Treatment of osteoarthritis.

Objectives: Although cyclooxygenase-2 inhibitors (coxibs) were developed to cause less gastrointestinal hemorrhage than nonselective nonsterodial antiinflammatory drugs (NSAIDs), there has been concern about their cardiovascular safety. The relative risk of acute myocardial infarction (AMI) was studied among users of celecoxib, rofecoxib, and NSAIDs in Medicare beneficiaries with a comprehensive drug benefit.

Methods: A matched case-control study was conducted of 54,475 patients 65 years of age or older who received their medications through two state-sponsored pharmaceutical benefits programs in the United States. All healthcare use encounters were examined to identify hospitalizations for AMI. Each of the 10,895 cases of AMI were matched to four controls on the basis of age, gender, and the month of index date. A matched logistic regression model was constructed, including indicators for patient demographics, healthcare use, medication use, and cardiovascular risk factors to assess the relative risk of AMI in patients who used rofecoxib compared with persons taking no NSAID, taking celecoxib, or taking NSAIDs.

Results: Current use of rofecoxib was associated with an elevated relative risk of AMI compared with celecoxib (OR 1.14; 95% CI, 1.05-1.46; P = 0.011), and with no NSAID (OR, 1.14; 95% CI, 1.00-1.31; P = 0.054). The adjusted relative risk of AMI was also elevated in dose-specific comparasions; rofecoxib [less than or equal to]25 mg versus celecoxib [less than or equal to]200 mg (OR 1.21; 95% CI, 1.01-1.44; P = 0.036) and rofecoxib >25 mg versus celecoxib >200 mg (OR 1.70; 95% CI, 1.07-2.71; P = 0.026). The adjusted relative risks of AMI associated with rofecoxib use of 1 to 30 days (OR, 1.40; 95% CI, 1.12-1.75; P = 0.005) and 31 to 90 days (OR, 1.38; 95% CI, 1.11-1.72; P = 0.003) were higher than >90 days (OR, 0.96; 95% CI, 0.72-1.25; P = 0.8) compared with celecoxib use of similar duration. Celecoxib was not associated with an increased relative risk of AMI in these comparisions.

Conclusions: In this study, current rofecoxib use was associated with an elevated relative risk of AMI compared with celecoxib use and no NSAID use. Dosages of rofecoxib greater than 25 mg were associated with a higher risk than dosages of 25 mg or less. The risk was elevated in the first 90 days of use, but not thereafter.

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Osteoarthritis (OA), or degenerative joint disease, is a common health problem in the population over the age of 40. OA effects more than 20 million individuals in the United States alone. It is the leading cause of pain and disability in the United States.

A resurgence of interest in this disease has been driven by both the magnitude and its social impact as well as recent advances in our understanding in the mechanisms leading to articular cartilage degeneration.

Treatment of OA includes nonpharmacologic modalities (patient education, physical and occupational therapy), pharmacologic agents, and surgical procedures.

Goals of OA management include control of pain, improvement in function and health-related quality of life, and avoidance, if possible, of toxic effects from therapy.

In this article, we will discuss many of the various treatment modalities used to manage osteoarthritis.

Nonpharmacologic Methods

Physical therapy

Physical therapy holds a prominent position in the treatment of osteoarthritis and involves modalities such as applications of heat or cold and an appropriate exercise program. Exercise should focus on muscle weakness, loss of joint motion, and pain in and around the involved joint. In devising a treatment plan, the practitioner should try to meet the following goals: reduction of impairment, improvement of strength, normalization of gait, and increased performance of daily activities; protection of the joint from further damage by reducing stress; prevention of disability and poor health secondary to inactivity by increasing the daily level of physical activity and improving physical fitness.

Aerobic exercise is the form of exercise therapy that increases aerobic capacity and muscle strength and will also help with weight loss. Typical exercises in this class include walking, biking, swimming, aerobic dance, and especially aerobic pool exercises. Swimming and pool exercises cause less joint stress than the other forms of aerobic exercise. If walking or jogging worsens symptoms, the patient should reduce the intensity of the activity or change to another form of aerobic exercise.

