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Glucosamine

Scientific Name(s): 2-amino-2-deoxyglucose.
Common Name(s): Chitosamine, Glucosamine, Glucosamine hydrochloride, Glucosamine sulfate

Clinical Overview

See also: Orencia

Use

Glucosamine is being investigated extensively for its action in osteoarthritis. However, there is a lack of consensus in clinical trials regarding its efficacy.

Dosing

In clinical studies of arthritis, glucosamine dosage has typically been 1.5 g/day, as a single dose or in divided doses.

Contraindications

Contraindicated in individuals with active bleeding.

Pregnancy/Lactation

Information regarding safety and efficacy in pregnancy and lactation is lacking.

Interactions

None well documented.

Adverse Reactions

Glucosamine is generally considered safe. Use caution when administering to individuals with poorly controlled diabetes or liver disease. Use with caution in individuals with allergy to shellfish, or asthma.

Toxicology

Mutagenicity studies are limited and conflicting.

Biology

Glucosamine is a component of mucopolysaccharides, mucoproteins, and chitin. Chitin is found in yeasts, fungi, arthropods, and various marine invertebrates as a major structural component of the exoskeleton. It also occurs in other animals and members of the plant kingdom.1

Chemistry

Chemically, chitin is a biopolymer that is like cellulose but differs in having predominantly unbranched chains of beta (1-4)-2-acetamido-2-deoxy-D-glucose or N-acetyl-D-glucosamine residues. It is thought of as a cellulose derivative in which the C-2 hydroxyl groups of the polymer have been replaced by acetamide moieties. Chitin is an important structural component of shellfish, such as crab, shrimp, and lobster.2, 3 Glucosamine is isolated from chitin and is chemically stated as 2-amino-2-deoxyglucose.3 It can also be prepared synthetically, and microbial production by bacteria and fungi has been explored.4 Glucosamine sulfate is the preferred form. N-acetyl-D-glucosamine (NAG) is also sold, but it has no advantages over glucosamine. The potential of NAG in a sustained-release or topical formulation hasn't shown any greater benefit either.2, 5, 6

Considerable effort has been applied to the design of analytical methods for quantitation of glucosamine in dietary supplements and in body fluids. Because glucosamine does not possess a chromophore, many methods require pre- or post-column derivatization. High performance liquid chromatography7, 8, 9, 10, 11, 12, 13, 14 and capillary electrophoresis methods15, 16, 17 have different advantages and limitations (speed, cost, sensitivity), depending on the application.

Glucosamine is extensively metabolized by the liver after oral administration, with a bioavailability of about 19% in rats.18 Levels of glucosamine in synovial fluid in horses peaked at 1 mcg/mL after nasogastric intubation with 20 mg/kg, while intravenous administration resulted in a peak of 50 mcg/mL.19 In humans, a single oral dose of glucosamine sulfate 500 mg led to peak serum levels of 0.4 mcg/mL, with a half-life of 5 hours,20 while another study found similar levels with a single oral dose of 1.5 g.21 Glucosamine is given as the hydrochloride salt or the sulfate salt; little data support superiority of one over the other.22 Combination of glucosamine with chondroitin sulfate reduced glucosamine peak levels,21 while ingestion with glucose led to a small but clinically insignificant increase in serum glucosamine in humans.23 Glucosamine in urine has also been measured; however, only 1.8% of the dose was found to be excreted by that route.24 The poor bioavailability and peak levels obtained via the oral route have led to research on topical formulations.25, 26

Uses and Pharmacology

Glucosamine is commercially available alone or in combination with chondroitin sulfate (with or without mineral elements). Only studies evaluating the effect of glucosamine alone are discussed in this monograph.

Osteoarthritis

In osteoarthritis, the most common form of arthritis, there is a progressive degeneration of cartilage glycosaminoglycans (GAG). Formation of glucosamine is the rate-limiting step in GAG biosynthesis. It is biochemically formed from the glycolytic intermediate fructose-6-phosphate by way of amination of glutamine as the donor, ultimately yielding glucosamine-6-phosphate. This is subsequently acetylated to galactosamine before being incorporated into growing GAG. Thus, glucosamine taken orally may provide an essential building block for cartilage regeneration; however, this may be an oversimplification.3, 27, 28, 29

