TY - JOUR
T1 - Thermoneutral housing does not rescue olanzapine-induced trabecular bone loss in C57BL/6J female mice
AU - Langlais, Audrie L.
AU - Mountain, Rebecca V.
AU - Kunst, Roni F.
AU - Barlow, Deborah
AU - Houseknecht, Karen L.
AU - Motyl, Katherine J.
N1 - Funding Information: The authors thank Megan Rue and Annika Treyball for assistance with data acquisition, Terry Henderson for technical assistance with μCT, and Drs. Christine Lary and Alexandre Lussier for their input on statistical methods. Funding: This work was supported by the NIH National Institute of General Medical Sciences ( P20GM121301 to KJM) and National Institute of Arthritis and Musculoskeletal and Skin Diseases ( R01AR076349 to KJM). This work was also supported by the National Institute of General Medical Sciences through the Northern New England Clinical and Translational Research (NNE-CTR) Network ( U54GM115516 to Clifford Rosen and Gary Stein), and the COBRE in Mesenchymal and Neural Regulation of Metabolic Networks ( P20GM121301 to Lucy Liaw). Publisher Copyright: © 2023 Elsevier B.V. and Société Française de Biochimie et Biologie Moléculaire (SFBBM)
PY - 2023/7
Y1 - 2023/7
N2 - Antipsychotic drugs are prescribed to a wide range of individuals to treat mental health conditions including schizophrenia. However, antipsychotic drugs cause bone loss and increase fracture risk. We previously found that the atypical antipsychotic (AA) drug risperidone causes bone loss through multiple pharmacological mechanisms, including activation of the sympathetic nervous system in mice treated with clinically relevant doses. However, bone loss was dependent upon housing temperature, which modulates sympathetic activity. Another AA drug, olanzapine, has substantial metabolic side effects, including weight gain and insulin resistance, but it is unknown whether bone and metabolic outcomes of olanzapine are also dependent upon housing temperature in mice. We therefore treated eight week-old female mice with vehicle or olanzapine for four weeks, housed at either room temperature (23 °C) or thermoneutrality (28–30 °C), which has previously been shown to be positive for bone. Olanzapine caused significant trabecular bone loss (−13% BV/TV), likely through increased RANKL-dependent osteoclast resorption, which was not suppressed by thermoneutral housing. Additionally, olanzapine inhibited cortical bone expansion at thermoneutrality, but did not alter cortical bone expansion at room temperature. Olanzapine also increased markers of thermogenesis within brown and inguinal adipose depots independent of housing temperature. Overall, olanzapine causes trabecular bone loss and inhibits the positive effect of thermoneutral housing on bone. Understanding how housing temperature modulates the impact of AA drugs on bone is important for future pre-clinical studies, as well as for the prescription of AA drugs, particularly to older adults and adolescents who are most vulnerable to the effects on bone.
AB - Antipsychotic drugs are prescribed to a wide range of individuals to treat mental health conditions including schizophrenia. However, antipsychotic drugs cause bone loss and increase fracture risk. We previously found that the atypical antipsychotic (AA) drug risperidone causes bone loss through multiple pharmacological mechanisms, including activation of the sympathetic nervous system in mice treated with clinically relevant doses. However, bone loss was dependent upon housing temperature, which modulates sympathetic activity. Another AA drug, olanzapine, has substantial metabolic side effects, including weight gain and insulin resistance, but it is unknown whether bone and metabolic outcomes of olanzapine are also dependent upon housing temperature in mice. We therefore treated eight week-old female mice with vehicle or olanzapine for four weeks, housed at either room temperature (23 °C) or thermoneutrality (28–30 °C), which has previously been shown to be positive for bone. Olanzapine caused significant trabecular bone loss (−13% BV/TV), likely through increased RANKL-dependent osteoclast resorption, which was not suppressed by thermoneutral housing. Additionally, olanzapine inhibited cortical bone expansion at thermoneutrality, but did not alter cortical bone expansion at room temperature. Olanzapine also increased markers of thermogenesis within brown and inguinal adipose depots independent of housing temperature. Overall, olanzapine causes trabecular bone loss and inhibits the positive effect of thermoneutral housing on bone. Understanding how housing temperature modulates the impact of AA drugs on bone is important for future pre-clinical studies, as well as for the prescription of AA drugs, particularly to older adults and adolescents who are most vulnerable to the effects on bone.
KW - Antipsychotic drugs
KW - Bone
KW - Sympathetic nervous system
KW - Thermoneutrality
UR - http://www.scopus.com/inward/record.url?scp=85160715609&partnerID=8YFLogxK
U2 - https://doi.org/10.1016/j.biochi.2023.05.002
DO - https://doi.org/10.1016/j.biochi.2023.05.002
M3 - Article
C2 - 37236340
SN - 0300-9084
VL - 210
SP - 50
EP - 60
JO - Biochimie
JF - Biochimie
ER -