Stretching or range of motion exercises can be helpful in OA and other rheumatic diseases. (1) Quadriceps-strengthening exercises can reduce joint pain and increase function in patients with knee osteoarthritis. For strengthening, isometric exercises are recommended initially because they are less likely to aggravate symptoms. (2)

In the Fitness and Seniors Trial (FAST), (3) patients with mild disability caused by knee osteoarthritis were randomly assigned to an aerobic exercise group, a muscle-strengthening exercise group, and an education or attention control group. Compared with the control subjects, both exercise groups had modest but significant improvement, which was sustained over an 18-month period. The level of adherence to the exercise regimen was directly associated with the degree of improvement in pain and function.

Occupational therapy

Proper use of a cane (in the hand contralateral to the affected knee) reduces loading forces on the joint and is associated with a decrease in pain and improvement of function. In addition, patients may benefit from wedged insoles to correct abnormal biomechanics caused by varus deformity of the knee. Lateral heel and sole wedge insoles, with an angle of 5 to 10 degrees on a frontal section, have been shown to be helpful for treatment of medial compartment knee osteoarthritis. Patients with knee osteoarthritis treated with the wedged insole and 50 mg/d indomethacin showed significantly greater improvement than those treated only with indomethacin. The insole was much more effective for patients with mild osteoarthritis than for those with advanced disease.

Knee braces

Two main types of braces are available: sleeves and unloading knee braces that attempt to decrease loads through the tibiofemoral compartment. Although no controlled trials have been published on the use of a simple sleeve for patients with osteoarthritis of the knee, positive outcomes have been described. Since these sleeves provide little mechanical support to the knee, it is believed that the perception of improved stability and reduced pain is largely the result of enhanced joint position sense or proprioception.

Diet

The Framingham Study demonstrated that being overweight as a young adult strongly predicted the appearance of knee osteoarthritis in later years. (4) Another study has demonstrated that weight loss of only 5 kg in women of medium height is associated with 50% reduction in the risk for symptomatic knee osteoarthritis. (5) Therefore, it is appropriate to instruct the obese patient in a weight reduction diet.

Unfortunately, the degree of inactivity imposed by osteoarthritis, as well as a characteristically low caloric requirement, make weight loss a difficult challenge.

Self-management and Education Programs

The evaluation of the impact of OA on daily function should include questions about the patient's ability to arise from a sofa or toilet seat as well as whether difficulties performing sexual activities are encountered.

The Arthritis Foundation's pamphlet, Living and Loving With Arthritis, is a useful guide for dealing with a variety of sexual problems. (6) Recent meta-analyses suggested that such arthritis self-management education programs lead to small but significant reductions in pain and disability. (7)

Pharmacologic Management

Drug therapy for osteoarthritis is aimed primarily at palliation of symptoms, because there is little evidence that we can currently alter the structural damage of the joint. (8)

Nonsteroidal anti-inflammatory drugs (NSAIDs) are effective in providing symptomatic relief for most patients with osteoarthritis. These agents have both analgesic and anti-inflammatory properties. Their toxicities, in particular the gastrointestinal (GI) and renal, have been their greatest liability. Among people 65 years of age and older, as many as 30% of all hospitalizations and deaths related to peptic ulcer disease can be attributed to NSAID use. (9)

Histamine [H.sub.2]-receptor antagonists have been shown to reduce the incidence of endoscopically diagnosed NSAID-induced duodenal ulcers, (10) whereas proton pump inhibitors and misoprostol, a prostaglandin [E.sub.1] analogue, (11) reduce the incidence of NSAID-induced ulcers of the stomach and duodenum.

Risk factors for upper GI bleeding in patients treated with traditional NSAIDs include age greater than 65 years, a history of peptic ulcer disease or of upper GI bleeding, concomitant use of oral glucocorticoids or anticoagulants, presence of comorbid conditions, and smoking and alcohol. The practitioner should make every effort to identify those patients with more than one of these factors, and consider whether alternative medications would be more appropriate.

Risk factors for reversible renal failure in patients with intrinsic renal disease who are treated with NSAIDs include age greater than 65 years, hypertension and/or congestive heart failure, and concomitant use of diuretics and ACE inhibitors.

COX-2 inhibitors (specific inhibitors of cyclooxygenase-2) are the new generation of NSAIDs that were introduced with the promise of less risk for upper GI complications. Endoscopic studies have shown that celecoxib and rofecoxib are both associated with an incidence of gastroduodenal ulcers lower than that of the traditional NSAIDs and similar to that of placebo. (12) However, the results of large, long-term studies that were designed to demonstrate differences between COX-2--specific inhibitors and nonselective NSAIDs with respect to major GI clinical outcomes have not yet been published.

