[en] ABSTRACT: Glucosamine in its acetylated form is a natural constituent of some glycosaminoglycans (for example, hyaluronic acid and keratan sulfate) in the proteoglycans found in articular cartilage, intervertebral disc and synovial fluid. Glucosamine can be extracted and stabilized by chemical modification and used as a drug or a nutraceutical. It has been approved for the treatment of osteoarthritis (OA) in Europe to promote cartilage and joint health and is sold over the counter as a dietary supplement in the United States. Various formulations of glucosamine have been tested, including glucosamine sulfate and glucosamine hydrochloride. In vitro and in vivo studies have uncovered glucosamine's mechanisms of action on articular tissues (cartilage, synovial membrane and subchondral bone) and justified its efficacy by demonstrating structure-modifying and anti-inflammatory effects at high concentrations. However, results from clinical trials have raised many concerns. Pharmacokinetic studies have shown that glucosamine is easily absorbed, but the current treatment doses (for example, 1,500 mg/day) barely reach the required therapeutic concentration in plasma and tissue. The symptomatic effect size of glucosamine varies greatly depending on the formulation used and the quality of clinical trials. Importantly, the effect size reduces when evidence is accumulated chronologically and evidence for the structure-modifying effects of glucosamine are sparse. Hence, glucosamine was at first recommended by EULAR and OARSI for the management of knee pain and structure improvement in OA patients, but not in the most recent NICE guidelines. Consequently, the published recommendations for the management of OA require revision. Glucosamine is generally safe and although there are concerns about potential allergic and salt-related side effects of some formulations, no major adverse events have been reported so far. This paper examines all the in vitro and in vivo evidence for the mechanism of action of glucosamine as well as reviews the results of clinical trials. The pharmacokinetics, side effects and differences observed with different formulations of glucosamine and combination therapies are also considered. Finally, the importance of study design and criteria of evaluation are highlighted as new compounds represent new interesting options for the management of OA.
Disciplines :
Rheumatology
Author, co-author :
Henrotin, Yves ; Université de Liège - ULiège > Département des sciences de la motricité > Unité de recherche sur l'os et le cartillage (U.R.O.C.)
Mobasheri, Ali
Marty, Marc
Language :
English
Title :
Is there any scientific evidence for the use of glucosamine in the management of human osteoarthritis?
Hamerman D. The biology of osteoarthritis. N Engl J Med 1989, 320:1322-1330. 10.1056/NEJM198905183202006, 2654632.
Zhang W, Moskowitz RW, Nuki G, Abramson S, Altman RD, Arden N, BiermaZeinstra S, Brandt KD, Croft P, Doherty M, Dougados M, Hochberg M, Hunter DJ, Kwoh K, Lohmander LS, Tugwell P. OARSI recommendations for the management of hip and knee osteoarthritis, Part I: Critical appraisal of existing treatment guidelines and systematic review of current research evidence. Osteoarthritis Cartilage 2007, 15:981-1000. 10.1016/j.joca.2007.06.014, 17719803.
Zhang W, Moskowitz RW, Nuki G, Abramson S, Altman RD, Arden N, BiermaZeinstra S, Brandt KD, Croft P, Doherty M, Dougados M, Hochberg M, Hunter DJ, Kwoh K, Lohmander LS, Tugwell P. OARSI recommendations for the management of hip and knee osteoarthritis, Part II: OARSI evidencebased, expert consensus guidelines. Osteoarthritis Cartilage 2008, 16:137-162. 10.1016/j.joca.2007.12.013, 18279766.
Zhang W, Doherty M, Arden N, Bannwarth B, Bijlsma J, Gunther KP, Hauselmann HJ, Herrero-Beaumont G, Jordan K, Kaklamanis P, Leeb B, Lequesne M, Lohmander S, Mazieres B, Martin-Mola E, Pavelka K, Pendleton A, Punzi L, Swoboda B, Varatojo R, Verbruggen G, Zimmermann-Gorska I, Dougados M, . EULAR Standing Committee for International Clinical Studies Including Therapeutics (ESCISIT) EULAR evidence based recommendations for the management of hip osteoarthritis: report of a task force of the EULAR Standing Committee for International Clinical Studies Including Therapeutics (ESCISIT). Ann Rheum Dis 2005, 64:669-681. 10.1136/ard.2004.028886, 1755499, 15471891, EULAR Standing Committee for International Clinical Studies Including Therapeutics (ESCISIT).
