To the Editor:

I read with interest the American College of Rheumatology 2012 recommendations for the use of therapies in hand, hip, and knee osteoarthritis (OA) published recently in Arthritis Care & Research (1). These recommendations provided welcome guidance for the management of OA. The guidelines conditionally recommended “against the use of glucosamine” for knee OA. This recommendation was based on the results from the Glucosamine/Chondroitin Arthritis Intervention Trial (GAIT) and 3 meta-analyses (2–5). However, the recommendation against the use of glucosamine appears to have been made using a surface-level argument because the authors did not address key factors, such as which form(s) of glucosamine may or may not be effective and whether glucosamine may have disease-modifying effects.

The first point to consider is that there is no generic equivalency between supplements such as glucosamine. Results from trials evaluating one form or preparation of glucosamine cannot be reliably extrapolated to other forms or preparations. There are different salt forms of glucosamine, primarily glucosamine hydrochloride and glucosamine sulfate, that may have different therapeutic effects. There are also different levels of manufacturing quality among glucosamine products, which also could result in different therapeutic effects. This is precisely why in the several meta-analyses cited by the guideline authors, different forms of glucosamine were separately analyzed (3, 5).

Along these lines, the GAIT should not be seriously considered in determining a recommendation for or against the use of glucosamine. This trial examined a form of glucosamine hydrochloride that is not commercially available. The results of the trial, therefore, pertain only to the studied product and not to any product that a consumer could potentially buy. Additionally, the GAIT should be considered a failed trial for a multitude of reasons. One reason is that no therapy in the trial provided a “clinically meaningful” benefit, as defined by the authors, not even celecoxib (2). This may be due to a high placebo response, which would have been difficult for any treatment to overcome. Additionally, celecoxib was found to be less effective than a combination of glucosamine plus chondroitin in patients with moderate to severe pain symptoms.

Regarding the findings from the meta-analyses cited by the authors, Towheed et al generally found no overall benefit of glucosamine supplements for the treatment of pain in OA. However, when the analysis was conducted using a specific glucosamine sulfate product (Dona, Rottapharm/Madaus), there was a significant benefit over placebo. Additionally, the analysis found that this form of glucosamine sulfate significantly slowed radiologic progression of knee OA (3).

Vlad et al found that there were no benefits for glucosamine hydrochloride products; however, their analysis of glucosamine sulfate showed there were significant benefits compared to placebo. This was especially true when a specific commercial preparation of glucosamine sulfate was used. The authors also pointed out that industry-sponsored studies of glucosamine sulfate appeared to be more likely to show a benefit compared to non–industry-sponsored studies (4).

Wandel et al found a significant benefit for treatment with glucosamine in general compared to placebo. However, when only glucosamine hydrochloride studies were analyzed, there was no statistically significant benefit. When only glucosamine sulfate studies were analyzed, there was a statistically significant benefit. This analysis also found a statistically significant effect on progression of OA in the knee. It is important to note that the effect size observed in this analysis was relatively small and, therefore, the authors concluded that these findings may not be clinically meaningful (5).

Taken as a whole, the data from these meta-analyses are surprisingly consistent. The data show that glucosamine hydrochloride formulations are ineffective for reducing the symptoms of knee OA. The data also consistently show that glucosamine sulfate preparations, especially a specific commercial formulation, significantly reduce pain symptoms in patients with OA of the knee. Glucosamine sulfate may also significantly slow disease progression as measured by joint space narrowing.

Clearly, based on data and experience, the impact of glucosamine sulfate on individual patients varies widely. Some patients may experience little to modest benefits, while others may experience very clinically meaningful benefits. Considering these data and their consistency, the guideline authors should reconsider their recommendations. While it is entirely appropriate to recommend against using glucosamine hydrochloride, it would also seem appropriate to consider recommending glucosamine sulfate preparations.

  • 1
    Hochberg MC, Altman RD, April KT, Benkhalti M, Guyatt G, McGowan J, et al. American College of Rheumatology 2012 recommendations for the use of nonpharmacologic and pharmacologic therapies in osteoarthritis of the hand, hip, and knee. Arthritis Care Res (Hoboken) 2012; 64: 46574.
  • 2
    Clegg DO, Reda DJ, Harris CL, Klein MA, O'Dell JR, Hooper MM, et al. Glucosamine, chondroitin sulfate, and the two in combination for painful knee osteoarthritis. N Engl J Med 2006; 354: 795808.
  • 3
    Towheed TE, Maxwell L, Anastassiades TP, Shea B, Houpt J, Robinson V, et al. Glucosamine therapy for treating osteoarthritis. Cochrane Database Syst Rev 2005; 2: CD002946.
  • 4
    Vlad SC, LaValley MP, McAlindon TE, Felson DT. Glucosamine for pain in osteoarthritis: why do trial results differ? Arthritis Rheum 2007; 56: 226777.
  • 5
    Wandel S, Juni P, Tendal B, Nuesch E, Villiger PM, Welton NJ, et al. Effects of glucosamine, chondroitin, or placebo in patients with osteoarthritis of hip or knee: network meta-analysis. BMJ 2010; 341: c4675.

Philip J. Gregory PharmD, FACN*, * Creighton University, Omaha, NE.