Effects of selective serotonin reuptake inhibitors on bone health in adults: Time for recommendations about screening, prevention and management?

doi:10.1016/j.bone.2009.07.083

Bone

Volume 46, Issue 1, January 2010, Pages 13-17

https://doi.org/10.1016/j.bone.2009.07.083 Get rights and content

Abstract

Evidence regarding a functional serotonin (5-hydroxytryptamine) signaling system in bone has generated considerable recent interest. The specific biochemical nature of serotoninergic pathways and their direct and/or indirect effects on bone metabolism are still unclear.

Clinical evidence supports an effect of serotonin and altered serotonin signaling on bone metabolism. Serotonin is involved in the pathophysiology of depression, and therefore studies of depression and antidepressant treatments (as modulators of the serotonin system) are relevant with regard to bone outcomes. Studies on the effect of depression on bone mineral density (BMD) and fractures have been mixed. Studies on the associations between antidepressant use and BMD and/or fractures are more consistent. SSRIs have been associated with lower BMD and increased rates of bone loss, as well as increased rates of fracture after accounting for falls. These studies are limited by confounding because depression is potentially associated with both the outcome of interest (BMD and fracture) and the exposure (SSRIs).

With mounting evidence for an effect on bone, this review considers the question of causality and whether selective serotonin reuptake inhibitors should be considered among those medications that contribute to bone loss, and therefore prompt clinicians to evaluate BMD proactively. Future research will be required to confirm the serotoninergic effects on bone and the biochemical pathways involved, and to identify clinical implications for treatment based on this novel pathway.

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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ReviewEffects of selective serotonin reuptake inhibitors on bone health in adults: Time for recommendations about screening, prevention and management?

Abstract

Introduction

Section snippets

Clinical evidence for a relationship between SSRI use and bone health

Decisions about causal relationships in clinical research

Limitations of current studies on SSRI effect on bone

Implications for screening and population health

Conclusion

Acknowledgments

Bone

J. Biol. Chem.

Cell

Cell

Bone

Am. J. Med.

Lancet

May Clin. Proc.

Bone

Mol. Cell. Endocrinol.

J Psychosom. Res.

Maturitas

Clin. Ther.

Bone

Am. J. Prev. Med.

Serotonin Rising—The Bone, Brain, Bowel Connection

N Engl J Med

Association of low bone mineral density with selective serotonin reuptake inhibitor use by older men

Arch. Intern. Med.

The impact of selective serotonin reuptake inhibitors on the risk of fracture

Arch. Intern. Med.

Selective serotonin reuptake inhibitor use and bone mineral density in women with a history of depression

Int. Clin. Pscyhopharmacol.

Use of antidepressants and rates of hip bone loss in older women: the study of osteoporotic fractures

Arch. Intern. Med.

Depressive symptoms, bone loss, and fractures in postmenopausal women

J. Gen. Intern. Med.

Anxiolytics, sedatives, antidepressants, neuroleptics and the risk of fracture

Osteoporos. Int.

Fracture risk from psychotropic medications: a population-based analysis

J. Clin. Psychopharmacol.

Psychotropic drug use and the risk of hip fracture

N. Engl. J. Med.

SSRI use is associated with increased risk of fracture among older men

JBMR

Predictors of non-spine fracture in elderly men: the MrOS study

J. Bone Miner. Res.

Central nervous system active medications and risk for fractures in older women

Arch. Intern. Med.

Designing clinical research

Selective serotonin reuptake inhibiting antidepressants are associated with an increased risk of nonvertebral fractures

J. Clin. Psychopharmacol.

Exposure to tricyclic and selective serotonin reuptake inhibitor antidepressants and the risk of hip fracture

Am. J. Epidemiol.

Serotonin (5-hydroxytryptamine) transporter inhibition causes bone loss in adult mice independently of estrogen deficiency

Menopause

Serotonin regulates osteoclast differentiation through its transporter

J. Bone Miner. Res.

Review
Effects of selective serotonin reuptake inhibitors on bone health in adults: Time for recommendations about screening, prevention and management?