Glucosamine sulfate and chondroitin sulfate supplements are the most widely used dietary supplements for the treatment of osteoarthritis, with an annual sales of nearly $730 million in 2004 . Glucosamine is an amino monosac-charide that is the most fundamental building block required for the biosynthesis of several classes of compounds that require amino sugars, such as glycosaminoglycans and proteoglycans . The raw material for glucosamine is derived from chitin, a biopolymer present in the exoskeleton of marine invertebrate animals . Chondroitin sulfates are a class of glycosaminoglycans required for the formation of proteoglycans found in joint cartilage .
The rationale for the use of glucosamine and chondroitin is based on the assertion that osteoarthritis is associated with a local deficiency in some key nutritional substances, and that providing these substances addresses this deficiency and supports cartilage repair [58,69]. Glucosamine sulfate has been shown to be capable of stimulating proteoglycan synthesis and regeneration of cartilage in animals after experimentally induced damage and inhibiting the degradation of proteoglycans [70,71]. It also has been suggested that chon-droitin sulfate may increase proteoglycan synthesis and inhibit the activity of degradative enzymes [72,73].
Clinical research with glucosamine sulfate and chondroitin sulfate
Numerous clinical trials have tested the efficacy of glucosamine sulfate and chondroitin sulfate to reduce pain and provide functional improvement in patients with joint disorders, such as osteoarthritis. These studies were evaluated in a meta-analysis by McAlindon and colleagues , who reviewed 15 placebo-controlled glucosamine or chondroitin trials. The authors of the meta-analysis reported that trials of glucosamine and chondroitin preparations for the management of osteoarthritis symptoms showed moderate-to-large effects, but that quality issues and likely publication bias suggest that these effects are exaggerated .
Many of the design flaws of glucosamine sulfate and chondroitin sulfate studies, including the failure to adhere to the intention-to-treat principle, the enrollment of small numbers of patients, potential bias because of sponsorship by a manufacturer of dietary supplements, and inadequate masking of the study agent, were addressed in the GAIT (Glucosamine/chondroitin Arthritis Intervention Trial), a study sponsored by the National Institutes of Health . In GAIT, Clegg and coworkers  investigated glucosamine sulfate, chondroitin sulfate, and the two supplements in combination in a multicenter, double-blind, placebo-controlled and celecoxib-controlled study with 1583 patients with symptomatic knee osteoarthritis who were randomly assigned to receive 1500 mg of glucosamine sulfate daily, 1200 mg of chondroitin sulfate daily, both glucosamine sulfate and chondroitin sulfate, 200 mg of celecoxib daily, or placebo for 24 weeks. Up to 4000 mg of acetaminophen daily was allowed as rescue analgesia. The mean age of the patients was 59 years, and 64% were women . The primary outcome measure was a 20% decrease in knee pain from baseline to week 24.
The investigators reported that glucosamine sulfate and chondroitin sulfate were not statistically significantly better than placebo in reducing knee pain by 20% (the primary outcome they had defined) . Compared with the rate of response to placebo, the rate of response to glucosamine sulfate was 3.9% higher (P = .30), the rate of response to chondroitin sulfate was 5.3% higher (P = .17), and the rate of response to combined treatment was 6.5% higher (P = .09), whereas the response in the celecoxib control group was 10% higher (P = .008) (Fig. 2) . The investigators concluded that glucosamine sulfate and chondroitin sulfate alone or in combination did not reduce pain effectively in the overall group of patients with osteoarthritis of the knee .
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