"In the overall study population, the supplements alone and in combination were not more effective than placebo," says lead author Daniel O. Clegg, MD, chief of the division of rheumatology at the University of Utah School of Medicine in Salt Lake City, Utah. Dr. Clegg adds, however, that "in an exploratory analysis of a subgroup of patients the combination of glucosamine and chondroitin appears to be more effective than placebo."
Yet detractors point out that the positive results only occurred in a small, exploratory subgroup of study patients. "This is a null study," David T. Felson, MD, MPH, professor of medicine and chair of clinical epidemiology at Boston University School of Medicine in Boston, Massachusetts, asserts. "There is no effect compared to placebo in this large, well-designed study."
About GAIT
The new study, the largest conducted to date in the US, comprised almost 1600 patients with knee OA from 16 US academic centers. Patients who had experienced significant knee pain (Western Ontario and McMaster Osteoarthritis index [WOMAC] pain: 125–400 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. Participants were randomly assigned to receive glucosamine hydrochloride (500 mg three times a day), sodium chondroitin sulfate (400 mg three times a day), both supplements, celecoxib, or placebo therapy. The patients were permitted to receive up to 4000 mg of acetaminophen daily 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.
Another arm of the study is slated to assess the rate of x-ray progression among glucosamine and chondroitin users.
Overall, the participants who took celecoxib had more pain relief than their counterparts who took placebo, the study showed. Among patients with mild-to-moderate pain, glucosamine and chondroitin was not statistically significant compared with placebo; however, the lack of response in these patients may have been attributed to what Dr. Clegg called a "floor effect," limiting ability to detect response.
Benefits observed in severe OA
Participants with moderate-to-severe knee pain taking both supplements had a 79.2% response rate, the study showed. By comparison, those patients with moderate-to-severe pain who took placebo had a 54.3% response rate. Patients taking celecoxib in this group experienced pain relief, as did 65.7% taking glucosamine alone and 61.4% taking chondroitin alone, according to the trial results.
Secondary outcomes in this group—50% WOMAC pain response, WOMAC stiffness, WOMAC function, HAQ, patient assessments, and use of rescue APAP—were consistent with the primary outcome. OMERACT-OARSI response criteria were added as a secondary outcome, and the results suggest improvements from the combination among all study participants, not just those in the moderate-to-severe category.
Adverse events were mild and evenly distributed throughout the groups. Reasons for withdrawal was similar and varied across all groups, although lack of efficacy was more frequently reported among all patient populations.
Calling the findings in the subgroup of severe OA patients "very positive," Roland Moscowitz, MD, tells CIAOMed that "I recommend that rheumatologists use these supplements because there is enough ‘smoke' and evidence supportive of using them. The risk is low and the cost is minimal. The data from this study even as an exploratory finding suggest that a number of people will respond," he says.
Dr. Moscowitz, professor of medicine at Case Western Reserve University in Cleveland, Ohio, points out that GAIT used glucosamine hydrochloride, while all the positive studies in Europe have utilized glucosamine sulfate, which may account for the failed primary outcome.
European study: Glucosamine controls knee OA pain better than acetaminophen
Another study, the European GUIDE (Glucosamine Unum In Die Efficacy),2 found that glucosamine sulfate taken once a day may have more ability to control pain due to knee osteoarthritis than acetaminophen.
In this study of 318 patients with symptomatic knee OA, patients took either oral glucosamine sulfate soluble powder (1500 mg once a day), acetaminophen (1000 mg three times a day), or placebo over a 6-month period. All groups were allowed ibuprofen as needed. Both glucosamine sulfate and acetaminophen showed greater efficacy than placebo in reducing pain, according to the study.
However, patients taking glucosamine sulfate appeared to experience more relief than did those on acetaminophen, according to the investigators.
Glucosamine sulfate is a slightly different substance than glucosamine hydrochloride. Also, the formulation used in GUIDE is not comparable to most formulations available in the US, the study authors point out.
