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Bisphosphonates: restrictions for vasculogenesis and angiogenesis: inhibition of cell function of endothelial progenitor cells and mature endothelial cells in vitro

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Abstract

Bisphosphonate-associated osteonecrosis of the jaws (BP-ONJ) is one of the main side effects in patients treated with bisphosphonates for metastasis to the bone or osteoporosis. BP-ONJ usually occurs in patients treated with highly potent nitrogen-containing bisphosphonates. The exact mechanism of action and etiopathology is still unknown. In addition to inhibition of bone remodelling, an anti-angiogenetic effect has become the focus of research. The aim of these study was to investigate the effect of different bisphosphonates on human umbilicord vein endothelial cells (HUVEC) and endothelial progenitor cells (EPC), which play an important role in angiogenesis. Using varying concentrations, the impact of one non-nitrogen-containing bisphosphonate (clodronate) and three nitrogen-containing bisphosphonates (ibandronate, pamidronate and zoledronate) on HUVEC and EPC was analysed. The biologic behaviour of HUVEC after incubation with different bisphosphonates was measured in a Boyden migration assay as well as in a 3D angiogenesis assay. The number of apoptotic cells was measured by Tunnel assay. To underline the importance of neoangiogenesis in the context of BP-ONJ, we measured the EPC number after incubation with different bisphosphonates in vitro. HUVEC and EPC were significantly influenced by bisphosphonates at different concentrations compared with the non-treated control groups. The nitrogen-containing bisphosphonates pamidronate and zoledronate had the greatest impact on the cells, whereas clodronate followed by ibandronate was less distinct on cell function. These results underline the hypothesis that inhibited angiogenesis induced by bisphosphonates might be of relevance in the development and maintenance of BP-ONJ. The increased impact by highly potent bisphosphonates on HUVEC and EPC may explain the high prevalence of BP-ONJ in patients undergoing this treatment.

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Conflict of interest statement

Professor Dr. W. Wagner, PD Dr. B. Al-Nawas and Dr. Ch. Walter gave speeches for Roche. Dr. Ch. Walter received a research fund for another project by Novartis.

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This study was not funded.

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Authors and Affiliations

  1. Klinik für Mund-, Kiefer-und Gesichtschirurgie, Johannes Gutenberg–Universität Mainz, Augustusplatz 2, 55131, Mainz, Germany

    Thomas Ziebart, Andreas Pabst, Marcus Oliver Klein, Peer Kämmerer, Leonie Gauss, Bilal Al-Nawas & Christian Walter

  2. Zahnärztliche Chirurgie, Johannes Gutenberg–Universität Mainz, Mainz, Germany

    Dan Brüllmann

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  1. Thomas Ziebart
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  2. Andreas Pabst
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  3. Marcus Oliver Klein
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  7. Bilal Al-Nawas
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  8. Christian Walter
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Correspondence to Thomas Ziebart.

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Ziebart, T., Pabst, A., Klein, M.O. et al. Bisphosphonates: restrictions for vasculogenesis and angiogenesis: inhibition of cell function of endothelial progenitor cells and mature endothelial cells in vitro. Clin Oral Invest 15, 105–111 (2011). https://doi.org/10.1007/s00784-009-0365-2

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  • DOI: https://doi.org/10.1007/s00784-009-0365-2

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