Glucosamine is an amino polysaccharide (a combination of an amino acid glutamine and sugar glucose). Glucosamine is concentrated in joint cartilage where it is incorporated into longer chains known as glycosaminoglycans and finally into very large structures known as proteoglycans. The proteoglycans function to attract water into the joint space for lubrication of the cartilage during movement. Glucosamine is available in supplements as glucosamine sulfste, glucosamine hydro-chloride, and N-acetylglucosamine. Chondroitin sulfate (also covered in this chapter) is often combined with glucosamine. These supplements are generally promoted with claims for protecting joints and joint cartilage from injury, alleviating the stiffness and pain of osteoarthritis, and reducing inflammation.

Glucosamine supplements typically take 1-3 months to exert noticeable effects (reduced pain and stiffness) in people with mi Id-to-moderate degrees of osteoarthritis. Because arthritis pain is one of the most debilitating conditions, most people dealing with such pain would gladly invest a dollar or two per day in a supplement that relieved their discomfort and helped repair their damaged cartilage tissue. For people with existing chronic joint pain, glucosamine supplements (whether or not combined with chondroitin sulfate) are worth the modest dollar investment for the benefits they deliver.

The major principle behind glucosamine supplementation is that the glucosamine is delivered to the joint space and incorporated into proteoglycans of joint cartilage to maintain structure and repair damage. Glucosamine may also stimulate chondrocytes (cartilage cells) to begin produ-ng healthy new cartilage matrix (both collagen and proteoglycans). Numerous European studies and a handful of North American reports low a clear benefit of glucosamine supplements for relief of joint pain and stiffness associated with arthritis. One Australian udy has even suggested a pain-relieving effect in osteoarthritis of topic-ly applied glucosamme/chondroitin (Cohen et al., 2003), but that “feet may have been the result of camphor in the topical formulation. rhile glucosamine supplements have been reported to modify disease ctivity in studies of rheumatoid arthritis (Lard etal., 2001), the majority Fglucosamine studies have examined osteoarthritis of mild-to-moder-te severity. Most studies examine patients with osteoarthritis of the nee and hip, but examples of glucosamine’s pain-relieving effects can e found in studies of osteoarthritis of die fingers and temporomandibu-ar joint (Nguyen et al., 2001; Thie et al., 2001). Several studies have ompared the pain-relieving effects of glucosamine (1,500 mg/day) to ISAIDs such as ibuprofen (1,200 mg/day). These studies generally find

that although NSAIDs tend to exert their pain-relieving effects faster (within the first week of treatment; Muller-Fassbender et al., 1994), the difference between treatments lessens with time (similar benefits at 2-4 weeks), with fewer side effects reported among glucosamine users (6% versus 35% on ibuprofen). When followed post treatment, glucosamine shows a carryover effect, whereby pain and use of pain relievers is reduced for 3-4 months following cessation of supplementation (Qiu ei al., 1998; Thieetal., 2001).

Many of the existing studies have been criticized for lack of scientific control, short duration, and small size (Towheed et al., 2000), and indeed not all studies of glucosamine supplementation show benefits in terms of relief of pain or stiffness (Houpt etal., 1999; Rindone et al., 2000).

Mela-analyses of several smaller studies, however, have supported the beneficial role of glucosamine supplements as a safe and effective approach to treating osteoarthritis (McAlindon et al., 2000a, 2000b; Towheed et al., 2000). In general, 1-3 months of glucosamine supplementation seems to be as effective as many analgesics and NSAIDs, like acetaminophen and ibuprofen, in reducing the joint pain of osteoarthritis. In perhaps the longest-duration trial to date (Reginster et al., 2001), 3 years of glucosamine supplementation (1,500 mg/day) improved pain scores (while symptoms with placebo worsened) and maintained radiographic joint space of the knee (while placebo users experienced significant losses). At least two studies have shown that glucosamine may even slow or stop the destruction of cartilage in the knee joints of people with osteoarthritis (Bruyere et al., 2003; Pavelka et al., 2002); this effect may be especially dramatic in patients with less severe radiographic knee damage in whom intervention is started early (Bruyere et al., 2003). In these studies, oral glucosamine supplements (1,500 mg/ day for 3 years) were shown to virtually halt the progressive joint space narrowing observed in the placebo group, suggesting a retardation of osteoarthritis progression. Studies of glucosamine supplementation in more severe forms of osteoarthritis are less positive than studies of mild to-moderate forms of the disease (Das and Hammad, 2000).

Occasional symptoms of gastrointestinal discomfort have been noted but no significant adverse effects are associated with glucosamine supple mentation. Although no long-term safety studies have been conduclec in humans, animal studies on glucosamine have found it to be nontoxic (Towheed et al., 2005). Diabetics have been cautioned about using glucosamine supplements, based on findings from several animal studies that have suggested an increase in blood sugar levels caused by glucosamine (Monauni et al., 2000). Most of the animal studies have used injections of glucosamine, and recent feeding studies in humans have shown no changes in plasma levels of glucose or insulin (Scroggie et al., 2003) insulin sensitivity (Pouwels et al., 2001), or glucose oxidation (Monauni et al., 2000), suggesting lhat glucosamine has no significant effect on blood sugar metabolism when used as directed.

No dose-response studies have been conducted with glucosamine supplements. Virtually all oral supplementation studies on glucosamine have used 1,500 mg/day, usually in 2-3 divided doses of 500-750 mg each, but some recent studies have used higher levels of glucosamine [2,000 mg/day; Braham et al., 2003) or higher levels combined with chondroitin and other ingredients (Das and 1 lammad, 2000). Although higher doses appear to be effective, there is no information to suggest that a higher dose works better or faster or that a lower dose is less effective.

Glucosamine is also routinely combined with chondroitin sulfate, but no information currently exists to suggest lhat sucli a combined formulation is superior lo either agent consumed alone at the proper dosage. There appear to be few, if any, differences among the various forms of glucosamine (sulfate, hydrochloride, N-acetyl), and each form has been shown to reduce pain and stiffness in studies of mild-to-moderate osteoarthritis (Talent and Cracy, 1996).

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