Possible mechanisms for the skeletal effects of antipsychotics in children and adolescents

The increasing use of antipsychotics (APs) to treat pediatric psychiatric conditions has led to concerns over the long-term tolerability of these drugs. While the risk of cardiometabolic abnormalities has received most of the attention, preclinical and clinical studies provide preliminary evidence that APs can adversely impact bone metabolism. This would be most concerning in children and adolescents as suboptimal bone accrual during development may lead to increased fracture risk later in life. However, the potential mechanisms of action through which APs may impact bone turnover and, consequently, bone mineral content are not clear. Emerging data suggest that the skeletal effects of APs are complex, with APs directly and indirectly impacting bone cells through modulation of multiple signaling pathways, including those involving dopamine D-2, serotonin, adrenergic, and prolactin receptors, as well as by affecting gonadotropins. Determining the action of APs on skeletal development is further complicated by polypharmacy. In children and adolescents, APs are frequently coprescribed with psychostimulants and selective serotonin reuptake inhibitors, which have also been linked to changes in bone metabolism. This review discusses the mechanisms by which APs may influence bone metabolism. Also covered are preclinical and pediatric findings concerning the impact of APs on bone turnover. However, the dearth of clinical information despite the potential public health significance of this issue underscores the need for further studies. The review ends with a call for clinicians to be vigilant about promoting optimal overall health in chronically ill youth with psychopathology, particularly when pharmacotherapy is unavoidable.