Glucosamine for Arthritis: Hope or Hype?
WRITTEN BY NANCY WALSH D'EPIRO
PATIENTCARE / JULY 15,1999 www.patientcareonline.com
The publication of The Arthritis Cure in 1997, "the medical miracle that can halt, reverse, and may even cure osteo- arthritis" according to the book's cover copy, was greeted with considerable skepticism by the medical community and with tremendous enthusiasm by patients.1 The program detailed in this book, which also includes exercise, diet, and "beating the blues," centers on treating osteoarthritis (OA) by supplement-ation with glucosamine and chondroitin, two substances naturally produced in the body that are structural components of cartilage.
Patients purchased millions of copies of The Arthritis Cure, and sales, particularly of glucosamine, soared. Concern in the medical community increased, however, primarily because of the authors' claim of possible cure with the program. The first chapter of the book states, "The traditionally minded American medical establishment has turned a deaf ear to the exciting studies pouring forth from research centers and hospitals all over Europe and Asia. But this growing body of evidence is beginning to force doctors to reevaluate their thinking, to open their minds to the promise of glucosamine and chondroitin sulfates. They are slowly beginning to realize that osteoarthritis is not inevitable, and that it may even be cured."1
A number of clinicians, both conventional and alternative, have begun to take another look at these agents, especially since evidence is growing that long-term use of some nonsteroidal anti-inflammatory drugs (NSAIDS) is not only associated with potentially severe GI side effects but also may contribute to accelerating the progression of OA.2 While the term "cure" only appears in the popular literature, data suggesting some efficacy for glucosamine and chondroitin do exist, and the National Institutes of Health is now organizing a large, randomized trial that authorities hope will provide some definitive answers (see the Commentary, page 18).
Rationale for use: Glucosamine is a natural compound present in most human tissue, an aminomonosaccharide utilized in the synthesis of glycosaminoglycan andproteoglycans by articular cartilage. Chondroitin is a larger compound,composed of repeating units of glucosamine and attached sugars. While the precise biochemical cause of OA remains unknown, the primary physiologic process is thought to be increased degradation of articular cartilage proteoglycans, and the rationale for using glucosamine is that increasing the amount of available glucosamine would improve the ratio of cartilage repair to degradation. Because glucosamine is a natural component of tissues, it is hypothesized to cause fewer side effects than NSAIDS.
Exogenous glucosamine has been shown in vitro to enter the metabolic pathway of cartilage biosynthesis, stimulating the repair and production of proteoglycans.3 Proponents of its use suggest that a similar process exists in vivo, rendering the compound chondroprotective. Glucosamine also inhibits the inflammatory response but, because it does not affect cyclooxygenase, some investigators have suggested that it should be classified as antireactive rather than anti- inflammatory.4
The published data: Studies have appeared in the European literature evaluating the effects of oral or IM glucosamine, comparing them to those of placebo and NSAIDS. While some of the studies have been small and short-term, limiting the clinical applicability of their findings, the results of at least 3 randomized, double-blind trials are promising.
Oral glucasamine versus placebo: In a prospective, double- blind trial, 80 patients with established OA were randomized to receive glucosamine, 500 mg po tid, or placebo.5 After 7 days, pain was significantly reduced in the active treatment group, and after 14 days improvements also were seen in joint tenderness, swelling, and restriction of active movement. After 21 days of treatment, restriction of passive movement also was significantly less in the glucosamine group. The overall reduction in symptoms scores was 73.3% for the glucosamine group, compared to 41.3% for the placebo group. Minor adverse events such as constipation were reported by a few patients, but the investigators judged these to be unrelated to the medication.
COMMENTARY
Roland W. Moskowitz, MD
A meeting was sponsored by the NIH's Office of Alternative Medicine in January 1998 to evaluate the feasibility, utility, and cost-effectiveness of a clinical trial of glucosamine and chondroitin for osteoarthritis, and to provide recommendations for the study protocol. The advisory group decided that the trial will be placebo-controlled and will compare glucosamine alone with a regimen combining glucosamine and chondroitin. Pain and function will be measured by the Lequesne index and the Womack scale.
Patient Care asked one of the meeting participants, Roland W. Moskowitz, MD, Professor of Medicine, Division of Rheumatic Diseases, Case Western Reserve University, Cleveland, Ohio, what he expected the study to accomplish. "After the -publication of The Arthritis Cure, many of us questioned the validity of these agents. While there are some studies that suggest efficacy, the trials thus far have been short term and have included relatively small numbers of patients. We hope this will be the pivotal study that will provide definitive answers about glucosamine's safety and efficacy. If this is a useful tool in the treatment of arthritis, clinicians need to know that, and we need to have information on dosage and administration. If it's hype, this study should let us know that too."
Dr. Moskowitz also explained some of the difficulties associated with conducting studies such as this. "Unlike traditional drug studies, which are funded by pharmaceutical companies with the expectation that their investment will pay off later, the glucosamine trial is being funded publicly. With the establishment of the Office of Alternative and Complementary Medicine at the NIH, funding for studies of alternative therapies has increased. Because these trials are very costly, however, careful prioritization is crucial, with the money being used to evaluate approaches that make the most sense. And although the NIH isn't expecting to gain anything, as a drug company would, the results should be less prejudiced and more authoritative."
