Osteoarthritis

What therapies for this disease of many causes?

Kerstin Morehead, MD; Kenneth E. Sack, MD

VOL 114 / NO 5 / NOVEMBER 2003 / POSTGRADUATE MEDICINE

CME learning objectives

• To learn the natural history and clinical presentation of osteoarthritis
• To appreciate the limitations of laboratory tests and imaging in diagnosis of osteoarthritis
• To understand the benefits and side effects of common treatments for osteoarthritis

The authors disclose no financial interests in this article and no unlabeled uses of any product mentioned.

This is the first of three articles on rheumatic disease.

Preview: Osteoarthritis is the most common joint disease in the world. A major cause of pain and disability, it usually develops in the smaller joints of the fingers, the weight-bearing joints of the leg, and the movable portions of the spine. Often, however, a patient's symptoms do not correspond with the clinical features. Here, Drs Morehead and Sack diagram the pathogenesis and diagnosis of osteoarthritis and delve into the treatments available today, acknowledging the controversial nature of some therapies. Morehead K, Sack KE. Osteoarthritis: What therapies for this disease of many causes? Postgrad Med 2003;114(5):11-7

Osteoarthritis is a condition of primary failure of cartilage, which is accompanied by subchondral thickening, bony outgrowths (osteophytes) at the joint margin, and juxtaarticular bone cysts (geodes). It typically affects the smaller joints of the fingers, the weight-bearing joints of the leg, and the movable portions of the spine, although any diarthrodial joint can be affected.

The exact prevalence of osteoarthritis is difficult to establish, because clinical symptoms often do not correlate with objective findings. Osteoarthritis is rare before age 40, yet 85% of the US population has either clinical or radiographic evidence of disease by age 75, making it the most common joint disease and a major cause of pain and disability (1).

Pathogenesis

Osteoarthritis was long thought to reflect the aging process, in which repetitive use of joints results in cartilage erosion. However, as more is understood about the molecular structure and function of cartilage, the pathogenesis of osteoarthritis appears to be the result of a complex interplay between mechanical, cellular, and biochemical forces.

Articular cartilage has a unique structure that enables it to both absorb shock and reduce friction at the bony interface. Collagen fibers provide the tensile strength that counters shear forces during movement under load. Coiled within this network of fibers are supramolecular aggregates of proteoglycans made of glycosaminoglycans attached to protein chains. The tight constraint that collagen fibers exert on the negatively charged proteoglycans produces a swelling pressure that gives cartilage its elasticity and ability to resist compression. Because of this deformability, cartilage can provide the largest possible surface area between subchondral bony plates under stress. In addition, the proteoglycans release water when compressed under high-load conditions, providing hydrostatic lubrication. Conversely, under low-shear conditions, proteoglycan aggregates become more viscous and less elastic, allowing the bony surfaces to glide smoothly (2).

As normal cartilage ages, it loses water and the link proteins become fragmented (3) (table 1). The levels of chondroitin sulfate, keratan sulfate, and hyaluronic acid in the cartilage change, causing decreased proteoglycan extractability but still allowing for normal aggregation. Thus, aging cartilage retains most of its functional ability. By contrast, the cartilage of osteoarthritis patients has an increased water content and normal link proteins, but a reduction of glycosaminoglycans, hyaluronic acid, and keratan sulfate leads to a decrease in proteoglycan macromolecular aggregates within the cartilage matrix. Along with the presence of thinned proteoglycans, structural changes in the collagen fibers significantly alter cartilage structure and impair function (4).

The alteration in cartilage composition reflects a disruption in the balance between cartilage synthesis and degradation. Cytokines such as tumor necrosis factor beta and interleukin-1, lipid mediators, free radicals, and even fragments of the cartilage itself induce chondrocytes to dedifferentiate. As a result, these cells produce variant types of collagen and increase their synthesis of proteinases, especially the family of matrix metalloproteinases that cause the breakdown of proteoglycans. At the same time, a reduction in proteinase inhibitors and growth factors occurs (5).

