US Pharm. 2006;5:49-55.     

Osteoarthritis is a common rheumatologic disorder. It is characterized by a gradual loss of cartilage from the joints and, in some people, joint inflammation. Symptoms of osteoarthritis include pain, stiffness, and loss of joint motion. It is estimated that 40 million Americans of all ages are affected by osteoarthritis and that 70% to 90% of Americans older than 75 have at least one joint involved.1 In the United States, women are more often affected by osteoarthritis, and older women are twice as likely to be affected by osteoarthritis of the hands and knees than comparably aged men.2 As the population of elderly patients continues to grow, osteoarthritis becomes a significant medical and financial concern. With recent issues surrounding NSAIDs and cyclooxygenase-2 (COX-2) inhibitors, managing osteoarthritis is now more complex and individualized. This article briefly discusses the background, prevalence, and diagnosis of osteoarthritis, then focuses on the treatment options available for this disease.

PREVALENCE
The number of osteoarthritis cases rises in people of advancing age, possibly beginning as early as the third decade of life. The exact prevalence is unknown due to uncertainties and variations in diagnostic definitions and reports of this disease. In Western countries, radiographic change evident of osteoarthritis is present in the majority of people by 65 years of age and in about 80% of people older than 75.3 Notably, structural changes are not necessarily associated with clinical symptoms of pain and inflammation. Many patients with radiographic changes are asymptomatic, and those with symptoms of osteoarthritis may not have evidence of radiographic changes of the affected joint. Thus, an accurate diagnosis should consider the patient's history, physical exam, and radiographic findings.

PATHOPHYSIOLOGY
The pathophysiology of osteoarthritis involves mechanical, biochemical, and cellular processes. The common pathway is that all these processes change the composition and properties of articular cartilage. Synovial fluid, along with articular cartilage, permits almost frictionless movement of joint bones at their points of contact. Healthy cartilage allows internal remodeling as chondrocytes replace macromolecules lost in degradation. This process is disrupted in osteoarthritis and is characterized by a progressive deterioration of cartilage, resulting in the formation of osteophytes and loss of cartilage.

Early changes to the joints do not result in any symptoms, since there are no nerve fibers in articular cartilage. Potential sources of pain in osteoarthritis include denuded bone, microfractures of bone, stress to ligaments due to loss of cartilage, low-grade synovitis, and spasms of surrounding muscles as the disease progresses.

CAUSES AND CLINICAL FEATURES
The precise cause of osteoarthritis is unknown. Multiple factors, such as heredity, trauma, and obesity, interact to cause this disorder. Osteoarthritis is not a systemic disease, and joint distribution often occurs in the knees, hands, and hips; however, other joints can also be affected. Table 1 lists joints often affected by osteoarthritis. Osteoarthritis tends to develop slowly and progresses over several years. The pain is often described as aching and is felt in the areas surrounding the affected joint. Bony enlargements and irregularities are typical, especially in the hands at the distal interphalangeal joints (Heberden's nodes) and less commonly in the proximal interphalangeal joints (Bouchard's nodes). Although these bony enlargements are asymptomatic, many patients view them as part of a disabling arthritic disorder or even an outward sign of aging. The clinical presentation of osteoarthritis depends on the number of joints affected and the duration and severity of the disease.




Patients with osteoarthritis of the hip may complain of gait problems. After a period of inactivity, hip stiffness is common and is usually a presenting factor. Patients with osteoarthritis that affects the hands often have problems with manual dexterity. This is evident when the first carpometacarpal joint is involved. Instability or buckling of the knee is often noted in patients with knee osteoarthritis. Some patients with erosive osteoarthritis may have signs of inflammation in the interphalangeal joints of the hands. However, osteoarthritis generally does not carry an inflammatory component, except in severe, advanced disease.

