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

Abstract

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.

Propranolol Attenuates Risperidone-Induced Trabecular Bone Loss in Female Mice

“…In this study, we hypothesized that RIS causes SNSmediated bone loss (26,31). In brief, we found high energy expenditure (EE) and markers of SNS activity in RIStreated mice, consistent with elevated SNS tone.…”

“…Potential sex differences and other mechanisms through which RIS affects bone (including via prolactin-induced hypogonadism and direct effects bone cells themselves) are currently under investigation. Although the mechanisms whereby RIS activates SNS outflow to bone remain unclear, the role of the SNS in mediating bone loss in humans treated with AA medications should be prospectively examined, particularly because some individuals are concomitantly treated with ␤-blockers (31). Future clinical studies will provide insight into the pathophysiologic consequences of AA treatment and help to inform clinical decision-making about this widely prescribed class of medications.…”

The Effect of Psychostimulants on Skeletal Health in Boys Co-Treated with Risperidone

“…Many of the participants had taken risperidone and SSRIs (95 and 46%, respectively; Table III). These medications affect bone metabolism, 18, 30 which could have masked an independent effect of psychostimulants. Thus, future studies should consider examining the skeletal effects of psychostimulants in the absence of polypharmacy.…”

Elucidating the Mechanism(s) Underlying Antipsychotic- and Antidepressant-Mediated Fractures

“…A prospective study found that BMD in 120 firstepisode inpatients with schizophrenia prescribed either clozapine, quetiapine or aripiprazole was significantly lower than in matched healthy controls (n=90), 12-months after drug initiation 17 . In pediatric patients, AA-associated fractures were increased 2-3 fold with an associated reduction in bone mass [20][21] . Given the devastating effects of fractures in elderly patient populations, as well as the potential of inhibiting peak bone accrual in pediatric patients, the antipsychotic-induced association with increased fracture risk should impact prescribing practices in vulnerable patient populations.…”

“…A popular hypothesis in the clinical literature is that the AA-induced increase in fractures is due to hyperprolactinemia induced hypogonadism 20 . It is well known that hypogonadism causes bone loss and increased fracture risk, and antipsychotic medications can cause hyperprolactinemia in women, men and children.…”