Neuro-osteo crosstalk: The sympathetic nervous system as a key driver of SCI-induced osteoporosis.

Bone loss is a significantly underestimated secondary consequence of spinal cord injury (SCI), affecting more than 80% of people living with SCI. While this form of bone loss has been traditionally attributed to disuse, the severity, rapid onset and resistance to conventional therapies suggest that there are additional mechanisms involved. This review explores preclinical and clinical evidence implicating sympathetic dysfunction as a key contributor to SCI-induced osteoporosis. Increasing evidence positions the SNS a central regulator of bone homeostasis and hematopoiesis. We describe the anatomical and functional innervation of bone by sympathetic fibers and detail how norepinephrine can act through distinct adrenergic receptor subtypes to differentially regulate osteoblast activity, osteoclastogenesis, mesenchymal lineage commitment, and immune cell activity within the bone marrow microenvironment. We further examine how SCI disrupts these processes across the acute and chronic phases following injury through a catecholamine storm, decentralized sympathetic reflexes, chronic inflammation, and circadian desynchronization. Collectively, these changes can drive uncoupled bone remodeling and accelerate bone loss. Finally, we discuss therapeutic implications of targeting SNS signaling, including receptor subtype-selective strategies, combination therapies, neuro-osteo-immune modulation, and biomarker-driven early detection. By reframing SCI-induced osteoporosis as a consequence of autonomic dysregulation rather than disuse alone, this review calls attention to new mechanistic insight and highlights the SNS as a promising therapeutic target for prevention and intervention.