A Model for Osteonecrosis of the Jaw with Zoledronate Treatment following Repeated Major Trauma

Abstract

This study aims to develop a reproducible rat model for post-traumatic bisphosphonate-related osteonecrosis of the jaw (BRONJ). In our previous studies using dental extraction as an inducing factor, only 30% - 60% of zoledronate-treated animals fulfilled the definition of clinical BRONJ. We modified the zoledronate regimen and introduced repeated surgical extraction to illicit quantifiable BRONJ in all animals. Eighty retired-breeder female Sprague-Dawley rats were divided between the treatment (IV zoledronate; 80 μg/kg/week for 13 weeks) and control (saline) groups. On week 13, the left mandibular first molar was surgically extracted, followed by the second molar a week later. Animals were euthanized at 1-week, 2-weeks, and 8-weeks following extraction. The occurrence and severity of BRONJ were scored in each animal based on gross and MicroCT analysis. Parameters of bone formation and osteoclast functions at the extraction site were compared between groups. All zoledronate-treated animals developed a severe case of BRONJ that fulfilled the clinical definition of the condition in humans. Osteoclast attachment continued to be defective eight weeks after stopping the treatment. There were no signs of kidney or liver toxicity. Our data confirmed that repeated surgical extraction (major trauma) by itself consistently precipitated massive bone necrosis in ZA-treated animals, eliminating the need to induce pre-existing infection or comorbidity. These results will be the basis for further studies examining the in-vivo pathogenesis and prevention of BRONJ.

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.…”

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.…”

“…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. In contrast, we proposed an experimental model that not only achieved 100% of BRONJ-like lesions in rodents, but that also resembled human disease from clinical, radiological, and histological aspects.…”

“…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.…”

“…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. 4,5 This finding could be related to an urgent requirement for wound healing after this surgical procedure, especially during initial phases, and, in the field of Bps, this is worsened since these drugs impair the angiogenesis and resorption process after tooth extractions.…”