Whilst none of the risk estimates was significantly different, a clear trend was evident and this supports the possibility that stronger

inhibition of the 5-HTT system on the bone could cause a greater disruption of the balance between osteoblasts click here and osteoclasts and hence have a greater detrimental effect on bone micro-architecture. Drug-induced changes in bone micro-architecture can be rapid. Analysis of the micro-architecture of femur bone in rats treated with 5-HT showed changes in trabecular bone volume and an increased femoral stiffness after just 3 months [10]. Other drug exposures had demonstrated similarly rapid effects on human bone, e.g. corticosteroids [42, 43]. It is possible that a rapid change in bone micro-architecture affected by anti-depressant use accounted for, or at least contributed to, the increased fracture risk during the early months of exposure. We found that as the duration of treatment with TCAs increased, the risk of fracture declined, whereas the risk for fracture with continuation of SSRIs fell after the initial increase but remained somewhat elevated thereafter.

It may be that with chronic administration of anti-depressants, adaptive changes occur [44]. These may result in an adjustment to the cardiovascular effect of TCAs and SSRIs, explaining the decrease in fracture risk after a few months of use, whereas changes in bone physiology are not subject to adaptive changes, explaining the sustained find more fracture risk in SSRI users. Limitations of our study include absence of potentially confounding data on body mass index (BMI), smoking status and exercise. In a US/Puerto Rican cohort study, it was likely that lack of adjustment for BMI, current smoking status, activities of daily living score, cognitive impairment and Rosow–Breslau physical impairment scale accounted for up to 30% of the increased risk of hip fractures amongst users of SSRIs [45]. We do not anticipate that missing data on these variables would have an important impact on our findings; therefore, as if our ORs were decreased by 30%, a positive association would remain. Another limitation lies in the potential for confounding by

indication, as depression Tyrosine-protein kinase BLK itself is associated with an increased risk of falls and fractures [46]. There is also the possibility of a channelling effect whereby, for some frail patients with depression, an SSRI was prescribed instead of a TCA because of the more favourable side-effect profile anticipated. This could have overestimated the risk associated with SSRIs observed here. These unmeasured types of confounding as well as selection bias (e.g. healthy user bias), which can change over time, may be alternative explanations for our observed associations between fracture risk and duration of anti-depressant use or discontinuation of anti-depressants. In Figs. 1 and 2, data beyond 4 years are sparse, which makes extrapolation uncertain. Lastly, the PAR calculation showed that 4.