進階搜尋


   電子論文尚未授權公開,紙本請查館藏目錄
(※如查詢不到或館藏狀況顯示「閉架不公開」,表示該本論文不在書庫,無法取用。)
系統識別號 U0026-0708201912284400
論文名稱(中文) 台灣停經後婦女骨質疏鬆症之骨折風險評估 – 比較雙磷酸鹽持續使用者與轉換為denosumab者之效果
論文名稱(英文) Fractures among postmenopausal women with osteoporosis in Taiwan – A head-to-head comparison between patients continuing on bisphosphonates vs transitioning to denosumab
校院名稱 成功大學
系所名稱(中) 臨床藥學與藥物科技研究所
系所名稱(英) Institute of Clinical Pharmacy and Pharmaceutical sciences
學年度 107
學期 2
出版年 108
研究生(中文) 葉品岑
研究生(英文) Pin-Tsen Yeh
學號 S66064026
學位類別 碩士
語文別 英文
論文頁數 66頁
口試委員 指導教授-高雅慧
指導教授-賴嘉鎮
口試委員-楊俊佑
口試委員-張志偉
中文關鍵字 停經後婦女  骨質疏鬆症  骨折風險  雙磷酸鹽  denosumab 
英文關鍵字 postmenopausal women  osteoporosis  fracture risk  bisphosphonates  denosumab 
學科別分類
中文摘要 研究背景:骨質疏鬆症為流行病學的重大議題之一。目前臨床試驗結果顯示,停經後婦女轉換為denosumab比起持續使用雙磷酸鹽更能增加骨質密度,然而,關於兩組病患的骨折風險尚未被確定。

研究目的: 本研究之目的為評估台灣停經後並患有骨質疏鬆症之婦女持續使用雙磷酸鹽類與轉換為denosumab之骨折風險。

研究方法: 本研究採用回溯性世代研究,資料來源為2005-2015之健保資料。研究對象為55歲(含)以上停經後患有骨質疏鬆症之婦女,我們從中挑選從雙磷酸鹽轉換為denosumab使用的病患,並以轉換日前後三十天為區間進行配對,挑選出持續使用雙磷酸鹽之對照組,比較兩組在一年觀察期間內發生髖骨骨折、脊椎骨骨折以及其他部位骨折(手腕及肱骨)之風險。本研究使用多變項Cox比例風險模型校正相關之共變數及評估相對危險比。

研究結果: 本研究總共收錄了24,730名病患,兩組人數各為12,365名。雙磷酸鹽組與denosumab組的平均年齡分別為78.4歲(SD 7.1)和79.0歲(SD 7.0)。研究發現,在一年的觀察期間,denosumab與雙磷酸鹽相比,髖骨骨折風險(adjusted HR, 0.39; 95% CI, 0.30-0.51)與脊椎骨骨折風險 (0.67; 0.56-0.81)皆較低。而兩組在其他骨折之危險比並無顯著差異 (0.90; 0.60-1.35)。

