研究目的：
本研究的目的在探討服藥與否及服用Bisphosphonate與Raloxifene類藥物的骨質疏鬆病患，其在不良反應與醫療資源利用的情形。

研究方法：
本研究是使用國家衛生研究院全民健康保險資料庫2007年至2012年之資料的回顧性研究。個案組為有接受藥物治療（Bisphosphonate和Raloxifene）之骨質疏鬆症的病患，對照組為未接受藥物治療的骨質疏鬆症病患。此外使用傾向分數配對法（PSM）來控制樣本選擇偏差。研究分析以描述性分析、邏輯斯迴歸和線性迴歸來進行數據分析，探討病人基本資料與其不良反應和醫療資源利用情形。

研究結果：
共有2946例患者納入我們的分析。個案組（N = 1022）和對照組（N = 1924）依年齡和Charlson合併指數（CCI）配對。使用藥物治療與否與骨折和中風的風險增加有顯著相關（p <0.05）。不同的服藥者也與骨折風險增加顯著相關（p <0.05）。個案組的醫療資源利用情形皆高於對照組。而除了住院部分外，服用Bisphosphonate之病患其醫療資源利用情形上也高於服用Raloxifene之病患。

研究結論：
本研究結果顯示服用Raloxifene藥物之病患產生骨折、冠心病、中風及死亡的風險都較服用Bisphosphonate藥物之病患低，而服用Bisphosphonate藥物之病患產生心房顫動或撲動及靜脈血栓栓塞的風險則較服用Raloxifene藥物之病患低；然而，上述皆無達顯著性相關。使用藥物治療需謹慎，也須注意病患服藥後有無產生不良反應。

Objectives：
The purpose of this study is to explore the issue of drug treatment and to compare adverse drug reaction and healthcare utilizations between Bisphosphonate and Raloxifene on Osteoporosis women.

Method：
This study is a retrospective study using the National Health Insurance Database. The study periods were from 2007 to 2012. Patients who received drug treatment (Bisphosphonate and Raloxifene) for osteoporosis were in the case group, and those who did not receive treatment were in the control group. We used the Propensity Score Matching Method (PSM) to control the sample selection bias. The data analysis was carried out in descriptive analyses, multivariate logistic regressions, and multiple linear regressions to examine patients’ basic information, adverse drug reaction and healthcare utilizations.

Results：
A total of 2946 patients were included in our analysis. The case group (N=1022) and control group (N=1924) were matched 1:2 in terms of age and the Charlson Comorbidity Index (CCI). Drug treatment was associated with a significant increased risk of fractures and CVA (p<0.05). Different drug users were also linked with a significant increased risk of fractures. The healthcare utilization was higher in the case group than in the control group. In addition to hospitalization, the healthcare utilization was also higher in Bisphosphonate group than in Raloxifene group.

Conclusion：
Patients receiving treatment with Raloxifene may have a lower risk of fractures, CHD, CVA and mortality than those treated with Bisphosphonate, while patients receiving treatment with Bisphosphonate may have a lower risk of AF and VTE. However, statistical significance was not reached. Medication should be administered with caution and the importance of adverse reactions to different drug users cannot be overemphasized.