Jordan KM, Arden NK, Doherty M, Bannwarth B, Bijlsma JW, Dieppe P, Gunther K, Hauselmann H, Herrero-Beaumont G, Kaklamanis P, Lohmander S, Leeb B, Lequesne M, Mazieres B, Martin-Mola E, Pavelka K, Pendleton A, Punzi L, Serni U, Swoboda B, Verbruggen G, Zimmerman-Gorska I, Dougados M, . Standing Committee for International Clinical Studies Including Therapeutic Trials ESCISIT EULAR Recommendations 2003: an evidence based approach to the management of knee osteoarthritis: Report of a Task Force of the Standing Committee for International Clinical Studies Including Therapeutic Trials (ESCISIT). Ann Rheum Dis 2003, 62:1145-1155. 10.1136/ard.2003.011742, 1754382, 14644851, Standing Committee for International Clinical Studies Including Therapeutic Trials ESCISIT.
American College of Rheumatology Subcommittee on Osteoarthritis G Recommendations for the medical management of osteoarthritis of the hip and knee: 2000 update. Arthritis Rheum 2000, 43:1905-1915. American College of Rheumatology Subcommittee on Osteoarthritis G.
Zhang W, Nuki G, Moskowitz RW, Abramson S, Altman RD, Arden NK, BiermaZeinstra S, Brandt KD, Croft P, Doherty M, Dougados M, Hochberg M, Hunter DJ, Kwoh K, Lohmander LS, Tugwell P. OARSI recommendations for the management of hip and knee osteoarthritis: Part III: changes in evidence following systematic cumulative update of research published through January 2009. Osteoarthritis Cartilage 2010, 18:476-499. 10.1016/j.joca.2010.01.013, 20170770.
Bassleer C, Rovati L, Franchimont P. Stimulation of proteoglycan production by glucosamine sulfate in chondrocytes isolated from human osteoarthritic articular cartilage in vitro. Osteoarthritis Cartilage 1998, 6:427-434. 10.1053/joca.1998.0146, 10343776.
Bassleer C, Henrotin Y, Franchimont P. In vitro evaluation of drugs proposed as chondroprotective agents. Int J Tissue React 1992, 14:231-241.
Noyszewski EA, Wroblewski K, Dodge GR, Kudchodkar S, Beers J, Sarma AV, Reddy R. Preferential incorporation of glucosamine into the galactosamine moieties of chondroitin sulfates in articular cartilage explants. Arthritis Rheum 2001, 44:1089-1095. 10.1002/1529-0131(200105)44:5<1089::AID-ANR189>3.0.CO;2-9, 11352240.
Sandy JD, Gamett D, Thompson V, Verscharen C. Chondrocyte-mediated catabolism of aggrecan: aggrecanase-dependent cleavage induced by interleukin-1 or retinoic acid can be inhibited by glucosamine. Biochem J 1998, 335:59-66. 1219752, 9742213.
Piperno M, Reboul P, Hellio Le Graverand MP, Peschard MJ, Annefeld M, Richard M, Vignon E. Glucosamine sulfate modulates dysregulated activities of human osteoarthritic chondrocytes in vitro. Osteoarthritis Cartilage 2000, 8:207-212. 10.1053/joca.1999.0291, 10806048.
McCulloch DR, Wylie JD, Longpre JM, Leduc R, Apte SS. 10 mM glucosamine prevents activation of proADAMTS5 (aggrecanase-2) in transfected cells by interference with post-translational modification of furin. Osteoarthritis Cartilage 2010, 18:455-463. 10.1016/j.joca.2009.10.014, 2826559, 19909832.
