The effect of nitrogen containing bisphosphonates,zoledronate and alendronate,on the production of pro-angiogenic factors by osteoblastic cells

Bisphosphonates (BPs) have been shown to influence angiogenesis. This may contribute to BP-associated side-effects such as osteonecrosis of the jaw (ONJ) or atypical femoral fractures (AFF). The effect of BPs on the production of angiogenic factors by osteoblasts is unclear. The aims were to investigate the effect of (1) alendronate on circulating angiogenic factors; vascular endothelial growth factor (VEGF) and angiopoietin-1 (ANG-1) in vivo and (2) zoledronate and alendronate on the production of VEGF and ANG-1 by osteoblasts in vitro. We studied 18 post-menopausal women with T score ? ?2 randomized to calcium/vitamin D only (control arm, n = 8) or calcium/vitamin D and alendronate 70 mg weekly (treatment arm, n = 10). Circulating concentrations of VEGF and ANG-1 were measured at baseline, 3, 6 and 12 months. Two human osteoblastic cell lines (MG-63 and HCC1) and a murine osteocytic cell line (MLO-Y4) were treated with zoledronate or alendronate at concentrations of 10^?12–10^?6 M. VEGF and ANG-1 were measured in the cell culture supernatant. We observed a trend towards a decline in VEGF and ANG-1 at 6 and 12 months following treatment with alendronate (p = 0.08). Production of VEGF and ANG-1 by the MG-63 and HCC1 cells decreased significantly by 34–39% (p < 0.01) following treatment with zoledronate (10^?9–10^?6 M). Treatment of the MG-63 cells with alendronate (10^?7 and 10^?6) led to a smaller decrease (25–28%) in VEGF (p < 0.05). Zoledronate (10^?10–10^?6 M) suppressed the production of ANG-1 by MG-63 cells with a decrease of 43–49% (p < 0.01). Co-treatment with calcitriol (10^?8 M) partially reversed this zoledronate-induced inhibition. BPs suppress osteoblastic production of angiogenic factors. This may explain, in part, the pathogenesis of the BP-associated side-effects.