Glucosamine for Arthritis: The Evidence Is Conflicting

Glucosamine for Arthritis:
The Evidence Is Conflicting

Stephen Barrett, M.D.

Osteoarthritis (OA), the most widespread type of arthritis, is a degenerative disease of the joints. Although sometimes capable of causing acute inflammation, it is most commonly a "wear-and-tear" disease involving degeneration of joint cartilage and formation of bony spurs within various joints. Trauma to the joints, repetitive occupational usage, and obesity are risk factors. Most people over 60 years of age have this affliction to some extent, with approximately 16 million sufferers requiring medical care. The main goal of treatment is to relieve pain.

In recent years, glucosamine and chondroitin have been widely promoted as a treatment for OA. Glucosamine, an amino sugar, is thought to promote the formation and repair of cartilage. Chondroitin, a carbohydrate, is a cartilage component that is thought to promote water retention and elasticity and to inhibit the enzymes that break down cartilage. Both compounds are manufactured by the body.

Research Findings

Laboratory studies suggest that glucosamine may stimulate production of cartilage-building proteins. Other research suggests that chondroitin may inhibit production of cartilage-destroying enzymes and fight inflammation too. Glucosamine supplements are derived from shellfish shells; chondroitin supplements are generally made from cow cartilage. Human studies have shown that either one may relieve arthritis pain and stiffness with fewer side effects than conventional arthritis drugs. But two problems remain. First, there has not been enough high-quality or long-range research to determine whether their use is practical. Second, because dietary supplement manufacture is not regulated, product quality (especially of chondroitin products) is not assured.

Some published studies comparing glucosamine or chondroitin to various standard medications have found that the drugs worked faster than the supplements. But they also found that several months after treatment ended, the analgesic effect of the supplements remained stronger.

In March 2000, a study in the Journal of the American Medical Association concluded:

Trials of glucosamine and chondroitin preparations for OA symptoms demonstrate moderate to large effects, but quality issues and likely publication bias suggest that these effects are exaggerated. Nevertheless, some degree of efficacy appears probable for these preparations [1].

An accompanying editorial cautioned:

As with many nutraceuticals that currently are widely touted as beneficial for common but difficult-to-treat disorders, the promotional enthusiasm often far surpasses the scientific evidence supporting clinical use. Until high-quality studies . . . are completed, work such as [the meta-analysis] is the best hope for providing physicians with information necessary to advise their patients about the risks and benefits of these therapies [2].

In 2001, the Lancet published the results of a three-year double-blind clinical trial involving 212 people with osteoarthritis who took either glucosamine or a placebo. The researchers found that symptoms improved 20% to 25% in the glucosamine group but worsened slightly in the placebo group. The x-ray examinations showed that serious narrowing of the knee-joint space—a sign of progression of the disease—occurred in only half as many patients taking glucosamine as in those receiving the placebo [3]. However, the Medical Letter has reported that the x-rays were questionably standardized; there was little correlation between the joint-space changes and the symptoms; and there was no difference between the glucosamine and placebo groups in the use of standard medication to "rescue" patients [4].

As for chondroitin, a controlled study of 300 patients with osteoarthritis of the knee found no effect on symptoms but indicated that long-term treatment with condroitin sulfate may retard progression of knee-joint narrowing as shown on x-ray films. However, the the authors stated that the clinical relevance of the structural results has to be further evaluated and further confirmatory studies would be needed [5].

The best-designed and most comprehensive study was published in 2006 in the New England Journal of Medicine. The 24-week study, which was funded by NIH, involved 1583 patients who were randomly assigned to receive 500 mg of glucosamine hydrochloride three times daily, 400 mg of sodium chondroitin sulfate three times daily, 500 mg of glucosamine plus 400 mg of chondroitin sulfate three times daily, 200 mg of celecoxib (Celebrex) daily, or a placebo. The study found that glucosamine and chondroitin, alone or together, did not reduce osteoarthritis knee pain more effectively than a placebo. The drug group did about 17% better than the placebo group [6].

