At least 20 million Americans have osteoarthritis (OA), and this number is projected to double during the next 20 years.^1,2 The most popular nutritional supplements for OA are glucosamine and chondroitin sulfate, which have been increasingly recommended to help control pain, improve quality of life, and possibly slow the process of structural deterioration. These agents have been widely touted in the lay press as safe and effective alternatives to analgesics and NSAIDs (including cyclooxygenase [COX]-2 inhibitors), which are not always optimally effective and may be associated with health risks. Estimated sales of glucosamine and chondroitin approached $730 million in 2004.³

Meta-analyses of randomized controlled trials have shown that the combination of glucosamine and chondroitin and chondroitin alone were more effective than placebo in the treatment of knee pain.^4-6 Two randomized controlled trials showed that 3 years of therapy with glucosamine sulfate slowed radiologic progression of arthritis of the knee.^7,8 Another study found that although 2 years of therapy with chondroitin slowed radiologic progression, it did not reduce symptoms or improve function.⁹ Other studies either had mixed results, did not find that these agents were more effective than placebo, or were considered flawed.

Against this background of uncertainty, the Glucosamine/chondroitin Arthritis Intervention Trial (GAIT), sponsored by the NIH, was undertaken in the hopes of providing definitive evidence about the efficacy and safety of glucosamine, chondroitin, and the combination in treatment of knee pain resulting from OA. The results of the trial were published in February.¹⁰

More than 1500 patients (mean age, 59 years) with symptomatic knee OA were randomly assigned to receive 1500 mg of glucosamine, 1200 mg of chondroitin, glu- cosamine plus chondroitin, 200 mg of celecoxib, or placebo daily for 24 weeks. The primary outcome measure was a 20% reduction in knee pain.

Analysis of the primary outcome measure showed that neither the individual supplements nor the combination significantly reduced mild knee pain. The response in the combination group was almost identical to that in the placebo group. However, a subgroup analysis of patients with moderate to severe pain demonstrated that combination therapy significantly decreased knee pain. In this group, 79% who took the combination experienced pain relief, compared with 66% who took glucosamine alone, 61% who took chondroitin alone, and 54% who took placebo.

A number of limitations prevented this study from being totally definitive, according to Roland Moskowitz, MD, professor of medicine at Case Western Reserve University School of Medicine in Cleveland, codirector of the Arthritis Translational Research Program at the Case Research Institute, and a coauthor of GAIT.

Formulation of glucosamine. Most of the European trials that showed a benefit with glucosamine used glucosamine sulfate. Most of the American trials—including GAIT—used glucosamine hydrochloride. This formulation was chosen by the GAIT investigators because at that time there was no FDA-approved facility that produced glucosamine sulfate. Glucosamine hydrochloride is the formulation most widely available in health food stores in this country.

Inability to detect benefit. The high rate of response to placebo (60.1%) and the fact that most patients had relatively mild OA may have limited the ability of the study to detect treatment benefit. Even the effects of celecoxib were smaller than those seen in other studies.

Insufficient numbers of patients with more severe disease. Combination therapy with glucosamine and chondroitin significantly decreased knee pain in the 22% of patients with moderate to severe pain. However, the fact that there was such a small number of patients in this group may have limited the study's power to demonstrate significant benefits of therapy.