結論: 研究結果指出,轉換為denosumab對於降低停經後婦女骨質疏鬆症之骨折風險能夠提供良好的效果。
英文摘要 Osteoporosis is a silent disease with increasing prevalence due to aging population. Randomized clinical trial demonstrated that patients transitioned to denosumab had better results of bone mineral density compared to patients continued on alendronate. However, risk profiles of fractures between groups remained uncertain. We conducted a retrospective cohort study using the Taiwan’s National Health Insurance Database (NHID) from 2005-2015. Study population consisted of postmenopausal women aged over 55 years diagnosed with osteoporosis. We selected patients who transitioned from bisphosphonates to denosumab, and matched patients continued on bisphosphonates with 30 days before and after the cohort entry. We compared the risk of hospitalization due to hip fracture, vertebral fracture and other fractures, including wrist or humerus fractures between two groups. We performed Cox proportional hazard model with adjustment of covariates including age, history of fractures, history of comorbidities and medication use to compare fracture risk between groups. We included a total of 12,365 patients transitioning to denosumab and matched to 12,365 patients continuing on bisphosphonates. We found patients transitioning to denosumab posed lower risk of hip fracture (adjusted HR, 0.39; 95% CI, 0.30-0.51) and vertebral fracture (0.67; 0.56-0.81). Compared with patients continuing on bisphosphonates, the risk of other fractures was similar between groups (0.90; 0.60-1.35). The findings indicated transitioning to denosumab might provide favorable profile in fracture risk in postmenopausal women with osteoporosis.
論文目次 摘要 i
誌謝 vi
CONTENTS viii
LIST OF FIGURES xi
LIST OF TABLES xii
Chapter 1 BACKGROUND INFORMATION 1
1.1 Introduction of osteoporosis 1
1.1.1 Definition and diagnosis criteria 1
1.1.2 Pathophysiology 2
Chapter 2 RELEVANT LITERATURE 4
2.1 Epidemiology of osteoporosis in Taiwan 4
2.2 Pharmacological treatment of osteoporosis 4
2.2.1 Mechanism of denosumab 5
2.2.2 Mechanism of bisphosphonates 5
2.2.3 Literature of comparing fracture risk between patients continuing on bisphosphonates or transitioning to denosumab 6
2.3 Insurance policy of anti-osteoporotic agents in Taiwan 6
Chapter 3 STUDY OBJECTIVES AND CLINICAL RELEVANCE 8
3.1 Study objective and aims 8
3.2 Clinical relevance 8
Chapter 4 STUDY METHOD 10
4.1 Study design 10
4.2 Data sources 10
4.3 Study population and Exposure 10
4.4 Outcome assessment 12
4.5 Study duration and follow-up 13
4.5.1 Wash out period 13
4.5.2 Observation period 13
4.5.3 Censored point 13
4.6 Analytic covariates and definition 14
4.7 Study scheme 16
4.8 Statistical analysis 16
4.9 Sensitivity analysis 17
4.10 Subgroup analysis 17
4.11 External validation study 18
Chapter 5 RESULTS 20
5.1 Cohort characteristics 20
5.2 Primary endpoint: Hip fracture 25
5.3 Secondary endpoints: Vertebral and Other fractures 25
5.4 Sensitivity analysis 25
5.5 Subgroup analysis 26
5.6 External validation analysis 26
Chapter 6 DISCUSSION 30
6.1 Baseline characteristics of study population 30
6.2 Incidence rate of fractures 31
6.3 Fracture risk between bisphosphonates and denosumab 32
6.4 Fracture risk in a washout period extended from 90 days to 180 days 33
6.5 Fracture risk between intravenous (IV) bisphosphonates and denosumab 34
6.6 Fracture risk in patients with previous hip fracture 36
6.7 Unmeasured confounders in claims data 37
6.8 Limitation 37
Chapter 7 FUTURE DIRECTION 39
Chapter 8 CONCLUSION 40
Chapter 9 臨床藥事服務 - 12C病房臨床藥師 41
9.1 服務緣起 41
9.2 服務內容 41
9.3 服務成果與病房特色 42
9.4 建議與未來方向 43
9.4.1 病房照護 43
9.4.2 生物製劑事前審查 45
9.5 感想與反思 46
REFERENCE 48
APPENDIX I Flow chart of study population selection in NHIS 55
APPENDIX II Baseline Characteristics of Study Population in NHIS 56
參考文獻 1. Trombetti A, Herrmann F, Hoffmeyer P, Schurch MA, Bonjour JP, Rizzoli R. Survival and potential years of life lost after hip fracture in men and age-matched women. Osteoporos Int. 2002;13(9):731-737.

2. Lin KB, Yang NP, Lee YH, et al. The incidence and factors of hip fractures and subsequent morbidity in Taiwan: An 11-year population-based cohort study. PLoS One. 2018;13(2):e0192388.

3. Singer A, Exuzides A, Spangler L, et al. Burden of illness for osteoporotic fractures compared with other serious diseases among postmenopausal women in the United States. Mayo Clin Proc. 2015;90(1):53-62.

