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研究生：	傅紹懷 Fu, Shau-Huai
論文名稱：	長期照護體系內老年族群之骨折風險評估與治療: 流行病學探討與篩檢工具發展 Fracture risk assessment and treatment of the elderly in long-term system: epidemiology and screening tool development
指導教授：	李中一 Li, Chung-Yi
學位類別：	博士 Doctor
系所名稱：	醫學院 - 公共衛生學系 Department of Public Health
論文出版年：	2022
畢業學年度：	111
語文別：	英文
論文頁數：	129
中文關鍵詞：	骨質疏鬆症、骨折、死亡率、篩檢、長期照護機構住民
外文關鍵詞：	osteoporosis, fracture, mortality rate, screening, long-term care resident
相關次數：	點閱：152 下載：40
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背景:
長期照護機構住民的骨質疏鬆症盛行率很高，但診斷嚴重不足。且在文獻中，此族群也有很高的骨折風險。然而，經過數十年預防和治療骨質疏鬆症的努力，長期機構住民的骨質疏鬆症治療率仍然非常低。
目的:
本研究的目的為:提高對長期照護機構住民骨質疏鬆症流行病學的認識，調查此族群骨折和死亡的風險，檢驗抗骨質疏鬆症藥物治療於此族群的有效性，並依此針對長期照護機構住民開發新的骨質疏鬆症篩檢工具。
材料與方法:
我們進行了一項為期兩年的前瞻性的前後對照研究。針對雲林縣20家長期照護機構裡面年齡 ≥ 50歲的住民進行了便利抽樣，抽樣的比例占雲林縣長照機構的30%。在收案時，我們收集與骨質疏鬆症流行病學相關的基本特性和資訊。然後我們追蹤了骨質疏鬆症治療效果、臨床骨折發生率、死亡率和藥物依從性等。進一步使用這些骨質疏鬆症和骨折風險相關資訊來測試現有骨質疏鬆症篩檢評估工具的有效性並據以開發新問卷。
結果:
我們總共收案785人，男女比例為43:57，平均年齡78.8歲。長期照護機構住民骨質疏鬆症的盛行率很高，估計男性和女性的盛行率分別為30-40%和75%。台灣長照機構住民骨折發生率和死亡率均低於西方國家文獻報告。經由篩檢和治療介入後，診斷率提高了三倍，治療率提高了五倍，且在機構的幫助下具有非常高的治療依從性和持久性。無論他們是男性、女性、< 80 歲還是 ≥ 80 歲，接受骨鬆藥物治療的患者的骨密度顯著增加，特別是在脊椎的骨密度可以增加4.6%。根據健保資料庫研究，停用 DMAB 的患者骨折風險明顯更高(HR：1.60)。本研究提供了關於現有骨質疏鬆症篩檢工具或骨折風險評估工具於篩檢此族群是否有骨質疏鬆，或者是否適合健保骨鬆治療的效度驗證。我們還開發了專門篩檢長期照護機構住民的新骨質疏鬆症篩檢問卷，此問卷能更準確地預測此族群是否有骨質疏鬆(AUROC~0.8)，並且具有計算分數所需變項更少的優點。除骨質疏鬆症外，在此族群還有一些與骨折有關的因子，如身體是否虛弱、帕金森氏症、既往骨折史、是否於跌倒後骨折等。
討論與結論:
我們的研究填補台灣長期照護機構住民在骨骼健康的知識缺口，但是還有很多研究需要持續努力，例如需要進行大規模隨機對照試驗來確定長期照護機構住民中的骨質疏鬆症篩檢是否對減少臨床骨折有效，另外也需要對我們的新篩檢問卷進行外部驗證，以提高其普遍性與適用性。最後，我們需要驗證骨質疏鬆症篩檢和治療以預防此族群骨折是否具有成本效益。
影響:
在考慮對長期照護機構住民進行骨質疏鬆藥物治療時，決策制定比治療一般人群更複雜和困難。選擇合適的高骨折風險且有足夠的存活時間讓藥物能發揮作用的人群應該是治療的第一步。

Background: Although the prevalence of osteoporosis is considered high in long-term care residents (LTCRs), it is believed to be under-diagnosed. The osteoporosis causes very high fracture risk when comparing community dwellers with similar ages. However, the treatment rate remained low in this segment of population after decades of efforts in preventing and treating osteoporosis among older people.
