BACKGROUND For patients with osteoporosis, bisphosphonate therapy can reduce the risk of fractures, but its effect on reducing mortality remains unclear. Previous studies on this topic have produced conflicting results and generally have been too small to definitively answer the question of whether bisphosphonate therapy reduces mortality. Therefore, a meta-analysis may help us arrive at a more conclusive answer. QUESTIONS/PURPOSES In a large meta-analysis of placebo-controlled randomized controlled trials (RCTs), we asked: (1) Does bisphosphonate use reduce mortality? (2) Is there a subgroup effect based on whether different bisphosphonate drugs were used (zoledronate, alendronate, risedronate, and ibandronate), different geographic regions where the study took place (Europe, the Americas, and Asia), whether the study was limited to postmenopausal female patients, or whether the trials lasted 3 years or longer? METHODS We conducted a systematic review using multiple databases, including Embase, Web of Science, Medline (via PubMed), Cochrane Library, and ClinicalTrials.gov, with each database searched up to November 20, 2023 (which also was the date of our last search), following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. We included randomized, placebo-controlled clinical trials with participants diagnosed with osteoporosis and receiving bisphosphonate treatment. We excluded papers posted to preprint servers, other unpublished work, conference abstracts, and papers that were registered on ClinicalTrials.gov but were not yet published. We collected 2263 records. After excluding records due to study type, study content not meeting the inclusion criteria, and duplicates, our meta-analysis included 47 placebo-controlled RCTs involving 59,437 participants. Data extraction, quality assessment, and statistical analyses were performed. The evaluation of randomized trials for potential bias was conducted using the revised Cochrane Risk of Bias tool. This assessment encompassed factors such as sequence generation, allocation concealment, subject blinding, outcome assessor blinding, incomplete outcome data, and reporting bias. Some studies did not provide explicit details regarding random sequence generation, leading to a high risk of selection bias. A few studies, due to their open-label nature, were unable to achieve double-blind conditions for both the subjects and the researchers, resulting in intermediate performance bias. Nevertheless, the overall study quality was high. Due to the low heterogeneity among the studies, as evidenced by the low statistical heterogeneity (that is, a low I2 statistic), we opted for a fixed-effects model, indicating that the effect size is consistent across the studies. In such cases, the fixed-effects model can provide more precise estimates. According to the results of the funnel plot, we did not find evidence of publication bias. RESULTS The use of bisphosphonates did not reduce the overall risk of mortality in patients with osteoporosis (risk ratio 0.95 [95% CI 0.88 to 1.03]). Subgroup analyses involving different bisphosphonate drugs (zoledronate, alendronate, risedronate, and ibandronate), regions (Europe, the Americas, and Asia), diverse populations (postmenopausal female patients and other patients), and trials lasting 3 years or longer revealed no associations with reduced overall mortality. CONCLUSION Based on our comprehensive meta-analysis, there is high-quality evidence suggesting that bisphosphonate therapy for patients with osteoporosis does not reduce the overall risk of mortality despite its effectiveness in reducing the risk of fractures. The primary consideration for prescribing bisphosphonates to individuals with osteoporosis should continue to be centered on reducing fracture risk, aligning with clinical guidelines. Long-term studies are needed to investigate potential effects on mortality during extended treatment periods. LEVEL OF EVIDENCE Level I, therapeutic study.

中文翻译：

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双膦酸盐治疗可以降低骨质疏松症患者的总体死亡率吗？随机对照试验的荟萃分析。


背景 对于骨质疏松症患者，双磷酸盐治疗可以降低骨折风险，但其对降低死亡率的作用尚不清楚。先前关于这一主题的研究产生了相互矛盾的结果，而且通常规模太小，无法明确回答双磷酸盐治疗是否会降低死亡率的问题。因此，荟萃分析可能有助于我们得出更结论性的答案。问题/目的在安慰剂对照随机对照试验 (RCT) 的大型荟萃分析中，我们提出以下问题：(1) 使用双膦酸盐是否会降低死亡率？ (2) 是否存在亚组效应，取决于是否使用不同的双膦酸盐药物（唑来膦酸盐、阿仑膦酸盐、利塞膦酸盐和伊班膦酸盐）、研究进行的不同地理区域（欧洲、美洲和亚洲）、研究是否受到限制针对绝经后女性患者，或者试验是否持续了 3 年或更长时间？方法 我们使用多个数据库进行了系统评价，包括 Embase、Web of Science、Medline（通过 PubMed）、Cochrane Library 和 ClinicalTrials.gov，每个数据库的检索时间截至 2023 年 11 月 20 日（这也是我们最后一次检索的日期）搜索），遵循系统评价和荟萃分析的首选报告项目（PRISMA）指南。我们纳入了随机、安慰剂对照临床试验，受试者被诊断患有骨质疏松症并接受双膦酸盐治疗。我们排除了发布到预印本服务器上的论文、其他未发表的作品、会议摘要以及在 ClinicalTrials.gov 上注册但尚未发表的论文。我们收集了 2263 条记录。 在排除因研究类型、不符合纳入标准的研究内容和重复而产生的记录后，我们的荟萃分析纳入了 47 项安慰剂对照随机对照试验，涉及 59,437 名参与者。进行数据提取、质量评估和统计分析。使用修订后的 Cochrane 偏倚风险工具对随机试验的潜在偏倚进行评估。该评估涵盖序列生成、分配隐藏、受试者盲法、结果评估者盲法、不完整的结果数据和报告偏差等因素。一些研究没有提供有关随机序列生成的明确细节，导致选择偏倚的风险很高。一些研究由于其开放标签性质，无法实现受试者和研究人员的双盲条件，导致中间性能偏差。尽管如此，总体研究质量还是很高的。由于研究之间的异质性较低，正如低统计异质性（即低 I2 统计量）所证明的那样，我们选择了固定效应模型，表明各个研究的效应大小是一致的。在这种情况下，固定效应模型可以提供更精确的估计。根据漏斗图的结果，我们没有发现发表偏倚的证据。结果 使用双磷酸盐并没有降低骨质疏松症患者的总体死亡风险（风险比 0.95 [95% CI 0.88 至 1.03]）。涉及不同双膦酸盐药物（唑来膦酸盐、阿仑膦酸盐、利塞膦酸盐和伊班膦酸盐）、地区（欧洲、美洲和亚洲）、不同人群（绝经后女性患者和其他患者）的亚组分析，以及持续 3 年或更长时间的试验显示与总体死亡率降低。 结论 根据我们全面的荟萃分析，有高质量的证据表明，骨质疏松症患者的双磷酸盐治疗虽然可以有效降低骨折风险，但并不能降低总体死亡风险。为骨质疏松症患者开出双磷酸盐处方的主要考虑因素应继续以降低骨折风险为中心，并与临床指南保持一致。需要长期研究来调查延长治疗期间对死亡率的潜在影响。证据级别 I 级，治疗研究。