The following review of DONA™ or glucosamine sulfate supplements, was borrowed with permission from the new arthritis book by Carol Eustice, the guide on arthritis for About.com since 1997, and Scott Zashin M.D., a widely respected and recognized arthritis specialist, the former primary arthritis consultant for About.com, and current arthritis expert for Web MD.
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Borrowed from Chapter 5The Buzz about Glucosamine
Published Clinical Trials / Studies for Glucosamine Sulfate
The GAIT TrialsThe Glucosamine/Chondroitin Arthritis Intervention Trial (GAIT) was a large, randomized, placebo-controlled trial conducted at 16 sites across the United States. In other words, it was the kind of study we are told to pay attention to—those that have a large number of study participants who are randomly assigned the treatment being tested (in this case, glucosamine) or the comparison treatment, which can be a placebo (an inactive substance or dummy pill). Still, in the end, the trial results left questions about the benefits of taking the supplement. Actually, the GAIT trial was conducted in two parts: a primary study that investigated whether glucosamine, either alone or together with chondroitin, was effective for relieving pain associated with knee osteoarthritis and an additional (ancillary) study that investigated whether glucosamine or chondroitin decreased structural damage associated with knee osteoarthritis.Primary GAIT 2006 The original GAIT trial was a four-year study to assess the effectiveness of glucosamine. The results were published in the New England Journal of Medicine on February 22, 2006. In what came as a surprise to some, study results revealed that the highly touted combination of glucosamine hydrochloride (HCL) and chondroitin sulfate did not provide significant pain relief among all of the study participants. A smaller subgroup of study participants with moderate to severe pain showed significant relief from a combination of the supplements, however. There were nearly 1,600 study participants with knee osteoarthritis enrolled in GAIT. They were randomly assigned to receive one of five daily treatment courses for 24 weeks:• Glucosamine HCL alone (1,500 mg)• Chondroitin sulfate alone (1,200 mg)• Glucosamine HCL (1,500 mg) and chondroitin sulfate(1,200 mg) in combination• Placebo• Celecoxib (200 mg) serving as a positive control A pain reduction of 20% or more at week 24 compared with pain at the study onset was defined as a positive treatment response. Here’s what researchers found: 70% of participants taking Celecoxib experienced 20% or greater pain relief compared with 60% of those taking placebo.This was considered statistically significant pain relief. But between the other treatments being tested and placebo, there were no significant differences among all participants. Notably, however, 79% of a subgroup of participants with moderate to severe pain experienced a 20% or greater reduction in pain while taking the combination of glucosamine HCL and chondroitin sulfate compared with 54% receiving placebo. Participants in the mild pain subgroup receiving glucosamine and chondroitin sulfate, together or alone, did not experience statistically significant pain relief compared with placebo. But the relatively small number of participants in the moderate to severe subgroup makes those encouraging results preliminary,” according to rheumatologist Daniel O. Clegg, MD, of the University of Utah School of Medicine, Salt Lake City (lead researcher of GAIT).7 Of the nearly 1,600 study participants, 78% were in the mild pain subgroup, and 22% were in the moderate to severe pain subgroup. It should be noted, too, that study participants were allowed to take up to 4,000 mg of acetaminophen daily for pain, except during the 24-hour period before they were assessed at weeks 4, 8, 16, and 24. The use of acetaminophen was reportedly low (averaging fewer than two 500-mg tablets per day). No other NSAIDs (nonsteroidal anti-inflammatory drugs) or opioid analgesics were permitted during the study.Ancillary GAIT 2008 With a subset of participants from the original GAIT study, researchers conducted a two-year ancillary GAIT study at nine sites to assess the prevention of structural damage of joints. Patients from the original GAIT trial were offered the chance to participate in the ancillary study for an additional 18 months—a total of two years. In the ancillary study, the randomly assigned treatments were:• Glucosamine HCL (500 mg, three times daily)• Sodium chondroitin sulfate (400 mg, three times daily)• Combination of glucosamine and chondroitin sulfate• Placebo• Celecoxib (200 mg daily) Enrolled for the ancillary study were 572 GAIT participants with x-ray evidence of moderate to severe knee osteoarthritis in one or both knees. The results, published in the journal Arthritis & Rheumatism in October 2008, revealed that glucosamine and chondroitin sulfate, together or alone, were no more effective than placebo in slowing cartilage loss in knee osteoarthritis (measured as a reduction in joint space width, the distance between the ends of bones in a joint