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Osteoarthritis is the most common chronic joint disease worldwide.¹ It generates a considerable healthcare burden, and has been identified by the World Health Organization as one of several musculoskeletal disorders for special study during the Bone and Joint Decade, initiated in January 2000.² In recent years, osteoarthritis has attracted increasing attention, with the development of classification criteria,³ radiographic standards,⁴ clinical trial guidelines,⁵ core set measures (ie, a minimum set of required outcome measures),⁶ responder criteria (ie, quantitative changes which differentiate treatment successes from treatment failures),⁷ and the conduct of clinical trials to evaluate the efficacy of treatments for symptom-modifying or structure (disease)-modifying effects.

Enthusiasm for the use of complementary medicines is not new, but recent years have seen formal evaluation of compounds that historically were not subject to the rigorous assessment standards required of commercial pharmaceuticals. Glucosamine sulfate is one such example. In the community of arthritis sufferers, products such as glucosamine sulfate are often viewed as having the potential for benefit with little or no risk of adverse events. Extensive marketing of these types of products exists within the popular literature and on the Internet and may drive consumer interest, particularly given the relatively low cost and emphasised "benefits" of these products. However, expectation and other forms of bias can distort an accurate appreciation of both the benefit and risk, distortions which can only be resolved by properly executed, double-blind, randomised controlled clinical trials. A small number of such trials have been conducted with glucosamine, and, over the short term, the general conclusions are that evidence exists for some degree of efficacy (measured by pain reduction and improved functional outcome) of glucosamine products. A recent meta-analysis of glucosamine and chondroitin⁸ noted that quality issues affect many available trials, and publication bias is likely to exist.

Current glucosamine trials may suffer from one or more of the following limitations:

• patient selection not based on standard classification criteria;⁹

• small sample sizes;¹⁰

• short duration of follow-up;¹⁰

• poor or absent description of radiographic grade of damage at point of entry;¹⁰

• heterogeneous patients,⁵ and

• non-use of standardised primary clinical outcome measures, such as the WOMAC or Lequesne indices (both used as primary outcome measures for lower-limb osteoarthritis studies).⁵

It is not surprising, therefore, that the most recent American College of Rheumatology management guidelines for knee osteoarthritis¹¹ state that:

While a number of studies support the efficacy of both glucosamine and chondroitin sulfate for palliation of joint pain in patients with knee OA, the subcommittee [on osteoarthritis guidelines] believes that it is premature to make specific recommendations about their use at this time because of methodologic considerations, including lack of standardized case definitions and standardized outcome assessments, as well as insufficient information about study design in a number of these published reports.

A recent Cochrane systematic review concurs with the College's position. The authors state, "Further research is necessary to confirm the long term effectiveness and toxicity of glucosamine therapy in OA".¹²

Reginster and colleagues¹³ recently reported a methodologically rigorous three-year study of glucosamine versus placebo in 212 patients with knee osteoarthritis, which demonstrated statistically significant, symptom-modifying and structure-modifying effects favouring the glucosamine group. The symptom-modifying effects appear to be clinically important in the short-term. However, the authors acknowledge that the long-term clinical efficacy remains to be established, and consensus has not yet been reached on the clinical importance of structural conservation effects.

There is thus a growing body of evidence for the efficacy of glucosamine in symptom modification, and, given the low level of adverse side effects noted from these products and the relatively low cost, it may be reasonable for some patients with knee osteoarthritis to try taking glucosamine. It should be noted, however, that a very recent review co-authored by a senior and highly respected academic rheumatologist in the United Kingdom concluded "there is more confusion and hype than magic about glucosamine". The authors cautioned against its wholesale use and recommended the need for "further large clinical trials without company interference".¹⁴

From a practical standpoint, glucosamine is not invariably effective for osteoarthritis, and its use should be approached with a degree of realism. It is well recognised that there is considerable interindividual variability in the response to treatments for osteoarthritis based on non-steroidal anti-inflammatory drugs (NSAIDs),¹⁵ and glucosamine is not likely to differ in this regard. It is likely that glucosamine may meet the symptom-modifying needs of some, but not all, patients. Furthermore, the patient profile and determinants of a glucosamine "responder" are yet to be discovered. Given the severity and multiplicity of joint involvement, it is likely that glucosamine will be taken as a monotherapy in some patients, but as a co-therapy in others. Furthermore, given the long time course of osteoarthritis, it is likely that glucosamine, even in respondents, may be suitable at some points in time, but not others, and discontinuations due to inefficacy can be anticipated.

To date, there does not appear to be a substantial basis for major concerns about safety, although this issue continues to attract occasional attention (concerning the effect of glucosamine in glucose metabolism).¹⁶

It is likely that, together with non-pharmacological therapies, analgesics, NSAIDs, selective and specific COX-2 inhibitors, viscosupplements, and intra-articular steroids, glucosamine will be useful in the management of patients with knee osteoarthritis, as all of these therapies have been shown to be superior to placebo in symptom-modifying studies. Whether glucosamine is efficacious in advanced disease, in particular patient subgroups, or, indeed, whether it is superior to any of the aforementioned interventions, remains to be evaluated.

The study of Reginster and colleagues raises the question of whether glucosamine may have structure-modifying potential, but this issue requires considerable further study before any general recommendation can be made for the use of glucosamine in this context. The best current advice for the use of glucosamine in osteoarthritis is for practitioners to be aware of, and follow, the general spirit of the American College of Rheumatology guidelines for the management of knee osteoarthritis, which include not only the use of pharmacological agents and devices, but also the role of non-pharmacological interventions such as patient education, self-management programs, weight reduction, aerobic exercise, muscle strengthening, and physical therapy.¹¹

For more information on the Bone and Joint Decade, see <www.bonejointdecade.org>

Nicholas Bellamy
Professor and Director

Sean G Lybrand
Musculoskeletal Research Associate
Centre of National Research on Disability and Rehabilitation Medicine
The University of Queensland, Brisbane, QLD
nbellamyATmedicine.uq.edu.au

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©MJA 2001
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