Potential mechanisms of bone loss in depression. The model implicating hypercortisolemia (i) as a major cause of osteoporosis is derived from the well-known effect of increased cortisol in subjects with Cushing syndrome. The other main effector branch of the stress system, the sympathetic system (ii), modulates the production of pro-inflammatory cytokines, including interleukin (IL)-6, a potent bone resorption agent. As evolutionarily appropriate in a situation of chronic stress such as depression, the processes for reproduction and growth become inhibited, which results in decreased levels of estrogens (iii) and growth hormone (GH)/insulin-like growth factor (IGF)-1 (iv). Taken together, the combination of increased cortisol, IL-6, decreased sex steroids and GH lead to reduced bone mass, as the net result of decreased bone formation and increased bone resorption according to the markers of bone turnover. Physiological amounts of osteocalcin regulate (v) insulin expression (vi) in the pancreas and adiponectin in (vii) adipose tissue. The complex endocrine and immune imbalances depicted in this figure predispose subjects with depression to other serious medical consequences such as central obesity, altered insulin sensitivity, subclinical inflammation, and increased cardiovascular morbidity and mortality. CRH, corticotropin-releasing hormone; ACTH, adrenocorticotropic hormone; GnRH, gonadotropin releasing hormone; NTX, N-telopeptides.