glucosamine

Glucosamine (C₆H₁₄NO₅) is an amino sugar that is an important precursor in the biochemical synthesis of glycosylated proteins and lipids. Glucosamine is commonly used as a treatment for osteoarthritis, although its acceptance as a medical therapy varies.

Biochemistry

D-Glucosamine is made naturally in the form of glucosamine-6-phosphate, and is the biochemical precursor of all nitrogen-containing sugars (Roseman et al., 2001). Specifically, glucosamine-6-phosphate is synthesized from fructose-6-phosphate and glutamine (Ghosh et al., 1960) as the first step of the hexosamine biosynthesis pathway [1]. The end-product of this pathway is UDP-N-acetylglucosamine, 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 (Buse, 2006).

Health effects

Treatment with oral glucosamine is commonly used for the treatment of osteoarthritis. Since glucosamine is a precursor for glycosaminoglycans, and glycosaminoglycans are a major component of joint cartilage, supplemental glucosamine may help to rebuild cartilage and treat arthritis. However, there is little evidence that any clinical effect of glucosamine works this way (Laverty et al., 2005; Biggee et al., 2005). Its use as a therapy for osteoarthritis appears safe but there is conflicting evidence as to its effectiveness.

Usage

A typical dosage of glucosamine salt is 1,500 mg per day. Glucosamine contains an amino group that is positively charged at physiological pH. The anion included in the salt may vary. Commonly sold forms of glucosamine are glucosamine sulfate and glucosamine hydrochloride. The amount of glucosamine present in 1500 mg of glucosamine salt will depend on which anion is present [2] and whether additional salts are included in the manufacturer's calculation. Glucosamine is often sold in combination with other supplements such as chondroitin sulfate and methylsulfonylmethane.

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, evidence of safety and efficacy is not required as long as it is not advertised as a treatment for a medical condition [3]. Nevertheless, glucosamine is a popular alternative medicine used by consumers for the treatment of osteoarthritis. Glucosamine is also extensively used in veterinary medicine as an unregulated but widely accepted supplement (Nolen RS, 2002).

In Europe, glucosamine is approved as a medical drug and is sold by Rottapharm (in the form of glucosamine sulfate).

Safety

Clinical studies of glucosamine have consistently reported that glucosamine appears safe. Since glucosamine is usually derived from shellfish, those allergic to shellfish may wish to avoid it. However, since glucosamine is derived from the shells of these animals while the allergen is within the flesh of the animals, it is probably safe even for those with shellfish allergy (Gray et al. 1994). 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 (Buse, 2006), but several investigations have found no evidence that this occurs (Scroggie et al., 2003). 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. [4]. Finally, in the United States, glucosamine is sold as a dietary supplement, so safety and formulation is solely the responsibility of the manufacturer.

Clinical studies

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 (Manson and Rahman, 2004).

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 short-comings in their methods, including small size, short duration, poor analysis of drop-outs, and unclear procedures for blinding (Adams, 1999; McAlindon et al., 2000). Rotta 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 (Reginster et al., 2001; Pavelká et al., 2002). 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 (Hughes et al., 2002; Cibere et al., 2004).

This situation led the National Institutes of Health to fund a large, multicenter clinical trial to test the effects of chondroitin sulfate, glucosamine, and the combination on painful osteoarthritis of the knee, compared to both placebo and celecoxib [5]. The results of this 6-month trial found 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 (Clegg et al., 2006). The group of patients who took celecoxib did have a statistically significant improvement in their symptoms. These results suggest that glucosamine and chondroitin do not effectively relieve pain in osteoarthritis patients.

Although the study found no effect for the supplements overall, a secondary analysis of a subgroup of patients suggested that the supplements might help people 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[PMID 15846645]" (Hochberg et al., 2006). 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"[6]. Thus the question of glucosamine's efficacy will not be resolved without further updates or trials.

References

• Roseman S. "Reflections on glycobiology," J Biol Chem, 2001 Nov 9; 276(45):41527-42. PMID 11553646. Full Text Online

• Ghosh S, Blumenthal HJ, Davidson E, Roseman S. "Glucosamine metabolism. V. Enzymatic synthesis of glucosamine 6-phosphate", J Biol Chem, 1960 May; 235:1265-73. PMID 13827775. PDF online.

• Buse MG. "Hexosamines, insulin resistance, and the complications of diabetes: current status," Am J Physiol Endocrinol Metab, 2006 Jan; 290(1):E1-E8. PMID 16339923.