論文審定書 i
致謝 ii
中文摘要 iii
Abstract iv
目錄 v
圖次 vi
表次 vii
第一章 緒論 1
第一節 研究背景與動機 1
第二節 研究目的 3
第二章 文獻探討 4
第一節 骨質疏鬆症定義與測量 4
第二節 骨質疏鬆症治療藥品 8
第三節 骨質疏鬆症治療與不良反應之探討 11
第四節 骨質疏鬆症治療與醫療資源利用之探討 18
第五節 文獻小結 19
第三章 研究方法 20
第一節 研究設計與架構 20
第二節 研究問題與假設 22
第三節 研究樣本及資料來源 23
第四節 研究變項操作型定義 29
第五節 研究分析工具及方法 31
第四章 研究分析與結果 32
第一節 描述性統計分析 32
第二節 推論性統計分析 50
第五章 研究討論 100
第一節 研究假設驗證 100
第二節 研究結果討論 103
第六章 結論與建議 106
第一節 研究結論 106
第二節 研究限制 107
第三節 研究建議 109
第四節 研究貢獻 110
參考文獻 111

一、中文文獻
中華民國骨質疏鬆症學會(2015)。2015台灣成人骨質疏鬆症防治之共識及指引。2015年5月5日取自：http://familyxms.hosp.ncku.edu.tw/xms/content/show.php?id=10416
行政院衛生署國民健康局(2011)。骨質疏鬆症臨床治療指引。2016年11月1日取自：http://health99.hpa.gov.tw/EducZone/edu_detail.aspx?CatId=21709
余傑明、吳岱穎、楊榮森、廖振焜、樓亞洲、陳建志(2012)。骨質疏鬆的藥物治療。臺灣老年醫學暨老年學雜誌，7(2)，77-90。
李敏瑋(2012)。台灣骨質疏鬆性骨折中老年病患之醫療資源使用情形與探討。國立中山大學醫務管理碩士學位學程碩士論文，未出版，高雄市。
吳至行(2013)。男性骨質疏鬆症。臺灣醫學，17(5)，502-509。
林詩淳、辜美安、陳妙文、蔡坤維（2013）。老年人骨質疏鬆症之預防及護理。志為護理-慈濟護理雜誌，12(4)，58-62。
洪國欽、徐仁熙、侯君正、翁志仁、莊天華、楊麗琼、盧國城(2015)。心血管疾病之骨質流失。內科學誌，26(2)，77-87。doi：10.6314/JIMT.2015.26(2).03
陳子和(2013)。骨質疏鬆症與婦女。血管醫學防治季刊，14，12-13。doi：10.6527/PVM.2013.14.6
楊南屏、楊榮森、周碧瑟(2008)。提早因應高齡化社會的特殊醫療保健需求：以骨質疏鬆症為例。台灣衛誌，27(3) 181-197。
蔡嘉仁、陳榮福（2013）。骨質疏鬆症的藥物治療。臺灣醫學，17(5) ，510-516。
衛生福利部中央健康保險署(2010)。骨質疏少症亦可得到健保給付。2016年11月1日取自：http://www.nhi.gov.tw/information/NewsDetail.aspx?menu=&menu_id=&wd_id=&No=898
衛生福利部國民健康署(2013)。更年期後女性 每4人有1人骨質疏鬆-IOF指出女性過了更年期後，每3位就有1位可能因骨質疏鬆症而骨折。2016年5月30日取自：http://www.hpa.gov.tw/Bhpnet/Web/News/News.aspx?no=201310200001
衛生福利部中央健康保險署(2016)。全民健康保險藥物給付項目及支付標準之藥品給付規定。2016年5月30日取自：http://www.nhi.gov.tw/webdata/webdata.aspx?menu=21&menu_id=713&WD_ID=849&webdata_id=2919
衛生福利部中央健康保險署(2016)。全民健康保險醫院醫療費用審查注意事項。2016年6月13日取自：http://www.nhi.gov.tw/webdata/webdata.aspx?menu=20&menu_id=710&WD_ID=813&webdata_id=3919
衛生福利部食品藥物管理署(2016)。公告「含雙磷酸鹽類成分藥品之藥品風險管理計畫書」。2016年11月20日取自：http://www.fda.gov.tw/TC/newsContent.aspx?id=21420&chk=7f6463fa-1104-4055-b93c-cd66a1b90df2&param=pn&cid=3&cchk=46552e96-810a-42c3-83e1-bd5e42344633#.WDCF8vl97IU
賴韋如、林藍萍、林金定(2015)。醫療照顧人員對骨質疏鬆症認知情形：文獻回顧分析。身心障礙研究季刊，13(3)，188-196。
譯碼簿。全民健康保險研究資料庫。2014年12月29日取自：http://nhird.nhri.org.tw/date_02.html



二、英文文獻
Barrett-Connor, E., Mosca, L., Collins, P., Geiger, M.J., Grady, D., Kornitzer, M., McNabb, M.A., Wenger, N.K. & Raloxifene Use for The Heart (RUTH) Trial Investigators(2006). Effects of raloxifene on cardiovascular events and breast cancer in postmenopausal women. The New England Journal of Medicine, 355(2), 125-137.
