Pharmacovigilance Department, Grenoble Alpes University Hospital, 38043, Grenoble, France.
University Bordeaux, INSERM, BPH, Team AHeaD, U1219, 33000, Bordeaux, France.
Drug Saf. 2023 Sep;46(9):905-916. doi: 10.1007/s40264-023-01336-x. Epub 2023 Aug 2.
Previous pre-clinical and pharmacovigilance disproportionality analyses highlighted a safety signal of cutaneous ulcer with bisphosphonate use. Therefore, our objective is to evaluate this risk and assess whether unmeasured confounding factors could explain this association.
This study is a population-based cohort study from a representative sample (1/97th) of the French health insurance claims database: Echantillon Généraliste des Bénéficiaires (EGB) from 2006 to 2019. To limit the impact of our study design and methodological choices on any association between skin ulceration and exposure to bisphosphonates, we used several methods: a Cox proportional hazards analysis and a prior event rate ratio (PERR) analysis, using two propensity matched control groups, and either the first episode of incident ulceration or multiple event-time outcomes.
There were 7402 individuals newly exposed to bisphosphonates matched to 29,605 unexposed individuals on propensity score. The primary outcome was skin ulcer occurrence assessed by at least 2 deliveries of wound dressing during the period of one month. Among 6911 individuals newly exposed to bisphosphonates and 28,072 unexposed individuals with no previous skin ulcer, the Cox regression yielded a hazard ratio (HR) of 1.40 (95% CI 1.26-1.56) for newly exposed individuals. Among 7402 exposed and 29,605 unexposed individuals, the PERR analysis found a non-significant HR of 1.03 (95% CI 0.87-1.24). Results were similar on the different sensitivity analyses.
No association between bisphosphonate and skin ulcers was found in the French population. The association observed in previous pharmacovigilance studies and in the Cox regression analysis is likely due to unmeasured confounding factors.
先前的临床前和药物警戒不稳定性分析强调了双膦酸盐使用与皮肤溃疡之间的安全信号。因此，我们的目标是评估这种风险，并评估是否有未测量的混杂因素可以解释这种关联。
本研究是一项基于人群的队列研究，来自法国健康保险索赔数据库的代表性样本（1/97）：2006 年至 2019 年的 Echantillon Généraliste des Bénéficiaires（EGB）。为了限制我们的研究设计和方法选择对皮肤溃疡与双膦酸盐暴露之间任何关联的影响，我们使用了几种方法：Cox 比例风险分析和先前事件率比（PERR）分析，使用两个倾向评分匹配的对照组，以及首次发生溃疡或多次事件时间结局。
共有 7402 名新暴露于双膦酸盐的个体与 29605 名未暴露的个体根据倾向评分相匹配。主要结局是通过一个月内至少 2 次伤口敷料治疗评估的皮肤溃疡发生。在 6911 名新暴露于双膦酸盐的个体和 28072 名无先前皮肤溃疡的未暴露个体中，Cox 回归得出新暴露个体的风险比（HR）为 1.40（95%CI 1.26-1.56）。在 7402 名暴露个体和 29605 名未暴露个体中，PERR 分析发现非显著 HR 为 1.03（95%CI 0.87-1.24）。在不同的敏感性分析中，结果相似。
在法国人群中，未发现双膦酸盐与皮肤溃疡之间存在关联。先前药物警戒研究和 Cox 回归分析中观察到的关联很可能是由于未测量的混杂因素所致。
