Glucosamine is a natural substance found in mucopolysaccharides, mucoproteins and chitin. It is found in relatively high concentrations in the joints. Some foods, such as crabs, oysters and the shells of prawns, are relatively rich in glucosamine, but supplements are the best source of additional glucosamine. It is available as a synthetically manufactured dietary supplement in the form of glucosamine sulphate and glucosamine hydrochloride.
Glucosamine is a hexosamine sugar and a basic building block for the biosynthesis of glycoprotein, glycolipids, hyaluronic acid, glycosaminoglycans and proteoglycans, which are important constituents of articular cartilage. Chondroitin sulphate (sometimes found together with glucosamine in supplements), which is synthesised by the chondrocytes, is one example of a glycosaminoglycan.
Glucosamine is important for maintaining the elasticity, strength and resilience of cartilage in joints. This helps to reduce damage to the joints. In addition to supporting cartilage and other connective tissue, glucosamine enhances both the production of hyaluronic acid and its anti-inflammatory action.
The mechanism of action is not fully understood, but administration of glucosamine is believed to stimulate production of cartilage components and allow rebuilding of damaged cartilage. In vitro studies have found that glucosamine can increase mucopolysaccharide and collagen synthesis in fibroblast tissue.1 Glucosamine also appears to activate core protein synthesis in human chondrocytes.2
Glucosamine is used to promote the maintenance of joint function and to treat pain, increase mobility, and help repair damaged joints in individuals with osteoarthritis and other joint disorders. It is sometimes provided in supplements with chondroitin, with which it may act synergistically. Both substances have anti-inflammatory activities,3,4 and both affect cartilage metabolism in vitro.5,6 Animal studies have also demonstrated that glucosamine has anti-arthritic effects.7,8
Since 1990, more than 50 studies have examined the effects of glucosamine on osteoarthritis. However, many of these studies have been short, and many have major design flaws and critical problems with data analysis and interpretation of results. Some of the largest RCTs are discussed below.
In a double-blind trial involving 80 inpatients with established arthritis randomly split into two groups, the first group received two 250-mg capsules of glucosamine sulphate and the second group an indistinguishable placebo.9 Each dose was given three times daily for 30 days. Articular pain, joint tenderness and restriction of movement were scored on a scale of 1 to 4 at 1-week intervals. Any adverse reactions were similarly scored. Safety was monitored by haematology; results of urine analysis and occult faecal blood were recorded before and after treatment. Samples of articular cartilage from two patients of each group and from one healthy subject were submitted for scanning electron microscopy after the end of treatment. Patients treated with glucosamine sulphate experienced a reduction in overall symptoms that was almost twice as great and twice as fast as those who had placebo. The results were supported by the electron microscopy findings.
Another double-blind trial used 252 outpatients who had suffered arthritis in the knee to a measurable amount for at least 6 months.10 The trial randomly allocated the patients to two groups, one receiving 250-mg tablets of glucosamine sulphate and the other placebo, three times daily. The trial was for 4 weeks, with assessment at enrolment and weekly thereafter. A statistically significant difference between glucosamine and placebo was observed, but only after the fourth week of treatment, and the clinical significance of the difference is open to debate.
A total of 155 outpatients with osteoarthritis of the knee were involved in another double-blind trial.11 Inclusion criteria included a requirement to have been suffering from symptoms for at least 6 months. The two groups, consisting of 79 and 76 patients, received 400 mg glucosamine sulphate and placebo respectively, administered as intramuscular injection twice weekly for 6 weeks. Assessment was carried out at enrolment, at 2-weekly intervals during the trial and once after the trial had been concluded. At the end of the trial the patients were assessed by the investigator and classified as good, moderate, unchanged, or worse. Safety was monitored by a number of biochemical tests. A significant improvement in symptoms was noted compared with placebo, but this occurred only during weeks 5 and 6 of the treatment. This may have been related to the twice-weekly dosing, or to the slow onset of action. However, methodological problems of lack of randomisation and missing data, such as symptom severity at baseline, make the clinical significance of the improvement questionable, and the observed differences may be meaningless.
