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To the Editor:

I wish to thank the authors of the 2 letters and Vlad and colleagues for their further comments regarding their glucosamine meta-analysis and my editorial. I share Dr. Greenwald's concern about the increasing number of reviews and meta-analyses about glucosamine. Unfortunately, all pharmacologic treatments for osteoarthritis (OA) have a small (I do not believe “marginal”) effect size, but high-quality glucosamine sulfate trials show that the efficacy of this substance in 6-month to 3-year trials is similar to that of nonsteroidal antiinflammatory drugs (NSAIDs) over much shorter periods, with effect sizes of 0.27 and 0.33 on pain and function, respectively (1), compared with respective effect sizes of 0.32 and 0.29, at best, for NSAIDs in trials shorter than 13 weeks (2). Nevertheless, I think it is important to continue clinical research on all drugs available at present and in the future, to improve our knowledge on how they should be used best in our patients, as Dr. Greenwald points out. In this respect, Vlad and colleagues seem to trust only trials performed under FDA supervision; this is not particularly respectful of the many European investigators performing high-quality clinical research, the authorities who supervise them, and even the FDA, which accepts clinical trials from Europe and elsewhere. Since I was able to get all glucosamine sulfate trial data and repeat the analyses, it is not clear why Vlad and colleagues did not do so as well.

I share the view of Moore and colleagues. I believe that a more transparent collaboration with the pharmaceutical industry is extremely important. Conversely, Vlad and colleagues suggest that “pivotal” trials are designated as such by the industry after favorable effects have been shown. The many companies that have discontinued their drugs after negative results in pivotal trials will be surprised to learn that. Pivotal trials are appropriately sized, controlled (with placebo, in OA), randomized, hypothesis-testing clinical studies of high quality, including double-blinding with adequate allocation concealment. In the case of glucosamine sulfate, in my opinion, they should be performed with the same substance, formulation, and dosage to avoid the problems of true heterogeneity introduced by the many manufacturers of dietary supplements with variable pharmacokinetic and pharmacodynamic properties. In my editorial I referred to the prescription medication, similar to what has recently been done in a meta-analysis of chondroitin sulfate that selected the 3 recent large-scale trials reported elsewhere (3). In the editorial (4) accompanying the report of that meta-analysis, Dr. Felson, the senior author in the meta-analysis by Vlad and colleagues, stated “I believe that, by identifying a subgroup of trials with high-quality, consistent evidence, they have provided a compelling estimate of the likely efficacy.” I believe that these principles should be applied here, where high-quality pivotal trials show the efficacy of the prescription formulation of glucosamine sulfate, with a credible effect size.

Acknowledgements

Dr. Reginster has received consulting fees from and/or served on paid advisory boards (less than $10,000 each) for Servier, Novartis, Negma, Lilly, Wyeth, Amgen, GlaxoSmithKline, Roche, Merckle, Nycomed, NPS, and Theramex. When speaking at the invitation of a commercial sponsor, he has received lecture fees (less than $10,000 each) from Merck, Sharp, and Dohme, Lilly, Rottapharm, IBSA, Genevrier, Novartis, Servier, Roche, Merckle, Teijin, Analis, Theramex, Nycomed, and Novo-Nordisk. Dr. Reginster also has received grant support (less than $10,000 each) from Bristol-Myers Squibb, Fondation Leon Frédéricq (Liège), Standard de Liège, Merck, Sharp, and Dohme, Novartis, Roche, and GlaxoSmithKline.

Jean-Yves Reginster MD, PhD*, * World Health Organization Collaborating Centre for Public Health Aspects of Rheumatic Disease, Centre Hospitalier Universitaire Sart Tilman, University of Liege, Liege, Belgium.