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Serotonin-reuptake inhibitors act centrally to cause bone loss in mice by counteracting a local anti-resorptive effect

Nature Medicine volume 22, pages 1170–1179 (2016)Cite this article

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Abstract

The use of selective serotonin-reuptake inhibitors (SSRIs) has been associated with an increased risk of bone fracture, raising concerns about their increasingly broader usage. This deleterious effect is poorly understood, and thus strategies to avoid this side effect remain elusive. We show here that fluoxetine (Flx), one of the most-prescribed SSRIs, acts on bone remodeling through two distinct mechanisms. Peripherally, Flx has anti-resorptive properties, directly impairing osteoclast differentiation and function through a serotonin-reuptake-independent mechanism that is dependent on intracellular Ca2+ levels and the transcription factor Nfatc1. With time, however, Flx also triggers a brain-serotonin-dependent rise in sympathetic output that increases bone resorption sufficiently to counteract its local anti-resorptive effect, thus leading to a net effect of impaired bone formation and bone loss. Accordingly, neutralizing this second mode of action through co-treatment with the β-blocker propranolol, while leaving the peripheral effect intact, prevents Flx-induced bone loss in mice. Hence, this study identifies a dual mode of action of SSRIs on bone remodeling and suggests a therapeutic strategy to block the deleterious effect on bone homeostasis from their chronic use.

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Figure 1: Biphasic effect of Flx treatment on bone mass.
Figure 2: Flx directly impairs osteoclast differentiation and function.
Figure 3: Flx affects osteoclastogenesis in a 5HTT-independent manner.
Figure 4: Flx-induced bone loss is dependent on brain serotonin and is mediated by the sympathetic tone.
Figure 5: Flx-induced bone loss mediated by the sympathetic tone also occurs in males.
Figure 6: Co-treatment with propranolol rescues the Flx-induced bone loss.

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References

  1. Wong, D.T., Bymaster, F.P. & Engleman, E.A. Prozac (fluoxetine, Lilly 110140), the first selective serotonin uptake inhibitor and an antidepressant drug: twenty years since its first publication. Life Sci. 57, 411–441 (1995).

    Article  CAS  PubMed  Google Scholar 

  2. Fox, M.A. et al. A pharmacological analysis of mice with a targeted disruption of the serotonin transporter. Psychopharmacology (Berl.) 195, 147–166 (2007).

    Article  CAS  Google Scholar 

  3. Mojtabai, R. & Olfson, M. Proportion of antidepressants prescribed without a psychiatric diagnosis is growing. Health Aff. (Millwood) 30, 1434–1442 (2011).

    Article  Google Scholar 

  4. Orleans, R.J. et al. FDA approval of paroxetine for menopausal hot flushes. N. Engl. J. Med. 370, 1777–1779 (2014).

    Article  CAS  PubMed  Google Scholar 

  5. Rizzoli, R. et al. Antidepressant medications and osteoporosis. Bone 51, 606–613 (2012).

    Article  CAS  PubMed  Google Scholar 

  6. Haney, E.M., Warden, S.J. & Bliziotes, M.M. Effects of selective serotonin-reuptake inhibitors on bone health in adults: time for recommendations about screening, prevention and management? Bone 46, 13–17 (2010).

    Article  CAS  PubMed  Google Scholar 

  7. Wu, Q., Magnus, J.H., Liu, J., Bencaz, A.F. & Hentz, J.G. Depression and low bone mineral density: a meta-analysis of epidemiologic studies. Osteoporos. Int. 20, 1309–1320 (2009).

    Article  CAS  PubMed  Google Scholar 

  8. Warden, S.J., Nelson, I.R., Fuchs, R.K., Bliziotes, M.M. & Turner, C.H. Serotonin (5-hydroxytryptamine) transporter inhibition causes bone loss in adult mice independently of estrogen deficiency. Menopause 15, 1176–1183 (2008).

    Article  PubMed  Google Scholar 

  9. Warden, S.J., Robling, A.G., Sanders, M.S., Bliziotes, M.M. & Turner, C.H. Inhibition of the serotonin (5-hydroxytryptamine) transporter reduces bone accrual during growth. Endocrinology 146, 685–693 (2005).

    Article  CAS  PubMed  Google Scholar 

  10. Bonnet, N. et al. Various effects of antidepressant drugs on bone microarchitectecture, mechanical properties and bone remodeling. Toxicol. Appl. Pharmacol. 221, 111–118 (2007).

    Article  CAS  PubMed  Google Scholar 

  11. Bliziotes, M., Gunness, M., Eshleman, A. & Wiren, K. The role of dopamine and serotonin in regulating bone mass and strength: studies on dopamine- and serotonin-transporter-null mice. J. Musculoskelet. Neuronal Interact. 2, 291–295 (2002).

