Glucosamine : Uses and Health Benefits

By MedlinePlus

Glucosamine is a natural compound that is found in healthy cartilage. Glucosamine sulfate is a normal constituent of glycoaminoglycans in cartilage matrix and synovial fluid. Available evidence from randomized controlled trials supports the use of glucosamine sulfate in the treatment of osteoarthritis, particularly of the knee. It is believed that the sulfate moiety provides clinical benefit in the synovial fluid by strengthening cartilage and aiding glycosaminoglycan synthesis. If this hypothesis is confirmed, it would mean that only the glucosamine sulfate form is effective and non-sulfated glucosamine forms are not effective. Glucosamine is commonly taken in combination with chondroitin, a glycosaminoglycan derived from articular cartilage. Use of complementary therapies, including glucosamine, is common in patients with osteoarthritis, and may allow for reduced doses of non-steroidal anti-inflammatory agents. Polysaccharides are becoming increasingly developed as therapeutics and medical products. Glycosaminoglycans that contain N-acetyl glucosamine constituents have been the focus of research leading to medical devices. A hemostatic bandage, the Syvek Patch, has been introduced in the recent past for the control of bleeding at vascular access sites in interventional cardiology and radiology procedures. This product consists of poly-N-acetyl glucosamine (pGlcNAc) isolated in a unique fiber crystalline structural form. Clo-Sur PAD and ChitoSeal, are also available as patch hemostats. These two products both use chitosan, another N-acetyl glucosamine containing glycosaminoglycan, as their active ingredient. Detailed use of these products will not be discussed in this review.

Evidence
These uses have been tested in humans or animals. Safety and effectiveness have not always been proven. Some of these conditions are potentially serious, and should be evaluated by a qualified healthcare provider.

Uses based on scientific evidence

Knee osteoarthritis (mild-to-moderate) Based on human research, there is good evidence to support the use of glucosamine sulfate in the treatment of mild-to-moderate knee osteoarthritis. Most studies have used glucosamine sulfate supplied by one European manufacturer (Rotta Research Laboratorium), and it is not known if glucosamine preparations made by other

manufacturers are equally effective. Results of a recent large clinical trial (GAIT) comparing the effects of glucosamine to celecoxib (Celebrex) for treatment of knee osteoarthritis have yet to be published. A recent study or postmenopausal women found that glucosamine reduced joint space narrowing compared to placebo treatment.Although some studies of glucosamine have not found benefits, these have either included patients with severe osteoarthritis, or used products other than glucosamine sulfate . The evidence for the effect of glycosaminoglycan polysulphate is conflicting and merits further investigation. More welldesigned clinical trials are needed to confirm safety and effectiveness, and to test different formulations of glucosamine. Osteoarthritis (general) Several human studies and animal experiments report benefits of glucosamine in treating osteoarthritis of various joints of the body, although the evidence is less plentiful than that for knee osteoarthritis. Some of these benefits include pain relief, possibly due to an antiinflammatory effect of glucosamine, and improved joint function. Overall, these studies have not been well designed. Analyses, which group the existing studies together and isolate higher-quality research (meta-analyses) have found conflicting results, with improvement in some scales measuring pain and disability, but not in others. Although there is some promising research, more study is needed in this area before a firm conclusion can be made. Chronic venous insufficiency "Chronic venous insufficiency" is a syndrome that includes leg swelling, varicose veins, pain, itching, skin changes, and skin ulcers. The term is more commonly used in Europe than in the United States. Currently, there is not enough reliable scientific evidence to recommend glucosamine in the treatment of this condition. Inflammatory bowel disease (Crohn's disease, ulcerative colitis) Preliminary research reports improvements with N-acetyl glucosamine as an added therapy in inflammatory bowel disease. Further scientific evidence is necessary before a recommendation can be made. Rheumatoid arthritis Preliminary human research reports benefits of glucosamine in the treatment of joint pain and swelling in rheumatoid arthritis. However, this is early information, and additional research is needed before a conclusion can be drawn. The treatment of rheumatoid arthritis

can be complicated, and a qualified healthcare provider should follow people with this disease. Temporomandibular joint (TMJ) disorders There is a lack of sufficient evidence to recommend for or against the use of glucosamine (or the combination of glucosamine and chondroitin) in the treatment of temporomandibular joint disorders.

