Lan Zhibin, Lin Xue, Xue Di, Yang Yang, Saad Muhammad, Jin Qunhua
The Third Ward of Orthopaedic Department, General Hospital of Ningxia Medical University, Yinchuan, PR China.
Institute of Osteoarthropathy, Ningxia Key Laboratory of Clinical and Pathogenic Microbiology, Institute of Medical Sciences, General Hospital of Ningxia Medical University, Yinchuan, PR China.
Clin Orthop Relat Res. 2025 Jan 1;483(1):91-101. doi: 10.1097/CORR.0000000000003204. Epub 2024 Aug 22.
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?
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 We excluded papers posted to preprint servers, other unpublished work, conference abstracts, and papers that were registered on ClinicalTrials.gov but were not yet published.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 I 2 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.
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.
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 I, therapeutic study.
对于骨质疏松症患者，双膦酸盐治疗可降低骨折风险，但其对降低死亡率的影响尚不清楚。此前关于该主题的研究结果相互矛盾，且规模普遍较小，无法明确回答双膦酸盐治疗是否能降低死亡率的问题。因此，荟萃分析可能有助于我们得出更具结论性的答案。
问题/目的：在一项对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）使用双膦酸盐是否能降低死亡率？（2）基于所使用的不同双膦酸盐药物（唑来膦酸、阿仑膦酸钠、利塞膦酸钠和伊班膦酸钠）、研究开展的不同地理区域（欧洲、美洲和亚洲）、研究是否仅限于绝经后女性患者，或试验是否持续3年或更长时间，是否存在亚组效应？
我们使用多个数据库进行系统评价，包括Embase、Web of Science、Medline（通过PubMed）、Cochrane图书馆和ClinicalTrials.gov，每个数据库检索至2023年11月20日（这也是我们最后一次检索的日期），遵循系统评价和荟萃分析的首选报告项目（PRISMA）指南。我们纳入了诊断为骨质疏松症并接受双膦酸盐治疗的参与者的随机、安慰剂对照临床试验。我们排除了发布在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、研究内容不符合纳入标准以及重复记录后，我们的荟萃分析纳入了47项安慰剂对照RCT，涉及59437名参与者。进行了数据提取、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。该评估涵盖了诸如序列生成、分配隐藏、受试者盲法、结果评估者盲法、不完整结果数据和报告偏倚等因素。一些研究未提供关于随机序列生成的明确细节，导致选择偏倚风险较高。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，导致中等程度的执行偏倚。然而，总体研究质量较高。由于研究之间的异质性较低，如低统计异质性（即低I²统计量）所示，我们选择了固定效应模型，这表明效应大小在各研究中是一致的。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，我们未发现发表偏倚的证据。
使用双膦酸盐并未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、阿仑膦酸钠、利塞膦酸钠和伊班膦酸钠）、区域（欧洲、美洲和亚洲）、不同人群（绝经后女性患者和其他患者）以及持续3年或更长时间的试验的亚组分析显示，与总体死亡率降低无关。
基于我们全面的荟萃分析，有高质量证据表明，尽管双膦酸盐治疗对骨质疏松症患者降低骨折风险有效，但并不能降低总体死亡风险。为骨质疏松症患者开具双膦酸盐的主要考虑因素应继续以降低骨折风险为中心，这与临床指南一致。需要进行长期研究以调查延长治疗期对死亡率的潜在影响。
I级，治疗性研究。