    CAS  PubMed  Google Scholar 

  12. Gebara, M.A. et al. Depression, antidepressants and bone health in older adults: a systematic review. J. Am. Geriatr. Soc. 62, 1434–1441 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  13. Yadav, V.K. et al. A serotonin-dependent mechanism explains the leptin regulation of bone mass, appetite and energy expenditure. Cell 138, 976–989 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Oury, F. et al. CREB mediates brain serotonin regulation of bone mass through its expression in ventromedial hypothalamic neurons. Genes Dev. 24, 2330–2342 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Seifert, C.F. & Wiltrout, T.R. Calcaneal bone mineral density in young adults prescribed selective serotonin reuptake inhibitors. Clin. Ther. 35, 1412–1417 (2013).

    Article  CAS  PubMed  Google Scholar 

  16. Aydin, H., Mutlu, N. & Akbas, N.B.G. Treatment of a major depression episode suppresses markers of bone turnover in premenopausal women. J. Psychiatr. Res. 45, 1316–1320 (2011).

    Article  PubMed  Google Scholar 

  17. Misra, M. et al. Use of SSRIs may impact bone density in adolescent and young women with anorexia nervosa. CNS Spectr. 15, 579–586 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  18. Bolo, N.R. et al. Brain pharmacokinetics and tissue distribution in vivo of fluvoxamine and fluoxetine by fluorine magnetic resonance spectroscopy. Neuropsychopharmacology 23, 428–438 (2000).

    Article  CAS  PubMed  Google Scholar 

  19. Boyce, B.F. Advances in the regulation of osteoclasts and osteoclast functions. J. Dent. Res. 92, 860–867 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Teitelbaum, S.L. & Ross, F.P. Genetic regulation of osteoclast development and function. Nat. Rev. Genet. 4, 638–649 (2003).

    Article  CAS  PubMed  Google Scholar 

  21. Zou, W. et al. Talin1 and Rap1 are critical for osteoclast function. Mol. Cell. Biol. 33, 830–844 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Fukunaga, T., Zou, W., Warren, J.T. & Teitelbaum, S.L. Vinculin regulates osteoclast function. J. Biol. Chem. 289, 13554–13564 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Battaglino, R. et al. Serotonin regulates osteoclast differentiation through its transporter. J. Bone Miner. Res. 19, 1420–1431 (2004).

    Article  CAS  PubMed  Google Scholar 

  24. Hodge, J.M. et al. Selective serotonin-reuptake inhibitors inhibit human osteoclast and osteoblast formation and function. Biol. Psychiatry 74, 32–39 (2013).

    Article  CAS  PubMed  Google Scholar 

  25. Fuller, R.W. & Wong, D.T. Serotonin uptake and serotonin-uptake inhibition. Ann. NY Acad. Sci. 600, 68–78, discussion 79–80 (1990).

    Article  CAS  PubMed  Google Scholar 

  26. Takayanagi, H. Osteoimmunology: shared mechanisms and cross-talk between the immune and bone systems. Nat. Rev. Immunol. 7, 292–304 (2007).

    Article  CAS  PubMed  Google Scholar 

  27. Chen, W. et al. C/EBP-α regulates osteoclast lineage commitment. Proc. Natl. Acad. Sci. USA 110, 7294–7299 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Sato, K. et al. Regulation of osteoclast differentiation and function by the CaMK–CREB pathway. Nat. Med. 12, 1410–1416 (2006).

    Article  CAS  PubMed  Google Scholar 

  29. Kuroda, Y., Hisatsune, C., Nakamura, T., Matsuo, K. & Mikoshiba, K. Osteoblasts induce Ca2+-oscillation-independent NFATC1 activation during osteoclastogenesis. Proc. Natl. Acad. Sci. USA 105, 8643–8648 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Hidaka, H., Asano, M. & Tanaka, T. Activity–structure relationship of calmodulin antagonists, naphthalenesulfonamide derivatives. Mol. Pharmacol. 20, 571–578 (1981).

    CAS  PubMed  Google Scholar 

  31. Best, J.L. et al. Identification of small-molecule antagonists that inhibit an activator–coactivator interaction. Proc. Natl. Acad. Sci. USA 101, 17622–17627 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Gobin, V. et al. Fluoxetine suppresses calcium signaling in human T lymphocytes through depletion of intracellular calcium stores. Cell Calcium 58, 254–263 (2015).

    Article  CAS  PubMed  Google Scholar 

  33. Okamoto, K. & Takayanagi, H. Regulation of bone by the adaptive immune system in arthritis. Arthritis Res. Ther. 13, 219 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Takayanagi, H. New developments in osteoimmunology. Nat. Rev. Rheumatol. 8, 684–689 (2012).