4. Keen RW. Burden of osteoporosis and fractures. Current osteoporosis reports. 2003;1(2):66-70.

5. Osteoporosis prevention, diagnosis, and therapy. JAMA. 2001;285(6):785-795.

6. Compston J. Bone quality: what is it and how is it measured? Arq Bras Endocrinol Metabol. 2006;50(4):579-585.

7. Kanis JA, McCloskey EV, Johansson H, Cooper C, Rizzoli R, Reginster JY. European guidance for the diagnosis and management of osteoporosis in postmenopausal women. Osteoporos Int. 2013;24(1):23-57.

8. Assessment of fracture risk and its application to screening for postmenopausal osteoporosis. Report of a WHO Study Group. World Health Organ Tech Rep Ser. 1994;843:1-129.

9. Looker AC, Orwoll ES, Johnston CC, Jr., et al. Prevalence of low femoral bone density in older U.S. adults from NHANES III. J Bone Miner Res. 1997;12(11):1761-1768.

10. Kelly T. Bone mineral density reference databases for American men and women. J Bone Miner Res. 1990;5(2):249.

11. Kanis JA, McCloskey EV, Johansson H, Oden A, Melton LJ, 3rd, Khaltaev N. A reference standard for the description of osteoporosis. Bone. 2008;42(3):467-475.

12. Feng X, McDonald JM. Disorders of bone remodeling. Annu Rev Pathol. 2011;6:121-145.

13. Hadjidakis DJ, Androulakis, II. Bone remodeling. Ann N Y Acad Sci. 2006;1092:385-396.

14. Dobbs MB, Buckwalter J, Saltzman C. Osteoporosis: the increasing role of the orthopaedist. The Iowa orthopaedic journal. 1999;19:43.
15. Cooper C, Melton LJ, 3rd. Epidemiology of osteoporosis. Trends Endocrinol Metab. 1992;3(6):224-229.

16. Wu TY, Hu HY, Lin SY, Chie WC, Yang RS, Liaw CK. Trends in hip fracture rates in Taiwan: a nationwide study from 1996 to 2010. Osteoporos Int. 2017;28(2):653-665.

17. Curtis EM, Moon RJ, Harvey NC, Cooper C. The impact of fragility fracture and approaches to osteoporosis risk assessment worldwide. Bone. 2017;104:29-38.

18. Chie WC, Yang RS, Liu JP, Tsai KS. High incidence rate of hip fracture in Taiwan: estimated from a nationwide health insurance database. Osteoporos Int. 2004;15(12):998-1002.

19. Pavone V, Testa G, Giardina SMC, Vescio A, Restivo DA, Sessa G. Pharmacological Therapy of Osteoporosis: A Systematic Current Review of Literature. Front Pharmacol. 2017;8:803.

20. FDA approves new treatment for osteoporosis in postmenopausal women at high risk of fracture. 2019.

21. Boyle WJ, Simonet WS, Lacey DL. Osteoclast differentiation and activation. Nature. 2003;423(6937):337-342.

22. Delmas PD. Clinical potential of RANKL inhibition for the management of postmenopausal osteoporosis and other metabolic bone diseases. J Clin Densitom. 2008;11(2):325-338.

23. Dunford JE. Molecular targets of the nitrogen containing bisphosphonates: the molecular pharmacology of prenyl synthase inhibition. Curr Pharm Des. 2010;16(27):2961-2969.

24. Lin T, Wang C, Cai XZ, et al. Comparison of clinical efficacy and safety between denosumab and alendronate in postmenopausal women with osteoporosis: a meta-analysis. Int J Clin Pract. 2012;66(4):399-408.

25. Wu J, Zhang Q, Yan G, Jin X. Denosumab compared to bisphosphonates to treat postmenopausal osteoporosis: a meta-analysis. J Orthop Surg Res. 2018;13(1):194.

26. Brown JP, Prince RL, Deal C, et al. Comparison of the effect of denosumab and alendronate on BMD and biochemical markers of bone turnover in postmenopausal women with low bone mass: a randomized, blinded, phase 3 trial. J Bone Miner Res. 2009;24(1):153-161.

