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예희 필
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1 대한류마티스학회지 Vol. 15, No. 3, September, 8 종설 Glucosamine Sulfate 와 Chondroitin Sulfate 의골관절염치료효과 고려대학교의과대학류마티스내과 이영호ㆍ지종대ㆍ송관규 =Abstract= Glucosamine Sulfate and Chondroitin Sulfate for the Treatment of Osteoarthritis Young Ho Lee, Jong Dae Ji, Gwan Gyu Song Division of Rheumatology, Department of Internal Medicine, College of Medicine, Korea University, Seoul, Korea Osteoarthritis (OA) is the most common form of arthritis often associated with morbidity, disability, functional impairment and impaired quality of life. A new perspective in OA management is to delay disease progression by modifying joint structure. Glucosamine sulfate (GS) and chondroitin sulfate (CS) have attracted a lot of interest as a specific drug for OA. Glucosamine is a constituent of glcosaminoglycans in cartilage matrix and synovial fluid and is involved in cartilage formation. Chondroitin sulfate (CS) belongs to the glycosaminoglycan group and is a major component of the articular cartilage. The meta-analyses have shown that GS (but not glucosamine hydrochloride) and CS have small-to-moderate symptomatic efficacy in OA. With respect to the structure-modifying effect, there is some evidence that GS and CS may interfere with structural progression of OA. Key Words: Glucosamine, Chondroitin, Osteoarthritis <접수일 :8년 8월 9일, 심사통과일 :8년 9월 4일> 통신저자 : 이영호서울시성북구안암동 5가 1번지고려대학교의과대학류마티스내과 Tel:) , ax:) , lyhcgh@korea.ac.kr 197

2 대한류마티스학회지제 15 권제 3 호 8 서론골관절염은가장흔한관절염으로노인에서만성장애의주요한원인이다 (1). 비스테로이드항염제 (Nonsteroidal anti-inflammatory drug) 가골관절염치료로자주사용되나위장관과심혈관계의심각한부작용을초래할수있고관절염증상완화이외에연골보호효과는없다. 골관절염의치료를위해서는관절염증상뿐만아니라연골손상의진행을막거나완화시킬수있는약물이요구된다. Glucosamine과 chondroitin은골관절염증상치료에효과가있다고알려져왔으며연골보호효과에대한여러연구들이있었다 (,3). Glucosamine은연골과관절액에존재하는 aminosaccharide로연골의 glycosaminoglycan 체인합성과 aggrecan과다른 proteoglycans 합성의기질로작용한다. Aggrecan은친수성이있어서 aggrecan의합성증가는골관절염에좋은효과를야기한다 (4). Glucosamine sulfate (GS) 는연골세포와활액막세포에서 prostaglandin E 합성을감소시키고 superoxide radicals의생성, lysosomal enzyme의활성과유발성 nitric oxide 합성을억제하여항염작용을 보인다. GS는 proteoglycans 합성을촉진하고 stromelysin, collagenase등의분해성 (catabolic) 효소의작용을억제한다. Glucosamine은치료효과는주로항분해성작용때문이며 GS는 glucosamine hydrochloride (GH) 보다더강한효과를보인다 (5,6). Chondroitin sulfate (CS) 는연골, 뼈, 피부, 인대와건등의교원조직의세포외기질의주요성분으로관절연골의 aggrecan에서 CS는 osmotic swelling 압력을만들어서기질을확대하고콜라겐망을형성한다. CS는항염작용, proteoglycan 합성촉진과연골기질의손상과연골세포를죽이는 proteolytic enzyme을억제하여분해성작용을억제한다 (7). Glucosamine의골관절염증상에대한치료효과 Glucosamine의골관절염의치료에대한많은연구가있어왔다. 이들연구들을종합한최근의메타분석은 glucosamine이골관절염의증상치료에효과가있음을보여주었다 (effect size (ES).35, 95% confidence interval (CI).14.56) (). 효과크기 (ES) 는.,.5 와.8을각각소, 중, 대의효과크기로본다. 가장최근에시행된 Vlad et al에의한연구에서 glucosamine ig. 1. Meta-analysis on the symptomatic efficacy of glucosamine in osteoarthritis. 198

