Effect of zoledronate on oral wound healing in rats

Clin Cancer Res. 2011 Mar 15;17(6):1405-14. doi: 10.1158/1078-0432.CCR-10-1614. Epub 2010 Dec 13.


Purpose: Osteonecrosis of the jaw (ONJ) is a growing concern in patients who receive bisphosphonates that target osteoclasts. As osteoclasts play multifunctional roles in the bone marrow, their suppression likely affects bone homeostasis and alters wound healing of the jaw. The objective was to delineate the impact of osteoclast suppression in the bone marrow and wound healing of the jaw.

Experimental design: Zoledronate was administered to senile rats for 14 weeks. A portion of the gingiva was removed to denude the palatal bone. Gene expression in the bone marrow was assessed and histologic sections were analyzed to determine the wound healing status.

Results: Angiogenesis-related genes, CD31 and VEGF-A, were not altered by zoledronate. VEGF-C, which plays a role in lymphangiogenesis, was suppressed. There was a decrease in gene expression of Tcirg1 and MMP-13. Bone denudation caused extensive osteocyte death indicative of bone necrosis. In zoledronate-treated rats, the necrotic bone was retained in the wound while, in controls, osteoclastic resorption of the necrotic bone was prominent. Even though large necrotic bone areas existed in zoledronate-treated rats, overlaying soft tissue healed clinically. Immunohistochemical staining showed rich vascularity in the overlaying soft tissue.

Conclusions: Zoledronate therapy impacts bone marrow by suppressing genes associated with lymphangiogenesis and tissue remodeling, such as VEGF-C and MMP-13. Zoledronate was associated with impaired osseous wound healing but had no effect on angiogenic markers in the bone marrow or soft tissue wound healing. Zoledronate selectively blunts healing in bone but does not affect soft tissue healing in the oral cavity.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Bone Marrow / metabolism
  • Diphosphonates / administration & dosage*
  • Diphosphonates / pharmacology
  • Gene Expression Regulation
  • Gingiva / drug effects
  • Homeostasis
  • Imidazoles / administration & dosage*
  • Imidazoles / pharmacology
  • Matrix Metalloproteinase 13 / biosynthesis
  • Osteonecrosis / pathology
  • Platelet Endothelial Cell Adhesion Molecule-1 / biosynthesis
  • Rats
  • Rats, Sprague-Dawley
  • Vacuolar Proton-Translocating ATPases / biosynthesis
  • Vascular Endothelial Growth Factor A / biosynthesis
  • Wound Healing / drug effects*
  • Zoledronic Acid


  • Diphosphonates
  • Imidazoles
  • Platelet Endothelial Cell Adhesion Molecule-1
  • TCIRG1 protein, human
  • Vascular Endothelial Growth Factor A
  • Zoledronic Acid
  • Matrix Metalloproteinase 13
  • Vacuolar Proton-Translocating ATPases