Uses based on tradition or theory

The below uses are based on tradition or scientific theories. They often have not been thoroughly tested in humans, and safety and effectiveness have not always been proven. Some of these conditions are potentially serious, and should be evaluated by a qualified healthcare provider. AIDS, athletic injuries, back pain, bleeding esophageal varices (blood vessels in the esophagus), cancer, congestive heart failure, depression, diabetes, fibromyalgia, joint pain, knee pain, kidney stones, migraine headache, osteoporosis, pain, patellofemoral pain syndrome (PFPS- pain behind the knee cap), psoriasis, skin rejuvenation, spondylosis deformans (growth of bony spurs on the spine), wound healing, immunosuppression, topical hypopigmenting agent (combination product containing multiple ingredients).

Glucosamine
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Glucosamine

IUPAC name Other names

[show]

2-Amino-2-deoxy-Dglucose chitosamine Identifiers

CAS number PubChem MeSH

3416-24-8, 66-84-2 (hydrochloride) 439213 Glucosamine

[show]

SMILES

Properties Molecular formula Molar mass Melting point

C6H13NO5

179.17 g/mol

150 C, 423 K, 302 F

Except where noted otherwise, data are given for materials in their standard state (at 25 C, 100 kPa) Infobox references

Glucosamine (C6H13NO5) is an amino sugar and a prominent precursor in the biochemical synthesis of glycosylated proteins and lipids. A type of glucosamine forms chitosan and chitin, which composes the exoskeletons of crustaceans and other arthropods, cell walls in fungi and many higher organisms. Glucosamine is one of the most abundant monosaccharides.[1] It is produced commercially by the hydrolysis of crustacean exoskeletons or, less commonly and more expensive to the consumer, by fermentation of a grain such as corn or wheat. Glucosamine is commonly used as a treatment for osteoarthritis, although its acceptance as a medical therapy varies.

Contents
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1 Biochemistry 2 Health effects

2.1 Use 2.2 Safety 2.3 Bioavailability and pharmacokinetics 2.4 Mechanisms of action 2.5 Clinical studies 3 See also 4 References 5 External links

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[edit] Biochemistry
Glucosamine was first identified in 1876 by Dr. Georg Ledderhose, but the stereochemistry was not fully defined until 1939 by the work of Walter Haworth.[1] D-Glucosamine is made naturally in the form of glucosamine-6-phosphate, and is the biochemical precursor of all nitrogencontaining sugars.[2] Specifically, glucosamine-6-phosphate is synthesized from fructose 6phosphate and glutamine[3] as the first step of the hexosamine biosynthesis pathway.[4] The endproduct of this pathway is UDP-N-acetylglucosamine (UDP-GlcNAc), which is then used for making glycosaminoglycans, proteoglycans, and glycolipids. As the formation of glucosamine-6-phosphate is the first step for the synthesis of these products, glucosamine may be important in regulating their production. However, the way that the hexosamine biosynthesis pathway is actually regulated, and whether this could be involved in contributing to human disease, remains unclear.[5]

[edit] Health effects

Oral glucosamine is commonly used for the treatment of osteoarthritis. Since glucosamine is a precursor for glycosaminoglycans, and glycosaminoglycans are a major component of joint cartilage, supplemental glucosamine may help to rebuild cartilage and treat arthritis. Its use as a therapy for osteoarthritis appears safe, but there is conflicting evidence as to its effectiveness. A Cochrane 2005 meta-analysis of glucosamine for osteoarthritis found that only "Rotta" preparations (including older studies) found beneficial effects for pain and functional impairment.[6] It also found that when only the studies using the highest-quality design were considered, there was no effect above placebo.[7] Studies reporting beneficial effects have generally used glucosamine sulfate.[7] Chondroitin is sometimes used in conjunction, and animal studies suggest that chondroitin may increase its efficacy.[7] In 2008 a randomized, double-blind, placebo-controlled trial found glucosamine sulfate is no better than placebo in reducing the symptoms or progression of hip osteoarthritis. [8] [edit] Use A typical dosage of glucosamine salt is 1,500 mg per day. Glucosamine contains an amino group that is positively charged at physiological pH. The anion included in the salt may vary. Commonly sold forms of glucosamine are glucosamine sulfate and glucosamine hydrochloride.

