Brain-bone axis dysregulation: Biological code underlying the bidirectional association between depression and musculoskeletal disorders.

UNLABELLED: Depression and musculoskeletal disorders including osteoporosis (OP), fractures, osteoarthritis (OA) and rheumatoid arthritis (RA) exhibit significant bidirectional epidemiological and pathophysiological links. Rising depression prevalence (approximately 2.7 % annually) is accompanied by the high global burden of musculoskeletal disorders. Shared mechanisms center on the neuroimmune-inflammatory axis: Depression-associated inflammation (e.g., IL-6, TNF-α) promotes bone resorption, cartilage degradation, and RA disease activity, while autonomic/endocrine dysregulation increases fracture risk through increased norepinephrine (NE) and cortisol. Contributing factors include oxidative stress, gut dysbiosis, and sex hormone imbalances. Antidepressants show divergent skeletal effects: selective serotonin reuptake inhibitors (SSRIs) may reduce bone mineral density (BMD) and increase fracture risk, while serotonin-norepinephrine reuptake inhibitors (SNRIs) can improve OA symptoms. Depression significantly worsens orthopedic outcomes, leading to increased fracture risk, pain and disability, reduced treatment response. Integrated care approaches and novel neuroimmune targets offer potential for improved comorbidity management.

THE TRANSLATIONAL POTENTIAL OF THIS ARTICLE: This review links depression with common orthopaedic disorders by synthesizing convergent neuro-immune-endocrine and metabolic pathways, and documents measurable skeletal deficits. These insights support immediate, low-cost actions: bidirectional screening, strengthened orthopaedics-psychiatry referral, and pragmatic combination care bundles. If implemented, this approach could reduce fracture risk, pain, and disability while improving recovery trajectories.