This house believes that we should advise our patients with osteoarthritis of the knee to take glucosamine

J. J. Manson and A. Rahman

Centre for Rheumatology, Department of Medicine, University College London, London, UK.

Introduction

Glucosamine is a natural aminomonosaccharide, which is a normal constituent of glycosaminoglycans in cartilage matrix and synovial fluid. Oral glucosamine is taken by patients with osteoarthritis in the belief that it can improve symptoms and act as a disease-modifying agent. It is not available for prescription as a drug, so that patients generally have to buy it. This can represent a significant cost. Rheumatologists have not reached a consensus as to whether the evidence in favour of glucosamine is strong enough to justify our advising patients to take it [1]. This issue was debated at the Centre for Rheumatology, University College Hospitals London NHS Trust on 6 February 2003. The debate is summarized below.

Proposition

Osteoarthritis of the knee is very common, and patients with this condition often suffer greatly from symptoms that may respond poorly to the available treatments. Some of those treatments, notably non-steroidal anti-inflammatory drugs (NSAIDs), have major adverse effects. Therefore, any new medication which is safe and which shows evidence of even mild beneficial effects should be welcomed. Glucosamine is the most convincing product of this type.

There are good biological reasons to believe that glucosamine could have beneficial effects on cartilage in osteoarthritis. Experiments on cultured human chondrocytes have shown that glucosamine increases the production of aggrecans [2], and reduces the formation of nitric oxide and interleukin 6 in response to interleukin 1ß [3]. It may therefore exert both chondroprotective and anti-inflammatory effects. Furthermore, experiments in animals have suggested that circulating glucosamine can localize in cartilage.

Although early trials were often of short duration and had methodological flaws, a meta-analysis by McAlinden et al. [4] showed that the evidence favoured a modest beneficial effect. Subsequently, two large trials of approximately 200 patients, followed for 3 yr in each case, have confirmed that impression. Both Pavelka et al. [5] and Reginster et al. [6] carried out methodologically sound, randomized, placebo-controlled double-blind studies. In each case, the group of patients treated with glucosamine showed reduced narrowing of the tibiofemoral joint space at 3 yr compared with the placebo group. This supports the hypothesis that glucosamine acts as a disease-modifying drug in osteoarthritis of the knee. Pavelka's group also reported that fewer patients in the glucosamine group reached a cut-off value of 0.5 mm joint space narrowing during the period of the study. This level was considered to represent severe narrowing of the tibiofemoral joint space.

Furthermore, the glucosamine-treated group in each study had significantly better functional outcomes than the placebo group, as measured on the Western Ontario and McMaster Universities (WOMAC) index.

Although mild adverse effects such as abdominal pain and dyspepsia were reported, these tended to be transient. There was no convincing evidence that glucosamine causes severe adverse effects such as diabetes mellitus.

In conclusion, glucosamine is a safe drug for which a body of evidence suggests effectiveness in relieving symptoms, increasing function and modifying disease progression in osteoarthritis of the knee. We should recommend it to our patients.

Opposition

Glucosamine is unproven as a treatment in osteoarthritis of the knee. Advising patients to buy it on the basis that it will improve their osteoarthritis cannot be justified on the basis of the available evidence, much of which is flawed.

The evidence from the study of cultured chondrocytes in vitro is of dubious relevance to the treatment of osteoarthritis in vivo. No evidence was advanced in these studies to suggest that osteoarthritic cartilage is deficient in glucosamine, or that the particular functional changes demonstrated in the cultured cells could reverse the changes found in cartilage of osteoarthritic joints. A more important criticism is that the concentrations of glucosamine used in these experiments probably exceed those which could be achieved in cartilage following oral administration of glucosamine. For this reason, the author of a paper on cultured chondrocytes stated that his results could not be applied for explanation of the therapeutic efficacy of glucosamine [3].

Although the systematic review of McAlinden et al. [4] of early trials of glucosamine in osteoarthritis concluded that there was a modest beneficial effect, these authors raised a number of serious concerns about the six trials that they reviewed. In particular, four were funded by drug manufacturers, five had inadequate evidence of allocation concealment and there was a suspicion of publication bias in view of the absence of small trials with negative results.

Despite the plea of McAlinden et al. for further studies independent of pharmaceutical industry funding, the three major placebo-controlled studies carried out since that systematic review were all supported by drug manufacturers.

Although the studies of Pavelka et al. [5] and Reginster et al. [6] did show statistically significant differences between groups of patients treated with glucosamine and with placebo, the clinical implications of these differences are not clear. Patients recruited to these studies had mild to moderate osteoarthritis (Kellgren and Lawrence grades 2 and 3 on radiographs). The mean scores on the WOMAC index at baseline were below the midpoints of the scales and many patients were not complaining of symptoms severe enough to require analgesia; 51% of the patients studied by Reginster et al. [6] had not required any pharmacological treatment for osteoarthritis in the 6 months prior to enrolment. It is therefore unclear whether the patients in this trial are representative of the majority of patients referred to rheumatology clinics with osteoarthritis of the knee.