In a further double-blind trial in patients with osteoarthritis of the knee, 80 subjects were randomised to receive either glucosamine sulphate 1500 mg daily for 6 months or placebo. Patients’ global assessment of pain in the affected knee did not differ between placebo and glucosamine. There was a statistically significant difference between the two groups in knee flexion, but the difference was small and could have been due to measurement error. Overall, as a symptom modifier in osteoarthritis patients with a wide range of severities, glucosamine sulphate was no more effective than placebo.12
A Czech trial involving 202 patients investigated the effect of glucosamine sulphate 1500 mg daily or placebo on progression of osteoarthritis of the knee. With placebo there was progressive narrowing of the joint space after 3 years, but no average change with glucosamine sulphate use, with a significant difference between groups. Symptoms improved modestly with placebo use but as much as 20–25% with glucosamine sulphate use. Safety was good, with no difference between groups. In this study, long-term treatment with glucosamine sulphate slowed the progression of knee osteoarthritis, possibly by influencing disease modification.13
A further study involving 212 patients over a period of 3 years investigated the effect of glucosamine sulphate on future progression of osteoarthritis. Patients with less severe radiographic knee osteoarthritis were found to experience, over 3 years, the most dramatic disease progression in terms of joint space narrowing. In these patients with mild osteoarthritis, glucosamine sulphate was associated with a trend (P = 0.01) towards a significant reduction in joint space narrowing, while in those with severe disease, joint space narrowing did not differ between glucosamine and placebo.14
In a trial involving 319 post-menopausal women, those taking glucosamine sulphate showed no joint space narrowing while participants in the placebo group experienced a narrowing of 0.33 mm, with a statistically significant difference between the two groups after 3 years.15
A more recent trial investigated the effect of continued use of glucosamine or placebo in 137 users of glucosamine with knee osteoarthritis who had experienced at least moderate improvement in knee pain after starting glucosamine. After 6 months, no differences were found between glucosamine and placebo patients in severity and time to disease flare, use of paracetamol and use of NSAIDs.16
Another trial recruited 205 patients with symptomatic knee arthritis from the Internet. Participants were randomly assigned to glucosamine 1500 mg daily or placebo. After 12 weeks, there was no difference between treatment and control groups in terms of change in pain score, stiffness, physical function or analgesic use.17
A trial in 142 patients suffering from knee osteoarthritis compared the efficacy and safety of glucosamine sulphate (1500 mg daily) with that of glucosamine hydrochloride (1440 mg daily). Symptoms improved in both groups, but there were no significant differences in efficacy and safety between the two groups. Glucosamine hydrochloride was as effective and safe as glucosamine sulphate in the treatment of knee osteoarthritis.18
Other trials have compared the efficacy of glucosamine with ibuprofen19,20 and piroxicam.21 Oral glucosamine sulphate 500 mg three times a day was reported to be at least as effective as oral ibuprofen 400 mg three times a day in a study involving 40 patients with osteo-arthritis of the knee.19 Pain scores decreased significantly in both groups, but the onset of action was more rapid with ibuprofen, with maximum effectiveness reached after 2 weeks, whereas glucosamine was associated with a gradual, progressive improvement throughout the trial.
In a randomised, double-blind, parallel-group study,20 glucosamine 500 mg three times daily was as effective as ibuprofen 400 mg three times daily for 4 weeks in the treatment of 200 inpatients with osteoarthritis of the knee. Again, therapeutic effect was generally obtained sooner with ibuprofen, but glucosamine was signifi-cantly better tolerated than ibuprofen. A total of six patients reported adverse effects (versus 35 with ibuprofen) and one discontinued treatment (versus seven with ibuprofen). However, the definition of treatment response, as well as short duration of the study, leave the results open to debate as to their clinical significance.
