Serotonin-reuptake inhibitors act centrally to cause bone loss in mice by counteracting a local anti-resorptive effect.
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.
Department of Genetics and Development, College of Physicians and Surgeons, Columbia University, New York, New York, USA.
María José
MJ
Ortuño
Department of Biomedical Engineering, Columbia University, New York, New York, USA.
Samuel T
ST
Robinson
Department of Physiology and Cellular Biophysics, Columbia University, New York, New York, USA.
Prakash
P
Subramanyam
Department of Genetics and Development, College of Physicians and Surgeons, Columbia University, New York, New York, USA.|Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, L'Aquila, Italy.
Riccardo
0000-0002-8688-9191
R
Paone
Department of Psychiatry, College of Physicians and Surgeons, Columbia University, New York, New York, USA.
Yung-Yu
YY
Huang
Department of Biomedical Engineering, Columbia University, New York, New York, USA.
X Edward
XE
Guo
Department of Physiology and Cellular Biophysics, Columbia University, New York, New York, USA.
Henry M
HM
Colecraft
Department of Psychiatry, College of Physicians and Surgeons, Columbia University, New York, New York, USA.
J John
JJ
Mann
Department of Pathology and Cell Biology, College of Physicians and Surgeons, Columbia University, New York, New York, USA.
Patricia
P
Ducy
D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000818:Animals; D016723:Bone Remodeling / Q000187:drug effects*; D001862:Bone Resorption; D001842:Bone and Bones / Q000000981:diagnostic imaging / Q000187:drug effects* / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D005473:Fluoxetine / Q000494:pharmacology*; D015870:Gene Expression / Q000187:drug effects; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D051379:Mice; D018345:Mice, Knockout; D050778:NFATC Transcription Factors / Q000187:drug effects / Q000378:metabolism; D061848:Optical Imaging; D010012:Osteogenesis / Q000187:drug effects*; D011433:Propranolol / Q000494:pharmacology; D050486:Serotonin Plasma Membrane Transport Proteins / Q000235:genetics; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology*; D013564:Sympathetic Nervous System / Q000187:drug effects*; D014365:Tryptophan Hydroxylase / Q000235:genetics; D055114:X-Ray Microtomography
D000319:Adrenergic beta-Antagonists; D002118:Calcium; D005473:Fluoxetine; D050778:NFATC Transcription Factors; D011433:Propranolol; D050486:Serotonin Plasma Membrane Transport Proteins; D017367:Selective Serotonin Reuptake Inhibitors; D014365:Tryptophan Hydroxylase; C494005:Nfatc1 protein, mouse; C493231:Slc6a4 protein, mouse; C487801:Tph1 protein, mouse