Glucosamine Hydrochloride or Glucosamine Sulfate: Does it Matter?

Glucosamine used for management of joint discomfort is available as either the hydrochloride or the sulfate salt, used alone or in combination with chondroitin sulfate. Variable degrees of effectiveness has been reported in clinical trials evaluating the effects of glucosamine alone, raising the question of whether one form is superior to the other. More clinical studies have reported on the effects of the sulfate form than on the hydrochloride form, but within the glucosamine sulfate studies results are not uniformly positive 1-4. Clinical studies on the combination of glucosamine hydrochloride with chondroitin sulfate have been uniformly positive, including the ongoing NIH-sponsored GAIT study 5-7. In this large study neither glucosamine hydrochloride alone nor chondroitin sulfate alone was significantly better than placebo in reducing pain, stiffness, and function measured with the WOMAC index. However, the combination of glucosamine hydrochloride with chondroitin sulfate significantly improved symptoms with an effect size beyond that of celecoxib to patients with moderate to severe joint pain 7. While these results might suggest that chondroitin sulfate combined with glucosamine sulfate might be better than a combination with glucosamine hydrochloride, close inspection of clinical outcomes, pharmacokinetic studies, and in vitro effects of glucosamine on cytokinestimulated chondrocytes suggest that glucosamine alone is the active component. A recent review of the clinical studies pointed out that WOMAC pain, function and stiffness outcomes did not reach statistical significance in the 10 randomized controlled trials in which the Rotta preparation was compared to placebo 8, results similar to those on glucosamine hydrochloride in the GAIT study (Clegg et al, 2005). Only 1 study of glucosamine sulfate shows significant improvement on the WOMAC index 9. Better comparisons could be made if the Leuquesnes Index had been used in all of these studies, but this was not done. Pharmacokinetic studies on bioavailability of either form of glucosamine, in humans 10-12 or companion animals 13-16, show that serum or synovial fluid levels of glucosamine only reach low ug/ml levels. While these micromolar levels may be too low to directly impact chondrocyte proteoglycan metabolism in the presence of millimolar levels of glucose 17,18, recent studies show that even low levels of glucosamine alone, either as the hydrochloride or sulfate form, can inhibit cytokine-stimulated expression of genes associated with inflammation and matrix degradation 19-22. This inhibitory effect was attributed to glucosamine alone, not the sulfate. In addition, the combination of glucosamine hydrochloride and chondroitin sulfate was shown to be substantially more effective at 1 ug/ml than either agent alone in reversing proteoglycan loss in cartilage depleted by exposure to fibronectin fragments 23. The role of sulfate supplementation in joint support is unclear. The hypothesis has been presented that levels of serum sulfate may be rate limiting for synthesis of proteoglycans and that an increase in serum sulfate, due to the sulfate in glucosamine sulfate or chondroitin sulfate, may improve proteoglycan metabolism 24. However a careful analysis of fasting serum sulfate levels in human subjects before and after development of cartilage breakdown found no evidence of a relationship between serum levels and development of symptoms 25. There are no large scale

published clinical trials of the effect of other sources of sulfate, such as MSM, that support a major role for sulfate in relieving symptoms. The only clear difference between glucosamine hydrochloride and glucosamine sulfate is the glucosamine content. The hydrochloride form contain contains substantially more glucosamine base than the sulfate form, which also contains either sodium or potassium along with sulfate. Upon dissolution glucosamine base is released both forms, with the hydrochloride form providing about 30% more than the sulfate form. Thus at a fixed dosage glucosamine hydrochloride provides more bioavailable glucosamine than glucosamine sulfate. Bibliography 1. 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 51(5): 738-745, 2004. 2. McAlindon T, Formica M, LaValley M, Lehmer M, Kabbara K: Effectiveness of glucosamine for symptoms of knee osteoarthritis: results from an internet-based randomized doubleblind controlled trial. Am J Med 117(9): 643-649, 2004. 3. McAlindon TE, LaValley MP, Gulin JP, Felson DT: Glucosamine and chondroitin for treatment of osteoarthritis: a systematic quality assessment and meta-analysis. Jama 283(11): 1469-1475, 2000. 4. McAlindon T: Why are clinical trials of glucosamine no longer uniformly positive? Rheum Dis Clin North Am 29(4): 789-801, 2003. 5. Das A, Jr., Hammad TA: Efficacy of a combination of FCHG49 glucosamine hydrochloride, TRH122 low molecular weight sodium chondroitin sulfate and manganese ascorbate in the management of knee osteoarthritis. Osteoarthritis Cartilage 8(5): 343-350, 2000. 6. Leffler CT, Philippi AF, Leffler SG, Mosure JC, Kim PD: Glucosamine, chondroitin, and manganese ascorbate for degenerative joint disease of the knee or low back: a randomized, double-blind, placebo-controlled pilot study. Mil Med 164(2): 85-91, 1999. 7. Clegg DO RD, Harris CL, Klein MA: The Efficacy of Glucosamine and Chondroitin Sulfate in Patients with Knee Osteoarthritis (OA); The Glucosamine/chondroitin Arthritis Intervention Trial (GAIT). American College or Rheumatology Annual Meeting, 2005. 8. Towheed TE, Maxwell L, Anastassiades TP, Shea B, Houpt J, Robinson V, Hochberg MC, Wells G: Glucosamine therapy for treating osteoarthritis. Cochrane Database Syst Rev (2): CD002946, 2005. 9. Herrero-Beaumont G RJ, Trabado MC, Blanco FJ, Benito P, Martin-Mola E, Paulino J, Marenco JL, Porto A, Laffon A, Arujo D, Figueroa M, Branco J, : Effects of Glucosamine Sulfate on 6-Month Control of Knee Osteoarthritis Symptoms vs Placebo and Acetaminophen: Results from the Glucosamine Unum in Die Efficacy (GUIDE) Trial. American College or Rheumatology Annual Meeting, 2005. 10. 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, 2005. 11. Persani S RR, Trisolino G, Delliponti L, Rovati L, Locatelli M, Roda A: Glucosamine Plasma and Synovial Fluid Concentration before and after Oral Administration of