"Once-daily 1500 mg oral doses of glucosamine sulfate might be the preferred treatment for symptoms of knee osteoarthritis," reports GUIDE study author Gabriel Herrero-Beaumont, MD, director of the rheumatology department at the Jiménez DÃaz Foundation - CAPIO, in Madrid, Spain. "Based on these results, physicians who typically recommended acetaminophen may well find their patients gain more comfort taking glucosamine sulfate."
GAIT shows supplements work "fantastically"
The new GAIT findings show that glucosamine and chondroitin "did work and worked fantastically, [with a 79% response rate]," says GAIT steering committee member Jason Theodosakis, MD, of the University of Arizona College of Medicine in Tucson, Arizona. The author of Arthritis Cure and Maximizing the Arthritis Cure, Dr. Theodosakis says, "I have not seen any drug trial that goes that high."
"People with low WOMAC scores are often just helped with lifestyle changes, occasional pain relievers, ice or rest or exercise," Dr. Theodosakis informs CIAOMed. "The folks that need the pain relief based on their WOMAC scores are the ones that need help, and the supplements work for them."
Dr. Theodosakis notes that "We have 45 people a day who die from anti-inflammatory drugs; so even if they are equal in efficacy, [supplements] should be used, and in this case they performed better, so it's a no-brainer that people should use supplements."
He suggests that patients take anti-inflammatory drugs for immediate relief along with supplements and try to wean off the drugs as soon as possible. "I think that is a perfectly appropriate use," he says.
"Glucosamine and chondroitin have a synergistic effect, which is no surprise, because the supplements activate different genes and have different mechanisms," Dr. Theodosakis explains.
Methodology accounts for less than stellar results
"Alone and together, [the supplements] beat placebo in every instance, but it wasn't always significant because the placebo rate was so high," Dr. Theodosakis says. Study participants tend to "try harder" in general, due to increased follow-up and interaction. "Any time you keep up with participants, they are more likely to do better regardless of the intervention," he says, noting that "too many folks with mild-to-moderate symptoms entered the study, and that washed out the data."
Overall, 78% of GAIT participants had mild knee pain. "The results should have been much better," Dr. Theodosakis asserts. "The dosing was thrice daily instead of once a day, which is recommended now. This is important, because we know that once-a-day dosing will give a higher concentration, and we want the amount to hit all at once; we don't want it spread throughout the day," he says, explaining that there is a certain concentration required to activate the cells.
Another limitation of the study was that participants were allowed to have used supplements in the past. "We don't know if there is a wash-out period for these compounds," he says.
Moreover, only primary OA patients were included in GAIT. "We know clinically that some of the secondary causes of OA respond better to supplements," Dr. Theodosakis says. "Most miracle cases occur in people with pseudo gout or gout-induced OA."
Notably, the Arthritis Foundation came out in favor of the supplement combination. "Based on this study and the supplements' safety and cost-effectiveness, the combination of glucosamine and chondroitin should be considered by patients and physicians as part of an overall treatment for painful knee OA," the agency declared in a written statement.
No comment yet from study sponsors
The National Center for Complementary and Alternative Medicine, along with its GAIT study cosponsor, the National Institute of Arthritis and Musculoskeletal and Skin Diseases, said in a joint written statement that they planned to withhold comment until the results are peer-reviewed and published.
References
- 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). Presented at: 69th Annual Meeting of the American College of Rheumatology; November 12–17, 2005; San Diego, Calif. Abstract 622.
- Herrero-Beaumont G, Román JA, Trabado MC, et al. Effects of glucosamine sulfate on 6-month control of knee osteoarthritis symptoms vs placebo and acetaminophen: results from the glucosamine unum in die efficacy (GUIDE) Trial. Presented at: 69th Annual Meeting of the American College of Rheumatology; November 12–17, 2005; San Diego, Calif. Abstract 1203.