Antifracture efficacy of antiresorptive agents are related to changes in bone density

There is a current debate about the extent to which antifracture efficacy o f antiresorptive drugs are related to changes in bone mineral density (BMD) . In vitro studies show that most of the variability in bone strength is re lated to BMD, and prospective studies have shown that low BMD is an importa nt predictor of fracture risk. It seems that higher levels of bone turnover are also associated with increased fracture risk. Over the short term, a r eduction in activation frequency or resorption depth would lead to fewer (a nd/or shallower) resorption sites and refilling of existing sites initially . There is also evidence that inhibiting resorption allows bone to respond to mechanical demands, preferentially thickening critical trabeculae, and t his may help compensate for reduced connectivity. Each of these mechanisms would increase BMD and would disproportionately improve bone strength. Over the long term, maintaining bone mass and preventing loss of structural ele ments would result in progressively greater differences in BMD and fracture risk over time, relative to untreated women. The conceptual model predicts that both the short- and long-term anti-fracture efficacy of antiresorptiv e drugs will depend on the extent to which treatment can increase and maint ain BMD. To examine this issue, we compiled data from clinical trials of an tiresorptive agents and plotted the relative risk of vertebral fractures ag ainst the average change in BMD for each trial. The confidence intervals ar e large for individual trials, and there was substantial variability in ant ifracture efficacy at any given level of change in BMD. Overall, however, t rials that reported larger increases in BMD tended to observe greater reduc tions in vertebral fracture risk. Poisson regression was used to quantify t his relationship. The model predicts that treatments that increase spine BM D by 8% would reduce risk by 54%; most of the total effect of treatment was explained by the 8% increase in BMD (41% risk reduction). These findings a re consistent with the short-term predictions of the conceptual model and w ith reports from randomized trials. The small but significant reductions in risk that were not explained by measurable changes in BMD might be related to publication bias, measurement errors, or limitations of current BMD tec hnology.