3 이영호외 : Glucosamine and Chondroitin Sulfate in OA 종류에따라 GS와 GH로나누어분석하였을때 GS 는골관절염증상완화에의미있는효과가있었으나 (ES.44, 95% CI.18.8) GH 는유의한효과를보이지못했다 (ES.6, 95% CI.8.7) ( 그림 1). 또한제약회사지원에따른연구를나누어분석하였을때제약회사가지원한연구는치료효과가있었으나 (ES.47, 95% CI.4.7) 그렇지않은연구는 glucosamine의치료효과를보이지못했다 (ES.5, 95% CI.3.41). 그러나 Vlad 등의연구결과해석에서주의해야할점은제약회사지원연구가일반적으로효과있는결과를보이는편견이있을수있으나반드시제약회사지원이연구결과의신뢰성에영향을미치는것은아니라는것이다 (8,9). 왜냐하면제약회사지원이연구계획및설계와질에영향을미칠수있는데제약회사의경우경험있는연구자가연구에영향을줄수있는교란요소들을피할수있는연구설계를더잘할수있고임상연구의원칙들을따르게되어있으므로연구의질을높일수있는장점이있기때문이다. GS는골관절염치료효과가있으나 GH는효과가없었는데다른메타연구에서도 Rottapharm (Italy) 제약회사에서만든 GS 1,5 mg (once daily) 가다른 GS 보다더효과적임을보여서 glucosamine 의성분차이가골관절염치료효과에영향을미칠수있음을시사한다 (1). 종합하면모든 glucosamine 이골관절염치료효과가있는것은아니며 GS는골관절염의증상치료에효과가있으나 GH는효과가없었다. 최근 개의 glucosamine에대한대규모연구는 glucosamine에대한새로운정보를주었다 (11,1). NIH 지원으로미국에서이루어진 Glucosmaine/chondroitin Arthritis Intervention Trial (GAIT) 연구는 GH (5 mg tid) 와 chondroitin sulfate (CS) (4 mg tid) 와위약을 6개월동안사용하여골관절염의치료효과를연구하였다. GH와 CS는위약과비교하여무릎통증을의미있게감소시키지못했다. 그러나중증도나증증의통증이있는환자에서는 GH와 CS를같이사용한군이위약보다의미있게효과가있었다 (79.% vs. 54.3%, p=.) (11). 유럽에서시행된다른 Glucosamine Unum In Die Efficacy (GUIDE) 연구는 GS (15 mg once daily) 와 acetaminophen (3, mg/day) 와위약을 6개월동안사용하여골관절염치 Table 1. Characteristics of individual studies on the structural efficacy of glucosamine sulfate and chondroitin sulfate in patients with osteoarthritis Study Ref Dose BMI (kg/m ) Drop rate (%) Age* Sex (%) Numbers ollow-up period OA C OA C OA C OA C OA C Variables analyzed ITT Quality analysis score Pavelka et al. 14 GS 1,5 mg once a day Reginster et al Kahan et al. GS 1,5 mg once a day CS 8 mg 6 once a day Michel et al. CS 8 mg 5 1 once a day Ubelhart-1 et al. 4 3 Ubelhart- et al CS 8 mg periods of 3 m during 1 yr CS 4 mg a day 61. (7.3) 66. (8.1) 63.5 (6.9) 65.5 (7.5) 8 (79) 79 (75) 77 (76) 83 (78) 5.7 (.1) 7.3 (.6) 5.7 (1.8) yrs Minimum JSN Severe narrowing Minimum JSN, 7.4 (.7) yrs Mean JSN Severe narrowing Yes 5 Yes 5 NA NA NA NA yrs Mean JSN Yes NA 6.5 (9.1) 63. (9.1) 63.1 (1.7) 76 (51) 78 (5) 7.7 (5.) 8.1 (5.5) yrs Minimum JSN, Mean JSN 63.7 (8.1) NA NA yr Minimum JSN, Mean JSN 6,13 5, NA NA yr Minimum JSN, Mean JSN Yes 5 Yes 3 No 3 Ref: Reference, OA: Rheumatoid arthritis, C: Control, ITT: Intention-to-treat, GS: Glucosamine sulfate, CS: Chondroitin sulfate, NA: Not available, JSN: Joint space narrowing *Mean (Standard deviation) 199

4 대한류마티스학회지제 15 권제 3 호 8 료효과를비교하였다. GS는 GAIT 연구에서와는달리위약에비해 Lequesne Algo-unctional index와 OARSI responder index를의미있게호전시켜치료효과를보였다 (1). 위두연구의결과들이차이가있어서고려해야할사항이있다 (8). 첫째, 북미에서 glucosamine은건강보조식품으로판매되고있으나유럽에서는치료약으로처방되어사용된다. 따라서 glucosamine 은유럽에서엄격히제조와판매에서약으로관리되고있으나북미에서는 glucosamine의용량이나순도등이약만큼엄격히통제되지않은건강보조식품으로사용된다. 둘째, glucosmaine 연구에서대부분의효과없음을보이는연구는 GH (5 mg tid) 를사용하였고효과를보인대부분의연구는 GS (15 mg once daily) 를사용하였다. GAIT 연구에서는 GH를사용하였고치료효과를보이지못했으나 CS를같이사용한일부의그룹에서는효과를보였 고 GUIDE연구에서는 GS를사용하였고치료효과를보였다. GAIT연구에서보여진대부분의효과는 CS 를같이사용했을때나타났다. 