Gouze JN, Bordji K, Gulberti S, Terlain B, Netter P, Magdalou J, Fournel-Gigleux S, Ouzzine M. Interleukin-1beta down-regulates the expression of glucuronosyltransferase I, a key enzyme priming glycosaminoglycan biosynthesis: influence of glucosamine on interleukin-1beta-mediated effects in rat chondrocytes. Arthritis Rheum 2001, 44:351-360. 10.1002/1529-0131(200102)44:2<351::AID-ANR53>3.0.CO;2-M, 11229466.
Gouze JN, Gouze E, Popp MP, Bush ML, Dacanay EA, Kay JD, Levings PP, Patel KR, Saran JP, Watson RS, Ghivizzani SC. Exogenous glucosamine globally protects chondrocytes from the arthritogenic effects of IL-1beta. Arthritis Res Ther 2006, 8:R173. 10.1186/ar2082, 1794517, 17109745.
Gouze JN, Bianchi A, Becuwe P, Dauca M, Netter P, Magdalou J, Terlain B, Bordji K. Glucosamine modulates IL-1-induced activation of rat chondrocytes at a receptor level, and by inhibiting the NF-kappa B pathway. FEBS Lett 2002, 510:166-170. 10.1016/S0014-5793(01)03255-0, 11801247.
Largo R, Alvarez-Soria MA, Diez-Ortego I, Calvo E, Sanchez-Pernaute O, Egido J, Herrero-Beaumont G. Glucosamine inhibits IL-1beta-induced NFkappaB activation in human osteoarthritic chondrocytes. Osteoarthritis Cartilage 2003, 11:290-298. 10.1016/S1063-4584(03)00028-1, 12681956.
Shikhman AR, Kuhn K, Al aaeddine N, Lotz M. N-acetylglucosamine prevents IL-1 beta-mediated activation of human chondrocytes. J Immunol 2001, 166:5155-5160.
Imagawa K, de Andres MC, Hashimoto K, Pitt D, Itoi E, Goldring MB, Roach HI, Oreffo RO. The epigenetic effect of glucosamine and a nuclear factorkappa B (NF-kB) inhibitor on primary human chondrocytes--implications for osteoarthritis. Biochem Biophys Res Commun 2011, 405:362-367. 10.1016/j.bbrc.2011.01.007, 21219853.
Calamia V, Ruiz-Romero C, Rocha B, Fernandez-Puente P, Mateos J, Montell E, Verges J, Blanco F. Pharmacoproteomic study of the effects of chondroitin and glucosamine sulfate on human articular chondrocytes. Arthritis Res Ther 2010, 12:R138. 10.1186/ar3077, 2945029, 20626852.
Igarashi M, Kaga I, Takamori Y, Sakamoto K, Miyazawa K, Nagaoka I. Effects of glucosamine derivatives and uronic acids on the production of glycosaminoglycans by human synovial cells and chondrocytes. Int J Mol Med 2011, 27:821-827.
Uitterlinden EJ, Koevoet JL, Verkoelen CF, Bierma-Zeinstra SM, Jahr H, Weinans H, Verhaar JA, van Osch GJ. Glucosamine increases hyaluronic acid production in human osteoarthritic synovium explants. BMC Musculoskelet Disord 2008, 9:120. 10.1186/1471-2474-9-120, 2553787, 18786270.
Mendis E, Kim M-M, Rajapakse N, Kim S-K. Suppression of cytokine production in lipopolysaccharide-stimulated mouse macrophages by novel cationic glucosamine derivative involves down-regulation of NF-[kappa]B and MAPK expressions. Bioorganic Med Chem 2008, 16:8390-8396.
Tat SK, Pelletier JP, Vergés J, Montell E, Lajeunesse D, Fahmi H, Lavigne M, Martel-Pelletier J. Chondroitin and glucosamine sulfate in combination decrease the pro-resorptive properties of human osteoarthritis subchondral bone osteoblasts. Arthritis Res Ther 2007, 9:R117. 10.1186/ar2325, 2246236, 17996099.
