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.

Variants of the serotonin transporter gene, selective serotonin reuptake inhibitors, and bone mineral density in risperidone-treated boys: a reanalysis of data from a cross-sectional study with emphasis on pharmacogenetics.

Objective: Selective serotonin reuptake inhibitors (SSRIs) may reduce bone mineral density (BMD). Here, we investigate whether variants of the serotonin transporter-linked polymorphic region (5-HTTLPR) of the serotonin transporter gene moderate this association in boys.

Method: Between November 2005 and August 2009, medically healthy boys, aged 7 to 17 years, were enrolled in a cross-sectional study exploring the effect of risperidone-induced hyperprolactinemia on BMD.

Update in serotonin and bone.

Context: Serotonin (5-HT) may be an important regulatory agent in bone, and agents that modify 5-HT signaling, such as selective serotonin reuptake inhibitors (SSRIs), are in widespread clinical use.

Evidence Acquisition: Evidence was obtained by PubMed search and the author's knowledge of the field.

Evidence Synthesis: Recent data suggest that gut-derived 5-HT may mediate the skeletal effects of LDL receptor-related protein 5, stimulating intense interest in a novel mechanism for regulating bone mass.

Psychotropic drugs have contrasting skeletal effects that are independent of their effects on physical activity levels.

Popular psychotropic drugs, like the antidepressant selective serotonin reuptake inhibitors (SSRIs) and tricyclic antidepressants (TCAs), and the mood stabilizer lithium, may have skeletal effects. In particular, preclinical observations suggest a direct negative effect of SSRIs on the skeleton. A potential caveat in studies of the skeletal effects of psychotropic drugs is the hypoactive (skeletal unloading) phenotype they induce.

Effects of selective serotonin reuptake inhibitors on bone health in adults: time for recommendations about screening, prevention and management?

Evidence regarding a functional serotonin (5-hydroxytryptamine) signaling system in bone has generated considerable recent interest. The specific biochemical nature of serotoninergic pathways and their direct and/or indirect effects on bone metabolism are still unclear. Clinical evidence supports an effect of serotonin and altered serotonin signaling on bone metabolism.

The emerging role of serotonin (5-hydroxytryptamine) in the skeleton and its mediation of the skeletal effects of low-density lipoprotein receptor-related protein 5 (LRP5).

Novel molecular pathways obligatory for bone health are being rapidly identified. One pathway recently revealed involves gut-derived 5-hydroxytryptamine (5-HT) mediation of the complete skeletal effects of low-density lipoprotein receptor-related protein 5 (LRP5). Mounting evidence supports 5-HT as an important regulatory compound in bone with previous evidence demonstrating that bone cells possess functional pathways for responding to 5-HT.

Serotonin (5-hydroxytryptamine) transporter inhibition causes bone loss in adult mice independently of estrogen deficiency.

Objective: Selective serotonin reuptake inhibitors (SSRIs) treat depression by antagonizing the serotonin (5-hydroxytryptamine) transporter (5-HTT). These drugs may also have skeletal effects given the presence of functional serotonergic pathways in bone and evidence demonstrating detrimental effects of SSRIs on postmenopausal bone changes. This study aimed to explore the influence of an SSRI (fluoxetine hydrochloride) on the bone changes associated with estrogen deficiency in adult mice.

Male osteoporosis: new insights in an understudied disease.

Purpose Of Review: Osteoporosis in men is increasingly recognized as an important health problem. New research contributes to our knowledge of gender differences in osteoporosis risk, diagnosis and management. We undertook this review to summarize recent developments in the field of male osteoporosis.

Association of low bone mineral density with selective serotonin reuptake inhibitor use by older men.

Background: Selective serotonin reuptake inhibitors (SSRIs) are a widely used class of antidepressants that block the serotonin transporter. Osteoblasts and osteocytes express functional serotonin transporters; serotonin transporter gene disruption in mice results in osteopenia; and SSRI use has been associated with increased risk of hip fracture.

Methods: To determine whether SSRI use is associated with lower bone mineral density (BMD) in older men and to compare the results for SSRIs with those of other antidepressants, we performed a cross-sectional analysis of data from 5995 men 65 years and older participating in the prospective cohort Osteoporotic Fractures in Men Study.

Use of antidepressants and rates of hip bone loss in older women: the study of osteoporotic fractures.

Background: Serotonin transporters have recently been described in bone, raising the possibility that medications that block serotonin reuptake could affect bone metabolism.

Methods: We assessed current use of selective serotonin reuptake inhibitors (SSRIs) and tricyclic antidepressants (TCAs) and obtained serial bone mineral density (BMD) measurements in a cohort of 2722 older women (mean age, 78.5 years) participating in the Study of Osteoporotic Fractures, a prospective cohort study of community-dwelling women.

Periosteal remodeling at the femoral neck in nonhuman primates.

Unlabelled: Periosteal bone turnover is poorly understood. We documented intramembranous periosteal bone turnover in the femoral neck in intact nonhuman primates and an increase in osteoclast numbers at the periosteal surface in sex steroid-deficient animals. Our studies are the first to systematically document periosteal turnover at the femoral neck.

Neural regulation of bone and the skeletal effects of serotonin (5-hydroxytryptamine).

There is increasing evidence for a contribution of the neural system to the regulation of bone metabolism. The skeleton is richly innervated by both sympathetic and sensory neurons. While these nerves serve sensory and vascular functions, they are also being found to influence bone cell activities.

Inhibition of the serotonin (5-hydroxytryptamine) transporter reduces bone accrual during growth.

Selective serotonin-reuptake inhibitors (SSRIs) antagonize the serotonin (5-hydroxytryptamine) transporter (5-HTT), and are frequently prescribed to children and adolescents to treat depression. However, recent findings of functional serotonergic pathways in bone cells and preliminary clinical evidence demonstrating detrimental effects of SSRIs on bone growth have raised questions regarding the effects of these drugs on the growing skeleton. The current work investigated the impact of 5-HTT inhibition on the skeleton in: 1) mice with a null mutation in the gene encoding for the 5-HTT; and 2) growing mice treated with a SSRI.