For years, most rheumatologists reserved judgment on the use of glucosamine and chondroitin in osteoarthritis (OA) until the release of the $14 million National Institutes of Health (NIH)–sponsored Glucosamine/Chondroitin Arthritis Intervention Trial (GAIT). The highly anticipated results,¹ which were presented earlier this month at the annual meeting of the American College of Rheumatology in San Diego, California, revealed that the combination supplement failed to show demonstrable efficacy in patients with mild-to-moderate knee osteoarthritis (OA), leaving rheumatologists and other physicians unsure of whether to recommend the supplement to their OA patients.

The study comprised close to 1600 patients with painful knee OA from 16 US academic rheumatology centers. Patients who had experienced significant knee pain (WOMAC Pain 125 mm to 400 mm) of at least 6 months and had radiographic evidence of knee OA (Kellgren-Lawrence [KL] Grades 2 or 3) were evaluated at the beginning of the study, and at weeks 4, 8, 16, and 24. Each patient was randomly assigned to receive glucosamine hydrochloride, sodium chondroitin sulfate, both supplements, celecoxib, or placebo therapy and allowed up to 4000 mg daily of acetaminophen as rescue anesthesia, except within 24 hours of study visits. The primary outcome measure was a 20% improvement from baseline in WOMAC Pain at week 24.

While the study clearly showed no benefit in patients with mild-to-moderate knee OA, a preselected (and now controversial) subgroup of patients with moderate-to-severe knee OA did benefit from the combined supplements. In these patients with WOMAC Pain 301–400 mm, the combination of supplements demonstrated a statistically significant response rate compared to placebo (79.2% vs 54.3% of patients). Also in this group, the response with glucosamine and chondroitin was higher than that seen with celecoxib (79.2% vs 69.4%), and the difference between celecoxib and placebo in this subgroup was not statistically significant. Adverse events in GAIT were mild and evenly distributed throughout the groups.

"Because of the high placebo response [which could have washed out the data], the use of glucosamine hydrochloride [as opposed to glucosamine sulfate], and the controversial subset analysis, the ‘beat will go on,'" asserts Steven B. Abramson, MD, a rheumatologist and professor in the department of rheumatology/medicine at New York University School of Medicine.

First do no harm, but where is the benefit?

 "I was not impressed with the results of the GAIT study, and do not feel that glucosamine/chondroitin sulfate has a great deal of benefit, [but] if a patient wants to try it, I have no objection," says Roy Fleischmann, MD, clinical professor of medicine at the University of Texas Southwestern Medical Center in Dallas.

Doyt L. Conn, MD, a professor of medicine at Emory University School of Medicine in Atlanta, Georgia, echoes Dr. Fleischmann's sentiments. "There is no obvious benefit from glucosamine or chondroitin sulfate, and I would not recommend them," he tells CIAOMed. On the other hand, "the patient can decide if they want to take them based on other information—usually word of mouth or advertising."

Other clinicians are more definitive in their assessments. "This is a null study," says David T. Felson, MD, MPH, professor of medicine and chair of clinical epidemiology at Boston University School of Medicine in Boston, Massachusetts. "There is no effect compared to placebo in this large, well-designed study."

Roland Moscowitz, MD, professor of medicine at Case Western Reserve University in Cleveland, Ohio, tells CIAOMed, "I recommend that rheumatologists use these supplements because there is enough ‘smoke' and evidence supportive of using them," he says. "The risk is low and the cost is minimal. The data from this study, even as an exploratory finding, suggests that a number of people will respond."

Sulfate vs hydrochloride

Some rheumatologists believe that the glucosamine formulation used in GAIT may be responsible for the lack of efficacy. 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, points out that the glucosamine hydrochloride formulation employed in the GAIT study (500 mg three times a day) may not be as effective as glucosamine sulfate.

"The efficacy of glucosamine is based on studies [supported by Rotta Research of Milan, Italy] of glucosamine sulfate given as a single dose of 1500 mg per day," Dr. Hochberg tells CIAOMed. "I recommend to my patients that they use the Dona brand of glucosamine sulfate marketed by the US subsidiary of Rotta."

Martin J. Bergman, MD, a rheumatologist and assistant clinical professor at MCP-Hahnemann University in Philadelphia, and chairman of the division of rheumatology at Taylor Hospital in Ridley Park, Pennsylvania, also supports the Dona brand. "When I recommend glucosamine, I specifically recommend Rotta/Dona, and have been doing so for at least two years. With that product I know that my patients are receiving something consistently."

Although glucosamine is not available in France, Maxime Dougados, MD, a professor of rheumatology at Université René Descartes and a rheumatologist at Hôpital Cochin, both in Paris, France, points out that there are two questions regarding GAIT and glucosamine/chondroitin in OA.

"The first question is related to the potentially different effects of glucosamine hydrochloride (usually available as a ‘diet supplement') and glucosamine sulfate (usually available in different countries as a drug manufactured by Rotta Research)," he says. "The second question is the quality control [difference between] a pill manufactured by a ‘true' drug company (such as Rotta Research) [and a pill manufactured] by another company specializing in diet supplements," he tells CIAOMed. "Because the study was conducted with the chloride, I am afraid that we will continue to discuss the [ability] of such drugs to improve the symptoms of our patients in a short period (6 months) of time," he says. Another arm of GAIT is slated to assess the rate of x-ray progression among glucosamine and chondroitin users.

Dr. Dougados concludes, "In my opinion, the most important issue is related to the potential beneficial effect of glucosamine sulfate on a very hard endpoint, such as requirement to surgery," he says, adding that preliminary studies have suggested that it may have a clinically relevant effect in this regard.

US regulatory hurdles may prevent more definitive answers

Lee Simon, MD, a rheumatologist and associate clinical professor of medicine at Harvard Medical School in Boston, Massachusetts, agrees with Dr. Dougados, but points out that the roots of the problem, unfortunately, lie in US drug laws. "A study to demonstrate the beneficial effects on structure would prove that glucosamine is not a nutraceutical, and would thus convert it to a drug, [with] all the attendant manufacturing issues, etc, that would be required," he says. "Furthermore, as proven by this last expensive and failed trial, the right trial would be probably too expensive for a ‘non-drug-industry' player to pay for, and for the NIH yet again to do, unless there was a massive patient-driven political statement to do [it].  

"We need the correct study to prove that the right glucosamine preparation, consistently provided, will benefit signs and symptoms, and that the right formulation will benefit a hard endpoint—delay of joint replacement."

Reference

1. Clegg DO, Reda DJ, Harris CL, et al. The efficacy of glucosamine and chondroitin sulfate in patients with painful knee osteoarthritis (OA): the Glucosamine/chondroitin Arthritis Intervention Trial (GAIT). 69th Annual Meeting of the American College of Rheumatology; November 12–17, 2005; San Diego, Calif.