[Reginster, JY. The Efficacy of Glucosamine Sulfate in Osteoarthritis: Financial and Nonfinancial Conflict of Interest. Arthr Rheum 2007;56(7):2105-10.]

Cochrane reviews are studies in which the collective scientific evidence on specific topics is examined by a team of scientists.  Such a review was undertaken to examine the collective evidence regarding the value of glucosamine for osteoarthritis.  The summary of their findings is listed below:

• The review included a total of 2592 adults in 20 randomized controlled trials (RCTs). The mean age of participants was generally 50–70 years. RCT duration was 3 weeks to 3 years
• Participants received glucosamine or placebo/active control. In all but one trial, glucosamine sulfate (as opposed to glucosamine hydrochloride) was used
• The results were mixed
• Glucosamine outperformed NSAIDs ibuprofen and piroxicam for pain in three trials, including one top quality trial that followed 319 participants for 20 weeks
• Overall, glucosamine helped pain more than placebo. However, concealment allocation was adequate in only eight of the 15 relevant trials, and seven out of these 8 trials found no difference between glucosamine and placebo
• It was unclear whether glucosamine improved function more than placebo
• Glucosamine was as safe as placebo
• After the Cochrane review was completed, a large RCT found glucosaminehydrochloride and chondroitin in combination but not individually to be effective for moderate to severe knee pain and to have no effect on mild pain. In half of patients on this combination, significant improvement occurred at 4 weeks. A further 15% of patients had improved significantly at 24 weeks12
• A subsequent large RCT found 4–24 weeks of glucosamine sulphate 1500 mg/day was highly effective for relieving pain and improving function in knee OA13

[Summary of Cochrane review on glucosamine for osteoarthritis (Towheed, T, Maxwell, L, Anastassiades, T, et al. Glucosamine therapy for treating osteoarthritis. Cochrane Database Syst Rev 2005 Issue 2; Art. No.:CD002946 DOI: 10.1002/14651858.CD002946.pub2.)]

Conflicting Studies

While a large number of studies show the benefits of glucosamine, a recent study has raised questions.  It is important to address the important concerns about this study.  In 2006, this new study on glucosamine hydrochloride and chondroitin sulfate was reported in the New England Journal of Medicine (2006;354:795-808).  This study was conducted at the National Institutes of Health (NIH) and is said to be conclusive in its determination that the results of the study showed that the treatments "alone or in combination did not reduce pain effectively."  Without going into a full analysis of the study here, it is important to point out one of the major criticisms of this study.

First, the form of glucosamine used was glucosamine hydrochloride.  Previous studies have shown questionable results from this form of glucosamine, because it contains chloride rather than sulfur.  Many doctors understand that connective tissue in joints has a high dependency upon sulfur atoms and that one reason for the success of glucosamine sulfate is that it provides these sulfur groups. (See The Importance of Sulfur).

Since the NIH osteoarthritis study used glucosamine hydrochloride rather than glucosamine sulfate, such sulfur groups were not part of the study.  Critics of the study, therefore, argue that one of the primary benefits of using glucosamine (delivering sulfur to the joints) was not even tested in the trial.  In other words, they were testing the effectiveness of glucosamine hydrochloride NOT glucosamine sulfate.  Viewed in this way, the study has to be viewed as inconclusive.  Because of this, we must continue to look at the large body of research data that incorporates glucosamine sulfate.  It also suggests that getting your glucosamine from glucosamine sulfate is probably better than getting it from glucosamine hydrochloride.

Another point should be noted.  While the study was long enough to assess acute pain relief, it was not extended long enough to answer the question of whether the treatments could slow the progression of osteoarthritis.

Recent Opinions on Use of Glucosamine

A recent article in the American Family Physician was written by doctors from Beth Israel Hospital at Harvard University, which summarized their current view of glucosamine in joint disorders.  A summary of their views on glucosamine is noted below: [Dahmer, S, Schiller, RM. Glucosamine. Am Fam Phys 2008;78(4):471-6..]

- Most clinical trials have focused on its use in osteoarthritis of the knee.

- The reported adverse effects have been relatively well studied and are generally uncommon and minor.

- No significant supplement-drug interactions involving glucosamine have been reported.

- Despite conflicting results in studies, there is no clear evidence to recommend against its use.

-  If physicians have patients who wish to try glucosamine, it would be reasonable to support a 60-day trial of glucosamine sulfate, especially in those at high risk of secondary effects from other accepted treatments.

- The decision to continue therapy can then be left to patients on an individual basis, while the physician monitors for possible adverse effects.

- Glucosamine should be used with caution in patients who have shellfish allergies or asthma, and in those taking diabetes medications or warfarin.

Is Glucosamine Safe for People with Diabetes?