Bauer, D.C., Glüter, C.C., & Cauley, J.A.(1997). Ultrasonographic attenuation predicted fractures in older women. American College of Physicians Journal Club,127,42.
Bauer, D.C., Palermo, L., & Black, D.(2002).Quantitative ultrasound and mortality: a prospective study. Osteoporosis International,13,606-612.
Bergland, A.,& Wyller, T.B.(2004).Risk factors for serious fall related injury in elderly women living at home. Injury Prevention,10,308-313.
Black, D.M., Cummings, S.R., Karpf, D.B., Cauley, J.A., Thompson, D.E., Nevitt, M.C., Bauer, D.C., Genant, H.K., Haskell, W.L., Marcus, R., Ott, S.M., Torner, J.C., Quandt, S.A., Reiss, T.F., & Ensrud, K.E. (1996). Randomised trial of effect of alendronate on risk of fracture in women with existing vertebral fractures. Fracture Intervention Trial Research Group. The Lancet, 348, 1535-1541.
Black, D.M., Delmas, P.D., Eastell, R., Reid, I.R., Boonen, S., Cauley, J.A., Cosman, F., Lakatos, P., Leung, P.C., Man, Z., Mautalen, C., Mesenbrink, P., Hu, H., Caminis, J., Tong, K., Rosario-Jansen, T., Krasnow, J., Hue, T.F., Sellmeyer, D., Eriksen, E.F., Cummings, S.R. & HORIZON Pivotal Fracture Trial. (2007) Once-yearly zoledronic acid for treatment of postmenopausal osteoporosis. The New England Journal of Medicine, 356(18), 1809-1822.
Cauley, J., Norton, L., Lippman, M.E., Eckert, S., Krueger, K.A., Purdie, D.W., Farrerons, J., Karasik, A., Mellstrom, D., Ng, K.W., Stepan, J.J., Powles, T.J., Morrow, M., Costa, A., Silfen, S.L., Walls, E.L., Schmitt, H., Muchmore, D.B., Jordan, V.C., & Ste-Marie, L.G.( 2001). Continued breast cancer risk reduction in postmenopausal women treated with raloxifene: 4- year results from the more trial. Breast Cancer Research and Treatment, 65(2), 125-134.
Chen, S.J., Lin, C.S., Lin, C.L., & Kao, C.H.(2015). Osteoporosis Is Associated With High Risk for Coronary Heart Disease: A Population-Based Cohort Study. Medicine, 94(27).doi:10.1097/MD.0000000000001146.
Chesnut III, C.H., Skag, A., Christiansen, C., Recker, R., Stakkestad, J.A., Hoiseth, A., Felsenberg, D., Huss, H., Gilbride, J., Schimmer, R.C., Delmas, P.D. & Oral Ibandronate Osteoporosis Vertebral Fracture Trial in North America and Europe (BONE) (2004). Effects of oral ibandronate administered daily or intermittently on fracture risk in postmenopausal osteoporosis. Journal of Bone and Mineral Research,19, 1241-1249.
Chie, W.C., Yang, R.S., Liu, J.P., & Tsai, K.S. (2004). High incidence rate of hip fracture in Taiwan estimated　from a nationwide health insurance database. Osteoporosis International, 15(12), 998-1002.
Cohen, F.J., & Lu,Y.(2000). Characterization of hot flashes reported by healthy postmenopausal women receiving raloxifene or placebo during osteoporosis prevention trials. Maturitas, 34(1), 65-73.
Cooper, C., Atkinson, E.J., Jacobsen, S.J., O’Fallon, W.M., & Melton, L.J. (1993). Population-based study of survival after osteoporotic fractures. American Journal of Epidemiology,137(9), 1001-1005.
