One in six older adults takes an antidepressant, usually serotonin reuptake inhibitors (SRIs) such as Prozac and Zoloft. Both preclinical and epidemiological studies suggest that SRIs accelerate bone loss, a major public health concern given the high human and economic burden of osteoporosis. Despite the public health significance, the relationship between SRIs and accelerated bone loss remains poorly understood and unproven. Serotonin is a prominent signaling molecule in many tissues outside of the brain including platelets, intestines, and bone. This, combined with the marked serotonergic effects of SRIs, suggests SRIs might elicit changes in cell signaling in non-neural tissues leading to accelerated bone loss. Our preliminary data suggest that genetic variation may contribute to susceptibility to SRI-mediated bone loss, and herein we propose a definitive study of bone turnover with SRI use to address this. We take advantage of a large, ongoing randomized controlled trial testing antidepressant treatment strategies in older adults. This trial provides an ideal parent trial to test the long-term effects of SRI exposure on bone health and to identify both common and rare genetic variants that modify risk for SRI-mediated bone loss. We will then rapidly validate the functional impact of candidate genes and variants using a CRISPRi-based screen in cells. This project leverages both an ongoing large-scale clinical trial of antidepressants and novel molecular techniques to demonstrate the effects of SRI-mediated bone loss and their genetic modifiers. It will clarify whether, why, and in whom SRIs lead to osteoporosis, improve patient care and health outcomes for older adults, and identify novel treatment targets for bone health.