Glucosamine is an
amino sugarIn chemistry, an amino sugar contains an amine group in place of a hydroxyl group. Derivatives of amine containing sugars, such as N-acetylglucosamine and sialic acid, while not formally containing an amine, are also considered amino sugars....
and a prominent precursor in the biochemical synthesis of
glycosylatedGlycosylation is the reaction in which a carbohydrate, i.e. a glycosyl donor, is attached to a hydroxyl or other functional group of another molecule . In biology glycosylation refers to the enzymatic process that attaches glycans to proteins, lipids, or other organic molecules...
proteins and lipids. Glucosamine is part of the structure of the
polysaccharidePolysaccharides are long carbohydrate molecules, of repeated monomer units joined together by glycosidic bonds. They range in structure from linear to highly branched. Polysaccharides are often quite heterogeneous, containing slight modifications of the repeating unit. Depending on the structure,...
s
chitosanChitosan is a linear polysaccharide composed of randomly distributed β--linked D-glucosamine and N-acetyl-D-glucosamine...
and
chitinChitin n is a long-chain polymer of a N-acetylglucosamine, a derivative of glucose, and is found in many places throughout the natural world...
, which compose the exoskeletons of crustaceans and other arthropods, cell walls in fungi and many higher organisms. Glucosamine is one of the most abundant
monosaccharideMonosaccharides are the most basic units of biologically important carbohydrates. They are the simplest form of sugar and are usually colorless, water-soluble, crystalline solids. Some monosaccharides have a sweet taste. Examples of monosaccharides include glucose , fructose , galactose, xylose...
s. It is produced commercially by the
hydrolysisHydrolysis is a chemical reaction during which molecules of water are split into hydrogen cations and hydroxide anions in the process of a chemical mechanism. It is the type of reaction that is used to break down certain polymers, especially those made by condensation polymerization...
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 and bone marrow. It is also present in some fungi, such as
Aspergillus nigerAspergillus niger is a fungus and one of the most common species of the genus Aspergillus. It causes a disease called black mold on certain fruits and vegetables such as grapes, onions, and peanuts, and is a common contaminant of food...
.
Glucosamine was first prepared in 1876 by
Georg LedderhoseDr. Georg Ledderhose was a German surgeon, December 15, 1855, Bockenheim, Regierungsbezirk Wiesbaden, Germany – February 1, 1925, Munich, Germany....
by the
hydrolysisHydrolysis is a chemical reaction during which molecules of water are split into hydrogen cations and hydroxide anions in the process of a chemical mechanism. It is the type of reaction that is used to break down certain polymers, especially those made by condensation polymerization...
of
chitinChitin n is a long-chain polymer of a N-acetylglucosamine, a derivative of glucose, and is found in many places throughout the natural world...
with concentrated
hydrochloric acidHydrochloric acid is a solution of hydrogen chloride in water, that is a highly corrosive, strong mineral acid with many industrial uses. It is found naturally in gastric acid....
. The
stereochemistryStereochemistry, a subdiscipline of chemistry, involves the study of the relative spatial arrangement of atoms within molecules. An important branch of stereochemistry is the study of chiral molecules....
was not fully defined until the 1939 work of
Walter HaworthSir Norman Haworth was a British chemist best known for his groundbreaking work on ascorbic acid while working at the University of Birmingham. He received the 1937 Nobel Prize in Chemistry "for his investigations on carbohydrates and vitamin C"...
. D-Glucosamine is made naturally in the form of glucosamine-6-phosphate, and is the biochemical precursor of all
nitrogen-containing sugarsIn chemistry, an amino sugar contains an amine group in place of a hydroxyl group. Derivatives of amine containing sugars, such as N-acetylglucosamine and sialic acid, while not formally containing an amine, are also considered amino sugars....
. Specifically, glucosamine-6-phosphate is synthesized from
fructose 6-phosphateFructose 6-phosphate is fructose sugar phosphorylated on carbon 6 . The β-D-form of this compound is very common in cells. The vast majority of glucose and fructose entering a cell will become converted to this at some point...
and
glutamineGlutamine is one of the 20 amino acids encoded by the standard genetic code. It is not recognized as an essential amino acid but may become conditionally essential in certain situations, including intensive athletic training or certain gastrointestinal disorders...
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
glycosaminoglycanGlycosaminoglycans or mucopolysaccharides are long unbranched polysaccharides consisting of a repeating disaccharide unit. The repeating unit consists of a hexose or a hexuronic acid, linked to a hexosamine .-Production:Protein cores made in the rough endoplasmic reticulum are posttranslationally...
s, 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 as a Dietary Supplement
Oral glucosamine is a
dietary supplementA dietary supplement, also known as food supplement or nutritional supplement, is a preparation intended to supplement the diet and provide nutrients, such as vitamins, minerals, fiber, fatty acids, or amino acids, that may be missing or may not be consumed in sufficient quantities in a person's diet...
