Mild antiresorptive activity of an anti-vascular endothelial growth factor A antibody and sunitinib in a rat model of bone resorption

Abstract

Medication-Related-Osteonecrosis-of-the-Jaw (MRONJ) is an adverse event linked to antiresorptives such as bisphosphonates and denosumab. While MRONJ predominantly affects cancer patients treated with these agents, it has been less frequently reported in cancer patients receiving angiogenesis inhibitors (AgIs) like bevacizumab and sunitinib, even without concurrent use of antiresorptives. We hypothesized that certain AgIs exhibit antiresorptive activity in addition to their antiangiogenic effects, potentially influencing the pathophysiology of MRONJ.

52 five-week-old SD rats were randomized to receive vehicle (VEH), an oncologic dose of zoledronic acid (ZOL), or low (LD) and high doses (HD) of either an anti-VEGFA antibody or sunitinib (SU) for 10 days. We used the Schenk assay to assess the in vivo antiresorptive properties of these drugs/agents. We evaluated serum biomarkers of bone resorption (TRACP 5b) and formation (P1NP), pQCT variables of the femurs/tibias, and bone resorption/formation variables by bone histomorphometry at the distal femur metaphysis.

ZOL reduced TRACP-5b levels, osteoclast number, and BFR while increasing vBMD, mineralized tissue volume, calcified cartilage volume, and bone volume. Both anti-VEGFA and SU decreased osteoclast number and increased calcified cartilage volume relative to total mineralized tissue volume, though to a lesser extent than ZOL. Anti-VEGFA (HD) also reduced TRACP-5b levels. Furthermore, both AgIs decreased P1NP levels, MAR, and bone elongation rate but increased growth cartilage thickness and induced physeal dysplasia.

In conclusion, AgIs, particularly anti-VEGFA, exhibit significant yet milder antiresorptive activity compared to ZOL. They also affect bone formation, suggesting a complex mechanism that may play a role in the pathophysiology of MRONJ.