Multimodal MRI reveals hypothalamic structural-functional alterations associated with bone mineral density loss in...

Emerging evidence implicates central nervous system dysregulation in the pathogenesis of osteoporosis. However, the role of hypothalamic subregions - a key central hub for homeostasis - in human bone health remains poorly understood. This study aimed to elucidate the structural and functional alterations of hypothalamic subregions in relation to bone mineral density (BMD) loss in postmenopausal women using multimodal MRI. Fifty-four postmenopausal women (18 with osteoporosis, 18 with osteopenia, and 18 healthy controls) underwent 3T MRI. A comprehensive analytical framework was employed, comprising: (1) deep learning-based segmentation of hypothalamic subregions; (2) seed-based functional connectivity analysis using these subregions as regions-of-interest; and (3) shape analysis of connected white matter bundles. Non-parametric statistics and partial correlations were applied to quantify associations between hypothalamic measures and BMD, controlling for covariates. Our analysis revealed multimodal alterations in hypothalamic subregions. Specifically, we observed region-specific volume changes in the right anterior inferior (decrease in osteoporosis) and left posterior hypothalamus (increase in osteoporosis), as well as enhanced functional connectivity between the left anterior inferior hypothalamus and the left superior lateral occipital cortex (sLOC)/precuneus (cluster-level FWE-corrected p = 0.030). Microstructural and shape alterations were also detected in white matter bundles connected to several subregions, though these findings should be interpreted as exploratory due to multiple comparisons. Furthermore, a significant positive correlation was found between the volume of the right anterior superior hypothalamus and BMD in the osteopenia group (r = 0.640, p = 0.004). This study provides preliminary in vivo evidence of multimodal hypothalamic alterations in postmenopausal osteoporosis. Our findings suggest that structural alterations in specific hypothalamic subregions and their functional connectivity with visual-attentional networks may be associated with BMD loss. The volume of the right anterior inferior hypothalamus warrants further investigation as a potential neuroimaging biomarker for fracture risk stratification.