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Significance of bisphosphonates on angiogenesis in vivo and their effect under geranyl-geraniol addition — could it alter the treatment of bisphosphonate-associated necrosis of the jaw?

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Abstract

Purpose

The aim of this study was to contribute to the understanding of the inhibitory effects of bisphosphonates on tissues, with a special focus on angiogenesis. Referring to bisphosphonate-associated osteonecrosis of the jaw (BP-ONJ), it should be shown that the local addition of the isoprenoid geranyl-geraniol (GGOH) prevents vascularization processes.

Methods

A mouse model with n = 24 animals which received an injection of a collagen matrix was used. In 4 subgroups (n = 6), we examined the effect of zoledronate on the sprouting of capillary-like structures into the matrix, with and without the presence of geranyl-geraniol, as well as testing against control groups with PBS injections or collagen matrix containing PBS instead of GGOH. This was followed by a histological evaluation of the capillary-like structures.

Results

Zoledronate inhibits the sprouting of blood vessels into a collagen matrix in vivo; in the presence of GGOH this effect is significantly weakened by a factor of 3.9 (p = 0.00068).

Conclusion

This work commits to the investigation of the pathophysiology of BP-ONJ and shows a possible causal therapeutic path via the topical application of GGOH.

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Acknowledgements

The authors would like to thank the AO Research Institute (ARI, Davos, Switzerland) and the co-funded AO project (Grant No. C-11-11-V). Thanks to Professor Dr. Dr. W. Wagner for the resources of his institute, Professor Dr. Dr. B. Al-Nawas and PD Dr. Dr. C. Walter, Department for Oral and Maxillofacial Surgery, University Medical Center Mainz for the intensive support and professional supervision of the work.

Funding

This study was co-funded by the AO Foundation by way of the AOCMF R&D Research Commission (Grant No. C-11–11-V). The study was conducted in an AAALAC accredited facility and followed the ARRIVE guidelines.

Author information

Authors and Affiliations

  1. Department for Pediatric Surgery, Pediatric Urology and Pediatric Orthopedics, DRK Children’s Hospital Siegen, Wellersbergstrasse 60, 57072, Siegen, Germany

    Marius Otto

  2. Interdisciplinary Head & Neck Oncology Laboratory, Department for Oral and Maxillofacial Surgery, University Hospital Giessen and Marburg, Campus Marburg, 35033, Baldingerstrasse, Germany

    Marius Otto, Julia Weigel, Thomas Ziebart & Juliana Lemound

  3. Clinic for Oral and Maxillofacial Surgery, DRK Hospital Alzey, Kreuznacher Str. 7-9, 55232, Alzey, Germany

    Thomas Ziebart

  4. Department of Oral and Maxillofacial-Plastic Surgery, Ruhr University of Bochum, Bochum, Germany

    Juliana Lemound

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  1. Marius Otto
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  2. Julia Weigel
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  4. Juliana Lemound
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Contributions

All authors contributed to the study conception and design. Material preparation, data collection, and analysis were performed by MO and JW. The first draft of the manuscript was written by MO and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Thomas Ziebart.

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All applicable international, national, and institutional guidelines for the care and use of animals were followed. All procedures performed in studies involving animals were in accordance with the ethical standards of the institution or practice at which the studies were conducted. A corresponding animal test application (animal experiment G 12–1-022) for the experiments was approved by the Landesuntersuchungsamt Rheinland-Pfalz in Koblenz and thus meets all §8 Paragraph 3 (2) of the German Animal Welfare Act required preconditions.

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Otto, M., Weigel, J., Ziebart, T. et al. Significance of bisphosphonates on angiogenesis in vivo and their effect under geranyl-geraniol addition — could it alter the treatment of bisphosphonate-associated necrosis of the jaw?. Oral Maxillofac Surg 27, 263–268 (2023). https://doi.org/10.1007/s10006-022-01053-2

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  • DOI: https://doi.org/10.1007/s10006-022-01053-2

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