Perioperative discontinuation of intravenous bisphosphonate therapy reduces the incidence and severity of bisphosphonate-related osteonecrosis of the jaw: A randomized, controlled, prospective experimental study in rats

Zandi, Mohammad; Dehghan, Arash; Ghadermazi, Khaled; Malekzadeh, Hamid; Akbarzadeh, Mahdi

doi:10.1016/j.jcms.2015.08.008

Cited by 26 publications

(30 citation statements)

References 19 publications

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“…Taken together these studies support but can not terminal confirm the theory, that a drug holiday during oral surgical procedures could be beneficial for normal keratinocytes function which support wound healing and tissue regeneration (28,29). Since during the administration an increased concentration of BP in these tissues is likely.…”

Section: Impact Of Bisphosphonates On Keratinocytesmentioning

confidence: 73%

Impact of Soft Tissue Pathophysiology in the Development and Maintenance of Bisphosphonate Related Osteonecrosis of the Jaw (BRONJ)

Ziebart¹,

Blatt²,

Jung³

et al. 2016

Preprint

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Abstract:Since the first description of bisphosphonate-related osteonecrosis of the jaw (BRONJ) numerous research groups have focused on possible pathological mechanisms including the suppression of the bone turnover of the jaw, antiangiogenic effects and soft tissue toxicity. In our review we focused on summarizing the role of the soft tissues in the development and progression of BRONJ. The biological behavior of fibroblasts can be significantly influenced by bisphosphonates (BP) such as a concentration dependent reduction of cell viability. High concentrations of BP can induce apoptosis and necrosis of the cells. Comparable effects could be detected for keratinocytes. Compared to non-nitrogen containing bisphosphonates nitrogen-containing BP have worse effects on cell biology by blocking the mevalonate pathway. Next to this the cell architecture and the expression levels of several genes and proteins are significantly disturbed by BP. These inhibitory effects of BP are in accordance with BP related reduced angiogenesis and neovascularization and could underline the hypothesis that inhibition of fibroblasts and keratinocytes results in delayed wound healing and can induce and trigger BRONJ.

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Section: Impact Of Bisphosphonates On Keratinocytesmentioning

confidence: 73%

Impact of Soft Tissue Pathophysiology in the Development and Maintenance of Bisphosphonate Related Osteonecrosis of the Jaw (BRONJ)

Ziebart¹,

Blatt²,

Jung³

et al. 2016

Preprint

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show abstract

“…Akita et al, Kuroshima & Yamashita, Park et al, and Yang et al showed that polymorphonuclear cells were significantly infiltrated in BRONJ‐like lesions vs control. Suppressed collagen production, pseudoepitheliomatous hyperplasia and the presence of Actinomyces , abnormal proliferation and migration of oral epithelial cells, and fistulas were also observed in BRONJ‐like lesions (Table ).…”

Section: Resultsmentioning

confidence: 97%

“…Anti‐sclerostin monoclonal antibody‐related ONJ was not investigated in this review. Maxillary and mandibular first molars were extracted in eight and two studies, respectively. Mandibular second molars were extracted in one study .…”

Section: Resultsmentioning

confidence: 99%

“…Many studies reported that ZA monotherapy induced impaired wound healing of tooth extraction sockets with uncovered mucosa and exposed bone at 2, 4 or 12 weeks after tooth extraction, although the dosages of ZA administered differed among the studies . Akita et al and Kuroshima & Yamashita reported that ZA and chemotherapeutic combination therapy significantly increased wound open area with exposed bone at 4 weeks after tooth extraction .…”

Section: Resultsmentioning

confidence: 99%

“…The prevalence of BRONJ‐like lesions ranged from 0% to 100%, with several variations by administered drugs, administration route and duration, total dosage and/or dose per one injection, and combination therapy with chemotherapeutic agents and/or dexamethasone (Table ). The prevalence of ZA monotherapy‐induced ONJ‐like lesions did not depend on dosage, administration route or administration duration of ZA from the selected articles (Table ) . ZA monotherapy and ZA/chemotherapeutic and/or steroid combination therapy increased the incidence of BRONJ‐like lesions when compared with no drug treatment (Figures and ).…”

