There is strong evidence to suggest that glucosamine is effective in treating the symptoms of OA, as well as being effective in slowing the disease progression. A Cochrane review of 16 RCTs has concluded that 'there is good evidence that glucosamine is both effective and safe in treating osteoarthritis' and that 'glucosamine therapy may indeed represent a significant breakthrough in the pharmacological management of osteoarthritis' (Towheed et al 2003). Although most studies have been of OA of the knee, there is some clinical evidence that it is also active against OA of the spine (Giacovelli 1993) and temporomandibular joint (Shankland 1998).

The first placebo-controlled clinical trials investigating glucosamine in OA were published in the early 1980s. Drovanti et al showed that a dose of 1 500 mg glucosamine sulfate significantly reduced symptoms of OA, almost twice as effectively and twice as fast as placebo (Drovanti et al 1980). Perhaps the most exciting results were found when electron microscopy analysis of cartilage showed that those taking glucosamine sulfate had cartilage more similar to healthy joints than the placebo group. Based on this finding, researchers suggested that glucosamine sulfate had not only provided symptom relief but also had the potential to induce rebuilding of the damaged cartilage.

Since that time, multiple human clinical trials lasting from a few weeks (Crolle & D'Este 1980, Drovanti et al 1980, Lopes Vaz 1982, McAlindon 2001, Pujalte et al 1980, Qiu et al 1998) to 3 years (Pavelka et al 2002, Reginster et al 2001), as well as systematic reviews (Poolsup et al 2005, Towheed et al 2003, 2006) and metaanalyses (McAlindon et al 2000, Richy et al 2003) have shown that glucosamine sulfate (1500 mg/day) can significantly improve symptoms of pain and functionality measures in patients with OA of the knee, with side-effects comparable to those of placebo. There is also evidence from two long-term (3-year) studies (Pavelka et al 2002, Reginster et al 2000) and one year-long study of glucosamine and chondroitin (Rai et al 2004) that in addition to providing symptomatic relief, glucosamine also slows disease progression, as evidenced by a reduction in joint space narrowing.

Reginster et al (2000) compared the effects of 1 500 mg glucosamine sulfate with placebo daily over 3 years in 212 patients aged over 50 years with primary knee OA. This was heralded as a landmark study at the time because it not only detected modest symptom-relieving effects, but was the first to identify significant joint-preserving activity with long-term use. Two years later, Pavelka etal confirmed these results in another randomised double-blind study that involved 202 patients with

knee OA (Pavelka et al 2002) and once again observed that long-term treatment with glucosamine sulfate retarded disease progression. A post hoc analysis of these studies found that the disease-modifying effect was evident in 319 post menopausal women (Bruyere et al 2004) and another subanalysis found that patients with less severe radiographic knee OA, who are likely to experience the most dramatic disease progression, may be particularly responsive to treatment with glucosamine (Bruyere et al 2003).

Not all clinical trials of glucosamine for OA have produced positive results. A 12-week, double-blind, randomised placebo-controlled trial of glucosamine performed over the internet involving 205 subjects with symptomatic knee OA found no difference in pain, stiffness, analgesic use or physical function between the glucosamine and placebo groups (McAlindon et al 2004). In another 6-month randomised, double-blind, placebo-controlled study of glucosamine sulfate in knee OA there was no significant difference in the time to disease flare, symptoms or analgesic medication use between the glucosamine and placebo groups (Cibere et al 2004). A further controlled trial of 80 OA patients using glucosamine sulfate over 6 months found no difference between the glucosamine group and placebo for symptoms, except for a small but significant difference in knee flexion, which was suggested to be caused by measurement error (Hughes & Carr 2002).

Most clinical trials have used a specific patented oral formulation of glucosamine sulfate from Rottapharm, Italy, which is available as a prescription medicine in Europe. Although other forms of glucosamine are used in practice, there is significantly more evidence supporting the use of glucosamine sulfate than others (Reginster et al 2005). An updated Cochrane review that looked at 20 studies involving a total of 2570 patients found that studies using a non-Rottapharm preparation failed to show benefit in pain and function, whereas studies of the Rottapharm preparation found glucosamine to be superior to placebo in the treatment of pain and functional impairment (Towheed et al 2006).

