背景及目的：台灣目前正逐漸進入老年型社會，因此，老化及退化性疾病也逐漸受到重視。在骨科方面，主要是退化性關節炎病人逐年增加，而治療方式也日新月異，目前較廣為接受的處理原則為ACR Guidelines 2000。除了口服藥物及手術外，侵犯性介於兩者之間的膝關節玻尿酸注射目前也是一個很普遍的治療方式。相關的研究報告也不在少數，本研究是比較兩種不同分子量的玻尿酸（sodium hyaluronate，Artz®，MW = 0.6-1.2 kDA及Hylan G-F 20，Synvisc®，MW = 6 kDA）分別注射不同膝關節，經六個月追蹤後，統計並比較這兩種玻尿酸對病人的療效、滿意度及經濟效益，以提供臨床治療之參考。
方法： 自94年10月1日起至95年12月31日止，共收集41位合乎膝關節玻尿酸注射適應症（參考第一章之附註）之退化性膝關節炎患者，其中37位完成完整治療追蹤之過程，受試者隨機接受Artz®（每週一次共五週）或Synvisc®（每週一次共三週），並分別以VAS，WOMAC，HSS score及Lequesne’s index作評估，評估的時間點為baseline（治療前）、第八、第十二、第十六、第二十、及第二十六週等六次。使用統計軟體做雙變數分析，配對檢定，以比較治療成效的差異。
統計假設：
Null hypothesis：兩種不同分子量玻尿酸治療26週後，療效無明顯差異。
Alternative hypothesis（two-sided）：兩者療效有明顯差異。
結果： 37位病人平均年齡為71.3 ± 7.5歲，作者使用two-way ANOVA做分析統計，經重複量數的比較，發現以VAS（圖六），WOMAC（圖八）或 Lequesne’s index（圖十）做評估，病人使用Artz®或Synvisc®做關節內注射，其疼痛都有顯著的改善，而且兩種藥物間有統計學上的差異（p < 0.05）。若Artz®及Synvisc®做關節內注射治療後，以WOMAC A1（圖七）及 HSS score（圖九）分別作症狀評估也可發現疼痛都有顯著的改善，但兩者間看不出差異。作者也比較兩膝在各評估點中VAS，WOMAC，Lequesne’s index 及HSS score等各種scores與baseline的差距，我們將之視為症狀改善的程度，經paired t-test分析（圖11-20）後發現HSS score的改善程度兩膝間無明顯差異（p > 0.05）；WOMAC A1評估兩種藥物在12週前有顯著差異（p < 0.05），12週後療效便無差異（p > 0.05）。而VAS，WOMAC及Lequesne’s index的評估結果中，兩種藥物在整個療程追蹤過程中其療效都有統計學上的差異，注射Synvisc®的膝關節其症狀改善程度較高（p < 0.05）。由以上的統計結果顯示，兩膝在治療前症狀的程度即有差異，而Synvisc®的短期疼痛緩解效果較Artz®為佳，但中期以後（12週後）兩種藥物對症狀的改善程度差異性減少。Artz®在台灣的健保給付價格為NT$1462，Synvisc®為NT$1962，Artz® 5劑為一個療程，Synvisc® 3劑為一個療程，一次療程二者藥費Synvisc®便宜NT$1424。病人在醫學中心就診一次的費用，不含交通費約需NT$460，三次為NT$1380，五次為NT$2300。若病人選擇注射Synvisc®，一次療程可比選擇Artz® 節省NT$2344（表8-9）。而且選擇Synvisc®的病人可減少兩次的侵入性治療，除了時間的節省以外，也可減少感染及其它併發症的機會。
結論：Synvisc®在短期緩解疼痛的效果比Artz®好，但在中期的效果則和Artz®較無明顯差異。在經濟效益方面，三劑Synvisc®比五劑Artz®在台灣的健保支付價格便宜NT$1424，且病人若選擇注射Synvisc®，只需來門診三次，而注射Artz®需來門診五次，則病人花費在交通費及其他額外費用如掛號費的支出等，明顯比Synvisc®的療程花費多。因此，以對病人的經濟效益而言，Synvisc®的注射療程顯比Artz®佔優勢。雖然Artz®和Synvisc®的中長期療效無明顯差異，但Synvisc®的短期效果顯著，病人可能直覺上會認為Synvisc®效果較佳，再以病人的就醫成本而言，選擇Synvisc®可以使病人減少時間及金錢的耗費，並可以減少兩次膝關節注射的疼痛，這對病人有極大的誘因，因此大部分會選擇繼續接受Synvisc®治療也就不難想像。至於兩種藥物半年以上的長期評估比較，則需要再進一步的研究設計。

This study was to determine whether hyaluronan （hyaluronic acid, HA） products with different molecular weight （MW） have significant differences in the treatment of early osteoarthritic （OA） knees. There were 41 patients with primary symptomatic OA of both knees, prospectively collected between October 2005 and December 2006 at our outpatient clinic. This study applied HA products with two different MW: sodium hyaluronate, Artz® （MW = 0.6-1.2 kDA） and Hylan G-F 20, Synvisc® （MW = 6 kDA）. Artz® injection was applied once a week for five consecutive weeks and Synvisc® intraarticular injection was applied once a week for three consecutive weeks. Based on the questionnaire, we compared the efficacy monthly for half a year to assess which HA product had better degrees of improvement. We also calculated and compared the total cost effectiveness.
