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OSTEOARTHRITIS Degenerative joint disease represents joint failure. It is the clinical manifestation of a net loss of articular cartilage. The amount of articular cartilage matrix represents the balance between the synthesis and catabolism of proteoglycans, collagen, and hyaluronic acid. Osteoarthritis develops when there is disproportion between the load applied to the articular cartilage and the quality of the cartilaginous matrix. In addition to mechanical stress, varying degrees of inflammation may exacerbate osteoarthritis. In certain patients, interleukin-1 (IL-1) and other products of inflammation activate gelatinase, a metalloenzyme that contributes to cartilage degradation. Along with a genetic predisposition, obesity, excessive use, aging, and previous trauma are associated with osteoarthritis. Risk factors for osteoarthritis range from those that cause mechanical damage to local joint geometry and structure to metabolic factors such as antioxidant status.1 As many as 1 in 10 adults may show radiologic evidence of osteoarthritis.

CLINICAL DIAGNOSIS Osteoarthritis is gradual in onset, and clinical manifestations vary from patient to patient. The disease is often asymmetric. The first metacarpophalangeal joint, knees, hips and lumbar and cervical spine are frequently involved. Classic signs and symptoms of osteoarthritis are as follows: ●

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Stiffness that is mild in the early morning and recurs after periods of rest Pain that worsens with prolonged joint use and is relieved by rest Loss of function

Prevalent findings on examination include local tenderness, soft tissue swelling, joint crepitus, and bony swelling, often unassociated with joint deformity. Mobility is restricted. An inflammatory variant is likely in patients with pain during rest and/or nocturnal pain, warm, tender joints, and/or joint effusion. Osteoarthritic joints show irregular loss of cartilage, sclerosis of subchondral bone, subchondral cysts, marginal osteophytes, and variable degrees of synovial inflammation. 363

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THERAPEUTIC STRATEGY Osteoarthritis appears to be a mechanically driven but chemically mediated disease process characterized by imperfect or aberrant cartilage repair. The prime objectives of management are reduction of pain, preservation of function, and prevention of further damage. The intervention strategy is to minimize cartilage breakdown, encourage cartilage replenishment, and limit cartilage damage caused by mechanical trauma or secondary synovitis. Nitric oxide, under certain conditions (e.g., septic arthritis), may have a protective anabolic effect on cartilage; however, in osteoarthritis, nitric oxide is consistently produced and associated with matrix degradation and chondrocyte apoptosis.2 Although nitric oxide does not appear to be the initiating signal for apoptosis in chondrocytes, in vivo nitric oxidase synthase inhibitors may be useful in the treatment of osteoarthritis because they block the catabolic activities of nitric oxide.3 Niacinamide and other inhibitors of adenosine diphosphate ribosylation have been shown to suppress cytokine-mediated induction of nitric oxide synthase in several types of cells.4 Adequate selenium nutrition may also downregulate cytokine signaling, and ample intake of fish oil can be expected to decrease synovial IL-1 production. Synovium-generated IL-1, by inducing nitric oxide synthase and thereby inhibiting chondrocyte synthesis of aggrecan and type II collagen, may be crucial to the pathogenesis of osteoarthritis. Management in osteoarthritis is problematic and continually being reviewed.5,6

LIFESTYLE CHANGES Maintaining an ideal body weight reduces the risk of joint damage. An energy-balanced diet rich in vegetables, fruits, and whole grains and low in fat is recommended. By losing 5 kg (2 body mass index units), women and men with a body mass index greater than 25 kg/m2 reduce their likelihood of knee osteoarthritis by 50% and 25%, respectively.7 Wearing soft-soled shoes or foam rubber innersoles and walking rather than jogging also reduce mechanical stress. The articular joint surface is avascular, and movement improves nutrient diffusion; therefore, regular exercise is advocated. Exposure to sunlight, resulting in adequate vitamin D synthesis, may also be protective. Avoidance of allergenic foods is reported to relieve symptoms such as pain and stiffness in some cases.8 The family Solanaceae is a rich source of glycoalkaloids, have been incriminated with tomato, potato, eggplant, peppers, and tobacco as possible triggering agents. It may take months of following a glycoalkaloid-free diet before improvement is noted.

