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Background: Medication related osteonecrosis of the jaws (MRONJ), a rare side-effect of antiresorptive medications, is described as exposed bone in the oral cavity that lasts for at least 8 weeks. Most studies report a female predilection for MRONJ; these findings could be due to the increased use of antiresorptives in females, or due to inherent differences between male versus female patients., Purpose: The purpose of this study was to measure and compare the incidence and severity of osteonecrosis of the jaws (ONJ) between male and female mice., Study Design, Setting, Sample: We designed a randomized in-vivo animal study utilizing male and female mice treated with zoledronic acid (ZA). Experimental periodontitis was induced in 24 male and 24 female mice using a silk ligature following administration of saline or a potent bisphosphonate. After 8 weeks, animals were evaluated radiographically and histologically., Independent Variable: The independent variables were sex (male vs female) and treatment group (ZA vs saline control). Treatment was randomly assigned with balanced distribution between male and female animals., Main Outcome Variable: The main outcome variable was ONJ status coded as present or absent. ONJ was defined as present if there was histologic contact between the ligature and the alveolar bone. Secondary outcomes of interest were radiographic and histologic parameters., Analysis: Statistical differences were analyzed using a two-way analysis of variance with Tukey's post hoc test using a P value of 0.05 for significance., Results: The final sample was composed of 24 vehicle treated and 24 ZA treated animals. In vehicle treated animals, 8% of female and 8% of male animals developed ONJ. In ZA treated animals, 83% of female and 92% of male animals developed ONJ. Sex was not associated with the risk (measured as incidence of disease) for developing ONJ or in the radiographic or histologic parameters that were assessed (P values >.1)., Conclusions: Sex does not appear to affect the incidence of MRONJ or the severity of the disease as assessed by the radiographic and histologic parameters., (Copyright © 2024 American Association of Oral and Maxillofacial Surgeons. Published by Elsevier Inc. All rights reserved.)

A majority of patients with orofacial cleft deformity requires cleft repair through a bone graft. However, elevated amount of bone resorption and subsequent bone graft failure remains a significant clinical challenge. Bisphosphonates (BPs), a class of anti-resorptive drugs, may offer great promise in enhancing the clinical success of bone grafting. In this study, we compared the effects of systemic and local delivery of BPs in an intraoral bone graft model in rats. We randomly divided 34 female 20-week-old Fischer F344 Inbred rats into four groups to repair an intraoral critical-sized defect (CSD): (1) Control: CSD without graft (n = 4); (2) Graft/Saline: bone graft with systemic administration of saline 1 week post-operatively (n = 10); (3) Graft/Systemic: bone graft with systemic administration of zoledronic acid 1 week post-operatively (n = 10); and (4) Graft/Local: bone graft pre-treated with zoledronic acid (n = 10). At 6-weeks post-operatively, microCT volumetric analysis showed a significant increase in bone fraction volume (BV/TV) in the Graft/Systemic (62.99 ±14.31%) and Graft/Local (69.35 ±13.18%) groups compared to the Graft/Saline (39.18±10.18%). Similarly, histological analysis demonstrated a significant increase in bone volume in the Graft/Systemic (78.76 ±18.00%) and Graft/Local (89.95 ±4.93%) groups compared to the Graft/Saline (19.74±18.89%). The local delivery approach resulted in the clinical success of bone grafts, with reduced graft resorption and enhanced osteogenesis and bony integration with defect margins while avoiding the effects of BPs on peripheral osteoclastic function. In addition, local delivery of BPs may be superior to systemic delivery with its ease of procedure as it involves simple soaking of bone graft materials in BP solution prior to graft placement into the defect. This new approach may provide convenient and promising clinical applications towards effectively managing cleft patients.

Osteonecrosis of the jaws (ONJ) is a significant complication of antiresorptive medications, such as bisphosphonates and denosumab. Antiresorptive discontinuation to promote healing of ONJ lesions remains highly controversial and understudied. Here, we investigated whether antiresorptive discontinuation alters ONJ features in mice, employing the potent bisphosphonate zoledronic acid (ZA) or the receptor activator of NF-κB ligand (RANKL) inhibitor OPG-Fc, utilizing previously published ONJ animal models. Mice were treated with vehicle (veh), ZA, or OPG-Fc for 11 weeks to induce ONJ, and antiresorptives were discontinued for 6 or 10 weeks. Maxillae and mandibles were examined by μCT imaging and histologically. ONJ features in ZA and OPG-Fc groups included periosteal bone deposition, empty osteocyte lacunae, osteonecrotic areas, and bone exposure, each of which substantially resolved 10 weeks after discontinuing OPG-Fc but not ZA. Full recovery of tartrate-resistant acid phosphatase-positive (TRAP+) osteoclast numbers occurred after discontinuing OPG-Fc but not ZA. Our data provide the first experimental evidence demonstrating that discontinuation of a RANKL inhibitor, but not a bisphosphonate, reverses features of osteonecrosis in mice. It remains unclear whether antiresorptive discontinuation increases the risk of skeletal-related events in patients with bone metastases or fracture risk in osteoporosis patients, but these preclinical data may nonetheless help to inform discussions on the rationale for a "drug holiday" in managing the ONJ patient., Competing Interests: All other authors state that they do not have any conflicts of interest., (© 2015 American Society for Bone and Mineral Research.)

