title: Effect of bisphosphonates on macrophagic THP-1 cell survival in bisphosphonate-related osteonecrosis of the jaw (BRONJ).
abstract: OBJECTIVE
  Immune deficiency and bacterial infection have been suggested to play a role in the pathophysiology of bisphosphonate-related osteonecrosis of the jaw (BRONJ). Zoledronate was previously found to promote THP-1 cell death. To examine this hypothesis with all commonly prescribed bisphosphonates, we tested the effect of (nitrogen-containing) ibandronate, risedronate, alendronate, pamidronate, and (non-nitrogen-containing) clodronate on macrophagic THP-1 cells.
  
  
  METHODS
  Activated THP-1 cells were exposed to .5 to 50 μM of nitrogen-containing bisphosphonates and .5 to 500 μM of clodronate. Cell adherence and survival were assessed in vitro using the xCELLigence real-time monitoring system. Results were confirmed histologically and verified with Live/Dead staining.
  
  
  RESULTS
  All bisphosphonates inhibited THP-1 cell adherence and survival dose and time dependently, significant for zoledronate, alendronate, pamidronate, and clodronate in high concentrations (50 μM and 500 μM; P < .05). Low concentrations (0.5 μM) of risedronate, alendronate, and pamidronate prolonged the inflexion points of THP-1 cell survival compared with controls (P < .05). THP-1 cells exhibited no cytomorphologic changes at all concentrations.
  
  
  CONCLUSIONS
  Commonly prescribed bisphosphonates inhibit the survival of macrophagic THP-1 cells dose-dependently without altering morphology. This may suggest a local immune dysfunction reflective of individual bisphosphonate potency leading to the pathogenesis of BRONJ.
authors.affiliation: Department of Oral and Maxillofacial Surgery, University Hospital Tuebingen, Tuebingen, Germany. Electronic address: sebastian.hoefert@med.uni-tuebingen.de.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Hoefert
authors.affiliation: Department of Oral and Maxillofacial Surgery, University Hospital Tuebingen, Tuebingen, Germany.
authors.forename: Claudia
authors.initials: C
authors.lastname: Sade Hoefert
authors.affiliation: Department of Oral and Maxillofacial Surgery, University Hospital Tuebingen, Tuebingen, Germany.
authors.forename: Adelheid
authors.initials: A
authors.lastname: Munz
authors.affiliation: Department of Pathology, BG-Hospital Bergmannsheil, Ruhr-University Bochum, Bochum, Germany.
authors.forename: Inge
authors.initials: I
authors.lastname: Schmitz
authors.affiliation: Department of Oral and Maxillofacial Surgery, University Hospital Tuebingen, Tuebingen, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Grimm
authors.affiliation: Department of Oral and Maxillofacial Surgery, University Hospital Tuebingen, Tuebingen, Germany.
authors.forename: Anna
authors.initials: A
authors.lastname: Yuan
authors.affiliation: Institute for Clinical and Experimental Transfusion Medicine, University Hospital Tuebingen, Tuebingen, Germany.
authors.forename: Hinnak
authors.initials: H
authors.lastname: Northoff
authors.affiliation: Department of Oral and Maxillofacial Surgery, University Hospital Tuebingen, Tuebingen, Germany.
authors.forename: Siegmar
authors.initials: S
authors.lastname: Reinert
authors.affiliation: Department of Oral and Maxillofacial Surgery, University Hospital Tuebingen, Tuebingen, Germany.
authors.forename: Dorothea
authors.initials: D
authors.lastname: Alexander
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D059266:Bisphosphonate-Associated Osteonecrosis of the Jaw / Q000276:immunology*; D050071:Bone Density Conservation Agents / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects*; D002478:Cells, Cultured; D004164:Diphosphonates / Q000494:pharmacology*; D006801:Humans; D008264:Macrophages
chemical_list: D050071:Bone Density Conservation Agents; D004164:Diphosphonates