Risk Factors for Osteonecrosis of the Jaws

Barasch, Andrei; Cunha‐Cruz, Joana; Curro, Frederick A.; Hujoel, Philippe P.; Sung, A.H.; Vena, Don; Voinea-Griffin, A. E.

doi:10.1177/0022034510397196

Cited by 177 publications

(73 citation statements)

References 32 publications

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“…ONJ occurs mainly after tooth extraction in patients treated with medications that target osteoclastic function and activity, such as BPs and Denosumab, for the treatment of neoplastic or metabolic bone disease [2, 36]. Several animal models have utilized tooth extraction and high-dose BPs to reproduce clinical, radiographic and histologic features of the human disease [21, 24, 37].…”

Section: Discussionmentioning

confidence: 99%

Spontaneous osteonecrosis of the jaws in the maxilla of mice on antiresorptive treatment: A novel ONJ mouse model

Molon

Cheong

Bezouglaia

et al. 2014

Bone

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Although osteonecrosis of the jaws (ONJ), a serious complication of antiresorptive medications, was reported a decade ago, the exact mechanisms of disease pathophysiology remain elusive. ONJ-like lesions can be induced in animals after antiresorptive treatment and experimental interventions such as tooth extraction or periapical or periodontal disease. However, experimental induction and manipulation of disease progression does not always reflect clinical reality. Interestingly, naturally occurring maxillofacial abscesses, inducing aggressive inflammation of the peri-radicular mucosa with significant osteolysis and alveolar bone expansion, have been reported in mice. Here, we aimed to explore whether osteonecrotic lesions would develop in areas of maxillary peri-radicular infections, in mice on antiresorptive medications with distinct pharmacologic action, thus establishing a novel ONJ animal model. Mice were treated with RANK-Fc or OPG-Fc that bind to RANKL or with the potent bisphosphonate zoledronic acid (ZA). Maxillae were assessed radiographically and histologically. μCT imaging of vehicle mice revealed several maxillae with altered alveolar bone morphology, significant ridge expansion and large lytic areas. However, in RANK-Fc, OPG-Fc and ZA treated animals the extent of bone loss was significantly less, but exuberant bone deposition was noted at the ridge periphery. BV and BV/TV were increased in the diseased site of antiresorptive vs. veh animals. Histologically, extensive inflammation, bone resorption and marginal gingival epithelium migration were seen in the diseased site of vehicle animals. Rank-Fc, OPG-Fc and ZA reduced alveolar bone loss, increased periosteal bone formation, and induced areas of osteonecrosis, and bone exposure that in many animals covered significant part of the alveolar bone. Collectively, our data demonstrate ONJ-like lesions at sites of maxillary peri-radicular infection, indistinguishable in mice treated with RAKL inhibitors vs. zoledronate. This novel mouse model of spontaneous ONJ supports a central role of osteoclast inhibition and infection/inflammation in ONJ pathogenesis and validates and complements existing animal models employing experimental interventions.

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Section: Discussionmentioning

confidence: 99%

Spontaneous osteonecrosis of the jaws in the maxilla of mice on antiresorptive treatment: A novel ONJ mouse model

Molon

Cheong

Bezouglaia

et al. 2014

Bone

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“…ONJ is clinically characterized as unresolved exposure of partially necrotic jawbone to the oral cavity and is frequently associated with dentoalveolar procedures in cancer patients receiving high doses of intravenously administered BPs [12, 14–17]. Repeated BP administrations are believed to result in the accumulation of bioavailable doses in bone and thus have been postulated to reach the accumulated “toxic” BP level causing ONJ [18].…”

Section: Introductionmentioning

confidence: 99%

Equilibrium-dependent bisphosphonate interaction with crystalline bone mineral explains anti-resorptive pharmacokinetics and prevalence of osteonecrosis of the jaw in rats