A further advantage that COX-2--specific inhibitors have over their older counterparts is that they do not have a clinically significant effect on platelet aggregation or bleeding time. This may have particular importance in perioperative treatment of patients with OA, in whom nonselective NSAIDs have traditionally been discontinued as long as 2 weeks before surgery. COX-2 inhibitors should be used with caution, as recent data show an increased rate of cardiovascular events with their use. (28)

For many patients, a simple analgesic may be as effective as an NSAID. (13) Currently, because of its safety record and low cost, acetaminophen remains the oral analgesic of choice for initial treatment of mild to moderate pain in patients with symptomatic osteoarthritis. This recommendation is consistent with the 2000 American College of Rheumatology guidelines for treatment of patients with osteoarthritis of the knee and osteoarthritis of the hip. (8)

Long-term opioid therapy has its place in the management of chronic OA joint pain. However, in the elderly, opioid side effects, such as constipation, urinary retention, mental confusion, and drowsiness, may be especially problematic. Tramadol (hydrochloride) is a centrally acting analgesic with relieving effects comparable to codeine. A preliminary report suggests that the efficacy of tramadol was comparable to that of ibuprofen in patients with hip or knee osteoarthritis. Tramadol may also help lessen the need of other, more potentially toxic medications. In patients with knee osteoarthritis pain who responded to 1000 mg/d naproxen, addition of tramadol permitted a reduction in the dose of NSAID without compromising pain relief. (14) This drug was reported to be a useful adjunct in patients with osteoarthritis at a variety of joint sites whose symptoms were inadequately controlled with NSAIDs but should not be used on subjects who are at risk for seizures. (15)

Persons with osteoarthritis who are taking an NSAID but have not incorporated nonpharmacologic measures into their treatment program need to be educated in this combined approach. By including nonpharmacologic measures, it may then be possible to reduce the dose of NSAID or to replace the NSAID with acetaminophen and/or tramadol.

There are many over-the-counter topical preparations used in the treatment of osteoarthritis. Evidence of effectiveness of many of these compounds is lacking, however, and their biggest risk may be to the patient's pocketbook.

Controlled clinical trials have shown that topical creams containing capsaicin can relieve joint pain in patients with osteoarthritis of the hand or knee (16); during this study, patients were permitted to continue their usual treatment with NSAIDs or analgesics.

Systemic corticosteroid treatment is not indicated for osteoarthritis, but intra-articular corticosteroid injection may result in substantial, although often temporary, relief of pain. (17) Despite extensive clinical experience, certain aspects of local corticosteroid treatment remain controversial, such as its questionable deleterious effects and potential chondroprotective properties. Traditionally, recommendations limited steroid injections to intervals of no less than 3 months (18); however, a recent placebo-controlled, randomized trial found no acceleration of disease progression with injections performed every 2 to 3 months for 2 years continuously. (19) The risk of introducing infection into an OA joint is exceedingly low if standard aseptic technique is used.

Intra-articular injection of hyaluronate (HA) has been approved for use as symptomatic therapy in patients with knee osteoarthritis. (20-22) Results have indicated that the efficacy may be comparable to that of NSAIDs without the risk of gastropathy associated with the latter. However, the dropout rate among those who received intra-articular HA injections in clinical trials has exceeded 30%. The onset of pain relief appears to be less rapid than that achieved with an intra-articular injection of glucocorticoid, but the duration of pain relief may be much longer than that after a steroid injection.

The benefit of this treatment lasts 6 months or more in some patients, even though the half-life of the available agents within the joint is only a few days. The mechanism of action is wholly unclear, but there is early evidence that chondrocyte health may be improved by these injections. Intra-articular HA injections have been approved for use in patients with knee osteoarthritis who have failed a program of nonpharmacologic therapy and acetaminophen. They may be of particular advantage in patients in whom NSAID use is contraindicated or in whom NSAIDs have been ineffective or associated with side effects. Limited data are available concerning the effectiveness of multiple courses of intra-articular HA therapy.

