Glucosamine

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Glucosamine (C6H13NO5) is an amino sugar and a prominent 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.

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Biochemistry

D-Glucosamine is made naturally in the form of glucosamine-6-phosphate, and is the biochemical precursor of all nitrogen-containing sugars.[1] Specifically, glucosamine-6-phosphate is synthesized from fructose-6-phosphate and glutamine[2] as the first step of the hexosamine biosynthesis pathway.[3] 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.[4][5]

Health effects

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. Its use as a therapy for osteoarthritis appears safe, but there is conflicting evidence as to its effectiveness.[6][7]

Use

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 sulphate and glucosamine hydrochloride. The amount of glucosamine present in 1500 mg of glucosamine salt will depend on which anion is present and whether additional salts are included in the manufacturer's calculation.[8] 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.[9] 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.[10]

In Europe, glucosamine is approved as a medical drug and is sold in the form of glucosamine sulphate.

Safety

Clinical studies of glucosamine have consistently reported that glucosamine appears safe. Since glucosamine is usually derived from shellfish, those allergic to shellfish or who have kosher concerns 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.[11] 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,[4] but several investigations have found no evidence that this occurs.[12] 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.[13] 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

A meta-analysis that includes all trials in the table except Rozendaal's and Wilken's negative negative trials of glucosamine sulfate concluded that glucosamine hydrochloride is not effective and that the effect of glucosamine sulfate is uncertain.[14]

Selected randomized controlled trials of glucosamine[15][16][17][18][19][20]
Trial Patients Intervention Outcome Results
Glucosamine Placebo
Reginster[15]
2001
Sponsored by manufacturer		 212 patients with knee osteoarthritis
30% dropped out		 1500 mg glucosamine sulphate for 3 years Loss of mean joint-space
Loss at minimum joint space (visual)
WOMAC pain score[21]
Did not use intention to treat analysis.		 0.06 mm†
0.40 mm†
-24.3%†		 0.31 mm
0.11 mm
+9.8%
Pavelka[16]
2002
Sponsored by manufacturer		 202 patients with hip osteoarthritis
40% dropped out		 1500 mg glucosamine sulphate for 3 years Loss at minimum joint space (visual)
WOMAC pain score[21]
Used intention to treat analysis.		 -0.40 mm† (space increased)
-2.0†		 0.19 mm
-1.3
GAIT[17]
2006		 1583 patients with knee osteoarthritis 1500 mg glucosamine hydrochloride daily for 24 weeks Response of 20% decrease in WOMAC pain score[21] All subjects: 64%
Mild OA: 64%
Moderate/severe OA: 66%‡		 All subjects: 60%
Mild OA: 62%
Moderate/severe OA: 54%
GAIT[18]
2008		 1583 patients with knee osteoarthritis 1500 mg glucosamine hydrochloride daily for 24 weeks Loss of joint space width at two years 0.013 mm 0.166 mm (not significant)
Rozendaal[19]
2008		 222 patients with hip osteoarthritis 1500 mg glucosamine sulfate daily for 2 years Loss at minimum joint space
WOMAC pain score[21]		 0.094 mm
-1.9		 0.057 mm
-0.3
Wilkens[20]
2010		 250 patients with lumbalgia and lumbar osteoarthritis 1500 mg glucosamine sulfate daily for 6 months Pain and disability No statistical significance
† p < 0.05
‡ All comparisons were insignificant and less than occurred with celecoxib; however, the combination of glucosamine and chondroitin gave significant 79% improvement among moderate/severe patients. However, longer follow-up of GAIT showed the combination group tended to have the most loss of joint space.[18]

Although earlier randomized controlled trials were conflicting, more recent and larger trials show that neither glucosamine sulfate[19] nor glucosamine hydrochloride[17][18] is effective for osteoarthritis. The evidence both for and against glucosamine's efficacy has led to debate among physicians about whether to recommend glucosamine treatment to their patients.[22]

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-outs, and unclear procedures for blinding.[23][24] Rottapharm 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 benefit for glucosamine treatment.[25][16] 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.[26][27]

This situation led the National Institutes of Health to fund a large, multicenter clinical trial studying reported pain in osteoarthritis of the knee, comparing groups treated with chondroitin sulfate, glucosamine, and the combination, as well as both placebo and celecoxib.[28] 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.[17] 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. However, exploratory analysis of a subgroup of patients suggested that the supplements may be effective in patients with pain classified as moderate to severe (see testing hypotheses suggested by the data).

