13 based on the treatment-by-study interaction term in the Poisson regression model. The estimated relative risk for AF SAEs was 1.25 (95% CI = 0.82, 1.93; p = 0.33, Fig. 1B) and was similar to the estimated odds ratio for all serious events of 1.24 (95% CI = 0.87, 1.87; p = 0.29; Table 2).

There were 55 participants with one or more AF SAEs for alendronate occurring in six JQ1 cost trials compared with 41 events for placebo occurring in eight trials. Twenty-two trials (68.8%) did not have any AF SAEs. Results for atrial fibrillation without including atrial flutter were similar (data not shown). Sensitivity analysis The stability of the estimates for all events and for SAEs was evaluated by conducting exact Poisson regression meta-analyses with each study eliminated one at a time. The order of magnitude of the relative risk for all events

of AF changed very little as each study was eliminated, although the 95% confidence interval became wider when the large GSK2245840 in vivo clinical fracture cohort of FIT, study 51.2, was eliminated (Fig. 2A). Fig. 2 Relative risk (RR) of all events (A) or serious events (B) of atrial fibrillation or atrial flutter cross-validation by eliminating one study at a time. For example, the first RR represents all trials except study 26, etc. Study 51.1 is the vertebral fracture cohort of FIT, and study 51.2 is the clinical fracture cohort of FIT The two cohorts for FIT, which represent 34% of the participants taking alendronate and 41% of Linsitinib molecular weight the participants taking placebo, experienced 87.3% of the AF SAEs for alendronate and 78.0% of the AF SAEs for placebo. The relative risk of AF SAEs including all studies was 1.25 (95% CI = 0.82, 1.93), but became Dichloromethane dehalogenase 0.97 (95% CI = 0.51, 1.85) when the clinical fracture cohort of FIT, study 51.2, was excluded (Fig. 2B), indicating that the results for serious

events were driven by the AF SAEs in that FIT cohort [RR 1.56 (95% CI = 0.86, 2.89) for AF SAEs in the clinical fracture cohort]. In the vertebral fracture cohort (study 51.1), the relative risk of AF SAEs was 1.37 (95% CI = 0.62, 3.15), but this cohort had a smaller contribution to the overall results because it represented approximately one third of the patient years of the clinical fracture cohort. Figure 3 summarizes the relative risk of AF and serious events of AF within the pre-specified subgroups. Both cohorts for FIT are included in the >65 group for age, length of study >1 year, and pivotal studies of osteoporosis. The clinical fracture cohort of FIT is not included in the elderly participants group because the average age was less than 70 years old (mean age 61 years). The results of the clinical fracture cohort of FIT overwhelm the results of the other studies to the extent that the subgroup analyses reflect the presence or absence of that cohort in the subgroup. Fig.