A randomized, double-blind, placebo-controlled trial in 201 patients with mild to moderate knee pain due to osteoarthritis found no evidence of benefit in structure, pain or function after 24 weeks of oral glucosamine supplementation (1,500 mg/day).149 The possibility of a preventative effect of glucosamine on osteoarthritis of the knee was assessed in a randomized, placebo-controlled trial in high-risk middle-aged women (N = 407). After 2.5 years, 17% of all knees showed evidence of osteoarthritis with no significant effect noted in patients receiving either oral glucosamine supplementation or participating in a diet-and-exercise program. When evaluated independently, each intervention reduced incidence of osteoarthritis (odds ratio [OR] 0.6; 95% confidence interval [CI], 0.31 to 1.12 and OR 0.69; 95% CI, 0.39 to 1.21, respectively) but not in participants receiving both interventions (OR 0.97; 95% CI, 0.55 to 1.71).155

Guidelines have been published discussing glucosamine's use in osteoarthritis of the knee and hip. The American College of Rheumatology 2012 guidelines for the management of osteoarthritis of the hand, hip, and knee conditionally recommend that patients with osteoarthritis of the knee or hip should not use glucosamine in the initial management based on significant heterogeneity in effect size found in meta-analyses.145 The American Academy of Orthopaedic Surgeons clinical practice guideline on the treatment of osteoarthritis of the knee (2010) recommends against the use of glucosamine and/or chondroitin sulfate or hydrochloride for patients with symptomatic osteoarthritis of the knee.146

Cellular studies

In vitro studies of the effects of glucosamine on chondrocytes, the cells responsible for synthesis of cartilage, include inhibition of oxidative damage,30, 31, 32, 33 promotion of the chondrogenic phenotype,34 modulation of proliferation and matrix synthesis,35 inhibition of chondrocyte differentiation,36 inhibition of hyaluronan and sulfated GAG synthesis,37 increased expression of aggrecan and collagen type II genes,38 and inhibition of mitogen-activating protein kinase phosphorylation.39 A proteomic study of chondrocytes treated with glucosamine sulfate found effects on 18 genes involved in a variety of pathways.40 Epigenetic mechanisms were also identified as important in another study.41

Synoviocytes are cells that produce synovial fluid in the joints. Glucosamine has been shown to suppress activation of synovial cells by IL-1beta,42 increase synovial GAG synthesis,43 increase hyaluronic acid production in synovial explants,44 and downregulate matrix metalloproteases and chemokines in synovial fibroblasts.45

Mineralization of mature osteoblasts, the cells that grow bone, was hastened by glucosamine, but it had little effect on early-stage osteoblasts.46 In endothelial cells, glucosamine suppressed cellular activation by both tumor necrosis factor alpha and LL-37.47, 48

A study of explant cultures of bovine tendon, ligament, and joint capsule found that glucosamine stimulated loss of proteoglycan from ligament but not from the other tissues. Large proteoglycan catabolism was also unaffected.49

Animal data

In a papain-injected model of osteoarthritis in mice, glucosamine 100 mg/kg/day in feed counteracted transient damage to the knee joint, which was attributed to an indirect effect via liver and gut cells consistent with cytokine alterations in serum.50 In a collagenase-induced mouse model, glucosamine 20 mg/kg/day inhibited bone resorption in joints via down-regulation of receptor activator of nuclear factor kappa-B ligand.51 In a spontaneous mouse model of osteoarthritis, glucosamine 200 and 400 mg/kg/day subcutaneously improved a variety of osteoarthritis markers, including Osteoarthritis Research Society International (OARSI) histopathology scores.52

Several studies of glucosamine in rats using the anterior cruciate ligament transaction model have been published.53 Enhancement of type II collagen synthesis and inhibition of degradation were found in one study,54 while decreases in p38 and c-Juno aminoterminal kinases with increases in extracellular signal-regulated protein kinase expression in cartilage were noted in a second study.55 Oral dosing of glucosamine in normal rats was shown to increase expression of transforming growth factor (TGF-beta) and connective tissue growth factor mRNA in cartilage.56

In Harley guinea pigs, which spontaneously develop osteoarthritis, oral glucosamine reduced cartilage destruction and down-regulated matrix metalloproteinase-3 in cartilage tissue.57 In rabbits, the effects of anterior cruciate ligament transaction were attenuated by glucosamine.58 In a vitamin A-induced model in rabbits, glucosamine produced osteoarthritis-protective effects on chondrocytes.59 Another rabbit model of atherosclerosis and rheumatoid arthritis found high-dose (500 mg/kg/day) glucosamine effective through a reduction of systemic and tissue inflammation.60