Risk factors

Among the risk factors for osteoarthritis are trauma, mechanical stress, heredity, and altered estrogen levels. In addition, several metabolic, endocrine, and nutritional characteristics can hasten both the onset and progression of osteoarthritis. Table 2 lists conditions that prompt the degeneration of cartilage and secondarily cause osteoarthritis (3).

Trauma and mechanical stress
Because of its limited vascular supply, cartilage is dependent on routine loading and motion to maintain normal metabolic function. However, a number of observations suggest that excessive force or inappropriate loading can affect cartilage structure and may act as the inciting event that disrupts chondrocyte homeostasis.

Certain occupations and sports activities are associated with high rates of osteoarthritis in specific joints, and repetitive fine motor tasks appear to correlate with the formation of Heberden's nodes and Bouchard's nodes (6). Obesity and conditions of increased bone density are associated with increased incidence of osteoarthritis in particular joints. Joint misalignment and leg length discrepancy may contribute to accelerated or premature osteoarthritis (7). Neuromuscular deficits, such as altered proprioception, may predispose to cartilage damage (8).

Heredity
Specific genetic defects account for a minority of cases of osteoarthritis. Studies have suggested that generalized osteoarthritis associated with Heberden's nodes shows an inheritance pattern typical of an autosomal gene that is dominant in females and recessive in males. Generalized osteoarthritis without nodes displays a more polygenic pattern of inheritance. However, these studies do not take into account occupational and recreational activities using the hands (9). Genes for the vitamin D receptor, insulinlike growth factor, cartilage oligomeric protein, and HLA subtypes may play a role in typical osteoarthritis. The type II procollagen gene, COL2A1, has been linked with familial forms of osteoarthritis, usually in association with chondrodystrophy (10).

Estrogen level
Cartilage contains estrogen receptors, and estrogen influences many inflammatory diseases by altering cell turnover, metabolism, and cytokine release. Perimenopausal women seem more prone to severe and inflammatory arthritis, suggesting a role for estrogen in the clinical course of osteoarthritis. Women who take estrogen replacement therapy appear less likely to have osteoarthritis, but animal studies of estrogen and osteoarthritis yield conflicting results (11).

Symptoms and signs

Pain with movement is the principal symptom of osteoarthritis. Cartilage contains no pain receptors; sensation likely results from inflammatory mediators, bone edema, and mechanoreceptors in the surrounding joint. The pain usually has an insidious onset and tends to increase with disease duration. Also, pain at rest and at night may accompany advanced disease. Morning stiffness is common but rarely lasts longer than 30 minutes.

Osteoarthritis can affect any movable joint. In the hands, proximal interphalangeal, distal interphalangeal, and first carpometacarpal joints are most commonly involved. Deformity tends to be gradual and in the lateral direction. Metacarpophalangeal joints are rarely affected, although patients with more advanced disease or a history of heavy manual labor may have some swelling or subluxation.

Wrist involvement is unusual and suggests another diagnosis, such as pseudogout or rheumatoid arthritis. Disease in the elbow is also atypical, except after trauma or as a result of metabolic disease. Acromioclavicular joints are often affected, but the glenohumeral joint is usually spared. However, rotator cuff injury or hydroxyapatite deposition (Milwaukee shoulder) can predispose the shoulder to osteoarthritis.

The spine, especially the cervical and lumbar regions, is susceptible to degenerative changes. Osteophytes in the cervical spine can cause foraminal narrowing and occasional radicular symptoms. Involvement of the hips is more common in men, particularly those of European descent. The accompanying weakness in hip abductors produces the classic waddling (Trendelenburg) gait. Osteoarthritis in the knees is associated with age, obesity, and deformities. However, physical activity, including running, does not predispose toward knee involvement. Despite the characteristic swelling of the first metatarsophalangeal joint, or bunion, feet and ankles are usually spared.

