Glucosamine: where are we now?

The GAIT trial (Glucosamine, chondroitin sulfate, and the two in combination for painful knee osteoarthritis) was recently published in the New England Journal of Medicine. The study was designed to answer the question of wether or not Glucosamine has any benefit in treating patients with osteoarthritis. It compared three treatment groups: Glucosamine, Chondroitin, Glucosamine and Chondroitin, Celebrex only, or placebo. The authors concluded that neither Glucosamine nor Chondroitin helped reduce pain in patients with osteoarthritis of the knee. However, a subgroup of patients with moderate to severe osteoarthritis may experience some benefit fromt he combination of Glucosamine in combination with condroitin.

I heard an interview with Dr. Mark Hochberg, one of the worlds leading authorities in osteoarthritis and editor of a major textbook of Rheumalogy. He discussed his recomendations to patients and views on the subject in light of the GAIT trial results. He stated that since this trial did not conclude there is any benefit from the medication, he is instructing his patients to discontinue the supplement. He then admitted that some of his patients felt worse after discontinuation of the drug and restarted the medication against his advice. I found this response very interesting. If I did the same thing in my practice I feel I would lose a tremendous amount of credibility. I'll elaborate my own views later.

There have been other studies prior to the GAIT trial that yielded mixed results. A study out of Prescott, Az VA Medical Center found that Glucosamine was no better than placebo. In contrast, a study out of Belgium published in the Lancet found that Glucosamine not only helped relieve symptoms of osteoarthritis but also helped delay progression of osteoarthritis by Xray of the knee. A study out of Prague, Czech Republic also found significant symptom relief and delay of progression by Xray while yet another study out of the UK found no benefit when compared to Placebo. The long-awaited study from the NIH (the GAIT tria) was supposed to answer all these questions. In my humble opinion, it raised more questions than answered.

The GAIT study however has been criticized for a number of reasons. First, the reduction of pain in the placebo group was unusually high - about 2/3 of patients in the placebo group found significant relief. Second, the investigators used Glucosamine HCL rather than Glucosamine Sulfate. The latter is more commonly prescribed and it is the prescription form available in Europe through Rottapharm. Third, there seemed to be some benefit in patients with moderate to severe osteoarthritis of the knee when glucosamine was combined with chondroitin. Finally, the results were surprising given that other studies found that patients derived significant pain relief.

So, what should doctors tell their patients? Since the therapy with glucosamine sulfate is very safe, I think a trial is worthwhile. Take glucosamine sulfate (not glucosamine hydrochloride) for 3 months. If you feel better, then continue the therapy. If you do not feel any improvement, then discontinue the product. This approach seems reasonable at least until the reusults of a disease modifying effect are available. That is, if the product prevents progression of arthritis so as to prevent the need for a joint replacement, then we may reconsider.


• N Engl J Med. 2006 Feb 23;354(8):858-60.

Glucosamine, chondroitin sulfate, and the two in combination for painful knee osteoarthritis.

• Arthritis Rheum. 2005 Aug 15;53(4):628-9; author reply 629-30.

Randomized, double-blind, placebo-controlled glucosamine discontinuation trial in knee osteoarthritis.
Arch Intern Med. 2002 Oct 14;162(18):2113-23.


Glucosamine sulfate use and delay of progression of knee osteoarthritis: a 3-year, randomized, placebo-controlled, double-blind study.

Rheumatology (Oxford). 2002 Mar;41(3):279-84.


A randomized, double-blind, placebo-controlled trial of glucosamine sulphate as an analgesic in osteoarthritis of the knee.

Lancet. 2001 Jan 27;357(9252):251-
Long-term effects of glucosamine sulphate on osteoarthritis progression: a randomised, placebo-controlled clinical trial.

• West J Med. 2000 Feb;172(2):95.

Randomized, controlled trial of glucosamine for treating osteoarthritis of the knee.

Joint Injections in Rheumatoid Arthritis

Over the last several months there has been a few articles that highlighted the benefits of intraarticular (IA) corticosteroid injections (cortisone shots to the joint). My bias in clinical practice has been for sometime to opt for IA injections in lieu of oral or intramuscular corticosteroid injections. I feel the clinical response is more robust and there appear to be less systemic side effects. So what are those benefits?

First and foremost is structural protection of the joint. Some studies have found that not only does the inflammation improve but there is less damage to the joint tissues. Second, the thickness of the synovium (the lining of the joint which is the source of inflammation and joint damage in Rheumatoid Arthritis) decreases resulting in less swelling and less erosion into the bone and cartilage. Third, there seems to be less "spill over" of inflammation from the injected joint to other joints. The result is that even the joints that were not injected improve to some extent. Fourth, there is less side effects. Since the medication is concentrated at the site of inflammation, there is less distribution to other tissues and thus less exposure to the potential harms of the medications. This includes the dreaded suppression of the adrenal glands. Fifth, there appears to be little consequence, if any, to the injected joint.

Finally, there is the surprising potential effect on lymphoma. We know that patients with Rheumatoid arthritis have a two-fold increase in risk of this cancer. Baecklund et al reported their findings from a large cohort study in Sweden. They followed more than seventy thousand patients with RA between 1964 and 1995. 378 patients developed lymphoma. When evaluating for risk factors, they found that the risk of lymphoma was primarily associated with the level of inflammation and not the medications prescribed (as it was previously believed). One surprise was that those patients who received corticosteroids at some point during their treatment had less inflammation and thus a lower risk of developing lymphoma. Actually, that may not seem particularly unexpected. But what was unexpected was that the lowest risk of lymphoma was found among patients who received a greater number of IA corticosteroid injections, more so than systemic corticosteroid therapy.

It seems that joint injections have an impact not only on the joint injected but on the disease process as whole. Following this line of thinking, researchers in Denmark prescribed methotrexate and injected up to four joints every two weeks. They had remarkable results that rivaled those of new biologics. The results are even more remarkable considering that they were using very low doses of methotrexate.

Given much of the recent evidence compounded with my favorable experience with IA corticosteroid therapy, my threshold for injection the joint has significantly decreased.


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Polyarticular corticosteroid injection versus systemic administration in treatment of rheumatoid arthritis patients: a randomized controlled study.
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The rheumatoid knee before and after arthrocentesis and prednisolone injection: evaluation by Gd-enhanced MRI.
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The systemic effect of intraarticular administration of corticosteroid on markers of bone formation and bone resorption in patients with rheumatoid arthritis.
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Balch HW, Gibson JM, El-Ghobarey AF, Bain LS, Lynch MP.
Repeated corticosteroid injections into knee joints.
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Hetland ML, et al
Combination treatment with methotrexate, cyclosporine, and intraarticular betamethasone compared with methotrexate and intraarticular betamethasone in early active rheumatoid arthritis: An investigator-initiated, multicenter, randomized, double-blind, parallel-group, placebo-controlled study.
Arthritis Rheum. 2006 Apr 27;54(5):1401-140

Baecklund E, et al
Association of chronic inflammation, not its treatment, with increased lymphoma risk in rheumatoid arthritis.
Arthritis Rheum. 2006 Mar;54(3):692-701.