A randomized clinical trial with dogs with osteoarthritis found statistically significant improvements in scores for pain and weight-bearing and osteoarthritis severity.61

Clinical data

An update of an older Cochrane meta-analysis includes high-quality clinical trials. An earlier review found that glucosamine sulfate 1,500 mg/day for 6 weeks resulted in an improvement in function and less pain,62 but the inclusion of newer, higher quality trial data show less consistent and less favorable results.27, 63 For the 20 included studies (N = 2,570), glucosamine demonstrated a 28% improvement in pain outcome and a 21% improvement in function using the Lequesne Index. Outcomes using the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) in pain, stiffness, and function indices did not reach statistical significance compared with placebo.27 A limitation of the analysis is the quality of the preparations used in the individual trials. Analysis of the studies using the Rotta brand of glucosamine (as sulfate; available in the United States) provides differing results from the non-Rotta studies. Studies using the Rotta preparation reported glucosamine as more effective in pain reduction compared with placebo. Studies using the non-Rotta preparation showed no statistical difference compared with placebo. Variations in the content of glucosamine compared with label amounts can be up to 100%.27, 63

The findings of 2 large trials were published subsequent to the Cochrane meta-analysis. The Glucosamine Unum In Die Efficacy (GUIDE) trial (N = 318) was conducted in a European population, while the Glucosamine/Chondroitin Arthritis Intervention Trial (GAIT) (N = 1,583) was sponsored by the National Institutes of Health and conducted in the United States.64, 65 Both trials considered a total daily dosage of glucosamine 1,500 mg for osteoarthritis of the knee. The GUIDE trial favored glucosamine over placebo using the Lequesne Index and WOMAC function index, but results were not significant for the WOMAC pain index. Acetaminophen achieved similar results to glucosamine for the WOMAC indices.64 Overall results of GAIT indicated no differences for glucosamine over placebo using the WOMAC and outcome measures in rheumatology clinical trials (Osteoarthritis Research Society International indices). However, a subgroup analysis, which was not part of the original study design, suggested glucosamine was effective in treating moderate to severe osteoarthritis (n = 354).65

Three studies using radiographic methodology have been conducted regarding the ability of glucosamine to protect cartilage from further loss. After 3 years, no further joint space narrowing was shown in postmenopausal women (319 of a total of 414 participants) taking glucosamine 1,500 mg/day. Total WOMAC indices were also favorable for glucosamine.27, 66, 67, 68

Other studies of glucosamine have been less favorable. A 2011 meta-analysis that included 10 trials with 3,803 osteoarthritis patients did not find clinical improvement in pain scores, with commercially sponsored trials showing larger effects than those conducted independently.69 The analysis has been criticized on methodological grounds.70, 71 A different 2010 meta-analysis with narrower inclusion limits pointed to more important effects with osteoarthritis of the knee after 2 to 3 years of treatment.72 The evaluation of another evidence-based analysis showed inconsistent efficacy.73 A systematic review and meta-analysis that compared relevant clinical outcomes with raw mean differences and network meta-analysis of 31 randomized clinical trials and quasi-experimental designs found no statistically or clinically relevant differences among glucosamine, diacerein, and placebo in pain visual analog scores, WOMAC or Lequesne scores or on delaying progression of joint space narrowing in osteoarthritis of the knee.156 Similarly, in 2017, a systematic review collected trial data from authors willing and/or permitted to release their study data. Of the 21 eligible trials identified through systematic searches, 6 participated and submitted data but 1 of these used green-lipped mussel extract as a comparator so was excluded. In all 5 trials (N=1,625), pain and physical function was measured with WOMAC questionnaire and duration of follow-up ranged from 3 months to 2 years. Pooled patient data revealed no significant main effect for overall or for subgroup analysis of glucosamine compared with placebo for osteoarthritis of the knee; risk of bias and heterogeneity among all trials was low.158 Several other reviews and commentaries have questioned the efficacy of glucosamine in osteoarthritis.74, 75, 76, 77, 78, 79, 80