Clinical presentation

Diagnosis of osteoarthritis is generally based on clinical findings. Physical examination of the affected area may demonstrate crepitation, bony enlargement, limited range of motion, misalignment, joint instability, and gait disturbance. Synovial swelling occasionally occurs and can be found on examination. The physician should inspect the surrounding soft tissue and bursal areas as well, to exclude periarticular disease.

Laboratory tests help rule out arthritis due to infection, inflammatory disorders, or endocrine and metabolic disease. The erythrocyte sedimentation rate should be normal or only mildly elevated; any notable elevation should prompt a search for polymyalgia rheumatica, an underlying malignancy, or chronic infection. Radiographic evidence of chondrocalcinosis should prompt investigation of serum levels of calcium, phosphorus, magnesium, and thyrotropin (TSH). Joint fluid is usually bland or shows mild inflammation, demonstrated by fluid that contains fewer than 200 white blood cells/microliter; crystals should be absent. Newer assays of cartilage are not diagnostically useful in osteoarthritis.

Radiographs may demonstrate bony proliferation and asymmetrical joint space narrowing, although this finding does not necessarily parallel symptom severity. Osteoporosis and bony erosions are not typical of osteoarthritis. Magnetic resonance imaging is able to image cartilage directly and is more sensitive for cartilage loss and the presence of osteophytes and subchondral cysts, but it remains too costly for routine use.

Treatment

At present, there are no means to replace or repair damaged cartilage. The primary goals of treatment, therefore, are to help patients understand their disease and to relieve their pain, minimize their disability, and limit the progression of their disease. Because most patients with osteoarthritis are older persons who have comorbidities and are more susceptible to medication side effects, care must be taken to individualize therapy on the basis of a patient's needs and to minimize potential drug toxicity.

Nonpharmacologic interventions
Treatment options include those that do not directly involve medications. Among them are patient education and self-help, weight loss, dietary changes, physical therapy and exercise, and physical methods.

General measures: Education, self-help, and frequent patient contact are powerful and underused interventions in osteoarthritis (12). Educational materials and self-help courses are available through the Arthritis Foundation (available online at http://www.arthritis.org) (see resource box at the end of this article).

The long-term prognosis in osteoarthritis is not catastrophic, despite the condition's chronic nature. Hand function is rarely impaired, even if pain and stiffness remain, and pain in the knee or hip may decrease even as the disease progresses. Surprisingly simple measures, such as a monthly phone call, can be a cost-effective way to reduce symptoms (13).

Weight loss: Obesity correlates strongly with osteoarthritis, particularly osteoarthritis of the knee. Persons with a high body mass index who lose a total of 10 lb in 10 years can reduce by half their odds of having knee osteoarthritis (14). It is not yet known whether weight loss can alleviate symptoms or slow the progression of already established disease.

Dietary intervention: Mechanical forces clearly play a role in the association of obesity and osteoarthritis, but results of animal studies suggest that a diet high in saturated fat may also contribute to cartilage destruction (3). A form of secondary osteoarthritis, Kashin-Bek disease, has been ascribed to a trace-element deficiency. Data from the Framingham Study (15) suggest that adequate intake of vitamin C, vitamin E, and beta-carotene may slightly reduce the risk of disease progression, while a low intake of vitamin D may increase the risk of progression.

Physical therapy and exercise: Healthy cartilage metabolism depends on normal joint loading. Regular exercise increases the joint's flexibility and strength and improves its biomechanics (16). Additional benefits of an exercise program include weight loss and enhanced aerobic power. Whether instituted by a trained physician or a physical therapist, the program should include range-of-motion and isometric exercises. Low-impact aerobic and recreational exercise, such as walking, biking, and swimming, should be added as tolerated. Compliance is best with simple regimens, specific goals, varied techniques, and social interactions (17).