이는 sulfate가 glucosamine 효과발현에중요한역할을할가능성을시사하며향후 glucosamine을 sulfate와같이사용하여효과가나타난것인지에대한연구가필요하다. 셋째, 일반적으로무릎골관절염연구에서위약효과는 3% 정도인데 GUIDE 연구에서는위약효과가 3% 정도이었으나 GAIT연구에서는 6.1% 으로높았다. GAIT연구에서높은위약효과의이유와의미는뚜렷하지않았다. Glucosamine의연골보호효과 Glucosamine의연골보호효과에대한연구는 1년과 3년째무릎관절엑스레이로관절강넓이를측정한 개의무작위이중맹검위약대조군연구가있 ig.. Standard difference in means and 95% CI of individual studies and pooled data for structural effect of glucosamine sulfate on minimum JSN of knee OA at follow-up period of 1 yr (A) and 3 yrs (B).

5 이영호외 : Glucosamine and Chondroitin Sulfate in OA 다 ( 표 1) (13,14). 첫번째연구에서 16명의위약군은 3년후평균관절강넓이가의미있게좁아졌으나 (.31 mm, 95% CI=.48.13) 16명의 GS치료군에서는의미있는관절강넓이의변화가없었다 (.6 mm, 95%=..9). 두번째연구에서도위약군의경우 3년후관절강넓이가의미있게좁아졌으나 (.19 mm, 95% CI=.9.9) GS 치료군에서는의미있는관절강넓이의변화가없었다 (.4 mm, 95%=.6.14). GS을 3년간복용한후에는연골보호효과를보였으나 1년복용후의관절강넓이의비교에서는의미있는연골보호효과가관찰되지않았다 ( 표 1) ( 그림 ). Glucosamine의안전성 Glucosamine의안정성에대한체계적고찰에서 1,486명의환자에서 7명이 glucosamine과연관된부작용으로 glucosamine을끊었고 48명이부작용을보고하였다 (15). 18명의환자를대상으로한연구에서 1% 가부작용을보고하였으나대개경미하였고주로설사, 속쓰림등위장관증상이었고, glucosamine을끊은후모두호전되었다 (16). Glucosamine 여러연구에서부작용은 6 16% 보고하였으나대조군에서는 1 5%, NSAID군에서는 16 4% 보고하여 glucosamine의부작용은위약과비교하여유의한차이가없었다. 동물실험에서 glucosamine이인슐린저항성증가와혈당을상승시키므로인간에서도 glucosamine이혈당대사이상과인슐린저항성을증가시킬가능성이제시되었으나과학적고찰연구를통해이런가능성은배제되었다 (17). 사람을대상으로고용량의 glucosamine 을주사하였으나동물실험에서나타난인슐린저항성, 분비등의이상소견은나타나지않았다. 단기와장기간의위약대조군연구에서도정상인뿐만아니라당뇨병환자에서도 glucosamine은혈당대사에이상을초래하지않았고공복혈당수치도증가시키지않았다. Chondroitin sulfate의골관절염증상에대한효과 CS의골관절염치료에대한많은연구가있어왔다. 이들연구들을종합한메타분석은 CS가골관절염의증상치료에효과가있음을보여주고있다 (ES.75, 95% CI ) (18). 그러나 Intention- to-treat 분석과 명이상을대상으로한최근세연구들의메타분석에서 CS는의미있는증상완화효과를보이지않았다 (ES.3, 95% CI.13.7) (19-1). CS의골관절염치료효과에대한최근의연구결과들은이전의결과와다른경향을보이므로향후 CS 의골관절염치료효과에대한연구가더필요하다. Chondroitin sulfate의연골보호작용 CS의골관절염연골보호효과에대한여러연구가있었다 ( 표 1) (,1,,3). CS를 년간복용한 Table. Meta-analysis of the structural effects of glucosamine sulfate and chondroitin sulfate on cartilage in osteoarthritis Drug Group No. of Studies Std diff in means Test of association Test of heterogeneity 95% CI p-val Model Q p-val I Glucosamine sulfate ollow-up for 1 yrs ollow-up for 3 yrs JSN>.5 mm * Chondroitin sulfate Minimum JSW Mean JSW ollow-up for 1 yrs ollow-up for yrs *Odds ratio : fixed effect model, R: random effect model, JSW: Joint space width, JSN: Joint space narrowing 1

6 대한류마티스학회지제 15 권제 3 호 8 군이위약군에비해작지만의미있는연골보호효과를보였다 (ES.317, 95% CI.136 to.497, p=.1). 그러나 GS 와마찬가지로 CS를 1년복용한후의비교에서는의의있는연골보호효과가관찰되지않았다 ( 표 ). Chondroitin sulfate의안전성 CS 복용초기에드물게오심, 설사등의위장관증상이보고되었으나 CS의부작용은거의없으며안전한것으로알려졌다. 1개의위약대조군연구들의메타분석에서부작용의상대위험도는.99 (95% CI ) 이었다 (18,4). 임상연구에서 CS와다른약물이나음식과의상호작용은관찰되지않았으며검사상의이상도없었고 CS의부작용은위약과비교하여의의있는차이가없었다. 결론유럽류마티즘학회와국제골관절염연구회 (OARSI) 의골관절염치료가이드라인은 GS와 CS가무릎골관절염증상치료에효과가있고연골보호효과가있을수있어서골관절염치료에사용할수있다고추천하고있다 ( 높은수준의근거, 1A와추천강도 A) (5,6). 