||Investigation on Effectiveness and Safety of Osteoporosis Drugs in Taiwan
||Institute of Clinical Pharmacy and Pharmaceutical sciences
骨質疏鬆症引起之骨鬆骨折及其併發症常見於老年人，不但影響生活品質，亦可能增加日後骨折再發甚至死亡的風險。臨床上有許多骨質疏鬆藥品(例如: 雙磷酸鹽類藥物、raloxifene及calcitonin)可降低已發生骨鬆骨折之病患再發的風險。但是，近幾年的研究也發現，發生骨鬆骨折之病患若屬用藥順從度不佳者，發生骨折的風險顯著高於用藥順從度較佳的病患；並且，用藥順從度必須達到一定的程度才有治療效果。值得注意的是，雙磷酸鹽類藥物在曾經發生骨鬆骨折的病患中預防骨折再發的效果雖然優於他類藥品，但是，osteonecrosis of the jaw (ONJ)與靜脈栓塞的案例自2002年起出現於使用雙磷酸鹽類藥物之通報而廣受注意，近年來亦陸續有研究探討使用雙磷酸鹽類藥物與發生ONJ與靜脈栓塞之相關性。骨質疏鬆症是老年族群不容忽視的醫療議題，惟國內相關研究仍然闕如。
採用回溯性世代研究法(retrospective cohort study)，由2003至2006年20歲以上曾經發生過骨鬆骨折的病患中，自第一次開始使用骨質疏鬆藥品 (alendronate, raloxifene或calcitonin)的時間點，往後追蹤。評估病人開始使用藥品前一年的基本特質、開始使用骨質疏鬆藥品後一年內之用藥持續性及順從度。髖關節與非脊椎骨折再發為探討順從度影響與藥品相對療效之主要臨床成果。而ONJ與靜脈栓塞則為探討骨鬆藥品安全性時之主要研究目標。於探討病患順從度之好壞對於未來髖關節骨折再發風險影響、骨鬆藥品相對療效與安全性時，本研究利用多變項Cox regression控制相關之共變數、評估相對危險比及描繪校正後之存活曲線。本研究亦會利用傾向分數 (propensity score)，以及一系列之敏感度測試來確認研究之可信度。所有資料處理及統計皆使用SAS 9.2版統計軟體。
本研究首先發現，台灣新發生骨鬆骨折之病患，於開始治療後一年內之順從度不佳。儘管如此，順從度高者相較與順從度低者，仍可有70%較低髖關節骨折再發之風險 (adjusted HR, 0.30; 95%CI:0.22-0.42)。此外，於骨鬆藥品中，raloxifene與calcitonin相較於alendronate使用者，皆有顯著較高之非脊椎骨折發生風險 (adjusted HR for raloxifene: 1.31, 95%CI, 1.14-1.51; adjusted HR for calcitonin: 1.47, 95%CI, 1.29-1.67). 不過，本研究發現，alendronate使用者相較於raloxifene或calcitonin使用者，並不會增加ONJ會靜脈栓塞之風險。
Osteoporotic fractures and their complications are serious problems for the elderly, due to their deleterious effects on quality of life and increased future fracture even mortality risk. Although there are effective treatments for preventing osteoporotic fractures, including bisphosphonates, raloxifene and calcitonin, the persistence and compliance of patients taking these drugs are suboptimal as reported in the literature. The fracture risks of poor compliant patients were significantly higher than compliant patients; furthermore, the compliance should be kept in certain level for the pharmacological agents to be effective. While bisphosphonates have demonstrated the superiority to the other osteoporotic regimen in patients with established osteoporotic fractures, cases of osteonecrosis of the jaw (ONJ) and venous thromboembolism (VTE) after using bisphosphonates since 2002 have drawn much attention. A few pilot studies regarding to the association between use of bisphosphonates and ONJ/VTE have been conducted in these years. Given osteoporosis and its complications are highly concerned, the effectiveness and risk of the osteoporotic treatment remains unknown in Taiwan.
By using National Health Insurance Research Database, we will describe the baseline characteristics and compliance of osteoporotic therapy in patients with new osteoporotic fractures in Taiwan. Regarding to outcome evaluation, we will analyze the association between patients' compliance and risk of fracture. This study also aims to investigate the comparative effectiveness of pharmacological agents in preventing osteoporotic fractures and the association between use of bisphosphonates and ONJ risk. Finally, the safety of bisphosphonates, in terms of the risk of ONJ/VTE was investigated as well.
