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Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is a known side effect of the therapy with bisphosphonates. No specific pathologic aspects or histological features are included in the most current definition. This study investigates characteristics of BRONJ with a special emphasis on histomorphologic aspects, evaluating the role ofActinomycesspp. as well as other disease-promoting factors in a formal pathogenetic context.We investigated 23 patients (14 female, nine male; mean age: 66 ± 11.8 years) who received bisphosphonates with a gender- /age-matched control group. Tissue specimens were treated according to local standards and analyzed histologically.In 18 (78.3%) BRONJ cases, we foundActinomycesspp. colonies. Bone remodeling could be found in three specimens (13%). Eight specimens (34.8%) showed signs of epithelial proliferation. Analysis of dental treatment before the onset of BRONJ did not reveal significant differences (P>0.20). In 10 patients (83%;P>0.05) of the reported cases a relationship between dental treatment and the occurrence of a purulent bone necrosis could be observed. Statistically significant differences in thickness of trabeculae were detected between the two study groups (P=0.04).This study demonstrates the important influence of the osteoblast–osteoclast balance in a histomorphologic analysis. Together with cofactors, which are able to trigger the onset of BRONJ, a new pathogenesis model was developed.