Uitterlinden EJ, Jahr H, Koevoet JL, Jenniskens YM, Bierma-Zeinstra SM, Degroot J, Verhaar JA, Weinans H, van Osch GJ. Glucosamine decreases expression of anabolic and catabolic genes in human osteoarthritic cartilage explants. Osteoarthritis Cartilage 2006, 14:250-257. 10.1016/j.joca.2005.10.001, 16300972.
Shikhman AR, Brinson DC, Valbracht J, Lotz MK. Differential metabolic effects of glucosamine and N-acetylglucosamine in human articular chondrocytes. Osteoarthritis and Cartilage 2009, 17:1022-1028. 10.1016/j.joca.2009.03.004, 2785807, 19332174.
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 2005, 13:387-394. 10.1016/j.joca.2005.01.003, 15882562.
Chan PS, Caron JP, Ort h MW. Effect of glucosamine and chondroitin sulfate on regulation of gene expression of proteolytic enzymes and their inhibitors in interleukin-1-challenged bovine articular cartilage explants. Am J Vet Res 2005, 66:1870-1876. 10.2460/ajvr.2005.66.1870, 16334942.
Chan PS, Caron JP, Orth MW. Effects of glucosamine and chondroitin sulfate on bovine cartilage explants under long-term culture conditions. Am J Vet Res 2007, 68:709-715. 10.2460/ajvr.68.7.709, 17605605.
Chan PS, Caron JP, Orth MW. Short-term gene expression changes in cartilage explants stimulated with interleukin beta plus glucosamine and chondroitin sulfate. J Rheumatol 2006, 33:1329-1340.
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 2004, 50:3574-3579. 10.1002/art.20609, 15529373.
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, 65:222-226. 10.1136/ard.2005.036368, 1798018, 16079170.
Chiusaroli R, Natali C, Colombo F, Ballanti P, Rovati LC, Caselli G. Glucosamine sulfate delays progression of spontaneous osteoarthritis in the STR/ORT mouse model. Osteoarthritis Cartilage 2007, 15:C227. (abstract 419).
Wen ZH, Tang CC, Chang YC, Huang SY, Hsieh SP, Lee CH, Huang GS, Ng HF, Neoh CA, Hsieh CS, Chen WF, Jean YH. Glucosamine sulfate reduces experimental osteoarthritis and nociception in rats: association with changes of mitogen-activated protein kinase in chondrocytes. Osteoarthritis Cartilage 2010, 18:1192-1202. 10.1016/j.joca.2010.05.012, 20510383.
Ivanovska N, Dimitrova P. Bone resorption and remodeling in murine collagenase-induced osteoarthritis after administration of glucosamine. Arthritis Res Ther 2011, 13:R44. 10.1186/ar3283, 3132029, 21410959.
Naito K, Watari T, Furuhata A, Yomogida S, Sakamoto K, Kurosawa H, Kaneko K, Nagaoka I. Evaluation of the effect of glucosamine on an experimental rat osteoarthritis model. Life Sci 2010, 86:538-543. 10.1016/j.lfs.2010.02.015, 20188111.
Meulyzer M, Vachon P, Beaudry F, Vinardell T, Richard H, Beauchamp G, Laverty S. Joint inflammation increases glucosamine levels attained in synovial fluid following oral administration of glucosamine hydrochloride. Osteoarthritis Cartilage 2009, 17:228-234. 10.1016/j.joca.2008.06.018, 18692410.
Meulyzer M, Vachon P, Beaudry F, Vinardell T, Richard H, Beauchamp G, Laverty S. Comparison of pharmacokinetics of glucosamine and synovial fluid levels following administration of glucosamine sulphate or glucosamine hydrochloride. Osteoarthritis Cartilage 2008, 16:973-979. 10.1016/j.joca.2008.01.006, 18295513.
McCarthy G, O'Donovan J, Jones B, McAllister H, Seed M, Mooney C. Randomised double-blind, positive-controlled trial to assess the efficacy of glucosamine/chondroitin sulfate for the treatment of dogs with osteoarthritis. Vet J 2007, 174:54-61. 10.1016/j.tvjl.2006.02.015, 16647870.
