雙磷酸鹽類治療腦血管相關疾病之研究:兩年內中風風險

The study of cerebrovascular disease associated with bisphosphonate therapy:The risk of stroke within two years

張麗雯(Li-Wen,Chang)

指導教授 ： 許秀蘊

共同指導教授 ： 林恆慶

臺北醫學大學/醫學院/醫學人文研究所/碩士(2012年)

摘要

背景：雙磷酸鹽類是用於治療骨質疏鬆症、惡性腫瘤與高血鈣症之適應症的藥物。然而，近年來各種方面研究，顯示雙磷酸鹽類直接連結於心血管疾病與骨質疏鬆症之間，尤以腦血管疾病的中風最為重要，本文研究動脈粥樣硬化與骨質疏鬆於何種情?起始疾病的過程，了解類似或共同危險因子交互作用的機制，探究在雙磷酸鹽類與血管疾病的依存關係。目的： 探討骨質疏鬆症患者使用雙磷酸鹽類，或使用該藥治療相關疾病，包括alendronate、clodronate、etidronate、ibandronic acid、pamidronate、riserdronate與zoledronic acid在高血壓、糖尿病、高血脂與冠狀動脈之代謝性心血管疾病的關聯，尤其是中風的風險評估。方法： 本研究為回溯性世代研究，確認大於40歲的2,148位患者，介於2003年1月1日∼2005年12月31日之間，接受雙磷酸鹽類的治療的全民健康保險資料檔進行研究分析。首選曾因椎骨或髖部骨折的住院患者在2004.1.1∼2006.12.31之間接受雙磷酸鹽類治療為對照組，進行相關心血管疾病的風險評估，並在中風方面個別地追蹤兩年，運用Log-rank檢驗，檢查中風的風險差異與施以Kaplan-Meier的方法計算中風的存活率。結果： 本研究對象包括8,592位的受試者，有85%是女性，年齡的平均數與標準差71.7±11.4歲。接受雙磷酸鹽類的治療組比對照組的患者，有較多可能有冠心症(p<0.001)與較少可能有糖尿病(p=0.019)。亞型中風形式間的風險比率，接受雙磷酸鹽類治療組與對照組的比較，復經統計上調整後，在蜘蛛網膜下或大腦內出血，僅有0.53倍(95% CI= 0.33∼0.91)，缺血性中風則有較少的0.81倍(95% CI = 0.66∼0.96)。關於這兩組對於中風發生的兩年的後續追蹤，有顯著兩年較高的無中風存活率。統計上調整後，顯示治療組在兩年的後續追蹤的期間，有較少發生中風的可能性(HR=0.77，95% CI = 0.65∼0.92，p=0.004)。結論： 本研究發現雙磷酸鹽類連結於心血管疾病的關係，治療組比對照組後續追蹤的期間，有較少發生腦血管中風的風險。然而，仍需注意雙磷酸鹽類的不良反應等變項因素的影響，因此，仍需後續大量的數據資料進行深入的研究。

關鍵字

雙磷酸鹽類 ； 骨質疏鬆症 ； 心血管疾病 ； 中風 ； 不良反應

並列摘要

Background: Bisphosphonates is the medication adopted for indication of osteoporosis, malignant neoplasms,and hypercalcemia treatment. However, various recent studies have shown direct link of bisphosphonates to cardiovascular disease and osteoporosis; among them, stroke is the most noticeable. This study intends to understand when atherosclerosis and osteoporosis disease process are initilized, and the interactions mechanism of similar or common risk factor, and explore the relationship among bisphosphonates and vascular diseases.Objectives: To study the patients with osteoporosis using bisphosphonates, or using the above mentioned medicine to treat related diseases, including the relations with alendronate, clodronate, etidronate, ibandronic acid, pamidronate, riserdronate, and zoledronic acid in hypertension,
diabetes, hypercholesterolaemia, and coronary heart associated metabolic cardiovascular disease, especially for the risk of stroke.Methods: This study is retrospective for generations, we execute the research & analysis through files of National Health Insurance data for those is identified 2,148 patients≥40 years of age who receive bisphosphonates therapy between January 1,2003 and December 31,2005.We asses the risk of related cardiovascular disease by way of first selected the patients who had been hospitalized for the treatment of vertebral fractures or hip fractures between January 1,2004 and December 31,2006 as comparison group of this study , we also individually track in the aspect of stroke for two years, applying the log-rank test to examine differences in the risk of stroke, adopting the Kaplan-Meier method to calculate the survival rates of stroke.Results: The objects of this study included 8,592 specimens, 85% female involved, mean and standard deviation of the age is 71.7±11.4 years old. Receive bisphosphonate study group than the comparison group of patients were more likely to have coronary artery disease (p<0.001)and were less likely to have diabetes (p=0.019),and further shows the analysis of hazard ratio of stroke between the two groups by stroke subtype.Statistical adjusted, for subarachnoid/intra-cerebral hemorrhage for patients who received bisphosphonates therapy was only 0.53 times (95% CI=0.33∼0.91)and ischemic stroke was 0.81 times lesser(95% CI =0.66∼0.96).Stroke occurred in a two-year follow-up on these two sets of number of people with stroke, and statistical adjusted, the study group in a two-year follow-up period, there is less risk of stroke(HR = 0.77,95% CI = 0.65~0.92,p =0.004).
Conclusion: This study found the relationship bisphosphonates link to cardiovascular disease, there is less risk of stroke in the comparison group than bisphosphonate study group in the follow-up period, However, it still need to be paid attention to the adverse reactions of variable factors for bisphosphonates, therefore, it still need a lot of data to
execute in-depth study.

並列關鍵字

Bisphosphonate ； osteoporosis ； cardiovascular disease ； stroke ； adverse reactions

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