骨質疏鬆症導致嚴重的疾病與醫療經濟負擔。隨著人口持續老化，此議題急需更多的探討與研究。而即使目前骨鬆的藥物治療相當有效與安全，世界各國的研究顯示仍有許多需要治療的族群並未確實接受藥物治療。此論文研究利用真實世界資料去估計台灣骨鬆的疾病負擔，探討未滿足之醫療需求，並針對治療族群，進一步探討骨鬆藥物適當起始治療時機對後續骨折事件的影響。

本研究利用台灣全民健康保險資料庫進行三階段性的研究分析。首先，我們利用橫斷性研究設計評估目前台灣骨鬆流行病學以及醫療經濟負擔。接著，在新發生主要骨鬆性骨折的族群中，我們分析這群病人在骨折後一年內處方抗骨鬆藥物的比例，並視覺化不同性別、年齡、骨折型態與地區之未滿足醫療需求。最後，在骨折後有開始使用抗骨鬆藥物的族群中，我們利用長期追蹤之世代研究，探討不同抗骨鬆藥物之起始治療時間，與抗骨鬆藥物之臨床療效的關係。

研究結果顯示，2013年，在台灣有253,565位女性與82,648位男性有被診斷為骨質疏鬆。而骨鬆與骨鬆性骨折的盛行率隨著年紀增長而增加，在80歲以上的族群中，有高於23%的人有骨鬆性骨折的診斷。而骨鬆性骨折所導致的直接醫療花費平均每人每年將近12萬台幣。骨鬆性骨折的族群平均年度醫療費用是一般族群的2-6倍。而骨折後族群的治療率相對偏低，且隨著性別年齡有所差異。從女性脊椎骨折後的32%治療率到男性的髖部骨折患者平均只有6%治療率。台灣的中南部縣市(彰化與嘉義)有較高的治療率，平均有30%的族群於骨折後使用抗骨鬆藥物。而在台灣，年紀增長，女性，脊椎骨折有較高的機率接受抗骨鬆藥物治療。

在骨折後使用抗骨鬆藥物的族群中，相較於骨折後15-84天內開始使用藥物的族群，骨折後252天之後才開始使用藥物的族群顯著增加後續骨折相關住院的風險。Hazard ratios (HR) = 1.93, 95% confidence intervals (CI) 1.29‒2.89)。值得注意的是，在抗骨鬆藥物的服藥順從性較佳的族群中，較晚用藥的族群所增加的後續骨折相關住院風險更加顯著(HR = 2.56 vs. 1.93)。本研究結果顯示，即使有相同的服藥順從性，適當的藥物起始治療時機仍是顯著的影響抗骨鬆藥物臨床療效。

本研究提供台灣骨質疏鬆症流行病學與相關疾病負擔之真實世界資料。在台灣，平均每十位經歷骨鬆性骨折的病患，只有三位在骨折後一年內接受抗骨鬆藥物治療。而當我們進一步考量適當起始治療時間對於抗骨鬆藥物的臨床療效時，只剩下不到兩位病人，能獲得抗骨鬆藥物的最佳治療效果。最後，此研究啟發了本人繼續相關研究以及臨床服務流程改善，期能協助政策制定者更適當地分配相關醫療資源，使骨質疏鬆族群的臨床照護能獲得真實的改善。

Osteoporosis incur substantial disease and healthcare cost. Despite the relative safe and effective treatment of osteoporosis, there are treatment gaps of osteoporosis existed worldwide. This study aims to provide real-world updated evidence for disease burden of osteoporosis, evaluate treatment patterns and the proper timing of initiation of anti-osteoporosis medications (AOMs) in Taiwan.

By using the National Taiwan Insurance Research Database, we conduct a cross-sectional study to evaluate the epidemiology and economic burden of osteoporosis for overall Taiwanese population. Second, among those encountered major osteoporotic fractures, we evaluated the treatment rate and visualized the differences in unmet treatment needs. Finally, we evaluated the effectiveness of AOMs initiated in different timing post hip fracture by conducting multivariate time-dependent survival analysis within a cohort study design.

In 2013, there are 253,565 and 82,648 women and men with a diagnosis of osteoporosis, respectively. The prevalence of osteoporosis and related fractures increased with age and the prevalence up to 23% among patients older than 80 years old. Major osteoporotic fractures incurred subsential incremental costs (men: 3935 USD; women:3352 USD), and the annual direct medical cost of patients with osteoporotic fracture was 2-6 times higher than that of the general population. The treatment rate of AOMs was diverse and suboptimal; range from 32% among female with vertebral fracture to 6% among male with hip fracture. Counties in the mid-southern Taiwan had the highest treatment rate, ranged from 30% to 35%. Older age, female sex, and a vertebral fracture were significantly associated with a higher probability of initiating AOMs.

