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Zoledronate Impairs Socket Healing after Extraction of Teeth with Experimental Periodontitis.

ABSTRACT: Osteonecrosis of the jaws (ONJ) is a rare but severe complication of antiresorptive medications, such as bisphosphonates, used in the treatment of bone malignancy or osteoporosis. Tooth extraction and dental disease have been strongly associated with ONJ development. Here, we investigated molecular and cellular markers of socket healing after extraction of healthy or teeth with experimental periodontitis (EP) in Wistar-Han rats treated with zoledronic acid (ZA). We included 4 experimental groups: vehicle-treated animals with extraction of healthy teeth or teeth with ligature-induced EP and ZA-treated animals with extraction of healthy teeth or teeth with EP. Animals were pretreated with vehicle or ZA for a week, and EP was induced. Four weeks later, the second maxillary molars were extracted; sockets were allowed to heal for 4 wk; animals were euthanized; and maxillae were isolated. Radiographically, extraction sockets in groups 1, 2, and 3 demonstrated normal healing. Contrary incomplete socket healing was noted after extraction of teeth with EP in ZA-treated rats of group 4. Histologically, persistent inflammation and extensive osteonecrosis were seen in group 4. Disorganization of the collagen network, collagen type III predominance, and lack of collagen fiber insertion in the necrotic bone were associated with impaired socket healing. Cells positive for MMP-9, MMP-13, and ?-SMA expression were present at the areas of epithelial invagination and adjacent to osteonecrotic bone. Importantly, human biopsies from patients with ONJ showed similar findings. Our data emphasize the importance of dental disease and tooth extraction in ONJ pathogenesis and help delineate an altered profile in wound-healing markers during ONJ development.

SUBMITTER: Soundia A

PROVIDER: S-EPMC5833182 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature

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Zoledronate Impairs Socket Healing after Extraction of Teeth with Experimental Periodontitis.

Soundia A A Hadaya D D Esfandi N N Gkouveris I I Christensen R R Dry S M SM Bezouglaia O O Pirih F F Nikitakis N N Aghaloo T T Tetradis S S

Journal of dental research 20170927 3

Osteonecrosis of the jaws (ONJ) is a rare but severe complication of antiresorptive medications, such as bisphosphonates, used in the treatment of bone malignancy or osteoporosis. Tooth extraction and dental disease have been strongly associated with ONJ development. Here, we investigated molecular and cellular markers of socket healing after extraction of healthy or teeth with experimental periodontitis (EP) in Wistar-Han rats treated with zoledronic acid (ZA). We included 4 experimental groups ...[more]

PMID: 28954199

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Project description:Bisphosphonate (BP)-related osteonecrosis of the jaw, previously known as BRONJ, now referred to more broadly as medication-related osteonecrosis of the jaw (MRONJ), is a morbid condition that represents a significant risk for oncology patients who have received high dose intravenous (IV) infusion of a potent nitrogen containing BP (N-BP) drug. At present, no clinical procedure is available to prevent or effectively treat MRONJ. Although the pathophysiological basis is not yet fully understood, legacy adsorbed N-BP in jawbone has been proposed to be associated with BRONJ by one or more mechanisms. We hypothesized that removal of the pre-adsorbed N-BP drug common to these pathological mechanisms from alveolar bone could be an effective preventative/therapeutic strategy. This study demonstrates that fluorescently labeled BP pre-adsorbed on the surface of murine maxillo-cranial bone in vivo can be displaced by subsequent application of other BPs. We previously described rodent BRONJ models involving the combination of N-BP treatment such as zoledronate (ZOL) and dental initiating factors such as tooth extraction. We further refined our mouse model by using gel food during the first 7 days of the tooth extraction wound healing period, which decreased confounding food pellet impaction problems in the open boney socket. This refined mouse model does not manifest BRONJ-like severe jawbone exposure, but development of osteonecrosis around the extraction socket and chronic gingival inflammation are clearly exhibited. In this study, we examined the effect of benign BP displacement of legacy N-BP on tooth extraction wound healing in the in vivo model. Systemic IV administration of a low potency BP (lpBP: defined as inactive at 100 μM in a standard protein anti-prenylation assay) did not significantly attenuate jawbone osteonecrosis. We then developed an intra-oral formulation of lpBP, which when injected into the gingiva adjacent to the tooth prior to extraction, dramatically reduced the osteocyte necrosis area. Furthermore, the tooth extraction wound healing pattern was normalized, as evidenced by timely closure of oral soft tissue without epithelial hyperplasia, significantly reduced gingival inflammation and increased new bone filling in the extraction socket. Our results are consistent with the hypothesis that local application of a rescue BP prior to dental surgery can decrease the amount of a legacy N-BP drug in proximate jawbone surfaces below the threshold that promotes osteocyte necrosis. This observation should provide a conceptual basis for a novel strategy to improve socket healing in patients treated with BPs while preserving therapeutic benefit from anti-resorptive N-BP drug in vertebral and appendicular bones.

Project description:BackgroundSince the discovery of adult mesenchymal stem cells extensive research has been conducted to determine their mechanisms of differentiation and effectiveness in cell therapy and regenerative medicine.Material and methodsTo assess the efficacy of autologous dental pulp mesenchymal stem cells delivered in a collagen matrix for post-extraction socket healing, a single-centre, double-blind, randomised, split-mouth, controlled clinical trial was performed. Both impacted mandibular third molars were extracted from 32 patients. Dental pulp was collected and dissociated; the resulting cell suspension, obtained by centrifugation, was incorporated into a resorbable collagen matrix and implanted in 32 experimental post-extraction sockets. Collagen matrices alone were implanted in 32 contralateral, control post-extraction sockets. Two neuroradiologists independently assessed the extent of bone repair at 6 months after the extractions. Computed tomography (CT, Philips Brilliance) and an advanced display platform (IntelliSpace Portal) was used to record extraction socket density, expressed as Hounsfield units (HU) and height (mm) of the distal interdental bone septum of the second molar. Measurements at 6 months post-extraction were compared with measurements obtained immediately after extraction. Data were analysed with the statistical program STATA 14.ResultsTwo patients dropped out of the study. The final sample consisted of 22 women and 8 men (mean age, 23 years; range: 18-30 years). Clinical, radiological, and surgical characteristics of impacted third molars of the control and experimental groups were homogeneous. Measurements obtained by the two neuroradiologists showed agreement. No significant differences were found in the extent of bone repair during analyses of density (p=0.4203 neuroradiologist 1; p=0.2525 neuroradiologist 2) or interdental septum height (p=0.2280 neuroradiologist 1; p=0.4784 neuroradiologist 2).ConclusionsIn our clinical trial, we were unable to demonstrate that autologous dental pulp mesenchymal stem cells reduce socket bone resorption after inferior third molar extraction.

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Zoledronate Impairs Socket Healing after Extraction of Teeth with Experimental Periodontitis.

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Zoledronate Impairs Socket Healing after Extraction of Teeth with Experimental Periodontitis.

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