Ozkan FU, Ozkan K, Ramadan S, Guven Z. Chondroprotective effect of N-acetylglucosamine and hyaluronate in early stages of osteoarthritis - an experimental study in rabbits. Bull NYU Hosp Jt Dis 2009, 67:352-357.
Silva F, Yoshinari N, Castro R, Girão V, Pompeu M, de Andrade Feitosa J, Rocha F. Combined glucosamine and chondroitin sulfate provides functional and structural benefit in the anterior cruciate ligament transection model. Clin Rheumatol 2009, 28:109-117. 10.1007/s10067-008-0988-8, 18791656.
Roda A, Sabatini L, Bar bieri A, Guardigli M, Locatelli M, Violante FS, Rovati LC, Persiani S. Development and validation of a sensitive HPLC-ESI-MS/MS method for the direct determination of glucosamine in human plasma. J Chromatogr B Analyt Technol Biomed Life Sci 2006, 844:119-126. 10.1016/j.jchromb.2006.07.013, 16931183.
Zhong S, Zhong D, Chen X. Improved and simplified liquid chromatography/electrospray ionization mass spectrometry method for the analysis of underivatized glucosamine in human plasma. J Chromatogr B Analyt Technol Biomed Life Sci 2007, 854:291-298. 10.1016/j.jchromb.2007.04.043, 17544344.
Huang TM, Cai L, Yang B, Zhou MX, Shen YF, Duan GL. Liquid chromatography with electrospray ionization mass spectrometry method for the assay of glucosamine sulfate in human plasma: validation and application to a pharmacokinetic study. Biomed Chromatogr 2006, 20:251-256. 10.1002/bmc.558, 16145658.
Pastorini E, Rotini R, Guardigli M, Vecchiotti S, Persiani S, Trisolino G, Antonioli D, Rovati LC, Roda A. Development and validation of a HPLC-ES-MS/MS method for the determination of glucosamine in human synovial fluid. J Pharm Biomed Anal 2009, 50:1009-1014. 10.1016/j.jpba.2009.07.008, 19647388.
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, 13:1041-1049. 10.1016/j.joca.2005.07.009, 16168682.
Persiani S, Rotini R, Trisolino G, Rovati LC, Locatelli M, Paganini D, Antonioli D, Roda A. Synovial and plasma glucosamine concentrations in osteoarthritic patients following oral crystalline glucosamine sulphate at therapeutic dose. Osteoarthritis Cartilage 2007, 15:764-772. 10.1016/j.joca.2007.01.019, 17353133.
Setnikar I, Rovati LC. Absorption, distribution, metabolism and excretion of glucosamine sulfate. A review. Arzneimittelforschung 2001, 51:699-725.
Persiani S, Matthews A, Larger P, Hall M, Rotini R, Trisolino G, Antonioli D, Zaccarelli L, Rovati LC. Glucosamine binding to proteins in plasma and synovial fluid and blood cell/plasma partitioning in mouse and man in vitro. Drug Metabol Drug Interact 2009, 24:211-227. 10.1515/DMDI.2009.24.2-4.211, 20408501.
Jackson CG, Plaas AH, Sandy JD, Hua C, Kim-Rolands S, Barnhill JG, Harris CL, Clegg DO. The human pharmacokinetics of oral ingestion of glucosamine and chondroitin sulfate taken separately or in combination. Osteoarthritis Cartilage 2010, 18:297-302. 10.1016/j.joca.2009.10.013, 2826597, 19912983.
Block JA, Oegema TR, Sandy JD, Plaas A. The effects of oral glucosamine on joint health: is a change in research approach needed?. Osteoarthritis Cartilage 2010, 18:5-11. 10.1016/j.joca.2009.07.005, 19733270.
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. 10.1001/jama.283.11.1469, 10732937.
Richy F, Bruyere O, Ethgen O, Cucherat M, Henrotin Y, Reginster JY. Structural and symptomatic efficacy of glucosamine and chondroitin in knee osteoarthritis: a comprehensive meta-analysis. Arch Intern Med 2003, 163:1514-1522. 10.1001/archinte.163.13.1514, 12860572.