Objective: To improve the understanding of epidemiology of osteoporosis, examine the effectiveness of anti-osteoporosis medication, determine the risk of fracture and mortality, test the safety of anti-osteoporosis medication, and develop new osteoporosis screening tools among LTCRs.
Materials and Methods: We conducted a prospective cohort study with a follow-up period of two years and prospectively enrolled elderly residents aged ≥ 50 years old from 20 LTC facilities in Yunlin County. The sampling ratio accounted for 30% of the long-term care institutions in Yunlin County. Basic characteristics and information related to osteoporosis epidemiology were collected. The outcome of interest were the clinical treatment effects of osteoporosis, clinical fracture, death, and drug adherence. Osteoporosis and fracture risk related information were used to test the validity of existed osteoporosis screening scores and developed new scores.
On the other hand, due to lack of evidence of safety evidence about new anti-osteoporosis medications in this fragile population, we conducted a comparative effectiveness study with nationwide population-based cohort study design by using National Health Insurance Research Data (NHIRD) to test the fracture risk after discontinuing denosumab or bisphosphonates.
Results: We recruited a total of 785 LTCRs, the male to female ratio was 43:57, and the average age was 78.8 years old. The prevalence of osteoporosis in this population was very high, the estimated prevalence of men and women were 30~40% and 75% respectively. Our screening and treat intervention improved the diagnosed rate and treatment rate. Bone mineral density increased significantly among those treated by anti-osteoporosis medication (AOM), mainly denosumab (DMAB), whether they were men, women, < 80 years old, or ≥ 80 years old. Especially in the spine bone mineral density can increase by 4.6%. The fracture risk was significantly higher in those discontinuing DMAB according to NHIRD (HR:1.60). Fortunately, this specific population had very high adherence and persistence of treatment under the assistance of long-term care institutions (LTCIs) and make the concern of elevated fracture risk after discontinuation of treatment minimally. We offered abundant information about the validity of ten existed osteoporosis screening tools or fracture risk assessment tools to screen osteoporosis or select those suitable for treatment according to NHI reimbursement criteria. We also developed two new osteoporosis screening tools specifically developed from LTCRs. Both new scores have the advantage of improved validity (AUROC~0.8) and less variables needed for calculating scores. The fracture incidence and mortality were both lower than those reported in the literature of western country. Some factors were related to fracture other than osteoporosis, such as frailty, Parkinsonism, previous fracture history, and fall with fracture.
Discussion & Conclusion:
In summary, we had done something to fill the knowledge gap and treatment gap for bone health of LTCRs. But there are still many things to do. Large scale randomized controlled trials are needed to determine whether osteoporosis screening among LTCRs is effective at solid outcome, such as clinical fracture. External validation of our new scores is needed to increase their generalizability. And finally, we need to determine whether screening and treating osteoporosis to prevent fracture in this population could be cost-effective
Implications:
When considering treatment with AOM among LTCRs, the decision making is more complicated and difficult than treating general population. Selecting the right population with high fracture risk and long-term survival should be the first step before treatment.

Contents
摘要	II
Abstract	IV
致謝	VII
Contents	VIII
Chapter 1	Introduction 1
Objective 1- Epidemiology of osteoporosis in LTCRs: 2
Objective 2-Effectiveness of anti-osteoporosis medication in LTCRs: 2
Objective 3-The risk of fracture and mortality of LTCRs: 2
Objective 4-Safety of anti-osteoporosis medication in LTCRs: 2
Objective 5-Osteoporosis screening tool for LTCRs:	2
Chapter 2	Literature review	3
2-1 Epidemiology of osteoporosis in LTCRs	3
2-2 Incidence and impact of osteoporotic fracture in LTCRs	6
2-3 Prescription of calcium, vitamin D, and anti-osteoporosis medication in LTCRs	8
2-4 Effectiveness of anti-osteoporosis medication in LTCRs: The reality and difficulty needed to face	10
2-5 Mortality in LTCRs	12
