Establishment of an Animal Model of Bisphosphonate-Related Osteonecrosis of the Jaws in Spontaneously Diabetic Torii Rats

Takaoka, Kazuki; Yamamura, Mitsuhiro; Nishioka, Toshihiro; Abe, Tetsuya; Tamaoka, Joji; Segawa, Emi; Shinohara, Masami; Ueda, Hiroyuki; Kishimoto, Hiroyuki; Urade, Masahiro

doi:10.1371/journal.pone.0144355

Cited by 15 publications

(11 citation statements)

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“…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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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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“… 27 – 31 The tissues investigated were bone, oral mucosa, periodontium, and blood vessel supply. 23 , 24 , 32 – 43 The studies differed in the type of BP used as well as the route of application. 25 , 44 – 49 Only 2 studies analyzed non-N-BPs (clodronate at 20 mg/kg and etidronate at 5 mg/kg); the remaining 44 trials used N-BPs with zoledronate (0.01–0.6 mg/kg) being the most commonly used (30 studies), followed by alendronate (0.01–1 mg/kg) (14 studies), pamidronate (0.01–3 mg/kg) (5 studies), and ibandronate (0.003–0.3 mg/kg) and risedronate (0.1–1 mg/kg) (1 study each).…”

Section: Resultsmentioning

confidence: 99%

Pathogenesis of medication-related osteonecrosis of the jaw: a comparative study of in vivo and in vitro trials

et al. 2018

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ObjectiveThis study was performed to determine whether the results of prevailing in vivo and in vitro studies offer a reliable model for investigation of medication-related osteonecrosis of the jaw (MRONJ).MethodsEmbase, Medline, and the Cochrane Library were searched for articles published from September 2003 to June 2017 involving experimental approaches to the pathogenesis of MRONJ. In vivo and in vitro trials were analyzed with respect to the scientific question, study design, methodology, and results.ResultsOf 139 studies, 87, 46, and 6 conducted in vivo, in vitro, and both in vivo and in vitro experiments, respectively. Rats, mice, dogs, minipigs, sheep, and rabbits were the preferred animal models used. Osteoblasts, osteoclasts, fibroblasts, keratinocytes, macrophages, and human umbilical vein endothelial cells were the preferred cell types. Zoledronate, alendronate, ibandronate, and risedronate were the most frequent bisphosphonates used. MRONJ was most reliably induced in minipigs because of the close relationship with human bone physiology. In vitro studies showed that reduced viability, growth, and migration of cells in the bone and soft tissues were causative for MRONJ. Other than exposed jawbone after tooth extraction, no reliable cofactors were found.ConclusionThe minipig is the most suitable animal model for MRONJ.

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“…However, necrotic bone persists in the region because of osteoclast suppression by ZOL. This is why dentoalveolar surgery is a risk factor for the development of BRONJ in patients receiving BPs (16). Empty osteocyte lacunae in the alveolar bone and palatal bone were increased by single treatment with ZOL or BSO, but not significantly.…”

Section: Discussionmentioning

confidence: 99%

“…Tartrate-resistant acid phosphatase (TRAP) staining was performed as described previously (16). Briefly, samples were placed in 0.2 M acetate buffer [0.2 M sodium acetate and 50 mM L(+) tartaric acid in double-distilled water; pH 5.0] for 20 min at room temperature.…”

Section: Methodsmentioning

confidence: 99%

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Osteonecrosis of the jaws caused by bisphosphonate treatment and oxidative stress in mice

et al. 2018

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Aging is a significant risk factor for the development of bisphosphonate-related osteonecrosis of the jaws (BRONJ). Accumulating evidence suggests that bone aging is associated with oxidative stress (OS), and OS is associated with osteonecrosis. To elucidate the mechanisms of the onset of BRONJ, the present study focused on OS and the effects of treatment with the pro-oxidant DL-buthionine-(S,R)-sulfoximine (BSO), an oxidative stressor, on healing of a surgically induced penetrating injury of the palate. Six-week-old C57BL/6J mice were randomly divided into four groups (n=5 each) and treated with or without zoledronic acid (ZOL) and with or without BSO (experimental groups: ZOL, BSO, and ZOL+BSO; control group: saline solution). A penetrating injury of the midline palate was surgically created using a root elevator. ZOL (250 µg/kg/day) was injected intraperitoneally every day from 7 days prior to the surgical treatment to 4 days following the surgical treatment. BSO (500 µg/kg/day) was administered 7 days prior to the surgical treatment as a single intraperitoneal injection. The maxillae were harvested at 5 days following the surgical treatment for histological and histochemical studies. The presence of empty osteocyte lacunae in the palatal bone was increased by ZOL and BSO treatment. The highest number of empty osteocyte lacunae was observed in the ZOL+BSO group. The number of tartrate-resistant acid phosphatase-positive cells was decreased by ZOL treatment and increased by BSO treatment. The number of canaliculi per osteocyte lacuna was significantly decreased by BSO treatment. The mineral apposition rate was significantly lower in the treatment groups than the control group. Bisphosphonates and OS suppressed bone turnover. The present study has demonstrated that BSO treatment affects osteocytes, and OS in osteocytes exacerbates impairment of the osteocytic canalicular networks. As a result, bisphosphonates and OS may induce osteonecrosis following invasive dentoalveolar surgery. OS has been identified as an additional risk factor for the development of BRONJ.

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Establishment of an Animal Model of Bisphosphonate-Related Osteonecrosis of the Jaws in Spontaneously Diabetic Torii Rats

Cited by 15 publications

References 49 publications

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

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

Pathogenesis of medication-related osteonecrosis of the jaw: a comparative study of in vivo and in vitro trials

Osteonecrosis of the jaws caused by bisphosphonate treatment and oxidative stress in mice

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