In a multicentre, randomised, parallel-controlled clinical trial of 142 patients comparing glucosamine sulfate and glucosamine hydrochloride, both agents were found to be equally effective in producing improvement in symptoms of OA of the knee after 4 weeks, with a remnant therapeutic effect also occurring in both groups 2 weeks after discontinuing treatment. The glucosamine sulfate group experienced significantly more adverse events, mainly mild stomach discomfort and constipation (Qiu et al 2005).

Combination therapy Chondroitin sulfate and glucosamine are frequently marketed together in combination products and some studies suggest that this

combination is effective in treating symptoms (Das & Hammad 2000, Leffler et al 1999, McAlindon et al 2000, Nguyen et al 2001) and reducing joint space narrowing (Rai et al 2004). This is supported by an in vitro study of horse cartilage that found that a combination of glucosamine and chondroitin was more effective than either product alone in preventing articular cartilage glycosaminoglycan degradation (Dechant et al 2005). Further support for combination therapy comes from an in vivo study of rats, which found that combined treatment with chondroitin and glucosamine prevented the development of cartilage damage and was associated with a reduction in IL-1 -beta and matrix metalloprotease-9 synthesis (Chou et al 2005).

The National Institutes of Health (NIH) recently spent US$14 million on a Glucosamine Chondroitin Arthritis Intervention Trial (GAIT), a 24-week, placebo-controlled, parallel, double-blind, five-arm trial involving 1 583 patients that aimed to answer the question as to the efficacy of glucosamine hydrochloride and chondroitin by comparing glucosamine alone, glucosamine plus chondroitin, chondroitin alone, placebo and the COX-2 inhibitor celecoxib (Clegg et al 2006, NIH 2002). The results of this study provide good evidence that glucosamine and chondroitin are more effective when given in combination than when either substance is given alone and that combined treatment with glucosamine and chondroitin is more effective than celecoxib for treating moderate to severe, but not mild, arthritis. The design of the GAIT trial can be criticised, however, for the fact that it included a large number of people with very mild disease who were more likely to be susceptible to placebo (as evidenced by the very high (60%) placebo response). Furthermore, the criteria for effectiveness as the primary outcome measure was set very high (20% reduction in WOMAC pain score) and that when the internationally accepted OMERACT-OARSI response criteria forjudging clinical trials of OA was used, the combined treatment was significantly better than placebo for patients with either mild or moderate to severe disease (Clegg et al 2006).

Although glucosamine has not been shown to have direct analgesic activity, certain combinations with non-opioid analgesics have demonstrated synergistic (e.g. ibuprofen and ketoprofen), additive (e.g. diclofenac, indomethacin, naproxen and piroxicam), or subadditive (e.g. aspirin and acetaminophen) antinociceptive interactions in the mouse abdominal irritant test, suggesting that combinations of certain ratios of glucosamine and specific NSAIDs might enhance pain relief or provide adequate pain relief with lower doses of NSAIDs (Tallarida et al 2003).

In a 12-week, randomised, placebo-controlled trial of glucosamine and methylsulfonylmethane involving 118 patients, combined therapy was found to

produce a greater and more rapid reduction in pain, swelling and loss of function than either agent alone (Usha & Naidu 2004).

In an in-vivo study of arthritic rats the combination of glucosamine and essence of chicken was more effective in reducing the histopathological severity of arthritis than glucosamine alone (Tsi et al 2003).

A topical preparation containing glucosamine with chondroitin and camphor has been shown to reduce pain from OA of the knee in one RCT (Cohen et al 2003). Comparisons with NSAIDs There are many studies suggesting that glucosamine is at least as effective as NSAIDs (e.g. 1200 mg ibuprofen) in treating the symptoms of OA (Muller-Fassbender et al 1994, Reichelt et al 1994, Rovati 1992, Ruane & Griffiths 2002), although glucosamine has a slower onset of action, taking 2-3 weeks to establish an effect. The recent GAIT trial (see earlier) found that the combination of glucosamine and chondroitin was more effective than celecoxib in treating moderate to severe OA, whereas glucosaminealonewas not (Clegg et al 2006).

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