ABSTRACT: Many patients with osteoarthritis (OA) try such complementary therapies as special diets, nutritional and herbal supplements, yoga, t'ai chi, magnets, and acupuncture-but only 40% of these patients tell their physicians. Glucosamine and chondroitin sulfate can produce at least symptomatic relief; in addition, glucosamine (1500 mg/d) may increase or stabilize cartilage in osteoarthritic knees. Alert patients to the potential toxicities of many herbal remedies, as well as the risks of harmful drug interactions and possible contaminants and impurities. Yoga postures may have a beneficial effect on knee OA; t'ai chi may reduce joint pain and swelling and increase mobility. Small studies have shown that applied pulsed electromagnetic fields can reduce pain and improve function in patients with chronic knee OA. Acupuncture has also been shown, in small studies, to alleviate the pain of OA. Autologous chondrocyte transplantation was recently approved for treatment of knee OA. The efficacy and safety of various types of gene therapy are currently being evaluated.
Unconventional therapies for osteoarthritis (OA) have been steadily gaining in popularity. Suboptimal results of conventional treatment, the widespread perception that "natural" equals "safe," and direct-to-consumer marketing drive many patients to seek complementary approaches.
In our 2 previous articles (CONSULTANT, January 2003, pages 53 and 88), we reviewed conventional therapies for OA. Here we examine the evidence for the many complementary therapies that are available; our goal is to sort out the approaches that can be helpful from those that are useless or even harmful. We also discuss cutting-edge-and controversial-developments in conventional therapy for OA.
COMPLEMENTARY APPROACHES: AN OVERVIEW
In recent years, complementary therapies for OA have generated much interest. Here we define complementary medicine as the use of unconventional therapies in conjunction with or in support of mainstream Western medicine.1 Examples include special diets, nutritional and herbal supplements, massage therapy, magnets, acupuncture, yoga, t'ai chi, and behavioral/cognitive strategies, such as prayer and meditation (Table 1).
The increasing use of unconventional therapies is a worldwide phenomenon. Between 6% and 73% of surveyed populations report using such therapies.2,3 The variations in prevalence appear to be related to differences in study design, population selection, and definitions of unconventional or complementary medicine.3 Geographic, economic, and ethnic factors appear less significant. In a recent survey, 79% of participants acknowledged at least some interest in complementary therapies for arthritis (Table 2).
An estimated 20,000 products are marketed as unconventional or complementary treatments for OA. One study found that patients using complementary medicine try between 1 and 18 different remedies, with an average of 4.5 remedies per person.1
However, only 40% tell their physicians that they are using complementary therapies.1 Among the reasons patients give for failing to discuss the use of unconventional approaches with their physicians are the following:
They do not believe the physician has enough knowledge to offer advice (61%).
They do not believe there is a reason to tell (17%).
They are afraid the physician will not approve (12%).
DIETS AND SUPPLEMENTS
Special diets. Dietary approaches that have been proposed for patients with OA include weight loss, "anti-inflammation diets," and nutritional supplements.4,5 Weight loss is beneficial insofar as a lower body weight decreases the load on weight-bearing joints. While short-term symptomatic relief has been demonstrated, no prospective studies to date have documented long-term improved outcome when weight loss is the sole management strategy for OA.
Proponents of anti-inflammation diets believe that different dietary fats have different effects on physiologic inflammatory pathways. For instance, polyunsaturated fats may be either omega-3 fatty acids (as found in fish, grapeseed, flaxseed, and evening primrose oils) or omega-6 fatty acids (arachidonic or linoleic acids, as found in soybean, corn, and sunflower oils). In vitrostudies have shown that arachidonic acid has a proinflammatory effect (increasing levels of prostaglandins and leukotrienes), while omega-3 fatty acids have an anti-inflammatory effect (acting ascompetitive inhibitors of these mediators). Thus, a diet rich in omega-3 fatty acids can theoretically decrease the inflammation and pain associated with OA. However, no invivodata support this view.