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
osteoarthritisOsteoarthritis also known as degenerative arthritis or degenerative joint disease, is a group of mechanical abnormalities involving degradation of joints, including articular cartilage and subchondral bone. Symptoms may include joint pain, tenderness, stiffness, locking, and sometimes an effusion...
. Commonly sold forms of glucosamine are glucosamine sulfate and glucosamine hydrochloride. Glucosamine is often sold in combination with other supplements such as
chondroitin sulfateChondroitin sulfate is a sulfated glycosaminoglycan composed of a chain of alternating sugars . It is usually found attached to proteins as part of a proteoglycan. A chondroitin chain can have over 100 individual sugars, each of which can be sulfated in variable positions and quantities...
and
methylsulfonylmethaneMethylsulfonylmethane is an organosulfur compound with the formula 2SO2. It is also known by several other names including DMSO2, methyl sulfone, and dimethyl sulfone. This colorless solid features the sulfonyl functional group and is considered relatively inert chemically...
.
Evaluation for health effects
Since glucosamine is a precursor for
glycosaminoglycanGlycosaminoglycans or mucopolysaccharides are long unbranched polysaccharides consisting of a repeating disaccharide unit. The repeating unit consists of a hexose or a hexuronic acid, linked to a hexosamine .-Production:Protein cores made in the rough endoplasmic reticulum are posttranslationally...
s, and glycosaminoglycans are a major component of
joint cartilageCartilage is a flexible connective tissue found in many areas in the bodies of humans and other animals, including the joints between bones, the rib cage, the ear, the nose, the elbow, the knee, the ankle, the bronchial tubes and the intervertebral discs...
, 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 suplementation were highest in industry-funded studies and lowest in independent studies.
A
CochraneThe Cochrane Collaboration is a group of over 28,000 volunteers in more than 100 countries who review the effects of health care interventions tested in biomedical randomized controlled trials. A few more recent reviews have also studied the results of non-randomized, observational studies...
2005
meta-analysisIn statistics, a meta-analysis combines the results of several studies that address a set of related research hypotheses. In its simplest form, this is normally by identification of a common measure of effect size, for which a weighted average might be the output of a meta-analyses. Here the...
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 effect above placebo.
There have been multiple
clinical trialClinical trials are a set of procedures in medical research and drug development that are conducted to allow safety and efficacy data to be collected for health interventions...
s 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.
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-outsIn epidemiology, an intention to treat analysis is an analysis based on the initial treatment intent, not on the treatment eventually administered. ITT analysis is intended to avoid various misleading artifacts that can arise in intervention research...
, and unclear procedures for
blindingA blind or blinded experiment is a scientific experiment where some of the people involved are prevented from knowing certain information that might lead to conscious or subconscious bias on their part, invalidating the results....
. Rottapharm then sponsored two large (at least 100 patients per group), three-year-long,
placebo-controlledA placebo is a simulated or otherwise medically ineffectual treatment for a disease or other medical condition intended to deceive the recipient...
clinical trials of the Rottapharm brand of glucosamine sulfate. These studies both demonstrated a clear benefit for glucosamine treatment. 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.
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
VASA visual analogue scale is a psychometric response scale which can be used in questionnaires. It is a measurement instrument for subjective characteristics or attitudes that cannot be directly measured. When responding to a VAS item, respondents specify their level of agreement to a statement by...
and
WOMACThe Western Ontario and McMaster Universities Arthritis Index is a set of standardized questionnaires used by health professionals to evaluate the condition of patients with osteoarthritis of the knee and hip. It can be self-administered and was developed at Western Ontario and McMaster Universities...
pain, Lequesne index and VAS mobility and good tolerability.
The confusion led the
National Institutes of HealthThe National Institutes of Health are an agency of the United States Department of Health and Human Services and are the primary agency of the United States government responsible for biomedical and health-related research. Its science and engineering counterpart is the National Science Foundation...
in the U.S.A. to fund a large,
multicenter clinical trialA multicenter research trial is a clinical trial conducted at more than one medical center or clinic. Most large clinical trials, particularly Phase III trials, are conducted at several clinical research centers...
(the GAIT trial) studying reported pain in osteoarthritis of the knee, comparing groups treated with
chondroitin sulfateChondroitin sulfate is a sulfated glycosaminoglycan composed of a chain of alternating sugars . It is usually found attached to proteins as part of a proteoglycan. A chondroitin chain can have over 100 individual sugars, each of which can be sulfated in variable positions and quantities...
, glucosamine, and the combination, as well as both placebo and
celecoxibCelecoxib INN is a sulfa non-steroidal anti-inflammatory drug and selective COX-2 inhibitor used in the treatment of osteoarthritis, rheumatoid arthritis, acute pain, painful menstruation and menstrual symptoms, and to reduce numbers of colon and rectum polyps in patients with familial...