Section: Discussionmentioning

confidence: 96%

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Medication‐related osteonecrosis of the jaw‐like lesions in rodents: A comprehensive systematic review and meta‐analysis

et al. 2019

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Objective The aim of this comprehensive systematic review and meta‐analysis was to investigate the pathology and pathogenesis of medication‐related osteonecrosis of the jaw (MRONJ) in rodents. Background Medication‐related osteonecrosis of the jaw occurs in patients taking antiresorptive drugs, such as bisphosphonates and denosumab, and anti‐angiogenesis agents. However, there is limited information about the pathology of MRONJ at the clinical level. Moreover, no information about the exact mechanisms of MRONJ is clinically available. Materials and methods The PubMed, SCOPUS and Medline databases were used to search for relevant articles up to April 2018 by two independent reviewers. A systematic review and meta‐analysis were performed. Results Of the 1841 studies, 10 articles met the eligibility criteria. The most commonly observed pathology of MRONJ‐like lesions was exposed bone without epithelial coverage, decreases in the number of osteocytes and increases in necrotic bone with more empty lacunae. No definitive pathogenesis of MRONJ‐like lesions was found. Both zoledronic acid (ZA) monotherapy and ZA/chemotherapeutic and/or dexamethasone combination therapy were significant high‐risk factors for developing MRONJ‐like lesions (P < 0.00001 and P < 0.0001, respectively). Conclusion Based on rodent studies, common pathological findings were extracted in bisphosphonate‐related ONJ (BRONJ)‐like lesions, whereas no definitive pathogenesis was identified. There is no information about the pathology and pathogenesis of denosumab‐related ONJ. These findings clearly suggest that accumulation of scientific evidence based on animal studies is absolutely necessary to explore the pathology and pathogenesis of MRONJ in humans. ZA administration would be a significant risk factor for developing BRONJ‐like lesions.

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Morphological and immunohistochemical features of tooth extraction sites in rats treated with alendronate, raloxifene, or strontium ranelate

et al. 2020

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Objective The aim of this study was to evaluate morphological and immunohistochemical features of tooth extraction sites in rats subjected to different antiresorptive drugs. Materials and methods Wistar rats were allocated into 4 groups according to the treatment: (1) alendronate, (2) raloxifene, (3) strontium ranelate, and (4) control. The animals underwent tooth extraction (60th day of treatment) and afterwards were euthanized (90th day of treatment). Tooth extraction sites were analyzed by means of scanning electron microscopy (SEM), hematoxylin-eosin staining (H&E), and immunohistochemical staining (RANKL and OPG).Results On H&E analysis, the alendronate group showed greater amounts of non-vital bone, biofilm, inflammatory infiltrate and root fragment, and smaller amount of vital bone. The strontium ranelate group showed great amount of non-vital bone. This group also had lower levels of OPG, while the alendronate group showed lower OPG and RANKL than the other groups. On SEM analysis, the alendronate group showed a considerable number of microcracks on the alveolar bone surface and few Howship lacunae and lack of bone cells as well. The raloxifene, strontium ranelate, and control groups showed a large number of bone cells and Howship lacunae on the bone surface and few microcracks. Conclusion Alendronate therapy is associated with macro-and microscopic features of medication-related osteonecrosis of the jaw at tooth extraction sites, whereas raloxifene therapy is not, and strontium ranelate therapy is associated with non-vital bone. Clinical relevance Osteonecrosis of the jaws is a serious side effect of alendronate therapy, where tooth extraction is a major risk factor. Considering the significant number of patients undergoing antiresorptive therapies worldwide, the present study investigated whether raloxifene and strontium ranelate interfere with bone repair after tooth extraction in a similar way to bisphosphonates.

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Perioperative discontinuation of intravenous bisphosphonate therapy reduces the incidence and severity of bisphosphonate-related osteonecrosis of the jaw: A randomized, controlled, prospective experimental study in rats

Cited by 26 publications

References 19 publications

Impact of Soft Tissue Pathophysiology in the Development and Maintenance of Bisphosphonate Related Osteonecrosis of the Jaw (BRONJ)

Impact of Soft Tissue Pathophysiology in the Development and Maintenance of Bisphosphonate Related Osteonecrosis of the Jaw (BRONJ)

Medication‐related osteonecrosis of the jaw‐like lesions in rodents: A comprehensive systematic review and meta‐analysis

Morphological and immunohistochemical features of tooth extraction sites in rats treated with alendronate, raloxifene, or strontium ranelate

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