    Article  CAS  PubMed  Google Scholar 

  35. Karsenty, G., Kronenberg, H.M. & Settembre, C. Genetic control of bone formation. Annu. Rev. Cell Dev. Biol. 25, 629–648 (2009).

    Article  CAS  PubMed  Google Scholar 

  36. Karsenty, G. & Ferron, M. The contribution of bone to whole-organism physiology. Nature 481, 314–320 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Wada, T., Nakashima, T., Hiroshi, N. & Penninger, J.M. RANKL–RANK signaling in osteoclastogenesis and bone disease. Trends Mol. Med. 12, 17–25 (2006).

    Article  CAS  PubMed  Google Scholar 

  38. Ruocco, M.G. et al. IκB kinase (IKK)β, but not IKKα, is a critical mediator of osteoclast survival and is required for inflammation-induced bone loss. J. Exp. Med. 201, 1677–1687 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Takeda, S. et al. Leptin regulates bone formation via the sympathetic nervous system. Cell 111, 305–317 (2002).

    Article  CAS  PubMed  Google Scholar 

  40. Elefteriou, F. et al. Leptin regulation of bone resorption by the sympathetic nervous system and CART. Nature 434, 514–520 (2005).

    Article  CAS  PubMed  Google Scholar 

  41. Gainetdinov, R.R., Premont, R.T., Bohn, L.M., Lefkowitz, R.J. & Caron, M.G. Desensitization of G-protein-coupled receptors and neuronal functions. Annu. Rev. Neurosci. 27, 107–144 (2004).

    Article  CAS  PubMed  Google Scholar 

  42. Bristow, L.J., O'Connor, D., Watts, R., Duxon, M.S. & Hutson, P.H. Evidence for accelerated de-sensitisation of 5-HT2C receptors following combined treatment with fluoxetine and the 5-HT1A receptor antagonist, WAY 100,635, in the rat. Neuropharmacology 39, 1222–1236 (2000).

    Article  CAS  PubMed  Google Scholar 

  43. Yamauchi, M., Tatebayashi, T., Nagase, K., Kojima, M. & Imanishi, T. Chronic treatment with fluvoxamine desensitizes 5-HT2C-receptor-mediated hypo-locomotion in rats. Pharmacol. Biochem. Behav. 78, 683–689 (2004).

    Article  CAS  PubMed  Google Scholar 

  44. Kennett, G.A. et al. Effect of chronic administration of selective 5-hydroxytryptamine- and noradrenaline-uptake inhibitors on a putative index of 5-HT2C/2B receptor function. Neuropharmacology 33, 1581–1588 (1994).

    Article  CAS  PubMed  Google Scholar 

  45. Chabbi-Achengli, Y. et al. Decreased osteoclastogenesis in serotonin-deficient mice. Proc. Natl. Acad. Sci. USA 109, 2567–2572 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Kim, H.J. et al. Fluoxetine suppresses synaptically induced [Ca2]i spikes and excitotoxicity in cultured rat hippocampal neurons. Brain Res. 1490, 23–34 (2013).

    Article  CAS  PubMed  Google Scholar 

  47. Deák, F. et al. Inhibition of voltage-gated calcium channels by fluoxetine in rat hippocampal pyramidal cells. Neuropharmacology 39, 1029–1036 (2000).

    Article  PubMed  Google Scholar 

  48. Hahn, S.J. et al. Inhibition by fluoxetine of voltage-activated ion channels in rat PC12 cells. Eur. J. Pharmacol. 367, 113–118 (1999).

    Article  CAS  PubMed  Google Scholar 

  49. Kecskeméti, V. et al. Norfluoxetine and fluoxetine have similar anticonvulsant and Ca2+-channel-blocking potencies. Brain Res. Bull. 67, 126–132 (2005).

    Article  CAS  PubMed  Google Scholar 

  50. Shenoy, A.R. et al. Citalopram suppresses thymocyte cytokine production. J. Neuroimmunol. 262, 46–52 (2013).

    Article  CAS  PubMed  Google Scholar 

  51. Kubera, M., Kenis, G., Bosmans, E., Scharpé, S. & Maes, M. Effects of serotonin, and serotonergic agonists and antagonists, on the production of interferon-γ and interleukin-10. Neuropsychopharmacology 23, 89–98 (2000).

    Article  CAS  PubMed  Google Scholar 

  52. Branco-de-Almeida, L.S. et al. Fluoxetine inhibits inflammatory response and bone loss in a rat model of ligature-induced periodontitis. J. Periodontol. 83, 664–671 (2012).

    Article  CAS  PubMed  Google Scholar 

  53. Pellegrino, T.C. & Bayer, B.M. Modulation of immune cell function following fluoxetine administration in rats. Pharmacol. Biochem. Behav. 59, 151–157 (1998).

