One in six Americans suffers from some form of arthritis. Osteoarthritis (OA), the most common type, is caused by the degeneration of joint cartilage, often resulting from physical injury or repetitive stress. The chronic pain and irritation produced by the damaged cartilage is typically managed by nonsteroidal anti-inflammatory drugs (NSAIDs).

Another therapeutic option is glucosamine sulfate, a naturally occurring form of amino sugar that aids in the body’s manufacturing of cartilage. In some studies, glucosamine, often combined with chondroitin, has been found as effective as low-dose NSAIDs.

Background

Glucosamine sulfate is derived from chitin, a crystalline compound found in the shells of crab, shrimp, and lobster.1 This supplement has long been used in Europe for the treatment of arthritis. In the United States, glucosamine first gained favor among veterinarians for use in dogs and horses. It wasn’t until the late 1990s, though, when The Arthritis Cure, by Jason Theodakis, lauded the supplement’s effects that glucosamine became a popular OA therapy. Today, Americans spend more than $700 million annually on glucosamine products.

Mechanism of action

The exact mechanism of action of glucosamine in OA treatment is not clear. It is known that glucose and glutamine form glycosaminoglycans. These amino sugars, together with other polysaccharides, connect to a core protein that is the precursor to as much as 50% of the hyaluronic acid produced. A gel-like aminoglycan, hyaluronic acid is essential for cartilage function. It serves as a constant lubricating fluid that bathes the joint for friction reduction and is a carrier for cellular metabolic needs.2

When used in sulfate form as glucosamine sulfate, the sulfate molecule degrades to its ionic form and is more readily absorbed in the GI system than the glucosamine alone. This renders it readily available for assisting in chondrocyte repair and regeneration.

Efficacy

Until recently, available studies showed that glucosamine sulfate was at least as effective in pain control for OA as NSAIDs and had a mild preventive effect when taken over long periods of time. A 2000 meta-analysis of 16 studies (N = 2,029) demonstrated that patients who took glucosamine sulfate 1,500 mg per day for six weeks had a 60% improvement in pain and a 33% improvement in function.3

Knee OA appears to be the most amenable to glucosamine therapy, probably due to the large bodies of fibrous cartilage in the knee joint. One randomized, double-blind, placebo-controlled trial assessed glucosamine sulfate’s effect on long-term progression of OA joint-structure changes and symptoms. After three years, patients taking glucosamine exhibited no significant joint-space loss compared with those on placebo.4

Recently, the National Center for Complementary and Alternative Medicine sponsored the first large-scale, multicenter trial of the effects of glucosamine on knee OA.5 Participants (N = 1,583) were randomized to receive 1,500 mg glucosamine daily, 1,200 mg chondroitin sulfate daily, glucosamine plus chondroitin sulfate, 200 mg celecoxib daily, or placebo. The trial lasted 24 weeks. Overall, glucosamine and chondroitin alone or in combination showed minimal pain reduction. The rate of response to glucosamine was 63.7%, compared with a 60.1% response to placebo.5 Although many other large previously conducted trials showed positive effect, all had various design and statistical flaws that made their data questionable. Despite the unfavorable new findings, more research is needed to fully evaluate glucosamine’s effectiveness.

Interactions and side effects

Glucosamine sulfate in high doses has been shown to produce drowsiness, headache, nausea, vomiting, anorexia, constipation or diarrhea, heartburn, and rare cases of rash and other hypersensitive reactions. Because the supplement is manufactured commercially from chitin, any known sensitivity to shellfish or iodine should be noted, and this product should not be used. To date, no studies have been conducted to assess safety in women who are pregnant or nursing. Pediatric data are also limited, but because OA is a disease of aging, the pediatric population is not likely to be a high priority for research.

High levels of glucosamine may cause an elevation in the international normalized ratio; therefore, the supplement should not be taken by those patients on warfarin. Theoretic evidence also suggests that glucosamine may inhibit the effect of oral antidiabetic agents, both those increasing beta-cell secretion and those enhancing cellular sensitivity.

Dose

Glucosamine sulfate is available in both capsule and tablet form for oral dosing. The general recommended daily dose for adults in either form is 1,500 mg for patients who weigh <200 lb and 2,000-2,250 mg for those >200 lb. Lower doses should be given to patients who are very thin or underweight. The total daily dose is usually divided into three 500-mg servings taken with food, although there are no dose-specific trials to confirm if thrice-daily use is superior to a single daily dose or if concomitant food intake enhances or impairs absorption.

Summary

Although improvement of OA with glucosamine has been clinically proven, symptom relief is a long-term process. Most available data agree that maximal relief is not noted until well into the second month of therapy (more usually the third) and continues to improve to a stable point at about three years. Glucosamine therapy is not intended to obviate the need for traditional conservative measures in treating OA, including weight loss, physical therapy, and joint-sparing lifestyle changes. In cases of severely degenerated joints, damage may be so severe that neither nutrapharmaceutical nor pharmaceutical therapy is sufficient and orthopedic surgical intervention is needed. 

References

1. Morelli V, Naquin C, Weaver V. Alternative therapies for traditional disease states: Osteoarthritis. Am Fam Physician. 2003;67:339-344.

2. Patient information: Treatment options. Hyaluronic acid. Available at uconnsportsmed.uchc.edu/patientinfo/whathurts/treatment/hyaluronic_acid.html. Accessed August 7, 2006.

3. Towheed TE, Anastassiades TP, Shea B, et al. Glucosamine therapy for treating osteoarthritis. Cochrane Database Syst Rev. 2001;(1):CD002946.

4. Reginster JY, Deroisy R, Rovati LC, et al. Long-term effects of glucosamine sulphate on osteoarthritis progression: a randomised, placebo-controlled clinical trial. Lancet. 2001;357:251-256.

5. Clegg DO, Reda DA, Harris CL, et al. Glucosamine, chondroitin sulfate, and the two in combination for painful knee osteoarthritis. N Engl J Med. 2006;354:795-808.