How to Interpret Surrogate Markers of Efficacy in Osteoporosis

Abstract

dence of the effectiveness of treatment. (6) The first issue raised is that changes in bone turnover are at least as informative as changes in BMD. We concur, and that is why changes in biochemical markers of bone turnover were an important secondary efficacy endpoint. Whereas the primary efficacy endpoint was the change in trochanter BMD at 12 months (for reasons noted in the paper), changes in four different biochemical markers of bone turnover measured at three different time-points (3, 6, and 12 months) were reported as secondary efficacy endpoints and discussed with equal prominence to the BMD changes. For all four markers, at all time-points measured, the reduction in the level of the marker from baseline was statistically greater with alendronate than with risedronate. The second point raised is that the relationship between changes in BMD and markers and fracture risk reduction may be nonlinear. Eastell et al. (7) reported that reductions in turnover during treatment with risedronate were associated with reductions in the risk of vertebral fractures, but appeared to reach a plateau beyond which fracture risk did not further decline. Data from a much larger study with alendronate reported no evidence of such a plateau over a wider range of reductions in turnover markers. (8) Moreover, in both publications, there was no evidence of a plateau or nonlinearity in the relationship between reduction in turnover markers and reduction in risk of nonvertebral fractures. It was also suggested that we did not evaluate cut-points for changes in bone turnover markers. These results are presented in a separate publication. (9) Analyses of data from the FIT and VERT studies are not comparable in design and did not reach the same conclusion as suggested by Drs Eastell and Delmas. (3,10) Although both studies addressed the issue of the relationship between incidence of spine fracture and changes in spine BMD on treatment, neither addressed the relationship between nonspine or hip fracture risk and changes in BMD. Thus, whereas we have acquired new information about the correlates of fracture reduction with antiresorptive treatments, the exact nature of those relationships are not yet clearly understood. fractures, it is important to recall that fractures were captured as adverse events. The fractures were self-reported, included any fracture (fingers, toes, face, etc.) regardless of location or cause, and were not verified by review of radiographic reports. In addition, this represents the total number of fractures, not the number of patients with fracture. As stated in the paper, there was no significant difference in the percent of patients reporting fractures as adverse events between treatment groups. We are certain that Drs Delmas and Eastell would agree that it is not prudent to make inferences from unadjudicated and underpowered fracture studies. Furthermore, in the recently completed FACTsInternational study of identical design, 18 fractures occurred in the alendronate treatment group and 20 fractures occurred in the risedronate treatment group. These results will be presented later this year, but serve to underscore the difficulty in interpreting fracture data from clinical trials not