title: Bisphosphonates: restrictions for vasculogenesis and angiogenesis: inhibition of cell function of endothelial progenitor cells and mature endothelial cells in vitro.
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.
authors.affiliation: Klinik für Mund-, Kiefer-und Gesichtschirurgie, Johannes Gutenberg-Universität Mainz, Augustusplatz 2, 55131 Mainz, Germany. ziebart@mkg.klinik.uni-mainz.de
authors.forename: Thomas
authors.initials: T
authors.lastname: Ziebart
authors.forename: Andreas
authors.initials: A
authors.lastname: Pabst
authors.forename: Marcus Oliver
authors.initials: MO
authors.lastname: Klein
authors.forename: Peer
authors.initials: P
authors.lastname: Kämmerer
authors.forename: Leonie
authors.initials: L
authors.lastname: Gauss
authors.forename: Dan
authors.initials: D
authors.lastname: Brüllmann
authors.forename: Bilal
authors.initials: B
authors.lastname: Al-Nawas
authors.forename: Christian
authors.initials: C
authors.lastname: Walter
mesh_terms: D000704:Analysis of Variance; D017209:Apoptosis; D050071:Bone Density Conservation Agents / Q000633:toxicity*; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D004002:Clodronic Acid / Q000633:toxicity; D004164:Diphosphonates / Q000633:toxicity*; D042783:Endothelial Cells / Q000187:drug effects*; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects*; D006801:Humans; D000077557:Ibandronic Acid; D007093:Imidazoles / Q000633:toxicity; D007963:Leukocytes, Mononuclear / Q000187:drug effects; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D000077268:Pamidronate; D018709:Statistics, Nonparametric; D013234:Stem Cells / Q000187:drug effects*; D014471:Umbilical Veins / Q000166:cytology; D000077211:Zoledronic Acid
chemical_list: D050071:Bone Density Conservation Agents; D004164:Diphosphonates; D007093:Imidazoles; D004002:Clodronic Acid; D000077211:Zoledronic Acid; D000077268:Pamidronate; D000077557:Ibandronic Acid