We have just explored some of the evidence relating to the effect of glucosamine sulfate on aiding symptoms of joint pain and osteoarthritis.  While these grow more positive, we must also explore one issue that is commonly raised about glucosamine in people who have diabetes.  Early animal studies seemed to show that glucosamine can lead to insulin resistance.  However, these studies used intravenous infusions of glucosamine, as opposed to oral consumption (which is the way humans get their glucosamine). Some human studies showed an adverse effect on glucose control in some people with diabetes, while others did not show an adverse effect.  Some of the studies are summarized below:

• 2007: Thirty-eight people were given 1500 mg of glucosamine for 6 weeks.  Small artery elasticity fell, and the decrease was higher in those with the highest baseline insulin resistance. The authors concluded, “Those with underlying poorer insulin sensitivity are at risk for worsening insulin resistance and vascular function with the use of [oral] glucosamine in doses used to treat osteoarthritis.”

[Pham T, Cornea A, Blick KE, et al. Oral glucosamine in doses used to treat osteoarthritis worsens insulin resistance. Am J Med Sci. 2007 Jun;333(6):333-9.]

• 2006: In a study at the National Institutes of Health (U.S.), oral glucosamine for 6 weeks. When compared with placebo, glucosamine did not cause insulin resistance or endothelial dysfunction in lean subjects or significantly worsen these findings in obese subjects. The authors stated, “We conclude that oral glucosamine at standard doses for 6 weeks does not cause or significantly worsen insulin resistance or endothelial dysfunction in lean or obese subjects.”

[Muniyappa, R, Karne, RJ, Hall, G, et al. Oral glucosamine for 6 weeks at standard doses does not cause or worsen insulin resistance or endothelial dysfunction in lean or obese subjects. Diabetes. 2006;55(11):3142-50.]

• 2007: Blood from people with osteoarthritis, but no other medical disorder, was tested after people ingested 75 grams of glucose with or without 1500 mg of glucosamine.  Three participants who were found to have previously undiagnosed abnormalities of glucose tolerance demonstrated significant incremental elevations in glucose levels after ingestion of glucosamine sulfate. The authors stated that, “The results suggest that [oral] glucosamine ingestion may affect glucose levels and consequent glucose uptake in patients who have untreated diabetes or glucose intolerance.”

[Biggee BA, Blinn CM, Nuite M, et al. Effects of oral glucosamine sulphate on serum glucose and insulin during an oral glucose tolerance test of subjects with osteoarthritis. Ann Rheum Dis. 2007 Feb;66(2):260-2.]

• 2006: A meta-analysis was undertaken to examine articles on glucosamine and blood sugar control between 1966 and 2006.  The review concluded that, ” Small, short-term studies suggest that glucosamine may be used in selected patients without affecting glucose control; however, data in patients with diabetes mellitus are limited, and close monitoring for potential changes in glucose control is recommended.”

[Stumpf, JL, Lin, SW. Effect of glucosamine on glucose control. Ann Pharmacother 2006;40(4):694-8.]

• 2007:  At doses of  1500 mg per day for two weeks, glucosamine had no significant effect after therapy on serum levels of HDL cholesterol nor in changes in apoAI levels. "These observations suggest that glucosamine at commonly consumed doses does not have significant effects on glycemic [blood sugar] control, lipid [blood fat] profile, or levels of apoAI in diabetic subjects after 2 weeks of supplementation."

[Albert, SG, Oiknine, RF, Parseghian, S, et al. The effect of glucosamine on serum HDL cholesterol and apolipoprotein A1 levels in people with diabetes. Diabetes Care 2007;30(11):2800-3.] 

A research group at the University of Kentucky wrote a summary paper on the matter of glucosamine and diabetes, which was published in Food & Chemical Toxicology in 2005.  In their review of clinical trial data for 3,063 humans taking oral glucosamine for 66 weeks, they note the following about glucosamine and blood sugar control:

• Oral administration of large doses of glucosamine in animals has no documented effects on glucose metabolism.
• In vitro studies demonstrating effects of glucosamine on glucose metabolism have used concentrations that are 100-200 times higher than tissue levels expected with oral glucosamine administration in humans.
• There were no adverse effects of oral glucosamine administration on blood, urine or fecal parameters.
• Side effects were significantly less common with glucosamine than non-steroidal anti-inflammatory drugs (NSAID).
• In contrast to NSAID, no serious or fatal side effects have been reported for glucosamine.
• Our critical evaluation indicates that glucosamine is safe under current conditions of use and does not affect glucose metabolism.

[Anderson, JW, Nicolosi, RJ, Borzelleca, JF. Glucosamine effects in humans: A review of effects on glucose metabolism, side effects, safety considerations, and efficacy. Food Chem Toxicol 2005;43(2):187-201.]

Forms of Glucosamine

There are five common forms of Glucosamine:

1. N-acetyl-glucosamine (NAG)
2. D-Glucosamine Sulphate NaCl
3. D-Glucosamine Sulphate 2KCl - (From either Shellfish or Vegetable Sources)
4. D-Glucosamine Hydrochloride (HCl) - (From either Shellfish or Vegetable Sources)
5. Poly N-acetyl-glucosamine (Poly NAG)