From depression to bone health: examining the skeletal effects of classical and rapid-acting antidepressants

Depression is a brain disorder with systemic consequences including effects on bone health. Clinical and preclinical evidence has associated major depressive disorder (MDD) with reduced bone mineral density (BMD), increased bone resorption, and higher fracture risk, particularly in older adults and postmenopausal women. Plausible mediators include chronic stress, hypothalamic-pituitary-adrenal axis dysregulation, pro-inflammatory cytokines, and altered serotonergic signaling, each of which can affect bone remodeling. Classical antidepressants, particularly selective serotonin reuptake inhibitors, have been associated with adverse skeletal outcomes in human studies, while in vitro evidence indicates effects on osteoblast differentiation, mineralization, and osteoclast activity. Human biomarker studies and preclinical evidence suggest that ketamine-related compounds can modulate bone-related pathways, although these effects appear context-, dose-, exposure-, and model-dependent. Acute and repeated ketamine administration in patients with depression has been associated with changes in bone-turnover markers, including osteoprotegerin (OPG)/receptor activator of nuclear factor kappa-B ligand (RANKL)-related, while rodent studies suggest that arketamine may attenuate stress- and ovariectomy-induced reductions in BMD and normalize the OPG/RANKL ratio. Conversely, preclinical bone-regeneration and explant data indicate that ketamine can reduce bone-cell viability and impair bone healing under specific experimental conditions. The skeletal effects of ketamine, its enantiomers, and its metabolites, including (2R,6R)-hydroxynorketamine, remain preliminary and is limited to human biomarker studies and preclinical rodent/in vitro models; no clinical longitudinal BMD, bone-microarchitecture, or fracture-outcome data are currently available. This review summarizes the evidence linking depression, classical, and rapid-acting antidepressant use and bone health, and identifies gaps and priorities for future investigation, including skeletal monitoring and physiotherapy-informed rehabilitation as adjunctive clinical considerations.