Not withstanding the growing skepticism, many new trials have been reported in recent years. No effect was found when using glucosamine for osteoarthritis of the jaw,81 and glucosamine was found to be no more effective than placebo in a study of hip osteoarthritis.82 A combination of glucosamine with circuit training and a weight loss program found benefit in osteoarthritis of the knee,83 while another similar trial did not consider the benefits sufficient to justify supplementation.84 Integration of a walking program with glucosamine supplementation yielded improvements over 24 weeks.85 No benefit over placebo was seen in pain, function, or mobility in a knee osteoarthritis study of glucosamine and chondroitin sulfate, with or without exercise.86 Glucosamine was inferior to hydrolyzed collagen for knee osteoarthritis in another study.87 A comparison with ibuprofen found that glucosamine, but not ibuprofen, altered cartilage turnover in osteoarthritis patients undergoing a program of strength training.88 A 2-year study of glucosamine versus celecoxib and placebo found statistically insignificant improvements in pain score for both treatments.89 Another study in which glucosamine and omega-3 fatty acids were combined found a superior effect on pain scores for the combination versus glucosamine alone.90 With osteoarthritis of the spine, no effect on chronic low back pain was seen with glucosamine for 6 months.91, 92, 148 Many other studies have also been published with mixed results.82, 93, 94, 95, 96, 97, 98, 99, 100, 101

A noninferiority, multicenter osteoarthritis intervention trial with symptomatic slow-acting drugs for osteoarthritis (MOVES) compared the combination of chondroitin sulfate (1,200 mg/day) plus glucosamine hydrochloride (1,500 mg/day) with celecoxib (200 mg/day) in adults 40 years and older (mean, 62.7 years) with primary knee osteoarthritis and severe pain. At 6 months, both groups experienced a 79% response rate and no differences in efficacy were seen between groups in stiffness, function score, visual analogue scale, or patients’ and physicians’ global assessment of disease activity. Use of rescue acetaminophen was higher during the 1st month in the chondroitin-glucosamine group but remained low and similar between the groups throughout the rest of the study period. Treatment-emergent adverse effects were also similar between groups.150

Glucosamine was bioavailable via oral administration and detectable at clinically relevant concentrations in serum and synovium of osteoarthritis patients when dosed at 1,500 mg/day for 14 days.102

Other uses

A clinical trial of glucosamine in multiple sclerosis found no benefit.111 Glucosamine was neuroprotective in a rat ischemia/reperfusion model via suppression of inflammation.112 Other anti-inflammatory effects in cells have been linked to inhibition of cyclooxygenase (COX)-2 glycosylation,113 transglutaminase inhibition,114 and cathepsin B inhibition.115 Glucosamine was active in rat models of trauma hemorrhage,116 colitis,117 and osteoporosis.118

Atopic dermatitis

In mouse models of atopic dermatitis119 and proliferative vitreoretinopathy,120, 121 glucosamine showed activity. In a randomized, placebo-controlled, double-blind, parallel clinical trial (n = 33), 8 weeks of combination therapy with glucosamine 25 mg/kg plus low-dose cyclosporine 2 mg/kg significantly improved atopic dermatitis severity scores compared with cyclosporine alone (P < 0.05) in patients 9 to 49 years of age. Clinical improvement was experienced in 93.8% of patients receiving combination therapy compared with 58.8% on cyclosporine monotherapy. Serum levels of chemokine ligand 17 were significantly correlated with clinical efficacy; however, IL-31 was not. Addition of glucosamine to cyclosporine did not result in an increase of adverse events or serum cyclosporine levels.154

Cancer

An early study found inhibition of Walker 256 cancer cell growth by glucosamine.103 A number of more recent studies have proposed induction of autophagy104, 105 proteasome inhibition,106 mitogen-activating protein kinase inhibition,107 suppression of IL-8 and ICAM-1 expression,108 and inhibition of STAT3 signaling109 as a mechanism of cell growth inhibition in various cancer cell lines. No activity has been reported in animal models or in clinical trials. However, an epidemiological study found a chemopreventative effect for glucosamine in human lung cancer.110

Use of chondroitin or glucosamine was observed to be associated with a decrease in colorectal cancer risk by 27% and 35%, respectively, and a 45% reduced risk in participants who used the combination of both for at least 4 days/week for at least 3 years in the Vitamins and Lifestyle study (VITAL). Based on this early but limited evidence, participants in the Nurses’ Health Study (NHS) and the Health Professionals Follow-up Study (HPFS) were queried over an 8-year period about supplement use, including that of glucosamine and chondroitin. Results from the final sample (N=96,400) aligned with those of the VITAL study revealed that when adjusted for age, any use of glucosamine or chondroitin was associated with a significant reduction (30% and 31%, respectively) in the risk of colorectal cancer. Similarly, combined use of both agents yielded a 32% reduced risk. Benefit held true when stratifying by aspirin use, body mass index, and physical activity, and results were comparable for both colon and rectum cancers. Among participants never screened, the combination of glucosamine plus chondroitin produced a significant 42% reduction in colorectal cancer risk. This latter association did not change when adjusted for nonsteroidal anti-inflammatory drug use, duration of aspirin or non-aspirin use, fiber intake, or vitamin E use. No reduced risk was found with use of "glucosamine only"; however, it was noted that a relatively small number of participants reported using glucosamine alone. Chondroitin was used in the presence of glucosamine 97% to 98% of the time, so it was not possible to evaluate the impact of glucosamine-only use on the risk of colorectal cancer.157

