Glucosamine and Chondroitin

• Glucosamine and chondroitin sulfate are popular dietary supplements for people who suffer from osteoarthritis.
• These supplements are thought to prevent the breakdown of cartilage and/or stimulate the production of cartilage although the exact biochemical mechanism is not known.
• Studies have shown that glucosamine and chondroitin sulfate are better than placebo and equal to but not better than nonsteroidal anti-inflammatory drugs to reduce pain and increase range of motion. However, the methods used in these studies have been highly criticized and the results may be overstated.
• The usual doses, 1500 mg glucosamine daily and 1,200 mg chondroitin sulfate daily, are thought to be safe in the short-term (up to 12 weeks). The long-term safety is not known.

Name
Glucosamine and Chondroitin (Chondroitin sulfate)

Description
Glucosamine is made from glucose and glutamine. It is incorporated into glycosaminoglycans (unbranched polysaccharides) which are incorporated into proteoglycans (proteins that contain glycosaminoglycans). Proteoglycans are found in every tissue in the body, primarily in the extracellular matrix, and are remarkable for their ability to attract water.

Chondroitin sulfate is one of at least seven glycosaminoglycans and is a primary component of cartilage. Because of its ability to attract water, chondroitin sulfate helps to “lubricate” joints. Unfortunately, the amount of chondroitin sulfate in the cartilage declines with age.

Glucosamine and chondroitin sulfate are made by the body and are not associated with dietary intake. The source of these compounds in supplements is often seashells or animal cartilage such as shark cartilage.

Usage
Glucosamine and chondroitin sulfate are marketed to people with osteoarthritis and to athletes who experience overuse injuries as a way to relieve pain and increase range of motion. They are sometimes referred to as “slow acting osteoarthritis drugs.”

Prevalence
The prevalence is unknown but sales in the United States are approximately 1 billion dollars.

Chemical Mechanism
Osteoarthritis (OA) is a degenerative disease that increases with age and currently affects approximately 21 million adults in the United States. It is characterized by the breakdown of cartilage, a narrowing of the joint space, and changes in subchondral bone. These changes cause pain and limit range of motion particularly in the hands, knees, and hips. Elite and recreational athletes of any age may suffer from OA in part from the stress of excessive, repeated motion. Common sites in athletes are shoulders, elbows, hips, knees, and ankles.

The biochemical cause of osteoarthritis is unknown but the outcome is well documented: the proteoglycans found in cartilage are degraded faster than they can be repaired. The cartilage becomes abraded, new bone is formed in the joint, the ability of the joint to function is compromised, and pain and inflammation result. Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used to treat the pain and inflammation. It is hypothesized that glucosamine and chondroitin sulfate could prevent the breakdown of cartilage and/or stimulate the production of cartilage, both of which could counter the loss of cartilage that occurs with osteoarthritis.

Approximately 90 percent of the glucosamine sulfate ingested is absorbed. Of that which is absorbed, 8-12 percent is retained in the tissues, 20-30 percent is excreted in the urine and the remainder is exhaled as CO₂. In addition to glucosamine, the synthesis of glycosaminoglycans requires a substantial amount of sulfate and it is known that sulfate depletion leads to a decrease in glycosaminoglycan synthesis. The sulfate found in either the glucosamine sulfate or the chondroitin sulfate may be an important element in the efficacy of these supplements. Absorption of chondroitin sulfate is limited, less than 10% of that ingested.

The mechanism of action of glucosamine or chondroitin sulfate is unknown but it is hypothesized that each may inhibit lysosomal enzymes or may stimulate proteoglycan synthesis. The mechanism is different from NSAIDs, which inhibit cyclooxygenase.

Clinical Evidence
At least 20 clinical studies totaling approximately 3,500 patients have been conducted using glucosamine. Nine chondroitin studies (n=799) have been published. There are no clinical studies in humans where glucosamine and chondroitin sulfate have been administered together although the two compounds are often sold together.

The studies, conducted mainly in Europe and Asia, suggest that glucosamine or chondroitin sulfate is better than placebo and equal to but not better than nonsteroidal anti-inflammatory drugs (NSAIDs). However, the results of these studies have been questioned (see scientific research section below) and at the present time the Arthritis Foundation does not recommend their use due to lack of conclusive evidence. These compounds have a slower response time and can not offer the immediate pain relief associated with NSAIDs. However, both appear to have a much lower toxicity when compared to NSAIDs (a particular problem with the elderly) and fewer adverse reactions than some NSAIDs. Some studies suggest that the effects of glucosamine and chondroitin sulfate persist up to four weeks after withdrawal (1-3).

A protective effect against the breakdown of cartilage has not been demonstrated in vivo but in vitro studies suggest that metabolic changes to the cells of the cartilage do occur. The addition of glucosamine or chondroitin sulfate to human chondrocytes (cartilage cells) has been shown to stimulate the synthesis of proteoglycan and decrease the release of lysosomal enzymes.

