Glucosamine

Scientific Name(s):2-Amino-2-deoxyglucose

Common Name(s): Chitosamine

Uses

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

No absolute contraindications have been identified.

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 persons with poorly controlled diabetes.

Toxicology

Mutagenicity studies are limited and conflicting.

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. Basically, it can be perceived as a cellulose derivative in which the C-2 hydroxyl groups of the polymer have been replaced by acetamide moieties. Chitin is a normal component of shellfish such as crab, shrimp, and lobster. 2 , 3 Glucosamine is isolated from chitin and is chemically 2-amino-2-deoxyglucose. 3 It can also be prepared synthetically. Glucosamine sulfate is the preferred form. N-acetyl-D-glucosamine (NAG) is also sold but has no advantages over glucosamine, nor has the potential of NAG in a sustained-release or topical formulation shown any greater benefit. 2 , 4 , 5

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 is proposed to provide an essential building block for cartilage regeneration; however, this may be an oversimplification. 3 , 6 , 7 , 8

Animal data

Animal studies have been conducted but are less important than the large number of clinical trials.

Clinical data

An update of an older Cochrane meta-analysis is available that 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, 9 but the inclusion of newer, higher quality trial data show less consistent and less favorable results. 6 , 10 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 osteoarthritis (WOMAC) pain, stiffness, and function indices did not reach statistical significance compared with placebo. 6 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 (available in the United States) provides differing results from the non- Rotta studies. Studies using the Rotta preparation reported glucosamine to be significantly better in reduction of pain compared with placebo. Studies using 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%. 6 , 10

The findings of 2 large trials have been published subsequent to the Cochrane meta-analysis. The Glucosamine Unum In Die Efficacy (GUIDE) trial (N = 318) was industry-sponsored and 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. 11 , 12 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. 11 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). 12

Three studies using radiographic methodology have been conducted regarding the ability of glucosamine to protect cartilage from further loss. A subgroup analysis of the results of 2 of these studies favored glucosamine over placebo. 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. 6 , 13 , 14 , 15

Other uses

Older studies evaluating the potential effect of glucosamine on viruses and cancer have not been adequately evaluated. 16 , 17 , 18

Dosage

Glucosamine dosage in clinical studies of arthritis has typically been 1.5 g/day, as a single dose or in divided doses up to 3 times per day. 3 , 6 Doses of up to 3,200 mg/day have been used in trials, but evidence for 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

Pregnancy/Lactation

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

Interactions

None well documented. Glucosamine metabolism does not depend on the CYP-450 pathway. 3

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 are fewer than those reported with nonsteroidal anti-inflammatory drugs. 6

Concern regarding the effect of glucosamine on glucose homeostasis has been raised based largely on theoretical considerations, animal studies, and case reports. 19 , 20 , 21 , 22 , 23 , 24 However, specifically designed studies have failed to show any detrimental effects associated with usual dosages, and no concerns have been raised regarding adverse reactions in the many randomized clinical trials conducted. 3 , 6 , 25 , 26 , 27 Long-term effects of glucosamine on insulin secretion and insulin resistance have not been established. Advise patients with poorly controlled diabetes to use caution. 25

A theoretical 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. 6

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 a significant increase in chromosome aberration frequency in mice bone marrow cells versus control, whereas no significant increases in micronucleated polychromatic erythrocyte and bone marrow cells were demonstrated in another experiment. 3

