Center for Molecular Medicine, MaineHealth Institute for Research, MaineHealth, Scarborough, ME, USA; Graduate School of Biomedical Science and Engineering, University of Maine, Orono, ME, USA.
Center for Molecular Medicine, MaineHealth Institute for Research, MaineHealth, Scarborough, ME, USA.
Biochimie. 2023 Jul;210:50-60. doi: 10.1016/j.biochi.2023.05.002. Epub 2023 May 24.
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.
抗精神病药物被广泛用于治疗包括精神分裂症在内的各种精神健康疾病。然而，抗精神病药物会导致骨质流失，增加骨折风险。我们之前发现，典型的抗精神病药物（AA）药物利培酮通过多种药理机制导致骨质流失，包括在接受临床相关剂量治疗的小鼠中激活交感神经系统。然而，骨质流失依赖于住房温度，而温度调节交感神经活动。另一种 AA 药物奥氮平具有显著的代谢副作用，包括体重增加和胰岛素抵抗，但目前尚不清楚奥氮平的骨骼和代谢结果是否也依赖于小鼠的住房温度。因此，我们用载体或奥氮平治疗 8 周龄雌性小鼠 4 周，分别在室温（23°C）或热中性（28-30°C）下饲养，之前的研究表明这对骨骼有益。奥氮平导致明显的小梁骨丢失（-13% BV/TV），可能是通过增加 RANKL 依赖性破骨细胞吸收所致，而热中性住房并不能抑制这种吸收。此外，奥氮平抑制了热中性条件下的皮质骨扩张，但在室温下不改变皮质骨的扩张。奥氮平还增加了棕色和腹股沟脂肪组织中与产热有关的标志物的表达，而与住房温度无关。总的来说，奥氮平导致小梁骨丢失，并抑制了热中性住房对骨骼的积极影响。了解住房温度如何调节 AA 药物对骨骼的影响对于未来的临床前研究以及 AA 药物的处方非常重要，特别是对于最容易受到骨骼影响的老年人和青少年。
