Risk of Fractures in Stroke Patients Treated With a Selective Serotonin Reuptake Inhibitor: A Systematic Review and Meta-Analysis

Background and Purpose: Stroke survivors have an increased risk of depression and bone fractures. Selective serotonin reuptake inhibitors (SSRIs) have been associated with an increased risk of fractures in observational studies. Several randomized controlled trials (RCTs) reporting the effect of SSRIs on the risk of fractures in stroke survivors have been published recently but have not been subject to a meta-analysis. We aimed to determine the risk of fractures associated with the use of SSRIs, and the risk of falls, seizures, and recurrent strokes as possible mediators of fractures, in stroke survivors. Methods: We conducted a systematic review and meta-analysis of RCTs of SSRIs in stroke survivors according to a protocol registered in PROSPERO (CRD42020192632). Web of Science, EMBASE, PsycINFO, and Ovid Medline/PubMed bibliographic databases, clinical trial registers, and grey literature sources were searched. RCTs of SSRIs versus placebo or no intervention that report the risk of fractures in adult survivors of hemorrhagic or ischemic stroke were included. Two reviewers independently screened search results and extracted data. Meta-analyses were conducted for each outcome using the Mantel-Haenszel random-effects models. Results: The searches yielded 683 records, of which 4 RCTs of 6 months duration with a total of 6549 participants were included in the meta-analysis: 3 studies of fluoxetine and 1 study of citalopram. Treatment with an SSRI for 6 months increased the risk of fractures with a risk ratio of 2.36 (95% CI, 1.64–3.39) compared with placebo. The risk of falls, seizures, and recurrent stroke was not statistically significantly increased. Only studies of fluoxetine and citalopram were available for inclusion in the review, and hence the generalizability of the findings to other SSRIs is uncertain. Conclusions: Based on available RCTs of fluoxetine and citalopram, SSRIs used for 6 months doubled the risk of fractures in stroke survivors. Registration: https://www.crd.york.ac.uk/prospero/; Unique identifier: CRD42020192632.