27. Kendler DL, Roux C, Benhamou CL, et al. Effects of denosumab on bone mineral density and bone turnover in postmenopausal women transitioning from alendronate therapy. J Bone Miner Res. 2010;25(1):72-81.


28. UK: NICE Pathway – Osteoporosis overview. https://pathways.nice.org.uk/pathways/osteoporosis. Accessed 4/9, 2019.

29. CADTH CANADIAN DRUG EXPERT COMMITTEE FINAL RECOMMENDATION-Common Drug Review: Denosumab. 2016; https://www.cadth.ca/sites/default/files/cdr/complete/SF0453_complete_RFA-Prolia_May-25-16_e.pdf. Accessed 4/9, 2019.

30. Osteoporosis Australia-Medical guide. 2014; https://www.osteoporosis.org.au/sites/default/files/files/oa_medical_medicine_2nd_ed.pdf. Accessed 4/9, 2019.

31. 全民健康保險藥物給付項目及支付標準第5.6 節 激素及影響內分泌機轉藥物.

32. Palacios S, Kalouche-Khalil L, Rizzoli R, et al. Treatment with denosumab reduces secondary fracture risk in women with postmenopausal osteoporosis. Climacteric. 2015;18(6):805-812.

33. Wells GA, Cranney A, Peterson J, et al. Alendronate for the primary and secondary prevention of osteoporotic fractures in postmenopausal women. The Cochrane database of systematic reviews. 2008(1):Cd001155.

34. Wells G, Cranney A, Peterson J, et al. Risedronate for the primary and secondary prevention of osteoporotic fractures in postmenopausal women. The Cochrane database of systematic reviews. 2008(1):Cd004523.

35. Saito T, Sterbenz JM, Malay S, Zhong L, MacEachern MP, Chung KC. Effectiveness of anti-osteoporotic drugs to prevent secondary fragility fractures: systematic review and meta-analysis. Osteoporos Int. 2017;28(12):3289-3300.

36. NATIONAL INSTITUTE FOR CLINICAL EXCELLENCE - Final Appraisal Determination: Bisphosphonates, selective oestrogen receptor modulators and parathyroid hormone for secondary prevention of osteoporotic fragility fractures. July 2004.

37. National Institute for health and Care ExcellenceTA204. https://www.nice.org.uk/guidance/ta204. Accessed 6/12, 2019.

38. Solomon DH, Avorn J, Katz JN, et al. Compliance with osteoporosis medications. Arch Intern Med. 2005;165(20):2414-2419.

39. National Health Insurance Administration, Ministry of Health and Welfare, Taiwan, R.O.C. (2014). National Health Insurance Annual Report 2014-2015.

40. 台灣更年期醫學會-衛教專區.


41. Chang C, Chow SN, Hu Y. Age of menopause of Chinese women in Taiwan. Int J Gynaecol Obstet. 1995;49(2):191-192.

42. Lindsay R, Silverman SL, Cooper C, et al. Risk of new vertebral fracture in the year following a fracture. JAMA. 2001;285(3):320-323.

43. van Geel TA, Huntjens KM, van den Bergh JP, Dinant GJ, Geusens PP. Timing of subsequent fractures after an initial fracture. Current osteoporosis reports. 2010;8(3):118-122.

44. Karl Wu C-HC, Rong-Sen Yang. Orthogeriatric Care and Treatment of Fragility Fractures in the Elderly Taiwan Geriatr Gerontol 2012; 7(2): 91-104. 2012.

45. Dennison EM, Compston JE, Flahive J, et al. Effect of co-morbidities on fracture risk: findings from the Global Longitudinal Study of Osteoporosis in Women (GLOW). Bone. 2012;50(6):1288-1293.

46. Mazziotti G, Canalis E, Giustina A. Drug-induced osteoporosis: mechanisms and clinical implications. Am J Med. 2010;123(10):877-884.

47. Ghosh M, Majumdar SR. Antihypertensive medications, bone mineral density, and fractures: a review of old cardiac drugs that provides new insights into osteoporosis. Endocrine. 2014;46(3):397-405.

48. National health interview survey (NHIS). https://www.hpa.gov.tw/Pages/Detail.aspx?nodeid=1077&pid=6198. Accessed 4/9, 2019.

