Validation of the Surrogate Threshold Effect for Change in Bone Mineral Density as a Surrogate Endpoint for Fracture Outcomes: The FNIH-ASBMR SABRE Project

The surrogate threshold effect (STE) is defined as the minimum treatment effect on a surrogate that is reliably predictive of a treatment effect on the clinical outcome. It provides a framework for implementing a clinical trial with a surrogate endpoint. The aim of this study was to update our previous analysis by validating the STE for change in total hip (TH) BMD as a surrogate for fracture risk reduction; the novelty of this study was this validation. To do so, we used individual patient data from 61,415 participants in 16 RCTs that evaluated bisphosphonates (nine trials), selective estrogen receptor modulators (four trials), denosumab (one trial), odanacatib (one trial), and teriparatide (one trial) to estimate trial-specific treatment effects on TH BMD and all, vertebral, hip, and nonvertebral fractures. We then conducted a random effects meta-regression of the log relative fracture risk reduction against 24-month change in TH BMD, and computed the STE as the intersection of the upper 95% prediction limit of this regression with the line of no fracture reduction. We validated the STE by checking whether the number of fractures in each trial provided 80% power and determining what proportion of trials with BMD changes ≥ STE reported significant reductions in fracture risk. We applied this analysis to (i) the trials on which we estimated the STE; and (ii) trials on which we did not estimate the STE. We found that the STEs for all, vertebral, hip, and nonvertebral fractures were 1.83%, 1.42%, 3.18%, and 2.13%, respectively. Among trials used to estimate STE, 27 of 28 were adequately powered, showed BMD effects exceeding the STE, and showed significant reductions in fracture risk. Among the validation set of 11 trials, 10 met these criteria. Thus STE differs by fracture type and has been validated in trials not used to develop the approach.