From the July 2000 Issue of Nutrition Science News
Carmia Borek, Ph.D.
When it comes to human movement, nothing helps quite so much as joints. Because of their location and constant utility, joints are prone to stress, injury and inflammation. A popular natural product is glucosamine sulfate--a molecule that builds the protective components of joints. Glucosamine is increasingly being used by people suffering from osteoarthritis, a disease that affects some 21 million Americans. Although glucosamine is also used for tendinitis and as a preventive measure against generalized joint pain, there are no studies yet to back these latter claims.
To understand glucosamine's role, it is important to understand joint structure and disease. Cartilage in the joints, called articular cartilage, acts as a shock absorber to cushion the blows of daily wear and tear. Articular cartilage is made of a unique connective tissue that consists of collagen and proteoglycans. Collagen is a strong, fibrous, insoluble protein. Proteoglycans are large, carbohydrate-rich protein chains made up of 95 percent polysaccharides and 5 percent protein called glycosaminoglycans (GAGs). GAGs are composed of repeating two-sugar units (disaccharides) that contain glucosamine sulfate and other amino sugars. Bathing the articular cartilage is synovial fluid, which contains many substances including its chief component, hyaluronic acid. Hyaluronic acid forms the backbone of other proteoglycans and is responsible for the high viscosity of synovial fluid and its lubricating and shock-absorbing properties.  As well, synovial fluid provides nutrition for the joint cartilage.
Osteoarthritis is caused by age-related cartilage breakdown as well as by metabolic changes including the secretion of cartilage-degrading enzymes that destroy collagen and proteoglycans. The proteoglycan that is depleted more than others is hyaluronic acid.
Osteoarthritis worsens with age. Its frequency rapidly increases beyond age 55, and by age 75 about 85 percent of individuals have evidence of osteoarthritis. [2 ] The disease can occur in younger individuals, especially due to sports trauma--witness the shoulder or elbow of a baseball player or knees of a basketball player. Women tend to suffer more often from osteoarthritis in their hands and knees and men in their hips.
A Therapeutic Agent
Glucosamine sulfate, a constituent of cartilage, is a small molecule that is easily absorbed into the blood and joints when taken as a supplement. In vitro studies using cells in culture show that glucosamine stimulates GAG production. [3 ] Glucosamine sulfate has been shown to decrease pain and improve joint function in osteoarthritis patients. Although its exact mechanism for improving osteoarthritis symptoms is not known, experiments suggest glucosamine may stimulate cartilage matrix formation, reduce enzymatic digestion of cartilage components and provide an anti-inflammatory effect. [4 ]
An alternative or, perhaps, additional explanation is that glucosamine stimulates the production of hyaluronic acid in joint synovial fluid. A review of clinical and veterinary studies shows that the injection of hyaluronic acid into osteoarthritic joints of patients suffering from low levels in the synovial fluid relieves pain and improves mobility. Glucosamine is a starting block for the synthesis of hyaluronic acid, and lack of glucosamine limits hyaluronic acid synthesis. Thus, injection of hyaluroic acid and supplemental glucosamine may share a common mechanism of action; namely, to normalize synovial production of hyaluronic acid. High doses of supplemental glucosamine sulfate may reverse the abnormally depleted hyaluronic acid, provide relief and, in the long run, aid in repairing damaged cartilage. [1 ]
Glucosamine sulfate -- as well as the related compound chondroitin sulfate and formulas that combine the two -- are sold as effective remedies for osteoarthritis. Evidence from studies in Asia and Europe shows that daily supplementation reduces pain and eases mobility in osteoarthritis patients. Critics -- including a recent meta-analysis of 15 trials published in the Journal of the American Medical Association -- say that although the substances show "moderate to large effects," the studies were small, short-term, had design flaws, and that large, long-term studies are needed for reliable clinical evidence of efficacy. [5 ] What does the evidence say about glucosamine sulfate itself?