An occupational therapist can provide assistive and ergonomic devices as well as instruction on joint protection techniques. Use of orthotic inserts, knee braces, and canes and walkers can improve gait and relieve pain.

Physical modalities: Heat and cold can reduce the pain threshold and provide local analgesia. However, patients should avoid prolonged application of a heating pad and should use a timer along with the pad. Patients with Raynaud's phenomenon should avoid contact with cold objects. Capsaicin cream and similar rubefacients modulate pain by stimulating the release of substance P from unmyelinated nerve fibers. Although these products may provide modest relief, they can produce local skin irritation and can be expensive when used four times daily as directed (18). There is conflicting evidence about the benefits of ultrasound and transcutaneous electrical nerve stimulation (TENS).

Pharmacologic therapies
Various agents offer possibilities for pharmacologic treatment of osteoarthritis. Among them are analgesics, nonsteroidal anti-inflammatory drugs (NSAIDs) and selective cyclooxygenase-2 (COX-2) inhibitors, glucosamine and chondroitin sulfate, intraarticular glucocorticoids, and viscosupplements.

Analgesics: Acetaminophen remains the first-line treatment for pain associated with osteoarthritis because of its efficacy and safety profile. Despite ongoing controversy about its potency relative to NSAIDs, no study has definitively disproved initial observations of acetaminophen's ability to provide pain relief and improve function (19). However, it may be necessary to maintain regular acetaminophen dosing of up to 4 g/day to have consistent results. At therapeutic levels, there is little risk of hepatotoxicity except in the setting of preexisting liver disease or excessive alcohol use.

Opioid-containing analgesics are occasionally required for severe pain, and they can also be an effective option in patients with comorbidities that preclude other medications. Because these agents can cause confusion, constipation, and increased falls, they should be used with caution.

NSAIDs: Inflammation may contribute to the pain of osteoarthritis, and for patients whose pain has not responded to use of simple analgesics, NSAIDs can be an effective treatment. NSAID-induced toxicities are not uncommon, however. These toxicities include rash, central nervous system disturbance, gastric and duodenal ulcers, gastrointestinal bleeding, hepatotoxicity, renal toxicity, platelet dysfunction, increased blood pressure, and exacerbation of congestive heart failure.

Which NSAID to use depends on a patient's individual medical profile and dosing preference. Nonacetylated salicylates tend to cause less gastrointestinal and renal toxicity. All NSAIDs should be started at the lowest possible dose for 2 to 4 weeks and then slowly increased to the maximum dose. If there is still no relief, a switch to a different drug class is occasionally helpful. Physicians should regularly monitor blood pressure, hematocrit, renal function, and liver function in osteoarthritis patients taking NSAIDs.

The selective COX-2 inhibitors have similar efficacy to nonselective NSAIDs in the treatment of osteoarthritis but are considerably more expensive than either nonselective NSAIDs or acetaminophen. Initial industry-sponsored trials that excluded high-risk patients demonstrated that compared with other NSAIDs, selective COX-2 inhibitors reduced, but by no means eliminated, significant gastrointestinal events. These agents demonstrate no advantage over nonselective NSAIDs in patients with a history of peptic ulcer disease, nor is an advantage seen with regard to renal function, liver function, or blood pressure.

In patients with coronary artery disease, there is some controversy as to whether use of COX-2 inhibitors can precipitate vascular events. All patients who have cardiac risk factors should continue on low-dose aspirin while taking a COX-2 inhibitor. Unfortunately, concurrent use of aspirin negates the gastrointestinal protective effects of these selective agents (20). Patients taking COX-2 inhibitors should be monitored in much the same way as patients taking nonselective NSAIDs.

Glucosamine and chondroitin sulfate: Glucosamine and chondroitin sulfate are routinely used in veterinary medicine, and studies showing benefit have received a good deal of attention in the media. Because these products are sold as over-the-counter supplements, they are not well regulated for quality or content, and several studies have failed to demonstrate efficacy. Adverse events may include increased insulin resistance, photosensitivity, hypertension, proteinuria, and elevated serum creatine kinase levels (21).

