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Do antidepressants decrease bone density? This has been a hard question to answer because it takes years of exposure to have appreciable effects and lots of other variables may have become involved during that time. Moreover, if there’s a statistically significant risk, is it clinically significant? Do people who have taken an antidepressant for a few years or more actually break their hips or vertebrae more often than those who have not?
Hi! Jim Phelps here for the Psychopharmacology Institute. A new literature review examines just that question, looking not at bone density but at fractures among people taking antidepressants relative to those who are not. It looks like there’s definitely an association between antidepressant use and fracture rates—a big one.
In this review, Dr. Renato de Filippis and colleagues screened over 3,000 papers and narrowed these down to 11 for quantitative synthesis. Across those 11 studies, the net effect size of antidepressants on hip and vertebral fractures was 1.0—large. You might be thinking, wait a minute, where did this come from? I hadn’t heard of bone risk of antidepressants being this big. Is it?
Well, here’s an example—just 1 of the papers analyzed by Dr. de Filippis and colleagues. A 2013 population-based study compared hip fracture rates in antidepressant users vs nonusers across 5 European countries and the United States. It estimated a 3%—7% increase in fracture rates attributable to antidepressants, with a higher rate if SRIs were considered alone. Of course, there’s potential confounding by indication here, as the jargon phrase goes, where it’s clear that depression itself increases fractures. And you can imagine reasons why, including reduced mobility, chronic inflammation, and metabolic syndrome, for example. So, do antidepressants add to this existing risk of decreasing bone density? There is a plausible mechanism because serotonin stimulates the proliferation of osteoblast precursor cells.
Another study examined by Dr. de Filippis and colleagues is helpful here. It looked at women with no psychiatric diagnoses who began taking paroxetine for vasomotor symptoms associated with menopause. Compared with an age-matched comparison group, women who started paroxetine had a higher rate of bone fractures starting about 1 year later. The hazard ratio over 5 years was 1.7—a 70% increase. My gosh, that sounds very concerning, doesn’t it? But wait, the incidence of fractures in the comparison group was very low—only 1.2 fractures per 1000 patient-years. The paroxetine group had 2.1 fractures per 1000 patient-years. In other words, for every 200 women followed for 5 years, there was roughly 1 more fracture in the paroxetine group.
Is all this enough to make you shy away from prescribing an antidepressant, particularly an SRI? The absolute risk seems trivial compared with the risk of having severe withdrawal symptoms on discontinuation, which is still uncertain. But it’s almost surely at least 10%, and some studies suggest it’s more like 30% or 40%. There’s a highly controversial survey by Davies and Read, which is linked here at the Psychopharmacology Institute, that I think is a good entry point on that controversy.
For more on antidepressant risk–benefit ratios, I’d suggest that we all look further into the continued controversies around depression, antidepressant efficacy, and antidepressant withdrawal. We’ll have Quick Takes on those coming up shortly.
Abstract
Although antidepressant drugs appear to play an active role in increasing fracture risk, their weight is still unclear. We conducted a PRISMA compliant systematic review and meta-analysis through PubMed/Scopus/Cochrane libraries and registered with PROSPERO (registration number CRD42021254006) to investigate the relationship between antidepressant drugs categories, including SSRIs, SNRIs, and TCAs, and the risk of hip and vertebral fractures. After screening 3122 items, we finally found 26 papers for qualitative analysis and 11 for quantitative synthesis. A total of 15,209,542 adult and elderly patients were identified, with a mean follow-up of 51 months and a major prevalence of women. We identified results largely for SSRIs, with only a small amount of data for SNRIs, TCAs, and NaSSA. No data were found among the most recent categories of antidepressants, such as vortioxetine and esketamine. All included studies reported hip fractures, while three of them also included vertebral fractures. Overall, we observed a significant effect of SSRIs on fracture risk with a mean effect of 0.98 (95% CI = 0.75–1.20). This meta-analysis reveals that the use of SSRIs increases the risk of fractures. Clinicians’ awareness in antidepressant prescription should optimize their potential while reducing this risk.
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Reference
de Filippis, R., Mercurio, M., Spina, G., De Fazio, P., Segura-Garcia, C., Familiari, F., Gasparini, G., & Galasso, O. (2022). Antidepressants and vertebral and hip tisk fracture: An updated systematic review and meta-analysis. Healthcare (Basel, Switzerland), 10(5), 803.
Related References
- Davies, J., & Read, J. (2019). A systematic review into the incidence, severity and duration of antidepressant withdrawal effects: Are guidelines evidence-based?. Addictive Behaviors, 97, 111-121.