Glucosamine sulphate was as effective as piroxicam alone or a combination of glucosamine and piroxicam in a randomised multicentre, double-blind, placebo-controlled trial involving 329 patients.21 Glucosamine sulphate 1500 mg daily, piroxicam 20 mg daily, a combination of glucosamine and piroxicam, or placebo was given for 60 days, followed by a 60-day observation period without treatment. Glucosamine appeared to have a persistent treatment effect after withdrawal compared to piroxicam, and significantly fewer adverse effects were recorded for glucosamine.
Several meta-analyses and systematic reviews have investigated the benefits of glucosamine in the treatment of osteoarthritis. One evaluated the benefit of both glucosamine and chondroitin for osteoarthritis symptoms.22 It used a meta-analysis combined with systematic quality assessment of clinical trials of these preparations in knee and/or hip osteoarthritis. Reviewers performed data extraction and scored each trial using a quality assessment instrument. Of the 37 trials identified, only 15 met their criteria of being double-blind (published or unpublished), randomised, placebo-controlled or of 4 or more weeks’ duration that tested glucosamine or chondroitin for knee or hip osteoarthritis and reported extractable data on the effect of treatment on symptoms. Of the 15 trials analysed, only six concerned glucosamine; the remaining nine, almost all of which were manufacturer-sponsored, were judged to be of inadequate quality by the authors. Nevertheless, they concluded that trials of glucosamine and chondroitin preparations for osteoarthritis symptoms did show moderate to large beneficial effects, but acknowledged that quality issues and likely publication bias might have exaggerated these benefits.
A further meta-analysis23 included 10 trials (three of which were also included in the above meta-analysis22). The trials included looked at glucosamine alone – not chondroitin. The method employed was a scoring system,24 and only five of the 10 trials achieved the arbitrary pass mark. The major problems in most of the trials in this meta-analysis were a lack of participants, a lack of detail about the randomisation process, and no monitoring of patients after the trial period had finished. Of the 10 clinical trials, six compared glucosamine sulphate to placebo.
Of the remaining four trials, two compared glucosamine to ibuprofen and the other two used glucosamine sulphate alone. The results of this meta-analysis were in broad agreement with those of the above study22 and were positive. However, the authors concluded that the variations in study methodology made it difficult to reach a firm decision as to the overall effectiveness of glucosamine for the treatment of osteoarthritis.
A mini-review compared the effectiveness of oral glucosamine with ibuprofen for relief of joint pain in arthritis. From the two RCTs included in the review, there were no significant differences between the two treatments with respect to pain reduction. Both were efficacious treatments and glucosamine appeared to be at least as effective as ibuprofen.25
A further meta-analysis assessed the structural and symptomatic efficacy of glucosamine sulphate and chondroitin sulphate in knee osteoarthritis through their effects on joint space narrowing, Lequesne Index, Western Ontario McMaster University Osteoarthritis Index (WOMAC), visual analogue scale for pain, mobility, safety and response to treatment. Suitable clinical trials performed between January 1980 and March 2002 were included. There was a highly significant effect of glucosamine on all outcomes, including joint space narrowing and WOMAC. Chondroitin was found to be effective on Lequesne Index, visual analogue scale pain, mobility and responding status. Joint mobility also improved markedly, with one person responding for every five patients treated (number needed to treat = 4.9). Safety was good for both compounds.26
Another meta-analysis investigated the structural and symptomatic efficacy and safety of glucosamine in knee osteoarthritis. Suitable trials up to August 2004 were included. Studies were included if they were double-blind RCTs, lasting at least 1 year, that evaluated oral glucosamine and reported symptom severity and disease progression as assessed by joint space narrowing. Glucosamine sulphate was more effective than placebo in delaying structural progression in knee osteoarthritis, reducing pain and improving physical function. Glucosamine sulphate caused no more adverse events than placebo. The authors concluded that due to the sparse data on structural efficacy and safety, more studies are warranted.27
