Major depressive disorder (MDD) is a pervasive chronic condition that contributes
substantially to the global burden of disease and disability. Adding to the complexity of this disorder are
numerous associated medical comorbidities with a bidirectional impact on morbidity and mortality. In recent
years, osteoporosis has been increasingly identified as a significant comorbidity of MDD. This narrative review
examines the literature to summarize key epidemiological studies and discuss postulated mechanisms of
interaction. Epidemiological studies have repeatedly shown an increased co-prevalence of fractures and
decreased bone mineral density (BMD) in MDD. The pathophysiological mechanism underlying this interaction
is undoubtedly complex and multifactorial, and proposed pathways have varying levels of evidence from
preclinical and clinical models. Conceptually, the mechanisms by which depression might influence bone
metabolism can be categorized into biological, behavioral, iatrogenic, and comorbidity-related factors.
Biological factors include the inflammatory-mood pathway, hypothalamic-pituitary-adrenal (HPA) axis
dysregulation, metabolic dysfunction, and serotonin’s direct and indirect effects on bone cells. Behavioral
factors incorporate lifestyle choices typical in depressed patients, such as increased tobacco use or limited
exercise. The prominent iatrogenic factor is the independent effects of anti-depressants on bone metabolism.
Psychiatric and medical comorbidities common to both osteoporosis and MDD are also important to consider.
Physical activity promotion, vitamin D supplementation, and routine BMD screening of MDD patients are
simple interventions that might lead to improved outcomes for both conditions. An improved understanding of
the underlying mechanisms may yield insights into novel prevention and treatment strategies to target
osteoporosis and fractures in the MDD population.
Keywords: Osteoporosis, bone mineral density (BMD), fractures, major depressive disorder (MDD),
antidepressants, cytokines, vitamin D, serotonin.
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