2-6 Comparison of different osteoporosis screening tools	14
Chapter 3	Materials and methods	19
3-1 Epidemiology of osteoporosis, effectiveness of anti-osteoporosis medication, and risk of fracture and mortality (objective 1,2,3)	19
3-1-1 Study design and aim	19
3-1-2 Study population	19
3-1-3 Procedure and treatment	20
3-1-4 Exposure	25
3-1-5 Outcomes measurements:	25
3-1-6 Other covariates:	27
3-1-7 Statistical analysis:	29
3-2 Safety of anti-osteoporosis medication (objective 4)	31
3-2-1 Study design and aim	31
3-2-2 Study population	31
3-2-3 Exposure ascertainment	32
3-2-4 Outcome ascertainment	34
3-2-5 Other covariates	38
3-2-6 Statistical analyses	38
3-3 Osteoporosis screening tools (objective 5)	38
3-3-1 Study design and aim	38
3-3-2 Study population	39
3-3-3 Measurements	39
3-3-4 Statistical analyses	40
Chapter 4	Results	42
4-1 Epidemiology of osteoporosis in LTCRs	42
4-1-1 Baseline characteristics, Ca and Vit D supplementation, and osteoporosis treatment rate	42
4-1-2 Fracture risk distribution, determined by FRAX	44
4-2 Effectiveness of anti-osteoporosis medication in LTCRs	51
4-2-1 Baseline characteristics of LTCRs treated with AOM	51
4-2-2 BMD improvement after AOM treatment	52
4-2-3 Fracture incidence and mortality after AOM treatment	56
4-3 The risk of fracture and mortality of LTCRs	58
4-3-1 Baseline characteristics of the study population	58
4-3-2 Incidence of fracture	58
4-3-3 Mortality	61
4-3-4 The factors related to fracture and survive for more than one year	63
4-4 Safety of anti-osteoporosis medication in LTCRs	65
4-4-1 Baseline characteristics and flow chart of selecting study patients	65
4-4-2 Fracture risk of persistent or non-persistent AOM users	70
4-4-3 Fracture risk of persistent or non-persistent AOM users at different situations: sensitivity analyses	74
4-5 Osteoporosis screening tool for LTCRs	77
4-5-1 Baseline characteristics of study population	77
4-5-2 Distribution of osteoporotic BMD, stratified by sex and age	79
4-5-3 Diagnostic accuracy of each existed osteoporosis screening tool	81
Chapter 5	Discussion	97
5-1 Epidemiology of osteoporosis in LTCRs	97
5-1-1 Summary	97
5-1-2 Ca and Vit D supplementation, and osteoporosis treatment rate	97
5-1-3 Fracture risk distribution, determined by FRAX	97
5-1-4 Estimated prevalence of osteoporosis	98
5-1-5 Strengths and limitations	98
5-2 Effectiveness of anti-osteoporosis medication in LTCRs	99
5-2-1 Summary	99
5-2-2 Why LTCRs remained neglected and untreated for decades?	99
5-2-3 Does the improvement of BMD really represent some clinical benefit?	100
5-2-4 Strengths and limitations	100
5-3 The risk of fracture and mortality of LTCRs	101
5-3-1 Summary	101
5-3-2 Does the fracture incidence of LTCRs really higher than general elderly in the community?	101
5-3-3 Why is the mortality rate of LTCRs in Taiwan lower than those reported in Western countries?	103
5-3-4 Who should be treated?	103
5-3-5 Treat or not to treat	104
5-3-6 Strengths and limitations	104
5-4 Safety of anti-osteoporosis medication in LTCRs	105
5-4-1 Summary	105
5-4-2 Why there is a conflict of fracture risk after discontinuation of DMAB between studies?	105
5-4-3 Why BP and DMAB are different in this issue?	106
5-4-4 Why not other area but vertebral?	106
5-4-5 The duration of DMAB treatment matters	106
5-4-6 Strengths and limitations	107
5-5 Osteoporosis screening tool for LTCRs data	109
5-5-1 Summary	109
5-5-2 Why modification of existed score is needed?	109
5-5-3 Reported versus verified facture history	110
5-5-4 Which score is better or suitable to screen osteoporosis among LTCRs?  Complexity or simplicity?	110
5-5-5 Strengths and limitations	111
Chapter 6	Conclusion	112
Chapter 7	References	115



List of Tables
Table 2 1 Prevalence of osteoporosis in long-term care residents	4
Table 2 2 Prevalence of “diagnosed” osteoporosis in long-term care residents	5
Table 2 3 Incidence of fracture of long-term care residents	7
Table 2 4 Prescription rate of Vitamin D, calcium, and anti-osteoporosis medication	9
Table 2 5 Treatment efficacy and effectiveness of anti-osteoporosis medications	11
Table 2 6 One-year mortality rate of long-term care residents	13
Table 2 7 Comparison of different osteoporosis screening tools	15
Table 3-1 Classification of fracture risk	24
Table 3-2 Covariates collected from baseline screening	28
Table 3 3 Validation of the diagnosis of hospitalization for primary hip fractures	35
Table 3 4 Validation of algorithms for subsequent vertebral, non-vertebral, and major osteoporotic fracture-related hospitalization	36
