Serotonin and Skeletal Health

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Serotonin is a key regulator of bone metabolism in animals. Murine models show that central (brain) serotonin positively regulates bone mass by inhibiting the deleterious effects of the sympathetic nervous system on osteoblasts. In mice, selective serotonin reuptake inhibitors (SSRIs) have time-dependent effects. Acutely, SSRIs directly inhibit osteoclastic bone resorption, but with chronic use the central effect of SSRIs predominate causing bone loss by increasing sympathetic nervous system (SNS) tone, which counteracts the early effects on resorption and reduces bone formation. In contrast, the role of endogenous serotonin in regulating human skeletal health is not well delineated. Recent work, however, indicates that (SSRIs) increase the risk of fracture by two times, but the mechanisms by which SSRIs do so in humans have not been clearly defined. Most human studies have focused on assessing areal bone mineral density and have not considered the important time-dependent effects of SSRIs, which has led to conflicting data. The effects of SSRIs on muscle function, which may also contribute to fracture risk, have only started to be explored. We have begun to make progress in this area using a multimodal approach with dual x-ray absorptiometry (DXA), high-resolution peripheral quantitative computed tomography (HRpQCT), body composition and measurement of physical function. Our data indicate this is a useful approach. Our recent work shows antidepressant use is associated with reduced physical performance as well as cortical deterioration, the latter of which can be detected with DXA and HR- pQCT. Supporting a role for serotonin in particular, participants taking antidepressants with moderate or high affinity for the serotonin transporter (such as SSRIs and serotonin norepinephrine reuptake inhibitors) had cortical deficits that were not present in those using other categories of antidepressants. Utilizing, DXA HRpQCT, transiliac bone biopsy as well as novel assays assessing osteoblast proliferation, differentiation and gene expression, the goal of this proposal is to determine if the tissue, cellular and molecular mechanisms by which SSRIs act on the musculoskeletal system in humans is analogous to those demonstrated in murine models. The overarching hypothesis of this proposal is that chronic use of SSRIs and antidepressants with high/moderate serotonin transporter affinity decrease bone formation by increasing sympathetic tone, which leads to bone loss and fracture. Effects on muscle mass and function will also be investigated. This work will help elucidate the role of serotonin as a regulator of human musculoskeletal health and guide the development of musculoskeletal screening and treatment strategies in those taking SSRIs and other antidepressants. Because long-term SSRI use is common, detrimental effects on skeletal health are important to elucidate and mitigate. Moreover, doing so may provide insight into targetable human musculoskeletal regulators.