There were no significant differences in long term clinical efficacy between the two HA products, but the Synvisc® showed significant benefit in short term symptoms relief. However, patients paid fewer in Synvisc® intraarticular injections than in Artz® intraarticular injections.
Some studies suggest that products with high MW have better therapeutic effects than those with low MW, whereas other studies show no significant differences between them. In our study, higher MW HA possessed a greater symptom-relieving effect than lower MW HA in short term follow-up; however, there were no significant differences between them in long term results. Synvisc® treatment resulted in better short term pain relief and a reasonable cost-effectiveness ratio for patients with early knee OA.

目錄
表目次…. 4
圖目次…. 5
中文摘要 7
第一章 緒論 11
第二章 文獻探討 14
第一節 退化性膝關節炎 14
第二節 病因及致病機轉 16
第三節 退化性關節炎的流行病學及現況 18
第四節 玻尿酸的應用 20
第三章 材料與方法 25
第一節 研究動機 25
第二節 研究對象 26
第三節 研究方法 26
第四節 評估標準 28
4.1 100 mm Visual Analog Scale（VAS） 29
4.2 Western Ontario and McMaster Universities Osteoarthritis Index pain score（WOMAC） 29
4.3 the Hospital for Special Surgery（HSS）score 31
4.4 Lequesne’s index 32
第四章 結果 33
第一節 資料統計 33
第二節 資料分析 45
第三節 圖表分析與配對比較 47
第四節 經濟效益與滿意度 58
第五章 討論 61
第六章 結論 69
第七章 英文摘要 70
Abstract.. 70
第八章 附錄 72
參考書目 78

1 ACR Guidelines 2000 American College of Rheumatology Subcommittee on osteoarthritis guidelines. Recommendations for the medical management of osteoarthritis of the hip and knee. 2000 Update. Arthritis & Rheumatism. 2000;43:1905-15.
2 Peyron JG, Balazs EA. Preliminary clinical assessment of Na-hyaluronate injection into human arthritic joints. Pathologie-Biologie (Paris). 1974;22:731-6.
3 Weiss C, Band P. Basic principles underlying the development of viscosupplementation for the treatment of osteoarthritis. Journal of Clinical Rheumatology. 1999;5:2-11.
4 Hou SM, Wang CT. Therapeutic effects of hyaluronic acid on osteoarthritis of the knee. The Journal of Bone and Joint Surgery. American Volume. 2004;86-A:2567.
5 Frizziero L, Pasquali Rochetti I. Intra-articular treatment of osteoarthritis of the knee: an arthroscopic and clinical comparison between sodium hyaluronate (500-730 kDa) and methylprednisolone acetate. Journal of Orthopaedics and Traumatology. 2002;3:89-96.
6 Leopold SS, Redd BB, Warme WJ, Wehrle PA, Pettis PD, Shott S. Corticosteroid compared with hyaluronic acid injections for the treatment of osteoarthritis of the knee. A prospective, randomized trial. The Journal of Bone and Joint Surgery. American Volume. 2003;85-A:1197-203.
7 Tsukamoto Y, Yamamoto M, Motegi M, Iwata H, Ryu J, Takagishi K, Sugawara S. A double-blind trial of intra-articular higher molecular weight hyaluronic acid (NRD 101) versus lower molecular weight hyaluronic acid (Artz®) in knee osteoarthritis. Rheumatology in Europe. 1995;24:333.