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NUTRIENT THERAPY/DIETARY SUPPLEMENTS Alternatives to traditional nonsteroidal anti-inflammatory drugs (NSAIDs) with fewer side effects are being sought.9,10 Nutrient therapy of osteoarthritis has a two-pronged focus. Some nutrients reduce inflammation and cartilage destruction (e.g., cyclooxygenase-2 inhibitors)9; others enhance cartilage synthesis and repair (e.g., glucosamine).10 In view of the documented efficacy of glucosamine in relieving pain, improving function, and possibly inhibiting structural progression,11 some suggest that glucosamine should be considered a potential first-line agent in patients with knee osteoarthritis and mild to moderate pain.10 However, others maintain that there is little or no scientific evidence for the effects of this and other nutrients in patients with knee, hip, or hand osteoarthritis.12 Despite reservations, there is scientific support for serious consideration of nutrients in the treatment of patients with osteoarthritis. The postulate that glucosamine and chondroitin sulfates halt or reverse joint degeneration by stimulating synthesis and inhibiting degradation of proteoglycans enjoys biologic and some clinical support.13 Joint cartilage consists of cells embedded in a matrix of fibrous collagen within a concentrated water-proteoglycan gel. Proteoglycans stabilize cell membranes and increase intracellular ground substance. They enhance flexibility and provide resistance to compression, which counteracts physical stress. Depletion of sulfated proteoglycans is an early manifestation of osteoarthritis. Both chondroitin and glucosamine sulfates serve as substrates for proteoglycan synthesis. The glucosamine component of glucosamine sulfate is quickly and almost completely absorbed from the gastrointestinal tract and is rapidly incorporated into articular cartilage. Articular cartilage concentrates glucosamine. Glucosamine acts as a substrate for glycosaminoglycans and hyaluronic acid, essential components of proteoglycans. Hyaluronic acid, in addition to contributing to the matrix of cartilage, suppresses the anti-catabolic effect of IL-1 in chondrocyte cell cultures. Most individuals taking glucosamine sulfate achieve a 50% to 70% reduction in articular pain, joint tenderness, and swelling.14 Approximately 95% of patients with osteoarthritis of the knee respond well to glucosamine sulfate, and in 60%, improvement is reputed to be excellent. Preliminary evidence suggests that patients with arthritis of the shoulder or elbow also respond well. The typical oral dose of glucosamine sulfate is 500 mg three times daily for a minimum of 6 weeks. Most individuals benefit from repeated courses. Improvement persists for 6 to 12 weeks after cessation of a 6-week course of treatment. In a review of 16 randomized, controlled trials Towheed et al15 concluded that glucosamine was both effective and safe for managing osteoarthritis.15 In addition, in a randomized, double-blind placebo-controlled trial of patients with knee osteoarthritis who took 1500 mg of glucosamine sulfate daily for 3 years, long-term combined structure-modifying and symptom-modifying effects were detected.16

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Glucosamine sulfate may be a disease-modifying agent in osteoarthritis. Since it is safe for long-term administration, continuous administration is appropriate. Glucosamine sulfate does cause mild side effects in 6% to 12% of cases. Gastrointestinal disturbances, drowsiness, headaches, and skin reactions have been reported. Individuals with active peptic ulcers and individuals taking diuretics tend to have an increased incidence of side effects. Although glucosamine has been described as effective when used alone, it is probably reasonable to use it in combination with chondroitin sulfate, pending further studies.17 In a meta-analysis of 13 double-blind placebocontrolled trials of more than 4 weeks’ duration, McAlindon et al18 concluded that oral or parenteral glucosamine or chondroitin for treatment of hip or knee osteoarthritis provided moderate to significant benefits. The majority of physiologic benefits from chondroitin sulfates appear to result from increased availability of the monosaccharide building blocks, glucuronic acid and N-acetylgalactosamine. Chondroitin sulfates are well tolerated after oral administration, although 3% of individuals report slight dyspepsia. The typical oral dosage is 400 mg twice daily; however, a single dose of 800 mg per day appears to be equally effective according to pharmacokinetic data. Repeated cycles of administration are needed to produce the best results. Various combination therapy options are available. A 16-week randomized, double-blind, placebo-controlled crossover trial showed that glucosamine hydrochloride (1500 mg/day), chondroitin sulfate (1200 mg/day), and manganese ascorbate (228 mg/day) relieved symptoms of knee osteoarthritis.19 Although clinical findings suggest that glucosamine sulfate (1500 mg) and chondroitin sulfate (1200 mg) are an effective and safe alternative to NSAIDs for alleviation of symptoms,20 glucosamine sulfate does not inhibit cyclooxygenase and proteolytic enzymes involved in inflammation. Low doses of NSAIDs may be added to this combination for treatment of patients with inflammatory osteoarthritis. Despite growing enthusiasm, it must be noted that unanimous agreement on use of these supplements is lacking. There are those who believe there is no reliable scientific evidence that either chondroitin sulfate or glucosamine sulfate have structure-modifying actions with respect to prohibiting or healing lesions or restoring cartilage synthesis.12 Furthermore, these agents have not been evaluated by the Food and Drug Administration or recommended for the treatment of osteoarthritis but are available as health food supplements. In addition to promotion of cartilage synthesis, management of osteoarthritis may be achieved by reducing cartilage destruction. Nutrients that may help in the maintenance and regeneration of cartilage are boron and vitamin D. Boron appears to participate in hydroxylation reactions influencing the synthesis of steroid hormones and vitamin D. A trial indicated that boron supplementation, 6 mg per day as sodium tetraborate decahydrate for 8 weeks, benefited 50% of individuals with osteoarthritis whose diets are likely to be low in boron.21

