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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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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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