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Bone mineralization and vascularization in bisphosphonate-related osteonecrosis of the jaw: an experimental study in the rat

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Abstract

Objectives

Pathogenesis of bisphosphonate-related osteonecrosis of the jaws (BRONJ) is not fully explained. An antiangiogenic effect of bisphosphonates (BPs) or an altered bone quality have been advocated. The aims of the present study were to analyze alveolar mandibular vascularization and bone quality in rats with BRONJ.

Materials and methods

Thirty-eight Sprague-Dawley rats were randomized into two groups: zoledronic acid (ZA), n = 27, and control (CTRL) n = 11. The ZA group received a weekly IV injection of ZA (100 μg/kg) during 10 weeks. The CTRL group received saline. After 6 weeks, extraction of the right mandibular molars was performed. Rats were sacrificed after 14 weeks. Microtomography characterized bone lesions and vascularization after injection of a radio-opaque material. Raman microspectroscopy evaluated bone mineralization.

Results

Fifty-five percent of ZA rats presented bone exposure and signs of BRONJ. None sign was found at the left hemimandible in the ZA group and in the CTRL group. Vascular density appeared significantly increased in the right hemimandibles of the CTRL group compared to the left hemimandibles. Vascularization was reduced in the ZA group. A significantly increased of the mineral-to-amide ratio was found in the alveolar bone of ZA rats by Raman microspectroscopy.

Conclusions

In a rat model of BRONJ, microtomography evidenced osteonecrosis in BRONJ. Raman spectroscopy showed an increased mineralization. Vascularization after tooth extraction was impaired by ZA.

Clinical relevance

Prolonged BP administration caused an increase in the mineralization and a quantitative reduction of the vascularization in the alveolar bone; both factors might be involved concomitantly in the BRONJ pathophysiology.

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Acknowledgments

The authors thank Mrs. N. Retailleau and S. Lemière for micro-CT. This work was made possible by funding from the French Minister of Research. Authors are greatly indebted to the SCAHU (Service commun d’animalerie hospitalo-universitaire) of Angers, especially to P. Legras and J. Roux for their help with the animal care.

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Authors and Affiliations

  1. Groupe d’Etude Remodelage Osseux et bioMatériaux GEROM, SFR 42-08, IRIS-IBS Institut de Biologie en Santé, Université d’Angers, CHU d’Angers 4, rue Larrey, 49933, Angers Cedex, France

    Jean-Daniel Kün-Darbois, Hélène Libouban, Guillaume Mabilleau, Florence Pascaretti-Grizon & Daniel Chappard

  2. Service de chirurgie maxillo-faciale et stomatologie, CHU d’Angers, 4, rue Larrey, 49933, Angers Cedex, France

    Jean-Daniel Kün-Darbois

  3. SCIAM Service Commun d’Imagerie et Analyses Microscopiques, IRIS-IBS Institut de Biologie en Santé, Université d’Angers, CHU d’Angers 4, rue Larrey, 49933, Angers Cedex, France

    Guillaume Mabilleau & Daniel Chappard

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  1. Jean-Daniel Kün-Darbois
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  2. Hélène Libouban
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  3. Guillaume Mabilleau
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  4. Florence Pascaretti-Grizon
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  5. Daniel Chappard
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Contributions

Jean-Daniel KÜN-DARBOIS performed animal handling, zoledronic acid injections, teeth extractions, and wrote the paper. Hélène LIBOUBAN performed animal handling and zoledronic acid injections, Guillaume MABILLEAU performed the SEM-qBEI analysis, Florence PASCARETTI performed Raman analysis, and Daniel CHAPPARD designed the study, performed micro-CT analysis, and wrote parts of the manuscript.

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Correspondence to Daniel Chappard.

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All procedures performed in the present study were in accordance with the ethical standards of the institutional and national research committee and with the 1964 Helsinki Declaration and its later amendments. This experimental protocol was approved by the local ethical committee of Angers University Hospital (France) and was done in accordance with the institutional guidelines of the French Ethical Committee (protocol number 2016-31).

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Kün-Darbois, JD., Libouban, H., Mabilleau, G. et al. Bone mineralization and vascularization in bisphosphonate-related osteonecrosis of the jaw: an experimental study in the rat. Clin Oral Invest 22, 2997–3006 (2018). https://doi.org/10.1007/s00784-018-2385-2

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