Scientific Research
At the heart of the controversy regarding the effectiveness of glucosamine and chondroitin sulfate is the quality of the scientific studies. While the results of the studies have shown that these supplements are better than placebo and equal to NSAIDs, they have been soundly criticized for their methodological flaws. Small sample size, short trial duration, lack of randomization of subjects, absence of double-blinding, and use of hospitalized patients rather than free-living subjects have raised questions about the reliability and validity of the results. A meta-analysis of studies conducted between 1980 and 1998 found only 15 of 37 studies were randomized, double-blind, placebo-controlled studies of sufficient duration. Fourteen of the 15 were supported by or performed by the supplement manufacturer. Statistical applications allowed the authors to analyze the 15 studies and judge the effectiveness of treatments on a scale of 0.2 (small effect) to 0.8 (large effect). The calculated effect of glucosamine was 0.44 (0.5 is considered moderate effect) and 0.78 for chondroitin sulfate. The authors noted that the effectiveness was decreased when only high quality or large sample size studies were considered (4). This meta-analysis has led several authorities to suggest that glucosamine and chondroitin sulfate may be effective, although the effectiveness may be overstated.

A recent (January 2001) study not included in the meta-analysis has shown that glucosamine sulfate can prevent structural changes that occur with osteoarthritis. This double-blind, randomized, placebo-controlled study is notable for its long duration (3 years) and its measurement of the narrowing of joint space in the knee. The authors concluded that glucosamine sulfate modified the structure of the tissue and as a result subjects experienced less pain and greater range of motion over a three-year period than those receiving a placebo (5).

Independent studies are needed and such a study is underway. The National Institutes of Health is funding a study of 1,500 subjects who will receive one of four treatments¬óGlucosamine, chondroitin sulfate, a combination of the two, or a COX-2 inhibitor (a newer treatment for OA with lower risk for gastrointestinal bleeding than traditional NSAIDs)¬óor placebo. The results of this well-designed study are eagerly awaited and are anticipated by March 2002.

Administration
Glucosamine and chondroitin supplements are ingested orally as tablets.

Dosage
The generally recommended doses are 1,500 mg of glucosamine daily and 1,200 mg of chondroitin sulfate daily. After 60 days, a daily maintenance dose of 750 mg glucosamine and 600 mg of chondroitin sulfate is often recommended. It should be pointed out that there are no dose-response studies of these compounds. Most clinical studies use 1,500 mg of glucosamine and 1,200 mg chondroitin sulfate daily in 4-12 week protocols and these doses have been used to judge short-term safety.

A widespread problem in the United States appears to be the amount of these compounds found in a given brand. Some products have been independently tested and found to have full potency while other brands have significantly less than that stated on the label. In Europe, glucosamine sulfate is a prescription drug and meets quality control standards.

Contraindications
No contraindications are known but it is always wise to consult with a physician before taking any dietary supplement.

Precautions/Warnings
Short-term studies suggest that glucosamine and chondroitin sulfate are safe. Long-term studies have not been conducted and the long-term safety of these compounds is not known.

Those allergic to shellfish should be cautious of supplements derived from seashells in case there may be any residual fish left after the cleaning process. Some environmentalists warn that because shark cartilage is a major source of these dietary supplements an increase in their use may decimate an already fragile shark population.

Banned/Permitted
Glucosamine and chondroitin supplements are listed as non-permissible under NCAA Bylaw 16.5.2.2 (Proposal No.99-72) Nutritional Supplements.

Legality
Glucosamine and chondroitin sulfate supplements are a legal substance.

References

1. Barclay, T.S., Tsourounis, C. and McCart, G.M. Glucosamine. Annals of Pharmacotherapy. 1998;32:574-579.

2. Deal, C.L. and Moskowitz, R.W. Nutraceuticals as therapeutic agents in osteoarthritis. Rheumatic Disease Clinics of North America. 1999;25(2):379-395.

3. Delafuente, J.C. Glucosamine in the treatment of osteoarthritis. Rheumatic Disease Clinics of North America. 2000;26(1):1-11.

4. McAlindon, T.E., LaValley, M.P., Gulin, J.P. and Felson, D.T, Glucosamine and chondroitin for treatment of osteoarthritis: A systemic quality assessment and meta-analysis. Journal of the American Medical Association. 2000;283(11):1469-1475.

5. Reginster, J.Y., Deroisy, R., Rovati, L.C., Lee, R.L., Lejeune, E., Bruyere, O., Giacovelli, G., Henrotin, Y., Dacre, J.E., and Gossett, C. Long-term effects of glucosamine sulphate on osteoarthritis progression: A randomised, placebo-controlled trial. Lancet. 2001;357:251-256.