When enrollment for the trial is scheduled to begin, information will be available on the National Institute of Arthritis and Musculoskeletal and Skin Disease (NIAMS) Web site, at http://www.nih. gov/niams/
IM glucosamine versus placebo: In a multicenter, placebo- controlled, double-blind trial conducted in Germany, 155 outpatients with OA of the knee were treated for 6 weeks with glucosamine, 400 mg IM twice weekly, or placebo IM.6Patients were considered responders if they showed a decrease in at least 3 points in the Lequesne scale,* along with a posi-tive overall impression as assessed by the investigators. At the conclusion of the study, 55% of patients in the glucosamine group were classified as responders, compared to 33% in the placebo group. The decrease in Lequesne index was signifi- cantly greater in the glucosamine group, and the clinical improvement in the active treatment group was maintained for 2 weeks after the end of treatment. Dropouts due to adverse effects were similar in the 2 groups.
Oral glucosamine versus ibuprofen: In a randomized, double-blind study, 40 outpatients with unilateral OA of the knee were given oral glucosamine, 500 mg tid with meals, or ibuprofen, 400 mg tid, also with meals.7 The study lasted 8 weeks. Pain scores dropped more quickly with ibuprofen treat-ment but tended to remain the same after week 2 of treatment. The response to glucosamine was slower, but improvement increased throughout the trial and was significantly greater than improvement with ibuprofen at week 8. Side effects were mild and did not differ significantly between the glucosamine and ibuprofen groups.
A subsequent, larger trial also compared glucosamine to ibuprofen in 199 patients with OA of one or both knees.8 Over the 4-week treatment period, using the same dosages as in the previous positive study, both groups showed similar degrees of improvement, with effects being seen more quickly in the ibuprofen group. Overall response rates were 52% for the ibuprofen group and 48% for the glucosamine group, a difference that was not statistically significant. Side effects were seen significantly more often in the ibuprofen group (35% compared to 6%).
*The Lequesne index is a standardized, subjective evaluation of symptom severity in osteoarthritis: 14 points, extremely severe; 11 to 13 points, very severe; 8 to 10 points, severe; 4 to 7 points, moderate; I to 3 points, mild.
Seven patients in the ibuprofen group and 1 in the glucosamine group dropped out of the study because of adverse effects, which were mild to moderate in degree and primarily gastrointestinal.
With all the glucosamine trials, critics point out numerous flaws in methodology and study design, including small numbers, imprecise diagnoses, and lack of quantification of rescue acetaminophen.9 Nonetheless, a recent review of the literature published through 1997 observed, "There appears to be increasing evidence suggesting that this agent may provide several therapeutic benefits for patients with OA. These include a progressive and gradual reduction of articular pain and tenderness, improved mobility, a lack of significant toxicity with short-term use, and sustained improvement after drug withdrawal .... While studies conducted with glucosamine sulfate show some promise for the treatment of OA, additional long-term, rigorously controlled and better designed clinical trials with larger numbers of patients are needed to fully elucidate the safety and efficacy of this agent."3
A word from the Arthritis Foundation:
Following the publication of The Arthritis Cure, the Arthritis Foundation issued a statement expressing concern about patients' use of glucosamine and chondroitin, noting that no FDA review has addressed the compound's safety or efficacy. "Above all," the statement emphasized, "the Arthritis Foundation recommends that the use of proven treatments and disease-management techniques not be stopped in favor of the supplements." A more recent statement suggested a shift to a more that to a more positive assessment, noting that subsequent abstracts and meeting presentations have shown encouraging results. The later statement continues, "We await the publication of definitive studies to guide us as to when in the course of OA glucosamine sulfate and chondroitin sulfate might be helpful . . ."
While the Arthritis Foundation continues to advocate the American College of Rheumatology treatment guidelines for OA, which emphasize weight loss, exercise, joint protection, heat/cold applications, and the use of analgesic and anti- inflammatory medications, it now, also offers advice for patients considering using glucosamine:
* They should discuss the treatment with their physicians. Synthetic glucosamine is made from the chitin of crab shells and chondroitin is de rived from bovine trachea. Because of the nature of these sources, allergic reactions are possible.
* Patients with diabetes should exercise caution and plan to monitor their blood glucose levels more frequently if they use the supplements. Some animal studies have suggested glucosamine can increase blood glucose levels.
* Patients taking heparin or warfarin-like drugs should not take the supplements because of concerns about potential interactions.
* All patients with OA should continue to use appropriate proven therapies to help alleviate pain and limit future disability.
I Theodoskis J, Adderly B, Fox B. The Arthritis Cure. New York. St Martin's Press. 1997.
2. Rashad S, Revell P, Hemingway A, et al. Effect of non-steroidal anti- inflammatory drugs on the course of osteoarthritis. Lancet 1989:2:519- 522.
3. de Camara CC, Dowless GV. Glucosamine sulfate for osteoatlhrftts. Ann Pharmacother. 1998:32:580-587.
4. Barclay TS, Tsourounis C, McCart GM. Glucosamine. Ann Pharmacother. 1998:32:574-579.
5. Drovanti A, Bignamini AA, Rovati AL. Therapeutic activity of oral glucosamine sulfate in osteoarthritis:: a placebo-controlled investigation. Clin. Ther. 1980:3:260-272.
6. Reichelt A, Forster KK, Fisher M, et al. Efficacy and safety of intramuscular giucosamine sulfate in osteoarthritis of the knee. A randomized, placebo- controlled, double-blind study. Arzneimittelforschung. 1994:44:75-80.
7. Rovati LC. Clinical research in Osteoarthritis: design and results of short- term and long-term trials with disease-modifying drugs. Int J Tissue React.1992,14:243-251.
8. Muller-Fassbender H, Bach GL, et al. Glucosamine sulfate compared to ibuprofen in osteoarthritis of the knee. Osteoarthritis Cartilage. 1994:2:61-69.
9 Heyneman CA, Rhodes RS. Glucosamine for osteoarthritis cure or conundrum? Ann Pharmacother. 1998:32:602-603
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