{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,23]],"date-time":"2026-08-23T02:17:19Z","timestamp":1787451439653,"version":"build-2736575974"},"reference-count":28,"publisher":"Oxford University Press (OUP)","issue":"4","license":[{"start":{"date-parts":[[2016,11,21]],"date-time":"2016-11-21T00:00:00Z","timestamp":1479686400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"name":"New York University College of Dentistry","award":["NIH 1 S10 OD010751-01A1"],"award-info":[{"award-number":["NIH 1 S10 OD010751-01A1"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2017,4,1]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n               <jats:sec>\n                  <jats:title>\u2003<\/jats:title>\n                  <jats:p>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 \u03bcCT 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. \u00a9 2017 American Society for Bone and Mineral Research.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1002\/jbmr.3045","type":"journal-article","created":{"date-parts":[[2016,11,21]],"date-time":"2016-11-21T11:36:43Z","timestamp":1479728203000},"page":"821-833","source":"Crossref","is-referenced-by-count":73,"title":["The Selective Serotonin Reuptake Inhibitor Fluoxetine Directly Inhibits Osteoblast Differentiation and Mineralization During Fracture Healing in Mice"],"prefix":"10.1093","volume":"32","author":[{"given":"Vivian","family":"Bradaschia-Correa","sequence":"first","affiliation":[{"name":"Department of Orthopaedic SurgeryLangone Medical Center\u2013Hospital for Joint DiseasesNew York UniversityNew YorkNYUSA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne M","family":"Josephson","sequence":"additional","affiliation":[{"name":"Department of Orthopaedic SurgeryLangone Medical Center\u2013Hospital for Joint DiseasesNew York UniversityNew YorkNYUSA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Devan","family":"Mehta","sequence":"additional","affiliation":[{"name":"Department of Orthopaedic SurgeryLangone Medical Center\u2013Hospital for Joint DiseasesNew York UniversityNew YorkNYUSA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew","family":"Mizrahi","sequence":"additional","affiliation":[{"name":"Department of Orthopaedic SurgeryLangone Medical Center\u2013Hospital for Joint DiseasesNew York UniversityNew YorkNYUSA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shane S","family":"Neibart","sequence":"additional","affiliation":[{"name":"Department of Orthopaedic SurgeryLangone Medical Center\u2013Hospital for Joint DiseasesNew York UniversityNew YorkNYUSA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chao","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Mechanical and Aerospace EngineeringTandon School of EngineeringNew York UniversityNew YorkNYUSA"},{"name":"Department of Orthopaedic SurgeryLangone Medical Center\u2013Hospital for Joint DiseasesNew York UniversityNew YorkNYUSA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Oran D","family":"Kennedy","sequence":"additional","affiliation":[{"name":"Department of Mechanical and Aerospace EngineeringTandon School of EngineeringNew York UniversityNew YorkNYUSA"},{"name":"Department of Orthopaedic SurgeryLangone Medical Center\u2013Hospital for Joint DiseasesNew York UniversityNew YorkNYUSA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alesha B","family":"Castillo","sequence":"additional","affiliation":[{"name":"Department of Mechanical and Aerospace EngineeringTandon School of EngineeringNew York UniversityNew YorkNYUSA"},{"name":"Department of Orthopaedic SurgeryLangone Medical Center\u2013Hospital for Joint DiseasesNew York UniversityNew YorkNYUSA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenneth A","family":"Egol","sequence":"additional","affiliation":[{"name":"Department of Orthopaedic SurgeryLangone Medical Center\u2013Hospital for Joint DiseasesNew York UniversityNew YorkNYUSA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philipp","family":"Leucht","sequence":"additional","affiliation":[{"name":"Department of Cell BiologySchool of MedicineNew York UniversityNew YorkNYUSA"},{"name":"Department of Orthopaedic SurgeryLangone Medical Center\u2013Hospital for Joint DiseasesNew York UniversityNew YorkNYUSA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2016,11,21]]},"reference":[{"key":"2024021014203653800_jbmr3045-bib-0001","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1016\/j.bone.2015.04.042","article-title":"Use of selective serotonin reuptake inhibitors and bone mass in adolescents: an NHANES study","volume":"78","author":"Feuer","year":"2015","journal-title":"Bone"},{"issue":"3","key":"2024021014203653800_jbmr3045-bib-0002","doi-asserted-by":"crossref","first-page":"233","DOI":"10.2165\/00019053-200624030-00003","article-title":"Trends in outpatient prescription drug use and related costs in the US: 