Bisphosphonates reduce bone loss by suppressing osteoclast activity and are currently used for the treatment of osteoporosis. As a side effect of bisphosphonates treatment, the emergence of osteonecrosis of the jaw (ONJ) has stimulated interest in elucidating how bisphosphonates affect the bone, but far less understanding exists as to the ONJ mechanism. In the present study, it was hypothesized that bisphosphonates may affect the healing of the alveolar socket by altering VEFG regulation. In vivo osteoporosis rat models were made by bilateral surgical ovariectomy. Pamidronate (3.5 mg/kg/wk) was IP injected for 8 wks and the maxillary 1st molars were bilaterally extracted. For in vitro test, periodontal ligament cells were treated with pamidronate. Unexpectedly, VEFG-A and -B mRNA and protein levels were increased in in vivo and in vitro by the high concentration treatment of bisphosphonates. However, VEGF-C level was not changed. In the socket at day 7 after the molar extraction, the socket was filled with infiltration of neutrophils which showed strong immunoreactivity against VEGF. VEGF-B mRNA was in particular upregulated by the pamidronate treatment. This result suggest that high dose pamidronate may alter VEGF expression that may serve as another mechanism of ONJ.