Treatment-related changes in total hip bone mineral density are applicable to trials of varied study designs and to drugs with differing mechanisms of action: meta-regression results from the FNIH-ASBMR SABRE study

Abstract

Emerging anti-osteoporosis therapies might present varied mechanisms of action and demand active control groups or sequential therapies due to ethical or mechanistic reasons. We previously showed a strong association between treatment-induced changes in total hip bone mineral density(THBMD) at 12 and 24 mo and reduced fracture risk in placebo-controlled trials. We determined the surrogate threshold effect(STE): the minimum THBMD difference (active-placebo) in a trial that would predict a significant reduction in fracture risk in trials. In this analysis, we investigated whether these associations are influenced by drug mechanism of action or trial design, including treatment with an anabolic followed by an anti-resorptive compared to active control or placebo. We analyzed individual patient data from 22 randomized, placebo-controlled trials (17 anti-resorptive, 3 PTH analogues, 1 odanacatib, and 1 romosozumab placebo-controlled phase), and three trials of an anabolic followed by an anti-resorptive(1 PTH analogue and 2 romosozumab). We established treatment-related differences in THBMD changes, calculated fracture risk reductions for radiologic vertebral and all clinical fractures, and estimated study-level associations between these features via meta-regression. We found consistent associations between treatment-related THBMD changes and fracture risk reduction across different drug mechanisms and trial designs. Among placebo-controlled trials, the r2 values for vertebral fractures were 0.73(p = .0001) and 0.78(p = .0002) at 24 mo, and 0.59(p = .0003) and 0.70(p = .0007) at 12 mo for all drugs versus only anti-resorptive drugs, respectively. Similarly, for all clinical fractures, the r2 were 0.71(p < .0001) and 0.65(p = .0009) at 24 mo and 0.46(p = .0007) and 0.51(p = .002) at 12 mo for all drugs versus only anti-resorptive drugs. For trials of an anabolic followed by an anti-resorptive, the association between THBMD change and fracture risk reduction was similar to that for the placebo-controlled monotherapy trials. Our analyses indicate robust associations between treatment-induced THBMD changes and fracture risk reduction across various anti-osteoporosis therapies and trial designs, suggesting that treatment-induced changes in THBMD predict anti-fracture efficacy regardless of drug mechanism or trial design.