Osteoimmuno-brain axis: a bridge connecting osteoporosis and cognitive decline and its clinical significance in dementia and Alzheimer's disease.

Osteoporosis and cognitive dysfunction, particularly Alzheimer's disease (AD), frequently co-occur in the elderly population, suggesting shared pathophysiological links. The emerging concept of the "osteoimmune-brain axis" provides a framework that emphasizes the immune system as the central mediator connecting skeletal and cerebral pathology. This review explores how the osteoimmune system-the dynamic interface between bone and immune interactions-influences brain function through pathways including systemic inflammation, cytokine release, and bone-derived hormones. We systematically synthesize evidence from basic mechanisms to clinical studies, with a critical appraisal of the strength and directionality of the evidence. Key questions addressed include: whether the observed associations are causal or merely associative; which bone-derived factors have human validation; and whether the axis primarily operates as a unidirectional driver, a bidirectional amplifier, or an epiphenomenon of shared aging processes. This review aims to provide a balanced theoretical foundation for future research and for developing prevention strategies targeting both skeletal and neurodegenerative diseases.