Many patients ask about such nontraditional supplements as glucosamine and chondroitin sulfate. Several placebo-controlled clinical trials have reported efficacy of glucosamine in patients with symptomatic knee osteoarthritis, with minimal side effects. (23)

Glucosamine has appeared to be as effective as low-dose ibuprofen in this setting. Oral chondroitin sulfate has been studied less extensively, but the results have been similar. No studies have compared the effects of the combination with those of either agent alone or with placebo. Glucosamine and chondroitin sulfate have not been approved by the US Food and Drug Administration but are purchased in large quantities from health food stores in this country. There are conflicting studies in the literature as to whether these agents may slow or prevent tissue damage in the osteoarthritic joint or diminish pain.

There are many other nontraditional approaches being evaluated at this time; for example, researchers have recently reported that the use of leeches may provide symptomatic relief of OA pain. (24,25)

Orthopedic Surgery

Surgical procedures are generally reserved for patients with severe osteoarthritis who have persistent pain and significantly impaired function. Osteotomy to correct malalignment may be of greatest benefit when the disease is only moderately advanced. By altering stresses of load bearing and bringing more normal cartilage surfaces into opposition, osteotomy of the knee may provide effective relief of pain.

Debridement of the joint, with removal of cartilage fragments, may prevent joint locking, eliminate pain, and prevent rapid wear of joint surfaces. Surgical removal of large osteophytes may increase range of motion in some cases.

In advanced osteoarthritis, partial or total arthroplasty or arthrodesis (joint fusion) can be expected to relieve pain. In weight-bearing joints, such as the hip and knee, arthrodesis is generally avoided.

Arthroscopic techniques permit debridement of osteoarthritic joints with removal of loose bodies, degenerated tissue fragments of damaged menisci, and articular cartilage flaps. Controlled studies showing that this favorably affects pain and function in patients with osteoarthritis, however, are lacking.

In uncontrolled studies, patients with symptoms related to an internal derangement appear to benefit most from arthroscopy. Those with moderate osteoarthritis without internal derangement benefit less frequently. People with significant joint instability but without an internal derangement appear to benefit least.

Abrasion of exposed subchondral bone to induce bleeding, with formation of a fibrin clot and subsequent articular cartilage repair, is used in treatment of knee osteoarthritis. No randomized, controlled trials of arthroscopic abrasion arthroplasty have been reported. In many patients with severe osteoarthritis, the joint space increased after abrasion arthroplasty, but this appears to result from fibrocartilage rather than articular cartilage. None of the patients became asymptomatic after treatment, and the procedure was considered to be only palliative.

Surgical techniques to graft cells that undergo chondroneogenesis and may lead to the resurfacing of articular cartilage defects appears promising. Perichondrial or periosteal grafts can lead to the resurfacing of large defects.

Brittberg et al (26) have reported that apparently normal articular cartilage developed after autologous chondrocyte implantation in articular cartilage defect. Although results of this procedure are promising, the technique has not been shown to be as effective in subjects with osteoarthritis as it is in young patients with traumatic cartilage injury.

Gene therapy may represent another potential approach to treatment of osteoarthritis. When the gene for the interleukin-1 receptor antagonist was transferred into the knee joints of a dog OA model, the severity of articular cartilage damage was reduced. (27)

More work is needed to determine whether this will prove to be a practical and effective treatment for osteoarthritis.

Summary

Osteoarthritis is the most common articular disease. With the aging of the population, there is growing need for better understanding of OA and for superior therapies. Presently, there are no proven structure/disease-modifying interventions and therefore current therapy is aimed at symptom relief and rehabilitation. Effective therapy should include the combination of both pharmacologic and nonpharmacologic modalities.

Being on the tightrope is living; everything else is waiting.
--Karl Wallenda

November 12, 2004.

References

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2. Minor MA, Hewett JE, Webel RR, et al. Exercise tolerance and disease related measures in patients with rheumatoid arthritis and osteoarthritis. J Rheumatol 1988;15:905-911.

3. Ettinger WH Jr, Burns R, Messier SP, et al. A randomized trial comparing aerobic exercise and resistance exercise with a health education program in older adults with knee osteoarthritis: the Fitness Arthritis and Seniors Trial (FAST). JAMA 1997;277:25-31.

