Bisphosphonate-related osteonecrosis of the jaw (BRONJ) has generated great interest in the medical and research communities yet remains an enigma, given its unknown pathogenesis. The goal of this review is to summarize the various proposed hypotheses underlying BRONJ. Although a role of the oral mucosa has been proposed, the bone is likely the primary tissue of interest for BRONJ. The most popular BRONJ hypothesis-manifestation of necrotic bone resulting from bisphosphonate--induced remodeling suppression--is supported mostly by indirect evidence, although recent data have shown that bisphosphonates significantly reduce remodeling in the jaw. Remodeling suppression would be expected, and has been shown, to allow accumulation of nonviable osteocytes, whereas a more direct cytotoxic effect of bisphosphonates on osteocytes has also been proposed. Bisphosphonates have antiangiogenic effects, leading to speculation that this could contribute to the BRONJ pathogenesis. Compromised angiogenesis would most likely be involved in post-intervention healing, although other aspects of the vasculature (eg, blood flow) could contribute to BRONJ. Despite infection being present in many BRONJ patients, there is no clear evidence as to whether infection is a primary or secondary event in the pathophysiology. In addition to these main factors proposed in the pathogenesis, numerous cofactors associated with BRONJ (eg, diabetes, smoking, dental extraction, concurrent medications) could interact with bisphosphonates and affect remodeling, angiogenesis/blood flow, and/or infection. Because our lack of knowledge concerning BRONJ pathogenesis results from a lack of data, it is only through the initiation of hypothesis-driven studies that significant progress will be made to understand this serious and debilitating condition
