Glucosamine for knee osteoarthritis – what's new?

BACKGROUND

Osteoarthritis involves damage to articular cartilage and other structures in and around joints, with variable levels of inflammation. Up to 10% of people aged over 55 years in the UK have painful knee osteoarthritis associated with mild to moderate disability.2 Every year, symptomatic knee osteoarthritis accounts for about 0.5% of all primary care consultations by those aged over 55 years, rising to 1% for those over 70 years.2

Non-surgical treatment options for knee osteoarthritis include lifestyle measures (e.g. weight loss, exercise); walking aids; wedged insoles; local therapy involving heat or cold; physiotherapy; transcutaneous electrical nerve stimulation (TENS); cognitive behavioural therapy; food supplements (e.g. glucosamine); topical capsaicin; simple analgesics; NSAIDs; opioids; and intra-articular injections of corticosteroid or hyaluronic acid.3

Marketed over-the-counter (OTC) oral glucosamine supplements most commonly include glucosamine sulphate or glucosamine hydrochloride. The supplements are produced synthetically or derived from the shells of shell fish. In the UK, over 50 different unlicensed preparations of glucosamine can be bought over the counter or via the internet, in strengths of 500 mg, 750 mg, 1,000 mg or 1,500 mg, and as tablet, capsule or liquid formulations (with or without chondroitin, another supplement).4

WHY GLUCOSAMINE?

Glucosamine, an amino monosaccharide, is a normal constituent of the polysaccharide chains of cartilage matrix and synovial fluid glycosaminoglycans, which provides the theoretical basis for its use in osteoarthritis.1^, 5 However, no mechanism of action for glucosamine in osteoarthritis has been clearly defined.1^, 5 Also, the period to onset of response with glucosamine has not been established, the available information on its pharmacokinetics is limited and its absolute bioavailability is unknown.5

LICENSED INDICATION AND DOSE

Alateris is licensed as a prescription-only medicine for the relief of symptoms in adults with mild to moderate osteoarthritis of the knee, but not as a treatment for acute painful symptoms.5 The licensed dose is two 625 mg tablets taken once daily.5 The summary of product characteristics (SPC) for the drug states that relief of symptoms (especially pain relief) with glucosamine may not be experienced until after several weeks of treatment and, in some cases, it may be even longer. It also advises that “if no relief of symptoms is experienced after 2–3 months, continued treatment with glucosamine should be re-evaluated”.5

CLINICAL STUDIES WITH GLUCOSAMINE

Alateris was licensed in the EU based on bibliographical data provided by the marketing authorisation holder (Navamedic ASA).6 No direct clinical trial evidence of the efficacy and safety of this specific glucosamine hydrochloride product is publicly available. There are several published trials of other formulations of glucosamine (mainly glucosamine sulphate).7 One small study in horses found that oral glucosamine sulphate resulted in significantly higher synovial fluid concentrations of glucosamine than an equivalent oral dose of glucosamine hydrochloride, but the clinical significance of this difference is questionable.8 The European Medicines Agency's Committee for Medicinal Products for Human Use (CHMP) did not consider that it was neccesary to have any study comparing the bioavailability of Alateris with those of the glucosamine products represented in the bibliographical data that formed part of the licensing application, because “glucosamine is considered to be an simple substance with a high solubility”.6

Collated data on glucosamine

Cochrane reviews

Our last article included an assessment of a Cochrane systematic review with 16 trials of glucosamine (15 of glucosamine sulphate and one of glucosamine hydrochloride) in patients with osteoarthritis.1 This found that oral glucosamine sulphate 1,500 mg daily produced a 60% reduction (from baseline) in pain and a 33% increase in function (change from baseline Lequesne index; see box) compared to placebo, without unwanted effects.

An updated version of the review (search date to January 2005) pooled data from 20 randomised controlled trials (either double-blind or single-blind, and either placebo-controlled or active comparator-controlled) evaluating the effectiveness and safety of glucosamine (sulphate and hydrochloride) in a total of 2,596 patients with osteoarthritis.7 In all, 16 of the trials involved knee osteoarthritis exclusively, two involved osteoarthritis at multiple sites (knee, hip, others) and two did not specify the location of osteoarthritis. Most trials (14 of 20) had a clear affiliation with Rotta Pharm (an Italian pharmaceutical manufacturer of glucosamine sulphate), with some specifically assessing the Rotta brand of glucosamine sulphate. Six of the trials did not use the Rotta brand of glucosamine, only one of which used glucosamine hydrochloride.

