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Bisphosphonates’ antiangiogenic potency in the development of bisphosphonate-associated osteonecrosis of the jaws: influence on microvessel sprouting in an in vivo 3D Matrigel assay

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Abstract

Objectives

Bisphosphonate-associated osteonecrosis of the jaw (BP-ONJ) is an adverse side effect of long-term bisphosphonate treatment. One theory of BP-ONJ etiology suggests a negative influence of these agents on angiogenesis and vascularization. This in vivo study analyzed the effects of bisphosphonates on angiogenesis in a 3D Matrigel assay.

Materials and methods

Matrigel plugs were implanted into fifty 6–8-week-old female nude mice. Ten animals each were treated either with clodronate, ibandronate, pamidronate, zoledronate, or carrier solution as controls. The microvessel density (MVD), microvessel area (MVA), and microvessel size (MVS) in Matrigel plugs were analyzed after 21 days of treatment by immunohistochemistry and exemplary 3D microvascular corrosion castings.

Results

All bisphosphonates induced a statistically significant decrease of MVD (p each <0.001), whereby the nitrogen-containing bisphosphonates (N-BPs) demonstrated a clearly stronger effect than non-nitrogen-containing bisphosphonates (NN-BP) clodronate (control 166, clodronate 99, ibandronate 48, pamidronate 47, zoledronate 35 microvessels/mm2). Referring to MVA, similar results could be detected. MVS was significantly increased especially by ibandronate (103 %) compared to control group (p < 0.001). Scanning electron microscope scans of the corrosion castings confirmed these results.

Conclusions

The stronger influence on MVD by N-BPs compared to the NN-BP clodronate may explain for the lack of BP-ONJ after treatment with NN-BPs.

Clinical relevance

Ibandronate induced a strong increase of MVS. In combination with the reduced MVD, this could result only in a fractional reduced perfusion which might be an explanation for the lower occurrence of BP-ONJ in patients receiving ibandronate compared to patients receiving pamidronate or zoledronate.

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Acknowledgments

The authors acknowledge the technical skillful assistance of Kerstin Bahr.

Conflict of interest

The authors declare that there is no conflict of interests. Funding for this study was received by University Medical Center Mainz. Christian Walter has received speaker fees from Roche and funding from Novartis for a different study.

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Authors and Affiliations

  1. Department of Oral and Maxillofacial Surgery, University Medical Center Mainz, Augustusplatz 2, 55131, Mainz, Germany

    A. M. Pabst, T. Ziebart & C. Walter

  2. Institute of Functional and Clinical Anatomy, University Medical Center Mainz, Johann-Joachim-Becher-Weg 13, 55099, Mainz, Germany

    M. Ackermann & M. A. Konerding

Authors
  1. A. M. Pabst
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  2. T. Ziebart
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  3. M. Ackermann
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  4. M. A. Konerding
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  5. C. Walter
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Corresponding author

Correspondence to C. Walter.

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Pabst, A.M., Ziebart, T., Ackermann, M. et al. Bisphosphonates’ antiangiogenic potency in the development of bisphosphonate-associated osteonecrosis of the jaws: influence on microvessel sprouting in an in vivo 3D Matrigel assay. Clin Oral Invest 18, 1015–1022 (2014). https://doi.org/10.1007/s00784-013-1060-x

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  • DOI: https://doi.org/10.1007/s00784-013-1060-x

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