Radiographic features and laboratory findings are not definitive in the diagnosis of osteoarthritis. Radiographic features of the disease show loss of joint space and presence of new bone formation or osteophytes. However, absence of these radiographic changes does not exclude a diagnosis of osteoarthritis. Analysis of synovial fluid tends to reveal a white blood cell count of less than 2,000 per millimeter.4

DIAGNOSIS
Diagnosis is often made through physical examination and a detailed history of symptoms. The American College of Rheumatology (ACR) has diagnostic criteria for osteoarthritis at various sites, including the hip, knee, and hand.5-7 The usual presenting symptom is pain involving one or a few joints, but joint involvement is usually asymmetric. Patients may complain of morning joint stiffness that resolves within 30 minutes, which distinguishes osteoarthritis from rheumatoid arthritis. As the disease progresses, joint stiffness can be prolonged, and crepitus--a grating sensation in the joint--can occur. Crepitus is caused by irregularities of the joint surfaces. Table 2 lists clinical features of osteoarthritis.




TREATMENTS
The goals of treatment for osteoarthritis are to control pain and swelling, minimize disability, improve the quality of life, and educate patients about their role in disease management. Treatment should be individualized to the patient's level of function and activity, expectations, occupational needs, joints involved, and disease severity, and to any coexisting medical problems.

Nonpharmacological Treatment
Nonpharmacologic treatment, e.g., patient education, exercise programs, weight loss, assistive devices, and alternative therapy supplements, appears to be the foundation for management of this disease. Educational materials for patients to better understand their diagnosis can be obtained from the Arthritis Foundation (www.arthritis.org). Table 3 provides examples of nonpharmacological therapy for osteoarthritis.



Patient Education: Education about the causes, effects, and symptoms of osteoarthritis, as well as a realistic understanding of what can be achieved with optimal therapy, is essential. Osteoarthritis has both physical and psychological effects. Its symptoms and limitations may cause feelings of frustration, dependency, and even depression. The more patients learn about the disease, the more they can participate in their own care. Social support can be achieved by building an informal support team or by participating in formal osteoarthritis groups.

 
Exercise Programs: The goals of an exercise program are to maintain range of motion, muscle strength, and general health. Patients with osteoarthritis are often concerned that using a joint will "wear out" the already damaged area. However, evidence shows that patients with osteoarthritic joints who participated in regular low-impact exercise (e.g., biking and elliptical machines) did not have an increased development of osteoarthritis.8 Patients should be encouraged to participate in aerobic exercises, such as swimming or walking. Exercise can help combat the depression that may accompany the chronic pain of osteoarthritis.9

Weight Loss: Although obesity appears to be a greater risk factor for women, an association exists between obesity and osteoarthritis of the knee in both genders.10 Weight loss has been shown to benefit patients with osteoarthritis.11 Symptoms associated with arthritis in the hips, knees, and feet are exacerbated by obesity. Thus, primary prevention strategies should include measures to achieve weight loss or avoid weight gain in overweight patients.

Assistive Devices: A variety of appliances can help relieve osteoarthritis symptoms by supporting the muscles linked to the affected joint. Examples of assistive devices include crutches, walking aids, shoes inserts, splints, braces, and special soles.11 Using special appliances may help patients feel more comfortable, move around independently, and have improved function.

Physical and occupational therapy may benefit patients with specific physical disabilities brought on by osteoarthritis. Incorporating individualized exercise programs and teaching patients how to manage activities of daily living may lead patients to feel more independent and less affected by their disease.

Alternative Therapy Supplements: Patients often seek alternative therapies for osteoarthritis after experiencing side effects or incomplete relief of symptoms from conventional medications. Since the herbal and supplement industry is not regulated by the FDA, supplement composition can vary.

Glucosamine sulfate, a popular treatment for osteoarthritis symptoms, is derived from oyster and crab shells. No published studies have documented arthroscopic improvement in arthritic cartilage with glucosamine use in humans. A meta-analysis concluded that glucosamine may show efficacy over placebo in relieving painful symptoms. 12 Glucosamine is usually dosed at 1,500 mg per day in three divided doses. Supplements should be taken for at least a month before improvement occurs.