A Cochrane review of 20 RCTs evaluating the effectiveness and toxicity of glucosamine in osteoarthritis found glucosamine more favourable than placebo, with a 28% improvement in pain and 21% improvement in function, using the Lequesne Index. However, the trials did not show uniformly positive results. In the 10 RCTs in which the Rotta (name of manufacturer) preparation of glucosamine was compared to placebo, glucosamine was found to be superior for pain and function. In those trials where a non-Rotta preparation of glucosamine was compared to placebo, statistical significance was not reached. In the four RCTs where the Rotta preparation of glucosamine was compared to a NSAID, glucosamine was superior in two and equivalent in two. Two RCTs using the Rotta preparation showed that glucosamine was able to slow radiological progression of osteoarthritis of the knee over a 3-year period. Glucosamine and placebo were of equivalent safety in terms of the number of subjects reporting adverse reactions.28
The multicentre, double-blind, placebo- and celecoxib-controlled Glucosamine/chondroitin Arthritis Intervention Trial (GAIT) evaluated the efficacy and safety of glucosamine and chondroitin as a treatment for knee pain from osteoarthritis. A total of 1583 patients with symptomatic knee osteoarthritis were randomised to receive 1500 mg glucosamine daily, 1200 mg chondroitin sulphate daily, both glucosamine and chondroitin sulphate, 200 mg of celecoxib daily or placebo for 24 weeks. Over-all, glucosamine and chondroitin sulphate were not significantly better than placebo in reducing knee pain by 20%. The rate of response to glucosamine was 3.9% higher than placebo, the rate of response to chondroitin was 5.3% higher, the rate of response to combined treatment was 6.5% higher and the rate of response to celecoxib was 10% higher. However, for the subgroup of patients with moderate to severe knee pain at baseline, the rate of response was significantly higher with combined therapy than with placebo (79.2% vs 54.3%, P = 0.002).
This suggests that glucosamine and chondroitin in combination may be effective in the group of patients with moderate to severe knee pain, but not in patients overall with osteoarthritis of the knee.29
A blinded RCT compared a topical cream containing glucosamine, chondroitin sulphate and camphor with placebo. The study included 63 patients with osteoarthritis of the knee. Intention-to-treat analysis showed that after 4–8 weeks, reduction in pain was greater in the treatment group than the placebo group.30
Glucosamine may alter glucose regulation/ insulin sensitivity.31,32 However, more recent research reports no significant effects on haemoglobin A1c levels in patients with type 1 diabetes after 90 days’ therapy,33 nor on serum insulin, plasma glucose and glycated haemoglobin after 12 weeks.34 However, until further studies are conducted, it would appear prudent for patients with diabetes taking glucosamine to be aware of its potential influence on glucose metabolism.
Pregnancy and breast-feeding
No problems have been reported, but there have not been sufficient studies to guarantee the safety of glucosamine in pregnancy and breast-feeding. Glucosamine is probably best avoided.
Glucosamine is relatively non-toxic, and does not appear to be associated with serious side-effects. Side-effects reported include constipation, diarrhoea, heartburn, nausea, drowsiness, headache and rash.
None are known, but in theory insulin or oral hypoglycaemics may be less effective.
Glucosamine is available in the form of tablets, capsules and powders as glucosamine sulphate, glucosamine hydrochloride and N-acetyl-D-glucosamine (NAG). It is also available in the form of cream. A review of 10 products containing glucosamine found that all products contained the labelled amounts of glucosamine, but six out of 13 products containing glucosamine and chondroitin did not pass, all due to low chondroitin levels.35
The dose is not definitely established. How-ever, a dose of glucosamine sulphate 500 mg three times a day (1500 mg daily) has been used in most studies and this is the dose recommended by many manufacturers. Full therapeutic benefit may take more than 4 weeks.
