Osteoarthritis Treatment
- Pharmacological Therapies
- Intraarticular Therapies
- Non-pharmacological Management
- Surgical Management
- Functional Assessment
- Future Directions
- References
- Discussion of Specific COX-2 Inhibitors
Current treatment for OA is relatively limited. Because there are currently no pharmacological agents capable of retarding or preventing disease, treatment is predominantly focused on relief of pain, and maintenance of quality of life and functional independence.
Non-steroidal Anti-inflammatory Agents
Several studies have shown acetaminophen to be superior to placebo and equivalent to nonsteroidal anti-inflammatory agents (NSAIDs) for the short-term management of OA pain. At present, acetaminophen (up to 4,000 mg/daily) is the recommended initial analgesic of choice for symptomatic OA. ( ACR Guidelines-Guidelines for Medical Management of OA of the knee) However, many patients eventually require NSAIDs or more potent analgesics to control pain.
COX-2 Inhibitors
Cyclooxygenase-2 (COX-2) inhibitors are a class of nonsteriodal anti-inflammatory agents (NSAIDs) that recently received Food and Drug Administration (FDA) approval. These specific COX-2 inhibitors appear to be as effective as current non-selective NSAIDs in treating the pain and inflammation of arthritis. Their theoretical advantage, however, is that they will cause significantly less toxicity than conventional NSAIDs, particularly in the GI tract. This theoretical enhanced safety profile will be a significant advantage in the management of all patients but especially those at high risk for peptic ulcers. Nonsteroidal anti-inflammatory drugs (NSAIDs) exert their anti-inflammatory effect primarily by inhibiting an enzyme called cyclooxygenase (COX), also known as prostaglandin (PG) synthase. COX catalyzes the conversion of the substrate molecule, arachidonic acid, to prostanoids.
Prostanoids consist of prostaglandins E, D and F2a, prostacyclin and thromboxane. The major inflammatory vasoactive prostanoids are PGE2 and prostacyclin. Thromboxane is critical for platelet clotting, while PGD2 is involved in allergic reactions and PGF2a in uterine contraction.
Non-steroidal Anti-inflammatory Agents
The mechanism by which NSAIDs exert their anti-inflammatory and analgesic effects is via inhibition of the prostaglandin-generating enzyme, cyclooxygenase (COX) (see image above). In addition to their inflammatory potential, prostaglandins also contribute to important homeostatic functions, such as maintenance of the gastric lining, renal blood flow, and platelet aggregation. Reduction of prostaglandin levels in these organs can result in the well-recognized side effects of traditional non-selective NSAIDs - that is, gastric ulceration, renal insufficiency, and prolonged bleeding time. The elderly are at higher risk for these side effects. For example, adults over the age of 60 who are taking NSAIDs have a 4-5 fold higher risk of gastrointestinal bleeding or ulceration then their age-matched counterparts. Other risk factors for NSAID-induced GI bleed include prior peptic ulcer disease and concomitant steroid use. Potential renal toxicities of NSAIDs include azotemia, proteinura, and renal failure requiring hospitalization. Hematologic and cognitive abnormalities have also been reported with several NSAIDs. Therefore, in elderly patients, and those with a documented history of NSAID-induced ulcers, traditional non-selective NSAIDs should be used with caution, usually in lower dose and in conjunction with a proton pump inhibitor. Renal function should be monitored in the elderly. In addition, prophylactic treatment to reduce risk of gastrointestinal ulceration, perforation and bleeding is recommended in patients > 60 years of age with: prior history of peptic ulcer disease; anticipated duration of therapy of > 3 months; moderate to high dose of NSAIDs; and, concurrent corticosteroids. Misoprostol, at a dose of 200 mg four times daily, constitutes effective anti-ulcer prophylaxis but is often poorly tolerated due to diarrhea. Omeprazole, and other proton pump inhibitors, are also very effective anti-ulcer prophylactic agents, although cost can be limiting. The development of selective cyclooxygenase-2 (COX-2) inhibitors (see full discussion on COX-2 inhibitors) offers a strategy for the management of pain and inflammation that is likely to be less toxic to the GI tract.
Analgesic Agents
Local analgesic therapies include topical capsaicin and methyl salicylate creams. Occasionally in late stage disease, patients will require narcotic analgesics to control pain. Oral glucosamine and chondroitin sulfate have been shown (each individually) to have a mild to moderate analgesic effect in several double-blind, placebo-controlled studies.
(top of section)
(top of page)
Judicious use of intra-articular glucocorticoid injections is appropriate for OA patients who cannot tolerate, or whose pain is not well controlled by, oral analgesic and anti-inflammatory agents. Periarticular injections may effectively treat bursitis or tendonitis that can accompany OA. The need for four or more intra-articular injections suggests the need for orthopedic intervention.
