Role of periodontal disease in bisphosphonate‐related osteonecrosis of the jaws in ovariectomized rats

Li, Chun Lei; Lu, Wenjia; Seneviratne, Chaminda Jayampath; Leung, W. Keung; Zwahlen, Roger A.; Zheng, Li Wu

doi:10.1111/clr.12502

Cited by 38 publications

(43 citation statements)

References 26 publications

(47 reference statements)

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“…However, there is no standard BRONJ experimental model, since most models fail to reproduce clinical reality and do not associate several co-factors that undertake a reliable cause-effect relationship between Bps and disease pathogenesis. 6,7,8,9,15,16,17,18,19,20,21,22,23,24 To the best of our knowledge, this is the first study to demonstrate 100% of BRONJ-like lesions by associating tooth extractions with alendronate in cumulative dosages for the management of rheumatic diseases. 12 The first advantage of our experimental model is the high percentage of bone necrosis achieved.…”

Section: Discussionmentioning

confidence: 85%

“…12 The first advantage of our experimental model is the high percentage of bone necrosis achieved. The rate of bone lesions in previously published experimental models varies from 0 to 100%, 6,7,8,9,15,16,17,18,19,20,21,22,23,24 and only four papers have reported 100% of BRONJ-like lesions. 8,9,17,18 However, models that reported a bone lesion rate of 100% were developed by exposing animals to supra-therapeutic dose regimens 9,17 or to a high-intensity trauma, 8,18 which represents an artificial scenario.…”

Section: Discussionmentioning

confidence: 99%

“…7,15,16,20,26 We do not rule out the relevance of these studies, but rather believe that healthy animals provide some relevant advantages. First, the more variables included in the experimental model, the more difficult it is to determine the true role of Bps in disease pathogenesis.…”

mentioning

confidence: 94%

“…20,24 Furthermore, most experimental models reproduced oncologic schedules with high dosages of zolendronate. 7,8,15,16,18,21,22,23,25 However, although zolendronate is undeniably important, it is essential to note that ALN is among the most common Bps prescribed worldwide and is specifically indicated for the treatment of benign diseases, such as osteoporosis, osteopenia, and rheumatic diseases. 1 In this context, to compensate for the differences in potency between alendronate and zolendronate, as well as for the lower plasma concentrations when the subcutaneous route rather than the intravenous route is used, 26 we conclude that the total Bps dose administered over a long period of time is important for the magnitude of the reduction in bone turnover.…”

mentioning

confidence: 99%

“…31 Although some authors have demonstrated spontaneous BRONJ lesions, 9 a local trigger factor seems highly relevant to the induction of this disease in animal models. The main local agents include periodontal disease, 15,23 bacterial injections in addition to bone defects, 22 and tooth extractions. 9,16,17,18,19,20,21,24,25,26 The last is undoubtedly the most relevant, since most patients develop BRONJ lesions after tooth extractions, as described in clinical studies.…”

mentioning

confidence: 99%

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Experimental osteonecrosis: development of a model in rodents administered alendronate

et al. 2016

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Abstract:The main objective of this study was to cause bisphosphonate-related osteonecrosis of the jaws to develop in a rodent model. Adult male Holtzman rats were assigned to one of two experimental groups to receive alendronate (AL; 1 mg/kg/week; n = 6) or saline solution (CTL; n = 6). After 60 days of drug therapy, all animals were subjected to first lower molar extraction, and 28 days later, animals were euthanized. All rats treated with alendronate developed osteonecrosis, presenting as ulcers and necrotic bone, associated with a significant infection process, especially at the inter-alveolar septum area and crestal regions. The degree of vascularization, the levels of C-telopeptide cross-linked collagen type I and bone-specific alkaline phosphatase, as well as the bone volume were significantly reduced in these animals. Furthermore, on radiographic analysis, animals treated with alendronate presented evident sclerosis of the lamina dura of the lower first molar alveolar socket associated with decreased radiographic density in this area. These findings indicate that the protocol developed in the present study opens new perspectives and could be a good starting model for future property design.