8 Yamamoto M, Sugawara Y, Tsukamoto Y, Motegi M, Iwata H, Rye J, Takagishi K, Nakashima M. Clinical evaluation of high molecular weight sodium hyaluronate (NRD 101) on osteoarthritis of the knee. A phase III comparative clinical study with Artz as a control drug. Japanese Pharmacology & Therapeutics. 1994;22:4059-87.
9 Karatosun V, Unver B, Gocen Z, Sen A, Gunal I. Intra-articular hyaluronic acid compared with progressive knee exercises in osteoarthritis of the knee: a prospective randomized trial with long-term follow-up. Rheumatology International. 2006;26:277-84.
10 Huang MH, Yang RC, Lee CL, Chen TW, Wang MC. Preliminary results of integrated therapy for patients with knee osteoarthritis. Arthritis and Rhemuatism. 2005;53:812-20.
11 Rejaili WA, Chueire AG, Cordeiro JA, Petean FC, De Carvalho Filho G. The evaluation of hilan GF-20 in the postoperative knee arthroscopies for arthrosis. Acta Ortopédica Brasileira. 2005;13:20-3.
12 Forster MC, Straw R. A prospective randomised trial comparing intra-articular Hyalgan injection and arthroscopic washout for knee osteoarthritis. The Knee. 2003;10:291-3.
13Ahlbäck S, Bauer GC, Bohne WH. Spontaneous osteonecrosis of the knee. Arthritis and Rheumatism. 1968;11:705-33.
14 Chan D, Cole WG, Chow CW, Mundlos S, Bateman JF. A COL2A1 mutation in achondrogenesis type II results in the replacement of type II collagen by type I and III collagens in cartilage. Journal of Biological Chemistry. 1995;270:1747-53.
15 Meulenbelt I, Bijkerk C, De Wildt SC, Miedema HS, Breedveld FC, Pols HA, Hofman A, Van Duijn CM, Slagboom PE. Haplotype analysis of three polymorphisms of the COL2A1 gene and associations with generalised radiological osteoarthritis. Annals of Human Genetics. 1999:393-400.
16 Hannan MT, Anderson JJ, Zhang Y, Levy D, Felson DT. Bone mineral density and knee osteoarthritis in elderly men and women. Arthritis and Rheumatism. 1993;36:1671-80.
17 Zhang Y, Hannan MT, Chaisson CE, McAlindon TE, Evans SR, Aliabadi P, Levy D, Felson DT. Bone mineral density and risk of incident and progressive radiographic knee osteoarthritis in women: the Framingham Study. The Journal of Rheumatology. 2000;27:1032-7.
18 Hart D, Mootoosamy I, Doyle D, Spector T. The relationship between osteoarthritis and osteoporosis in the general population: the Chingford Study. Annals of the Rheumatic Diseases. 1994;53:158-62.
19 Eli Steigelfest, Carlos J Lozada. Osteoarthritis. eMedicine. January 22, 2002.
20 Zhang Y, Xu L, Nevitt MC, Aliabadi P, Yu W, Qin M, Lui LY, Felson DT. Comparison of the prevalence of knee osteoarthritis between the elderly Chinese population in Beijing and Whites in the United States. The Beijing Osteoarthritis Study. The Journal of Rheumatology. 2001;44:2065-71.
21蔡怡萱、周正亮. 常見膝與手的退化性關節炎. 臨床醫學. 民國95年12月 第58卷第6期：423-7.
22 Rydell N, Balazs EA. Effect of intraarticular injection of hyaluronic acid on the clinical symptoms of osteoarthritis and on granulation tissue formation. Clinical Orthopaedics and Related Research. 1971;80:25-32.
23 Hsieh YS, Yang SF, Chu SC, Chen PN, Chou MC, Hsu MC, Lu KH. Expression changes of gelatinases in human osteoarthritic knees and arthroscopic debridement. Arthroscopy. 2004;20:482-8.
24 Murphy G, Knauper V, Atkinson S, Butler G, English W, Hutton M, Stracke J, Clark I. Matrix metalloproteinases in arthritic disease. Arthritis Research. 2002;4:39-49.
25 Mazzieri R, Masiero L, Zanetta L, Monea S, Onisto M, Garbisa S, Mignatti P. Control of type IV collagenase activity by components of the urokinase-plasmin system: a regulatory mechanism with cell-bound reactants. The EMBO Journal. 1997;16:2319-32.
