Several studies have found a 1.5- to twofold increase in the risk of bone fractures in elderly patients taking TCAs or SSRIs. In a cohort study of more than 8,000 community-dwelling older women followed for almost 5 years, the risk of nonspinal fractures increased by a factor of 1.7 for those taking TCAs or SSRIs (Ensrud et al. 2003). More recently, a randomized cohort of 5,008 community-dwelling adults older than 50 years followed for a 5-year period found a 2.1-fold increase in the rate of fractures for those taking SSRIs (Richards et al. 2007). In this study, SSRI use was also associated with increased risk of falls, lower bone mineral density at the hip, and a trend toward lower bone mineral density at the spine in a dose- dependent fashion.

Animal models have so far failed to consistently demonstrate significant changes in bone architecture as a result of SSRI exposure, and the exact mechanism by which SSRIs may lead to fractures in humans is still unclear. There does appear to be, however, a functional serotonin 5-HT system in osteoclasts and osteoblasts involving both receptor activation and 5-HT reuptake (Battaglino et al. 2007).

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