Dosing

Glucosamine dosage in clinical studies of arthritis has typically been 1.5 g/day as a single dose or in divided doses of up to 3 times per day.3, 27 Doses of up to 3,200 mg/day have been used in trials, but evidence of improved efficacy at this dosage has not been established.3 Healthy young adults had no adverse reactions from infusions of 9.7 g, while 1 in 5 subjects experienced headache when 30.5 g was infused.3 A systematic study of glucosamine supported safety at doses of up to 2 g/day.122, 123

Pregnancy / Lactation

A study of 54 women who used glucosamine during pregnancy found no increased risk of major malformations and no other adverse fetal effects.124

Interactions

Agents with antiplatelet properties: Glucosamine may enhance the antiplatelet effect of agents with antiplatelet properties. Monitor therapy.125, 126, 127

Warfarin: Glucosamine may enhance the anticoagulant effect of warfarin. Monitor therapy.128, 129, 130

An increase in the international normalized ratio (INR) may occur in patients taking anticoagulants, such as warfarin, with glucosamine alone or in combination with chondroitin. In case reports,151, 152 2 patients previously stabilized on warfarin therapy with INRs in therapeutic ranges, developed elevated INRs after an increase in dosage or initiation of a total daily dosage of glucosamine 3,000 mg/chondroitin 2,400 mg. In one patient, INRs were stabilized at doses of glucosamine 500 mg/chondroitin 400 mg twice daily and did not become supratherapeutic until the dosage was increased.151

In a literature review151 of 20 cases of potential interactions with warfarin reported to the United States Food and Drug Administration MedWatch database, the majority of cases (n = 15) involved the combination of glucosamine and chondroitin. Only one case involved chondroitin alone, and the remaining 4 reported using glucosamine. Causality assessment was difficult to assess as dosages and quality of report submissions were variable.

It is uncertain if these reports are a result of warfarin with either agent alone or the combination of the 2 in higher than usual dosages. It has been suggested that a pharmacokinetic interaction is unlikely; the mechanism of action may be related to an additive pharmacodynamic effect on coagulation.153

Adverse Reactions

The majority of adverse reactions reported have been mild, including itching and gastric discomfort (eg, diarrhea, heartburn, nausea, vomiting). These reactions are similar to those experienced with placebo, but fewer than those reported with nonsteroidal anti-inflammatory drugs.27

Concerns regarding the effect of glucosamine on glucose homeostasis have been based primarily on theoretical considerations, animal studies, and case reports.131, 132, 133, 134, 135, 136 However, specifically designed studies have not shown any detrimental effects associated with usual dosages, and no concerns have been raised regarding adverse reactions in the many randomized clinical trials conducted.3, 27, 137, 138, 139, 140 Long-term effects of glucosamine on insulin secretion and insulin resistance have not been established, and 2 systematic literature reviews concluded that oral glucosamine supplementation does not pose a risk to diabetic patients.141, 142 Glucosamine should be used with caution in patients with poorly controlled diabetes.137

A link between glucosamine and the development of atherosclerosis is suspected, but there is no supporting clinical evidence. Glucosamine has been found to have a stimulatory effect on the growth rate and toughness of nails. A case of possible exacerbation of asthma with the use of a glucosamine/chondroitin preparation has been reported, as well as an immediate hypersensitivity reaction to glucosamine.27

Five case reports of acute liver injury associated with glucosamine use have been documented, 2 of these were in elderly patients with chronic hepatitis C.143, 147 A single case of chondritis of the ear improved only partially with cessation of the glucosamine-based supplement.144

Toxicology

Mutagenicity studies have shown variable results. Glucosamine failed to show mutagenicity in Escherichia coli reverse mutation and Salmonella typhimurium studies, but it induced breaks in bacteriophage DNA. Glucosamine produced an increase in chromosome aberration frequency in mice bone marrow cells versus control, whereas no increases in micronucleated polychromatic erythrocyte and bone marrow cells were demonstrated in another experiment.3

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