4. Felson DT, Anderson JJ, Naimark A, et al. Obesity and knee osteoarthritis: the Framingham Study. Ann Intern Med 1988;109:18-24.

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8. American College of Rheumatology Subcommittee on Osteoarthritis Guidelines. Recommendations for the medical management of osteoarthritis of the hip and knee: 2000 update. Arthritis Rheum 2000;43:1905-1915.

9. Griffin MR, Ray WA, Schaffner W. Nonsteroidal anti-inflammatory drug use and death from peptic ulcer in elderly persons. Ann Intern Med 1988;109:359-363.

10. Langman MJ. Treating ulcers in patients receiving anti-arthritic drugs. Q J Med 1989;73:1089-1091.

11. Roth S, Agrawal N, Mahowald M, et al. Misoprostol heals gastroduodenal injury in patients with rheumatoid arthritis receiving aspirin. Arch Intern Med 1989;149:775-779.

12. Hawkey CJ. COX-2 inhibitors. Lancet 1999;353:307-314.

13. Bradley JD, Brandt KD, Katz BP, et al. Comparison of an antiinflammatory dose of ibuprofen, an analgesic dose of ibuprofen, and acetaminophen in the treatment of patients with osteoarthritis of the knee. N Engl J Med 1991;325:87-91.

14. Schnitzer TJ, Kamin M, Olson WH. Tramadol allows reduction of naproxen dose among patients with naproxen-responsive osteoarthritis pain: a randomized, double-blind, placebo-controlled study. Arthritis Rheum 1999;42:1370-1377.

15. Roth SH, Agrawal N, Mahowald M. Efficacy and safety of tramadol HCI in breakthrough musculoskeletal pain attributed to osteoarthritis. J Rheumatol 1998;25:1358-1363.

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18. Gray RG, Gottlieb NL. Intra-articular corticosteroids: an updated assessment. Clin Orthop 1983;177:235-263.

19. Raynauld JP, Buckland-Wright C, Ward R, et al. Safety and efficacy of long-term intraarticular steroid injections in osteoarthritis of the knee: a randomized, double-blind, placebo-controlled trial. Arthritis Rheum 2003;48:370-377.

20. Adams ME, Atkinson MH, Lussier AJ, et al. The role of viscosupplementation with hylan G-F 20 (Synvisc) in the treatment of osteoarthritis of the knee: a Canadian multicenter trial comparing hylan G-F 20 alone, hylan G-F 20 with non-steroidal anti-inflammatory drugs (NSAIDs) and NSAIDs alone. Osteoarthritis Cartilage 1995;3:213-225.

21. Altman RD, Moskowitz R. Intraarticular sodium hyaluronate (Hyalgan) in the treatment of patients with osteoarthritis of the knee: a randomized clinical trial: Hyalgan Study Group. J Rheumatol 1998;25:2203-2212.

22. Simon LS. Viscosupplementation therapy with intra-articular hyaluronic acid: fact or fantasy? Rheum Dis Clin North Am 1999;25:345-357.

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24. Michalsen A, Moebus S, Spahn G, et al. Leech therapy for symptomatic treatment of knee osteoarthritis: results and implications of a pilot study. Altern Ther Health Med 2002;8:84-88.

25. Michalsen A, Klotz S, Ludtke R, et al. Effectiveness of leech therapy in osteoarthritis of the knee: a randomized, controlled trial. Ann Intern Med 2003;139:724-730.

26. Brittberg M, Lindahl A. Nilsson A, et al. Treatment of deep cartilage defects in the knee with autologous chondrocyte transplantation. N Engl J Med 1994;331:889-895.

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RELATED ARTICLE: Key Points

* Osteoarthritis is the most common cause of chronic pain and disability in the US.

* Nonpharmacologic modalities are underutilized in the treatment of osteoarthritis.

* Weight loss is an important component in both the prevention of osteoarthritis and in the lessening symptoms.

* Pharmacologic therapy for osteoarthritis is directed at pain relief so that function can be maintained.

Elena V. Barnes, M.D., and N. Lawrence Edwards, M.D.

From the Division of Rheumatology, Department of Medicine, University of Florida.

Reprint requests to Dr. Elena Barnes, Division of Rheumatology, Department of Medicine, University of Florida, PO Box 100221, Gainesville, FL 32610. Email: [e-mail]