Glucosamine and chondroitin sulfate. These 2 dietary supplements have been studied extensively as treatments for OA.6-9 Glucosamine and chondroitin are constituents of proteoglycan, the "building block" of articular cartilage and connective tissue. Interest in glucosamine and chondroitin as therapeutic supplements arose after in vitro studies indicated that they could stimulate proteoglycan synthesis and thus theoretically prevent cartilage loss.
A number of randomized, double-blind studies have compared the efficacy of glucosamine and chondroitin with that of placebo and NSAIDs in the treatment of OA. A recent meta-analysis of all reported trials demonstrated generally positive effects ofvariable magnitude.10 However, interpretation of these results is confounded by methodologic flaws, such as inadequate blinding and lack of intent-to-treat analysis, as well as publication bias related to sponsorship support and selective publication of positive trials. Nonetheless, the data indicate that these agents can produce at least symptomatic relief.
A more recent study suggests that glucosamine (1500 mg daily) can increase or stabilize cartilage in osteoarthritic knees.11 Interestingly, prevention of joint-space narrowing did not correlate with symptoms; however, the suboptimal radiographic methodology used in the study mandates caution in interpretation of these results. A large-scale, long-term NIH-sponsored study currently in progress is designed to more definitively examine symptom relief as well as the structure-modifying effects associated with glucosamine and chondroitin.
Although patients generally tolerate these agents well, several risks have emerged. Glucosamine is contraindicated in patients who are allergic to shellfish; in addition, it may raise blood insulin levels, which makes glucosamine therapy unwise for patients with diabetes until further information is available. Chondroitin sulfate may affect warfarin levels. There may be other risks as well, related to the lack of FDA oversight of the dietary and nutritional supplement industry.
Shark cartilage. No convincing data support the claims that shark cartilage has anti-inflammatory or chondroprotective effects. It inhibits angiogenesis and therefore is contraindicated in children, pregnant women, and patients with recent myocardial infarction.
MSM and SAMe. MSM (methylsulfonylmethane sulfur powder) and SAMe (S-adenosylmethionine) are other supplements for which efficacy in the management of OA has been claimed. Proponents assert that SAMe is chondroprotective and that MSM exerts an anti-inflammatory effect on cartilage and thus hastens recovery of damaged tissue. However, there are no clinical trials to support such claims.12
Herbal medicine is the most ancient form of health care known. An herb is defined as a plant or plant part used to make medicine, spices, or aromatic oils.13 The exact mechanisms by which most herbs influence human physiology are not known. Common herbal remedies marketed as treatments for OA are listed in Table 3. Very few herbals have been studied in randomized, double-blind, placebo- controlled trials.
OTHER COMPLEMENTARY APPROACHES
Yoga. This ancient practice has been described as a way "to join the body to the mind and together join to the self (soul)."14 Yoga involves breathing control and postures intended to cleanse the mind, body, and spirit, and it is viewed as a holistic approach that helps increase flexibility, strength, and stamina.
For persons with OA, postures are used that realign the skeletal structure and loosen stiff joints. No double-blind, randomized studies have been conducted that compare the efficacy of yoga with that of NSAIDs, one of the mainstays of therapy for OA. However, observers note that yoga postures used for knee OA emphasize frequent stretching and full extension of the knee. This mechanical movement of the knee is believed to have physiologic effects at the cellular level. In vitroproduction of proinflammatory interleukin-1 and tumor necrosis factor decreases under low-level intermittent fluid pressure. Thus, proponents of yoga maintain that frequent joint motion reduces fluid pressure, which, in turn, preserves cartilage that would allegedly be lost by immobilization; however, this proposition is not yet proved.
T'ai chi. This form of traditional Chinese medicine consists of a series of exercises and movements that increase joint range of motion, strength, and balance. T'ai chi allows patients to perform weight-bearing exercises in a controlled manner, which can potentially result in decreased joint pain and swelling and increased mobility.15 Proponents of t'ai chi offer it as an alternative to standard physical therapy.
