Aging and Disease · Oct 11, 2026

Sympathetic Regulation of Bone Metabolism: Mechanisms across Homeostasis, Aging and Disease

By Deng L, Liu Y, Che Z et al.

Bone remodeling is regulated by endocrine, mechanical, paracrine, immune, vascular, and neural signals. This narrative review examines sympathetic regulation of bone metabolism within an asymmetric bidirectional brain-bone neural network. Its comparatively well-supported descending arm comprises distributed central autonomic circuits, sympathetic outflow, intraosseous norepinephrine (NE) handling, and adrenergic signaling in skeletal and marrow cells, whereas bone-derived sensory afferents represent an emerging ascending component whose influence on subsequent bone-directed sympathetic output remains incompletely established. We synthesize evidence on skeletal innervation and neurovascular organization, local NE release and clearance, adrenergic receptor signaling, and downstream effects on osteoblast-lineage cells, osteocytes, osteoclast precursors, and marrow niche populations across homeostasis, aging, chronic stress and depression, estrogen deficiency, fracture healing, and cancer-associated bone disease. Preclinical studies support context-dependent effects of sympathetic signaling on bone formation and resorption, with the strongest receptor-specific evidence involving β₂-adrenergic mechanisms. However, skeletal outcomes vary with species, skeletal site, disease stage, intervention timing, neural and vascular status, transmitter clearance, physical activity, glucocorticoid exposure, metabolic inflammation, and marrow composition. Aging is treated as a multilevel modifier involving changes in autonomic rhythmicity, neural integrity, neurovascular coupling, NE handling, receptor responsiveness, marrow adiposity, inflammaging, cellular senescence, and stem-cell competence. Human beta-blocker data remain predominantly observational and do not establish skeletal therapeutic efficacy. Future studies should prioritize age-, sex-, site-, and stage-resolved neural mapping, direct measurement of intraosseous catecholamine dynamics, cell-specific causal interventions, and prospective human skeletal outcomes.

doi.org/10.14336/ad.2026.0886 Open access PubMed 42970310 Mechanisms