Chondroition sulfate has demonstrated efficacy by acting as a building block of proteoglycan molecules to improve the symptoms of osteoarthritis.13 Chondroitin is derived mostly from shark and cow cartilage. Chondroitin is usually dosed at 1,200 mg per day in three divided doses, and results may not be achieved for at least a month.

Little evidence exists showing that the combination of glucosamine and chondroitin is more effective than either supplement alone.14 However, the use of the two together is popular for the treatment of osteoarthritis. The Glucosamine/Chondroitin Arthritis Intervention Trial (GAIT) was a six-month, five-arm trial involving 1,500 osteoarthritis patients with mild to severe pain. Patients were given glucosamine, chondroitin, glucosamine and chondroitin combined, celecoxib, or placebo daily. The GAIT abstract posted on the ACR Web site concludes that glucosamine and chondroitin together are beneficial in treating moderate to severe knee pain due to osteoarthritis. Results have yet to be presented.

S-adenosylmethionine (SAMe) is a naturally occurring compound found in all living cells that is commercially produced in yeast-cell cultures. Several studies have found SAMe to be more effective than placebo in improving pain and stiffness related to osteoarthritis.15,16 Dosages range from 400 to 1,200 mg per day.

Pharmacological Treatment
At present, there are no specific pharmacologic therapies that can prevent the progression of joint damage due to osteoarthritis. Because no medication has been shown to cure this disease, patients should clearly understand the risks and benefits of their treatment options. Pain relief is the primary indication for the use of pharmacologic agents in patients with osteoarthritis who do not respond to nonpharmacologic interventions. When quality of life becomes affected, it would be appropriate to initiate pharmacotherapy to minimize disability and control pain. This article focuses on analgesics, NSAIDs, COX-2 inhibitors, and intra-articular glucocorticoids and hyaluronate. Table 4 provides a list of agents used to treat osteoarthritis.


Analgesics, NSAIDs, and COX-2 Inhibitors: The nonprescription analgesic acetaminophen, at doses of 1,000 mg four times a day or 650 mg every four hours (up to a maximum of 4 g/day), is the drug of choice for pain relief for noninflammatory osteoarthritis. The ACR guidelines emphasize the use of acetaminophen as first-line treatment for osteoarthritis of the knee and hip.17 This analgesic can significantly improve function and decrease pain. Therapeutic doses of acetaminophen produce minimum adverse effects, but hepatotoxicity can occur, especially in patients who consume large quantities of alcohol.

NSAIDs are appropriate choices for treating moderate or severe arthritis pain, as well as the swelling, stiffness, and warmth of inflammation when present. NSAIDs carry a risk of gastrointestinal (GI) toxicity, even at a low dose. GI complications occur over the course of one year in about 2% to 4% of patients, and incidence increases with age.9 Reduced prostaglandins in the gastric mucosa from COX inhibition attributes to the GI side effects of NSAIDs. Proton pump inhibitors may help control the GI symptoms associated with chronic NSAID use. Misoprostol, a synthetic prostaglandin E1, can help prevent gastric ulcers in patients on long-term NSAID therapy. Several risk factors appear to increase the risk of NSAID-induced toxicity, especially in patients over age 65; patients with previous ulcer or upper GI bleeding; and patients taking concomitant oral cortico­ steroids, anticoagulants, or multiple NSAID therapy. 18 The ACR guidelines recommend starting NSAIDs at low analgesic doses and increasing to full anti-inflammatory doses only if the lower dose did not provide adequate relief.17 The concurrent use of acetaminophen with NSAIDs may allow the NSAID dosage to be reduced, thereby limiting toxicities.

