title: Zoledronate and pamidronate depress neutrophil functions and survival in mice.
abstract: OBJECTIVE
  Bisphosphonate-related osteonecrosis of the jaw (BRONJ) has been identified as a severe complication of patients previously treated with i.v. bisphosphonates. It has been noted that necrotic bone from BRONJ sites display signs of bacterial infection suggesting that an immune defect may play a role in the pathophysiology of BRONJ. Here, we have examined the effect of two potent bisphosphonates, zoledronate and pamidronate, on neutrophil function, differentiation and survival.
  
  
  METHODS
  The effect of bisphosphonates on chemotaxis, NADPH oxidase activity and neutrophil survival were assessed in vitro using bone marrow-derived primary neutrophils or in vitro differentiated haematopoetic progenitors from mice. The same parameters and the number of circulating neutrophils were quantified in neutrophils isolated from mice treated in vivo with zoledronate. In vivo recruitment of neutrophils was assessed by sodium periodate-induced peritonitis.
  
  
  RESULTS
  Zoledronate and pamidronate inhibited in vitro neutrophil chemotaxis and NADPH oxidase activity in a dose-dependent manner. In vivo recruitment of neutrophils was also suppressed. Zoledronate did not affect in vitro differentiation of neutrophils but shortened their life span in a granulocyte-colony stimulating factor-dependent manner. fMLP-induced activation of RhoA activity was decreased by zoledronate treatment.
  
  
  CONCLUSIONS
  Our results show that bisphosphonate exposure leads to impaired neutrophil chemotaxis, neutrophil NADPH oxidase activity and reduced circulating neutrophil counts. This work suggests that bisphosphonates have the potential to depress the innate immune system for a prolonged time, possibly contributing to the pathogenesis of BRONJ.
authors: Matrix Dynamics Group, Faculty of Dentistry, University of Toronto, Toronto, ON, Canada.
authors: J W P
authors: JW
authors: Kuiper
authors: C
authors: C
authors: Forster
authors: C
authors: C
authors: Sun
authors: S
authors: S
authors: Peel
authors: M
authors: M
authors: Glogauer
mesh_terms: D000818:Animals; D050071:Bone Density Conservation Agents / Q000494:pharmacology*; D002454:Cell Differentiation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002634:Chemotaxis, Leukocyte / Q000187:drug effects; D004164:Diphosphonates / Q000494:pharmacology*; D007093:Imidazoles / Q000494:pharmacology*; D007958:Leukocyte Count; D051379:Mice; D008810:Mice, Inbred C57BL; D019255:NADPH Oxidases / Q000378:metabolism; D009504:Neutrophils / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D000077268:Pamidronate; D000077211:Zoledronic Acid
chemical_list: D050071:Bone Density Conservation Agents; D004164:Diphosphonates; D007093:Imidazoles; D000077211:Zoledronic Acid; D019255:NADPH Oxidases; D000077268:Pamidronate