Glucosamine and chondroitin sulfate alone or in combination did not reduce pain in the overall group of patients with knee osteoarthritis (OA), although the supplements in combination may be effective in the subgroup of patients with moderate-to-severe pain, according to the publication of the National Institutes of Health (NIH)–sponsored Glucosamine/Chondroitin Arthritis Intervention Trial (GAIT) in the February 23 issue of the New England Journal of Medicine.¹ The preliminary results were reported at the 2005 American College of Rheumatology meeting in San Diego, California.

GAIT comprised 1583 patients with symptomatic knee OA who received 1500 mg of glucosamine daily, 1200 mg of chondroitin sulfate daily, 1500 mg glucosamine plus 1200 mg chondroitin sulfate daily, 200 mg of celecoxib daily, or placebo for 24 weeks. Up to 4000 mg of acetaminophen daily was allowed as rescue analgesia. Assignment was stratified according to the severity of knee pain (mild [N = 1229] vs moderate to severe [N = 354]). Primary outcome was a 20% decrease in the summed score on the pain subscale of the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) from baseline to week 24. Numerous secondary outcomes were examined and these results were generally consistent with those for the primary outcome.

The study showed that in the overall patient group, glucosamine and chondroitin sulfate were not significantly better than placebo in reducing knee pain (P = .30 and P = .17, respectively). The response rate was somewhat better when both supplements were used (P = .09). Importantly, there was a significant reduction when patients were treated with celecoxib (P = .008), providing internal validity to the study.

Exploratory analyses, however, suggest that glucosamine and chondroitin sulfate in combination may be effective in the subgroup of patients with moderate-to-severe knee pain, (P = .002) according to the study. However, patients treated with either supplement alone or celecoxib did not improve significantly.

"It was found that patients who have moderate-to-severe knee pain and received the combination of glucosamine and chondroitin had clinically and statistically significant improvements in knee pain, but the study was not designed to conclusively interpret this finding and should be interpreted with caution," says lead GAIT researcher Daniel O. Clegg, MD, a professor of medicine and chief of the division of rheumatology at the University of Utah School of Medicine in a National Center for Complementary and Alternative Medicine (NCCAM) sponsored teleconference Wednesday. "There was no efficacy in the overall patient population."

What should rheumatologists tell their patients?

"On the basis of the results from GAIT, it seems prudent to tell our patients with symptomatic osteoarthritis of the knee that neither glucosamine hydrochloride nor chondroitin sulfate alone has been shown to be more efficacious than placebo for the treatment of knee pain," writes Marc C. Hochberg, MD, MPH, a professor of medicine and the head of the division of rheumatology and clinical immunology at the University of Maryland Medical Center in Baltimore, Maryland, in an editorial accompanying the new study.²

"If patients choose to take dietary supplements to control their symptoms, they should be advised to take glucosamine sulfate rather than glucosamine hydrochloride and, for those with severe pain, that taking chondroitin sulfate with glucosamine sulfate may have an additive effect," Dr. Hochberg suggests. Moreover, "three months of treatment is a sufficient period for the evaluation of efficacy; if there is no clinically significant decrease in symptoms by this time, the supplements should be discontinued."

Both the editorial and the original study point out that the high rate of response in the placebo group (60.1%) is a limitation of the study and that this effect has been seen in other OA trials. In addition, Dr. Hochberg also points out that GAIT was limited by an attrition rate of at least 20% in the placebo group as well as each of the dietary-supplement groups.

Will glucosamine and/or chondroitin sulfate modify OA progression?

An ancillary arm of GAIT designed to study the supplements' effects on radiographic disease progression at 1 and 2 years is now completing enrollment. Results from this arm should be informative, Dr. Hochberg says, asking, "Should glucosamine sulfate and chondroitin sulfate be given in conjunction with other treatments for symptomatic osteoarthritis of the knee because of their potential ability to modify the rate of structural deterioration, even if they have no effect on symptoms? More data to help answer this question may become available later this year when the GAIT group releases its findings on the structure-modifying effect of these agents."

Calling it an "important study," NCCAM director Stephen E. Straus, MD, points out that arthritis patients routinely turn to complementary and alternative medicine. "Based upon data from the Federal Centers for Disease Control and Prevention in 2002, an estimated 5.2 million people were using glucosamine with or without chondroitin in the prior year, and among those who used complementary and alternative medicine, arthritis, joint pain and stiffness were among the leading conditions for which complementary and alternative practices were sought."

References

1. Clegg DO, Reda DJ, Harris CL, et al. Glucosamine, chondroitin sulfate, and the two in combination for painful knee osteoarthritis. N Engl J Med. 2006;354:795-808.
2. Hochberg M. Nutritional supplement for knee osteoarthritis--still no resolution. N Engl J Med. 2006;354:858-859.