropriate for traditional therapy. In normal joints synovial fluid changes from viscous to elastic with increasing load, providing a frictionless surface. Hyaluronic acid, a high molecular weight component of synovial fluid, is composed of N-acetyl glucosamine and glucuronic acid. Enzymes and free radicals generated during inflammation in osteoarthritis degrade hyaluronic acid causing it to lose its viscous and elastic properties. The degraded hyaluronic acid itself contributes to articular damage. Viscosupplementation with hyaluronic acid may delay and possibly halt progression of osteoarthritis. Two preparations have been approved for treatment of knee osteoarthritis. One preparation (Hyalgan®), isolated from rooster combs, requires five weekly injections while the other (Synvisc®), a higher molecular weight product, made by cross-linking hyaluronic molecules with formaldehyde and vinylsulfone, requires three weekly injections. There have been few clinical trials of good design with both products; nevertheless, both have demonstrated efficacy compared to either placebo injection with saline or treatment with NSAIDs[38],[39] A growing body of data in animal models suggests that injection of hyaluronic acid increases the level of endogenous hyaluronic acid, decreases degradation of cartilage proteoglycans, inhibits the release of arachidonate and inhibits prostaglandin E2 synthesis. Tidal lavage of an osteoarthritic joint with saline has not stood the clinical test of time. A new synthetic form of viscosupplementation offering one injection, with efficacy lasting up to six months, is now in phase III testing.

Nutraceuticals

Since the publication of The Arthritis Cure and Maximizing the Arthritis Cure by Jason Theodosakis, MD, the use of nutritional supplements containing glucosamine and chondroitin sulfate has skyrocketed. Both publications claimed that these agents treat the symptoms of osteoarthritis and retard structural damage. Several European clinical trials suggested that these agents have effects in osteoarthritis similar to that of NSAIDs but have slower onset of action. Two recent meta-analyses concluded that, although the agents may show benefit, available studies provide insufficient information about study design and route of administration to allow definitive evaluation.[40] A recent publication reported on a three-year study in patients with osteoarthritis of the knee randomized to either glucosamine sulfate 1500 mg per day or placebo. After three years, the patients on glucosamine appeared not only to have clinical improvement, but there was also less progression seen in their radiographs. This represents the first well-controlled study on this subject. It did not, however, look at the addition of chondroitin sulfate, which has been touted to have synergistic properties when added to glucosamine.[41] The Office of Alternative Medicine of the National Institutes of Health has initiated a large placebo-controlled trial of glucosamine, chondroitin sulfate, and the combination of both. Pending completion of this trial, since these are nutritional supplements, they can be sold without approval by any governmental agency without safety standards. One only has to remember the epidemic of eosinophilic fasciitis that occurred with widespread use of L-tryptophan to understand the possible risk.

What should be the response of the physician faced with the question, Should I use glucosamine or chondroitin sulfate?" or "My aunt says this works for her?" I counsel my patients that I can and should inform them of therapies that have been scientifically proven and safe. In addition, I acknowledge their frustration and explain that we don't have all the answers. I recognize that in the treatment of arthritis anecdotes abound, but I feel strongly about recommending only products that I am convinced are safe and effective. Lastly, regardless of what the patient does, even if I don't condone it, I will still be available to treat him. I always stress that we look forward to scientific studies (such as the NIH one described above) that will answer the questions they have raised about an unproved remedy.

S-Adenosyl-L-Methionine (SAMe), advertised as effective for osteoarthritis, is a natural compound involved in sulfuration and methylation reactions. These reactions are important in both the generation of cytokines, which affect synovial cell function, as well as reactions involved in proteoglycan synthesis. Although some animal studies are encouraging in demonstrating improvement in cartilage histology, a few short-term clinical studies have not demonstrated any superiority over standard drug therapy. Although a "natural substance", SAMe is a regulator of homocysteine metabolism and possible effects on cardiovascular disease remains an unknown possibility.

Future: Experimental Therapies

Unlike rheumatoid arthritis, the development of agents that will not only decrease symptoms but also prevent further destruction (disease modifying anti-rheumatic drugs or DMARDs, also known as structural modifying antirheumatic drugs or SMARDS) for osteoarthritis has suffered from methodological problems - the least of which is the long time it takes for the disease to manifest itself. Nevertheless, several compounds are now being tested, e.g., risedronate (Actonel) in OA, The Guinea Pig Model. Use of Actonel in this model decreases chondrocyte loss and slows x-ray progression. This observation has been extended to clinical trials now in progress looking at the role of Actonel in preventing or stabilizing joint space narrowing in patients with moderate knee osteoarthritis.

The potential long-term treatment or cure of osteoarthritis lies in the development of agents that reverse the balance between degradative and synthetic processes of the chondrocyte. In animal studies doxycycline inhibits cartilage collagenase activity and reduces the severity of osteoarthritis. Transforming growth factor beta (TGFß), packaged in liposomes, can repair partial thickness articular cartilage lesions in animal models. Many pharmaceutical companies are testing pharmacological inhibitors of enzymes responsible for cartilage matrix destruction (metalloproteinases) and blockers of cytokines. Tetracyclines are inhibitors of tissue metalloproteinases (MMPs), possibly through their action on nitric oxide or via chelating the zinc present in the active site of MMPs. This function is separate from their antimicrobial activity. A national multi-center double blind randomized placebo-controlled trial looking at disease or structural modification in obese females with knee osteoarthritis is presently in progress.