    Article  CAS  PubMed  Google Scholar 

  54. Schett, G. & Teitelbaum, S.L. Osteoclasts and arthritis. J. Bone Miner. Res. 24, 1142–1146 (2009).

    Article  PubMed  Google Scholar 

  55. Baharav, E. et al. Immunomodulatory effect of sertraline in a rat model of rheumatoid arthritis. Neuroimmunomodulation 19, 309–318 (2012).

    Article  CAS  PubMed  Google Scholar 

  56. Hochberg, M.C., Wohlreich, M., Gaynor, P., Hanna, S. & Risser, R. Clinically relevant outcomes based on analysis of pooled data from two trials of duloxetine in patients with knee osteoarthritis. J. Rheumatol. 39, 352–358 (2012).

    Article  CAS  PubMed  Google Scholar 

  57. Sacre, S., Medghalchi, M., Gregory, B., Brennan, F. & Williams, R. Fluoxetine and citalopram exhibit potent anti-inflammatory activity in human and murine models of rheumatoid arthritis and inhibit toll-like receptors. Arthritis Rheum. 62, 683–693 (2010).

    Article  CAS  PubMed  Google Scholar 

  58. Blardi, P. et al. Plasma catecholamine levels after fluoxetine treatment in depressive patients. Neuropsychobiology 51, 72–76 (2005).

    Article  CAS  PubMed  Google Scholar 

  59. Diem, S.J. et al. Effects of escitalopram on markers of bone turnover: a randomized clinical trial. J. Clin. Endocrinol. Metab. 99, E1732–E1737 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Yadav, V.K. et al. Lrp5 controls bone formation by inhibiting serotonin synthesis in the duodenum. Cell 135, 825–837 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Underwood, M.D., Arango, V., Bakalian, M.J., Ruggiero, D.A. & Mann, J.J. Dorsal raphe nucleus serotonergic neurons innervate the rostral ventrolateral medulla in rat. Brain Res. 824, 45–55 (1999).

    Article  CAS  PubMed  Google Scholar 

  62. Ducy, P. & Karsenty, G. Two distinct osteoblast-specific cis-acting elements control expression of a mouse osteocalcin gene. Mol. Cell. Biol. 15, 1858–1869 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Angoa-Pérez, M., Kane, M.J., Briggs, D.I., Francescutti, D.M. & Kuhn, D.M. Marble burying and nestlet shredding as tests of repetitive, compulsive-like behaviors in mice. J. Vis. Exp. 82, 50978 (2013).

    Google Scholar 

  64. Nicolas, L.B., Kolb, Y. & Prinssen, E.P.M. A combined marble-burying–locomotor activity test in mice: a practical screening test with sensitivity to different classes of anxiolytics and antidepressants. Eur. J. Pharmacol. 547, 106–115 (2006).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We thank N. Luo for help with histomorphometry, T. Hanna for handling the mouse colony, and G. Karsenty and S. Kousteni for critically reading the manuscript. The US National Institutes of Health grant AG032959 (P.D.) supported this work.

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Authors and Affiliations

  1. Department of Genetics and Development, College of Physicians and Surgeons, Columbia University, New York, New York, USA

    María José Ortuño & Riccardo Paone

  2. Department of Biomedical Engineering, Columbia University, New York, New York, USA

    Samuel T Robinson & X Edward Guo

  3. Department of Physiology and Cellular Biophysics, Columbia University, New York, New York, USA

    Prakash Subramanyam & Henry M Colecraft

  4. Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, L'Aquila, Italy

    Riccardo Paone

  5. Department of Psychiatry, College of Physicians and Surgeons, Columbia University, New York, New York, USA

    Yung-yu Huang & J John Mann

  6. Department of Pathology and Cell Biology, College of Physicians and Surgeons, Columbia University, New York, New York, USA

    Patricia Ducy

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  1. María José Ortuño
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Contributions

P.D. conceived the study; M.J.O. performed most of the experiments; S.T.R. performed the μ-CT analysis under X.E.G.'s supervision; P.S. assisted with the calcium signaling analysis under H.M.C.'s supervision; R.P. assisted with the histomorphometry analysis; Y.H. performed the HPLC analysis under J.J.M.'s supervision. M.J.O., H.M.C., J.J.M. and P.D. analyzed and discussed the results; and M.J.O. and P.D. wrote and revised the manuscript.

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Correspondence to Patricia Ducy.

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Ortuño, M., Robinson, S., Subramanyam, P. et al. Serotonin-reuptake inhibitors act centrally to cause bone loss in mice by counteracting a local anti-resorptive effect. Nat Med 22, 1170–1179 (2016). https://doi.org/10.1038/nm.4166

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