Glucosamine Update: A New Study and a New Product

When I recently wrote about glucosamine, I discussed the evidence up through the New England Journal of Medicine study of 2006, which I thought was a pretty definitive study showing that neither glucosamine, chondroitin or a combination of the two was more effective than placebo.  Subsequent studies have continued to fuel the controversy. One 2007 study showed that glucosamine sulfate was better than placebo for knee osteoarthritis.  Another 2007 study showed that glucosamine HCl and chondroitin, with or without exercise, were no better than placebo for knee osteoarthritis. Sources like the Natural Medicines Comprehensive Database believe the evidence favors glucosamine sulfate but not glucosamine hydrochloride.

A new study was published 19 February 2008 in the prestigious Annals of Internal Medicine.  It is arguably the best study to date, and may shed some light on the controversy. Carried out in the Netherlands in a primary care setting, it studied 222 patients with hip osteoarthritis over a 2 year period. Half the patients took glucosamine sulfate 1500 mg a day; half took a placebo. They concluded that glucosamine sulfate was no better than placebo in reducing symptoms and progression of hip osteoarthritis.

Some of the highlights:

1. It was done with glucosamine sulfate, the form preferred by advocates.
2. It was independently funded,  without pharmaceutical company or supplement manufacturer support.
3. It had adequate numbers of subjects (111 per group).
4. It had a low dropout rate.
5. It was carefully double-blinded.
6. At the end of the study they confirmed that patients had not been able to guess which group they were in.
7. The study lasted for 2 years, much longer than previous studies.
8. In addition to subjective (pain) endpoints, they measured an objective endpoint:  joint space narrowing on x-ray.  They tried to improve on the methods used for this measurement in previous studies, which had been questioned. They achieved excellent inter-observer agreement.
9. They did quality control checks to insure accurate dosage.
10. They followed the published guidelines for clinical trials in osteoarthritis as formulated by a task force of the Osteoarthritis Research Society over 16 months of deliberations.
11. It was published in one of the most prestigious peer-reviewed medical journals.

It seems to me that this study should put an end to the controversy.  Previous research can be characterized as inconclusive, with 8 out of 15 trials showing no effect, and with higher quality trials less likely to show an effect.  This study did its level best to avoid the pitfalls of previous studies and provide as definitive an answer as possible.

Of course, it won’t put an end to the controversy, because there are too many people who are invested (emotionally, financially or otherwise)  in the idea that glucosamine works. They can always complain that maybe it works for knees but not for hips, or that a different dosage might have worked better, or that it works for some small sub-set of patients. There will always be “one more study” to do.

Rozendaal, R.M., et al, . (2008). Effect of Glucosamine Sulfate on Hip Osteoarthritis. Annals of Internal Medicine, 148(4), 268-277.

Part 2 – JointFlex Cream.

In another bizarre development, a cream containing glucosamine and chondroitin is now on the market – you simply rub it on wherever the pain is. The trademarked Fusome proprietary delivery system allows it to penetrate into the joint and work its magic. It offers instant relief and a money-back guarantee. I saw an ad for JointFlex in the newspaper and looked into the science behind its claims. There is one published study from Australia that supposedly supports its use.

The study, published in The Journal of Rheumatology in 2003, compared a topical preparation to placebo in 63 patients over an 8-week period. They concluded that it was effective in relieving pain in osteoarthritis of the knee, and improvement was evident within 4 weeks. The test cream  contained glucosamine sulfate, chondroitin sulfate, shark cartilage, camphor and peppermint oil. The rationale for this mixture is not explained, but they claim chondroitin acts as a transfer agent for dermal drugs. The test cream also contained high efficiency emulsifiers, skin emollients, and micro-encapsulation of the active ingredients. The placebo cream used conventional skin emollients, petrolatum and mineral oil, conventional emulsifiers, and stearic acid and glycerol stearate rather than the proprietary technology. It also contained a lesser amount of peppermint oil.  They comment that “there may have been some slight differences in the texture of the placebo and active creams” but they made no effort to ask patients which they thought they were getting, or to verify that the lesser amount of peppermint could not be used to identify the placebo. The endpoints were subjective.  They made no effort to determine whether the active ingredients had actually penetrated into the joint. The study has not been replicated elsewhere.

In the first place, the quality of this research was inferior in almost every way to the study described above in Part 1. In the second place, the study appears to show that glucosamine and chondroitin are effective topically, but the marketer completely disregards that, even while using the study to validate its product!

The real surprise for me was the list of ingredients in JointFlex on the Natural Medicines Comprehensive Database website. Only one active ingredient is listed, and that is camphor 3.1%!! There is a long list of inactive ingredients: Acetylated lanolin, acrylates/C10-30, alkyl acrylate, crosspolymer, Aloe Vera, C12-15 alkyl benzoate, Chondroitin Sulfate, purified water, diazolidnyl urea, dimethicone, dimethiconol stearate, disodium EDTA, dl panthenol, Glucosamine Sulfate, glycerin, Glycerol stearate, glycosaminoglycans, hydroxylated lanolin, hydroxypropylene methylcellulose, lodopropynyl, butylcarbomate, methyl gluceth-20, methyl glucose, sesquistearate, Peppermint oil, polysorbate 20, Potassium carbomer, tocopheryl acetate.

I went back to the JointFlex website and noticed a strange disclaimer: “These nutrients have been added as part of the skin conditioning base. We believe that the healthier and moister the skin, the better we can deliver the active pain relieving ingredients [sic – the NMCD lists only one active ingredient] to the spot where they are needed most making JointFlex® effective at relieving pain. We do not make any other claims at this time regarding these nutrients.”

This is really weird. I don’t know what’s going on here, and I’m not sure I want to know.  I can’t see my way to recommending glucosamine in any form until I see more credible evidence that it works.

Is doing more glucosamine studies a good use of our research dollars, or is it time to turn to more promising avenues of research?

REFERENCE:

Rozendaal, R.M., Koes, B.W., van Osch, G.V., Uitterlinden, E.J., Garling, E.H., Willemsen, S.P., Ginai, A.Z., Verhaar, J.A., Weinans, H., Bierma-Zeinstra, S.M. (2008). Effect of Glucosamine Sulfate on Hip Osteoarthritis. Annals of Internal Medicine, 148(4), 268-277.