Cummings, S.R., Black, D.M., Thompson, D.E., Applegate, W.B., Barrett-Connor, E., Musliner, T.A., Palermo, L., Prineas, R., Rubin, S.M., Scott, J.C., Vogt, T., Wallace, R., Yates, A.J., & LaCroix, A.Z. (1998). Effect of alendronate on risk of fracture in women with low bone density but without vertebral fractures: results from the Fracture Intervention Trial. The Journal of the American Medical Association, 280, 2077-2082.
Cummings, S.R., & Melton, L.J.(2002). Epidemiology and outcomes of osteoporotic fractures. The Lancet,359(9319),1761-1767.
Cummings, S. & Multiple Outcomes of Raloxifene Evaluation Investigators. (2004). Safety and adverse effects associated with raloxifene: multiple outcomes of raloxifene evaluation. Obstet Gynecol.104(4), 837-844.Delmas, P.D., Bjarnason, N.H., Mitlak, B.H., Ravoux, A.C., Shah, A.S., Huster, W.J., Draper, M., & Christiansen, C. (1997). Effects of raloxifene on bone mineral density, serum cholesterol concentrations, and uterine endometrium in postmenopausal women. The New England Journal of Medicine, 337(23), 1641-1647.
Delmas, P.D., Ensrud, K.E., Adachi, J.D., Harper, K.D., Sarkar, S., Gennari, C., Reginster, J.Y., Pols, H.A., Recker, R.R., Harris, S.T., Wu, W., Genant, H.K., Black, D.M., Eastell, R. & Mulitple Outcomes of Raloxifene Evaluation Investigators. (2002). Efficacy of raloxifene on vertebral fracture risk reduction in postmenopausal women with osteoporosis: four-year results from a randomized clinical trial. The Journal of Clinical Endocrinology & Metabolism, 87(8), 3609-3617.
Duque, G., & Troen, B.R. (2008). Understanding the mechanisms of senile osteoporosis: new facts for major geriatric syndrome. Journal of the American Geriatrics Society, 56(5), 935-941. doi: 10.1111/j.1532-5415.2008.01764.x.
Eisman, J.A., Civitelli, R., Adami, S., Czerwinski, E., Recknor, C., Prince, R., Reginster, J.Y., Zaidi, M., Felsenberg, D., Hughes, C., Mairon, N., Masanauskaite, D., Reid, D.M., Delmas, P.D., & Recker, R.R. (2008). Efficacy and tolerability of intravenous ibandronate injections in postmenopausal osteoporosis: 2-year results from the DIVA study. The Journal of Rheumatology, 35, 488-497.
Foster, S.A., Foley, K.A., Meadows, E.S., Johnston, J.A., Wang, S., Pohl, G.M., & Long, S.R.(2008). Characteristics of patients initiating raloxifene compared to those initiating bisphosphonates. BioMed Central Women’s Health. 8(24). doi: 10.1186/1472-6874-8-24.
Grady, D., Ettinger, B., Moscarelli, E., Plouffe, L. Jr., Sarkar, S., Ciaccia, A., Ettinger, B., Black, D.M., Mitlak, B.H., Knickerbocker, R.K., Nickelsen, T., Genant, H.K., Christiansen, C., Delmas, P.D., Zanchetta, J.R., Stakkestad, J., Glüer, C.C., Krueger, K., Cohen, F.J., Eckert, S., Ensrud, K.E., Avioli, L.V., Lips, P., & Cummings, S.R. (1999). Reduction of vertebral fracture risk in postmenopausal women with osteoporosis treated with raloxifene: results from a 3-year randomized clinical trial. Multiple Outcomes of Raloxifene Evaluation (MORE) Investigators. The Journal of the American Medical Association, 282, 637-645.
Green, J., Czanner, G., Reeves, G., Watson, J., Wise, L., & Beral, V.(2010). Oral bisphosphonates and risk of cancer of oesophagus, stomach, and colorectum: case-control analysis within a UK primary care cohort. British Medical Journal, 341-c4444, doi: 10.1136/bmj.c4444.
