Rat Model of Bisphosphonate Induced Osteonecrosis of the Jaw (BIONJ)

Osteonecrosis of the jaw has been linked to bisphosphonate use with invasive dental treatment as an important risk factor. Objective: To establish a rat model predictive of the development of BIONJ following exodontias. Methods: Thirty retired breeder female rats were used after IACUC approval, and randomized into two groups: control (n=15), and experimental (n=15). The experimental group received an IV injection of zoledronate (50µg/kg) at day 1 and three weeks later when the mesial buccal root of the right mandibular first molar was extracted. At weeks 0, 4 and 8, five experimental rats and five controls for each week (0, 4, and 8), were sacrificed. Serum analysis included PYD (collagen breakdown) and VEGF (angiogenesis). Mandibles were processed for microCT, and after analysis the same mandibles were decalcified for histology. Results: Baseline average bone mineral density (BMD in g/cm2) apical to socket area was 0.23. At four weeks, control BMD was 0.15, and experimental 0.25. PYD levels (nmol/L) were 2.71 at baseline for both groups, at 8 weeks post wounding, the control was 3.14 while the experimental was 2.62. Serum VEGF (pg/ml) averaged 129.5 for both groups at week 0. At 8 weeks of healing the experimental was 223.9 while the control was 152.7. H&E-stained slides from both 4 week groups showed the socket area filled with granulation tissue and scattered collagen fibers. At 8 weeks slides showed normal maturation and oriented collagen fibers with isolated osteoid for both groups. Slides corresponding to the 8 week experimental group also contained areas of empty osteocytic lacunae. Conclusions: Our study showed that zoledronate increased bone density and decreased collagen breakdown which may have reduced vasculature perfusion increasing the expression of VEGF. The finding of empty osteocytic lacunae in the 8 week experimental group is consistent with BIONJ in humans.