Glucosamine therapy for osteoarthritis: an update.

Since our 1999 editorial in The Journal on the interesting and evolving field of glucosamine (GlcN) therapy for osteoarthritis (OA)1, a number of important developments have taken place. We will highlight the most significant recent developments. We recently updated our Cochrane Review of the efficacy and toxicity of GlcN therapy in OA2. The 2005 update includes a systematic review and metaanalysis of 20 randomized controlled trials (RCT). Collectively, the 20 RCT found GlcN to be superior to placebo, with a 28% (change from baseline) improvement in pain and a 21% (change from baseline) improvement in function using the Lequesne Index. The standardized mean differences were equivalent to 0.61 for pain and 0.51 for function. In the 4 RCT in which the Rotta preparation of GlcN was compared with a nonsteroidal antiinflammatory drug, GlcN was superior in 2 and equivalent in 2. It is importance to recognize, however, that the results from the 20 RCT were not uniformly positive, and that the reasons for this discrepancy remain largely unexplained3,4. Five RCT failed to show that GlcN was more effective than placebo in OA5-9. In addition, the Cochrane Review reported that, in patients administered GlcN, the Western Ontario and McMaster University Osteoarthritis Index (WOMAC) outcomes of pain, function, and stiffness did not reach statistical significance. Analysis restricted to 8 RCT with adequate allocation concealment also failed to show a benefit of GlcN for pain and WOMAC function. Therefore, the impressive degree of improvement with GlcN that was noted in the earlier Cochrane Review in 1999 was found to be significantly less in the updated Cochrane Review in 2005. The recently published trial by Clegg, et al10 also failed to show any overall efficacy of GlcN.HCl in subjects with OA of the knee. A discrepancy was also observed when subgroup analyses were performed comparing the Rotta preparation of glucosamine sulfate (GlcN.S) versus other GlcN preparations. In the 10 RCT in which the Rotta preparation of GlcN was compared to placebo, GlcN was found to be superior in terms of pain and functional impairment resulting from symptomatic OA. Pooled results from studies using a non-Rotta preparation failed to show a benefit for both pain and function. Why are the favorable results from the published RCT no longer uniformly positive2,3? Several explanatory factors might help account for this discrepancy, including differences in the subjects enrolled and the outcomes evaluated, the methodological quality of the trials, and the degree of cointervention that was allowed in the RCT. Also, there is a possibility that the GlcN.S preparation utilized could contain small amounts of a contaminant(s) with biological activity. Such a possibility could account for differences between studies performed with GlcN.HCl versus GlcN.S, or even between different GlcN.S preparations (e.g., Rotta vs non-Rotta). However, that an additional molecule is contained within such preparations has not been shown. Another important limitation with extrapolating the generally favorable results from the GlcN RCT lies in the fact that most of the studies (65%) in the updated Cochrane Review evaluated exclusively the prescription medicine made by the Rotta Pharmaceutical Company — a GlcN.S preparation that is approved as a prescription drug for OA in the European Union. In North America, GlcN is not considered a conventional prescription drug, rather it is considered as a dietary supplement, which is widely available as an over the counter preparation. Since the content and purity of the various over the counter preparations is known to vary markedly, the relative efficacy and safety of the various preparations may also vary markedly11-14. It is apparent that if GlcN is to be used as a therapeutic agent in OA, it is important that GlcN products conform to a standard in their description. It is important to define in chemical terms, at the outset, what is meant by “glucosamine” (GlcN) and by “glucosamine sulfate” (GlcN.S). The latter term can be confusing as it is not clear if it means that the compound administered contains GlcN as an ionically-bound sulfate salt, or if the molecule of GlcN is covalently bound to sulfate, at one or more positions around the sugar ring. The type of chemical binding of GlcN to the sulfate could greatly affect the biological and chemical properties of the compound being tested. We suggest that “glucosamine sulfate salt” should be abbreviated as GlcN.S, to mean GlcN and an ionically bound sulfate salt. Correspondingly, “glucosamine hydrochloride salt” should be abbreviated as GlcN.HCl. For “glucosamine sulfate,” where a SO4 molecule(s) is covalently bound to a specific carbon of the GlcN molecule, standard biochemical notation should be employed, as for example GlcN-3-SO4 or GlcN-6-SO4. In this