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Vitamin D plays a role in the normal turnover of articular cartilage. Studies suggest that vitamin D (400-1600 IU) may slow the progression of and possibly help prevent the development of osteoarthritis. Certainly, osteoarthritis is three times more likely in persons with low serum and dietary levels of vitamin D.22 S-adenosylmethionine, another proven therapy for osteoarthritis, functions as a methyl donor and upregulates the proteoglycan synthesis of chondrocytes.8 In vitro studies have shown that S-adenosylmethionine stimulates the synthesis of proteoglycans by human articular chondrocytes. Human studies suggest that S-adenosylmethionine, in doses of 1200 mg per day, may be as effective as NSAIDs.8 Such intervention is particularly important in patients with inflammatory osteoarthritis. IL-1 targets synovial cells and liberates prostaglandin E2, proteases, collagenases, and glycosidases. It appears to decrease S-adenosylmethionine levels in chondrocytes, a situation that may be reversed by supplementation with S-adenosylmethionine. Synovium-generated IL-1 induces nitric oxide synthase, thereby inhibiting chondrocyte synthesis of aggrecan and type II collagen. Aspirin, steroids, and niacinamide can suppress nitric oxide synthase and may blunt the antianabolic impact of IL-1 on chondrocytes. Clinical studies have shown that treatment with niacinamide, 900 to 4000 mg per day, usually increases joint mobility and decreases joint discomfort, inflammation, and pain after 3 to 4 weeks of treatment.4,8 Progressive improvement occurs for up to 3 years if niacinamide administration is continued. Patients who stop taking niacinamide gradually revert to their pretreatment state. Niacinamide was most effective when taken in frequent, divided doses. It is generally well tolerated and appears to be relatively safe for long-term use. Patients taking large amounts of this vitamin (e.g., 1500 mg/day or more) should have periodic tests to monitor liver function. Although not believed to initiate the process, oxidative stress is believed to contribute to the progression of osteoarthritis. Vitamins A, C, and E may influence osteoarthritis by protecting against oxidative damage and modulating the inflammatory response.8 High intakes of antioxidants, especially vitamin C, may reduce the risk of cartilage loss and disease progression in osteoarthritis.23 Because the antioxidant efficiency of vitamin C does not increase linearly with its serum concentration and because efficiency for scavenging free radicals declines as the concentration of ascorbate increases, the optimal intake may be 150 mg daily.24 In addition to its antioxidant effect, vitamin C may promote cartilage health. Vitamin C deficiency may reduce mechanical integrity of cartilage, since vitamin C is involved in electron donation in the synthesis of type II collagen, hydroxylation of proline to hydroxyproline in collagen synthesis, and glycosaminoglycan synthesis as a sulfate carrier. Like vitamin C, vitamin E is a free radical scavenger. Vitamin E, in doses of 600 IU three times daily, reduced pain in a 10-day trial.25 Its antiinflammatory activity may be mediated by inhibiting prostaglandin synthesis and stabilizing lysosomal membranes. In vitro studies suggest that normal

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plasma levels of vitamin E enhance lipoxygenation of arachidonic acid and that higher concentrations have a suppressive effect.26 The efficacy of nutrient supplementation in suppressing inflammation varies, depending on the degree of inflammation involved. This may partially explain the apparent failure of trace element, vitamin combination of selenium-ACE, in a controlled double-blind trial, to demonstrate any significant efficacy at 3 or 6 months in the treatment of osteoarthritis.27 Selenium may downregulate cytokine signaling. Clinical trials have demonstrated individual benefit from sodium selenite (140 μg daily), superoxide dismutase, cartilage extract, and molybdenum.28 Results of an animal study confirmed that a diet supplemented with vitamins and selenium might be useful in prevention or therapy of mechanically induced osteoarthritis.29 There are at least four mechanisms, ranging from oxidative stress to cellular differentiation, by which the nutrient vitamins A, C, D, and E may be related to the processes that impede or give rise to osteoarthritis30; and recent data indicate that low intake of these micronutrients may adversely influence the progression of knee osteoarthritis and the incidence of hip osteoarthritis.31 A controlled, double-blind, crossover study has also demonstrated that folate and cobalamin supplementation provide benefit.32

