Drugs & Aging

, Volume 33, Issue 1, pp 21–25 | Cite as

Effects of Depression and Serotonergic Antidepressants on Bone: Mechanisms and Implications for the Treatment of Depression

  • Brisa S. Fernandes
  • Jason M. Hodge
  • Julie A. Pasco
  • Michael Berk
  • Lana J. Williams
Review Article


Osteoporosis is a chronic skeletal disease marked by microarchitectural deterioration of the bone matrix and depletion of bone mineral density (BMD), with a consequent increased risk for fragility fractures. It has been frequently associated with depression, which is also a chronic and debilitating disorder with high prevalence. Selective serotonin reuptake inhibitors (SSRIs), first-line agents in the pharmacological treatment of mood and anxiety disorders, have also been shown to negatively affect bone metabolism. SSRIs are the most prescribed antidepressants worldwide and a large number of persons at risk of developing osteoporosis, including older patients, will receive these antidepressants. Therefore, a proper musculoskeletal evaluation of individuals who are being targeted for or using SSRIs is a priority. The aim of this article is to review the evidence regarding the effects of depression and serotonergic antidepressants on bone and its implications for clinical care.


Osteoporosis Serotonin Bone Mass Osteoporotic Fracture Fragility Fracture 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Compliance with Ethical Standards

Funding Body Agreements and Policies

The study was supported by the National Health and Medical Research Council (NHMRC), Australia (projects 1026265, 1009367, 628582, 509103).

Brisa S. Fernandes is supported by a scholarship and by a research grant MCTI/CNPQ/Universal 14/2014 461833/2014-0, both from CNPq, Brazil. Michael Berk is supported by a National Health and Medical Research Council (NHMRC) Senior Principal Research Fellowship (1059660). Lana J. Williams is supported by an NHMRC Career Development Fellowship (1064272).

Conflict of interest

Brisa S. Fernandes, Jason M. Hodge, Julie A. Pasco, Michael Berk, and Lana J. Williams have no conflicts of interest regarding this subject.


