Bony changes in the jaws of rats treated with zoledronic acid and dexamethasone before dental extractions mimic bisphosphonate-related osteonecrosis in cancer patients

Sonis, Stephen T.; Watkins, Brynmor A.; Lyng, Gregory; Lerman, Mark A.; Anderson, Kenneth C.

doi:10.1016/j.oraloncology.2008.04.013

Cited by 186 publications

(191 citation statements)

References 21 publications

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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: 83%

“…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%

“…The inflammation was evaluated according to quantity and quality based on the density, type, and distribution of inflammatory cell infiltrate. 6 Qualitatively, the inflammation was classified as acute (predominance of neutrophil infiltration), chronic (predominance of mononuclear cell infiltration, such as macrophages and lymphocytes), and mixed (presence of cells of both acute and chronic processes in similar proportions). Furthermore, the degree of vascularization (number of vessels) was also evaluated.…”

Section: Histological and Stereometric Analysesmentioning

confidence: 99%

“…4,5 Thus, the effects of Bps therapy on the healing of alveolar sockets have been the focus of several in vivo studies. 6,7,8 Recently, we demonstrated the development of BRONJ-like lesions in rodents by associating tooth extractions with daily high dosages of alendronate (ALN) in a long-term study. 9 However, studies using lower dosages of Bps showed only a transient impairment of alveolar socket healing after tooth extractions.…”

Section: Introductionmentioning

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: 83%

Section: Discussionmentioning

confidence: 99%

Section: Histological and Stereometric Analysesmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Experimental osteonecrosis: development of a model in rodents administered alendronate

et al. 2016

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“…In healthy rats, the covering epithelium is observed 17 days after tooth extraction, and complete closure is observed after 28 days 18,19) .…”

Section: Discussionmentioning

confidence: 99%

Jawbone Changes in Sodium Zoledronic Acid- and Dexamethasone-Treated Rats

Tezuka

Tanaka

2016

J. Hard Tissue Biology.

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Previous studies have evaluated bisphosphonate-related osteonecrosis of the jaw (ONJ) after tooth extraction with concurrent administration of bisphosphonate zoledronic acid (ZOL) and steroids. However, details of jawbone changes after administration of ZOL and steroids without tooth extraction remain unclear. In this study, we administered ZOL and dexamethasone (DEX) in rats and compared changes in the jawbone with and without tooth extraction. The right maxillary first molar (M 1 ) was extracted from 8-week-old rats treated with ZOL, ZOL+DEX or DEX. The right maxillary M 1 region as the extraction sample and the left maxillary M 1 region as the non-extraction sample were compared with macroscopic, radiological, histologic and immunohistochemical examinations. In the extraction samples, we detected incomplete mucosal closure macroscopically and found ONJ on histological examination. In addition, immunohistochemical and threedimensional analysis of trabecular bone structure showed inhibition of remodeling and angiogenesis in the extraction samples. In the non-extraction samples, we observed inhibition of remodeling, reduced activity of osteoclasts and osteoblasts and suppression of angiogenesis. These findings demonstrate that ONJ can develop under the mucosa with ZOL and DEX treatment, even without invasive procedures. The data suggest that ZOL and DEX can induce ONJ in rats under both invasive and noninvasive conditions because ZOL suppresses osteoclast activity and DEX inhibits remodeling by suppressing osteoblast activity. The results also suggest that surgical stress, such as tooth extraction or bacterial infection, might lead to more severe bisphosphonaterelated ONJ.

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