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

Abstract

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.

Osteoclast profile of medication-related osteonecrosis of the jaw secondary to bisphosphonate therapy: a comparison with osteoradionecrosis and osteomyelitis

“…2a). These morphological features of osteoclasts were also described in animals and patients after bisphosphonate treatment [21, 54, 55]. The bisphosphonate-associated interference in the farnesyl and mevalonate pathway and the consecutive loss of small guanosine triphosphate—binding proteins might explain the detachment of osteoclasts from the bone surface.…”

Zoledronate induces osteonecrosis of the jaw in sheep

“…Voss et al / Journal of Cranio-Maxillo-Facial Surgery xxx (2015) 1e6 4 evolution seems to be frequent (Vescovi et al, 2011). Despite one mouse model that recently showed spontaneous osteonecrosis of the jaw after antiresorptive treatment, no other animal study displayed this phenomenon (de Molon et al, 2014).…”

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

“…The presence of periradicular disease was recorded. The distance from the cemento-enamel junction (CEJ) to the alveolar crest (AC) was measured at the distal surface of the second molar, as previously described [24, 25]. Buccal cortical thickness was measured on axial slices oriented parallel to the occlusal plane, in the area of the 2 nd molar at the level of the apical third of the roots [24, 25].…”

“…It is noteworthy that no experimental intervention was performed in these animals and the ONJ-like lesions, characterized by periosteal bone apposition, osteonecrosis, severe inflammation and bone exposure, developed spontaneously [24]. Here, taking advantage of this ONJ model, we have combined the two methodologies of local risk factors (extraction and dental disease), in association with systemic treatment with two different types of antiresorptives, a BP or a RANKL inhibitor, to more closely replicate the clinical setting and investigate ONJ pathogenesis.…”