Purpose: Bisphosphonates (BPs) are widely used for the management of bone diseases such as osteoporosis and bone malignancy. However, osteonecrosis of the jaws (ONJ) is a serious complication of BP treatment. ONJ lesions mainly occur after extraction of teeth deemed unrestorable or around teeth with active periodontal or periapical disease. Because socket healing or dental disease shows higher bone turnover, the authors hypothesized that preferentially high BP accumulation would be observed in these areas., Materials and Methods: The authors tested the uptake of fluorescein-labeled zoledronic acid (5-FAM-ZOL) in sites of tooth extraction or experimental periapical disease in mice. Maxillary molars were extracted or the crowns of mandibular molars were drilled to induce pulp exposure. Animals were injected with 5-FAM-ZOL 200 μg/kg at various times after intervention and fluorescence was measured at healthy versus intervention sites. Fluorescein injections were used as controls. Data were analyzed by t test and mixed effects linear models were constructed because the animals had repeated measurements over time and at the 2 sites., Results: A statistically significant (P≤.001 to .002) time-dependent uptake of 5-FAM-ZOL was detected in the areas of extraction socket and in the alveolar ridge around teeth with periapical disease compared with the healthy contralateral sites of the same animals. For the 2 conditions, the uptake reached a maximum 3 days after experimental intervention and decreased thereafter., Conclusions: These data suggest that sites with increased bone turnover, such as extraction sites or areas of periapical inflammation, are exposed to higher BP doses than the remaining alveolar ridge and could explain, at least in part, the susceptibility of such areas to ONJ., (Copyright © 2014. Published by Elsevier Inc.)

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., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Osteonecrosis of the jaw (ONJ) is a well-recognized complication of antiresorptive medications, such as bisphosphonates (BPs). Although ONJ is most common after tooth extractions in patients receiving high-dose BPs, many patients do not experience oral trauma. Animal models using tooth extractions and high BP doses recapitulate several clinical, radiographic, and histologic findings of ONJ. We and others have reported on rat models of ONJ using experimental dental disease in the absence of tooth extraction. These models emphasize the importance of dental infection/inflammation for ONJ development. Here, we extend our original report in the rat, and present a mouse model of ONJ in the presence of dental disease. Mice were injected with high dose zoledronic acid and pulpal exposure of mandibular molars was performed to induce periapical disease. After 8 weeks, quantitative and qualitative radiographic and histologic analyses of mouse mandibles were done. Periapical lesions were larger in vehicle-treated versus BP-treated mice. Importantly, radiographic features resembling clinical ONJ, including thickening of the lamina dura, periosteal bone deposition, and increased trabecular density, were seen in the drilled site of BP-treated animals. Histologically, osteonecrosis, periosteal thickening, periosteal bone apposition, epithelial migration, and bone exposure were present in the BP-treated animals in the presence of periapical disease. No difference in tartrate-resistant acid phosphatase (TRAP)+ cell numbers was observed, but round, detached, and removed from the bone surface cells were present in BP-treated animals. Although 88% of the BP-treated animals showed areas of osteonecrosis in the dental disease site, only 33% developed bone exposure, suggesting that osteonecrosis precedes bone exposure. Our data further emphasize the importance of dental disease in ONJ development, provide qualitative and quantitative measures of ONJ, and present a novel mouse ONJ model in the absence of tooth extraction that should be useful in further exploring ONJ pathophysiological mechanisms., (Copyright © 2013 American Society for Bone and Mineral Research.)

Bisphosphonates (BPs) are medications used commonly to treat primary and metastatic bone cancer, as well as osteoporosis. Although BPs improve bone mineral density, reduce fracture risk, and reduce hypercalcemia of malignancy, some patients develop BP-related osteonecrosis of the jaws (BRONJ). This devastating complication is defined as clinically exposed bone in the maxillofacial region for more than 8 weeks. Despite an increasing number of BRONJ cases since first reported, the disease pathophysiology remains largely unknown. Since published studies suggest a significant role for dental disease in the pathophysiology of BRONJ, we developed a BRONJ animal model where aggressive periodontal disease is induced by ligature placement around the crown of the right maxillary first molar in the presence of vehicle (veh) or zoledronic acid (ZA), a potent BP. Ligature placement induced significant alveolar bone loss, which was attenuated by ZA treatment. Osteonecrosis was observed associated with ligature-induced periodontitis in the ZA-treated group. This was seen as sequestration and extensive periosteal alveolar bone formation on micro-computed tomography (µCT) in the ligated site of BP-treated animals. Histologic examination confirmed these findings, seen as necrotic bone with diffuse loss of osteocytes and empty lacunae, rimming of the necrotic bone by squamous epithelium and inflammation, and exposure to the oral cavity. Importantly, the rat lesions were strikingly similar to those of BRONJ patients. Our data suggest that dental disease and potent BP therapy are sufficient for BRONJ development in the rat., (Copyright © 2011 American Society for Bone and Mineral Research.)