From 2003-2006, Enrollees in the National Health Insurance Research Database (NHIRD) aged above 50 years, with vertebral/hip fracture and new to osteoporosis therapy were recruited. Patients had Paget’s disease or cancer during baseline period were excluded. Patients were classified into alendronate or calcitonin/raloxifene (control) group according to the exposure after follow-up. The impact of patient adherence on secondary hip fracture risk, the relative effectiveness of osteoporosis drugs and the safety of bisphosphonates were estimated by using Cox modeling to correct effects of covariates and their correlation with outcomes, estimate hazard ratio and plot corrected survival curves. Results were examined in series sensitivity analyses, including different cumulative doses group. SAS 9.2 will be used for data management and statistical purpose.
We found only 38% of the study population remained compliant during the first year of treatment. Over the 4-year follow-up period, the risk of hip fracture among the compliant patients was 70% lower than in non-compliant patients (adjusted HR, 0.30). As for the relative effectiveness, the fracture rates were highest in calcitonin recipients (4.57/100 person-years), followed by raloxifene and alendronate. Results from Cox analyses showed raloxifene (HR, 1.47; 95%CI, 1.29-1.67) and calcitonin (HR, 1.51; 95%CI, 1.29-1.75) had higher non-vertebral fracture risk as compared with alendronate. We also did not observe higher incidence and risk of ONJ/VTE for alendronate recipients, as compared with raloxifene/calcitonin recipients.
The compliance of osteoporosis population in Taiwan is suboptimal. The effectiveness of alendronate in Taiwan is best within drug classes, and the potential risks for serious adverse events (ONJ, VTE) were low. Efforts and policies should be implanted to osteoporosis patients by the regulatory agencies and healthcare professionals to improve their compliance.
Part I. Introduction 1
1. Introduction to Osteoporosis 1
1.1 Pathology and risk factors for osteoporosis 2
1.2 Diagnosis of osteoporosis 4
2. Pharmacological Treatments for Osteoporosis 9
2.1 Mechanism of action of osteoporosis drugs 9
2.2 Clinical efficacies of the osteoporosis drugs 12
3. Statement of the Research Questions 16
4. Specific Aims 18
5. Significance 19
Part II. Compliance with Alendronae and Its Impact on Hip Fracture Risk among Established Osteoporosis Patients in Taiwan 20
1. Literature review 20
1.1 Researches using health insurance database to assess patients compliance to osteoporosis drugs and its impact on fracture risk 21
2. Methods 24
2.1 Data Source 24
2.2 Study Design and Population 24
2.3 Compliance with Alendronate 25
2.4 Covariates and Outcomes 26
2.5 Statistical Analysis 26
3. Results 28
3.1 1st Year Compliance and Cohort Characteristics 28
3.2 The Impacts of Compliance on the Incident Hip Fracture Risk 29
4. Discussion 32
5. Strength and limitations 37
6. Conclusion and Clinical Implications 39
Part III. The Relative Effectiveness of Osteoporosis Drugs in Preventing Secondary Non-vertebral fractures in Taiwan 47
1. Literature review 47
1.1 Current evidences from clinical trials 47
1.2 Current evidences from observational studies 48
2. Methods 51
2.1 Data source 51
2.2 Study design and population 51
2.3 Exposure to osteoporosis drugs 52
2.4 Outcomes and Covariates 52
2.5 Statistical analysis 53
3. Results 55
3.1 Baseline Characteristics of Osteoporosis drug users 55
3.2 Fracture Rates and Relative Effectiveness of Osteoporosis drugs 55
4. Discussion 57
5. Strength and Limitation 61
6. Conclusion and clinical implication 63
Part IV. Incidence and Risk of Osteonecrosis of the Jaw among the Taiwan Osteoporosis Population 71
1. Literature review 71
1.1 Introduction to ONJ 71
1.2 Incidence of ONJ and methodological challenges 72
2. Methods 74
2.1 Data source 74
2.2 Study design and population 74
2.3 Exposure to osteoporosis drugs 75
2.4 Covariates and Outcomes 75
2.5 Statistical analysis 76
3. Results 78
3.1 Baseline Characteristics 78
3.2 Risk and Incidence of possible ONJ 79
3.3 Sensitivity analysis 80
4. Discussion 81
5. Strength and limitations 85
6. Conclusion and clinical implications 87
Part V. Incidence and Risk of Venous Thromboembolism among Taiwan Osteoporotic Fracture Population 94
1. Literature review 94
1.1 Potential adverse cardiovascular events associated with the osteoporosis drugs 94
1.2 Risk of VTE in the bisphosphonates and raloxifene 95
2. Methods 97
2.1 Data source 97
2.2 Study design and population 97
2.3 Exposure to osteoporosis drugs 98
2.4 Outcomes and Covariates 98
2.5 Statistical analysis 100
3. Results 102
3.1 Baseline Characteristics of Osteoporosis drug users 102
3.2 Incidence and risk of VTE for alendronate or raloxifene compared with calcitonin 103
4. Discussion 105
5. Strength and limitations 108
6. Conclusion and clinical implications 110
Part VI. Summary 117
Part VII. Reference 119
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