26 Andreasen PA, Georg B, Lund LR, Riccio A, Stacey SN. Plasminogen activator inhibitors:hormonally regulated serpins. Molecular and Cellular Endocrinology. 1990;68:1-19.
27 Ramos-DeSimone N, Hahn-Dantona E, Sipley J, Nagase H, French DL, Quigley JP. Activation of matrix metalloproteinase-9 (MMP-9) via a converging plasmin/stromelysin-1 cascade enhances tumor cell invasion. Journal of Biological Chemistry. 1999;274:13066-76.
28 Matsuo O, Tanaka S, Kikuchi H. Effect of urinary trypsin inhibitor on osteoarthritis. Thrombosis Research. 1988;52:237-245.
29 Ghosh P, Guidolin D. Potential mechanism of action of intra-articular hyaluronan therapy in osteoarthritis: are the effects molecular weight dependent? Seminars in Arthritis and Rheumatism. 2002;32:10-37.
30 Bellamy N, Buchanan WW, Goldsmith CH, Campbell J, Stitt LW. Validation study of the 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. The Journal of Rheumatology. 1988;15:1833-40.
31 Founded in 1863, the Hospital for Special Surgery is a world leader in orthopedics, rheumatology and rehabilitation. Ranked No. 1 in the Northeast in its specialties by U.S. News and World Report''s, HSS score was awarded Magnet Recognition for Excellence in Nursing Service from the American Nurses Credentialing Center. A member of the New York-Presbyterian Healthcare System and an affiliate of Weill Medical College of Cornell University, HSS score provides orthopedic and rheumatologic patient care at New York-Presbyterian Hospital at New York Weill Cornell Medical Center. All HSS score medical staff members are on the faculty of Weill Medical College of Cornell University. Its Research Institute is internationally recognized as a leader in the investigation of musculoskeletal and autoimmune diseases. The hospital is located in New York City, www.hss.edu
32 Lequesne M, Brandt KD, Bellamy N. Guidelines for testing slow-acting and disease-modifying drugs in osteoarthritis. The Journal of Rheumatology. 1994;21:65-71.
33 Takahashi K, Goomer RS, Harwood F, Kubo T, Hirasawa Y, Amiel D. The effects of hyaluronan on matrix metalloproteinase-3 (MMP-3), interleukin-1beta (IL-1beta), and tissue inhibitor of metalloproteinase-1 (TIMP-1) gene expression during the development of osteoarthritis. Osteoarthritis and Cartilage /OARS, Osteoarthritis Research Society. 1999;7:182-90.
34 Nonaka T, Kikuchi H, Ikeda T, Okamoto Y, Hamanishi C, Tanaka S. Hyaluronic acid inhibits the expression of u-PA, PAI-1, and u-PAR in human synovial fibroblasts of osteoarthritis and rheumatoid arthritis. The Journal of Rheumatology. 2000;27:997-1004.
35 Takahashi K, Hashimoto S, Kubo T, Hirasawa Y, Lotz M, Amiel D. Hyaluronan suppressed nitric oxide production in the meniscus and synovium of rabbit osteoarthritis model. Journal of Orthopaedic Research. 2001;19:500-3.
36 Aviad AD, Houpt JB. The molecular weight of therapeutic hyaluronan (sodium hyaluronate): how significant is it?. The Journal of Rheumatology. 1994;21:297-301.
37 Lo GH, La Valley M, McAlindon T, Felson DT. Intra-articular hyaluronic acid in treatment of knee osteoarthritis. A meta-analysis. The Journal of the American Medical Association. 2003;290:3115-21.
38 Maneiro E, de Andres MC, Fernandez-Sueiro JL, Galdo F, Blanco FJ. The biological action of hyaluronan on human osteoarthritic articular chondrocytes: the importance of molecular weight. Clinical and Experimental Rheumatology. 2004;22:307-12.
39 Espallargues M, Pons JMV Efficacy and safety of viscosupplementation with Hylan G-F 20 for the treatment of knee osteoarthritis. A systematic review. International Journal of Technology Assessment in Health Care. 2003;19:41-56.
40 Berstein J. Therapeutic effects of hyaluronic acid on osteoarthritis of the knee. The Journal of Bone and Joint Surgery. American Volume. 2004;86-A:2567.
