Chemotherapeutic and antiresorptive combination therapy suppressed lymphangiogenesis and induced osteonecrosis of the jaw-like lesions in mice

Kuroshima, Shinichiro; Yamashita, Junro

doi:10.1016/j.bone.2013.05.013

Cited by 44 publications

(63 citation statements)

References 49 publications

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“…However, loss of osteocytes and presence of empty osteocytic lacunae consistent with osteonecrosis were also present in these animals. Presence of osteonecrosis has been described in animals on antiresorptives after tooth extraction or experimental disease, emphasizing the resemblance of the spontaneous ONJ-like lesions observed in our studies with other ONJ-animal models [19–30]. The similar radiographic and histologic disease presentation between this and other ONJ models [19–30], which parallels findings in ONJ patients validates such animal models as capturing essential features of disease pathophysiology that lead to alveolar bone osteonecrosis.…”

Section: Discussionsupporting

confidence: 84%

“…However, experimental induction and manipulation of disease progression does not always reflect clinical reality. To that effect, several ONJ animal models utilize extraction of healthy teeth [21, 24, 25, 27–30], which are rarely extracted in ONJ patients. Similarly, ONJ animal models utilizing periodontitis [20, 22, 26] employ experimental procedures that depict some, but not necessarily all the components of the pathological process of human periodontal disease [40].…”

Section: Discussionmentioning

confidence: 99%

“…Thus, infection/inflammation due to dental disease appears to be present in most ONJ cases. Paralleling these clinical observations, animal findings demonstrate ONJ-like lesions after experimental interventions such as tooth extraction or periapical or periodontal disease [19–30]. These interventions are employed to simulate clinical scenaria that precipitate disease pathogenesis in a controlled and reproducible manner.…”

Section: Introductionmentioning

confidence: 95%

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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: Discussionsupporting

confidence: 84%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 95%

See 1 more Smart Citation

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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show abstract

“…This variability has been hypothesized to be due to the type, route of administration, and dose regimen of BP delivery, in combination with the lack of well-defined outcome measures that define the presence of ONJ in rodents [30]. It is noteworthy, that studies consistently reporting ONJ-like features in mice or rat extraction models include in their experimental design systemic risk factors such as steroid or chemotherapy treatment, vitamin D deficiency, or diabetes all of which alter soft tissue and/or bone homeostasis and compound wound healing [6–8, 10, 12, 37–39]. …”

Section: Discussionmentioning

confidence: 99%

Osteonecrosis of the jaws (ONJ) in mice after extraction of teeth with periradicular disease

Soundia

Hadaya

Esfandi

et al. 2016

Bone

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Osteonecrosis of the jaws (ONJ) is a complication of antiresorptive medications, such as denosumab or bisphosphonates, prescribed to patients with bone malignancy or osteoporosis. The most common instigating local factor in ONJ pathogenesis is tooth extraction. However, in adults the great majority of teeth are extracted due to dental disease. Here, we have investigated alveolar bone healing after extraction of healthy teeth or teeth with naturally occurring periradicular disease in mice treated with high dose zoledronic acid (ZA), a potent bisphosphonate, or OPG-Fc, a RANKL inhibitor. C57BL/6 mice were treated for eight weeks and in vivo micro-CT was performed to identify spontaneously occurring periradicular lesions around the roots of maxillary molars. Then, extractions of molars with and without dental disease were performed in all groups. Four weeks later, animals were euthanized and maxillae were dissected and analyzed. Clinically, all vehicle animals with extraction of healthy or diseased teeth, and most OPG-Fc or ZA animals with extraction of healthy teeth showed normal mucosal healing. On the contrary, most animals with OPG-Fc or ZA treatment and extraction of diseased teeth demonstrated impaired healing with visible mucosal defects. Radiographically, bone socket healing was significantly compromised in OPG-Fc and ZA-treated mice with periradicular disease in comparison to other groups. Histologically, all vehicle animals showed normal mucosal healing and socket remodeling. OPG-Fc and ZA animals with extraction of healthy teeth showed normal mucosal healing, woven bone formation in the socket, and decreased remodeling of the original socket confines. OPG-Fc and ZA animals with extraction of diseased teeth showed mucosal defects, persistent prominent inflammatory infiltrate, bone exposure and areas of osteonecrosis. These findings support that dental disease is critical in the pathogenesis of ONJ, not only as the instigating cause for tooth extraction, but also as a compounding factor in ONJ development and pathophysiology.

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“…Interestingly, before the first case series of bisphosphonateassociated ONJ (Marx, 2003;Migliorati, 2003) and before recent animal models (Allen, 2009;Hokugo et al, 2010;Kikuiri et al, 2010;Pautke et al, 2012;Kuroshima and Yamashita, 2013) were published, the same jawbone pathology was described in an animal model by Gotcher and Jee (1981). Soon after the first publications of ONJ, a similarity of this pathology to the historical 'phossy jaw' was recognized (Miles, 1972;Abu-Id et al, 2008;Marx, 2008).…”

Section: Medication-related Osteonecrosis Of the Jawmentioning

confidence: 86%

Surgical treatment of bisphosphonate-associated osteonecrosis: Prognostic score and long-term results

Reich

Bilkenroth²,

Schubert

et al. 2015

Journal of Cranio-Maxillofacial Surgery

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Chemotherapeutic and antiresorptive combination therapy suppressed lymphangiogenesis and induced osteonecrosis of the jaw-like lesions in mice

Cited by 44 publications

References 49 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

Osteonecrosis of the jaws (ONJ) in mice after extraction of teeth with periradicular disease

Surgical treatment of bisphosphonate-associated osteonecrosis: Prognostic score and long-term results

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