The role of exercise in enhancing brain and cerebrovascular health via the bone–brain axis: implications for surgical and clinical interventions

Abstract The bone–brain axis constitutes an interactive bidirectional signaling network integrating skeletal, neural, and muscular systems, serving critical functions across both normal physiological operations and disease mechanisms. Exercise, a non-pharmacological intervention, significantly influences this axis by enhancing bone-derived factors like osteocalcin, which in turn affect cognitive function, neuroplasticity, and systemic metabolism. This review delves into the molecular and cellular mechanisms underlying the bone–brain axis, with a particular focus on exercise-induced pathways. Physical activity stimulates the secretion of myogenic and neuromodulatory mediators including brain-derived neurotrophic factor (BDNF) and irisin, which augment synaptic adaptability, suppress inflammatory responses, and facilitate neuronal regeneration. These effects are critical in alleviating neurodegenerative diseases, osteoporosis, and mood disorders. The review also examines the endocrine role of bone-derived factors like uncarboxylated osteocalcin and sclerostin in modulating neurotransmitter synthesis and neuroimmune responses, including regulating osteoblast activity and bone remodeling, stimulating BDNF expression in the brain, regulating bone marrow-derived macrophages, and modulating cytokine pathways to alleviate neuroinflammation. Findings suggest that the bone–brain axis not only mitigates age-related degeneration but also holds therapeutic potential for chronic disease management. This review emphasizes the innovative application of exercise in optimizing bone–brain axis functionality, offering critical insights into its capacity to enhance cognitive performance, stabilize affective states, and promote systemic physiological resilience. By elucidating the intricate interplay between skeletal and neurobiological systems, this work paves the way for developing targeted interventions that can improve clinical outcomes in various surgical, orthopedic surgery and neurorehabilitation. Novel insights into the bone–brain axis: exercise-induced endocrine roles in cognitive and mental health This review synthesizes emerging evidence linking skeletal system signaling to brain function, with a specific focus on the bone–brain axis as a mediator of exercise benefits. By integrating findings from molecular biology, neuroscience, and exercise physiology, we highlight novel endocrine roles of osteokines such as osteocalcin and irisin in promoting cognition and mental health. This interdisciplinary perspective contributes to the growing understanding of exercise as a systemic intervention for neurodegeneration. Learning points : Exercise-induced bone signaling pathways, especially those involving osteocalcin and irisin, support cognitive function, neuroplasticity, and emotional regulation. The bone–brain axis represents a novel and promising therapeutic target for delaying or preventing neurodegenerative diseases. Creatine supplementation combined with exercise demonstrates synergistic potential in promoting both neurological and musculoskeletal health. Emerging interdisciplinary tools, including neuroimaging, artificial intelligence, and gene delivery systems, offer new avenues for personalized exercise-based interventions.