It is also unclear whether the differences in tibiofemoral joint space between the glucosamine and placebo groups represent an outcome that is relevant to the progression of disease in these patients. There was no correlation between radiological outcome and symptoms in either trial. Furthermore, neither trial demonstrated any difference in the use of rescue medications (paracetamol and/or NSAIDs) between the glucosamine and placebo groups. This argues against the use of glucosamine as a drug that can reduce the need for NSAIDs in osteoarthritis of the knee.

In contrast, a third placebo-controlled trial studied an outcome of immediate clinical relevance in a less circumscribed population. The patients studied by Hughes and Carr [7] had a wide range of degrees of severity of osteoarthritis (including some with Kellgren and Lawrence grade 4 disease) and all of them had suffered discomfort in the affected knee on most days in the 3 months before enrolment. The primary outcome measure was global assessment of pain, analysed by an area under the curve technique. These authors found no difference between glucosamine and placebo groups in the primary outcome measure or WOMAC scales, despite the fact that the study was adequately powered.

Thus, whereas two studies (funded by a single company) concluded that glucosamine is better than placebo, a third study (funded by a different company) found no such difference. The third study was smaller (80 patients) and of shorter duration (6 months) than the first two. However, the first two studies had much higher dropout rates (33–46%) in both the glucosamine and placebo groups than the third (5 patients out of 80 dropped out), though statistical calculations allowed for this and still showed a difference between glucosamine and placebo in those studies.

The opposition therefore concluded that, at best, the published data could only show that glucosamine manufactured by one particular company has a mild beneficial effect in patients who have mild symptoms in the first place. This is not sufficient evidence to justify asking patients to spend their money on this product, especially as there is no clear rationale to explain its mode of action in osteoarthritis.

Discussion

Contributions from the floor showed a range of opinions, underlining the difficulty of reaching a consensus about this issue.

A number of speakers explained that they already recommend glucosamine to some patients with osteoarthritis because it is safe and may offer some symptomatic relief in patients who have few other therapeutic options. This particularly applies to patients who are highly symptomatic, but in whom structural damage is not sufficient to justify knee replacement surgery. These speakers felt that the range of patients included in the trials of Pavelka et al. and Reginster et al. was broad enough to be relevant to their own populations of patients. The cost of purchasing glucosamine may be a barrier for some patients, and may be considered before recommending it in individual cases.

In contrast, some other speakers were troubled by the fact that most of the major studies supporting use of glucosamine were funded by manufacturers of this product. Some felt that, in advising a patient to spend his or her money on glucosamine, rheumatologists might confer a degree of approval on this product that is not justified by the evidence. Conversely, it could be argued that many drugs of undisputed efficacy are available today as a result of trials funded by the pharmaceutical industry. The beneficial effects of glucosamine seem to be relatively modest, and it may be unreasonable to deprive patients of this therapeutic option just because the evidence is not yet perfect.

Interestingly, the vote showed equal numbers for and against the motion, with several abstentions. We were unable to reach a clear decision and have therefore not adopted a policy on glucosamine. Individual doctors in our unit must continue to make their own decisions about whether to recommend this product to patients, and it is hoped that this debate will help them to make that choice.

The authors have declared no conflicts of interest.

References

  1. Chard J, Dieppe P. Glucosamine for osteoarthritis: magic, hype or confusion? Br Med J 2001;322:1439–40.[Free Full Text]
  2. Bassleer C, Rovati LC, Franchimont P. Glucosamine sulfate stimulates proteoglycan production in human chondrocytes in vitro. Osteoarthritis Cartilage 1998;6:427–34.[CrossRef][ISI][Medline]
  3. Shikhman AR, Kuhn K, Alaaeddine N, Lotz M. N-acetylglucosamine prevents IL-1ß mediated activation of human chondrocytes. J Immunol 2001;155:5155–60.
  4. McAlinden TE, Lavalley MP, Gulin JP, Felson DT. Glucosamine and chondroitin for treatment of osteoarthritis: a systematic quality assessment and meta-analysis. J Am Med Assoc 2000;283:1469–75.[Abstract/Free Full Text]
  5. Pavelka K, Gatterova J, Olejarova M, Machacek S, Giacovelli G, Rovati LC. Glucosamine sulfate use and delay of progression of knee osteoarthritis. Arch Intern Med 2002;162:2113–23.[Abstract/Free Full Text]
  6. Reginster JY, Deroisy R, Rovati LC et al. Long term effects of glucosamine sulfate on osteoarthritis progression: a randomized placebo-controlled clinical trial. Lancet 2001;357:251–6.[CrossRef][ISI][Medline]
  7. Hughes R, Carr A. A randomized, double-blind, placebo-controlled trial of glucosamine sulfate as an analgesic in osteoarthritis of the knee. Rheumatology 2002;41:279–84.[Abstract/Free Full Text]




This Article
Full Text (PDF)
All Versions of this Article:
43/1/100    most recent
keg458v1
Alert me when this article is cited
Alert me if a correction is posted
Services
Email this article to a friend
Similar articles in this journal
Similar articles in ISI Web of Science
Similar articles in PubMed
Alert me to new issues of the journal
Add to My Personal Archive
Download to citation manager
Disclaimer
Request Permissions
Google Scholar
Articles by Manson, J. J.
Articles by Rahman, A.
PubMed
PubMed Citation
Articles by Manson, J. J.
Articles by Rahman, A.