Impacts of bisphosphonates on the bone and its surrounding tissues: mechanistic insights into medication-related osteonecrosis of the jaw

Bisphosphonates are widely used as anti-resorptive agents for the treatment of various bone and joint diseases, including advanced osteoporosis, multiple myeloma, bone metastatic cancers, Paget's disease of bone, and rheumatoid arthritis. Bisphosphonates act as an anti-osteoclast via the induction of osteoclast apoptosis, resulting in a decreased rate of bone resorption. Unfortunately, there is much evidence to demonstrate that the long-term use of bisphosphonates is associated with osteonecrosis. The pathogenesis of osteonecrosis includes the death of osteoblasts, osteoclasts, and osteocytes. In addition, the functions of endothelial cells, epithelial cells, and fibroblasts are impaired in osteonecrosis, leading to disruptive angiogenesis, and delayed wound healing. Osteonecrosis is most commonly found in the jawbone and the term medication-related osteonecrosis of the jaw (MRONJ) has become the condition of greatest clinical concern among patients receiving bisphosphonates. Although surgical treatment is an effective strategy for the treatment of MRONJ, several non-surgical interventions for the attenuation of MRONJ have also been investigated. With the aim of increasing understanding around MRONJ, we set out to summarize and discuss the holistic effects of bisphosphonates on the bone and its surrounding tissues. In addition, non-surgical interventions for the attenuation of bisphosphonate-induced osteonecrosis were reviewed and discussed.