Harris, S.T., Watts, N.B., Genant, H.K., McKeever, C.D., Hangartner, T., Keller, M., Chesnut, C.H. 3rd, Brown, J., Eriksen, E.F., Hoseyni, M.S., Axelrod, D.W., & Miller, P.D. (1999). Effects of risedronate treatment on vertebral and nonvertebral fractures in women with postmenopausal osteoporosis: a randomized controlled trial. Vertebral Efficacy with Risedronate Therapy (VERT) Study Group. The Journal of the American Medical Association, 282, 1344-1352.
Homik, J., Cranney, A., Shea, B., Tugwell, P., Wells, G.A., Adachi, J., & Suarez-Almazor, M.E. (2010). Bisphosphonates for steroid induced osteoporosis. Cochrane Database of Systematic Reviews Issue 7
Hough, F.S., Brown, S.L., Cassim, B., Davey, M.R., de Lange, W., de Villiers, T.J., Ellis, G.C., Lipschitz, S., Lukhele, M., & Pettifor, J.M.(2014). National Osteoporosis Foundation of South Africa. South African Medical Journal. 104(4), 279-282.
Huang, W.F., Tsai, Y.W., Wen, Y.W., Hsiao, F.Y., Kuo, K.N., & Tsai, C.R.(2010).Osteoporosis treatment and atrial fibrillation: alendronate versus raloxifene. Menopause.17(1), 57-63. doi: 10.1097/gme.0b013e3181b34749.
Kim, S.Y., Kim, M.T., Cadarette, S.M., & Solomon, D.H.(2010). Bisphosphonates and risk of atrial fibrillation: a meta-analysis. Arthritis Research & Therapy.12(1): R30. doi: 10.1186/ar2938.
Kim, J., Shin, J.Y., Lee, J., Song, H.J., Choi, N.K., & Park, B.J.(2015). Comparison of the prescribing pattern of bisphosphonate and raloxifene in Korean women with osteoporosis: from a national health insurance claims database. PLoS One, 10(6). doi: 10.1371/journal.pone.0127970.
Khan, A.A., Sándor, G.K., Dore, E., Morrison, A.D., Alsahli, M., Amin, F., Peters, E., Hanley, D.A., Chaudry, S.R., Lentle, B., Dempster, D.W., Glorieux, F.H., Neville, A.J., Talwar, R.M., Clokie, C.M., Mardini, M.A., Paul, T., Khosla, S., Josse, R.G., Sutherland, S., Lam, D.K., Carmichael, R.P., Blanas, N., Kendler, D., Petak, S., Ste-Marie, L.G., Brown, J., Evans, A.W., Rios, L., Compston ,J.E. & Canadian Taskforce on Osteonecrosis of the Jaw (2009). Bisphosphonate associated osteonecrosis of the jaw. The Journal of Rheumatology, 36, 478-490
Khosla, S., & Riggs, B.L. (2005). Pathophysiology of age-related bone loss and osteoporosis. Endocrinology Metabolism Clinics of North America, 34(4), 1015-1030.
Lips, P., Cooper, C., Agnusdei, D., Caulin, F., Egger, P., Johnell, O., Kanis, J.A., Kellingray, S., Leplege, A., Liberman, U.A., McCloskey, E., Minne, H., Reeve, J., Reginster, J.Y., Scholz, M., Todd, C., de Vernejoul, M.C., & Wiklund, I. (1999). Quality of life in patients with vertebral fractures: validation of the Quality of Life Questionnaire of the European Foundation for Osteoporosis (QUALEFFO). Osteoporosis International, 10(2), 150-160.
Loke, Y.K., Jeevanantham, V., & Singh, S.(2009). Bisphosphonates and atrial fibrillation: systematic review and meta-analysis. Drug Safety. 32(3), 219-228. doi: 10.2165/00002018-200932030-00004.
