title: Selective serotonin reuptake inhibitors inhibit human osteoclast and osteoblast formation and function.
abstract: BACKGROUND
  Selective serotonin reuptake inhibitors (SSRIs) are widely used antidepressants and one of the most commonly used medications. There is growing concern that SSRIs, which sequester in bone marrow at higher concentrations than brain or blood, increase bone fragility and fracture risk. However, their mechanism of action on human osteoclasts (OC) and osteoblasts (OB) differentiation remains unclear.
  
  
  METHODS
  Expression of serotonin receptors (5-HTR), transporter (5-HTT), and tryptophan hydroxylase 1 (TPH1) was assessed in human OC (precursors and mature) and OB (nonmineralizing and mineralizing) by polymerase chain reaction. OC formation and resorption was measured in the presence of 5 SSRIs. OBs cultured with SSRIs for 28 days were assessed for alkaline phosphatase (ALP) and bone mineralization. Cell viability and apoptosis were determined by annexin V flow cytometry.
  
  
  RESULTS
  OCs and OB expressed TPH1, 5-HTT, and 5-HTR1B. The 5-HTR2A was expressed only in OB, whereas 5-HTR2B expression increased from precursor to mature OC. All SSRIs (except citalopram) dose-dependently inhibited OC formation and resorption between 1 μmol/L and 10 μmol/L; order of potency: sertraline > fluoxetine > paroxetine > fluvoxamine > citalopram. Similarly, SSRIs (except citalopram) inhibited ALP and bone mineralization by OB but only at 30 μmol/L. Apoptosis was induced by SSRIs in OC and OB in an identical pattern to inhibitory effects. Serotonin treatment had no effect on either OC or OB parameters.
  
  
  CONCLUSIONS
  These data demonstrate that SSRIs differentially inhibit bone cell function via apoptosis. This may explain the mechanisms of bone loss with chronic use and aid clinical choices.
authors.affiliation: Barwon Biomedical Research, The Geelong Hospital, Geelong, Victoria, Australia.
authors.forename: Jason M
authors.initials: JM
authors.lastname: Hodge
authors.forename: Yiming
authors.initials: Y
authors.lastname: Wang
authors.forename: Michael
authors.initials: M
authors.lastname: Berk
authors.forename: Fiona M
authors.initials: FM
authors.lastname: Collier
authors.forename: Tania J
authors.initials: TJ
authors.lastname: Fernandes
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Constable
authors.forename: Julie A
authors.initials: JA
authors.lastname: Pasco
authors.forename: Seetal
authors.initials: S
authors.lastname: Dodd
authors.forename: Geoffrey C
authors.initials: GC
authors.lastname: Nicholson
authors.forename: Richard L
authors.initials: RL
authors.lastname: Kennedy
authors.forename: Lana J
authors.initials: LJ
authors.lastname: Williams
mesh_terms: D000928:Antidepressive Agents / Q000276:immunology*; D017209:Apoptosis / Q000187:drug effects; D006801:Humans; D010006:Osteoblasts / Q000166:cytology / Q000187:drug effects*; D010010:Osteoclasts / Q000166:cytology / Q000187:drug effects*; D011985:Receptors, Serotonin / Q000235:genetics / Q000378:metabolism; D050486:Serotonin Plasma Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology*; D014365:Tryptophan Hydroxylase / Q000235:genetics / Q000378:metabolism
chemical_list: D000928:Antidepressive Agents; D011985:Receptors, Serotonin; D050486:Serotonin Plasma Membrane Transport Proteins; D017367:Selective Serotonin Reuptake Inhibitors; D014365:Tryptophan Hydroxylase