HERBAL THERAPY A review of herbal therapy for osteoarthritis indicated that avocado-soybean unsaponifiables were effective.33 Symptomatic pain relief and improvement of functional disability were reported with the use of avocado-soybean extracts. An avocado-soybean extract and Ayurvedic preparation (ArticulinF), an herbal remedy that contains (per capsule) 450 mg of Withania somnifera root, 100 mg of Boswellia serrata stem, 50 mg of Curcuma longa rhizome, and 50 mg of a zinc complex have been reported to be beneficial.8 Other herbs that appear to have some therapeutic usefulness include devil’s claw, willow bark, and nettle. A number of studies suggest that Harpagophytum procumbens extract (devil’s claw) has a beneficial effect.34 Although H. procumbens has no demonstrable anti-inflammatory effect, it does appear to have an analgesic effect. In a randomized, double-blind study over 4 weeks, two daily doses of oral H. procumbens extract (600 and 1200, respectively, containing 50 and 100 mg of the marker harpagoside) were found to reduce low back pain with no evidence of side effects, except possibly mild and infrequent gastrointestinal symptoms.35 White willow bark contains salicin, which acts more slowly than aspirin, lasts longer, and has fewer side effects. A 4-week blinded trial showed that oral administration of willow bark (Salix spp.) extract resulted in dosedependent pain relief.36 Doses of 120 mg and 240 mg of salicin were used. In doses of 60 to 120 mg a day, salicin is used to treat musculoskeletal pain and headaches.

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A randomized, controlled, double-blind, crossover study of patients with osteoarthritic pain at the base of the thumb or index finger indicated that stinging nettle leaf (Urtica dioica), applied locally each day for 1 week, reduced pain and disability.37 Other nutriceuticals, including ginger extracts, require more extensive investigation.11

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Cayenne (Capsicum spp.) may be helpful in osteoarthritis but not rheumatoid arthritis. Capsaicin, an effective pain killer when applied in a thin layer to the skin over the affected area and rubbed in well at least four times daily, is available in cream or ointment form. Analgesia from acetaminophen (paracetamol) in doses up to 1.0 g six times per day may be prescribed. Aspirin may inhibit proteoglycan synthesis and should be avoided by patients with osteoarthritis. In inflammatory osteoarthritis, NSAIDs may be protective by inhibiting synovial production of IL-1, which induces synthesis and release of matrixdegrading proteinases from chondrocytes. Glucosamine use is reputed to halve the effective dose of NSAIDs required. Boron may induce remission in some patients with osteoarthritis. Niacinamide, 500 to 1000 mg three times daily, may benefit patients with osteoarthritis.

REFERENCES 1. Sowers M: Epidemiology of risk factors for osteoarthritis: systemic factors, Curr Opin Rheumatol 13:447-51, 2001. 2. Lotz M: The role of nitric oxide in articular cartilage damage, Rheum Dis North Am 25:269-82, 1999. 3. Greisberg J, Bliss M, Terek R: The prevalence of nitric oxide in apoptotic chondrocytes of osteoarthritis, Osteoarthritis Cartilage 10:207-11, 2002. 4. McCarty MF, Russell AL: Niacinamide therapy for osteoarthritis—does it inhibit nitric oxide synthase induction by interleukin 1 in chondrocytes? Med Hypotheses 53:350-60, 1999. 5. Rollins G: Updated guidelines include new drugs and therapies for the treatment of osteoarthritis, Rep Med Guidel Outcomes Res 11:1-2, 5, 2000. 6. McKinney RH, Ling SM: Osteoarthritis: no cure, but many options for symptom relief, Cleve Clin J Med 67:665-71, 2000. 7. Meisler JG, St Jeor S: Foreword, Am J Clin Nutr 63(suppl 3):409S-411S, 1996. 8. Gaby AR: Natural treatments for osteoarthritis, Altern Med Rev 4:330-41, 1999. 9. Wildy KS, Wasko MC: Current concepts regarding pharmacologic treatment of rheumatoid and osteoarthritis, Hand Clin 17:321-38, xi, 2001.