COX-2 inhibitors may be appropriate to initiate for patients with moderate to severe pain when non­ selective COX inhibitors have proven ineffective or for those patients who have a history of GI disease. COX-2 inhibitors have at least a 200- to 300-fold selectivity for inhibition of COX-2 over COX-1. Celecoxib is recommended in doses of 200 mg per day for the treatment of osteoarthritis pain. COX-2 inhibitors are associated with lower gastroduodenal toxicity, but an increased risk of cardiovascular events has led to the withdrawal of two previous agents (rofecoxib and valdecoxib) from the market. Although elderly patients may choose to use celecoxib because of less GI effects, they need to be made aware of the risks and benefits by their physician before beginning treatment.

Treatment options for osteoarthritis have been further complicated by the potential cardiovascular risk associated with the use of naproxen and other NSAIDs. All NSAIDS, both over-the-counter and prescription, and COX-2 inhibitors carry a warning regarding cardiovascular and GI risks.19

Tramadol is usually given as a rescue medication for symptomatic relief and can be considered an option if NSAIDs fail. Use of this central-acting oral analgesic allows for a lower dose of NSAIDs to be used. The recommended dose is 50 mg given every four to six hours, with a total daily dose not exceeding 400 mg.9 Opioids can be considered for patients with severe osteoarthritic pain that does not respond to nonopioid analgesic agents. These agents are not recommended for prolonged time periods because they cause constipation and increase the fall risk, especially in the elderly.

Topical capsaicin, a pepper-plant derivative, has been shown to relieve pain relating to osteoarthritis better than placebo. Capsaicin cream 0.025% applied four times a day was effective in managing pain caused by osteoarthritis of the knee, ankle, wrist, and shoulder in a double-blind, randomized, controlled trial. 20 One common side effect is a localized burning sensation, and patients should be advised to wash hands after application to avoid spreading to the eyes or other mucous membranes. Capsaicin is available over the counter in concentrations of 0.025%, 0.075%, and 0.25%.

Intra-Articular Glucocorticoids and Hyaluronate: Patients who suffer from painful flares of osteoarthritis in the knee may benefit from intra-articular injections of corticosteroids, such as methylprednisolone or triamcinolone. Short-term pain relief can be obtained with aspiration of the joint fluid, followed by intra-articular injection of the corticosteroid when the joint is painful and swollen. Injections should not be made in the joints more than three or four times a year, to prevent potential cartilage damage from repeated injections. Patients may have to consider surgical intervention if they require more than three to four shots per year to control symptoms.

Hyaluronic acid provides viscoelastic and lubricating properties to the joint. It is a major nonstructural component of the synovial and cartilage matrix makeup. The molecular weight and concentration of hyaluronic acid is thought to be decreased in patients with osteoarthritis. The FDA has approved hylan G-F 20 and sodium hyaluronate injections for the treatment of pain caused by osteoarthritis of the knee. The 2-mL dose is injected once weekly for three and five weeks, respectively. The injections are well tolerated; however, local skin reactions and pain with injection have been shown.

Intra-articular injections must be administered using the aseptic technique, and the aspirated joint fluid should be examined to rule out infections. Patients should minimize activity and stress on the joint for several days following an intra-articular injection.

Surgery
Osteoarthritis often progresses to a degree where no cartilage remains and bone is rubbing on bone. These patients who have symptoms that are not controlled with pharmacologic or nonpharmacologic therapy and who have moderate to severe pain and functional impairment may be candidates for orthopedic surgery. Depending on the joint involved, some replacement procedures have become almost routine. Patients should understand all the risks and benefits of orthopedic surgery before making a decision.

Conclusion
Osteoarthritis is a common, slowly progressive disorder that affects the body's joints. Treatment of osteoarthritis should focus on the minimization of pain and loss of function. An individualized approach is best for all aspects of the disease, and the goals of the patient should be considered before selecting a treatment plan. Nonpharmacologic therapy is the foundation of care for this disease, and new therapies may become available to prevent further joint progression in the future. It is important for providers to address with compassion and understanding both the physical and emotional concerns these patients may have.

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