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, 357:251-256. 10.1016/S0140-6736(00)03610-2, 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, 162:2113-2123. 10.1001/archinte.162.18.2113, 12374520.
Vlad SC, LaValley MP, McAlindon TE, Felson DT. Glucosamine for pain in osteoarthritis: why do trial results differ?. Arthritis Rheum 2007, 56:2267-2277. 10.1002/art.22728, 17599746.
Poolsup N, Suthisisang C, Channark P, Kittikulsuth W. Glucosamine long-term treatment and the progression of knee osteoarthritis: systematic review of randomized controlled trials. Ann Pharmacother 2005, 39:1080-1087. 10.1345/aph.1E576, 15855241.
Bruyere O, Burlet N, Delmas PD, Rizzoli R, Cooper C, Reginster JY. Evaluation of symptomatic slow-acting drugs in osteoarthritis using the GRADE system. BMC Musculoskelet Disord 2008, 9:165. 10.1186/1471-2474-9-165, 2627841, 19087296.
Wandel S, Juni P, Tenda l B, Nuesch E, Villiger PM, Welton NJ, Reichenbach S, Trelle S. Effects of glucosamine, chondroitin, or placebo in patients with osteoarthritis of hip or knee: network meta-analysis. BMJ 2010, 341:c4675. 10.1136/bmj.c4675, 2941572, 20847017.
Clegg DO, Reda DJ, Harris CL, Klein MA, O'Dell JR, Hooper MM, Bradley JD, Bingham CO 3, Weisman MH, Jackson CG, Lane NE, Cush JJ, Moreland LW, Schumacher HR, 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. N Engl J Med 2006, 354:795-808. 10.1056/NEJMoa052771, 16495392.
Herrero-Beaumont G, Ivorra JA, Del Carmen Trabado M, Blanco FJ, Benito P, Martin-Mola E, Paulino J, Marenco JL, Porto A, Laff on A, Araújo D, Figueroa M, Branco J. Glucosamine sulfate in the treatment of knee osteoarthritis symptoms: a randomized, double-blind, placebo-controlled study using acetaminophen as a side comparator. Arthritis Rheum 2007, 56:555-567. 10.1002/art.22371, 17265490.
Sawitzke AD, Shi H, Finco MF, Dunlop DD, Bingham CO 3, Harris CL, Singer NG, Bradley JD, Silver D, Jackson CG, Lane NE, Oddis CV, Wolfe F, Lisse J, Furst DE, Reda DJ, Moskowitz RW, Williams HJ, Clegg DO. 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 2008, 58:3183-3191. 10.1002/art.23973, 2836125, 18821708.
Rozendaal RM, Uitterlinden EJ, van Osch GJ, Garling EH, Willemsen SP, Ginai AZ, Verhaar JA, Weinans H, Koes BW, Bierma-Zeinstra SM. Effect of glucosamine sulphate on joint space narrowing, pain and function in patients with hip osteoarthritis; subgroup analyses of a randomized controlled trial. Osteoarthritis Cartilage 2009, 17:427-432. 10.1016/j.joca.2008.05.022, 18848470.
Lee Y, Woo J-H, Choi S, Ji J, Song G. Effect of glucosamine or chondroitin sulfate on the osteoarthritis progression: a meta-analysis. Rheumatol Int 2010, 30:357-363. 10.1007/s00296-009-0969-5, 19544061.
Rozendaal RM, Koes BW, va n Osch GJ, Uitterlinden EJ, Garling EH, Willemsen SP, Ginai AZ, Verhaar JA, Weinans H, Bierma-Zeinstra SM. Effect of glucosamine sulfate on hip osteoarthritis: a randomized trial. Ann Intern Med 2008, 148:268-277.
Bruyere O, Pavelka K, Rovati LC, Gatterova J, Giacovelli G, Olejarova M, Deroisy R, Reginster JY. Total joint replacement after glucosamine sulphate treatment in knee osteoarthritis: results of a mean 8-year observation of patients from two previous 3-year, randomised, placebo-controlled trials. Osteoarthritis Cartilage 2008, 16:254-260. 10.1016/j.joca.2007.06.011, 17681803.