Lay press reports of autologous chondrocyte transplantation for traumatic osteoarthritis has excited the public.[42] This procedure consists of removing cartilage cells from a non-weight-bearing portion of the knee via arthroscopy, growing the cells with growth factors in tissue culture, then transplanting them back into a defect under a periosteal patch. The investigators have had some success repairing weight-bearing cartilage defects of less than 3 cm. While this procedure may be applied to young individuals with traumatic injuries less than 3 cm., for whom the goal is to prevent secondary osteoarthritis, this procedure will not rejuvenate an end-stage osteoarthritic knee.

Gene therapy is another strategy in which non-replicating viral vectors can deliver genes that have either anti-arthritic or synthetic properties to the synovium and articular cartilage. Two human trials are presently underway in which a retrovirus transfers human IL-1ra cDNA to the synovial lining of metacarpophalangeal joints of patients with rheumatoid arthritis. In experimental osteoarthritis, IL-1ra transferred to the synovial lining of canine knee joints shortly after ACL transection reduced early cartilaginous lesions in the tibial plateau. However, the transfer by gene therapy of TGF-b and bone morphogenic protein 7 (BMP-7) to synovium and chrondroprogenitor cells resulted in death of some animals, possibly through overproduction of the proteins generated.

VII. Long-term Management Issues Including Surgery

When conservative measures of treating osteoarthritis fail, and when pain in a specific joint disables an active individual, then targeted surgical intervention may restore a patient to normal activity. The general physician will be expected to counsel his patient about the proper procedure and to the proper timing of these interventions. A few guidelines follow. Surgery relieves pain more than it restores range of motion. Thus, the decision to operate is one more of personal than of medical priorities. The best candidate for surgery is the patient who has a definite interruption in some activity of daily living (can't walk more than a block, awakens from sleep with pain in the affected joint) and who has failed exercise and pharmacological therapy. For this patient the result will be outstanding because he will be pain-free in the involved joint.

In hip and knee osteoarthritis for patients over the age of fifty total joint replacement is the therapy of choice. The decision between cemented or non-cemented prosthesis is a technical one revolving around the age of the patient, the condition of the joint, and the surgeon's experience. Since total joint replacements have an average 15-20 year life before they risk of failure, young patients may need two or more revisions. With each revision the bone stock is less and the procedure more difficult. For this reason many surgeons suggest that younger patients undergo an osteotomy of the hip and knee before total joint arthroplasty. In this procedure the joint is realigned to distribute weight more evenly to the remaining articular cartilage. Although the recovery period is considerably more than that of total joint arthroplasty, this procedure generally relieves pain for up to five years and delays the need for a total joint replacement.

For the ankle, total joint replacement is not yet well perfected, but arthrodesis is a good procedure that limits pain by eliminating motion in the affected joint without great loss of mobility.

In the hand, distal interphalangeal involvement should not be surgically treated. If persistent mucous cysts are bothersome they can be excised. For the carpometacarpal joint of the thumb, implants have failed, but reconstruction interposing a part of the flexor carpi radialis tendon has shown remarkable results in relief of pain without loss of stability.

Total joint replacements are never stronger than the original joint. Post surgery, competitive sports are not usually possible, but golf, walking, and even doubles tennis are permissible. The risk of infection in the hands of an experienced orthopaedist should be less than 1% if the patient remains careful and treats the joint like a new heart valve. The total joint replacement patient should use prophylactic antibiotics for invasive procedures such as dental work, cystoscopy, and colonoscopy.

Antibiotic Prophylaxis for Invasive Procedures

Amoxicillin 2 Grams (4/X 500mg Tabs) 1 Hour Prior to the Procedure

Patients Allergic to Penicillin:

Clindamycin(Cleocin, And Others) 600 Mg 1 Hour Prior to Procedure

Or

Cephalexin(Keflex) 2 Grams 1 Hour Before the Procedure

Or

Azithromycin(Zithromax) or Clarithromycin

(Biaxin) 500 Mg 1 Hour Prior to the Procedure

From: The Medical Letter, vol 41 (Issue 1060), August 27,1999

In my opinion, the physician should refer the patient to an orthopaedic surgeon who not only has specific training in joint arthroplasty, but who spends the majority of his time doing only these procedures. Specialists in joint arthroplasty should be associated with medical centers that have laminar flow operating rooms or similar infection control procedures.

VIII. Prognosis

The prognosis for patients with osteoarthritis is good, but definitely dependent on the joint involved and the occupation or physical needs of the patient. For example a patient with osteoarthritis of carpometacarpal joint of the thumb is not disabled unless he requires constant use of his hand. Disability due to advanced disease of the hip and knees in most cases easily responds to surgical therapy, but involvement of the spine that compresses nerves may cause neurologic damage that does not reverse after surgical relief. Patients with a large number of osteoarthritic joints tend to experience more rapid progression to knee osteoarthritis than do those with fewer joints involved, and those with bilateral knee osteoarthritis also have a fast rate of deterioration.

Although medication has not been proven to prevent progression of osteoarthritis, it controls pain and improves quality of life. New treatments are being tested to stop the progression of cartilage damage. Disability is uncommon, and outlook for those temporarily incapacitated is excellent with treatment.

IX. When to Refer to a Rheumatologist

The primary care physician, using the guidelines outlined, if quite careful when diagnosing osteoarthritis, need refer few patients. Referral to a rheumatologist will be helpful to:

A. Confirm a questionable diagnosis;

B. Sort out causes of secondary osteoarthritis and their potential treatments;

C. Initiate programs of proper physical therapy and joint protection;

D. Manage complex medication problems; and

E. Consult as to the type and place for surgery in the treatment plan. After evaluation, the rheumatologist ought refer the patient back to the primary care physician for management, with appropriate recommendations.

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