observed on x-ray). But the interpretation of those results was less straightforward than just stated: participants taking placebo had a smaller loss of cartilage than what was predicted. Confusion continued to mount about the effectiveness of glucosamine, and no definite conclusions were drawn. Two-Year GAIT 2010While the original and ancillary studies looked at the effectiveness of glucosamine HCL and chondroitin sulfate, taken alone or together, on pain, the two-year GAIT study, published in the Annals of the Rheumatic Diseases in June 2010 (http://ard.bmj.com/content/69/8/1459.abstract), evaluated the safety and effectiveness (in terms of pain and function) of the supplements. Participants who took glucosamine and chondroitin, separately or in combination, had outcomes similar to the experiences of patients who took Celebrex or placebo. In the two-year GAIT, 662 participants were enrolled with moderate to severe knee osteoarthritis. They were randomized to use one of the five treatments in the ancillary study. Researchers concluded that over the two-year period, none of the treatments was clinically different in pain response or function from placebo. Glucosamine and Celecoxib did show “beneficial but not significant trends.” Adverse reactions were similar for all treatment groups. Serious adverse events were rare for all treatments.Dr. Theodakis disputes validity of GAITSome people, including Dr. Theodakis (author of The Arthritis Cure) had questions—questions about the validity of GAIT. On his own Web site, Dr. Theodakis said, “The study failed. The results shouldn’t have even been published. Perhaps this explains the long delay. It appears that the authors manipulated data with a number of statistical adjustments. They refer to this in the article. The study was submitted and subsequently revised.”Many doctors recommend DONA glucosamine if you are going to try the supplement. You may be wondering, Why DONA? Quite simply, DONA is the glucosamine sulfate that has been in 90% of clinical trials, and it is the brand with the most clinical evidence for safety and effectiveness. (Recall that glucosamine HCL was used in the disappointing GAIT study). DONA is the trademark name of the original glucosamine sulfate product from Rotta Pharmaceuticals Inc. The recommended dosage and directions from DONA is 2 caplets (750mg each) together daily with water or juice. The product is also available in a powder form.At the annual meeting of the American College of Rheumatology (ACR) in November 2000, results from a three year independent clinical trial were presented. The results supported previous study results of DONA glucosamine that concluded it had a positive effect on supporting joint health. The study reported at ACR in 2000 was conducted in the Prague Institute of Rheumatology and enrolled 202 patients with osteoarthritis who were randomly assigned 1,500 mg glucosamine sulfate once daily or a placebo. The findings verified those reported at the 1999 ACR meeting: glucosamine sulfate significantly decreases progression of knee osteoarthritis over three years.9 Both studies were carried out according to international guidelines for conducting clinical trials on osteoarthritis drugs.DONA is sold as a prescription drug in Europe, so it must meet European standards, as do drugs in the United States that are regulated by the U.S. Food and Drug Administration. While DONA is up against tough standards in Europe, you can purchase it off the shelf, without prescription, in the United States. While DONA has been a prescription drug in many countries for a decade, it became available in the United States and Canada in 2001. Among patients who do well when taking DONA glucosamine, some experience relief from joint stiffness in just two weeks, but the full benefit is realized after about three months.Cochrane ReviewA Cochrane review, first published in 2001, updated in 2005, and reviewed again in 2008, assessed randomized, controlled trials that evaluated the effectiveness and toxicity of glucosamine as a treatment for osteoarthritis. The update included 25 studies that involved 4,963 osteoarthritis patients.Here’s what researchers found: High-quality studies indicated that pain improved similarly whether the participant was randomized to receive glucosamine or placebo. When all studies were considered (high-quality, low-quality, and old studies), glucosamine improved pain more than placebo. Studies that tested only the Rotta brand of glucosamine (DONA) showed that glucosamine improved pain more than placebo. This was the case whether the study was high quality, low quality, or old. High-quality studies showed that DONA glucosamine improved function more than placebo when one type of pain scale was used but not when a different pain scale was used. In terms of safety, side effects affected the same number of participants whether they took glucosamine or placebo. Stomach upset and joint pain appeared to be the main side effects. The Cochrane review concluded that people with osteoarthritis taking glucosamine may reduce their pain, may improve their physical function, and probably will not experience side effects.