Stick-and-ball model of the glucosamine molecule (from the Wikimedia Commons, image by Benjah-bmm27)

Stick-and-ball model of the glucosamine molecule (from the Wikimedia Commons, image by Benjah-bmm27)

Osteoarthritis, the “wear-and-tear” type of arthritis, affects a great many of us as we grow older. Knee pain is a common symptom. The diet supplements glucosamine and chondroitin have been proposed as a more “natural” treatment than pharmaceuticals, and they are components of a number of proprietary “joint health” formulations like Osteo Bi-Flex. The GAIT study (Glucosamine/Chondroitin Arthritis Intervention Trial), compared glucosamine, chondroitin, a combination of the two, and a pharmaceutical (celecoxib) to a placebo in patients with knee pain from osteoarthritis. The only one that worked better than placebo was celecoxib. I wrote about the GAIT trial in 2008. The study was reported in the media as both negative and positive. The positive reports emphasized the subgroup analysis: in one of ten subgroups, patients with moderate to severe pain, the combination of glucosamine and chondroitin outperformed placebo. But in the subgroup of patients with mild to moderate pain, it did not. The authors themselves commented that their study was not powered to draw any conclusions from subgroups and that further studies would be required. (The “power” of a study is a measure of its ability to show an association or relationship between two variables if such a relationship exists.) Now a further study with sufficient power claims to have confirmed the subgroup findings. This may encourage some people to try glucosamine/chondroitin, but I remain skeptical.

Contradictory evidence

Following the GAIT trial, there were several other studies showing that glucosamine was ineffective for osteoarthritis. There are other studies showing it is effective. There are a lot of studies out there, with varying quality. I think it’s fair to say the evidence is mixed and still questionable even when the new study is added into the mix. I was particularly impressed by a 2004 discontinuation study that followed-up on a group of patients who had had a positive response to glucosamine. It compared continuance of glucosamine with one half of the group to substitution with a placebo in the other; it found no difference in disease flares or any of the secondary outcomes they looked at. Pain is particularly susceptible to placebo responses, and studies of pain must be interpreted with more caution than studies with more objective outcomes. The American Academy of Orthopaedic Surgeons reviewed the evidence and recommended against the use of glucosamine, chondroitin, and the combination. They said:

Glucosamine and chondroitin sulfate have been extensively studied. Despite the availability of the literature, there is essentially no evidence that minimum clinically important outcomes have been achieved compared to placebo, whether evaluated alone or in combination.

The new study

The new study, “Combined chondroitin sulfate and glucosamine for painful knee osteoarthritis“, was published in the Annals of the Rheumatic Diseases on Jan 14, 2015. The full text is available online. It was a randomized double-blind study of patients with moderate to severe knee pain from osteoarthritis. 264 patients were given a prescription drug sold in Europe that contains 400 mg chondroitin sulfate plus 500 mg glucosamine (taken 3 times daily) and 258 were given celecoxib, a non-steroidal anti-inflammatory drug (NSAID), in a dose of 200mg once daily, plus placebo capsules to provide the same number of pills. Celecoxib outperformed glucosamine/chondroitin for the first four months of treatment, but by 6 months there was no difference. They concluded that glucosamine/chondroitin was equivalent to celecoxib. The authors recognize that current evidence-based guidelines advise against glucosamine/chondroitin, but think their study supports its use in patients with cardiovascular or gastrointestinal conditions where NSAIDs are inadvisable.

Why I remain skeptical

A Medscape reporter contacted me about the new study because I had written a letter to the editor that was published in American Family Physician where I identified misconceptions about the GAIT trial. She asked me several questions, and in the resulting article she devoted two paragraphs to my answers. I expressed my reservations and said I would withhold judgment until the weight of evidence falls more clearly on one side or the other. In the comments to the Medscape article, a pathologist said:

I doubt that dietary glucosamine or chondroitin sulfate are absorbed from the gut as such. Further, human cartilage contains N-acetyl galactosamine, not glucosamine. Depending on source, the dietary CS may have a different structure than human CS. Finally, the cartilaginous glycosaminoglycan matrix is synthesized by the chondrocytes, and it is naive to assume that dietary supplements will “home” to that avascular tissue. It is all placebo effect, making lots of money for manufacturers.

I don’t know enough about that to comment on it, but I remain skeptical for several reasons of my own:

  • Neither drug alone has been shown effective, only the combination. A synergistic effect can’t be ruled out, but such an effect would be unusual.
  • Glucosamine and chondroitin are produced in the body in far greater amounts than the pills contain. Wallace Sampson, one of the founders of SBM, wrote: “Glucosamine is not an essential nutrient like a vitamin or an essential amino acid, for which small amounts make a large difference. How much difference could that small additional amount make? If glucosamine or chondroitin worked, this would be a medical first and worthy of a Nobel. It probably cannot work.”
  • Patients who responded continued to respond when their glucosamine was replaced by placebo.
  • I don’t know of any other medication for pain that is effective only for more severe pain and ineffective for less severe pain.
  • The study was done with a prescription formulation that is not available in the US; patients who buy it over the counter may not be getting the equivalent of the study drug.
  • Celecoxib was more effective in the first 4 months and was equally safe; I’d think most patients would want the faster-acting option.

Conclusion

Glucosamine/chondroitin might work for osteoarthritis, and might be worth trying in patients who can’t take NSAIDs, but the evidence is still far from clear. Based on the currently available evidence, I wouldn’t feel comfortable prescribing it or telling patients “it works;” but if a patient wanted to try it, I wouldn’t have any objections to a therapeutic trial. There don’t appear to be any worrisome side effects, and even if patients only had a placebo response, they might feel better.

Posted by Harriet Hall

Harriet Hall, MD also known as The SkepDoc, is a retired family physician who writes about pseudoscience and questionable medical practices. She received her BA and MD from the University of Washington, did her internship in the Air Force (the second female ever to do so),  and was the first female graduate of the Air Force family practice residency at Eglin Air Force Base. During a long career as an Air Force physician, she held various positions from flight surgeon to DBMS (Director of Base Medical Services) and did everything from delivering babies to taking the controls of a B-52. She retired with the rank of Colonel.  In 2008 she published her memoirs, Women Aren't Supposed to Fly.