Periapical Disease and Bisphosphonates Induce Osteonecrosis of the Jaws in Mice

Abstract

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 utilizing 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 utilizing 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 executed. Periapical lesions were larger in vehicle- vs. 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 TRAP+ cell numbers was observed, but round, detached, and removed from the bone surface cells were present in BP animals. Although 88% of the BP 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.

Experimental osteonecrosis: development of a model in rodents administered alendronate

“…However, there is no standard BRONJ experimental model, since most models fail to reproduce clinical reality and do not associate several co-factors that undertake a reliable cause-effect relationship between Bps and disease pathogenesis. 6,7,8,9,15,16,17,18,19,20,21,22,23,24 To the best of our knowledge, this is the first study to demonstrate 100% of BRONJ-like lesions by associating tooth extractions with alendronate in cumulative dosages for the management of rheumatic diseases. 12 The first advantage of our experimental model is the high percentage of bone necrosis achieved.…”

“…12 The first advantage of our experimental model is the high percentage of bone necrosis achieved. The rate of bone lesions in previously published experimental models varies from 0 to 100%, 6,7,8,9,15,16,17,18,19,20,21,22,23,24 and only four papers have reported 100% of BRONJ-like lesions. 8,9,17,18 However, models that reported a bone lesion rate of 100% were developed by exposing animals to supra-therapeutic dose regimens 9,17 or to a high-intensity trauma, 8,18 which represents an artificial scenario.…”

“…20,24 Furthermore, most experimental models reproduced oncologic schedules with high dosages of zolendronate. 7,8,15,16,18,21,22,23,25 However, although zolendronate is undeniably important, it is essential to note that ALN is among the most common Bps prescribed worldwide and is specifically indicated for the treatment of benign diseases, such as osteoporosis, osteopenia, and rheumatic diseases. 1 In this context, to compensate for the differences in potency between alendronate and zolendronate, as well as for the lower plasma concentrations when the subcutaneous route rather than the intravenous route is used, 26 we conclude that the total Bps dose administered over a long period of time is important for the magnitude of the reduction in bone turnover.…”

“…31 Although some authors have demonstrated spontaneous BRONJ lesions, 9 a local trigger factor seems highly relevant to the induction of this disease in animal models. The main local agents include periodontal disease, 15,23 bacterial injections in addition to bone defects, 22 and tooth extractions. 9,16,17,18,19,20,21,24,25,26 The last is undoubtedly the most relevant, since most patients develop BRONJ lesions after tooth extractions, as described in clinical studies.…”

Effects of Zoledronic Acid in Experimental Periapical Lesions in Rats: An Imaging and Histological Analysis

“…However, they did not diagnose any ulcers or osteonecrosis. On the other hand, Kang et al (11) evaluated the effect of zoledronic acid on periapical lesions in rats and found BRONJ cases in these animals.…”