  1. 1.
    Consensus development conference: prophylaxis and treatment of osteoporosis. Am J Med. 1991;90:107–10Google Scholar
  2. 2.
    Cummings SR, Melton LJ. Epidemiology and outcomes of osteoporotic fractures. Lancet. 2002;359(9319):1761–7.PubMedCrossRefGoogle Scholar
  3. 3.
    Pasco JA, Sanders KM, Hoekstra FM, Henry MJ, Nicholson GC, Kotowicz MA. The human cost of fracture. Osteoporos Int. 2005;16(12):2046–52.PubMedCrossRefGoogle Scholar
  4. 4.
    American Psychiatric Association. Diagnostic and statistical manual of mental disorders, 5th ed (DSM-5). Washington, DC: American Psychiatric Association; 2013.Google Scholar
  5. 5.
    Aloumanis K, Mavroudis K. The, “depressive” face of osteoporosis and the “osteoporotic” face of depression. Hormones (Athens). 2013;12(3):350–62.PubMedGoogle Scholar
  6. 6.
    Williams LJ, Berk M, Henry MJ, Stuart AL, Brennan SL, Jacka FN, et al. Depression following fracture in women: a study of age-matched cohorts. BMJ Open. 2014;4(2):e004226.PubMedPubMedCentralCrossRefGoogle Scholar
  7. 7.
    Mezuk B, Eaton WW, Golden SH. Depression and osteoporosis: epidemiology and potential mediating pathways. Osteoporos Int. 2008;19(1):1–12.PubMedPubMedCentralCrossRefGoogle Scholar
  8. 8.
    Williams LJ, Pasco JA, Jacka FN, Henry MJ, Dodd S, Berk M. Depression and bone metabolism. A review. Psychother Psychosom. 2009;78(1):16–25.PubMedCrossRefGoogle Scholar
  9. 9.
    Yirmiya R, Bab I. Major depression is a risk factor for low bone mineral density: a meta-analysis. Biol Psychiatry. 2009;66(5):423–32.PubMedCrossRefGoogle Scholar
  10. 10.
    Bab I, Yirmiya R. Depression, selective serotonin reuptake inhibitors, and osteoporosis. Curr Osteoporos Rep. 2010;8(4):185–91.PubMedCrossRefGoogle Scholar
  11. 11.
    Gebara MA, Shea ML, Lipsey KL, Teitelbaum SL, Civitelli R, Muller DJ, et al. Depression, antidepressants, and bone health in older adults: a systematic review. J Am Geriatr Soc. 2014;62(8):1434–41.PubMedPubMedCentralCrossRefGoogle Scholar
  12. 12.
    Pirraglia PA, Stafford RS, Singer DE. Trends in prescribing of selective serotonin reuptake inhibitors and other newer antidepressant agents in adult primary care. Prim Care Companion J Clin Psychiatry. 2003;5(4):153–7.PubMedPubMedCentralCrossRefGoogle Scholar
  13. 13.
    Vaswani M, Linda FK, Ramesh S. Role of selective serotonin reuptake inhibitors in psychiatric disorders: a comprehensive review. Prog Neuropsychopharmacol Biol Psychiatry. 2003;27(1):85–102.PubMedCrossRefGoogle Scholar
  14. 14.
    Bliziotes M. Update in serotonin and bone. J Clin Endocrinol Metab. 2010;95(9):4124–32.PubMedPubMedCentralCrossRefGoogle Scholar
  15. 15.
    Hodge JM, Wang Y, Berk M, Collier FM, Fernandes TJ, Constable MJ, et al. Selective serotonin reuptake inhibitors inhibit human osteoclast and osteoblast formation and function. Biol Psychiatry. 2013;74(1):32–9.PubMedCrossRefGoogle Scholar
  16. 16.
    Robbins J, Hirsch C, Whitmer R, Cauley J, Harris T. The association of bone mineral density and depression in an older population. J Am Geriatr Soc. 2001;49(6):732–6.PubMedCrossRefGoogle Scholar
  17. 17.
    Williams LJ, Bjerkeset O, Langhammer A, Berk M, Pasco JA, Henry MJ, et al. The association between depressive and anxiety symptoms and bone mineral density in the general population: the HUNT study. J Affect Disord. 2011;131(1–3):164–71.PubMedCrossRefGoogle Scholar
  18. 18.
    Eskandari F, Martinez PE, Torvik S, Phillips TM, Sternberg EM, Mistry S, et al. Low bone mass in premenopausal women with depression. Arch Intern Med. 2007;167(21):2329–36.PubMedCrossRefGoogle Scholar
  19. 19.