Hokugo

Sun

Park

et al. 2013

Bone

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Bisphosphonates (BPs) are chemically stable analogs of pyrophosphate exhibiting strong affinity to bone and have been used for the treatment of diseases characterized by excessive bone resorption. Contrary to the widely accepted BP accumulation model in bone after repeated applications, we report here that an equilibrium-dependent BP-crystalline bone mineral interaction may better explain BP bio-distribution and anti-catabolic bone remodeling and may be relevant to the appearance of osteonecrosis of the jaw (ONJ) in rats. Fluorescent-labeled BP analogs were synthesized and used to evaluate the mode of bone adsorption. After fluorescent-labeled BP adsorbed on crystalline calcium phosphates in vitro, subsequent BP application replaced the previously absorbed BP depending on the dose and the relative binding affinity to hydroxyapatite. The in vivo intravenous zoledronate (ZOL) injection of repeated fractional doses resulted in lower serum CTX and TRAP5b measurements than a single bolus injection in spite of the equivalent cumulative dose. Repeated injections resulted in the distribution of fluorescent-labeled BP on the large area of bone surfaces; whereas the single bolus injection gave rise to the intense BP bio-distribution at selected bone sites such as the alveolar process of jawbones. Necrotic maxillary alveolar bone was predominantly observed in vitamin D deficiency rats treated with bolus ZOL injection. The palatal necrotic bone was characteristically sequestrated by the fistulation of hyperplastic oral epithelium, suggesting the initial development of ONJ-like lesions in rats. Our results suggest that equilibrium-dependent BP-bone interaction may, in part, determine the effectiveness and influence side effects of long-term and repeated applications of BPs.

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“…Additionally, treatment with denosumab, a fully humanized monoclonal antibody against RANKL, also leads to marked suppression of bone formation markers in human [42,43]. Denosumab has also been associated with increased risk of osteonecrosis of the jaw [44], which has also been seen with bisphosphonates [45,46]. Unlike these other compounds, in vivo data from this report showed that SI-591, in contrast, did not affect the coupling of bone resorption and formation.…”

Section: Discussionmentioning

confidence: 64%

Effect of SI-591, a new class of cathepsin K inhibitor with peptidomimetic structure, on bone metabolism in vitro and in vivo

Fujii

Ishikawa

Kubo

et al. 2015

Bone

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SI-591[N-[1-[[[(1S)-3-[[(3S)-hexahydro-2-oxo-1H-azepin-3-yl]amino]-1-(1-methylethyl)-2,3-dioxopropyl]amino]carbonyl]cyclohexyl]-2-furancarboxamide] is an orally bioavailable compound that was synthesized as one of several unique peptidomimetic compounds without a basic group. This compound was found to have the ability to inhibit cathepsin K, a lysosomal cysteine protease. Cathepsin K is known to be expressed in osteoclasts and involved in bone loss processes. In this study, SI-591 was shown to inhibit the activity of various purified cathepsin molecules at nanomolar concentrations but had high selectivity for cathepsin K over other subtypes including B and L. SI-591 also decreased the level of CTX-I, a bone resorption marker, which was released from osteoclasts in vitro in a dose-dependent manner. The mobilization of calcium from the bones to the blood stream is known to increase in rats fed with a low calcium diet; SI-591 inhibited this increase in serum calcium level at an oral dose of 3mg/kg. Furthermore, SI-591 significantly decreased the level of CTX-I and DPD, bone resorption markers, at oral doses of 10mg/kg or less in ovariectomized rats, while it did not affect the level of BGP, a bone formation marker. In addition, SI-591 prevented bone mineral density loss in the lumber vertebrae and femurs in ovariectomized rats. These results suggest that SI-591 inhibits bone resorption without affecting osteoblast maturation. Therefore, SI-591, a novel cathepsin K inhibitor, could be a promising agent for the treatment of postmenopausal osteoporosis.

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Risk Factors for Osteonecrosis of the Jaws

Cited by 177 publications

References 32 publications

Spontaneous osteonecrosis of the jaws in the maxilla of mice on antiresorptive treatment: A novel ONJ mouse model

Spontaneous osteonecrosis of the jaws in the maxilla of mice on antiresorptive treatment: A novel ONJ mouse model

Equilibrium-dependent bisphosphonate interaction with crystalline bone mineral explains anti-resorptive pharmacokinetics and prevalence of osteonecrosis of the jaw in rats

Effect of SI-591, a new class of cathepsin K inhibitor with peptidomimetic structure, on bone metabolism in vitro and in vivo

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