Multimodal integration of neuroimaging, transcriptomics and single-cell analysis reveals molecular correlates linking osteoporosis to brain abnormalities

<h4>Background</h4>Osteoporosis (OP) and cognitive decline are highly prevalent comorbidities; however, the molecular mechanisms linking them remain unclear. We adopted a multimodal integrative strategy combining neuroimaging, transcriptomics, single-cell analysis, and in vivo validation to elucidate potential mechanisms.<h4>Methods</h4>Fifty-six patients and fifty-three healthy controls underwent resting-state functional MRI (fMRI) to assess regional homogeneity (ReHo) and amplitude of low-frequency fluctuation (ALFF). Transcriptomic data from the Allen Human Brain Atlas (AHBA), single-nucleus RNA sequencing (snRNA-seq) of the human hippocampus, and validation using ovariectomized (OVX) mouse models were integrated.<h4>Results</h4>fMRI revealed significant ALFF/ReHo alterations in the hippocampus, prefrontal cortex, and posterior cingulate cortex of OP patients, with the left hippocampal ALFF mediating the association between bone mineral density (BMD) and Montreal Cognitive Assessment (MoCA) scores. Spatial correlation analyses have linked these brain functional changes to neurotransmitter receptors (5-HT1a, D1, GABAa, etc.) and genes enriched in synaptic function, neurogenesis, and dopaminergic signaling. snRNA-seq identified the caudal hippocampus as a key region, with astrocytes enriched in OP-associated Gene Program 5 (involving NR4A3 and KCNIP1) and functional pathways such as glutamatergic synapses and calcium signaling. OVX mice showed bone loss, spatial learning/memory impairment, hippocampal astrocyte abnormalities, and upregulation of GFAP, RGS7, and RGS6 proteins.<h4>Conclusion</h4>Our multimodal study establishes a molecular framework for the bone-brain axis, highlighting astrocytes and synaptic signaling as potential targets for the dual protection of bone and brain health.