Sawitzke AD, Shi H, Finco MF, Dunlop DD, Harris CL, Singer NG, Bradley JD, Silver D, Jackson CG, Lane NE, Oddis CV, Wolfe F, Lisse J, Furst DE, Bingham CO, Reda DJ, Moskowitz RW, Williams HJ, Clegg DO. Clinical efficacy and safety of glucosamine, chondroitin sulphate, their combination, celecoxib or placebo taken to treat osteoarthritis of the knee: 2-year results from GAIT. Ann Rheum Dis 2010, 69:1459-1464. 10.1136/ard.2009.120469, 3086604, 20525840.
Petersen SG, Saxne T, Heinegard D, Hansen M, Holm L, Koskinen S, Stordal C, Christensen H, Aagaard P, Kjaer M. Glucosamine but not ibuprofen alters cartilage turnover in osteoarthritis patients in response to physical training. Osteoarthritis Cartilage 2010, 18:34-40. 10.1016/j.joca.2009.07.004, 19679221.
Adrogue HJ, Madias NE. Sodium and potassium in the pathogenesis of hypertension. N Engl J Med 2007, 356:1966-1978. 10.1056/NEJMra064486, 17494929.
Kurtz TW, Al-Bander HA, M orris RC. "Salt-sensitive" essential hypertension in men. Is the sodium ion alone important?. N Engl J Med 1987, 317:1043-1048. 10.1056/NEJM198710223171702, 3309653.
Dostrovsky NR, Towheed TE, Hudson RW, Anastassiades TP. The effect of glucosamine on glucose metabolism in humans: a systematic review of the literature. Osteoarthritis Cartilage 2011, 19:375-380. 10.1016/j.joca.2011.01.007, 21251987.
Pham T, Cornea A, Blick KE, Jenkins A, Scofield RH. Oral glucosamine in doses used to treat osteoarthritis worsens insulin resistance. Am J Med Sci 2007, 333:333-339. 10.1097/MAJ.0b013e318065bdbe, 17570985.
Biggee BA, Blinn CM, Nuite M, Silbert JE, McAlindon TE. Effects of oral glucosamine sulphate on serum glucose and insulin during an oral glucose tolerance test of subjects with osteoarthritis. Ann Rheum Dis 2007, 66:260-262. 1798503, 16818461.
Chien CS, Cheng SC, Wu HT, Tsao CW, Cheng JT. Insulin resistance induced by glucosamine in fructose-fed rats. Horm Metab Res 2009, 41:542-547. 10.1055/s-0029-1216344, 19373748.
Simon RR, Marks V, Leeds AR, Anderson JW. A comprehensive review of oral glucosamine use and effects on glucose metabolism in normal and diabetic individuals. Diabetes Metab Res Rev 2011, 27:14-27. 10.1002/dmrr.1150, 3042150, 21218504.
Stumpf JL, Lin SW. Effect of glucosamine on glucose control. Ann Pharmacother 2006, 40:694-698. 10.1345/aph.1E658, 16569816.
Dworkin RH, Peirce-Sandner S, Turk DC, McDermott MP, Gibofsky A, Simon LS, Farrar JT, Katz NP. Outcome measures in placebo-controlled trials of osteoarthritis: responsiveness to treatment effects in the REPORT database. Osteoarthritis Cartilage 2011, 19:483-492. 10.1016/j.joca.2011.02.020, 21396467.
Gruenwald J, Petzold E, Busch R, Petzold H-P, Graubaum H-J. Effect of glucosamine sulfate with or without omega-3 fatty acids in patients with osteoarthritis. Adv Ther 2009, 26:858-871. 10.1007/s12325-009-0060-3, 19756416.
Das A, 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 2000, 8:343-350. 10.1053/joca.1999.0308, 10966840.
NICE Clinical Guidelines: The care and management of osteoarthritis in adults. , http://www.nice.org.uk/CG059