    Wu Q, Magnus JH, Liu J, Bencaz AF, Hentz JG. Depression and low bone mineral density: a meta-analysis of epidemiologic studies. Osteoporos Int. 2009;20(8):1309–20.PubMedCrossRefGoogle Scholar
  20. 20.
    Williams LJ, Pasco JA, Jacka FN, Hodge JM, Kotowicz MA, Berk M. Quantitative Heel Ultrasound (QUS) measures of bone quality in association with mood and anxiety disorders. J Affect Disord. 2013;146(3):395–400.PubMedCrossRefGoogle Scholar
  21. 21.
    Haney EM, Warden SJ, Bliziotes MM. Effects of selective serotonin reuptake inhibitors on bone health in adults: time for recommendations about screening, prevention and management? Bone. 2010;46(1):13–7.PubMedPubMedCentralCrossRefGoogle Scholar
  22. 22.
    Chen F, Hahn TJ, Weintraub NT. Do SSRIs play a role in decreasing bone mineral density? J Am Med Dir Assoc. 2012;13(5):413–7.PubMedCrossRefGoogle Scholar
  23. 23.
    Tsapakis EM, Gamie Z, Tran GT, Adshead S, Lampard A, Mantalaris A, et al. The adverse skeletal effects of selective serotonin reuptake inhibitors. Eur Psychiatry. 2012;27(3):156–69.PubMedCrossRefGoogle Scholar
  24. 24.
    Wu Q, Bencaz AF, Hentz JG, Crowell MD. Selective serotonin reuptake inhibitor treatment and risk of fractures: a meta-analysis of cohort and case-control studies. Osteoporos Int. 2012;23(1):365–75.PubMedCrossRefGoogle Scholar
  25. 25.
    Wu Q, Qu W, Crowell MD, Hentz JG, Frey KA. Tricyclic antidepressant use and risk of fractures: a meta-analysis of cohort and case-control studies. J Bone Miner Res. 2013;28(4):753–63.PubMedCrossRefGoogle Scholar
  26. 26.
    Haney EM, Warden SJ. Skeletal effects of serotonin (5-hydroxytryptamine) transporter inhibition: evidence from clinical studies. J Musculoskelet Neuronal Interact. 2008;8(2):133–45.PubMedGoogle Scholar
  27. 27.
    Rizzoli R, Cooper C, Reginster JY, Abrahamsen B, Adachi JD, Brandi ML, et al. Antidepressant medications and osteoporosis. Bone. 2012;51(3):606–13.PubMedCrossRefGoogle Scholar
  28. 28.
    Eom CS, Lee HK, Ye S, Park SM, Cho KH. Use of selective serotonin reuptake inhibitors and risk of fracture: a systematic review and meta-analysis. J Bone Miner Res. 2012;27(5):1186–95.PubMedCrossRefGoogle Scholar
  29. 29.
    Richards JB, Papaioannou A, Adachi JD, Joseph L, Whitson HE, Prior JC, et al. Effect of selective serotonin reuptake inhibitors on the risk of fracture. Arch Intern Med. 2007;167(2):188–94.PubMedCrossRefGoogle Scholar
  30. 30.
    Ziere G, Dieleman JP, van der Cammen TJ, Hofman A, Pols HA, Stricker BH. Selective serotonin reuptake inhibiting antidepressants are associated with an increased risk of nonvertebral fractures. J Clin Psychopharmacol. 2008;28(4):411–7.PubMedCrossRefGoogle Scholar
  31. 31.
    Williams L, Pasco JA, Stuart AL, Jacka FN, Brennan SL, Dobbins AG, et al. Psychiatric disorders, psychotropic medication use and falls among women: an observational study. BMC Psychiatry. 2015;15:75.PubMedPubMedCentralCrossRefGoogle Scholar
  32. 32.
    Vestergaard P, Rejnmark L, Mosekilde L. Anxiolytics, sedatives, antidepressants, neuroleptics and the risk of fracture. Osteoporos Int. 2006;17(6):807–16.PubMedCrossRefGoogle Scholar
  33. 33.
    Diem SJ, Blackwell TL, Stone KL, Yaffe K, Haney EM, Bliziotes MM, et al. Use of antidepressants and rates of hip bone loss in older women: the study of osteoporotic fractures. Arch Intern Med. 2007;167(12):1240–5.PubMedCrossRefGoogle Scholar
  34. 34.
    Raggatt LJ, Partridge NC. Cellular and molecular mechanisms of bone remodeling. J Biol Chem. 2010;285(33):25103–8.PubMedPubMedCentralCrossRefGoogle Scholar
  35. 35.
    Yadav VK, Ryu JH, Suda N, Tanaka KF, Gingrich JA, Schutz G, et al. Lrp5 controls bone formation by inhibiting serotonin synthesis in the duodenum. Cell. 2008;135(5):825–37.PubMedPubMedCentralCrossRefGoogle Scholar