Compared with placebo (data from 15 trials), glucosamine (all types) reduced levels of pain (measured by various methods) from baseline by 28% (standardised mean difference [SMD] −0.61, 95% CI −0.95 to −0.28) and resulted in a 21% improvement in function from baseline using the Lequesne index (SMD −0.51, 95% CI −0.96 to −0.05).7 However, the Western Ontario and McMaster Universities (WOMAC) Osteoarthritis Index (see box) outcomes of pain, stiffness and function or WOMAC total scores for all types of glucosamine did not reach statistical significance. In the review, results from studies that used a non-Rotta preparation failed to show benefit in pain and function compared to placebo using the WOMAC Index, while those studies evaluating a Rotta preparation compared to placebo suggested that this was superior to placebo in reducing pain (SMD −1.31, 95% CI −1.99 to −0.64) and functional impairment (SMD −0.51, 95% CI −0.96 to −0.05) using the Lequesne index. Two trials found that a Rotta preparation was more effective than an NSAID for pain, while another found such a preparation to be equivalent to an NSAID for pain. Two trials of a Rotta preparation suggested that glucosamine slowed radiological progression of knee osteoarthritis over a 3-year period (SMD 0.24, 95% CI 0.04 to 0.43). Similar numbers of patients reported an adverse reaction with glucosamine (all types) as with placebo (relative risk [RR] 0.97, 95% CI 0.88 to 1.08). This led the reviewers to conclude that glucosamine (of any type) was as safe as placebo.

Other collated data

In another systematic review, data were pooled from two double-blind randomised controlled trials (both included in the systemic review discussed above) that had evaluated oral glucosamine sulphate (Rotta preparations in both) as long-term (at least 1 year) treatment for knee osteoarthritis; outcome measures included symptom severity and disease progression as assessed by joint space narrowing.9 A total of 414 patients were included. Glucosamine sulphate was more effective than placebo in delaying structural progression as assessed by joint space width (pooled relative risk [RR] 0.46, 95% CI 0.28 to 0.73, p = 0.0011). The pooled effect sizes for pain reduction and improvement in physical function (measured using the WOMAC Index) were 0.41 (95% CI 0.21 to 0.60, p<0.0001) and 0.46 (95% CI 0.27 to 0.66, p<0.0001), respectively, in favour of glucosamine sulphate. Glucosamine sulphate seemed similarly likely to placebo to cause unwanted effects (pooled RR 1.02, 95% CI 0.93 to 1.11).

A meta-analysis pooled data from 15 double-blind randomised placebo-controlled trials of glucosamine for knee or hip osteoarthritis.10 The pooled effect size for all types of glucosamine compared with placebo was 0.35 (95% CI 0.14 to 0.56). For glucosamine sulphate, it was 0.44 (95% CI 0.18 to 0.70) and for glucosamine hydrochloride it was 0.06 (95% CI −0.08 to +0.20). The reviewers concluded that “glucosamine hydrochloride lacks efficacy for pain” in osteoarthritis and that, among glucosamine sulphate trials, “enough heterogeneity existed such that no definitive conclusion about efficacy is possible”.

Individual trials of glucosamine

Since publication of the systematic reviews described above, two further double-blind randomised placebo-controlled trials of glucosamine have been published, one of which assessed glucosamine hydrochloride11 and the other glucosamine sulphate.12

The first trial included 1,583 patients with symptomatic knee osteoarthritis and randomised them to one of five regimens: oral glucosamine hydrochloride (500 mg three times daily); oral sodium chondroitin sulphate (400 mg three times daily); both these supplements (at the above doses); oral celecoxib (200 mg daily); or placebo.11 The primary outcome measure was a response to treatment, defined a priori by expert consensus as a 20% decrease in the summed score for the WOMAC pain subscale from baseline to week 24. Up to 4 g of paracetamol daily was allowed as rescue analgesia. Overall, glucosamine hydrochloride and chondroitin sulphate, given alone or in combination, were not significantly better than placebo in reducing knee pain by 20% (rate of response 64.0% with glucosamine hydrochloride, 65.4% with chondroitin sulphate and 66.6% with the combination, vs. 60.1% with placebo; p = 0.30, p = 0.17 and p = 0.09, respectively, for comparisons with placebo). The rate of response with celecoxib was 70.1% (p = 0.008 vs. placebo). The investigators suggested that the study had limitations (e.g. a high rate of response to placebo) and that, at baseline, the participants had relatively mild pain from osteoarthritis.

The second trial included 318 patients with knee osteoarthritis randomised to a Rotta preparation of glucosamine sulphate (1,500 mg orally once daily), paracetamol (3 g daily; i.e. not the maximum daily dose) or placebo.12 The primary outcome measure was change from baseline in the Lequesne index of severity for knee osteoarthritis at 6 months. There was a greater change in this index with glucosamine sulphate than with placebo (−3.1 vs. −1.9, p = 0.032). The change with paracetamol was not significantly different from that with placebo (p = 0.18).