Magnets. Electromagnetic wave technology-used in microwave ovens and cellular phones-also has medical applications. In rabbits with cartilaginous defects, those treated with applied pulsed electromagnetic fields (PEMF) had faster rates of repair than those that did not receive PEMF.16-18 PEMF is believed to exert a beneficial effect on damaged connective tissue by increasing glycosaminoglycan content within a joint as well as by preventing degradation of existing glycosaminoglycans. Small studies involving patients with chronic OA of the knee demonstrate between 29% and 36% improvement in pain level and functional ability.17 PEMF may also be cost-effective because it may forestall the need for total knee arthroplasty.
No evidence exists to validate the concern that PEMF may increase the risk of cancer by augmenting DNA synthesis. Nevertheless, advise pregnant women and patients who have cancer or permanent pacemakers to avoid PEMF.
Acupuncture. An estimated 1 million Americans currently use acupuncture; most of them are seeking relief from musculoskeletal disorders.19 Traditional acupuncture theory holds that certain patterns of energy flowing through the body are necessary for good health. Imbalances in this flow of energy can allegedly be corrected by puncturing the skin with a long needle. The Chinese use meridians, or channels, to identify energy imbalances and then restore balance.
The Western view of acupuncture is quite different. This view holds that acupuncture-induced analgesia results from stimulation of large-diameter nerves which then inhibit small- diameter nerves in the dorsal horn of the spinal cord that are involved in pain signaling. A large-scale, randomized, sham-controlled, NIH-supported trial to evaluate the efficacy of acupuncture inthe treatment of OA is nearly complete. Smaller studies of acupuncture, including several with sham controls, have demonstrated pain reduction in patients with OA.
Caution patients about the risks of acupuncture, which include infection, pneumothorax, dermatitis, bleeding, syncope, and dyspnea. Acupuncture is contraindicated in patients with HIV infection, viral hepatitis, bleeding diatheses, skin infections, or cardiac arrhythmias.
SAFETY OF COMPLEMENTARY APPROACHES
Potential toxic effects. One study found that only 22.2% of internal medicine patients and 26.6% of rheumatology patients who took dietary supplements knew of any associated potential toxicities.4 Thus, it is important to advise patients that the reported adverse effects associated with herbals include allergic reactions ranging from transient dermatitis to anaphylactic shock; anticholinergic and hallucinogenic effects; persistent catharsis that results in lazy bowel syndrome; and such systemic toxicities as hemolytic anemia, nephropathy, colitis, and even death (Table 4).
Absence of regulation. Because the United States does not have a licensing agency to oversee the production of herbal and dietary supplements, the potential for harm is great. Labels on dietary supplements may contain statements describing a nutrient and its intended effect on the human body, yet these declarations need not be substantiated by scientific studies.20 Moreover, because the federal government does not mandate controlled testing of supplements and related products, they may contain contaminants and impurities, such as microorganisms, artificial additives, or heavy metals, including arsenic or mercury (Table 5).
Interaction with conventional therapies. In addition, patients who take prescription drugs such as NSAIDs may also be using unconventional remedies without telling their health care providers. This practice is certainly risky-although further study is required to define the full spectrum of interactions between medications and herbs or dietary supplements.
Failure to report adverse effects. Finally, many patients use unconventional remedies without medical supervision and do not report associated adverse reactions. As a result, patients who self-treat with unconventional therapies-especially early in the course of the disease-may confound diagnostic efforts and delay treatment.
Despite such warnings, many patients still choose to take nutritional or herbal remedies. Advise them that they may reduce their risk of exposure to poor-quality products by purchasing only those with United States Pharmacopeia or National Formulary symbols on the packaging.
