Use of Bisphosphonates and the Risk of Skin Ulcer: A National Cohort Study Using Data from the French Health Care Claims Database.

INTRODUCTION: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Placebo response in Raynaud's Phenomenon clinical trials: The prominent role of regression towards the mean: Placebo response in Raynaud's Phenomenon.

BACKGROUND: Substantial placebo response has been observed in trials assessing treatments in Raynaud's Phenomenon (RP), which makes any treatment effect difficult to detect. However, whether this response is due to a real placebo effect or to other nonspecific effects, such as regression towards the mean (RTM), has not been explored. Our objectives were to explore and quantify placebo response in RP, and to evaluate the magnitude of RTM contribution. METHODS: We combined trial-level and individual-level data from a series of n-of-1 trials and a network meta-analysis, respectively. Main outcomes were the daily frequency and the mean duration of RP attacks, as well as the Raynaud's Condition Score (RCS). We estimated the placebo response by the mean difference between the placebo period (or arm) and the baseline. RTM was estimated by the relationship between placebo response and baseline, and with Galton squeeze plots. Finally, we simulated the effect of the threshold used for inclusion in clinical trials on RTM. FINDINGS: We observed a large and significant placebo response from both individual and trial data for RCS [-1.20 (-1.63, -0.77) and -0.65 (-0.89, -0.41)] and the daily frequency of RP [-0.61 (-0.85, -0.37) and -0.75 (-0.95, -0.54)]. Outcome at baseline was significantly associated with placebo response, suggesting the presence of RTM. The latter was confirmed on individual data, through Galton squeeze plots. INTERPRETATION: Placebo response is large in RP trials, and likely due to regression towards the mean rather than 'true' placebo effect. This should be carefully considered when designing future trials. FUNDING: This work has been partially supported by MIAI @ Grenoble Alpes (ANR-19-P3IA-0003).