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Glucosamine

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Glucosamine
Stereo structural formula of glucosamine ((2S,6R)-6-meth,-2-ol)
Stereo structural formula of glucosamine ((2S,6R)-6-meth,-2-ol)
Ball and stick model of glucosamine ((2R,6R)-6-meth,-2-ol)
Ball and stick model of glucosamine ((2R,6R)-6-meth,-2-ol)
Names
IUPAC name
(3R,4R,5S)-3-Amino-6-(hydroxymethyl)oxane-2,4,5-triol
Other names
2-Amino-2-deoxy-glucose
Chitosamine
Identifiers
3D model (JSmol)
1723616
ChEBI
ChEMBL
ChemSpider
DrugBank
ECHA InfoCard 100.020.284 Edit this at Wikidata
EC Number
  • 222-311-2
720725
KEGG
MeSH Glucosamine
UNII
  • InChI=1S/C6H13NO5/c7-3-5(10)4(9)2(1-8)12-6(3)11/h2-6,8-11H,1,7H2/t2?,3-,4-,5-,6?/m1/s1 ☒N
    Key: MSWZFWKMSRAUBD-SPZCMYQFSA-N ☒N
  • N[C@H]1C(O)OC(CO)[C@@H](O)[C@@H]1O
Properties
C6H13NO5
Molar mass 179.172 g·mol−1
Melting point 150 °C (302 °F; 423 K)
log P -2.175
Acidity (pKa) 12.273
Basicity (pKb) 1.724
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
☒N verify (what is checkY☒N ?)

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, 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 by fermentation of a grain such as corn or wheat.[2] In the US it is one of the most common non-vitamin, non-mineral, dietary supplements used by adults.[3]

Biochemistry

Glucosamine is naturally present in the shells of shellfish, animal bones and bone marrow. It is also present in some fungi, such as Aspergillus niger.[4]

Glucosamine was first prepared in 1876 by Georg Ledderhose by the hydrolysis of chitin with concentrated hydrochloric acid.[5][6] The stereochemistry was not fully defined until the 1939 work of Walter Haworth.[1] D-Glucosamine is made naturally in the form of glucosamine-6-phosphate, and is the biochemical precursor of all nitrogen-containing sugars.[7] Specifically, glucosamine-6-phosphate is synthesized from fructose 6-phosphate and glutamine by glucosamine-6-phosphate deaminase[8] as the first step of the hexosamine biosynthesis pathway.[9] 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.[10]

Use as a dietary supplement

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.[11] 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. [12]

Evaluation for health effects

Since glucosamine is a precursor for glycosaminoglycans, and glycosaminoglycans are a major component of joint cartilage, supplemental glucosamine may help to prevent cartilage degeneration and treat arthritis. Its use as a therapy for osteoarthritis appears safe, but there is conflicting evidence as to its effectiveness. A systematic review found that effect sizes from glucosamine supplementation were highest in industry-funded studies and lowest in independent studies. [13] 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.[14] However, when the low quality and older studies were discounted and only those using the highest-quality design were considered, there was no effect above placebo.[15]

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.[16]

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.[17][18] 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.[19][20] 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.[21][22]

Due to these controversial results, some reviews and meta-analyses have evaluated the efficacy of glucosamine. Richie 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.[23]

The confusion led the National Institutes of Health in the U.S.A. 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.[24] The results of this 6-month trial were published in 2006, and the publication explained 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.[25] 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"[26][27] 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".[28] 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) - it was published in 2007. The abstract of the publication reads: "At baseline, the study patients had moderately severe OA symptoms (mean Lequesne index approximately 11 points). Glucosamine sulfate was more effective than placebo in improving the Lequesne score, with a final decrease of 3.1 points, versus 1.9 with placebo (difference between glucosamine sulfate and placebo -1.2 [95% confidence interval -2.3, -0.8]) (P = 0.032). The 2.7-point decrease with acetaminophen was not significantly different from that with placebo (difference -0.8 [95% confidence interval -1.9, 0.3]) (P = 0.18). Similar results were observed for the WOMAC. There were more responders to glucosamine sulfate (39.6%) and acetaminophen (33.3%) than to placebo (21.2%) (P = 0.004 and P = 0.047, respectively, versus placebo). Safety was good, and was comparable among groups." [29]

A subsequent meta-analysis of randomized controlled trials was published in 2007 (it included the NIH trial by Clegg); the article concluded that hydrochloride is not effective and that there was too much heterogeneity among trials of glucosamine sulfate to draw a conclusion.[30] 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.[31]

A 2009 review concluded that "Little evidence suggests that glucosamine is superior to a placebo treatment in restoring articular cartilage."[32]

A 2009 scientific review of available studies concluded that glucosamine sulfate, "glucosamine hydrochloride, and chondroitin sulfate have individually shown inconsistent efficacy in decreasing arthritis pain", though "many studies confirmed pain relief with glucosamine and chondroitin sulfate in combined use".[33]

A meta-analysis published in the British Medical Journal published in 2010 concluded: "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." .[34]

A subsequent paper criticised the 2010 meta-analysis, suggesting the findings were "questionable and likely due to heterogeneity" (mixing unrelated types of studies inappropriately).[35]

However, currently OARSI (OsteoArthritis Research Society International) is recommending glucosamine as the second most effective treatment[citation needed] 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.[31]

Use of glucosamine in veterinary medicine is seemingly accepted, but there is no proof of efficacy and the quality of published clinical trials of glucosamine in horses was recently judged too low to be of any value in guiding treatment of horses.[36]

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 drug. Beyond recommended dosages, researchers found in preliminary studies that glucosamine may damage pancreatic cells, possibly increasing the risk of developing diabetes.[37]

Adverse effects, which are usually mild and infrequent, include stomach upset, constipation, diarrhea, headache and rash.[38]

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.[39] 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.[40] [41] Alternative, non-shellfish derived forms of glucosamine are available.[42][43]

Another concern has been that the extra glucosamine could contribute to diabetes by interfering with the normal regulation of the hexosamine biosynthesis pathway,[10] but several investigations have found no evidence that this occurs.[44][45][46] 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.[47] 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.[48][49][50]

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.[51][52] 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.[53]

Preliminary research

If glucosamine sulfate actually is proven to be effective in patients with osteoarthritis, it may result from anti-inflammatory activity,[54][55] stimulation of proteoglycan synthesis,[56] decrease in catabolic activity of chondrocytes inhibiting the synthesis of proteolytic enzymes and other substances that contribute to cartilage integrity,[57][58][59][60] or have no effect at all.

As a substrate of the GAG matrix,[61] glucosamine is postulated to stimulate synovial production of hyaluronic acid or possibly to inhibit liposomal enzymes.[61]

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.[62] 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.[63]

Europe

In most of Europe, glucosamine is approved as a medical drug and is sold in the form of glucosamine sulfate.[64] 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,[64] and recent OARSI (OsteoArthritis Research Society International) guidelines for hip and knee osteoarthritis indicate an acceptable safety profile.[65]

See also

References

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  33. ^ Attention: This template ({{cite pmid}}) is deprecated. To cite the publication identified by PMID 19111223, please use {{cite journal}} with |pmid=19111223 instead.
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  35. ^ Attention: This template ({{cite doi}}) is deprecated. To cite the publication identified by doi: 10.1136/ebm1164 , please use {{cite journal}} (if it was published in a bona fide academic journal, otherwise {{cite report}} with |doi= 10.1136/ebm1164 instead.
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