Products

In the United States, glucosamine and chondroitin products are marketed as "dietary supplements." Glucosamine is available in many forms, including glucosamine sulfate, glucosamine hydrochloride (HCl), and N-acetylglucosamine (NAG), and may also contain a potassium chloride or sodium chloride salt. However, there appears to be no conclusive evidence that one form is better than another [7]. Chondroitin is typically sold as chondroitin sulfate. In December 1999 and January 2000, ConsumerLab.com tested 25 brands of glucosamine, chondroitin and combination products and found that (a) all 10 glucosamine-only products, passed the test but 2 chondroitin-only and 6 out of 13 combination products did not (because their chondroitin levels were too low). In January 2001, one of the combination products was removed because its manganese level was judged to be too high.

In 2001, Consumer Reports evaluated 19 products and reported:

Most . . . were reasonably well standardized, delivering at least 90 percent of the amount of glucosamine or chondroitin promised on the label, thereby meeting a new standard for the supplements proposed by the U.S. Pharmacopeia, which sets standards for drugs and proposes them for supplements. But four products —Now Double Strength Glucosamine & Chondroitin, ArthxDS Glucosamine Chondroitin, Solgar Extra Strength Glucosamine Chondroitin Complex, and Now Chondroitin Sulfate—failed to meet that standard. Two products—Solgar Extra Strength Glucosamine Chondroitin Complex and Twinlab CSA (Chondroitin Sulfate)—recommended too few pills per day to supply the dose used in the successful clinical trials. Several others listed the recommended number of pills as a range that permits consumers to take a dose that may be inadequate [8].

In 2001, Vital Nutrients recalled two products (Vital Nutrients Joint Ease and Verified Quality Joint Comfort) that had been found to contain aristolochic acid, a substance that can cause kidney toxicity and cancer [9].

Safety Considerations

No study so far has found any serious side effects from either glucosamine or chondroitin. The most common side effects are increased intestinal gas and softened stools. However, animal research has raised the possibility that glucosamine may worsen insulin resistance, a major cause of diabetes. So far, studies in humans have not substantiated that risk. Nevertheless, people with diabetes should monitor their blood-sugar level particularly carefully when using that supplement. There have been no reports of allergic reactions to glucosamine. But since it's made from shellfish shells, people who are allergic to seafood should use it cautiously, watching for reactions, or avoid it entirely. As for chondroitin, it can cause bleeding in people who have a bleeding disorder or take a blood-thinning drug.

Authorities Disagree

Respected medical authorities regard use of these compounds as plausible and agree that more research is needed to place them in proper perspective. However, disagreement exists about how practical it is to use them now. The organizations I trust most give different advice. In 2002, Consumer Reports stated:

The long-term safety and efficacy of glucosamine and chondroitin remain unclear. Still, our medical consultants say there's enough evidence to conclude that products containing the amounts of glucosamine, chondroitin, or both that worked in the clinical trials might be worth trying for people with osteoarthritis—particularly if they've experienced or are likely to experience significant side effects from conventional painkillers. (Those amounts were 1,500 milligrams per day of glucosamine salt—glucosamine bound to another molecule—and 1,200 milligrams of chondroitin salt.)

While no one knows which formulation works best, it makes sense to try one of the least expensive combination products, such as Puritan's Pride Maximum Strength Glucosamine Chondroitin or Spring Valley Glucosamine Chondroitin Double Strength; they deliver both of the ingredients at lower cost than the chondroitin-only products and, in most cases, at a similar cost to the glucosamine-only products. For those who are concerned mainly with cost, however, Spring Valley Glucosamine Complex was the least expensive product we tested (although to get the clinical-trial dosage, you need to ignore the range of daily pills recommended on the label and take the maximum, three per day).

It may take two months . . . to produce any significant improvement. If you see no effect by then, it's probably best to try a different approach [10].