  36. 36.
    Yadav VK, Oury F, Suda N, Liu ZW, Gao XB, Confavreux C, et al. A serotonin-dependent mechanism explains the leptin regulation of bone mass, appetite, and energy expenditure. Cell. 2009;138(5):976–89.PubMedPubMedCentralCrossRefGoogle Scholar
  37. 37.
    Ducy P, Karsenty G. The two faces of serotonin in bone biology. J Cell Biol. 2010;191(1):7–13.PubMedPubMedCentralCrossRefGoogle Scholar
  38. 38.
    Chabbi-Achengli Y, Coudert AE, Callebert J, Geoffroy V, Cote F, Collet C, et al. Decreased osteoclastogenesis in serotonin-deficient mice. Proc Natl Acad Sci USA. 2012;109(7):2567–72.PubMedPubMedCentralCrossRefGoogle Scholar
  39. 39.
    de Vernejoul MC, Collet C, Chabbi-Achengli Y. Serotonin: good or bad for bone. Bonekey Rep. 2012;1:120.PubMedPubMedCentralCrossRefGoogle Scholar
  40. 40.
    Cui Y, Niziolek PJ, MacDonald BT, Zylstra CR, Alenina N, Robinson DR, et al. Lrp5 functions in bone to regulate bone mass. Nat Med. 2011;17(6):684–91.PubMedPubMedCentralCrossRefGoogle Scholar
  41. 41.
    Bliziotes MM, Eshleman AJ, Zhang XW, Wiren KM. Neurotransmitter action in osteoblasts: expression of a functional system for serotonin receptor activation and reuptake. Bone. 2001;29(5):477–86.PubMedCrossRefGoogle Scholar
  42. 42.
    Westbroek I, van der Plas A, de Rooij KE, Klein-Nulend J, Nijweide PJ. Expression of serotonin receptors in bone. J Biol Chem. 2001;276(31):28961–8.PubMedCrossRefGoogle Scholar
  43. 43.
    Collet C, Schiltz C, Geoffroy V, Maroteaux L, Launay JM, de Vernejoul MC. The serotonin 5-HT2B receptor controls bone mass via osteoblast recruitment and proliferation. FASEB J. 2008;22(2):418–27.PubMedCrossRefGoogle Scholar
  44. 44.
    Warden SJ, Bliziotes MM, Wiren KM, Eshleman AJ, Turner CH. Neural regulation of bone and the skeletal effects of serotonin (5-hydroxytryptamine). Mol Cell Endocrinol. 2005;242(1–2):1–9.PubMedCrossRefGoogle Scholar
  45. 45.
    Warden SJ, Haney EM. Skeletal effects of serotonin (5-hydroxytryptamine) transporter inhibition: evidence from in vitro and animal-based studies. J Musculoskelet Neuronal Interact. 2008;8(2):121–32.PubMedPubMedCentralGoogle Scholar
  46. 46.
    Warden SJ, Hassett SM, Bond JL, Rydberg J, Grogg JD, Hilles EL, et al. Psychotropic drugs have contrasting skeletal effects that are independent of their effects on physical activity levels. Bone. 2010;46(4):985–92.PubMedPubMedCentralCrossRefGoogle Scholar
  47. 47.
    Brommage R, Liu J, Doree D, Yu W, Powell DR, Yang QM. Adult Tph2 knockout mice without brain serotonin have moderately elevated spine trabecular bone but moderately low cortical bone thickness. Bonekey Rep. 2015;4:718.PubMedCrossRefGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2015

Authors and Affiliations

  • Brisa S. Fernandes
    • 1
    • 2
  • Jason M. Hodge
    • 3
    • 4
  • Julie A. Pasco
    • 1
    • 5
  • Michael Berk
    • 1
    • 6
  • Lana J. Williams
    • 1
  1. 1.IMPACT Strategic Research Centre, School of MedicineDeakin UniversityGeelongAustralia
  2. 2.Laboratory of Calcium Binding Proteins in the Central Nervous System, Department of BiochemistryFederal University of Rio Grande do SulPorto AlegreBrazil
  3. 3.Barwon Biomedical ResearchBarwon Health University HospitalGeelongAustralia
  4. 4.MMR Strategic Research Centre, School of MedicineDeakin UniversityGeelongAustralia
  5. 5.Department of MedicineThe University of MelbourneSt AlbansAustralia
  6. 6.Florey Institute for Neuroscience and Mental Health, Department of Psychiatry and OrygenThe National Centre of Excellence in Youth Mental Health, University of MelbourneParkvilleAustralia

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