1998-2003","volume":"24","author":"Wysowski","year":"2006","journal-title":"Pharmacoeconomics"},{"issue":"3","key":"2024021014203653800_jbmr3045-bib-0003","doi-asserted-by":"crossref","first-page":"606","DOI":"10.1016\/j.bone.2012.05.018","article-title":"Antidepressant medications and osteoporosis","volume":"51","author":"Rizzoli","year":"2012","journal-title":"Bone"},{"issue":"1","key":"2024021014203653800_jbmr3045-bib-0004","first-page":"7","article-title":"The non-antidepressant effects of citalopram: a clinician's perspective","volume":"35","author":"Richter","year":"2014","journal-title":"Neuro Endocrinol Lett"},{"issue":"3","key":"2024021014203653800_jbmr3045-bib-0005","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1007\/s40263-015-0231-5","article-title":"Serotonin-norepinephrine reuptake inhibitor and selective serotonin reuptake inhibitor use and risk of fractures: a new-user cohort study among US adults aged 50 years and older","volume":"29","author":"Lanteigne","year":"2015","journal-title":"CNS Drugs"},{"issue":"2","key":"2024021014203653800_jbmr3045-bib-0006","doi-asserted-by":"crossref","first-page":"685","DOI":"10.1210\/en.2004-1259","article-title":"Inhibition of the serotonin (5-hydroxytryptamine) transporter reduces bone accrual during growth","volume":"146","author":"Warden","year":"2005","journal-title":"Endocrinology"},{"issue":"6","key":"2024021014203653800_jbmr3045-bib-0007","doi-asserted-by":"crossref","first-page":"429","DOI":"10.3109\/09537104.2010.487582","article-title":"Platelet serotonin transporter (5HTt): physiological influences on kinetic characteristics in a large human population","volume":"21","author":"Banovic","year":"2010","journal-title":"Platelets"},{"key":"2024021014203653800_jbmr3045-bib-0008","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1016\/j.bone.2016.05.003","article-title":"Effects of antidepressants on postmenopausal bone loss\u2014a 5-year longitudinal study from the OSTPRE cohort","volume":"89","author":"Rauma","year":"2016","journal-title":"Bone"},{"issue":"7","key":"2024021014203653800_jbmr3045-bib-0009","doi-asserted-by":"crossref","first-page":"1321","DOI":"10.1038\/sj.npp.1300433","article-title":"Effects of chronic fluoxetine in animal models of anxiety and depression","volume":"29","author":"Dulawa","year":"2004","journal-title":"Neuropsychopharmacology"},{"issue":"1","key":"2024021014203653800_jbmr3045-bib-0010","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1002\/jor.1100020115","article-title":"Production of a standard closed fracture in laboratory animal bone","volume":"2","author":"Bonnarens","year":"1984","journal-title":"J Orthop Res"},{"issue":"4","key":"2024021014203653800_jbmr3045-bib-0011","doi-asserted-by":"crossref","first-page":"919","DOI":"10.1016\/j.bone.2006.10.027","article-title":"Effect of mechanical stimuli on skeletal regeneration around implants","volume":"40","author":"Leucht","year":"2007","journal-title":"Bone"},{"issue":"29","key":"2024021014203653800_jbmr3045-bib-0012","doi-asserted-by":"crossref","first-page":"29ra30","DOI":"10.1126\/scitranslmed.3000231","article-title":"Wnt proteins promote bone regeneration","volume":"2","author":"Minear","year":"2010","journal-title":"Sci Transl Med"},{"issue":"6","key":"2024021014203653800_jbmr3045-bib-0013","doi-asserted-by":"crossref","first-page":"1357","DOI":"10.1016\/j.bone.2012.03.008","article-title":"Micro-computed tomography assessment of the progression of fracture healing in mice","volume":"50","author":"O'Neill","year":"2012","journal-title":"Bone"},{"key":"2024021014203653800_jbmr3045-bib-0014","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.bone.2014.07.022","article-title":"A method for isolating high quality RNA from mouse cortical and cancellous bone","volume":"68","author":"Kelly","year":"2014","journal-title":"Bone"},{"key":"2024021014203653800_jbmr3045-bib-0015","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1016\/j.bone.2014.01.019","article-title":"Jagged1 is essential for osteoblast development during maxillary ossification","volume":"62","author":"Hill","year":"2014","journal-title":"Bone"},{"issue":"2","key":"2024021014203653800_jbmr3045-bib-0016","doi-asserted-by":"crossref","first-page":"418","DOI":"10.1096\/fj.07-9209com","article-title":"The serotonin 5-HT2B receptor controls bone mass via osteoblast recruitment and proliferation","volume":"22","author":"Collet","year":"2008","journal-title":"FASEB J"},{"issue":"6","key":"2024021014203653800_jbmr3045-bib-0017","first-page":"779","article-title":"New insights into tryptophan and its metabolites in the regulation of bone metabolism","volume":"66","author":"Michalowska","year":"2015","journal-title":"J Physiol Pharmacol"},{"issue":"4","key":"2024021014203653800_jbmr3045-bib-0018","doi-asserted-by":"crossref","first-page":"985","DOI":"10.1016\/j.bone.2009.12.031","article-title":"Psychotropic