Intra-articular glucocorticoids: Although their mechanism of action is unclear, intra-articular glucocorticoids can reduce pain and inflammation in patients with osteoarthritis. Injections should be performed under sterile conditions, and aspirated fluid should be sent for analysis. The concern that such injections will increase cartilage destruction is unfounded (22).

Viscosupplements: Hyaluronic acid (Hyalgan, Synvisc) is a glycosaminoglycan and the most popular formulation of viscosupplementation. Its mechanism of action is unclear, but injections are reportedly effective for up to 1 year. However, a recent review (23) has shown them to not be significantly better than placebo injections.

Surgery, arthroscopic lavage
Although the nonpharmacologic and pharmacologic interventions previously discussed can provide therapeutic effects, they are not successful for everyone with osteoarthritis. Some patients may need a surgical procedure.

Total joint replacement surgery can successfully alleviate joint pain in patients whose medical therapy failed to reduce osteoarthritic pain and altered function. Perioperative mortality and short-term complications are rare. The failure rate of a joint arthroplasty correlates most strongly with the duration of its use (24).

Arthroscopic lavage is being analyzed as a potential treatment. Tidal lavage was initially reported to be as effective as intra-articular glucocorticoid injection, but in recent randomized controlled studies, its efficacy was equivalent to that of placebo.

Summary

Osteoarthritis is a common and sometimes disabling disease. New directions in therapy include inhibitors of selective proteins and transplantation of cultured chondrocytes. At the present time, treatment continues to be in response to a patient's symptoms. Thus, the challenge to physicians is to devise individual treatment plans that safely maximize relief and preservation of joint function.

