T9. BRAIN–BONE CROSSTALK IN SCHIZOPHRENIA-ASSOCIATED OSTEOPOROSIS: FROM BRAIN-CENTERED THERAPY TO BRAIN–BONE CO-TREATMENT

Background Schizophrenia is increasingly recognized as a systemic disorder rather than a purely brain-centered psychiatric disease. Osteoporosis and fragility fractures are underrecognized but clinically important comorbidities in patients with schizophrenia, who often show reduced bone mineral density, increased fracture risk, and poorer post-fracture outcomes. This review summarizes the evidence linking schizophrenia to osteoporosis and proposes a brain–bone axis framework to explain this comorbidity. Methods We synthesized evidence from epidemiological studies, meta-analyses, genetic association studies, Mendelian randomization analyses, mechanistic experiments, pharmacological research, artificial intelligence-based drug repurposing studies, and traditional Chinese medicine-related investigations. The evidence was organized around clinical associations, shared biological mechanisms, medication-related skeletal toxicity, and potential interdisciplinary prevention and treatment strategies. Results Current evidence indicates that schizophrenia-associated osteoporosis is driven by multiple interacting factors, including genetic susceptibility, neuroimmune dysregulation, neuroendocrine disturbance, lifestyle-related risks, nutritional deficiency, and long-term psychotropic medication exposure. Shared genetic architecture and immune-developmental pathways may predispose individuals to both psychiatric dysfunction and skeletal fragility. Complement components C3 and C4 may connect excessive microglia-mediated synaptic pruning with osteoclast activation and bone resorption. Similarly, the CX3CL1/CX3CR1 axis may link neuron–microglia communication in the brain with osteoblast–osteoclast interactions in bone. Antipsychotic-induced hyperprolactinemia, hypogonadism, HPA-axis dysregulation, inflammation, oxidative stress, and selective serotonin reuptake inhibitor exposure may further accelerate bone loss. These findings support the concept that schizophrenia-associated osteoporosis represents a brain–bone comorbidity shaped by genetic, neuroendocrine, immune-inflammatory, and toxicological interactions. Discussion The management of schizophrenia should move beyond a brain-centered model toward brain–bone co-treatment. Routine bone density screening, fracture risk assessment, vitamin D and calcium supplementation, exercise intervention, lifestyle modification, prolactin and sex hormone monitoring, and antipsychotic optimization should be incorporated into long-term care. Pharmacogenomics may help identify patients at high risk of drug-induced skeletal adverse effects, while artificial intelligence-based drug repurposing may reveal compounds targeting shared mechanisms such as neuroinflammation, complement activation, microglial dysfunction, and osteoclast overactivation. Multi-target traditional Chinese medicine strategies may also provide exploratory therapeutic potential. Future longitudinal cohorts, mechanistic studies, and clinical trials are needed to clarify causal pathways, validate biomarkers, and establish precision prevention and treatment strategies for schizophrenia-associated osteoporosis.