Bibliography

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3. Anderson JW , Nicolosi RJ , Borzelleca JF . Glucosamine effects in humans: a review of effects on glucose metabolism, side effects, safety considerations and efficacy . Food Chem Toxicol . 2005;43(2):187-201.
4. Brown MB , Jones SA . Hyaluronic acid: a unique topical vehicle for the localized delivery of drugs to the skin . J Eur Acad Dermatol Venereol . 2005;19(3):308-318.
5. Rubin BR , Talent JM , Kongtawelert P , Pertusi RM , Forman MD , Gracy RW . Oral polymeric N-acetyl-D-glucosamine and osteoarthritis . J Am Osteopath Assoc . 2001;101(6):339-344.
6. Towheed TE , Maxwell L , Anastassiades TP , et al. Glucosamine therapy for treating osteoarthritis . Cochrane Database Syst Rev . 2005;(2):CD002946.
7. Simanek V , Kren V , Ulrichova J , Gallo J . The efficacy of glucosamine and chondroitin sulfate in the treatment of osteoarthritis: are these saccharides drugs or nutraceuticals? Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub . 2005;149(1):51-56.
8. Herrero-Beaumont G , Rovati LC . Use of crystalline glucosamine sulfate in osteoarthritis . Future Med . 2006;1(4):397-414.
9. Towheed TE , Anastassiades TP , Shea B , Houpt J , Welch V , Hochberg MC . Glucosamine therapy for treating osteoarthritis . Cochrane Database Syst Rev . 2001;(1):CD002946.
10. Gatti JC . Glucosamine treatment for osteoarthritis . Am Fam Physician . 2006;73(7):1189-1191.
11. Herrero-Beaumont G , Ivorra JA , Del Carmen Trabado M , et al. Glucosamine sulfate in the treatment of knee osteoarthritis symptoms . Arthritis Rheum . 2007;56(2):555-567.
12. Clegg DO , Reda DJ , Harris CL , et al. Glucosamine, chondroitin sulfate, and the two in combination for painful knee osteoarthritis . N Engl J Med . 2006;354(8):795-808.
13. Bruyere O , Pavelka K , Rovati LC , et al. Glucosamine sulfate reduces osteoarthritis progression in postmenopausal women with knee osteoarthritis: evidence from two 3-year studies . Menopause . 2004;11(2):138-143.
14. Reginster JY , Bruyere O , Fraikin G , Henrotin Y . Current concepts in the therapeutic management of osteoarthritis with glucosamine . Bull Hosp Jt Dis . 2005;63(1-2):31-36.
15. Fox BA , Schmitz ED , Wallace R . FPIN's clinical inquiries. Glucosamine and chondroitin for osteoarthritis . Am Fam Physician . 2006;73(7):1245-1246.
16. Valcavi U , Albertoni C , Brandt A , et al. New potential immunoenhancing compounds. Synthesis and pharmacological evaluation of a new long-chain 2-amido-2-deoxy-D-glucose derivatives . Arzneimittelforschung . 1989;39(10):1190-1195.
17. Delgadillo R , Vanden Berghe DA . Inhibition of the multiplication of enveloped and non-enveloped viruses by glucosamine . J Pharm Pharmacol . 1988;40(7):488-493.
18. Bekesi J , Winzler RJ . Inhibitory effects of D-glucosamine on the growth of Walker 256 carcinosarcoma and on protein, RNA, and DNA synthesis . Cancer Res . 1970;30(12):2905-2912.
19. Baron AD , Zhu JS , Zhu JH , Weldon H , Maianu L , Garvey WT . Glucosamine induces insulin resistance in vivo by affecting GLUT 4 translocation in skeletal muscle. Implications for glucose toxicity . J Clin Invest . 1995;96(6):2792-2801.
20. Virkamaki A , Yki-Jarvinen H . Allosteric regulation of glycogen synthase and hexokinase by glucosamine-6-phosphate during glucosamine-induced insulin resistance in skeletal muscle and heart . Diabetes . 1999;48(5):1101-1107.
21. Patti ME , Virkamaki A , Landaker EJ , Kahn CR , Yki-Jarvinen H . Activation of the hexosamine pathway by glucosamine in vivo induces insulin resistance of early postreceptor insulin signaling events in skeletal muscle . Diabetes . 1999;48(8):1562-1571.
22. Miles PD , Higo K , Romeo, OM , Lee MK , Rafaat K , Olefsky JM . Troglitazone prevents hyperglycemia-induced by not glucosamine-induced insulin resistance . Diabetes . 1998;47(3):395-400.
23. Monauni T , Zenti MG , Cretti A , et al. Effects of glucosamine infusion on insulin secretion and insulin action in humans . Diabetes . 2000;49(6):926-935.
24. Mooradian AD , Haas MJ , Wong NC . The effect of select nutrients on serum high-density lipoprotein cholesterol and apolipoprotein A-I levels . Endocr Rev . 2006;27(1):2-16.
25. Marshall PD , Poddar S , Tweed EM , Brandes L . Clinical injuries: do glucosamine and chondroitin worsen blood sugar control in diabetes? J Fam Pract . 2006;55(12):1091-1093.
26. Tannis AJ , Barban J , Conquer JA . Effect of glucosamine supplementation on fasting and non-fasting plasma glucose and serum insulin concentrations in healthy individuals . Osteoarthritis Cartilage . 2004;12(6):506-511.
27. Muniyappa R , Karne RJ , Hall G , et al. Oral glucosamine for 6 weeks at standard doses does not cause or worsen insulin resistance or endothelial dysfunction in lean or obese subjects . Diabetes . 2006;55(11):3142-3150.

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