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Response to Comparison of Teriparatide and Strontium Ranelate in Postmenopausal Women With Osteoporosis

Thank you for asking us to respond to the comments in the letter by Meunier et al. regarding our study of the comparative effects of teriparatide and strontium ranelate (SrR) in postmenopausal women. In our study, the mean serum levels of 25-hydroxyvitamin D were normal in both the SrR and teriparatide groups at baseline. Therefore, we believe that it is very unlikely that the small, nonsignificant differences observed between the two groups would adversely affect the outcomes for the SrR group. Although slightly more women received prior calcitonin or hormone replacement therapy (HRT) in the SrR group compared with the teriparatide group, it is doubtful that this could ‘‘dramatically’’ interfere with the effects of SrR treatment because both calcitonin and HRT are weak antiresorptives. Furthermore, according to protocol, these agents had to be stopped at least 12 mo before randomization and both are known to completely and rapidly wash out. Importantly, baseline bone turnover markers and the intact endogenous PTH levels were similar at baseline, with no statistically significant differences between the groups. As indicated in our study, compliance with the daily dosing, monitored through the quantity of the study material returned, was very high in the two groups. Indeed, only one patient in the teriparatide group (3.4%) and none in the SrR group received <85% of the total scheduled daily doses, which was the predefined noncompliance threshold, in the 6-mo treatment period. We believe that the measurement of blood strontium content was unnecessary because this was a postauthorization trial where the approved dose of SrR for the treatment of postmenopausal osteoporosis was used and proper instructions to ensure correct administration of SrR were given to the patients. Although we are aware that measurements of blood strontium levels were used to eliminate patients from histomorphometric analyses in a recent analysis of patients included in phase 3 trials of women receiving SrR, we believe that this may conflict with the standard methodology of intent-to-treat analyses in comparator studies of treatments. The increased transient cortical porosity induced by teriparatide has been described previously in controlled studies in nonhuman primates and in a comparative study of teriparatide and alendronate in humans. This finding would be expected in the context of increased bone remodeling induced by teriparatide. It has been shown that the teriparatide-induced increase in cortical porosity does not adversely affect the mechanical integrity of monkey proximal femora and humerus, because the enhanced cortical area and trabecular bone volume more than compensate for the porosity. Additionally, the intracortical porosity was spatially localized toward the endocortical surface where the mechanical effect is smaller than radially distributed bone in the periosteal region. Increases in bone strength in humans, after teriparatide treatment, have been shown using finite element analyses techniques at the spine and biomechanical measurements derived from QCT at the hip and distal radius. Also, it has been shown that teriparatide reduces the incidence of nonvertebral fractures. Thus, we believe that the concern expressed by Meunier et al. on the bone quality of teriparatide-treated patients is not justified. In our report, it was clearly stated that the numerically greater changes in the dynamic parameters of bone formation in the teriparatide group compared with the SrR group were not statistically significant. Furthermore, the results are fully disclosed in the manuscript, and in our opinion, the statement cannot be considered misleading to the reader. However, we are concerned that the title of the letter from Meunier et al., that describes both agents as anabolic, could be misleading. Their interpretation, that the lack of statistically significant differences in the histomorphometric parameters between the two treatments suggest that SrR has anabolic effects on bone microarchitecture, is untenable. The statistical principles for clinical trials included in the ICH-E9 states that ‘‘concluding equivalence or non-inferiority based on observing a non-significant test result of the null hypothesis that there is no difference between the investigational product and the active comparator is inappropriate.’’ This study was planned to provide evidence that teriparatide was superior to strontium and, although we did not find sufficient evidence to reject the null hypothesis of no difference, neither did we find any evidence that the two treatments are equivalent. Considering our primary endpoint, percent of mineralization surface (MS/BS%) at the trabecular level, we showed with 95% certainty the mean mineralization surface after 6 mo of teriparatide treatment was between 4.8% and 10.6% (95% CI) and after 6 mo of strontium the mean was between 3.0% and 7.5%. With such imprecise estimates of the mean, it is not possible to conclude that the two treatments are equivalent. It was of interest that, at the endocortical surface, the difference in MS/BS% (17.22% and 9.70% in the teriparatide and the SrR groups, respectively) were only borderline nonsignificant (p = 0.052). Moreover, Meunier et al. did not comment on our findings with regard to the biochemical markers of bone turnover. The statistically significant reductions compared with baseline in serum amino-terminal propeptide of type I collagen (PINP) and b-C-terminal teleopeptide of type I collagen (b-CTX) in the SrR group indicate a weak inhibition of bone turnover activity at the