References

1. Lawrence RC, Hochberg MC, Kelsey JL, et al. Estimates of the prevalence of selected arthritic and musculoskeletal diseases in the United States. J Rheumatol 1989;16(4):427-41
2. Sledge CB, Reddi AH, Walsh DA, et al. Biology of the normal joint. In: Ruddy S, Harris ED, Sledge CB, eds. Kelley's textbook of rheumatology. 6th ed. Philadelphia: WB Saunders, 2001:9-13
3. Sack KE. Osteoarthritis: a continuing challenge. West J Med 1995;163(6):579-86
4. Brandt KD, Fife RS. Ageing in relation to the pathogenesis of osteoarthritis. Clin Rheum Dis 1986;12(1):117-30
5. Pelletier JP, DiBattista JA, Roughley P, et al. Cytokines and inflammation in cartilage degradation. Rheum Dis Clin North Am 1993;19(3):545-68
6. Hadler NM, Gillings DB, Imbus HR, et al. Hand structure and function in an industrial setting. Arthritis Rheum 1978;21(2):210-20
7. Radin EL, Swann DA, Paul IL, et al. Factors influencing articular cartilage wear in vitro. Arthritis Rheum 1982;25(8):974-80
8. O'Connor BL, Brandt KD. Neurogenic factors in the etiopathogenesis of osteoarthritis. Rheum Dis Clin North Am 1993;19(3):581-605
9. Doherty M, Spector TD, Serni U. Epidemiology and genetics of hand osteoarthritis. Osteoarthritis Cartilage 2000;8 Suppl A:S14-5
10. Holderbaum D, Haqqi TM, Moskowitz RW. Genetics and osteoarthritis: exposing the iceberg. Arthritis Rheum 1999;42(3):397-405
11. Zhang Y, McAlindon TE, Hannan MT, et al. Estrogen replacement therapy and worsening of radiographic knee osteoarthritis: the Framingham Study. Arthritis Rheum 1998;41(10):1867-73
12. Lorig KR, Mazonson PD, Holman HR. Evidence suggesting that health education for self-management in patients with chronic arthritis has sustained health benefits while reducing health care costs. Arthritis Rheum 1993;36(4):439-46
13. Weinberger M, Tierney WM, Cowper PA, et al. Cost-effectiveness of increased telephone contact for patients with osteoarthritis: a randomized, controlled trial. Arthritis Rheum 1993;36(2):243-6
14. Felson DT. Does excess weight cause osteoarthritis and, if so, why? Ann Rheum Dis 1996;55(9):668-70
15. McAlindon TE, Felson DT, Zhang Y, et al. Relation of dietary intake and serum levels of vitamin D to progression of osteoarthritis of the knee among participants in the Framingham Study. Ann Intern Med 1996;125(5):353-9
16. Fransen M, Crosbie J, Edmonds J. Physical therapy is effective for patients with osteoarthritis of the knee: a randomized controlled clinical trial. J Rheumatol 2001;28(1):156-64
17. Chamberlain MA, Care G, Harfield B. Physiotherapy in osteoarthrosis of the knees: a controlled trial of hospital versus home exercises. Int Rehabil Med 1982;4(2):101-6
18. Lequesne M, Brandt K, Bellamy N, et al. Guidelines for testing slow acting drugs in osteoarthritis. J Rheumatol Suppl 1994;41:65-73
19. Shamoon M, Hochberg MC. Treatment of osteoarthritis with acetaminophen: efficacy, safety, and comparison with nonsteroidal anti-inflammatory drugs. Curr Rheumatol Rep 2000;2(6):454-8
20. DeMaria AN, Weir MR. Coxibs--beyond the GI tract: renal and cardiovascular issues. J Pain Symptom Manage 2003;25(2 Suppl):S41-9
21. Towheed TE, Anastassiades TP. Glucosamine therapy for osteoarthritis. J Rheumatol 1999;26(11):2294-7
22. 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(2):370-7
23. Brandt KD, Smith GN Jr, Simon LS. Intraarticular injection of hyaluronan as treatment for knee osteoarthritis: What is the evidence? Arthritis Rheum 2000;43(6):1192-203
24. Kirwan JR, Currey HL, Freeman MA, et al. Overall long-term impact of total hip and knee joint replacement surgery on patients with osteoarthritis and rheumatoid arthritis. Br J Rheumatol 1994;33(4):357-60

Resources for patients with osteoarthritis American College of Rheumatology 404-633-3777 http://www.rheumatology.org/patients/factsheet/oa.shtml Arthritis Foundation 404-872-7100 800-283-7800 http://www.arthritis.org/conditions/diseasecenter/oa.asp National Institute of Arthritis and Musculoskeletal and Skin Diseases National Institutes of Health 301-495-4484 (voice) 301-565-2966 (TTY) 877-226-4267 http://www.niams.nih.gov/hi/topics/arthritis/oahandout.shtml

Dr Morehead is a clinical fellow and Dr Sack is professor of clinical medicine, department of medicine, University of California, San Francisco, School of Medicine. Dr Sack is also director, clinical programs in rheumatology, UCSF Medical Center. Correspondence: Kenneth E. Sack, MD, Division of Rheumatology, University of California, San Francisco, School of Medicine, 400 Parnassus Ave, Plaza Level, Box 0326, San Francisco, CA 94143. E-mail: kensac@medicine.ucsf.edu.

Symposium Index

• INTRODUCTION TO THE SYMPOSIUM. By Kenneth E. Sack, MD
• OSTEOARTHRITIS: What therapies for this disease of many causes? By Kerstin Morehead, MD, Kenneth E. Sack, MD
• RHEUMATOID ARTHRITIS: Targeted interventions can minimize joint destruction. By Eleanor Anderson Williams, MD, Kenneth H. Fye, MD, FACP, FACR
• SYSTEMIC LUPUS ERYTHEMATOSUS: How to manage, when to refer. By Maria Dall'Era, MD, John C. Davis, MD, MPH

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