Intraarticular injection of hyaluronate preparations has been demonstrated in several small clinical trials to reduce pain in OA of the knee. These injections are given in a series of 3 or 5 weekly injections (depending on the specific preparation) and may reduce pain for up to 6 months in some patients.
Non-pharmacological Management
Weight reduction in obese patients has been shown to significantly relieve pain, presumably by reducing biomechanical stress on weight bearing joints. (more info on OA and Body Weight) Exercise has also been shown to be safe and beneficial in the management of OA. It has been suggested that joint loading and mobilization are essential for articular integrity. In addition, quadricep weakness, which develops early in OA, may contribute independently to progressive articular damage. Several studies in older adults with symptomatic knee OA have shown consistent improvements in physical performance, pain and self-reported disability after 3 months of aerobic or resistance exercise. Other studies have shown that resistive strengthening improves gait, strength and overall function. Low-impact activities, including water-resistive exercises or bicycle training, may enhance peripheral muscle tone and strength and cardiovascular endurance, without causing excessive force across, or injury, to joints. Studies of nursing home and community-dwelling elderly clearly demonstrate that one additional important benefit of exercise is a reduction in the number of falls.
Patients in whom function and mobility remain compromised despite maximal medical therapy, and those in whom the joint is structurally unstable, should be considered for surgical intervention. Patients in whom pain has progressed to unacceptable levels-that is, pain at rest and/or nighttime pain-should also be considered as surgical candidates. Surgical options include arthroscopy, osteotomy and arthroplasty. Arthroscopic removal of intra-articular loose bodies and repair of degenerative menisci may be indicated in some patients with knee OA. Tibial osteotomy is an option for some patients who have a relatively small varus angulation (less than 10 degrees) and stable ligamentous support. Total knee arthroplasty is recommended for patients with more severe varus, or any valgus, deformity and ligamentous instability. Arthroplasty is also indicated for patients who have had ineffective pain relief following a tibial osteotomy, and for those with advanced hip OA. Patients who have not yet developed appreciable muscle weakness, generalized or cardiovascular deconditioning and who would medically withstand the stress of surgery are ideal surgical candidates. In contrast, full mobility and function may not be realistically expected in patients with significant cognitive impairment or symptomatic cardiopulmonary disease, since these conditions can impede post-operative rehabilitation.
Several questionnaires have been established as validated, reliable research instruments for assessing functional outcomes in patients with arthritis. These include the Lequesne index, the Western Ontario McMaster Arthritis scale (WOMAC), activities of daily living (ADL), etc. Several performance-based tests of function can be done rapidly and easily in the office, however, and may be more sensitive in predicting impending disability than direct questions about disability and impairment. Such measures include grip strength, a timed walk, sequential chair-stands, and others listed below.
These tests can provide the clinician with valuable information on the patientís current level of function, as well as serve longitudinally to assess decline in function.
The development of selective COX-2 inhibitors has been an exciting advance in the management of pain and inflammation, as discussed above. If the safety profile of the specific COX-2 inhibitors is confirmed in additional long-term studies to be superior to non-selective COX inhibitors, they are likely to replace traditional NSAIDs in the management of arthritis and other painful, inflammatory conditions. It should be kept in mind, however, that no matter what their degree of selectivity, COX inhibitors (NSAIDs) do not alter the natural history of OA and a "disease modifying" agent is still critically needed.
One disease modifying strategy is to suppress the progressive degradation of cartilage that occurs in OA. To accomplish this, the ratio of MMP inhibitors to MMP enzymes must be shifted in favor of the former. This could be accomplished by enhancing articular levels of TIMP by recombinant gene therapy or by administration of exogenous TIMP. Studies of exogenous TIMP administration to animals with OA-like disease have had inconclusive results, however, perhaps due to ineffective penetration of this relatively high molecular weight protein into the cartilage matrix. An alternate approach, that has progressed more rapidly, is to develop oral inhibitors of MMPs. In fact, several synthetic small molecular weight inhibitors of MMPs have proven efficacious in animal models of arthritis and are entering Phase III clinical trials in humans. The antibiotic, tetracycline, and its semisynthetic derivatives, doxycycline and minocycline, have modest MMP inhibitory properties and have prompted investigations of these agents in the treatment of both OA and RA. Finally, inhibition of IL-1, via administration of a soluble IL-1 receptor or receptor antagonist, represents another rational strategy for suppressing MMP synthesis, and preliminary studies in RA are also promising.
Enhancing the repair of damaged cartilage constitutes another rational strategy for the treatment and/or prevention of OA. Administration of exogenous growth factors, such as IGF and bFGF, to stimulate chondrocyte proliferation and/or matrix synthesis has had beneficial effects in animals models of OA, and TGF-ß has the added advantage of suppressing MMP synthesis. The same effect could also be achieved theoretically by transplanting healthy autologous chondrocytes that have been genetically engineered to over-express one or more of these growth factors site. However, because the area of cartilage loss in OA can be quite extensive and because older chondrocytes are metabolically less active than young chondrocytes, it is unclear that either autologous or heterologous transplants will be practical for the management of OA.
