Antidepressants and Fracture Risk: Is There a Real Connection?

To the Editor: It is with great interest we read the retrospective cohort study by Tamblyn et al. investigating the association between antidepressant drugs (ADs) and fracture risk in adults aged 65 and older among five jurisdictions in four countries (United States, Canada, United Kingdom, and Taiwan). Selective serotonin reuptake inhibitors (SSRIs) were primarily associated with a significant increase in fracture risk, except in Taiwan. The authors concluded that the SSRIs citalopram and sertraline, serotonin norepinephrine reuptake inhibitor (SNRI) duloxetine, and tricyclic antidepressants (TCAs) imipramine and doxepin are associated with increased risk of fractures, whereas paroxetine (SSRI), venlafaxine (SNRI), and amitriptyline (TCA) are not. The risk estimates varied based on the jurisdiction. For example, TCAs were “significantly protective in Montreal, with similar protective but nonsignificant point estimates in Quebec and the United Kingdom, and significantly increased fracture risk in the United States and Taiwan. ” The authors proposed various hypotheses to explain the difference in outcomes across jurisdictions and different countries. It is imperative to interpret carefully the postulated findings from this study. Depressive disorders are among the most common reasons for an SSRI prescription. Depressive disorders are prevalent in 1% to 5% of older adults. Depression is often inadequately treated in older adults leading to a poor quality of life and inadequate treatment of medical comorbidities. Falls have been proposed as one of the major reasons for fractures among older adults. Both depression and falls are common in older adults. Among community dwelling adults aged 65 years and older, about 30% to 40% fall every year. Medications with a high anticholinergic burden increase the risk of falls. TCAs and paroxetine are highly anticholinergic and sedating with a much higher risk of orthostatic hypotension and are recommended to avoid in older adults. Retrospective studies have an inherent risk and confounding bias. They have a possibility of confounding by indication, in which the presence of indication modifies the association between the exposure (ADs) and outcome (fracture). A recent large sample size study revealed a higher risk of hip fracture before the initiation of ADs, highlighting the issue of residual confounding. Several factors, modifiable and nonmodifiable, are attributed to falls in older adults. In this study, the authors have adjusted falls to multiple risk factors but have been unable to adjust for multiple other risk factors (frailty/sarcopenia, visual impairment, vestibular impairment, peripheral neuropathy, orthostatic hypotension, alcohol use, antihypertensives, antihyperglycemic agents and other drugs, and environmental factors). This is a limitation that falsely estimates the risk of falls associated with ADs. Osteoporosis is common in the older population and increases the risk of fractures and falls. A total of 50% of women and 25% of men aged 50 and older with osteoporosis will sustain a fragility fracture in their lifetime. Metaanalyses of observational studies have reported increased risk of fractures among users of SSRIs and TCAs as compared with nonusers. This increased risk occurs early on during AD therapy and reduces over time. However, a meta-analysis investigating the association between ADs and bone mineral density (BMD) in women reported that the use of ADs was not associated with lower or higher BMD. Thus the association was attributed to impaired balance due to ADs and altered bone microarchitecture. In their article, Tamblyn et al. reported the association between several ADs with fracture risk especially in the United States; however, this risk was not evident for many ADs after adjusting for dose. Also, it is known that depression itself is associated with reduced BMD. In addition to the fracture risk, reporting BMD data and fracture classification (osteoporotic vs nonosteoporotic) would have helped differentiate if fracture risk was associated with depression itself or ADs. This is a clinical conundrum faced by geriatricians, primary care physicians, and psychiatrists while caring for older adults with depression and fall risk. To initiate or continue ADs for depression or anxiety disorders in older adults, we highlight the importance of assessing a patient’s modifiable and nonmodifiable risk factors, the role of comorbidities, and potential interacting medications. The benefit of ADs should be weighed against the risk of falls attributed solely to ADs. Those drugs with lower risk for falls should be preferentially used until high-quality data from prospective studies are available.