Mechanisms of Bone-Brain Axis Involvement in Concurrent Nervous and Skeletal System Impairments Associated with Narcotic Drug Addiction: a Review

Narcotic drug addiction is characterized not only by compulsive drug use and persistent craving after withdrawal but also by systemic consequences of long-term exposure. These include alterations in neural circuits subserving reward, stress, and executive control, as well as skeletal impairments such as reduced bone mineral density and strength, disrupted bone turnover, muscle weakness, and elevated fracture risk. The bone-brain axis, which mediates bidirectional communication between the central nervous system and the skeleton via neural, endocrine, immune, metabolic, and bone-derived signaling, offers an integrative framework for understanding the concurrent neuro-skeletal impairments seen in addiction. Such impairments may not arise independently; rather, they may reflect cross-system pathology driven by interactions among neuroendocrine dysregulation, inflammatory and immune activation, oxidative stress, neurotransmitter disturbances, and feedback from bone-derived factors. Specifically, prolonged drug exposure can alter bone remodeling through the sympathetic nervous system, the hypothalamic-pituitary-adrenal (HPA) axis, and the hypothalamic-pituitary-gonadal (HPG) axis, while simultaneously disrupting the tissue microenvironment of both brain and bone via inflammatory/immune activation and redox imbalance. Abnormalities in monoamines-dopamine, serotonin, and norepinephrine-may further link addiction-related neurobehavioral changes to bone cell dysfunction. Meanwhile, bone-derived factors such as osteocalcin, sclerostin, lipocalin-2, and bone-derived extracellular vesicles may contribute to feedback regulation of brain function by skeletal tissue. This review summarizes the concurrent impairments of the nervous and skeletal systems associated with narcotic drug addiction, analyzes the potential pathways by which bone-brain axis dysregulation may mediate their interrelationship, and aims to provide a reference for elucidating the mechanisms of somatic comorbidity in addiction and for informing comprehensive intervention strategies.