Glucosamine

Glucosamine (C6H13NO5) is an amino sugar and a prominent precursor in the biochemical synthesis of glycosylated proteins and lipids. Glucosamine is part of the structure of the polysaccharides chitosan and chitin, which compose the exoskeletons of crustaceans and other arthropods, as well as the cell walls of fungi and many higher organisms. Glucosamine is one of the most abundant monosaccharides. It is produced commercially by the hydrolysis of crustacean exoskeletons or, less commonly by fermentation of a grain such as corn or wheat. In the US it is one of the most common non-vitamin, non-mineral, dietary supplements used by adults.

Biochemistry
Glucosamine is naturally present in the shells of shellfish, animal bones, bone marrow, and fungi.

Glucosamine was first prepared in 1876 by Georg Ledderhose by the hydrolysis of chitin with concentrated hydrochloric acid. The stereochemistry was not fully determined until the 1939 work of Walter Haworth. D-Glucosamine is made naturally in the form of glucosamine-6-phosphate, and is the biochemical precursor of all nitrogen-containing sugars. Specifically, glucosamine-6-phosphate is synthesized from fructose 6-phosphate and glutamine by glucosamine-6-phosphate deaminase as the first step of the hexosamine biosynthesis pathway. The end-product of this pathway is Uridine diphosphate 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.

Use in nutrition and medicine
Oral glucosamine is a dietary supplement and is not a pharmaceutical drug. It is illegal in the US to market any dietary supplement as a treatment for any disease or condition. Glucosamine is marketed to support the structure and function of joints and the marketing is targeted to people suffering from osteoarthritis. Commonly sold forms of glucosamine are glucosamine sulfate, glucosamine hydrochloride, and N-acetylglucosamine. Glucosamine is often sold in combination with other supplements such as chondroitin sulfate and methylsulfonylmethane. Of the three commonly available forms of glucosamine, only glucosamine sulfate is given a "likely effective" rating for treating osteoarthritis.

Evaluation as osteoarthritis treatment
Since glucosamine is a precursor for glycosaminoglycans, and glycosaminoglycans are a major component of joint cartilage, some have hoped that supplemental glucosamine could beneficially influence cartilage structure, and alleviate arthritis. Its use as a therapy for osteoarthritis appears safe, but there is no unequivocal evidence for its effectiveness. There have been multiple clinical trials testing glucosamine as a potential medical therapy for osteoarthritis, but the results have not supported its use.

In general, the clinical trials of the mid-1990s that furnished positive results showing glucosamine efficacy were later deemed to be of poor quality due to shortcomings in their methods, including small size, short duration, poor analysis of drop-outs, and unclear procedures for blinding. At the same time, several independent studies did not detect any benefit of glucosamine supplementation on osteoarthritis.

A Cochrane 2005 meta-analysis of glucosamine therapy for osteoarthritis found that only the Rotta brand of glucosamine appeared to be superior to placebo in the treatment of pain and functional impairment resulting from symptomatic osteoarthritis. However, when the low quality and older studies were discounted and only those using the highest-quality design were considered, there was no difference from placebo treatment.

In 2006, the U.S. National Institutes of Health (NIH) funded a 24 week, 12.5 million-dollar multicenter clinical trial (the GAIT trial) to study the effect of chondroitin sulfate, glucosamine hydrochloride, chondroitin/glucosamine in combination, and celecoxib as a treatment for knee-pain in two groups of patients with osteoarthritis of the knee: Patients with mild pain (n=1229), and patients with moderate to severe pain (n=354). When the data from both groups were pooled and analyzed, there was no statistically significant difference between groups taking glucosamine HCl, chondroitin sulfate, glucosamine/chondroitin; and those taking a placebo. The authors of the study analyzed the moderate-to-severe pain group and found that "the difference did not reach statistical significance." Another systematic review in 2007 found that effect sizes from glucosamine supplementation were highest in industry-funded studies and lowest in independent studies.

In a follow-up study in 2008, 572 patients from the GAIT trial continued their supplementation for 2 years. After 2 years of supplementation with glucosamine and chondroitin sulfate, alone or in combination, there was no benefit in slowing the loss of cartilage, in terms of joint space width, when compared to a placebo. In another 2-year follow-up study involving 662 patients from the GAIT trial, published in 2010, there was neither significant pain reduction nor improved function when comparing glucosamine and/or chondroitin to a placebo.

Due to the controversy engendered by these results, additional meta-analyses have been undertaken in an attempt to evaluate them. One published in 2010 in the British Medical Journal arrived at the following conclusions."Compared with placebo, glucosamine, chondroitin, and their combination do not reduce joint pain or have an impact on narrowing of joint space. Health authorities and health insurers should not cover the costs of these preparations, and new prescriptions to patients who have not received treatment should be discouraged."

Adverse effects
Clinical studies have consistently reported that glucosamine appears safe. However, a recent Université Laval study shows that people taking glucosamine tend to go beyond recommended guidelines, as they do not feel any positive effects from the dietary supplement. Beyond recommended dosages, researchers found in preliminary studies that glucosamine may damage pancreatic cells, possibly increasing the risk of developing diabetes.

Adverse effects, which are usually mild and infrequent, include stomach upset, constipation, diarrhea, headache and rash.

Since glucosamine is usually derived from the shells of shellfish while the allergen is within the flesh of the animals, it is probably safe even for those with shellfish allergy. However, many manufacturers of glucosamine derived from shellfish include a warning that those with a seafood allergy should consult a healthcare professional before taking the product. Alternative, non-shellfish derived forms of glucosamine 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, but several investigations have found no evidence that this occurs. A manufacturer-supported 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. 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.

Use in veterinary medicine
Use of glucosamine in veterinary medicine exists, but one study judged extant research too flawed to be of value in guiding treatment of horses.

Possibility of bioavailability
Recent studies provide preliminary evidence that glucosamine may be bioavailable in the synovial fluid after oral administration of crystalline glucosamine sulfate in osteoarthritis patients, as steady state glucosamine concentrations in plasma and synovial fluid were correlated. If eventually proven, glucosamine sulfate uptake in synovial fluid may be as much as 20%, or as little as a negligible amount, indicating no biological significance.

United States
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. 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.

Europe
In most of 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. The Task Force of the European League Against Rheumatism (EULAR) committee has granted glucosamine sulfate a level of toxicity of 5 in a 0-100 scale, and recent OARSI (OsteoArthritis Research Society International) guidelines for hip and knee osteoarthritis indicate an acceptable safety profile.

Class action lawsuits
In 2013, without admitting fault, manufacturer Rexall Sundown, Inc., and NBTY, Inc., agreed to pay up to $2 million to settle consumer claims related to the wording of certain claims on the packaging of glucosamine bottles sold at Costco under the Kirkland label.

In August 2012, a class action lawsuit was filed in New York claiming that 21st Century Healthcare, Inc. falsely advertises that its “Glucosamine 750 Chondroitin 600 Triple Strength” dietary supplements will restore lost cartilage. In April 2013, a San Diego man launched a proposed class action lawsuit in California Federal Court accusing Nutramax Laboratories, Walmart and Rite Aid of falsely advertising the effectiveness of glucosamine. The two class actions are still pending.