• Laverty S, Sandy JD, Celeste C, Vachon P, Marier JF, Plaas AH. "Synovial fluid levels and serum pharmacokinetics in a large animal model following treatment with oral glucosamine at clinically relevant doses," Arthritis Rheum, 2005 Jan; 52(1):181-91. PMID 15641100.

• Gray H, Hutcheson P, Slavin R. "Is glucosamine safe in patients with seafood allergy?" J Allergy Clin Immunol, 2004; 114(2):459-60. PMID 15341031.

• Nolen RS. "Facing crackdown, dietary supplement companies promise changes," JAVMA News. 2002 Aug 15.

• Biggee BA, Blinn CM, McAlindon TE, Nuite M, Silbert JE. "Low levels of human serum glucosamine after ingestion of glucosamine sulphate relative to capability for peripheral effectiveness," Ann Rheum Dis. 2006 Feb; 65(2):222-6. PMID 16079170.

• Scroggie DA, Albright A, Harris MD. "The effect of glucosamine-chondroitin supplementation on glycosylated hemoglobin levels in patients with type 2 diabetes mellitus: a placebo-controlled, double-blinded, randomized clinical trial," Arch Intern Med, 2003 Jul 14; 163(13):1587-90. PMID 12860582.

• Adams ME. "Hype about glucosamine," Lancet, 1999 Jul 31;354(9176):353-4. PMID 10437858.

• McAlindon TE, LaValley MP, Gulin JP, Felson DT. "Glucosamine and Chondroitin for Treatment of Osteoarthritis: A Systematic Quality Assessment and Meta-analysis," JAMA, 2000; 283:1469-1475. PMID 10732937.

• Manson JJ, Rahman A. "This house believes that we should advise our patients with osteoarthritis of the knee to take glucosamine," Rheumatology (Oxford), 2004 Jan; 43(1):100-1. Full text online

• Reginster JY, Deroisy R, Rovati LC, Lee RL, Lejeune E, Bruyere O, Giacovelli G, Henrotin Y, Dacre JE, Gossett C. "Long-term effects of glucosamine sulphate on osteoarthritis progression: a randomised, placebo-controlled clinical trial," Lancet, 2001 Jan 27; 357(9252):251-6. PMID 11214126.

• Pavelka K, Gatterova J, Olejarova M, Machacek S, Giacovelli G, Rovati LC. "Glucosamine sulfate use and delay of progression of knee osteoarthritis: a 3-year, randomized, placebo-controlled, double-blind study," Arch Intern Med, 2002 Oct 14;162(18):2113-23. PMID 12374520.

• Hughes R, Carr A. "A randomized, double-blind, placebo-controlled trial of glucosamine sulphate as an analgesic in osteoarthritis of the knee," Rheumatology (Oxford), 2002 Mar; 41(3):279-84. Full text online.

• Cibere J, Kopec JA, Thorne A, Singer J, Canvin J, Robinson DB, Pope J, Hong P, Grant E, Esdaile JM, "Randomized, double-blind, placebo-controlled glucosamine discontinuation trial in knee osteoarthritis," Arthritis Rheum. 2004 Oct 15; 51(5):738-45. PMID 15478160.

• Clegg DO, Reda DJ, Harris CL, Klein MA, O'Dell JR, Hooper MM, Bradley JD, Bingham CO 3rd, Weisman MH, Jackson CG, Lane NE, Cush JJ, Moreland LW, Schumacher HR Jr, Oddis CV, Wolfe F, Molitor JA, Yocum DE, Schnitzer TJ, Furst DE, Sawitzke AD, Shi H, Brandt KD, Moskowitz RW, Williams HJ. "Glucosamine, chondroitin sulfate, and the two in combination for painful knee osteoarthritis," New Engl J Med, 2006 Feb 23; 354(8):795-808. PMID 16495392.

• Hochberg MC. "Nutritional supplements for knee osteoarthritis--still no resolution," N Engl J Med, 2006 Feb 23; 354(8):858-60. PMID 16495399.

External links

• "UDP-N-acetylglucosamine Biosynthesis," Diagram including IUBMB nomenclature and links.

• PDR Health Summary of drug information on glucosamine from the publishers of the Physician's Desk Reference.

• "Glucosamine/Chondroitin Arthritis Intervention Trial (GAIT)," ClinicalTrials.gov registration and information.

• "Effects of Oral Glucosamine on Insulin and Blood Vessel Activity in Normal and Obese People," ClinicalTrials.gov information.

• "NIH News: Efficacy of Glucosamine and Chondroitin Sulfate May Depend on Level of Osteoarthritis Pain," Wednesday, February 22, 2006.

• "Glucosamine, Chondroitin Not Much Help For Arthritic Knees," HealthDay, March 14, 2006.