Effects of bisphosphonates on keratinocytes and fibroblasts having a role in the development of osteonecrosis of the jaw

Bisphosphonates (BPs) have became the treatment of choice for the prevention of skeletal complications in cancer patients with bone metastases as well as in patients suffering from osteoporosis, Paget's disease and rheumatoid arthritis. Osteonecrosis of the jaw (ONJ) is a recently described complication associated with the use of BPs in which the key finding is exposed necrotic bone in the oral cavity. Often, the precipitating event appears to be a dental invasive procedure. We recently provided evidence that ONJ is associated with dental extractions and use of dentures. It has been reported that the primary lesion lies in the bone and it 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 the jawbone. We propose that BP could be impairing molecular signalling not only of osteoblasts and osteoclasts but also of fibroblasts and keratinocytes, via cell to cell endocrine and paracrine interactions in a double manner. Such an impairment would result to fibroblast and keratinocyte impaired multiplication, proliferation and migration thereby leading to defective mucosal wound healing. This provides an open entry point for the oral flora to reach the underlying jawbone which is considered to have poor metabolic and immune properties when under BP treatment. We demonstrate that ONJ is associated with mucosal damage, which could be mediated via BP induced soft tissue toxicity. BPs have been reported to promote keratinocyte and fibroblast apoptosis and to impair various cellular activities like apoptosis, RANK, RANK-L and OPG signalling, bone morphogenetic protein signalling, growth factor signalling, immune homeostasis and wound healing. We discuss potential consequences of the above hypothesis for practitioners and investigators.