Dear Editor, We appreciate the response from Dr Corpechot and colleagues to our recently published communication on fracture cases observed in the phase 3 RESPONSE trial for seladelpar in primary biliary cholangitis (PBC) and reported in product labeling.1,2 In particular, we are pleased that the authors included previously unpublished data on the fracture rates during the BEZURSO trial. These data are helpful for contextualizing the fracture events observed in the registrational trials of seladelpar and elafibranor. However, certain statements by the authors merit comment. Corpechot et al.3 reported comparable fracture rates (95% CI) of 2.2 (0.6–8.8) per 100 subject-years in the placebo group and 3.1 (1.0–9.5) per 100 subject-years in the bezafibrate group and conjectured that bezafibrate may have a lower risk of fractures than seladelpar or elafibranor. It is premature to imply that bezafibrate has a benefit with respect to bone health for several reasons. First, the fracture rates the authors cite are similar to those we reported with seladelpar: 4.1, 3.0, and 2.7 per 100 subject-years in year 1, year 2, and year 3 exposures to seladelpar, respectively—all of which are within the confidence intervals reported for the BEZURSO study. Second, the fractures reported for the BEZURSO placebo group were of the toe, thumb, and rib. The first 2 of these would not be considered osteoporotic, as fractures of the fingers and toes are generally not attributed to low bone mass.4 Thus, there may in fact be an imbalance in fractures of concern with bezafibrate versus placebo. Third, peroxisome proliferator-activated receptor (PPAR)-gamma agonism has an established mechanistic explanation for an increased fracture risk due to loss of bone mass.5 There is no rationale to support the conclusion that a pan-PPAR agonist such as bezafibrate might have a decreased fracture risk compared with an agent such as seladelpar, which is selective for PPAR-delta.1 We do agree with the authors that additional studies are warranted to refine our understanding of bone health and fracture risk in patients with PBC undergoing treatment with PPAR agonists. Moreover, we wish to stress that assessment of bone mineral density and fracture risk, and appropriate treatment for osteoporosis, should be included in the care plan for every PBC patient.
Vierling et al. (Fri,) studied this question.