03352nas a2200277 4500008004100000245010600041210006900147260002400216300001400240490000700254520240400261100002202665700001902687700001902706700001802725700001902743700001902762700002202781700002002803700002502823700002302848700002002871700002002891700002102911856014202932 2015 eng d00aPeriosteal microcirculatory reactions in a zoledronate-induced osteonecrosis model of the jaw in rats0 aPeriosteal microcirculatory reactions in a zoledronateinduced os bSpringercJuly 2015 a1279-12880 v193 a

Objectives

Nitrogen-containing bisphosphonates induce osteonecrosis mostly in the jaw and less frequently in other bones. Because of the crucial role of periosteal perfusion in bone repair, we investigated zoledronate-induced microcirculatory reactions in the mandibular periosteum in comparison with those in the tibia in a clinically relevant model of bisphosphonate-induced medication-related osteonecrosis of the jaw (MRONJ).

Materials and methods

Sprague–Dawley rats were treated with zoledronate (ZOL; 80 i.v. μg/kg/week over 8 weeks) or saline vehicle. The first two right mandibular molar teeth were extracted after 3 weeks. Various systemic and local (periosteal) microcirculatory inflammatory parameters were examined by intravital videomicroscopy after 9 weeks.

Results

Gingival healing disorders (∼100 %) and MRONJ developed in 70 % of ZOL-treated cases but not after saline (shown by micro-CT). ZOL induced significantly higher degrees of periosteal leukocyte rolling and adhesion in the mandibular postcapillary venules (at both extraction and intact sites) than at the tibia. Leukocyte NADPH-oxidase activity was reduced; leukocyte CD11b and plasma TNF-alpha levels were unchanged.

Conclusion

Chronic ZOL treatment causes a distinct microcirculatory inflammatory reaction in the mandibular periosteum but not in the tibia. The local reaction in the absence of augmented systemic leukocyte inflammatory activity suggests that topically different, endothelium-specific changes may play a critical role in the pathogenesis of MRONJ.

Clinical relevance

This model permits for the first time to explore the microvascular processes in the mandibular periosteum after chronic ZOL treatment. This approach may contribute to a better understanding of the pathomechanism and the development of strategies to counteract bisphosphonate-induced side effects.

 

1 aJanovszky, Ágnes1 aSzabó, Andrea1 aVarga, Renáta1 aGarab, Dénes1 aBoros, Mihály1 aMester, Csilla1 aBeretka, Nikolett1 aZombori, Tamás1 aWiesmann, Hans-Peter1 aBernhardt, Ricardo1 aOcsovszki, Imre1 aBalázs, Péter1 aPiffkó, József uhttps://www.inf.szte.hu/publication/periosteal-microcirculatory-reactions-in-a-zoledronate-induced-osteonecrosis-model-of-the-jaw-in-rats