The study by Richards and colleagues1 indicates an association between selective serotonin reuptake inhibitor (SSRI) use and fracture risk in elderly persons by ascertaining daily SSRI use in a cohort of patients at baseline and 5 years later and the fracture incidence in this cohort after controlling for potentially confounding variables. There are several limitations to this study. The authors are incorrect when they argue that inhaled corticosteroids have not been clearly associated with fracture. Recent data clearly demonstrate the link between inhaled corticosteroids and fracture.2 Furthermore, depression has also been linked to earlier perimenopause, another condition strongly linked to fracture risk.3 Most important, the authors fail to discuss the relationship between depression and osteoporosis that has been known for decades and did not account for it in their statistical analysis. Several studies indicate that depression is a risk factor for reduced bone mineral density and fractures, demonstrating a 6% to 15% lower bone mineral density in depressed patients.4,5 Their attempt to control for baseline depressive symptoms did not factor into account the length of depressive episodes, history of depression, and its severity or treatment. In fact, one can argue that their study demonstrates that depression is associated with an increased fracture risk, since SSRI use is only a proxy for depression. To bolster this argument, Yirmiya et al5 recently demonstrated that mice subjected to chronic mild stress, an established model of depression in rodents, displayed symptoms of depression accompanied by bone loss and fewer osteoblasts, leading to impaired bone formation. The bone loss was associated with a substantial increase in bone norepinephrine levels and serum glucocorticoids, suggesting that the sympathetic nervous system mediates the skeletal effects of stress-induced depression. They then demonstrated that successful antidepressant treatment of these mice completely inhibited the decrease in bone formation and markedly reduced chronic mild stress–induced bone loss. This suggests that successful antidepressant therapy might help prevent or treat osteoporosis. Finally, in contrast to the conclusion of the authors, if there were indeed a relationship between SSRI use and fracture risk, one would expect the risk to be higher for the recurrent users than it was for those who only used it at baseline. Patients with depression are more likely to have myocardial infarctions, strokes, diabetes, and osteoporosis, as it is increasingly being recognized that depression is a whole body disease, affecting not only the brain but also the endocrine, immune, and cardiovascular systems, among others.
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