An apparent decrease in the size of risk reduction

achieved with greater treatment PF-01367338 duration has been reported in previous studies of other anti-osteoporotic drugs. For risedronate, risk reductions of 65% and 61% seen at 1 year decreased to 41% and 49%, respectively, over 3 years [29, 30]. Comparisons of cumulative endpoints at different times during a long-term study must therefore be interpreted with caution. The patients at risk of a given endpoint, although well balanced between treatment groups in terms of disease characteristics and level of risk at randomization, become progressively unbalanced (for example, due to censoring of fracture cases, attrition of more severely affected patients, and introduction of concomitant Alvocidib osteoporosis medication) over time if treatments differ in efficacy. Attrition of high-risk patients will be more

rapid in the low efficacy (generally placebo) group. In the later parts of the study, therefore, the placebo group will effectively contain fewer high-risk patients than the active treatment group, and the effects of active treatment will appear to be reduced. The vertebral antifracture efficacy of strontium ranelate over 4 years in this study has also been confirmed over 5 years in the Treatment of Peripheral Osteoporosis study [16]. Many factors contribute to bone fragility that leads to osteoporotic fractures [31]. One important mechanism is the progressive net loss of bone due to a greater degree of bone resorption than formation at focal remodeling sites, leading to an overall deficit in bone formation in later adult life. In postmenopausal women, the rate of net bone loss is accelerated by an increase in the intensity of bone remodeling in response to reduced estrogen levels. Antiresorptive agents such as bisphosphonates Ibrutinib manufacturer and Selleck Baf-A1 raloxifene reduce the

rate of bone remodeling, reflected in decreases in markers of both bone formation and bone resorption [32, 33]. Strontium ranelate appears to have a different mode of operation. In various animal models, strontium ranelate has been shown to prevent bone loss by increasing bone formation and decreasing bone resorption [34]. These in vivo results were consistent with in vitro data where strontium ranelate has been shown to reduce bone resorption by osteoclasts and to stimulate bone formation by osteoblasts [34, 35]. It has been demonstrated in vitro that strontium ranelate is an agonist of the CaR and is able to stimulate the replication of osteoblasts through the activation of CaR [36]. CaR is one of the major molecular determinants involved in controlling the cations concentration through regulation of PTH [37]. The slight decrease in serum calcium and PTH in association with a slight increase in blood phosphorus observed in this study is in agreement with an action mediated through the CaR in postmenopausal women.