Severe compromise of preosteoblasts in a surgical mouse model of bisphosphonate-associated osteonecrosis of the jaw

J Craniomaxillofac Surg. 2016 Sep;44(9):1387-94. doi: 10.1016/j.jcms.2016.07.015. Epub 2016 Jul 22.


Objectives: The effect of amino-bisphosphonates on osteoblastic lineage and its potential contribution to the pathogenesis of bisphosphonate-associated osteonecrosis of the jaw (BONJ) remain controversial. We assessed the effects of zoledronic acid (ZOL) on bone and vascular cells of the alveolar socket using a mouse model of BONJ.

Material and methods: Thirty-two mice were treated twice a week with either 100 μg/kg of ZOL or saline for 12 weeks. The first left maxillary molar was extracted at the third week. Alveolar sockets were assessed at both 3 weeks (intermediate) and 9 weeks (long-term) after molar extraction by semi-quantitative histomorphometry for empty lacunae, preosteoblasts (Osterix), osteoclasts (TRAP), and pericyte-like cells (CD146). Also, the bone microarchitecture was assessed by micro-CT.

Results: Osteonecrotic-like lesions were observed in 21% of mice. Moreover, a decreased number of preosteoblasts contrasted with the increased number of osteoclasts at both time points. In addition, osteoclasts display multinucleation and detachment from the endosteal surface. Furthermore, the number of pericyte-like cells increased at the intermediate time point. The alveolar bone mass increased exclusively with long-term ZOL treatment.

Conclusion: The severe imbalance between bone-forming cells and bone-resorbing cells shown in this study could contribute to the pathogenesis of BONJ.

Keywords: Alveolar bone; Basic multicellular unit; Osteoblast; Osteoclast; Osteonecrosis of the jaw; Zoledronic acid.

MeSH terms

  • Animals
  • Bisphosphonate-Associated Osteonecrosis of the Jaw / pathology*
  • Bone Density Conservation Agents / administration & dosage
  • Bone Density Conservation Agents / toxicity*
  • Cell Differentiation
  • Diphosphonates / administration & dosage
  • Diphosphonates / toxicity*
  • Disease Models, Animal
  • Imidazoles / administration & dosage
  • Imidazoles / toxicity*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Molar / surgery
  • Osteoblasts / pathology*
  • Tooth Extraction
  • Tooth Socket / drug effects*
  • X-Ray Microtomography
  • Zoledronic Acid


  • Bone Density Conservation Agents
  • Diphosphonates
  • Imidazoles
  • Zoledronic Acid