The amount of glucosamine present in 1500 mg of glucosamine salt will depend on which anion is present and whether additional salts are included in the manufacturer's calculation.[9] Glucosamine is often sold in combination with other supplements such as chondroitin sulfate and methylsulfonylmethane. Glucosamine is a popular alternative medicine used by consumers for the treatment of osteoarthritis. Glucosamine is also extensively used in veterinary medicine as an unregulated but widely accepted supplement. Other uses based mostly on tradition have not been thoroughly tested, and safety and effectiveness have not always been proven in a serious double blind test. Some of these conditions may be potentially serious and should be evaluated by a healthcare provider. These include immunosuppression, autoimmune diseases, osteoporosis, pain, psoriasis, skin rejuvenation, depression, fibromyalgia, athletic injuries, back pain, bleeding esophageal varices (blood vessels in the esophagus), AIDS, cancer, congestive heart failure, kidney stones, migraine headache, spondylosis deformations, ankylosing spondylitis, topical hypopigmenting agent, and wound healing. [edit] Safety Clinical studies have consistently reported that glucosamine appears safe. Since glucosamine is usually derived from shellfish, those allergic to shellfish may wish to avoid it. However, since glucosamine is derived from the shells of these animals while the allergen is within the flesh of the animals, it is probably safe even for those with shellfish allergy.[10] Alternative sources using fungal fermentation of corn are available. Another concern has been that the extra glucosamine could contribute to diabetes by interfering with the normal regulation of the hexosamine biosynthesis pathway,[5] but several investigations have found no evidence that this occurs.[11].[12][13] A review conducted by Anderson et al in 2005 summarizes the effects of glucosamine on glucose metabolism in in vitro studies, the effects of oral administration of large doses of glucosamine in animals and the effects of glucosamine supplementation with normal recommended dosages in humans, concluding that glucosamine does not cause glucose intolerance and has no documented effects on glucose metabolism.[14] Other studies conducted in lean or obese subjects concluded that oral glucosamine at standard doses does not cause or significantly worsen insulin resistance or endothelial dysfunction.[15][16][17] The U.S. National Institutes of Health is currently conducting a study of supplemental glucosamine in obese patients, since this population may be particularly sensitive to any effects of glucosamine on insulin resistance.[18] In the United States, glucosamine is not approved by the Food and Drug Administration for medical use in humans. Since glucosamine is classified as a dietary supplement in the US, safety and formulation are solely the responsibility of the manufacturer; evidence of safety and efficacy is not required as long as it is not advertised as a treatment for a medical condition.[19] In Europe, glucosamine is approved as a medical drug and is sold in the form of glucosamine sulfate. In this case, evidence of safety and efficacy is required for the medical use of

glucosamine and several guidelines have recommended its use as an effective and safe therapy for osteoarthritis. Actually, the Task Force of the European League Against Rheumatism (EULAR) committee recently granted glucosamine sulfate a level of toxicity of 5 in a 0-100 scale,[20] and recent OARSI (OsteoArthritis Research Society International) guidelines for hip and knee osteoarthritis also confirm its excellent safety profile.[21] [edit] Bioavailability and pharmacokinetics Two recent studies confirm that glucosamine is bioavailable both systemically and at the site of action (the joint) after oral administration of crystalline glucosamine sulfate in osteoarthritis patients. Steady state glucosamine concentrations in plasma and synovial fluid were correlated and in line with those effective in selected in vitro studies.[22][23] [edit] Mechanisms of action The benefit of glucosamine sulfate in patients with osteoarthritis is likely the result of a number of effects including its anti-inflammatory activity,[24][25] the stimulation of the synthesis of proteoglycans,[26] and the decrease in catabolic activity of chondrocytes inhibiting the synthesis of proteolytic enzymes and other substances that contribute to damage cartilage matrix and cause death of articular chondrocytes.[27][28][29][30] [edit] Clinical studies There have been multiple clinical trials of glucosamine as a medical therapy for osteoarthritis, but results have been conflicting. The evidence both for and against glucosamine's efficacy has led to debate among physicians about whether to recommend glucosamine treatment to their patients.[31] Multiple clinical trials in the 1980s and 1990s, all sponsored by the European patent-holder, Rottapharm, demonstrated a benefit for glucosamine. However, these studies were of poor quality due to shortcomings in their methods, including small size, short duration, poor analysis of drop-outs, and unclear procedures for blinding.[32][33] Rottapharm then sponsored two large (at least 100 patients per group), three-year-long, placebo-controlled clinical trials of the Rottapharm brand of glucosamine sulfate. These studies both demonstrated a clear benefit for glucosamine treatment.[34][35] There was not only an improvement in symptoms but also an improvement in joint space narrowing on radiographs. This suggested that glucosamine, unlike pain relievers such as NSAIDs, can actually help prevent the destruction of cartilage that is the hallmark of osteoarthritis. On the other hand, several subsequent studies, independent of Rottapharm, but smaller and shorter, did not detect any benefit of glucosamine.[36][37] Due to these controversial results, some reviews and meta-analyses have evaluated the efficacy of glucosamine. Richy et al. performed a meta-analysis of randomized clinical trials in 2003 and found efficacy for glucosamine on VAS and WOMAC pain, Lequesne index and VAS mobility and good tolerability.[38]