49. Lin T-C. Investigation on Effectiveness and Safety of Osteoporosis Drugs in Taiwan. 2013.

50. Chen FP, Hsu KH, Fu TS, et al. Risk factor for first-incident hip fracture in Taiwanese postmenopausal women. Taiwan J Obstet Gynecol. 2016;55(2):258-262.

51. 衛生福利部統計處-國人高血壓之現況按性別及年齡. 2017; https://dep.mohw.gov.tw/DOS/cp-1720-7324-113.html. Accessed 6/19, 2019.

52. 衛生福利部統計處-國人高血脂之現況按性別及年齡. 2017; https://dep.mohw.gov.tw/DOS/cp-1720-7330-113.html. Accessed 6/19, 2019.

53. 衛生福利部統計處-國人糖尿病血症之現況按性別及年齡. 2017; https://dep.mohw.gov.tw/DOS/cp-1720-7326-113.html. Accessed 6/19, 2019.

54. Srikanth VK, Fryer JL, Zhai G, Winzenberg TM, Hosmer D, Jones G. A meta-analysis of sex differences prevalence, incidence and severity of osteoarthritis. Osteoarthritis Cartilage. 2005;13(9):769-781.


55. 林易申, 顏銘傭, 張耀文, et al. 台灣地區老年人使用玻尿酸注射液治療膝部退化性關節炎之回溯分析. 台灣家庭醫學雜誌. 2010;20(2):53-63.

56. Hart DJ, Mootoosamy I, Doyle DV, Spector TD. The relationship between osteoarthritis and osteoporosis in the general population: the Chingford Study. Ann Rheum Dis. 1994;53(3):158-162.

57. Nevitt MC, Lane NE, Scott JC, et al. Radiographic osteoarthritis of the hip and bone mineral density. The Study of Osteoporotic Fractures Research Group. Arthritis Rheum. 1995;38(7):907-916.

58. Rizou S, Chronopoulos E, Ballas M, Lyritis GP. Clinical manifestations of osteoarthritis in osteoporotic and osteopenic postmenopausal women. J Musculoskelet Neuronal Interact. 2018;18(2):208-214.

59. Bertoldi I, Frediani B. Osteoarthritis and osteoporosis: correlations between two clinical entities. Reumatismo. 2013;65(2):51-54.

60. Im GI, Kim MK. The relationship between osteoarthritis and osteoporosis. J Bone Miner Metab. 2014;32(2):101-109.

61. Pedersen AB, Heide-Jorgensen U, Sorensen HT, Prieto-Alhambra D, Ehrenstein V. Comparison of Risk of Osteoporotic Fracture in Denosumab vs Alendronate Treatment Within 3 Years of Initiation. JAMA network open. 2019;2(4):e192416.

62. Cummings SR, San Martin J, McClung MR, et al. Denosumab for prevention of fractures in postmenopausal women with osteoporosis. N Engl J Med. 2009;361(8):756-765.

63. Bilezikian JP, Lin CJF, Brown JP, et al. Long-term denosumab treatment restores cortical bone loss and reduces fracture risk at the forearm and humerus: analyses from the FREEDOM Extension cross-over group. Osteoporos Int. 2019.

64. Wei CJ, Tsai WC, Tiu CM, Wu HT, Chiou HJ, Chang CY. Systematic analysis of missed extremity fractures in emergency radiology. Acta Radiol. 2006;47(7):710-717.

65. Kung JW, Melenevsky Y, Hochman MG, et al. On-call musculoskeletal radiographs: discrepancy rates between radiology residents and musculoskeletal radiologists. AJR Am J Roentgenol. 2013;200(4):856-859.

66. Er E, Kara PH, Oyar O, Unluer EE. Overlooked extremity fractures in the emergency department. Ulus Travma Acil Cerrahi Derg. 2013;19(1):25-28.

67. Recknor C, Czerwinski E, Bone HG, et al. Denosumab compared with ibandronate in postmenopausal women previously treated with bisphosphonate therapy: a randomized open-label trial. Obstet Gynecol. 2013;121(6):1291-1299.

