Efficacy Still Uncertain for Widely Used Supplements for ArthritisEfficacy Still Uncertain for Widely Used Supplements for Arthritis

While researchers continue to search for drugs targeting the cartilage loss that occurs with osteoarthritis, many patients with this condition and other causes of joint pain are emptying drug store shelves of the over-the-counter dietary supplements glucosamine and chondroitin sulfate. An estimated 1 million people take these products regularly, spending between $800 and $1000 per person per year, said Marc Hochberg, MD, MPH, of the University of Maryland School of Medicine, in Baltimore.

Although glucosamine and chondroitin sulfate are often touted in the lay press as remedies for osteoarthritis, which affects at least 20 million US adults, their effectiveness in easing joint pain and preventing disease progression is unproven. Anecdotal reports from patients and results from studies in animals, particularly horses (Goodrich LR and Nixon AJ. Vet J. 2006;171:51-69), indicate that the supplements' effects are not likely solely attributable to a placebo effect.

Interpretation of results from clinical trials testing these supplements varies among rheumatologists, primary care physicians, and other clinicians, as was evident from discussions by researchers and clinicians at the recent annual conference of the American College of Rheumatology and the Association of Rheumatology Health Professionals.

Many clinical studies have tested the potential for the treatment of osteoarthritis of glucosamine, an amino sugar that may play a role in cartilage formation and repair, and chondroitin sulfate, part of proteoglycan molecules that give cartilage elasticity. “A number of double-blind, controlled, randomized trials and meta-analyses support efficacy of these agents,” said Roland Moskowitz, MD, of the Case Western Reserve University School of Medicine, in Cleveland, who is cochair of the OsteoArthritis Research Society International's Committee on Treatment Guidelines for Osteoarthritis. However, there are differences in opinion concerning interpretation of the studies' findings, he added.

Research has also generated conflicting results regarding the extent to which these supplements are absorbed from the gastrointestinal tract and make their way into the joints (Persiani S et al. Osteoarthritis Cartilage. 2005;13:1041-1049; Biggee BA et al. Ann Rheum Dis. 2006;65:222-226). “Information on pharmacokinetics and pharmacodynamics, absorption, and distribution are all limited,” said Daniel Clegg, MD, of the University of Utah School of Medicine, in Salt Lake City. While their mechanisms of action are not fully understood, the supplements are thought to increase production of proteoglycan and hyaluronic acid and reduce degradation of cartilage (Matheson AJ and Perry CM. Drugs Aging. 2003;20:1041-1060). Some studies have suggested that glucosamine and chondroitin sulfate may also act as anti-inflammatory agents.

Several studies have found positive results for glucosamine compared with nonsteroidal anti-inflammatory drugs (NSAIDs) for the management of osteoarthritis (Muller-Fassbender H et al. Osteoarthritis Cartilage. 1994;2:61-69; Qiu GX et al. Arzneimittelforschung. 1998;48:469-474; Lopes Vaz A. Curr Med Res Opin. 1982;8:145-149). A meta-analysis of 15 clinical trials conducted before 2000 assessing the effects of glucosamine and chondroitin sulfate in patients with knee and/or hip osteoarthritis found the evidence suggests that the supplements have moderate to large effects, “but quality issues and likely publication bias suggest that these effects are exaggerated,” the authors wrote (McAlindon TE et al. JAMA. 2000;283:1469-1475). Nevertheless, some degree of efficacy appears probable for these supplements, they concluded.

More recently, clinical trials have reported results ranging from no effect to significant decreases in pain and cartilage loss (Arch Intern Med. 2003;163:1514-1522). A recent Cochrane review of 20 studies with 2570 patients found that glucosamine improved pain more than placebo when measured by one type of scale but was similar to placebo when measured by another scale (Towheed TE et al. Cochrane Database Syst Rev. 2005;[2]:CD002946). The GUIDE (Glucosamine Unum In Die [once a day] Efficacy) trial, a double-blind placebo-controlled study performed in Europe that compared glucosamine sulfate with acetaminophen for the treatment of knee osteoarthritis, found that a once-daily 1500-mg dose of glucosamine sulfate provided greater pain relief than placebo. But critics have noted that the study, which was presented at the 2005 conference of the American College of Rheumatology and the Association of Rheumatology Health Professionals, was sponsored by the glucosamine manufacturers and may therefore suffer from industry bias.

The largest study to date on the efficacy of glucosamine and chondroitin sulfate is the Glucosamine/Chondroitin Arthritis Intervention Trial (GAIT), funded by the National Institutes of Health (http://clinicaltrials.gov/show/NCT00032890). This multicenter, double-blind phase 3 trial included 1583 patients randomized to receive daily doses of 1500 mg of glucosamine, 1200 mg of chondroitin sulfate, both glucosamine and chondroitin sulfate, 200 mg of celecoxib, or placebo for 24 weeks. The investigators found that treatment with glucosamine or chondroitin sulfate alone or in combination did not reduce pain overall, but the combination may be effective in the subgroup of patients with moderate to severe knee pain (Clegg DO et al. N Engl J Med. 2006;354:795-808).

“The outcome of GAIT was not straightforward, so it was difficult to give a distinct and clear message,” said Clegg, GAIT's principal investigator. Media reports of the study reflected this ambiguity, with some announcing that the supplements showed great promise while others claimed they provided no benefit.

GAIT had several shortcomings, including an unusually high response rate (60%) in the placebo group and a controversial subgroup analysis. While the trial found that the subgroup of patients with moderate to severe pain (22%) experienced a significant reduction in knee pain, there was no such predefined subset analysis according to the written protocol.

“The subset analysis . . . is not persuasive given that it was a post hoc analysis,” said David Felson, MD, MPH, of the Boston University School of Medicine and principal investigator of the National Institutes of Health-funded Boston University Multipurpose Arthritis and Musculoskeletal Disease Center. In addition, the study did not fulfill many of the criteria necessary for valid subset analyses, such as a small number of outcomes tested and a comparison of results of different subgroups (Assmann SF et al. Lancet. 2000;355:1064-1069; Yusuf S et al. JAMA. 1991;266:93-98).

This and other trials with glucosamine and chondroitin sulfate have faced challenges in design, implementation, and analysis, said Clegg. “The stakeholders are really remarkably polarized on these issues.” And because supplements are not regulated by the US Food and Drug Administration to the extent that drugs are, a lack of standardization and quality control can make it difficult to accurately interpret and compare studies (Reginster JY et al. Bull Hosp Jt Dis. 2005;63:31-36).

Felson and his colleagues will soon publish a meta-analysis of clinical trials of glucosamine and chondroitin sulfate that he said revealed marked differences in trial results that are not due to chance. Aspects such as the duration of the trials and the severity of pain at baseline also did not explain these differences, he said. But methods of allocating patients into treatment groups and funding issues may have played a role. Most trials without industry funding or participation reported null findings, but several trials sponsored by industry reported effects that were equivalent or better than the effect of a total knee replacement, “a result that I regard as hard to believe,” said Felson.

While researchers and physicians have yet to agree on the efficacy of glucosamine and chondroitin sulfate, almost all agree on two things: that glucosamine and chondroitin sulfate are safe and that they are popular among patients. But widespread use of the supplements “is not about the efficacy of glucosamine and chondroitin sulfate, it's about our unfortunate ability to generate highly efficacious medical therapies for osteoarthritis,” said Felson.

The Arthitis Foundation has published a free patient brochure on glucosamine and chondroitin sulfate, with information including how to take the supplements, who should avoid them, and how to choose among products. Available at http://www.arthritis.org/conditions/alttherapies/Glucosamine.asp