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.

Effects of a low-level diode laser on oral keratinocytes, oral fibroblasts, endothelial cells and osteoblasts incubated with bisphosphonates: An in vitro study

“…In vitro studies support the negative impact of bisphosphonates on osteoblasts, fibroblasts and endothelial cells (9,11).…”

“…ii) Another theory stresses the anti-angiogenic effect of bisphosphonates resulting in the development of avascular osteonecrosis of the jaws. The negative influence of bisphosphonates on endothelial cells is supported by the negative effect on the number of circulating endothelial cells (8,9). iii) Bisphosphonates also have a negative effect on bone covered by soft tissues; this bone is more likely to be exposed (10,11).…”

“Bisphosphonates: Possible Modes of Action and Implications for Dental Implant Treatment. A Review of the Literature”

“…Bone tissue is particularily vascularised, and endothelial cells have been proven to play an essential role during bone remodelling [122]. Indeed during bone healing and remodelling, an adequate vascular system is essential, with blood vessels in the canaliculi, Volkmans canals and the Haversian systems playing key roles.…”

“…It is these vessels that involute, leaving bone dead and avascular in BRONJ [97,123]. Ziebart et al [122], highlighted the importance of differentiating between angiogenesis and vasculogenesis. Angiogenesis being defined as the sprouting from pre-existing vessels of mature endothelial cells, whereas vasculogenesis is the potential creation of new primordial vessels from bone marrow derived, circulating endothelial progenitor cells [122].…”

Microcirculatory aspects of bisphosphonate-related osteonecrosis of the jaw

“…In vitro és in vivo tanulmányok alátámasztották egyes intravénásan adagolt BIS-készítmények angiogenesist gátló hatását [40,41], és ennek a jelenségnek szintén szerepe lehet a kórkép patogenezisében. Ezt támasztják alá azok a közlemények is, amelyekben leírják, hogy bár a malignus tumorok kezelésénél kifejezetten előnyösnek bizonyult az angiogenesist gátló terápia, mégis a BIS és angiogenesist gátló együttes adása mellett a MRONJ incidenciája jelentősen emelkedhet.…”