Recently, a review by Bruyere et al. about glucosamine and chondroitin sulfate for the treatment of knee and hip osteoarthritis concludes that both products act as valuable symptomatic therapies for osteoarthritis disease with some potential structure-modifying effects.[39] This situation led the National Institutes of Health to fund a large, multicenter clinical trial (the GAIT trial) studying reported pain in osteoarthritis of the knee, comparing groups treated with chondroitin sulfate, glucosamine, and the combination, as well as both placebo and celecoxib.[40] The results of this 6-month trial found that patients taking glucosamine HCl, chondroitin sulfate, or a combination of the two had no statistically significant improvement in their symptoms compared to patients taking a placebo.[41] The group of patients who took celecoxib did have a statistically significant improvement in their symptoms. These results suggest that glucosamine and chondroitin did not effectively relieve pain in the overall group of osteoarthritis patients, but it should be interpreted with caution because most patients presented only mild pain (thus a narrow margin to appraise pain improvement) and because of an unusual response to placebo in the trial (60%). However, exploratory analysis of a subgroup of patients suggested that the supplements taken together (glucosamine and chondroitin sulfate) may be significantly more effective than placebo (79.2% versus 54%; p = 0.002) and a 10% higher than the positive control, in patients with pain classified as moderate to severe (see testing hypotheses suggested by the data). In an accompanying editorial, Dr. Marc Hochberg also noted that "It is disappointing that the GAIT investigators did not use glucosamine sulfate ... since the results would then have provided important information that might have explained in part the heterogeneity in the studies reviewed by Towheed and colleagues"[42][43] But this concern is not shared by pharmacologists at the PDR who state, "The counter anion of the glucosamine salt (i.e. chloride or sulfate) is unlikely to play any role in the action or pharmacokinetics of glucosamine".[9] Thus the question of glucosamine's efficacy will not be resolved without further updates or trials. In this respect, a 6-month double-blind, multicenter trial has been recently performed to assess the efficacy of glucosamine sulfate 1500 mg once daily compared to placebo and acetaminophen in patients with osteoarthritis of the knee (GUIDE study). The results showed that glucosamine sulfate improved the Lequesne algofunctional index significantly compared to placebo and the positive control. Secondary analyses, including the OARSI responder indices, were also significantly favorable for glucosamine sulfate.[44] A subsequent meta-analysis of randomized controlled trials, including the NIH trial by Clegg, concluded that hydrochloride is not effective and that there was too much heterogeneity among trials of glucosamine sulfate to draw a conclusion.[45] In response to these conclusions, Dr. J-Y Reginster in an accompanying editorial suggests that the authors failed to apply the principles of a sound systematic review to the meta-analysis, but instead put together different efficacy outcomes and trial designs by mixing 4-week studies with 3-year trials, intramuscular/intraarticular administrations with oral ones, and low-quality small studies reported in the early 1980s with high-quality studies reported in 2007.[46] However, currently OARSI (OsteoArthritis Research Society International) is recommending glucosamine as the second most effective treatment for moderate cases of osteoarthritis.

Likewise, recent European League Against Rheumatism practice guidelines for knee osteoarthritis grants to glucosamine sulfate the highest level of evidence, 1A, and strength of the recommendation, A.