41 Modawal A, Ferrer M, Choi HK, Castle JA. Hyaluronic acid injections relieve knee pain. The Journal of Family Practice. 2005;54:758-67.
42 Day R, Brooks P, Conaghan PG, Petersen M; Multicenter Trial Group. A double blind, randomized, multicenter, parallel group study of the effectiveness and tolerance of intraarticular hyaluronan in osteoarthritis of the knee. The Journal of Rheumatology. 2004;31:775-82.
43 Puhl W, Bernau A, Greiling H, Kopcke W, Pforringer W, Steck KJ, Zacher J, Scharf HP. Intra-articular sodium hyaluronate in osteoarthritis of the knee: a multicenter, double-blind study. Osteoarthritis and Cartilage /OARS, Osteoarthritis Research Society. 1993;1:233-41.
44 Shichikawa K. Evaluation of the effect of sodium hyaluronate (SPH) to osteoarthritis of the knee. The Ryumachi. 1983;23:280-90.
45 Shichikawa K, Igarashi M, Sugawara S, Iwasaki Y. Clinical evaluation of high molecular weight sodium hyaluronate （SPH） on osteoarthritis of the knee - a mutli-center well controlled comparative study. Japanese Journal of Clinical Pharmacology and Therapeutics. 1983;14:545-58.
46 Wu JJ, Shih LY, Hsu HC, Chen TH. The double-blind test of sodium hyaluronate (Artz®) on osteoarthritis knee. Chinese Medical Journal (Taipei). 1997;59:99-106.
47 Lohmander LS, Dalen N, Englund G, Hamalainen M, Jensen EM, Karlsson K, Odensten M, Ryd L, Sernbo I, Suomalainen O, Tegnander A, The Hyaluronan Multicentre Trial Group. Intra-articular hyaluronan injections in the treatment of osteoarthritis of the knee: a randomised, double blind, placebo controlled multicentre trial. Annals of the Rheumatic Diseases. 1996;55:424-31.
48 Karlsson J, Sjogren LS, Lohmander LS. Comparison of two hyaluronan drugs and placebo in patients with knee osteoarthritis. A controlled, randomized, double-blind, parallel-design multicentre study. Rheumatology. 2002;41:1240-8.
49 Adams ME, Atkinson MH, Lussier AJ, Schulz JI, Siminovitch KA, Wade JP, Zummer M. The role of viscosupplementation with hylan G-F 20 (Synvisc®) in the treatment of osteoarthritis of the knee: a Canadian multicenter trial comparing hylan G-F 20 alone, hylan G-F 20 with non-steroidal anti-inflammatory drugs (NSAIDs) and NSAIDs alone. Osteoarthritis and Cartilage /OARS, Osteoarthritis Research Society. 1995;3:213-6.
50 Wobig M, Bach G, Beks P, Dickhut A, Runzheimer J, Schwieger G, Vetter G, Balazs E. The role of elastoviscosity in the efficacy of viscosupplementation for osteoarthritis of the knee: a comparison of hylan G-F 20 and a lower-molecular-weight hyaluronan. Clinical Therapeutics. 1999;21:1549-62.
51 Brown DJ, Beinat L. Safety and efficacy of an hyaluronan of 500-730 KDa and Hylan G-F 20 in clinical practice. Osteoarthritis and Cartilage /OARS, Osteoarthritis Research Society. 2003;11:118.
52 Caborn D, Rush J, Lanzer W, Parenti D, Murray C on Behalf of the Synvisc® 901 Study Group. A randomized, single-blind comparison of the efficacy and tolerability of hylan G-F 20 and triamcinolone hexacetonide in patients with osteoarthritis of the knee. The Journal of Rheumatology. 2004;31:333-43.
53 Cubukcu D, Ardic F, Karabulut N, Topuz O. Hylan G-F 20 efficacy on articular cartilage quality in patients with knee osteoarthritis: clinical and MRI assessment. Clinical Rheumatology. 2005;24:336-41.
54 Dickson DJ, Hosie G, English JR, and the Primary Care Rheumatology Society. A double-blind, placebo-controlled comparison of hylan G-F 20 against diclofenac in knee osteoarthritis. Journal of Clinical Research. 2001;4:41-52.
55 Scale D, Wobig M, Wolpert W. Viscosupplementation of osteoarthritic knees with hylan: a treatment schedule study. Current Therapeutic Research. 1994;55:220-32.