# Project 4: Neural and metabolic mechanisms of atypical antipsychotic drug-induced bone loss

> **NIH NIH P20** · MAINEHEALTH · 2020 · $303,861

## Abstract

Atypical antipsychotic (AA) drugs are widely prescribed to adolescents, adults, and the elderly for
schizophrenia, bipolar disorder and dementia. Patients taking AA drugs have increased fracture risk and
young adults may have impaired bone accrual, although the mechanisms have not been delineated.
Additional side effects include sleep disruption, hyperphagia, hyperglycemia and obesity. Although AA
drugs are necessary for the well being of many patients, understanding the mechanisms of their side effects
is critical for improving drug design. Risperidone (RIS) is a commonly prescribed AA, and we showed that
RIS-treated mice have significant trabecular bone loss due to increased bone resorption and reduced bone
formation (uncoupled remodeling). Because AA drugs have complex receptor pharmacology, there are
many potential mechanisms for AA-induced bone loss. We demonstrated direct effects of RIS on
osteoclasts, and found evidence for centrally-mediated effects of RIS on bone. Moreover we showed that
the β-blocker propranolol blocks RIS-induced bone loss, suggesting sympathetic nervous system (SNS)
activation is involved. Another critical observation is the effect of RIS on brown adipose tissue (BAT), the
function of which has been associated with bone changes in a variety of models. Interestingly, AA drugs are
also known to cause circadian disruption and altered fuel utilization to fatty acid oxidation (fuel switching).
My major hypotheses are that RIS acts centrally to disrupt circadian rhythms in the brain and causes fuel
switching and BAT activation, which ultimately lead to bone loss and fractures. Understanding how RIS
imparts these changes will have a significant impact on bone and metabolic health. To test these tenets I
propose two aims: Specific Aim 1. Test the hypothesis that RIS acts centrally to disrupt the circadian
rhythm of bone. Regions of the brain that bind RIS and also connect to the innervation of bone are
unknown. We will perform neuron tracing from bone to brain, coupled with RIS binding assays to identify
candidate regions of the brain that are targeted by RIS and also innervate bone. RIS will then be
administered through intracerebroventricular injection or oral gavage and target gene expression analyzed
in the brain and bone. Specific Aim 2. Test the role of RIS-induced fuel switching and BAT activation in
mediating trabecular bone loss. RIS causes fuel switching to fatty acid oxidation, which is required for
maintaining normal body temperature. We hypothesize that bone loss from RIS is due to sympathetic drive
for thermogenesis. However, an indirect effect of BAT on bone may also uncouple remodeling. We will test
this using denervation and a selective β3-adreneric receptor inhibitor to block BAT thermogenesis after RIS
treatment. The proposed work will broaden our understanding of the adipose-neural-bone network and
impact the health of patients treated with AA drugs.

## Key facts

- **NIH application ID:** 10009420
- **Project number:** 5P20GM121301-04
- **Recipient organization:** MAINEHEALTH
- **Principal Investigator:** Katherine Jean Motyl
- **Activity code:** P20 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $303,861
- **Award type:** 5
- **Project period:** 2017-09-01 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10009420

## Citation

> US National Institutes of Health, RePORTER application 10009420, Project 4: Neural and metabolic mechanisms of atypical antipsychotic drug-induced bone loss (5P20GM121301-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10009420. Licensed CC0.

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