drugs have contrasting skeletal effects that are independent of their effects on physical activity levels","volume":"46","author":"Warden","year":"2010","journal-title":"Bone"},{"issue":"6","key":"2024021014203653800_jbmr3045-bib-0019","doi-asserted-by":"crossref","first-page":"1176","DOI":"10.1097\/gme.0b013e318173566b","article-title":"Serotonin (5-hydroxytryptamine) transporter inhibition causes bone loss in adult mice independently of estrogen deficiency","volume":"15","author":"Warden","year":"2008","journal-title":"Menopause"},{"issue":"1","key":"2024021014203653800_jbmr3045-bib-0020","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1007\/s40266-015-0323-4","article-title":"Effects of depression and serotonergic antidepressants on bone: mechanisms and implications for the treatment of depression","volume":"33","author":"Fernandes","year":"2016","journal-title":"Drugs Aging"},{"issue":"1","key":"2024021014203653800_jbmr3045-bib-0021","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1016\/j.biopsych.2012.11.003","article-title":"Selective serotonin reuptake inhibitors inhibit human osteoclast and osteoblast formation and function","volume":"74","author":"Hodge","year":"2013","journal-title":"Biol Psychiatry"},{"issue":"12","key":"2024021014203653800_jbmr3045-bib-0022","doi-asserted-by":"crossref","first-page":"912","DOI":"10.1002\/bdra.23323","article-title":"Selective serotonin reuptake inhibitor exposure alters osteoblast gene expression and craniofacial development in mice","volume":"100","author":"Cray","year":"2014","journal-title":"Birth Defects Res A Clin Mol Teratol"},{"issue":"5","key":"2024021014203653800_jbmr3045-bib-0023","doi-asserted-by":"crossref","first-page":"477","DOI":"10.1016\/S8756-3282(01)00593-2","article-title":"Neurotransmitter action in osteoblasts: expression of a functional system for serotonin receptor activation and reuptake","volume":"29","author":"Bliziotes","year":"2001","journal-title":"Bone"},{"issue":"11","key":"2024021014203653800_jbmr3045-bib-0024","doi-asserted-by":"crossref","first-page":"1575","DOI":"10.1302\/0301-620X.95B11.31158","article-title":"Effects of commonly used medications on bone tissue mineralisation in SaOS-2 human bone cell line: an in vitro study","volume":"95-B","author":"Salai","year":"2013","journal-title":"Bone Joint J"},{"issue":"1","key":"2024021014203653800_jbmr3045-bib-0025","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1016\/j.tripleo.2009.01.006","article-title":"The effect of fluoxetine on bone regeneration in rat calvarial bone defects","volume":"108","author":"Mortazavi","year":"2009","journal-title":"Oral Surg Oral Med Oral Pathol Oral Radiol Endod"},{"issue":"7","key":"2024021014203653800_jbmr3045-bib-0026","doi-asserted-by":"crossref","first-page":"1680","DOI":"10.1359\/jbmr.091116","article-title":"Origin matters: differences in embryonic tissue origin and Wnt signaling determine the osteogenic potential and healing capacity of frontal and parietal calvarial bones","volume":"25","author":"Quarto","year":"2010","journal-title":"J Bone Miner Res"},{"issue":"17","key":"2024021014203653800_jbmr3045-bib-0027","doi-asserted-by":"crossref","first-page":"2845","DOI":"10.1242\/dev.023788","article-title":"Embryonic origin and Hox status determine progenitor cell fate during adult bone regeneration","volume":"135","author":"Leucht","year":"2008","journal-title":"Development"},{"issue":"6","key":"2024021014203653800_jbmr3045-bib-0028","doi-asserted-by":"crossref","first-page":"268","DOI":"10.1007\/s10334-004-0033-0","article-title":"Long-term sequestration of fluorinated compounds in tissues after fluvoxamine or fluoxetine treatment: a fluorine magnetic resonance spectroscopy study in vivo","volume":"16","author":"Bolo","year":"2004","journal-title":"MAGMA"}],"container-title":["Journal of Bone and Mineral Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fjbmr.3045","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/academic.oup.com\/jbmr\/article-pdf\/32\/4\/821\/56654085\/jbmr3045.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jbmr\/article-pdf\/32\/4\/821\/56654085\/jbmr3045.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,3,13]],"date-time":"2024-03-13T14:58:13Z","timestamp":1710341893000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jbmr\/article\/32\/4\/821-833\/7605800"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2016,11,21]]},"references-count":28,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2016,11,21]]},"published-print":{"date-parts":[[2017,4,1]]}},"URL":"https:\/\/doi.org\/10.1002\/jbmr.3045","relation":{},"ISSN":["0884-0431","1523-4681"],"issn-type":[{"value":"0884-0431","type":"print"},{"value":"1523-4681","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2017,4,1]]},"published":{"date-parts":[[2016,11,21]]}}}