CONTROVERSIES AND CUTTING-EDGE TREATMENTS
Analgesic arthropathy. While pain relief is a major goal in OA management, some observers have suggested that symptom reduction may actually be detrimental, because it can lead to overloading of the osteoarthritic joint and resultant acceleration of disease progression.21,22 Clarification of the utility of this concept, termed "analgesic arthropathy," requires further careful prospective investigation.
Possible adverse effects of NSAIDs. Some in vitrostudies have linked certain NSAIDs to adverse effects on cartilage metabolism. This has raised concern that these agents could contribute to joint damage.23 Study results have been inconsistent, however; thus, this issue should not influence the current risk-benefit analysis of NSAID use in OA.
Structure-modifying therapies. A disease- or structure-modifying approach to OA remains elusive. Population-based studies suggest that antioxidants, such as vitamins C and E, may help prevent OA or slow its progression.24,25 Adequate calcium intake (1000 to 1500 mg/d) may also slow the progression of OA. The mechanism of action and biologic effects of intra- articular hyaluronan injection remain to be clarified. As noted above, studies are currently under way to assess whether glucosamine has chondroprotective as well as analgesic effects. Other potential structure-modifying therapies under active investigation include doxycycline, sodium pentosan polysulfate,26 and matrix metalloproteinase inhibitors.27
Autologous chondrocyte transplantation. This procedure, which was recently approved for use in the United States, involves arthroscopic harvesting of a specimen of a patient's cartilage and culturing of the chondrocytes in vitro.28 After suitable growth, the surgeon transplants the cartilage into a focal cartilage defect at the knee and seals the site with a periosteal patch. Localized cartilage defects are also amenable to repair by osteochondral autografts and cadaveric allografts.29 While these reparative approaches are viable for knee joints that contain mostly healthy cartilage, they remain investigational for patients with the diffuse or multicompartmental cartilage loss that is common in OA.
Gene therapy. This is an exciting new potential therapy for OA.30 Possibly useful gene products include growth factors, proteinase inhibitors, and cytokine antagonists, all of which either enhance or maintain matrix synthesis at sites of cartilage erosion. Vectors such as viruses, naked DNA, and liposomes facilitate the introduction of gene products. Trials are currently under way to evaluate the efficacy and safety of gene therapy for OA.
REFERENCES:1. Arnold WJ, Berman B, Hollister JR, Liang MH, eds. The Arthritis Foundation's Guide to Alternative Therapies. Atlanta: Arthritis Foundation; 1999.
2. Eisenberg DM, Davis RB, Ettner SL, et al. Trends in alternative medicine use in the United States, 1990-1997: results of a follow-up national survey. JAMA. 1998;280:1569-1575.
3. Ramos-Remus C, Gutierrez-Urena S, Davis P. Epidemiology of complementary and alternative practices in rheumatology. Rheum Dis Clin North Am. 1999;25:789-804.
4. Mikuls TR, O'Dell JR, Moore GF, et al. Dietary supplement use by rheumatology and internal medicine clinic patients: result of a survey questionnaire. J Clin Rheumatol. 1999;5:255-260.
5. Maheu E, Mazieres B, Valat JP, et al. Symptomatic efficacy of avocado/soybean unsaponifiables in the treatment of osteoarthritis of the knee and hip: a prospective, randomized, double-blind, placebo-controlled, multicenter clinical trial with a six-month treatment period and a two-month followup demonstrating a persistent effect. Arthritis Rheum. 1998; 41:81-91.
6. Delafuente JC. Glucosamine in the treatment of osteoarthritis. Rheum Dis Clin North Am. 2000;26:1-11.
7. Leeb BF, Schweitzer H, Montag K, Smolen JS. A metaanalysis of chondroitin sulfate in the treatment of osteoarthritis. J Rheumatol. 2000;27:205-211.
8. Deal CL, Moskowitz RW. Nutraceuticals as therapeutic agents in osteoarthritis. The role of glucosamine, chondroitin sulfate, and collagen hydrolysate. Rheum Dis Clin North Am. 1999;25:379-395.