68. Miller PD, Pannacciulli N, Brown JP, et al. Denosumab or Zoledronic Acid in Postmenopausal Women With Osteoporosis Previously Treated With Oral Bisphosphonates. J Clin Endocrinol Metab. 2016;101(8):3163-3170.

69. Alexander LK, Lopes B, Ricchetti-Masterson K, Yeatts KB. Sources of systematic error or bias: information bias. ERIC Notebook 2nd ed Chapel Hill (NC): The University of North Carolina at Chapel Hill. 2015.

70. Wellek S, Blettner M. On the proper use of the crossover design in clinical trials: part 18 of a series on evaluation of scientific publications. Deutsches Arzteblatt international. 2012;109(15):276-281.

71. Li T, Yu T, Hawkins BS, Dickersin K. Design, Analysis, and Reporting of Crossover Trials for Inclusion in a Meta-Analysis. PLoS One. 2015;10(8):e0133023.

72. Kamimura M, Nakamura Y, Ikegami S, Uchiyama S, Kato H. Bisphosphonate Pre-Treatment Diminishes the Therapeutic Benefits of Teriparatide in Japanese Osteoporotic Patients. Tohoku J Exp Med. 2016;239(1):17-24.

73. Keel C, Kraenzlin ME, Kraenzlin CA, Muller B, Meier C. Impact of bisphosphonate wash-out prior to teriparatide therapy in clinical practice. J Bone Miner Metab. 2010;28(1):68-76.

74. Nakamura Y, Suzuki T, Kato H. Denosumab significantly improves bone mineral density with or without bisphosphonate pre-treatment in osteoporosis with rheumatoid arthritis : Denosumab improves bone mineral density in osteoporosis with rheumatoid arthritis. Archives of osteoporosis. 2017;12(1):80.

75. McClung MR, Lewiecki EM, Cohen SB, et al. Denosumab in postmenopausal women with low bone mineral density. N Engl J Med. 2006;354(8):821-831.

76. CHMP ASSESSMENT REPORT FOR Prolia. 2010.

77. Rabenda V, Mertens R, Fabri V, et al. Adherence to bisphosphonates therapy and hip fracture risk in osteoporotic women. Osteoporos Int. 2008;19(6):811-818.

78. Siris ES, Harris ST, Rosen CJ, et al. Adherence to bisphosphonate therapy and fracture rates in osteoporotic women: relationship to vertebral and nonvertebral fractures from 2 US claims databases. Mayo Clin Proc. 2006;81(8):1013-1022.

79. Huybrechts KF, Ishak KJ, Caro JJ. Assessment of compliance with osteoporosis treatment and its consequences in a managed care population. Bone. 2006;38(6):922-928.

80. Choi NK, Solomon DH, Tsacogianis TN, Landon JE, Song HJ, Kim SC. Comparative Safety and Effectiveness of Denosumab Versus Zoledronic Acid in Patients With Osteoporosis: A Cohort Study. J Bone Miner Res. 2017;32(3):611-617.
81. Freemantle N, Cooper C, Diez-Perez A, et al. Results of indirect and mixed treatment comparison of fracture efficacy for osteoporosis treatments: a meta-analysis. Osteoporos Int. 2013;24(1):209-217.

82. Kanis JA, Borgstrom F, De Laet C, et al. Assessment of fracture risk. Osteoporos Int. 2005;16(6):581-589.

83. Kanis JA. Diagnosis of osteoporosis and assessment of fracture risk. Lancet. 2002;359(9321):1929-1936.

84. Yoshida K, Solomon DH, Kim SC. Active-comparator design and new-user design in observational studies. Nat Rev Rheumatol. 2015;11(7):437-441.
論文全文使用權限
  • 同意授權校內瀏覽/列印電子全文服務,於2024-08-01起公開。
  • 同意授權校外瀏覽/列印電子全文服務,於2024-08-01起公開。


  • 如您有疑問,請聯絡圖書館
    聯絡電話:(06)2757575#65773
    聯絡E-mail:etds@email.ncku.edu.tw