Bisphosphonate-related osteonecrosis of the jaw: is pH the missing part in the pathogenesis puzzle?

Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is a side effect of bisphosphonate therapy, primarily diagnosed in patients with cancer and metastatic bone disease and receiving intravenous administrations of nitrogen-containing bisphosphonates. If diagnosis or treatment is delayed, BRONJ can develop to a severe and devastating disease. Numerous studies have focused on BRONJ, with possible pathomechanisms identified to be oversuppression of bone turnover, ischemia due to antiangiogenetic effects, local infections, or soft tissue toxicity. However, the precise pathogenesis largely remains elusive and questions of paramount importance await to be answered, namely 1) Why is only the jaw bone affected? 2) Why and how do the derivatives differ in their potency to induce a BRONJ? and 3) Why and when is BRONJ manifested? The present perspective reflects on existing theories and introduces the hypothesis that local tissue acidosis in the jaw bone offers a conclusive pathogenesis model and may prove to be the missing link in BRONJ.