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10. Hochberg MC: What a difference a year makes: reflections on the ACR recommendations for the medical management of osteoarthritis, Curr Rheumatol Rep 3:473-8, 2001. 11. Reginster JY, Gillot V, Bruyere O, Henrotin Y: Evidence of nutriceutical effectiveness in the treatment of osteoarthritis, Curr Rheumatol Rep 2:472-7, 2000. 12. Hauselmann HJ: Nutripharmaceuticals for osteoarthritis, Best Pract Res Clin Rheumatol 15:595-607, 2001. 13. Kelly GS: The role of glucosamine sulfate and chondroitin sulfates in the treatment of degenerative joint disease, Altern Med Rev 3:27-39, 1998. 14. Glucosamine sulfate, Altern Med Rev 4:193-5, 1999. 15. Towheed TE, Anastassiades TP, Shea B, et al: Glucosamine therapy for treating osteoarthritis (Cochrane Review), Cochrane Database Syst Rev 1:CD002946, 2001. 16. Reginster JY, Deroisy R, Rovati LC, et al: Long-term effects of glucosamine sulphate on osteoarthritis progression: a randomised, placebo-controlled clinical trial, Lancet 357:251-60, 2001. 17. Deal CL, Moskowitz RW: Nutraceuticals as therapeutic agents in osteoarthritis. The role of glucosamine, chondroitin sulfate, and collagen hydrolysate, Rheum Dis Clin North Am 25:379-95, 1999. 18. McAlindon TE, LaValley MP, Gulin JP, et al: Glucosamine and chondroitin for treatment of osteoarthritis: a systematic quality assessment and meta-analysis, JAMA 283:1469-75, 2000. 19. Leffler CT, Philippi AF, Leffler SG, et al: Glucosamine, chondroitin, and manganese ascorbate for degenerative joint disease of the knee or low back: a randomized, double-blind, placebo-controlled pilot study, Mil Med 164:85-91, 1999. 20. de los Reyes GC, Koda RT, Lien EJ: Glucosamine and chondroitin sulfates in the treatment of osteoarthritis: a survey, Prog Drug Res 55:81-103, 2000. 21. Newnham RE: Essentiality of boron for healthy bones and joints, Environ Health Perspect 102(suppl 7): 83-5, 1994. 22. McAlindon T, 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 125:353-9, 1996. 23. McAlindon P, Jacques P, Zhang Y et al: Do antioxidant micronutrients protect against the development and progression of knee osteoarthritis? Arthritis Rheum 39:648-56, 1996. 24. Frei B, England L, Ames BN: Ascorbate is an outstanding antioxidant in human blood plasma, Proc Natl Acad Sci U S A 86:6377-81, 1989. 25. Machtey I, Ouaknine L: Tocopherol in osteoarthritis. A controlled pilot study, J Am Geriat Soc 26:328-30, 1978. 26. Goetzl EJ: Vitamin E modulates lipoxygenation of arachidonic acid in leukocytes, Nature 288:183-5, 1980. 27. Hill J, Bird HA: Failure of selenium-ace to improve osteoarthritis, Br J Rheumatol 29:211-3, 1990. 28. Werbach MR: Textbook of nutritional medicine, Tarzana, CA, 1999, Third Line Press. 29. Kurz B, Jost B, Schunke M: Dietary vitamins and selenium diminish the development of mechanically induced osteoarthritis and increase the expression of antioxidative enzymes in the knee joint of STR/1N mice, Osteoarthritis Cartilage 10:119-26, 2002.

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30. Sowers M, Lachance L: Vitamins and arthritis. The roles of vitamins A, C, D, and E, Rheum Dis Clin North Am 25:315-32, 1999. 31. Perkins PJ, Doherty M: Nonpharmacologic therapy of osteoarthritis, Curr Rheumatol Rep 1:48-53, 1999. 32. Flynn MA, Irvin W, Krause G: The effect of folate and cobalamin on osteoarthritic hands, J Am Coll Nutr 13:351-6, 1994. 33. Little CV, Parsons T: Herbal therapy for treating osteoarthritis (Cochrane Review), Cochrane Database Syst Rev 1:CD002947, 2001. 34. Ernst E, Chrubasik S: Phyto-anti-inflammatories. A systematic review of randomized, placebo-controlled, double-blind trials, Rheum Dis Clin North Am 26:13-27, vii, 2000. 35. Chrubasik S, Junck H, Breitschwerdt H, et al: Effectiveness of harpagophytum extract WS 1531 in the treatment of exacerbation of low back pain: a randomized, placebo-controlled, double-blind study, Eur J Anaesthesiol 16: 118-29, 1999. 36. Chrubasik S, Eisenberg E, Balan E, et al: Treatment of low back pain exacerbations with willow bark extract: a randomized double-blind study, Am J Med 109:9-14, 2000. 37. Randall C, Randall H, Dobbs F, et al: Randomized controlled trial of nettle sting for treatment of base-of-thumb pain, J R Soc Med 93:305-9, 2000.