Among those initiated AOMs therapy, AOM initiation later than 252 days after the incident hip fracture was associated with significantly increased risk of subsequent osteoporotic fracture-related hospitalization compared to patients who started AOMs between 15 and 84 days. (Hazard ratios (HR) = 1.93, 95% confidence intervals (CI) 1.29‒2.89) Noteworthy, among patients with a medication possession ratio ≥ 80% (high AOM adherence) within 1 year after initiating AOMs, the risk of subsequent osteoporotic fracture-related hospitalization was even higher for very late users compared with the original cohort (HR = 2.56 vs. 1.93). After adjusting factors associated with AOM initiation timing and patients’ adherence, the anti-fracture benefit of AOMs still depends crucially on the timely initiation of AOMs.

In summary, among every 10 patients encountered osteoporotic fracture in Taiwan, only 3 patients initiated AOMs within 1-year post fracture. In addition, when further considering the proper initiation of AOMs, less than 2 patients could realize the optimal benefit of AOMs therapy. Further studies and continued clinical applications help policymakers allocate resource appropriately and make clinical improvement of osteoporosis care a reality.

Contents Ⅵ
Chapter 1 Introduction 1
1-1 Background and motivation 1
1-2 Study objectives 4
Chapter 2 Literature review 5
2-1 Disease burden of osteoporosis 5
2-1-1 Western countries 5
2-1-2 Asia Pacific region 7
2-1-3 Taiwan 10
2-2 Pharmacological treatment of osteoporosis
17
2-3 Unmet treatment needs of osteoporosis 18
2-4 Proper timing of initiating AOMs therapy 19
Chapter 3 Methods 21
3-1 Conceptual framework and study design 21
3-2 Study design 22
3-3 Data source 23
3-4 Study population and study flow chart 26
3-4-1 Prevalence of diagnosed osteoporosis and major osteoporotic fracture 26
3-4-2 Incident case of major osteoporotic (hip or vertebral) fracture 27
3-4-3 Incident cases of hospitalized hip fracture
28
3-5 The anti-osteoporosis medications (AOMs)
30
3-6 Outcome measurement and operational definition
31
3-6-1 Epidemiology and economic burden 31
3-6-2 Unmet treatment needs 34
3-6-3 Visualization of the unmet treatment needs
34
3-6-4 Proper timing of initiating AOMs 35
3-7 Statistical analyses 38
3-7-1 Epidemiology and economic burden 38
3-7-2 Unmet treatment needs 39
3-7-3 Properly timing of initiating AOMs 39
3-7-4 Unmeasured confounding evaluation - Rule out method
40
Chapter 4 Results 42
4-1 Epidemiology and economic burden 42
4-1-1. Epidemiology of osteoporosis 42
4-1-2 Use of anti-osteoporosis medications (AOMs)
42
4-1-3 Economic burden 46
4-2 Unmet treatment needs 51
4-2-1 Current treatment status 51
4-2-2 Visualization of the unmet treatment needs in different geographical area 52
4-3 Timing of initiating osteoporosis therapy
57
4-3-1 Baseline characteristics 57
4-3-2 AOM initiation timing and risk of fracture-related hospitalization 60
4-3-3 Factors associated with timing of AOMs initiation
63
4-3-4 Propensity score matching and unmeasured confounding analysis 65
Chapter 5 Discussion and potential contribution
68
5-1 Epidemiology and Economic burden 68
5-1-1 Summary 68
5-1-2 Prevalence of osteoporosis and major osteoporotic fracture 68
5-1-3 Treatment status of osteoporosis population (cross-sectional analysis) 69
5-1-4 Economic burden of osteoporosis 70
5-1-5 Strengths and limitations 70
5-2 Unmet treatment needs of osteoporosis 72
5-2-1 Summary 72
5-2-2 Treatment rate of major osteoporotic fracture in Taiwan and worldwide 72
5-2-3 The influence of reimbursement rule of NHI on treatment rate 73
5-2-4 The influence of the Fracture Liaison Service
74
5-2-5 The timing of initiating AOMs prescription
74
5-2-6 Application of qualitative geographical information systems 75
5-2-7 Strengths and limitations 76
5-3 Proper timing of initiating osteoporosis therapy
78
5-3-1 Summary 78
5-3-2 Influence of adherence 78
5-3-3 Very early users 79
5-3-4 Compare with non-users 80
5-3-5 Strengths and limitations 80
Chapter 6 Conclusion 82
Chapter 7 References 85
Chapter 8 Appendix 97

 

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