. 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 significantIn statistics, a result is called statistically significant if it is unlikely to have occurred by chance. The phrase test of significance was coined by Ronald Fisher....
improvement in their symptoms compared to patients taking a placebo. 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 dataIn statistics, hypotheses suggested by the data, if tested using the data set that suggested them, are likely to be accepted even when they are not true...
).
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" But this concern is not shared by pharmacologists at the
PDRThe Physicians' Desk Reference is a commercially published compilation of manufacturers' prescribing information on prescription drugs, updated annually...
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". 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."
A subsequent
meta-analysisIn statistics, a meta-analysis combines the results of several studies that address a set of related research hypotheses. In its simplest form, this is normally by identification of a common measure of effect size, for which a weighted average might be the output of a meta-analyses. Here the...
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. 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.
A 2009 review concluded that "Little evidence suggests that glucosamine is superior to a placebo treatment in restoring articular cartilage."
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".
A meta-analysis published in the
British Medical JournalBMJ is a partially open-access peer-reviewed medical journal. Originally called the British Medical Journal, the title was officially shortened to BMJ in 1988. The journal is published by the BMJ Group, a wholly owned subsidiary of the British Medical Association...
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." .
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.
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.
Dangers of glucosamine
Clinical studies have consistently reported that glucosamine appears safe. However, a recent
Université LavalLaval University is the oldest centre of education in Canada and was the first institution in North America to offer higher education in French...
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.
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
shellfishShellfish is a culinary and fisheries term for exoskeleton-bearing aquatic invertebrates used as food, including various species of molluscs, crustaceans, and echinoderms. Although most kinds of shellfish are harvested from saltwater environments, some kinds are found only in freshwater...
while the
allergenAn allergen is any substance that can cause an allergy. In technical terms, an allergen is a non-parasitic antigen capable of stimulating a type-I hypersensitivity reaction in atopic individuals....
is within the flesh of the animals, it is probably safe even for those with shellfish allergy. 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, 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.
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.
The bioavailability of glucosamine sulfate is around 20%.
Pharmacodynamics
The possible effects of glucosamine sulfate in patients with osteoarthritis may be the result of its
anti-inflammatoryAnti-inflammatory refers to the property of a substance or treatment that reduces inflammation. Anti-inflammatory drugs make up about half of analgesics, remedying pain by reducing inflammation as opposed to opioids, which affect the central nervous system....
activity, the stimulation of the synthesis of
proteoglycanProteoglycans are proteins that are heavily glycosylated. The basic proteoglycan unit consists of a "core protein" with one or more covalently attached glycosaminoglycan chain. The point of attachment is a Ser residue to which the glycosaminoglycan is joined through a tetrasaccharide bridge...
s, and the decrease in
catabolic activityCatabolism is the set of metabolic pathways that break down molecules into smaller units and release energy. In catabolism, large molecules such as polysaccharides, lipids, nucleic acids and proteins are broken down into smaller units such as monosaccharides, fatty acids, nucleotides, and amino...
of
chondrocyteChondrocytes are the only cells found in cartilage. They produce and maintain the cartilaginous matrix, which consists mainly of collagen and proteoglycans...
s inhibiting the synthesis of
proteolytic enzymesA protease is any enzyme that conducts proteolysis, that is, begins protein catabolism by hydrolysis of the peptide bonds that link amino acids together in the polypeptide chain forming the protein....
and other substances that contribute to damage cartilage matrix and cause death of articular chondrocytes.
Glucosamine is an essential substrate in the natural formation of the
GAGGlycosaminoglycans or mucopolysaccharides are long unbranched polysaccharides consisting of a repeating disaccharide unit. The repeating unit consists of a hexose or a hexuronic acid, linked to a hexosamine .-Production:Protein cores made in the rough endoplasmic reticulum are posttranslationally...
matrix.
Glucosamine is thought to stimulate synovial production of hyaluronic acid and is also claimed to inhibit cartilage degrading liposomal enzymes.
United States
In the United States, glucosamine is not approved by the
Food and Drug AdministrationThe Food and Drug Administration is an agency of the United States Department of Health and Human Services, one of the United States federal executive departments...
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 HealthThe National Institutes of Health are an agency of the United States Department of Health and Human Services and are the primary agency of the United States government responsible for biomedical and health-related research. Its science and engineering counterpart is the National Science Foundation...
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 resistanceInsulin resistance is a physiological condition where the natural hormone insulin becomes less effective at lowering blood sugars. The resulting increase in blood glucose may raise levels outside the normal range and cause adverse health effects, depending on dietary conditions. Certain cell types...
.
Europe
In most of Europe, glucosamine is approved as a medical drug and is sold in the form of glucosamine sulphate. 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 also confirm its excellent safety profile.
External links