Is bisphosphonate-associated osteonecrosis of the jaw caused by soft tissue toxicity?

Osteonecrosis of the jaw (ONJ) is a complication of high-dose bisphosphonate use, characterized by the finding of exposed bone in the oral cavity. It has been assumed that the primary lesion lies in bone and is related to over-suppression of bone turnover, but it is unclear why such a lesion should present with loss of the soft tissue covering of the mandible or maxilla as the primary clinical feature. A possible explanation of this paradox is that bisphosphonate is accumulated in bone in concentrations sufficient to be directly toxic to the oral epithelium. This would result in the failure of healing of soft tissue lesions (such as those caused by invasive dental procedures or by subclinical trauma from dentures) leading to secondary infection of the underlying bone. This model would explain why bone resection is unhelpful in managing this problem, suggests that low bone turnover caused by non-bisphosphonate drugs should not cause the same problem, and raises the possibility that agents which reverse bisphosphonate effects in vitro might have a role in the management of ONJ.