Development of a Rat Model of Bisphosphonate-Related Osteonecrosis of the Jaw (BRONJ)
The purpose of this study was to develop a rat model predictive of bisphosphonate-related osteonecrosis of the jaw (BRONJ) after exodontias. Thirty female rats were randomized into 2 groups, control and experimental. The experimental group received 2 intravenous injections of zoledronate (20 μg/kg). The mesial root of the right mandibular first molar was extracted. Rats were euthanized at 0, 4, and 8 weeks. Bone mineral density (BMD), collagen breakdown (pyridinium [PYD]), vascular regeneration (VEGF), and histology were examined. A trend toward higher PYD values was suggested in control vs experimental groups after wounding. Serum VEGF increased significantly after wounding for both control and experimental groups. After 8 weeks, VEGF continued to rise for the experimental group only. In the extraction socket area, BMD was significantly lower after wounding in control vs. zoledronate-treated rats. Histology sections from experimental groups showed bacteria and bone necrosis. Consistent findings of BRONJ features similar to those in humans were observed after zoledronate treatment.
Figure 1. Micro-computerized images. (a) Mesial buccal root before extraction. (b) Empty socket after extraction. Figure 2. Areas of interest for bone mineral density measurements: (1) the anterior area (mesial to the first molar), (2) the socket area (apical to the extraction site), (3) the second molar area (apical to the roots of the second molar), and (4) the ramus.
Figure 3. Effect of zoledronate injection on the serum pyridinium levels of adult rats. Figure 4. Effect of zoledronate on vascular endothelial growth factor at baseline, at wounding, and at 4 weeks and 8 weeks of healing. Figure 5. Bone mineral density of the socket area at wounding and at 4 weeks and 8 weeks of healing.
Figure 6. Intraoral images of the first molar extraction sites in (a) a zoledronic acid–treated rat and (b) a control rat 8 weeks after wounding. Note the appearance of inflammation and exposed bone in the zoledronic acid–treated rat. Figure 7. Histopathology of mandibular bone from control and zoledronate-treated rats 4 weeks after wounding. (a and b) Hematoxylin and eosin–stained section of a representative control rat showing normal bone remodeling, cellular lacunae, normal osteocytes within lacunae, and vascularity. (c) Representative section from a bisphosphonate-treated rat showing osteonecrosis with sequestration of the buccal cortex (arrow) and mixed inflammatory cellular infiltration associated with bone remodeling (arrow heads) adjacent to osteonecrosis (arrow). (d) Higher-magnification image showing the lack of vascularity and bacteria within interstices (arrow).
Figure 8. Histopathology of mandibular bone from control and zoledronate-treated rats 8 weeks after wounding. (a) Hematoxylin and eosin–stained section of a representative control rat showing normal bone remodeling, cellular lacunae, normal osteocytes within lacunae, and vascularity. (b and c) Representative sections of bisphosphonate-treated rats after 8 weeks of healing showing osteonecrosis with empty osteocytic lacunae, sequestration of the buccal cortex, and lack of vascularity. Figure 9. Brown and Brenn stain for bacteria in mandibular bone sections from (a) zoledronic acid-treated rats and (b) control rats 8 weeks after wounding.
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