One randomised controlled trial, which was published in full only in Chinese, compared a glucosamine hydrochloride product with a glucosamine sulphate product.13 The abstract (published in English) reports that there were no significant differences in efficacy and safety between the two products on treatment for knee osteoarthritis in 142 patients. However, the supplements were only given for 4 weeks, which is less time than in most of the previous trials,7 and is possibly not long enough to see an effect with glucosamine.1^, 5

UNWANTED EFFECTS AND PRECAUTIONS

Common unwanted effects (i.e. occurring in 1–10% of people) listed in the SPC for Alateris include nausea, abdominal pain, indigestion, constipation, diarrhoea, headache and tiredness.5 Rash, itching and flushing are uncommon unwanted effects (i.e. in 0.1–1%).5

The SPC recommends that, because the effects of glucosamine (a naturally occurring sugar) have not been widely studied, patients with impaired glucose tolerance should have their blood glucose concentrations checked before treatment begins and “periodically” during treatment.5 It also recommends that, because of rare reports of hypercholesterolaemia in people taking glucosamine, those with a known risk factor for cardiovascular disease should have their blood lipid concentrations monitored.5 There has been a report of exacerbation of asthma after the initiation of glucosamine therapy, so the SPC states that patients with asthma should be made aware that their symptoms might worsen with glucosamine.5

The SPC warns that Alateris should not be given to patients who are allergic to shellfish, as the active substance is obtained from this source.5 Also, because of limited data on glucosamine use in pregnant women, the use of Alateris is contraindicated during pregnancy, and its use during breastfeeding is not recommended.5

There have been several reports of patients on warfarin having an increase in their previously stable INRs after starting to take glucosamine supplements.14^, 15 The Medicines and Healthcare products Regulatory Agency (MHRA) recommends that patients on warfarin should not take glucosamine.14 The SPC advises that patients treated with coumarin anticoagulants (e.g. warfarin) should be “closely monitored” when starting or stopping treatment with glucosamine.5

COSTS

The annual cost to the NHS of Alateris is £224. This is more expensive than many of the glucosamine OTC brands available,4 most of which can be prescribed on the NHS. Only a few are blacklisted in Schedule 10 (these being Biocare N-acetyl glucosamine tablets, Boots glucosamine sulphate tablets, Healthaid glucosamine sulphate tablets, Health Perception glucosamine tablets, Lamberts glucosamine sulphate tablets, Solgar glucosamine sulphate tablets, Vega glucosamine sulphate capsules).16 Prices for glucosamine sulphate tablets (1,000 mg) advertised on the internet start from around £7.50 for 365 tablets.

PRACTICAL CONSIDERATIONS

The National Institute for Health and Clinical Excellence (NICE) guideline on osteoarthritis does not recommend the use of glucosamine for the treatment of patients with this condition.17 It found that “overall, those trials which used glucosamine sulfate as a single dose of 1,500 mg, rather than hydrochloride 500 mg tds, showed a small benefit over placebo for treatment of knee OA [osteoarthritis]”.18 It concluded that “evidence to support the efficacy of licensed glucosamine hydrochloride as a symptom modifier is poor”, “for the non-licensed product (glucosamine sulfate), the evidence is not strong enough to warrant recommending that it should be prescribed on the NHS”, and “a wide range of incremental cost-effectiveness ratios reported and the poorest estimates of efficacy would take it beyond the threshold of affordability in the NHS”.18 The Scottish Medicines Consortium has advised that glucosamine (as hydrochloride) is not recommended for use within NHS Scotland for relief of symptoms in people with mild to moderate osteoarthritis of the knee.19

There may be variability in the relative purity and content of glucosamine in preparations obtained from different manufacturers, because available glucosamine formulations, apart from Alateris, are considered food supplements in the UK, and there are no statutory monitoring or good manufacturing requirements for such products.

CONCLUSION

There are no published trials of ▼Alateris, the first and currently only glucosamine (hydrochloride) to be licensed as a medicine the UK as a treatment for knee osteoarthritis. Alateris should not be prescribed on the NHS until such evidence is available. Published evidence suggests that oral glucosamine sulphate (1,500 mg once daily) provides modest pain relief in knee osteoarthritis and appears to be relatively safe. There are questions about the cost-effectiveness of glucosamine sulphate that make it difficult to advise prescribing such treatment on the NHS. Nevertheless, patients might wish to purchase and try glucosamine sulphate and the evidence suggests that this is a reasonable strategy. The Medicines and Healthcare products Regulatory Agency recommends that patients on warfarin should not take glucosamine supplements, since this combination makes bleeding more likely.