Osteoarthritis is the most prevalent articular disease in the elderly. Disease markers that will detect early disease, and agents that will slow down or halt disease progression are critically needed. Current management should include safe and adequate pain relief using systemic and local therapies, and should include medical and rehabilitative interventions that limit functional deterioration.
Moskowitz RW et al. Osteoarthritis: Diagnosis and Medical/Surgical Management. 2nd ed., Philadelphia: W. B. Saunders Company Harcourt Brace Jovanovich, Increase., 1992, p 761.
Ling SM and Bathon JM. Osteoarthritis in Older Adults. J Am Ger Soc 46:216-225, 1998.
Hochberg MC et al. Guidelines for the medical management of osteoarthritis Part I Osteoarthritis of the hip. Arthritis Rheum 38:1535-1540, 1995.
Blackburn Jr., WD. Management of osteoarthritis and rheumatoid arthritis: prospects and possibilities. Am J Med 100(suppl 2A):2A-24S-2A-30S, 1996.
Dieppe P. Therapeutic targets in osteoarthritis. J Rheumatol 22:136-139, 1995
Bradley DJ, Brandt K, Katz BP, et al. Comparison of an anti-inflammatory dose of ibuprofen, an analgesic dose of ibuprofen, and acetaminophen in the treatment of patients with osteoarthritis of the knee. New Engl J Med 325(2): 87-91, 1991.
Polisson R. Nonsteroidal anti-inflammatory drugs: practical and theoretical considerations in their selection. Am J Med 100:2A-31S-2A36S, 1996.
Sager DS, Bennet RM. Individualizing the risk/benefit ratio of NSAIDs in older patients. Geriatrics 47:24-31, 1992.
Gabrile SE, Jaakkimainen L, Bombardier C. Risk for serious gastrointestinal complications related to use of nonsteroidal anti-inflammatory drugs. Ann Int Med 115(10):787-96, 1991.
Smalley WE, Ray WA, Daugherty JR, Griffin MR. Nonsteroidal anti-inflammatory drugs and the incidence of hospitalizations for peptic ulcer disease in elderly persons. Am J Epid 141: 539-45, 1995.
Silverstein FE, Graham DY, Senior JR, et al. Misoprostol reduces serious gastrointestinal complications in patients with rheumatoid arthritis receiving nonsteroidal anti-inflammatory drugs. Ann Int Med 123: 241-9, 1995.
McCarthy G, McCarthy D. Effect of topical capsaicin in the therapy of painful osteoarthritis of the hands. J Rheumatol 19:604-607, 1992.
Palmoski MJ, Bolyer RA, Brandt KD. Joint motion in the absence of normal loading does not maintain normal articular cartilage. Arthritis Rheum 23:325-34, 1980.
Brandt KD, Heilman DK, Mazzuca S et al. Quadriceps weakness and osteoarthritis of the knee. Ann of Int Med 127:97-104, 1997.
Ettinger Jr., WH 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). J Am Med Assoc 277:25-31, 1997.
Kovar PA et al. Supervised fitness walking in patients with osteoarthritis of the knee. A randomized, controlled trial. (See comments). Ann Intern Med 116:529-534, 1992.
Baragi VM et al. Transplantation of transduced chondrocytes protects articular cartilage from interleukin 1-induced extracellular matrix degradation. J Clin Invest 96:2454-2460, 1995.
Vinceti MP, Clark IM, Brinckerhoff CE. Using inhibitors of metalloproteinases to treat arthritis: easier said than done? Arthritis Rheum 37:1115-1125, 1994.
Conway JG et al. Inhibition of cartilage and bone destruction in adjuvant arthritis in the rat by a matrix metalloproteinase inhibitor. J Exp Med 182:449-57, 1995.
Seed MP et al. Inhibition of interleukin 1 beta induced rat and human cartilage degradation in vitro by the metalloproteinase inhibitor U27391. Ann Rheum Dis 52:37-43, 1993.
Brandt KD. Modification by oral doxycycline administration of articular cartilage breakdown in osteoarthritis. J Rheumatol 22:149-151, 1995.
Chandrasekhar S, Harvey AK. Transforming growth factor beta is a potent inhibitor of IL-1 induced protease activity and cartilage proteoglycan degradation. Biochem Biophys Res Commun 157:1352, 1988.
Brittberg M et al. Treatment of deep cartilage defects in the knee with autologous chondrocyte transplantation. N Engl J Med 331:889-895, 1994.
Brandt, KD. Putting some muscle into osteoarthritis. Ann Intern Med 127: 154-156, 1997.
