Background and objectives : Bisphosphonates (BIS) has a beneficial effect in patients whosuffer from osteoporosis and bone metastasis, however, adverse consequences such as osteonecrosis of the jawmayoccur. Our aim was to assess whether inflammatory processes mediated by microcirculatory dysfunction are associated with the development of BIS-related osteonecrosis. This study evaluated themicrocirculatory effects of BIS in the mandibular periosteum after standardizeddental procedures, and in the tibialperiosteum in order to compare the effects of BIS in different osseous locations.

Methods : Sprague-Dawley rats were randomly allotted into vehicle-treated control ( n = 15) or chronic BIS-treated (ivzoledronate, 80 g/kg once a week, over eight weeks, n = 20) groups, respectively. At the end of the chronic treatment, first molarextraction was performed at one side of the mandible. Leukocyte–endothelial interactions were measured at both sides of mandibular periosteum by intravital fluorescence video microscopy as well as in the tibial periosteum. Systemic, inflammatory parameters were measured such as NADPH-oxidase activity of neutrophil leukocytes by luminometry, expression of neutrophil-derived adhesion molecule CD11b by flow cytometry, and plasma levels of TNF-? by ELISA.

Results : Spontaneous osteonecrosis of the jaw could not be revealed by microCT due to BIS. BIS administration increased the leukocyte–endothelial interactionsin the mandibular postcapillary venules compared to the control and tibial periosteum. According to the acute dental procedure, these inflammatory reactions showed a remarkable elevation. NADPH oxidase activity was significantly lower compared to the control. Other parameters were not affected by BIS treatment.

Conclusion : These data provide evidence that chronic BIS treatment is accompanied by characteristic mandibular periosteal microcirculatory inflammatory reactions which are enhanced after an acute dental procedure. This suggests a potential role for leukocytes in the pathogenesis of BIS-induced osteonecrosis.

Grant support : TÁMOP 4.2.4.A/2-11-1-2012-0001, TÁMOP 4.2.2A-11/1/KONV-2012-0035, TÁMOP 4.2.2A-11/1/KONV-2012-0073

Key words: bisphosphonate-related osteonecrosis of the jaw, rat, microcirculatory inflammation, tooth extraction