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Section: Discussionmentioning

confidence: 85%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 94%

mentioning

confidence: 99%

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confidence: 99%

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Experimental osteonecrosis: development of a model in rodents administered alendronate

et al. 2016

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Long-Term Ligature-Induced Periodontitis Exacerbates Development of Bisphosphonate-Related Osteonecrosis of the Jaw in Mice

Williams

Ho²,

Lenon³

et al. 2020

Journal of Bone and Mineral Research

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Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is a detrimental intraoral lesion that occurs in patients with long-term or high-dose use of anti-resorptive agents such as bisphosphonates. Tooth extraction is a known risk factor for BRONJ, and such intervention is often performed to eliminate existing pathological inflammatory conditions. Previously, we determined that ligatureinduced periodontitis (LIP) is a risk factor for the development of osteonecrosis in mice, but it remains unclear whether the chronicity of LIP followed by extraction influences osteonecrosis development. In this study, we assess the effect of short-term and long-term LIP (ligature placed for 3 weeks [S-LIP] or 10 weeks [L-LIP], respectively) on osteonecrosis development in mice receiving 250 μg/kg/ week zoledronic acid (ZOL). When compared to S-LIP, L-LIP caused 70% (p ≤ 0.0014) more bone loss without altering microbe composition. In the presence of ZOL, bone loss mediated by LIP was prevented and bone necrosis was induced. When the ligated tooth was extracted, histologic hallmarks of osteonecrosis including empty lacunae and necrotic bone were increased by 88% (p = 0.0374) and 114% (p = 0.0457), respectively, in L-LIP compared to S-LIP. We also observed significant increases in serum platelet factor 4 (PF4) and macrophage inflammatory factor 1 γ (MIP1γ) in mice that received ZOL treatment and had tooth extractions compared to controls, which may be systemic markers of inflammation-associated osteonecrosis development. Additionally, CD3+ T cells were identified as the major immune population in both health and disease, and we observed a 116% (p = 0.0402) increase in CD3+IL23R+ T cells in L-LIP compared to S-LIP lesions following extraction. Taken together, our study reveals that extracting a periodontally compromised tooth increases the formation of necrotic bone compared to extracting a periodontally healthy tooth and that osteonecrosis may be associated with the duration of the preexisting pathological inflammatory conditions.

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Management of medication‐related osteonecrosis of jaw: Comparison between icariin and teriparatide in a rat model

Liu

Mattheos

Deng

et al. 2020

Journal of Periodontology

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Background The aim of this study is to compare the effects of icariin and teriparatide on the treatment of medication‐related osteonecrosis of the jaw (MRONJ) using a rat model. Methods Fifty rats undergoing ovariectomy were randomly assigned to control group (n = 10) and the MRONJ model group (n = 40). Zoledronic acid (0.2 mg/kg) and dexamethasone (2 mg/kg) were injected into rats in the model group for 8 weeks while saline was applied in control group, then all rats underwent tooth extraction and bone defect. Eight weeks later, rats diagnosed with MRONJ (n = 33) were randomly distributed to icariin (n = 11), teriparatide (n = 11), and the untreated (n = 11) group, and rats received daily 150 mg/kg icariin, 20 µg/kg teriparatide, and no intervention, respectively, for 8 weeks. Then, mandibulars were dissected for later examination. Results Rats diagnosed with MRONJ (33/40) demonstrated significantly larger area of soft tissue wound and necrotic bone with higher ratio of empty bone lacuna. Area of soft tissue wound and ratio of empty bone lacuna were significantly decreased in the icariin group compared with the untreated group, while teriparatide group revealed significantly higher ratio of receptor activator of NF‐kB ligand (RANKL)‐positive osteocytes, smaller area of necrotic bone and lower ratio of empty lacuna. The two agents were related to higher expression of BMP‐2 in osteocytes but were not statistically significant. Conclusions Icariin benefits MRONJ in terms of the area of soft tissue wound and ratio of empty lacuna. Teriparatide activates expression of RANKL and reduces the area of bone necrosis and ratio of empty lacuna in a MRONJ lesion. The data suggest possible healing improvement in patients with MRONJ and further studies to prove the efficacy of icariin.

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Role of periodontal disease in bisphosphonate‐related osteonecrosis of the jaws in ovariectomized rats

Abstract: Bisphosphonates inhibit alveolar bone resorption in progressive periodontal disease, which might benefit the management of periodontitis, but increase the risk of developing BRONJ.

Cited by 38 publications

References 26 publications

Experimental osteonecrosis: development of a model in rodents administered alendronate

Experimental osteonecrosis: development of a model in rodents administered alendronate

Long-Term Ligature-Induced Periodontitis Exacerbates Development of Bisphosphonate-Related Osteonecrosis of the Jaw in Mice

Management of medication‐related osteonecrosis of jaw: Comparison between icariin and teriparatide in a rat model

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