Glucosamine and also chondroitin are likely to be effective therapies for the symptoms of osteoarthritis, but the degree of benefit apparent in the literature is probably overestimated because of methodological flaws in the studies. Further long-term, adequately designed, rigorous controlled studies are required before the role of glucosamine in the treatment of bone and joint disorders can be fully determined. In addition, further trials are needed to determine whether glucosamine can significantly modify the radiological progression of osteoarthritis.
McCarty MF. The neglect of glucosamine as treat-ment for osteoathritis. Med Hypotheses 1994; 42: 323–327.
Bassleer C, Henroitin Y, Franchimont P. In vitro evaluation of drugs proposed as chondroprotective agents. Int J Tissue React 1992; 14: 231–241.
Sentnikar I, Cereda R, Pacini MA, Revel L. Anti-reactive properties of glucosamine sulphate. Arznemittelforschung 1991; 41: 157–161.
Ronca F, Palmieri L, Panicucci P, Ronca G. Anti-inflammatory activity of chondroitin sulphate. Osteoarthritis Cartilage 1998; 6 (Suppl. A): 14–21.
Bassleer CT, Combal JP, Bougaret S, Malaise M. Effects of chondroitin sulphate and interleukin-1 beta on human articular chondrocytes cultivated in clusters. Osteoarthritis Cartilage 1998; 6:196–204.
Bassleer CT, Rovati L, Franchimont P. Stimulation of proteoglycan production by glucosamine sulphate in chondrocytes isolated from human osteoarthritic articular cartilage in vitro. Osteoarthritis Cartilage 1998; 6: 196–204.
Setnikar I, Pacini MA, Revel L. Antiarthritic effects of glucosamine sulfate studied in animal models. Arzneimittelforschung 1991; 41: 542–545.
Uebelhart D, Thonar EJ, Zhang J, Willaims JM. Pro-tective effect of exogenous chondroitin 4,6-sulfate in the acute degradation of articular cartilage in the rabbit. Osteoarthritis Cartilage 1998; 6 (Suppl. A) 6–13.
Drovanti A, Bignamini AA, Rovati AL. Therapeutic activity of oral glucosamine sulphate in osteoarthri-tis: a placebo controlled double blind investigation. Clin Ther 1980; 3: 260–272.
Noack W, Fischer M, Forster K, et al. Glucosamine in osteoarthritis of the knee. Osteoarthritis Cartilage 1994; 2: 51–59.
Reichelt A, Forster KK, Fischer M, et al. Efficacy and safety of intramuscular glucosamine sulphate in osteoarthritis of the knee. Arzneimittelforschung 1994; 44: 75–80.
Hughes R, Carr A. A randomized, double-blind, placebo-controlled trial of glucosamine sulphate as an analgesic in osteoarthritis of the knee. Rheuma-tology (Oxford) 2002; 41: 279–284.
Pavelka K, Gatterova J, Olejarova M, et al. Glu-cosamine sulfate use and delay of progression of knee osteoarthritis: a 3-year, randomized, placebo-controlled, double-blind study. Arch Intern Med 2002; 162: 2113–2123.
Bruyere O, Honore A, Ethgen O, et al. Correlation between radiographic severity of knee osteoarthritis and future disease progression. Results from a 3-year prospective, placebo-controlled study evaluating the effect of glucosamine sulfate. Osteoarthritis Carti-lage 2003; 11: 1–5.
Bruyere O, Pavelka K, Rovati LC, et al. Glu-cosamine sulfate reduces osteoarthritis progression in postmenopausal women with knee osteoarthritis: evidence from two 3-year studies. Menopause 2004; 11: 134–135.
Cibere J, Kopec JA, Thorne RA, et al. Random-ized, double-blind, placebo-controlled glucosamine discontinuation trial in knee osteoarthritis. Arthritis Rheum 2004; 51: 738–745.
McAlindon T, Formica M, LaValley M, et al. Effectiveness of glucosamine for symptoms of knee osteoarthritis: results from an internet-based ran-domized double-blind controlled trial. Am J Med 2004; 117: 643–649.