Crystalline Glucosamine Sulfate in Knee Osteoarthritis Patients. OASIS - Online Abstract Submission and Invitation System, 2005. 12. Persiani S, Roda E, Rovati LC, Locatelli M, Giacovelli G, Roda A: Glucosamine oral bioavailability and plasma pharmacokinetics after increasing doses of crystalline glucosamine sulfate in man. Osteoarthritis Cartilage, 2005. 13. Adebowale A, Du J, Liang Z, Leslie JL, Eddington ND: The bioavailability and pharmacokinetics of glucosamine hydrochloride and low molecular weight chondroitin sulfate after single and multiple doses to beagle dogs. Biopharm Drug Dispos 23(6): 217225, 2002. 14. Du J WN, Eddington ND: The bioavailability and pharmacokinetics of glucosamine hydrochloride and chondroitin sulfate after oral and intravenous single dose administration in the horse. Biopharmacy and Drug Disposition 25(3): 109-116, 2004. 15. 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 52(1): 181-191, 2005. 16. Tiraloche G, Girard C, Chouinard L, Sampalis J, Moquin L, Ionescu M, Reiner A, Poole AR, Laverty S: Effect of oral glucosamine on cartilage degradation in a rabbit model of osteoarthritis. Arthritis Rheum 52(4): 1118-1128, 2005. 17. Mroz PJ, Silbert JE: Effects of [3H]glucosamine concentration on [3H]chondroitin sulphate formation by cultured chondrocytes. Biochem J 376(Pt 2): 511-515, 2003. 18. Mroz PJ, Silbert JE: Use of 3H-glucosamine and 35S-sulfate with cultured human chondrocytes to determine the effect of glucosamine concentration on formation of chondroitin sulfate. Arthritis Rheum 50(11): 3574-3579, 2004. 19. Chan PS, Caron JP, Orth MW.: Glucosamine and chondroitin sulfate regulate IL-1 induced gene expression. Osteoarthritis Cartilage 2004 12(Supplement B): S133-134, 2004. 20. Chan PS, Caron JP, Rosa GJ, Orth MW: Glucosamine and chondroitin sulfate regulate gene expression and synthesis of nitric oxide and prostaglandin E(2) in articular cartilage explants. Osteoarthritis Cartilage 13(5): 387-394, 2005. 21. Piepoli T ZT, Letari O, Persiani S, Rovati LC, Caselli G: Glucosamine Sulfate Inhibits IL-1Stimulated Gene Expression at Concentrations Found in Humans after Oral Intake. OASIS - Online Abstract Submission and Invitation System, 2005. Piepoli T, Zanelli T, Letari O, Persiani S, Rovati LC, Caselli G: Glucosamine Sulfate Inhibits IL1-Stimulated Gene Expression at Concentrations Found in Humans after Oral Intake. Arthritis & Rheumatism 2005; 52 (9): S502-503 22. Chan PS, Caron, J.P., Orth, M.W.: Effect of glucosamine and chondroitin sulfate on regulatiion of gene expression of proteolytic enzymes and their inhiitors in interleukin-1 challenged bovine articular cartilage explants. American Journal Veterinay Research 66(11): 1870-1876, 2005. 23. Ray LM GD, Homandberg GA: Mixtures of Glucosamine and Chondroitin Sulfate Reverse Fibronectin Fragment Mediated Damage to Cartilage More Effectively Than Either Agent Alone. Osteoarthritis Cartilage 12(Supplement B): S135, 2004. and Osteoarthritis and Cartilage 14, 2006, in press. 24. Cordoba F, Nimni ME: Chondroitin sulfate and other sulfate containing chondroprotective agents may exhibit their effects by overcoming a deficiency of sulfur amino acids. Osteoarthritis Cartilage 11(3): 228-230, 2003.

25. Blinn CM, Dibbs ER, Hronowski LJ, Vokonas PS, Silbert JE: Fasting serum sulfate levels before and after development of osteoarthritis in participants of the veterans administration normative aging longitudinal study do not differ from levels in participants in whom osteoarthritis did not develop. Arthritis Rheum 52(9): 2808-2813, 2005.