Table 4-1 Baseline characteristics of the enrolled study participants	43
Table 4-2 Distributions of the FRAX score of the enrolled study participants	45
Table 4-3 Baseline characteristics of long-term care residents in Changhua County (rural) and Taichung City	46
Table 4-4 FRAX fracture risk distribution of long-term care residents in Changhua County (rural) and Taichung City	47
Table 4-5 Baseline characteristics of the study participants who completed the osteoporosis work up	49
Table 4-6 Percentage of osteoporosis in each fracture risk category of the study participants who completed the osteoporosis work up	51
Table 4-7 Comparisons of bone mineral density at various body sites who completed the osteoporosis work up before and after AOMs therapy	54
Table 4-8 Comparison of LTCRs treated and non-treated by AOM: before and after matching	57
Table 4-9 Comparison of incidence rate per 1000 person-years between treated and non-treated patients	58
Table 4-10 Comparison of incidence rate per 1000 person-years between treated and non-treated patients (delete those died within one year and matching)	58
Table 4-11 Incidence of fracture of LTCRs	60
Table 4-12 Mortality of LTCRs	62
Table 4-13 Univariate analyses of factors associated with  high fractur risk and low mortality	64
Table 4-14 Baseline characteristics of denosumab and bisphosphonate exposure groups	69
Table 4-15 Fracture rates in denosumab and bisphosphonate exposure groups	71
Table 4-16 Comparisons of risks of fracture and death according to anti-osteoporosis medications (AOMs) type and level of adherence	73
Table 4-17 Demographics of study cohort. LTCRs were included from two independent institutes, the National Taiwan University Hospital Yun-Lin branch (YL) and Kaohsiung Veterans General Hospital (KH)	78
Table 4-18 Distribution of osteoporotic BMD, stratified by sex and age	80
Table 4-19 Operating Characteristics of Each Clinical prediction Rule among all patients	82
Table 4-20 Discrimination and calibration of algorithms on repeated cross-validation of validation set, n = 111	83
Table 4-21 Operating Characteristics of Each Clinical prediction Rule among female patients	85
Table 4-22 Operating Characteristics of Each Clinical prediction Rule among male patients	86
Table 4-23 Operating Characteristics of each test at optimum cutoff based on Youden's Index among all patients	88
Table 4-24 Operating Characteristics of each test at optimum cutoff based on Youden's Index among female patients	89
Table 4-25 Operating Characteristics of each test at optimum cut-off based on Youden's Index among male patients	90
Table 4-26 Covariate adjusted odds ratio and risk scores of new clinical prediction rule (any site T-score ≤ -2.5) in the training dataset	92
Table 4-27 Operating Characteristics of new score at optimum cutoff based on Youden's Index- test in the training dataset	94
Table 4-28 Operating Characteristics of new score in the testing dataset	94
Table 4-29 Operating Characteristics of new score 2 at optimum cutoff based on Youden's Index- test among female patients	96
Table 4-30 Operating Characteristics of new score 2 at optimum cutoff based on Youden's Index- test among male patients	96

 
List of Figures

Figure 3 1 Fracture Risk Assessment Tool (FRAX)	23
Figure 3 2 Study flow chart	25
Figure 3 3 Illustration of exposure groups according to AOMs and level of adherence	33
Figure 3 4 Algorithm for determining subsequent major osteoporotic fracture-related hospitalization by using claims data	37
Figure 4-1 The examination and treatment flow chart	52
Figure 4-2 Bone mineral density change after anti-osteoporosis treatment	55
(A)Spine (B)Total hip (C)Femoral neck	55
Figure 4-3 Flow chart of selecting study patients.	66
Figure 4-4 Flow chart for patients who used AOMs for a least 2 years	67
Figure 4-5 The Kaplan–Meier curves of osteoporotic fracture for four groups after completion of 1-year anti-osteoporosis medication (AOM) treatment.	74
Figure 4-6 Main and sensitivity analyses for the risk of vertebral fracture-related hospitalization	76
Figure 4-7 ROC of different osteoporosis screening scores. R: fracture history reported by LTCR themselves; V: the fracture was verified by x-ray or medical record.	84
Figure 4-8 ROC of new score 1 (Left) and new score 2 (Right)	95
Figure 4-9 Calibration of new score 1 (Left) and new score 2 (Right)	95
                                    

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