1). The symptoms associated with extrapyramidal effects often start soon after the initiation of treatment and may be transient [35]. In addition, the sedative and orthostatic hypotensive side effects of antipsychotics often occur immediately after

the start of treatment. The NVP-BGJ398 second period of increased risk after several months of use may reflect the effects of long-term hyperprolactinemia on bone density. Indeed, Hugenholtz et al. [20] found an increased risk only among long-term users of antipsychotics and attributed this to the prolactin-raising properties of antipsychotics. We did not find an association between the sedative and orthostatic hypotensive side effects and fracture risk in our analyses. One of the VEGFR inhibitor strengths of our study is the size of the study population (6,763 cases and 26,341 controls) and that it is representative for the general population of the Netherlands, although the absolute number of users of atypical antipsychotics was low. All prescribing information was collected routinely and we do not expect our findings to be Geneticin biased with regards to exposure status. Also, as fractures

invariably result in hospitalization, we are confident that cases, controls, and index dates were identified reliably. Nevertheless, given the observational nature of this study, the results should be interpreted with knowledge of its limitations. First, cases and controls were not matched on the period of observation available in the database and the results could be affected by information bias. However, the exclusion of patients with less than 1 year of follow-up did not affect the results substantially. Second, information about relevant diagnoses and co-morbidities may have been recorded upon hospitalization for a fracture and it is likely that the information available for cases was more complete and up-to-date than that available for controls. It could be argued that

we did not consider the use of bisphosphonates as a potential confounder. However, there should be a priori evidence, that a confounder is associated PDK4 both with antipsychotic exposure and hip fracture risk. As far as we know, there is no clear evidence that antipsychotic users are more likely to be exposed to bisphosphonates, compared to non-users. Moreover, in a case–control study, the use of bisphosphonates may act as an intermediate variable between exposure and outcome, rather than a confounder. This is supported by the positive association between bisphosphonate use and hip fracture (crude OR 1.71 [95% CI 1.47, 1.99], Table 2). Another potential limitation is the unavailability of data on smoking and alcohol consumption for a population that may include individuals with high levels of nicotine and/or alcohol consumption. Both are well-known risk factors of fracture risk [36, 37].