A double-blind clinical study on 178 Chinese osteoarthritis patients carried out in Beijing, China, reported the effectiveness of glucosamine sulfate in reducing pain. The patients had osteoarthritis of the knee and were randomized into two groups. One group received 1,500 mg/day glucosamine sulfate in three divided doses -- the standard therapeutic dose. The other group received 1,200 mg/day ibuprofen, a popular non-steroidal anti-inflammatory drug (NSAID). Researchers then evaluated knee swelling and pain at rest, at movement and with pressure. After two weeks, patients showed symptom improvement with both glucosamine and ibuprofen -- but glucosamine generally showed a stronger effect and was better tolerated than ibuprofen. 
In another double-blind study, 252 German patients with osteoarthritis of the knee received 1,500 mg/day glucosamine sulfate in three divided doses. After four weeks, glucosamine sulfate was more effective than placebo in reducing pain and improving mobility. 
A synthesis of data from several studies on glucosamine sulfate given orally, intravenously or injected into the muscle or joints of osteoarthritis patients shows that glucosamine gradually lowers joint pain and tenderness while improving ease of movement and walking speed. One meta-analysis of studies conducted mostly in Europe and Asia performed by researchers at the School of Pharmacy at Campbell University in North Carolina reports glucosamine sulfate produces an overall 50 percent improvement in pain and mobility in patients. [8 ] Another review from the Medical College of Virginia in Richmond, published earlier this year, found glucosamine sulfate to be as effective as ibuprofen in treating osteoarthritis of the knee. 
A recent review of two meta-analyses, conducted at Case Western Reserve University School of Medicine in Cleveland, Ohio, reported positive effects of glucosamine sulfate for treating knee and hip osteoarthritis. [10 ] The amount generally administered was 1,500 mg/day glucosamine sulfate. The review included six double-blind, placebo-controlled trials that lasted longer than four weeks. The authors saw the trial as positive if pain and joint motion improved in the treatment group by 25 percent more than placebo. Glucosamine proved to be from 17.6 to 61.4 percent better than controls. The authors concluded that glucosamine showed a "substantial benefit" for treating osteoarthritis, but the studies provided insufficient information on the design and conduct to allow definite evaluation.
The authors suggested that differences of effectiveness reported in the literature may relate to the quality of the nutritional supplement used. Studies in the United States have revealed a number of preparations claiming to contain certain doses of glucosamine have less than the dosages described. [10 ]
In contrast to positive outcomes, a recent double-blind, randomized, placebo-controlled clinical study at the Veterans Medical Center in Prescott, Ariz., did not agree.  The study examined the effects of glucosamine sulfate on 98 patients with osteoarthritis of the knee. Half of the patients, ages 34 to 81, received 1,500 mg/day glucosamine in three divided doses, and half took placebo. The end point of the study was effects on pain intensity at rest and while walking compared to baseline, after 30 and 60 days of treatment. The results showed no statistical difference in pain reduction between the glucosamine group and placebo.
When asked to explain the negative results, lead researcher Joseph P. Rindone, Ph.D., says the group did not know why glucosamine did not work, but notes patients were older, heavier and had worse cases of arthritis as seen by radiographs than patients in many other studies. This may have something to do with the negative findings, he says.
The safety profile of glucosamine has been good aside from occasional reports of minor stomach upset. However, a preliminary trial unveiled in April suggests glucosamine sulfate may increase the risk of developing insulin resistance and may aggravate blood-sugar control in diabetic patients. The double-blind, randomized, placebo-controlled 12-week study involved 15 patients and was conducted in 1999 by scientists at Los Angeles College of Chiropractic and MetaResponse Sciences. 
Realizing the need for more studies on glucosamine, the National Center for Complementary and Alternative Medicine, at the National Institutes of Health in Silver Spring, Md., recently announced its sponsorship of the first U.S. multicenter clinical trial, allotting $6.6 million for the study. The trial is to involve 1,124 patients in nine centers and will examine the efficacy of both glucosamine and chondroitin sulfate, used separately or in combination, given over 16 weeks, on reducing pain and improving function in patients with osteoarthritis of the knee. If the results are as positive as the evidence amassed so far, it ought to firmly establish glucosamine in the mainstream of American health care and health care products.
Carmia Borek, Ph.D., is a research professor at Tufts University School of Medicine in Boston. She is author of "Maximize our Healthspan with Antioxidants: The Baby Boomer's Guide" (Keats Publishing, 1995).
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