An accompanying editorial 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]"[29] 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".[30] Finally, a randomized controlled trial of glucosamine sulfate was also negative.[19]

References

  1. ↑ Roseman S. "Reflections on glycobiology," J Biol Chem, 2001 Nov 9; 276(45):41527-42. PMID 11553646. Full Text Online
  2. ↑ Ghosh S, Blumenthal HJ, Davidson E, Roseman S. "Glucosamine metabolism. V. Enzymatic synthesis of glucosamine 6-phosphate", J Biol Chem, 1960 May; . PMID 13827775. PDF online.
  3. ↑ International Union of Biochemistry and Molecular Biology
  4. ↑ 4.0 4.1 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.
  5. ↑ Biggee BA, Blinn CM, McAlindon TE, Nuite M, Silbert JE (February 2006). "Low levels of human serum glucosamine after ingestion of glucosamine sulphate relative to capability for peripheral effectiveness". Ann. Rheum. Dis. 65 (2): 222–6. DOI:10.1136/ard.2005.036368. PMID 16079170. PMC 1798018. Research Blogging.
  6. ↑ 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.
  7. ↑ 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.
  8. ↑ PDR Health
  9. ↑ FDA
  10. ↑ Nolen RS. "Facing crackdown, dietary supplement companies promise changes," JAVMA News. 2002 Aug 15.
  11. ↑ 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.
  12. ↑ 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.
  13. ↑ Clinicaltrials.gov
  14. ↑ Vlad SC, Lavalley MP, McAlindon TE, Felson DT (2007). "Glucosamine for pain in osteoarthritis: Why do trial results differ?". Arthritis Rheum 56 (7): 2267-2277. DOI:10.1002/art.22728. PMID 17599746. Research Blogging.
  15. ↑ 15.0 15.1 Reginster JY, Deroisy R, Rovati LC, et al (January 2001). "Long-term effects of glucosamine sulphate on osteoarthritis progression: a randomised, placebo-controlled clinical trial". Lancet 357 (9252): 251–6. DOI:10.1016/S0140-6736(00)03610-2. PMID 11214126. Research Blogging.
  16. ↑ 16.0 16.1 16.2 Pavelká K, Gatterová J, Olejarová M, Machacek S, Giacovelli G, Rovati LC (October 2002). "Glucosamine sulfate use and delay of progression of knee osteoarthritis: a 3-year, randomized, placebo-controlled, double-blind study". Arch. Intern. Med. 162 (18): 2113–23. PMID 12374520. [e] Cite error: Invalid <ref> tag; name "pmid12374520" defined multiple times with different content
  17. ↑ 17.0 17.1 17.2 17.3 Clegg DO, Reda DJ, Harris CL, et al (February 2006). "Glucosamine, chondroitin sulfate, and the two in combination for painful knee osteoarthritis". N. Engl. J. Med. 354 (8): 795–808. DOI:10.1056/NEJMoa052771. PMID 16495392. Research Blogging. Cite error: Invalid <ref> tag; name "pmid16495392" defined multiple times with different content
  18. ↑ 18.0 18.1 18.2 18.3 Sawitzke AD, Shi H, Finco MF, et al (October 2008). "The effect of glucosamine and/or chondroitin sulfate on the progression of knee osteoarthritis: a report from the glucosamine/chondroitin arthritis intervention trial". Arthritis Rheum. 58 (10): 3183–91. DOI:10.1002/art.23973. PMID 18821708. Research Blogging. Cite error: Invalid <ref> tag; name "pmid18821708" defined multiple times with different content Cite error: Invalid <ref> tag; name "pmid18821708" defined multiple times with different content
  19. ↑ 19.0 19.1 19.2 19.3 Rozendaal RM, Koes BW, van Osch GJ, et al (February 2008). "Effect of glucosamine sulfate on hip osteoarthritis: a randomized trial". Ann. Intern. Med. 148 (4): 268–77. PMID 18283204. [e] Cite error: Invalid <ref> tag; name "pmid18283204" defined multiple times with different content Cite error: Invalid <ref> tag; name "pmid18283204" defined multiple times with different content
  20. ↑ 20.0 20.1 Wilkens P, Scheel IB, Grundnes O, Hellum C, Storheim K (2010). "Effect of glucosamine on pain-related disability in patients with chronic low back pain and degenerative lumbar osteoarthritis: a randomized controlled trial.". JAMA 304 (1): 45-52. DOI:10.1001/jama.2010.893. PMID 20606148. Research Blogging.
  21. ↑ 21.0 21.1 21.2 21.3 Bellamy N, Buchanan WW, Goldsmith CH, Campbell J, Stitt LW (December 1988). "Validation study of WOMAC: a health status instrument for measuring clinically important patient relevant outcomes to antirheumatic drug therapy in patients with osteoarthritis of the hip or knee". J. Rheumatol. 15 (12): 1833–40. PMID 3068365. [e]
  22. ↑ Manson and Rahman, 2004
  23. ↑ Adams ME. "Hype about glucosamine," Lancet, 1999 Jul 31;354(9176):353-4. PMID 10437858.
  24. ↑ 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.
  25. ↑ 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.
  26. ↑ 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.
  27. ↑ 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.
  28. ↑ Clinicaltrials.gov
  29. ↑ Hochberg MC. "Nutritional supplements for knee osteoarthritis--still no resolution," N Engl J Med, 2006 Feb 23; 354(8):858-60. PMID 16495399.
  30. ↑ PDR Health

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