停經後婦女骨質疏鬆症藥物的療效與副作用評估

Comparative Efficacy and Safety of Osteoporosis Treatment: A Systematic Review and Meta-analysis

張世甫(Shih-Fu Chang)

指導教授 ： 張瑞青

共同指導教授 ： 孫瑞昇(Jui-Sheng Sun)

國立臺灣大學/醫學院/臨床牙醫學研究所/碩士(2021年)

https://doi.org/10.6342/NTU202103823

摘要

骨質疏鬆（osteoporosis）是現今高齡化社會的一項常見疾病，患者以停經後婦女（postmenopausal women）為高危險族群。多數患者在日常意外中發生無預警性骨折，且依據骨折的不同部位伴隨不同的重症率與死亡率。臨床診斷主要是根據雙光子能量檢測（DEXA）所得到的骨密度（bone mineral density, BMD）數值作為參考，骨密度低於2.5標準差而被診斷為骨質疏鬆的患者，藥物是常見的治療方式，然而藥物引起的嚴重副作用也是臨床醫師使用的考量重點之一。骨鬆的藥物機轉可能會干擾嗜骨細胞（osteoclast）與成骨細胞（osteoblast）的平衡，甚至在牙科治療中偶有顎骨壞死的案例報告出來。
此篇論文以系統性回顧及網絡統合分析比較藥物的治療效果及副作用。我們從PubMed, EMBASE, MEDLINE, ClinicalTrial.gov, Cochrane library和Google scholar等資料庫搜索回顧，並選用隨機分派對照試驗（randomized controlled trial, RCT）之文章，計算SUCRA（surface under the cumulative ranking curve）值並比較藥物與副作用發生次數的排名。排名顯示在最容易發生骨折的三個部位中，髖骨（total hip）以鍶鹽類藥物（SrRan），腰椎（lumbar spine）以氟化類藥物（Fluoride），手腕骨（radius）以賀爾蒙替代療法（hormone replacement therapy, HRT）所獲得之骨密度改善療效最佳。若將此三部位做集群分析（clustered analysis），單株抗體（monoclonal antibody, mAb）與雙磷酸鹽類藥物（bisphosphonate, BP）對三大部位平均性骨密度提升的綜合效用最佳。
正向療效的結果除了將三大部位骨密度提升的百分率當成主要療效指標外，我們另外將藥物能否降低髖骨骨折的發生率當成次要指標，群集分析顯示接受單株抗體、雙磷酸鹽類與副甲狀腺素的病人在髖骨部位骨密度有顯著改善之餘對於降低髖骨骨折的發生率也有幫助。
副作用的個別考量中，單株抗體對於治療後死亡率的報告是所有藥物中最低，選擇性雌激素受體調節劑（selective estrogen-receptor modulator, SERM）則在癌症與心血管併發症中引起的風險最小。
藥物引起的顎骨壞死（MRONJ）是骨鬆病人至牙科門診常引起牙醫師擔心的嚴重併發症，在我們的文獻回顧中顎骨壞死的發生率並不高，三年內追蹤的文獻僅有一報告案例並且為接受單株抗體注射之患者。追蹤年限拉長至十年可觀察到發生人數有明顯增加。因本篇的研究族群皆為停經後婦女，此類患者相較其他治療族群（如癌症的骨轉移）使用的藥物劑量相對較低，且隨機分派試驗中雙磷酸鹽類的比較組別也不多。儘管低劑量使用骨質疏鬆藥物在停經後婦女短期內顎骨壞死的發生率可能較為稀少，如要考量其他骨質疏鬆相關疾病全體族群則需擴大研究條件才能提供更全面的系統性回顧。

關鍵字

骨質疏鬆症 ； 停經後婦女骨質疏鬆症 ； 藥物治療 ； 副作用 ； 顎骨壞死 ； 網絡統合分析 ； 系統性回顧 ； 隨機分派對照試驗

並列摘要

Osteoporosis is a more common disease in an aging society of many countries and postmenopausal women are at a higher risk to cause weak bone. Most of them experience bone fracture accidently with various mortality and morbidity rate which is depending on the fracture sites. Diagnosis criteria are mainly through dual-energy x-ray absorptiometry (DEXA) and thus bone mineral density (BMD) for each patient can be acquired. Serious side effects caused by pharmacologic treatments are also considered by clinicians. The mechanism of drugs for osteoporosis causes imbalance between osteoclast and osteoblast-related pathways and may lead to severe complications such as osteonecrosis of the jaw (ONJ).
This study followed PRISMA guideline for systematic review and network meta-analysis was performed for comparisons of treatment efficacy and side effects among diverse pharmacologic interventions. PubMed, EMBASE, MEDLINE, ClinicalTrial.gov, Cochrane library and Google scholar were searched to filter into randomized controlled trials conforming to the study population. From the analysis results for lumber spine (LS), total hip (TH) and radius (RU), strontium ranelate (SrRan) is top-ranked for BMD percentage change at TH; fluoride at LS, and hormone replacement therapy (HRT) at RU. From the clustered analysis, monoclonal antibody (mAb) and bisphosphonate (BP) have balanced effects at three bone locations for BMD percentage change.
As for the incidence rate of hip fracture, which is measured as the secondary outcome, clustered analysis described that mAb, BP and parathyroid hormone (PTH) all increase BMD at total hip effectively with decreased risk of hip fracture.
While concerned about specific side effects, mAb showed least risk of death among all the interventions, and selective estrogen-receptor modulator (SERM) revealed least risk of cancer and CVD.
The incidence rate of ONJ is rare from our review and there was one reported case during 3-year follow up. There is little chance that the low-dose treatment for postmenopausal osteoporosis in a relatively short-term period gives rise to ONJ, whereas administration of high cumulative doses may increase the likelihood especially in patients with bone metastasis.

並列關鍵字

osteoporosis ； postmenopausal osteoporosis ； pharmacologic treatment ； side effect ； ONJ ； meta-analysis ； systematic review ； randomized controlled trial

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