NPC Archive Item: Glucosamine in hip osteoarthritis — still no evidence for its effectiveness

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Rozendaal RM, et al. Effect of glucosamine sulfate on hip osteoarthritis. A randomized trial. Ann Intern Med 2008; 148: 268–77

What is the background to this?
Glucosamine is commonly used for the relief of pain and symptoms associated with osteoarthritis (OA) and other joint disorders. Available studies have reported inconsistent effects of glucosamine on symptoms and joint changes. Most of the studies have been in knee OA, and therefore, data from this study of glucosamine in hip OA is a welcome contribution to the clinical evidence.

What does this study claim?
The study found that glucosamine sulphate, 1500mg daily for 2 years, was no better than placebo in reducing symptoms and progression of hip osteoarthritis. No significant differences from placebo were obtained with regard to changes in WOMAC pain or function scores or in joint space narrowing. There were no significant differences in the incidence of adverse events.

How does this relate to other studies?
A Cochrane review of glucosamine in OA from 2005 identified 20 studies with 2570 patients; however 80% of the trials only considered knee OA, and none considered hip OA specifically. Although identifying a significant effect for glucosamine preparations overall, there was considerable heterogeneity between studies. Subgroup analysis identified that there was no significant benefit when only those trials of high quality (i.e. with concealed allocation) were included or if studies with one particular preparation of glucosamine sulphate was excluded.

Indirect evidence from two, more recent six-month studies in OA, also suggests that there may be a difference in efficacy between different preparations of glucosamine. A USA publicly funded randomised controlled trial (RCT) of glucosamine hydrochloride 1500mg daily in knee OA (n=1583), found that there was no significant difference in the proportion of patients who experienced a 20% decrease in WOMAC pain scores compared with placebo whether given alone (64% vs. 60%, P=0.3) or together with chondroitin (67% vs. 60%, P=0.09). In contrast, another RCT of glucosamine sulphate 1500mg daily (n=318) identified a statistically significant decrease in Lequesne score (–3.1 vs. –1.9, P = 0.032). There were more responders (Osteoarthritis Research Society International criteria) to glucosamine sulfate (40%) and paracetamol (33%) than to placebo (21%) (P=0.004 and P=0.047, respectively, vs. placebo).

So what?
Results of this study showed no clinically important benefits for glucosamine sulphate for treating hip osteoarthritis. Because of the suspicions of variability in potency between glucosamine products, it might be argued that the results should only apply to the particular product tested in this study (manufactured by Nutricia Manufacturing in the USA). However, we cannot assume efficacy for any preparation of glucosamine in hip osteoarthritis based on current evidence.

In the absence of evidence to support its use, glucosamine (sulphate or hydrochloride) should not routinely be prescribed for the treatment of hip osteoarthritis. While glucosamine hydrochloride is licensed in the UK, the largest study of this preparation found no benefit. There is currently no licensed preparation of glucosamine sulphate.

Prescribers should be aware of recent NICE guidance (issued February 27th 2008) that does not recommend glucosamine for treating osteoarthritis. However, recognising that there is evidence of some benefit (albeit insufficient to recommend use in the NHS) and very little evidence of harm in clinical practice, the full guideline contains the following statement:

“… the GDG [Guideline Development Group] felt that it would be beneficial to advise people who wanted to trial over-the-counter glucosamine that the only potential benefits identified in early research are purely related to a reduction of pain (to some people, and to only mild or modest degree) with glucosamine sulfate 1500 mg daily. They could also benefit from advice on how to perform their own trial of therapy, that is, to evaluate their pain before starting glucosamine and ensure they review the benefits of glucosamine after three months.”

Study details – This double-blind RCT included 222 patients with hip osteoarthritis, recruited by their general practitioners in the Netherlands. Patients received treatment for two years with glucosamine sulphate 1500mg or placebo once daily. The primary outcome measures were scores on the WOMAC pain and function subscales and joint space narrowing after 24 months. Secondary outcome measures were WOMAC pain, function, and stiffness. At 24 months, WOMAC pain did not differ significantly between groups (mean difference [glucosamine sulphate minus placebo] –1.54, 95%CI –5.43 to 2.36), nor did WOMAC function (mean difference –2.01, 95%CI –5.38 to 1.36). Joint space narrowing also did not differ significantly after 24 months (mean difference, –0.029, 95%CI –0.122 to 0.064]). There were no significant differences between groups in any of the secondary outcomes, in the amount of pain medication used, or in the proportion of patients experiencing adverse events (glucosamine sulfate 51%, placebo 53%).

Although the study was well designed, it does have a number of limitations. As pointed out in an accompanying editorial, the study only included people at an early stage in the development of their osteoarthritis, and it is possible that a study in patients with severe OA, where the disease is progressing more rapidly, may have shown a benefit. There were a number of hip replacements in study participants during the course of the study. An analysis of the impact of this identified that a statistical difference may have been hidden; however, any difference would have been clinically unimportant.

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