Microcirculatory aspects of bisphosphonate-related osteonecrosis of the jaw
Bisphosphonates (BISs) are widely used for the treatment of osteoporosis and tumors with bone metastasis to inhibit osteoclast activity and bone resorption. Although BIS treatment undoubtedly improves the quality of life, osteonecrosis is a rare, but serious adverse effect that occurs mainly after i...
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| Dokumentumtípus: | Disszertáció |
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2014-11-18
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| doi: | 10.14232/phd.2466 |
| mtmt: | 2780698 |
| Online Access: | http://doktori.ek.szte.hu/2466 |
| Tartalmi kivonat: | Bisphosphonates (BISs) are widely used for the treatment of osteoporosis and tumors with bone metastasis to inhibit osteoclast activity and bone resorption. Although BIS treatment undoubtedly improves the quality of life, osteonecrosis is a rare, but serious adverse effect that occurs mainly after invasive dental procedures, e.g. tooth extraction, with an increased incidence particularly after the use of third-generation BISs (e.g. zoledronate, ZOL). BISs together with other antiresorptive and antiangiogenic drugs induce necrosis of the oral bones, usually referred to as medication-related osteonecrosis of the jaw (MRONJ), but bone destruction is also seen less frequently in other bones of the skeleton. We hypothesized that a disturbed mandibular microcirculation may play a role in the pathogenesis of MRONJ. In this context, we designed a rat model where chronic BIS treatment was combined with an invasive dental procedure and where the processes of mucosal healing and bone destruction resembled the clinical manifestations of MRONJ. ZOL was applied intravenously (in a dose of 80 µg/kg/week) over 8 weeks, the first two right mandibular molar teeth were extracted in the third week, and various systemic and local parameters of the inflammatory cascade were investigated 6 weeks after tooth extraction. The incidence and severity of the gingival lesions were determined on the basis of a new scoring system, while jaw osteonecrosis was diagnosed by means of computed micro tomography. We also developed a method by which the mandibular periosteum can be visualized relatively simply and highly reproducibly by means of different microscopy methods (fluorescence intravital microscopy, orthogonal spectral imaging and confocal laser scanning microscopy) in rats. Furthermore, we compared the effects of chronic ZOL administration on the mandibular and tibial periosteal microcirculatory reactions (with or without tooth extraction). Intravital fluorescence videomicroscopy revealed significantly increased leukocyte–endothelial interactions (leukocyte rolling and adhesion on the endothelial surface) in the mandibular periosteum, but not in the tibia. Only the leukocyte count and NADPH-oxidase activity of the leukocytes displayes significant reductions, the other systemic inflammatory parameters not being affected by ZOL. We conclude that 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. |
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