근거들을종합해보면 GS와 CS는무릎골관절염의증상치료에효과가있으며연골보호에도효과가있음을보인다. 그러나 GS의골관절염치료효과결과처럼 GH나건강보조식품으로판매되는다른 glucosamine도같은치료효과를나타낸다고볼수는없다. GS가약으로엄격히관리되고사용되었을때효과가있었으나 GH는효과가없었으며대부분의건강보조식품으로판매되는 glucosmaine이 GH이고 glucosamine의순도, 용량등이엄격히통제관리가되지않고있다. 시중에서사용되고있는 14개의 glucosmaine 제품의함량연구에서 glucosamine의실제함량은표시용량의 41% 에서 11% 로다양하였다 (7). 최근의 CS의골관절염치료효과에대한연구들은이전의연구결과와달리골관절염치료효과가적거나없는결과들을보여향후 CS의골관절염치료효과에대해서더연구가필요하다. 골관절염의연골보호작용에대한 GS와 CS의연구들은 년이상복용시의의있게연골손상을줄이는효과를보였으나 1년복용시에는연골보호효과를보이지못해서의미있는연골보호효과를보기위해서는 GS나 CS를 년이상장기적인복용이필요할수있을가능성을시사한다. 참고문헌 1) Jinks C, Jordan K, Croft P. Osteoarthritis as a public health problem: the impact of developing knee pain on physical function in adults living in the community: (KNEST 3). Rheumatology (Oxford) 7;46: ) Vlad SC, LaValley MP, McAlindon TE, elson DT. Glucosamine for pain in osteoarthritis: why do trial results differ? Arthritis Rheum 7;56: ) Bruyere O, Reginster JY. Glucosamine and chondroitin sulfate as therapeutic agents for knee and hip osteoarthritis. Drugs Aging 7;4: ) Setnikar I, Cereda R, Pacini MA, Revel L. Antireactive properties of glucosamine sulfate. Arzneimittelforschung 1991;41: ) Largo R, Alvarez-Soria MA, Diez-Ortego I, Calvo E, Sanchez-Pernaute O, Egido J, et al. Glucosamine inhibits IL-1beta-induced NkappaB activation in human osteoarthritic chondrocytes. Osteoarthritis Cartilage 3;11:9-8. 6)Altman RD, Abramson S, Bruyere O, Clegg D, Herrero-Beaumont G, Maheu E, et al. Commentary: osteoarthritis of the knee and glucosamine. Osteoarthritis Cartilage 6;14: ) Bali JP, Cousse H, Neuzil E. Biochemical basis of the pharmacologic action of chondroitin sulfates on the osteoarticular system. Semin Arthritis Rheum 1; 31: ) Reginster JY. The efficacy of glucosamine sulfate in osteoarthritis: financial and nonfinancial conflict of interest. Arthritis Rheum 7;56: ) Drenth JP, Verheugt W. Do COX- inhibitors give enough gastrointestinal protection? Lancet 7;369: ) Towheed TE, Maxwell L, Anastassiades TP, Shea B, Houpt J, Robinson V, et al. Glucosamine therapy for treating osteoarthritis. Cochrane Database Syst Rev 5;CD ) Clegg DO, Reda DJ, Harris CL, Klein MA, O'Dell

7 이영호외 : Glucosamine and Chondroitin Sulfate in OA JR, Hooper MM, et al. Glucosamine, chondroitin sulfate, and the two in combination for painful knee osteoarthritis. N Engl J Med 6;354: ) Herrero-Beaumont G, Ivorra JA, Del Carmen TM, Blanco J, Benito P, Martin-Mola E, et al. Glucosamine sulfate in the treatment of knee osteoarthritis symptoms: a randomized, double-blind, placebocontrolled study using acetaminophen as a side comparator. Arthritis Rheum 7;56: ) Reginster JY, Deroisy R, Rovati LC, Lee RL, Lejeune E, Bruyere O, et al. Long-term effects of glucosamine sulphate on osteoarthritis progression: a randomised, placebo-controlled clinical trial. Lancet 1;357: ) Pavelka K, Gatterova J, Olejarova M, Machacek