Macrophage and osteoclast polarization in bisphosphonate associated necrosis and osteoradionecrosis

Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is a complication of antiresorptive therapy with nitrogen-containing bisphosphonates (BP). With various suggestions as to pathogenesis, the etiology of BRONJ is not sufficiently understood. Osteoclasts and their precursors, that is, macrophages, are the main target cells of BP. BP can repolarize regeneration- and healing-associated M2 macrophages towards the tissue destructive M1-type. The current study aims to elucidate differences in macrophage and osteoclast polarization in BRONJ, osteoradionecrosis (ORN) and healthy control specimens.A total of 39 jaw bone samples (18 BRONJ, 8 ORN and 13 healthy controls) were processed for immunohistochemistry to detect CD68-, CD11c- and CD163-positive cells. Macrophages and osteoclasts were distinguished on the basis of morphological differences. Samples were digitized, and the macrophage and osteoclast cell counts were quantitatively analyzed.In jaw bone affected by BRONJ, a significantly increased macrophage infiltration and M1 polarization of macrophages can be seen. The density of CD68-expressing osteoclasts is significantly increased in BRONJ specimens compared to ORN and to healthy controls.A bisphosphonate-derived shift of macrophage polarization towards M1-polarized macrophages might impair bone tissue homeostasis and thus contribute to the pathogenesis of BRONJ. The observed increase in osteoclast density might be caused by BP-induced prolonged osteoclast survival.