title: The Selective Serotonin Reuptake Inhibitor Fluoxetine Directly Inhibits Osteoblast Differentiation and Mineralization During Fracture Healing in Mice.
abstract: Chronic use of selective serotonin reuptake inhibitors (SSRIs) for the treatment of depression has been linked to osteoporosis. In this study, we investigated the effect of chronic SSRI use on fracture healing in two murine models of bone regeneration. First, we performed a comprehensive analysis of endochondral bone healing in a femur fracture model. C57/BL6 mice treated with fluoxetine, the most commonly prescribed SSRI, developed a normal cartilaginous soft-callus at 14 days after fracture and demonstrated a significantly smaller and biomechanically weaker bony hard-callus at 28 days. In order to further dissect the mechanism that resulted in a smaller bony regenerate, we used an intramembranous model of bone healing and revealed that fluoxetine treatment resulted in a significantly smaller bony callus at 7 and 14 days postinjury. In order to test whether the smaller bony regenerate following fluoxetine treatment was caused by an inhibition of osteogenic differentiation and/or mineralization, we employed in vitro experiments, which established that fluoxetine treatment decreases osteogenic differentiation and mineralization and that this effect is serotonin-independent. Finally, in a translational approach, we tested whether cessation of the medication would result in restoration of the regenerative potential. However, histologic and μCT analysis revealed non-union formation in these animals with fibrous tissue interposition within the callus. In conclusion, fluoxetine exerts a direct, inhibitory effect on osteoblast differentiation and mineralization, shown in two disparate murine models of bone repair. Discontinuation of the drug did not result in restoration of the healing potential, but rather led to complete arrest of the repair process. Besides the well-established effect of SSRIs on bone homeostasis, our study provides strong evidence that fluoxetine use negatively impacts fracture healing. © 2017 American Society for Bone and Mineral Research.
authors.affiliation: Department of Orthopaedic Surgery, Langone Medical Center-Hospital for Joint Diseases, New York University, New York, NY, USA.
authors.forename: Vivian
authors.initials: V
authors.lastname: Bradaschia-Correa
authors.affiliation: Department of Orthopaedic Surgery, Langone Medical Center-Hospital for Joint Diseases, New York University, New York, NY, USA.
authors.forename: Anne M
authors.initials: AM
authors.lastname: Josephson
authors.affiliation: Department of Orthopaedic Surgery, Langone Medical Center-Hospital for Joint Diseases, New York University, New York, NY, USA.
authors.forename: Devan
authors.initials: D
authors.lastname: Mehta
authors.affiliation: Department of Orthopaedic Surgery, Langone Medical Center-Hospital for Joint Diseases, New York University, New York, NY, USA.
authors.forename: Matthew
authors.initials: M
authors.lastname: Mizrahi
authors.affiliation: Department of Orthopaedic Surgery, Langone Medical Center-Hospital for Joint Diseases, New York University, New York, NY, USA.
authors.forename: Shane S
authors.initials: SS
authors.lastname: Neibart
authors.affiliation: Department of Orthopaedic Surgery, Langone Medical Center-Hospital for Joint Diseases, New York University, New York, NY, USA.|Department of Mechanical and Aerospace Engineering, Tandon School of Engineering, New York University, New York, NY, USA.
authors.forename: Chao
authors.initials: C
authors.lastname: Liu
authors.affiliation: Department of Orthopaedic Surgery, Langone Medical Center-Hospital for Joint Diseases, New York University, New York, NY, USA.|Department of Mechanical and Aerospace Engineering, Tandon School of Engineering, New York University, New York, NY, USA.
authors.forename: Oran D
authors.initials: OD
authors.lastname: Kennedy
authors.affiliation: Department of Orthopaedic Surgery, Langone Medical Center-Hospital for Joint Diseases, New York University, New York, NY, USA.|Department of Mechanical and Aerospace Engineering, Tandon School of Engineering, New York University, New York, NY, USA.
authors.forename: Alesha B
authors.initials: AB
authors.lastname: Castillo
authors.affiliation: Department of Orthopaedic Surgery, Langone Medical Center-Hospital for Joint Diseases, New York University, New York, NY, USA.
authors.forename: Kenneth A
authors.initials: KA
authors.lastname: Egol
authors.affiliation: Department of Orthopaedic Surgery, Langone Medical Center-Hospital for Joint Diseases, New York University, New York, NY, USA.|Department of Cell Biology, School of Medicine, New York University, New York, NY, USA.
authors.forename: Philipp
authors.initials: P
authors.lastname: Leucht
mesh_terms: D000818:Animals; D001861:Bone Regeneration / Q000187:drug effects*; D002113:Calcification, Physiologic / Q000187:drug effects*; D002454:Cell Differentiation / Q000187:drug effects*; D004195:Disease Models, Animal; D005264:Femoral Fractures / Q000378:metabolism / Q000473:pathology; D005473:Fluoxetine / Q000494:pharmacology; D017102:Fracture Healing / Q000187:drug effects*; D008297:Male; D051379:Mice; D010006:Osteoblasts / Q000378:metabolism / Q000473:pathology; D017367:Selective Serotonin Reuptake Inhibitors / Q000009:adverse effects* / Q000494:pharmacology
chemical_list: D005473:Fluoxetine; D017367:Selective Serotonin Reuptake Inhibitors
keywords: BONE; DEPRESSION; OSTEOBLAST; OSTEOPOROSIS; OSTEOPROGENITOR CELL