ReviewEffects of selective serotonin reuptake inhibitors on bone health in adults: Time for recommendations about screening, prevention and management?
Introduction
A functional signaling system in bone for the centrally acting neurotransmitter serotonin (5-hydroxytryptamine or 5-HT) was identified by two groups in 2001 [1], [2]. Evidence regarding this system has accumulated slowly, but the recent publication from Yadav et al. has provided an unexpected twist and stimulated great interest in a novel mechanism for regulating bone mass [[3], [4], [5], [6]]. This mechanism involves gut-derived serotonin as the mediator for LRP-5 action on bone cells [3]. However, the specific biochemical nature of serotoninergic pathways and their direct and/or indirect effects on bone metabolism are still unclear. In this issue, Warden et al. have reviewed in detail the pre-clinical evidence for an effect of serotonin and altered serotonin signaling on bone metabolism [7]. This review will expand on those findings, bringing to light the current knowledge about clinical findings of serotonin and bone, particularly as they relate to individuals using selective serotonin reuptake inhibitors (SSRIs) and provide perspective for clinical practice: that is, screening, case finding and population health.
Section snippets
Clinical evidence for a relationship between SSRI use and bone health
Selective serotonin reuptake inhibitors, or SSRIs, are a class of medications that selectively and potently block the serotonin transporter (5-HTT). Serotonin transporters are located in the central nervous system (CNS) and in the periphery, including bone. SSRIs appear to effect CNS and bone 5-HTT with similar potency [1]. In the CNS, these medications serve to effectively increase the extra-cellular levels of serotonin thereby relieving symptoms of depression. SSRIs are first-line therapy and
Decisions about causal relationships in clinical research
Acceptance of causality requires a complementary set of studies that address several aspects of the associations in question. First and most important are the consistency and strength of the associations demonstrated [22]. In the case of SSRIs, associations have been demonstrated in several distinct populations, using various study designs and with bone density, bone loss or fractures as outcomes. The associations are consistent after adjustment for confounding variables such as age, body mass
Limitations of current studies on SSRI effect on bone
Complicating the interpretation of current SSRI studies in terms of causality are several methodologic issues, inherent to epidemiologic studies. One is the issue of confounding by indication, which can exist if a disease and the treatment both have potential to be associated with the outcome of interest [29]. In this case, depression has also been associated with low bone density in some [30], [31], [32], [33], [34], [35], [36], [37] but not all [13], [38], [39], [40], [41], [42] studies; [43]
Implications for screening and population health
Findings that suggest a detrimental effect of SSRI use on bone imply that clinicians should be vigilant about detection of bone disease in patients who have perturbation of the serotonin system (whether by depression or by SSRIs), and should perhaps consider earlier testing of BMD by dual x-ray absorptiometry (DXA) for patients on these medications as they do for patients taking corticosteroids [55], [56], [57], depomedroxyprogesterone, or anti-epileptic medications, among others. Indeed
Conclusion
This is an exciting time for bone biologists, clinicians, and all those doing translational research. The neuroendocrine aspects of bone metabolism are only beginning to be understood. Efforts to confirm the serotoninergic effects on bone, the biochemical pathways utilized, and the feedback loops involved among bone, gut and perhaps brain are underway. Additional work is needed on the potential role of estrogen as a modulator of the SSRI response through its effect on the serotonin transporter,
Acknowledgments
Dr. Haney is supported by a K23 award (051926) from the National Institute of Arthritis and Musculoskeletal and Skin Diseases.
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