The Medical Letter, which is the medical profession's most respected drug advisory publication, has been more conservative:

Glucosamine with or without chondroitin may have some beneficial effect on osteoarthritis, and studies up to 3 years in duration have found no more adverse effects than with placebo, but most Medical Letter consultants are skeptical. Whether glucosamine offers any advantages over better established drugs such as acetaminophen, traditional NSAIDS or selective Cox-2 inhibitors remains to be determined. As with other dietary supplements, the quality and purity of the ingredients may vary [4].

The 2006 New England Journal report was accompanied by an editorial which concluded:

[Based on this study], it seems prudent to prudent to tell our patients with symptomatic osteoarthritis of the knee that neither glucosamine hydrochloride nor chondroitin sulfate alone has been shown to be more efficacious than placebo
for the treatment of knee pain. If patients choose to take dietary supplements to control their symptoms, they should be advised to take glucosamine sulfate rather than glucosamine hydrochloride and, for those with severe pain, that taking
chondroitin sulfate with glucosamine sulfate may have an additive effect. Three months of treatment is a sufficient period for the evaluation of efficacy; if there is no clinically significant decrease in symptoms by this time, the supplements
should be discontinued. Furthermore, there is no evidence that these agents prevent osteoarthritis in healthy persons or in persons with knee pain but normal radiographs [11].

The Bottom Line

Decisions to use glucosamine or chondroitin must be based on information that is less complete than is desirable. In addition, product quality control may be a significant problem. Here's my advice:

The first step in seeking care for arthritic symptoms should be to obtain a competent diagnosis.
The next step should be to explore the pros and cons of treatment options with a competent physician
Whether glucosamine and/or chondroitin are useful is conflicting. This usually means that negative evidence will eventually prevail. If you decide to try them anyway, have a knowledgeable physician guide how you do it.
Consumer Reports, ConsumerLab.com, or your physician can help in choosing the product.
Ignore any practitioner or seller who promises a "miracle cure" for arthritis. Never buy a dietary supplement in response to a solicitation by mail or though s radio or television ad.
Shop carefully for price. The Puritan's Pride mail-order division, which has frequent "2-for-1" and "3-for-one" sales, sells products that cost only $4 to $5 per month. (Be sure, of course, to ignore claims the company makes for its products. No seller of dietary supplements, herbs, or homeopathic remedies should be trusted for advice on whether they are useful.)

References

McAlindon TE and others. Glucosamine and chondroitin for treatment of osteoarthritis: A systematic quality assessment and meta-analysis JAMA 283:1469-1475, 2000. [Full-text version is accessible online for JAMA subscribers.]
Tanveer E, Anastassiades TP. Glucosamine and chondroitin for treating symptoms of osteoarthritis: Evidence is widely touted but incomplete. JAMA 283:1483-1484, 2000. [Full-text version is accessible online for JAMA subscribers.]
Reginster JY and others. Long-term effects of glucosamine sulfate on osteoarthritis progression: a randomized, placebo-controlled trial. Lancet 357:251-256, 2001. Archives of Internal Medicine 163:1514-1522, 2003.
Update on glucosamine for osteoarthritis. Medical Letter 43:111-112, 2001.
Michel BA. Chondroitins 4 and 6 sulfate in osteoarthritis of the knee: a randomized, controlled trial.
Richy F. and others. Structural and symptomatic efficacy of glucosamine and chondroitin in knee osteoarthritis: A comprehensive meta-analysis.
Product review: GLUCOSAMINE and CHONDROITIN. ConsumerLab Web site, accessed Jan 22, 2002.
Joint remedies. Consumer Reports, Jan 2002.
Vital Nutrients recalls Joint Ease & Verified Quality Brand Joint Comfort Complex because of adverse health risk associated with aristolochic acid. News release, May 24, 2001.
Clegg DO and others. Glucosamine, chondroitin sulfate, and the two in combination for painful knee osteoarthritis. New England Journal of Medicine 354:795-808, 2006.
Hochberg MC. Nutritional supplements for knee osteoarthritis—Still no resolution. New England Journal of medicine 354:848-850, 2006.

This article was revised on April 7, 2006.