9. Rindone JP, Hiller D, Collacott E, et al. Randomized, controlled trial of glucosamine for treating osteoarthritis of the knee. West J Med. 2000;172:91-94.
10. McAlindon TE, LaValley MP, Gulin JP, Felson DT. Glucosamine and chondroitin for treatment of osteoarthritis: a systematic quality assessment and meta-analysis. JAMA. 2000;283:1469-1475.
11. Reginster JY, Deroisy R, Rovati LC, et al. Long-term effects of glucosamine sulphate on osteoarthritis progression: a randomised, placebo-controlled clinical trial. Lancet. 2001;357:251-256.
12. Ernst E. Harmless herbs? A review of the recent literature. Am J Med. 1998;104:170-178.
13. Bauer BA. Herbal therapy: what a clinician needs to know to counsel patients effectively. Mayo Clin Proc. 2000;75:835-841.
14. Garfinkel M, Schumacher HR Jr. Yoga. Rheum Dis Clin North Am. 2000;26:125-132.
15. Lumsden DB, Baccala A, Martire J. T'ai chi for osteoarthritis: an introduction for primary care physicians. Geriatrics. 1998;53:84, 87-88.
16. Trock DH, Bollet AJ, Dyer RH Jr, et al. A double-blind trial of the clinical effects of pulsed electromagnetic fields in osteoarthritis. J Rheumatol. 1993; 20:456-460.
17. Trock DH, Bollet AJ, Markoll R. The effect of pulsed electromagnetic fields in the treatment of osteoarthritis of the knee and cervical spine. Report of randomized, double blind, placebo-controlled trials. J Rheumatol. 1994;21:1903-1911.
18. Trock DH. Electromagnetic fields and magnets. Investigational treatment for musculoskeletal disorders. Rheum Dis Clin North Am. 2000;26:51-62.
19. Berman BM, Swyers JP, Ezzo J. The evidence for acupuncture as a treatment for rheumatologic conditions. Rheum Dis Clin North Am. 2000;26: 103-115.
20. Borins M. The dangers of using herbs. What your patients need to know. Postgrad Med. 1998;104: 91-95, 99-100.
21. Sharma L. Proprioceptive impairment in knee osteoarthritis. Rheum Dis Clin North Am. 1999;25: 299-314.
22. Hurwitz DE, Sharma L, Andriacchi TP. Effect of knee pain on joint loading in patients with osteoarthritis. Curr Opin Rheumatol. 1999;11:422-426.
23. Brandt KD, Palmoski MJ. Effects of salicylates and other nonsteroidal anti-inflammatory drugs on articular cartilage. Am J Med. 1984;77:65-69.
24. Felson DT, Zhang Y. An update on the epidemiology of knee and hip osteoarthritis with a view to prevention. Arthritis Rheum. 1998;41:1343-1355.
25. Sowers M, Lachance L. Vitamins and arthritis. The roles of vitamins A, C, D, and E. Rheum Dis Clin North Am. 1999;25:315-332.
26. Ghosh P. The pathobiology of osteoarthritis and the rationale for the use of pentosan polysulfate for its treatment. Semin Arthritis Rheum. 1999;28: 211-267.
27. Malemud CJ, Goldberg VM. Future directions for research and treatment of osteoarthritis. Front Biosci. 1999;4:D762-D771.
28. Ghazavi MT, Visram F, Davis AM, et al. Long-term results of fresh osteochondral allografts for post-traumatic osteochondral defects of the knee. Orthop Trans. 1995;19:454.
29. 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.
30. Evans CH, Robbins PD. Potential treatment of osteoarthritis by gene therapy. Rheum Dis Clin North Am. 1999;25:333-344.
31. McRae S. Elevated serum digoxin levels in a patient taking digoxin and Siberian ginseng. Can Med Assoc J. 1996;165:293-295.