DataSheet4_Risk of Fracture During Androgen Deprivation Therapy Among Patients With Prostate Cancer: A Systematic Review and Meta-Analysis of Cohort Studies.pdf

Background: Androgen deprivation therapy (ADT) suppresses the production of androgen, and ADT is broadly used for intermediate or higher risk disease including advanced and metastatic cancer. ADT is associated with numerous adverse effects derived from the pharmacological properties. Previous meta-analysis on fracture risk among ADT users possessed limited data without further subgroup analysis. Risk estimation of updated real-world evidence on ADT-related fracture remains unknown.
Objectives: To assess the risk of fracture and fracture requiring hospitalization associated with ADT among prostate cancer population on different disease conditions, treatment regimen, dosage level, fracture sites.
Methods: The Cochrane Library, PubMed, and Embase databases were systematically screened for eligible cohort studies published from inception to March 2020. Two authors independently reviewed all the included studies. The risks of any fracture and of fracture requiring hospitalization were assessed using a random-effects model, following by leave-one-out, stratified, and sensitivity analyses. The Grading of Recommendations Assessments, Development and Evaluations (GRADE) system was used to grade the certainty of evidence.
Results: Sixteen eligible studies were included, and total population was 519,168 men. ADT use is associated with increasing fracture risk (OR, 1.39; 95% CI, 1.26–1.52) and fracture requiring hospitalization (OR, 1.55; 95% CI, 1.29–1.88). Stratified analysis revealed that high-dose ADT results in an elevated risk of fracture with little statistical heterogeneity, whereas sensitivity analysis restricted to adjust for additional factors indicated increased fracture risks for patients with unknown stage prostate cancer or with no restriction on age with minimal heterogeneity. The GRADE level of evidence was moderate for any fracture and low for fracture requiring hospitalization.
Conclusion: Cumulative evidence supports the association of elevated fracture risk with ADT among patients with prostate cancer, including those with different disease conditions, treatment regimens, dose levels, and fracture sites. Further prospective trials with intact information on potential risk factors on fracture under ADT use are warranted to identify the risky population.

背景：雄激素剥夺疗法（Androgen deprivation therapy, ADT）可抑制雄激素的合成与分泌，目前广泛应用于包括晚期及转移性癌症在内的中高危疾病的治疗。ADT的药理学特性可引发多种不良反应。既往针对ADT使用者骨折风险的荟萃分析因数据量有限，未开展进一步亚组分析。基于最新真实世界证据的ADT相关骨折风险评估仍有待明确。
研究目标：评估不同疾病状态、治疗方案、给药剂量及骨折部位下，前列腺癌患者接受ADT治疗后发生骨折及需住院治疗的骨折的风险。
方法：系统检索考克兰图书馆、PubMed及Embase数据库，筛选建库至2020年3月发表的合格队列研究。由两名研究者独立完成所有纳入研究的筛选与评价。采用随机效应模型评估任意骨折及需住院治疗的骨折的发生风险，随后开展逐一剔除分析、亚组分析及敏感性分析。采用推荐分级、评估、制定与评价（Grading of Recommendations Assessments, Development and Evaluations, GRADE）系统对证据确定性进行分级。
结果：本研究共纳入16项合格研究，涉及男性受试者总计519168例。研究结果显示，ADT使用与骨折风险升高显著相关（比值比（Odds Ratio, OR）=1.39，95%置信区间（95% Confidence Interval, 95% CI）：1.26~1.52），同时也与需住院治疗的骨折风险升高相关（OR=1.55，95%CI：1.29~1.88）。亚组分析结果显示，高剂量ADT可显著升高骨折风险，且该分析的统计学异质性极低；而校正额外混杂因素后的敏感性分析表明，前列腺癌分期未知或未限定年龄的患者骨折风险显著升高，此类分析的异质性同样极低。针对任意骨折的证据确定性GRADE分级为中等，针对需住院治疗的骨折的证据确定性GRADE分级为低等。
结论：现有累积证据表明，前列腺癌患者接受ADT治疗后骨折风险升高，且该关联在不同疾病状态、治疗方案、给药剂量及骨折部位的亚组中均存在。未来需开展纳入ADT治疗下骨折潜在危险因素完整信息的前瞻性研究，以明确高风险人群。