Lyles, K.W., Colón-Emeric, C.S., Magaziner, J.S., Adachi, J.D., Pieper, C.F., Mautalen, C., Hyldstrup, L., Recknor, C., Nordsletten, L., Moore, K.A., Lavecchia, C., Zhang, J., Mesenbrink, P., Hodgson, P.K., Abrams, K., Orloff, J.J., Horowitz, Z., Eriksen, E.F., Boonen, S. & HORIZON RecurrentFracture Trial (2007). Zoledronic acid and clinical fractures and mortality after hip fracture. The New England Journal of Medicine, 357, 1799-1809.
Marx, R.E.(2003). Pamidronate (Aredia) and zoledronate (Zometa) induced avascular necrosis of the jaws: a growing epidemic. Journal of Oral and Maxillofacial Surgery.61(9), 1238-1239.
McClung, M.R., Geusens, P., Miller, P.D., Zippel, H., Bensen, W.G., Roux, C., Adami, S., Fogelman, I., Diamond, T., Eastell, R., Meunier, P.J., Reginster, J.Y. & Hip Intervention Program Study Group (2001). Effect of risedronate on the risk of hip fracture in elderly women. Hip Intervention Program Study Group. The New England Journal of Medicine, 344, 333-340.
Mosca, L.(2001). Rationale and overview of the Raloxifene Use for the Heart (RUTH) trial. Annals of the New York Academy of Sciences, 949,181-185.
Mosca, L., Grady, D., Barrett-Connor, E., Collins, P., Wenger, N., Abramson, B.L., Paganini-Hill, A., Geiger, M.J., Dowsett, S.A., Amewou-Atisso, M., & Kornitzer, M.(2009). Effect of raloxifene on stroke and venous thromboembolism according to subgroups in postmenopausal women at increased risk of coronary heart disease. Stroke, 40(1),147-55. doi: 10.1161/STROKEAHA.108.518621.
NIH Osteoporosis and Related Bone Diseases ~ National Resource Center (2015).Osteoporosis and Asian American Women.2016年5月30日取自： http://www.niams.nih.gov/Health_Info/Bone/Osteoporosis/Background/asian_american_women.asp
Orsini, L.S., Rousculp, M.D., Long, S.R., & Wang,S.(2005). Health care utilization and expenditures in the United States: a study of osteoporosis related fractures. Osteoporosis International, 16(4),359-371.
O'Donnell, S., Cranney, A., Wells, G.A., Adachi, J.D., & Reginster, J.Y.(2006).Strontium ranelate for preventing and treating postmenopausal osteoporosis. Cochrane Database Systemic Reviews,18(4),CD005326.
Reginster, J., Minne, H.W., Sorensen, O.H., Hooper, M., Roux, C., Brandi, M.L., Lund, B., Ethgen, D., Pack, S., Roumagnac, I., & Eastell, R. (2000). Randomized trial of the effects of risedronate on vertebral fractures in women with established postmenopausal osteoporosis.Vertebral Efficacy with Risedronate Therapy (VERT) Study Group. Osteoporosis International, 11, 83-91
Silverman, S.L., & Landesberg, R. (2009). Osteonecrosis of the jaw and the role of bisphosphonates: a critical review. American Journal of Medicine, 122, 33-45
Su, F.M., Chen, Y.C., Cheng, T.T., Lin, W.C., & Lui, C.C.(2015).Is raloxifene associated with lower risk of mortality in postmenopausal women with vertebral fractures after vertebroplasty? a hospital-based analysis. BioMed Central Musculoskelet Disord, 16(209) .doi: 10.1186/s12891-015-0670-7.
Urushihara, H., Kikuchi, N., Yamada, M., Yoshiki, F., & Miyauchi, A. (2009). Raloxifene and stroke risks in Japanese postmenopausal women with osteoporosis on postmarketing surveillance. Menopause, 16(5), 971-977. doi: 10.1097/gme.0b013e3181a15622.
Wells, G.A., Cranney, A., Peterson, J., Boucher, M., Shea, B., Welch, V., Coyle, D., & Tugwell, P. (2010). Alendronate for the primary and secondary prevention of osteoporotic fractures in postmenopausal women. Cochrane Database of Systematic Reviews Issue 7 .