title: In vitro effect of bisphosphonates on oral keratinocytes and fibroblasts.
abstract: OBJECTIVE
  Osteonecrosis of the jaws is a potential complication of bisphosphonate (BP) therapy. The underlying mechanisms remain unclear. Although most research has concentrated on the effects of BPs on osteoclast and osteoblast functions, the disease is diagnosed and classified based on of mucosal breakdown, suggesting that oral soft tissues may be involved in its pathogenesis. The aim of this study was to determine the effect of 3 different BP drugs (alendronate, zoledronate, and clodronate) on the function of oral keratinocytes and fibroblasts.
  
  
  METHODS
  Human oral keratinocytes (OKF6) and fetal foreskin fibroblasts (HFFF2) were exposed to each drug at several concentrations and the effect on cell proliferation was assessed by counting the viable cells after different lengths of treatment. The effect on cell migration was examined using Transwell migration assays. An organotypic coculture model using keratinocytes and fibroblasts, which recapitulated the morphology of the oral mucosa, was used to assess the effect of the drugs on epithelial stratification and differentiation.
  
  
  RESULTS
  The 3 BPs affected the viability and proliferation of OKF6 and HFFF2 cells at concentrations in keeping with their known relative in vitro potencies. There was no effect on cell migration or tissue architecture in organotypic cultures at subtoxic concentrations.
  
  
  CONCLUSIONS
  The lack of effect of these drugs on cell migration below concentrations known to affect cell viability suggests that BP-related osteonecrosis is not caused through suppression of keratinocyte or fibroblast motility.
authors.affiliation: Specialist Registrar, Department of Oral and Maxillofacial Surgery, Queen Alexandra Hospital, Portsmouth, United Kingdom. Electronic address: niall.mcleod@nhs.net.
authors.forename: Niall M H
authors.initials: NM
authors.lastname: McLeod
authors.affiliation: Research Fellow, Cancer Sciences Division, University of Southampton, Southampton; Clinical Lecturer, Cancer Sciences Division, University of Southampton, Southampton, United Kingdom.
authors.forename: Karwan A
authors.initials: KA
authors.lastname: Moutasim
authors.affiliation: Professor, Department of Oral and Maxillofacial Surgery, Queen Alexandra Hospital, Portsmouth, United Kingdom.
authors.forename: Peter A
authors.initials: PA
authors.lastname: Brennan
authors.affiliation: Professor, Cancer Sciences Unit, University of Southampton, Southampton, United Kingdom.
authors.forename: Gareth
authors.initials: G
authors.lastname: Thomas
authors.affiliation: Senior Research Fellow, Cancer Sciences Unit, University of Southampton, Southampton, United Kingdom.
authors.forename: Veronika
authors.initials: V
authors.lastname: Jenei
mesh_terms: D019386:Alendronate / Q000009:adverse effects; D050071:Bone Density Conservation Agents / Q000009:adverse effects; D002465:Cell Movement / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004002:Clodronic Acid / Q000009:adverse effects; D018920:Coculture Techniques; D004164:Diphosphonates / Q000009:adverse effects*; D005333:Fetus; D005347:Fibroblasts / Q000187:drug effects*; D052816:Foreskin / Q000166:cytology / Q000187:drug effects; D006801:Humans; D007093:Imidazoles / Q000009:adverse effects; D015603:Keratinocytes / Q000187:drug effects*; D008297:Male; D009061:Mouth Mucosa / Q000166:cytology / Q000187:drug effects; D000077211:Zoledronic Acid
chemical_list: D050071:Bone Density Conservation Agents; D004164:Diphosphonates; D007093:Imidazoles; D004002:Clodronic Acid; D000077211:Zoledronic Acid; D019386:Alendronate