Qui GX, Weng XS, Zhang K, et al. A multi-central, randomized, controlled clinical trial of glucosamine hydrochloride/sulfate in the treatment of knee osteoarthritis. Zhingua Yi Xue Za Zhi 2005; 85: 3067–3070 (in Chinese)
Vaz AL. Double-blind clinical evaluation of the relative efficacy of ibuprofen and glucosamine sul-phate in the management of osteoarthritis of the knee in outpatients. Curr Med Res Opin 1983; 3: 145–149.
Muller-Fassbender H, Bach G, Haase W, et al. Glucosamine sulphate compared with ibuprofen in osteoarthritis of the knee. Osteoarthritis Cartilage 1994; 2: 61–69.
Rovati LC, Giacovelli G, Annefeld M, et al. A large, randomized, placebo-controlled, double-blind study of glucosamine sulfate vs piroxicam and vs their association on the kinetics of the symptomatic effect in knee osteoarthritis (abstract). Osteoarthritis Cartilage 1994; 2 (Suppl. 1): 56.
McAlindon TE, LeValley MP, Gulin JP, Fel-son DT. Glucosamine and chondroitin for treat-ment of osteoarthritis. A systematic quality assessment and meta-analysis. JAMA 2000; 283: 169–175.
Kayne SB, Wadeson K, MacAdam A. Glucosamine – an effective treatment for osteoarthritis? A meta-analysis. Pharm J 2000; 265: 759–763.
Kleijnen J, Knipschild P, ter Riet G. Clinical trials of homoeopathy. BMJ 1991; 302: 316–323.
Ruane R, Griffiths P. Glucosamine therapy com-pared to ibuprofen for joint pain. Br J Community Nurs 2002; 7: 148–152.
Richy F, Bruyere O, Ethgen O, et al. Structural and symptomatic efficacy of glucosamine and chon-droitin in knee osteoarthritis: a comprehensive meta-analysis. Arch Intern Med 2003; 163: 1514–1522.
Poolsup N, Suthisisang C, Channark, P Kittikulsuth W. Glucosamine long-term treatment and the pro-gression of knee osteoarthritis: systematic review of randomized controlled trials. Ann Pharmacother 2005; 39: 1080–1087.
Towheed TE, Maxwell L, Anastassiades TP, et al. Glucosamine therapy for treating osteoarthri-tis. Cochrane database, issue 2, 2005. London: Macmillan.
Clegg DO, Reda DJ, Harris CL, et al. Glucosamine, chondroitin sulfate and the two in combination for painful knee osteoarthrtitis. N Engl J Med 2006; 354: 795–808.
Cohen M, Wolfe R, Mai T, et al. A randomized, double blind, placebo controlled trial of a topical cream containing glucosamine sulfate, chondroitin sulfate, and camphor for osteoarthritis of the knee. J Rheumatol 2003; 30: 523–528.
Balkan B, Dunning BE. Glucosamine inhibits glu-cokinase in vitro and produces a glucose-specific impairment of in vivo insulin secretion in rats. Diabetes 1994; 43: 1173–1179.
Shankar RR, Zhu JS, Baron AD. Glucosamine infusion in mice mimics the beta-cell dysfunction of non-insulin dependent diabetes mellitus. Metabolism 1998; 47: 573–577.
Scroggie DA, Albright A, Harris MD. The effect of glucosamine-chondroitin supplementation on gly-cosylated hemoglobin levels in patients with type 2 diabetes mellitus: a placebo-controlled, double-blinded, randomized controlled trial. Arch Intern Med 2003; 163: 1587–1590.
Tannis AJ, Barban J, Conquer JA. Effect of glu-cosamine supplementation on fasting and non-fasting plasma glucose and serum insulin concentra-tions in healthy individuals. Osteoarthritis Cartilage 2004; 12: 506–511.
Consumerlab. Product review. Glucosamine and chondroitin. http://www.consumerlab.com (accessed 6 November 2006).