S, Giacovelli G, Rovati LC, et al. Glucosamine sulfate use and delay of progression of knee osteoarthritis: a 3-year, randomized, placebo-controlled, double-blind study. Arch Intern Med ;16: ) Towheed TE, Anastassiades TP. Glucosamine therapy for osteoarthritis. J Rheumatol 1999;6: ) Tapadinhas MJ, Rivera IC, Bignamini AA. Oral glucosamine sulphate in the management of arthrosis: report on a multi-centre open investigation in Portugal. Pharmatherapeutica 198;3: ) Rovati LC, Annefeld M, Giacovelli G, Schmid K, Setnikar I. Glucosamine in osteoarthritis. Lancet 1999; 354: ) Reichenbach S, Sterchi R, Scherer M, Trelle S, Burgi E, Burgi U, et al. Meta-analysis: chondroitin for osteoarthritis of the knee or hip. Ann Intern Med 7;146: ) Clegg DO, Reda DJ, Harris CL, Klein MA, O'Dell JR, Hooper MM, et al. Glucosamine, chondroitin sulfate, and the two in combination for painful knee osteoarthritis. N Engl J Med 6;354: ) Kahan A. STOPP (Study on Osteoarthritis Progression Prevention): a new two-year trial with condroitin 4 & 6 sulfate (CS). Accessed at 6_amsterdam_vignon-.pdf on 18 september 6. 1) Michel BA, Stucki G, rey D, De Vathaire, Bignon E, Buehlmann P, et al. Chondroitins 4 and 6 sulfate in osteoarthritis of the knee: a randomized controlled trial. Arthritis Rheum 5;5: ) Uebelhart D, Thonar EJ, Delmas PD, Chantraine A, Vignon E. Effects of oral chondroitin sulfate on the progression of knee osteoarthritis: a pilot study. Osteoarthritis Cartilage 1998;6 Suppl A:39-46S. 3) Uebelhart D, Malaise M, Marcolongo R, de Vathaire, Piperno M, Mailleux E, et al. Intermittent treatment of knee osteoarthritis with oral chondroitin sulfate: a one-year, randomized, double-blind, multicenter study versus placebo. Osteoarthritis Cartilage 4;1: ) Hathcock JN, Shao A. Risk assessment for glucosamine and chondroitin sulfate. Regul Toxicol Pharmacol 7;47: ) Zhang W, Moskowitz RW, Nuki G, Abramson S, Altman RD, Arden N, et al. OARSI recommendations for the management of hip and knee osteoarthritis, Part II: OARSI evidence- based, expert consensus guidelines. Osteoarthritis Cartilage 8;16: ) Jordan KM, Arden NK, Doherty M, Bannwarth B, Bijlsma JW, Dieppe P, et al. EULAR Recommendations 3: an evidence based approach to the management of knee osteoarthritis: Report of a Task orce of the Standing Committee for International Clinical Studies Including Therapeutic Trials (ESCISIT). Ann Rheum Dis 3;6: ) Russell AS, Aghazadeh-Habashi A, Jamali. Active ingredient consistency of commercially available glucosamine sulfate products. J Rheumatol ;9:

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A 617 Special Issue Diabetic Retinopathy Won Ki Lee, M.D. Department of Ophthalmology The Catholic University of Korea College of Medicine Kangnam St. Mary s Hospital E mail : wklee@catholic.ac.kr Abstract R