A novel animal model to study non‐spontaneous bisphosphonates osteonecrosis of jaw

Abstract

The aim of this study was to evaluate a novel animal model of bisphosphonates-associated osteonecrosis, which realistically recapitulates the same pathological human condition. Five Wistar rats were given intravenous zoledronic acid 0.04 mg once a week for 5 weeks. After 2 weeks, the animals underwent the extraction of an upper molar, producing a 4 mm-diameter bone defect on the same site. After 7 weeks from the extraction, the animals were clinically examined and a bone scintigraphy was carried out. After an additional week, the rats were killed and both Computerized Tomography and histological analysis were performed. Five rats, not treated with zoledronic acid and exposed to the same surgical treatment, were used as controls. At 7 weeks after the extraction, all the rats treated with zoledronic acid showed expansion of the defect and bone exposure. These features were confirmed by bone scintigraphy. The rats of the control group demonstrated epithelialization of the bone defect and a normal uptake of the contrast medium during the scan. The Computerized Tomography scan disclosed irregularity of the cortical margin and bone destruction, which were not evident in the control group. On microscopy, the samples showed necrotic bone, loss of osteocytes and peripheral resorption without inflammatory infiltrate, while the controls showed normal bone healing. The rat treated with zoledronic acid can be considered a novel, reliable and reproducible animal model to understand better the pathophysiology of osteonecrosis of the jaw and to develop a therapeutic approach.

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.…”

“…4,5 Thus, the effects of Bps therapy on the healing of alveolar sockets have been the focus of several in vivo studies. 6,7,8 Recently, we demonstrated the development of BRONJ-like lesions in rodents by associating tooth extractions with daily high dosages of alendronate (ALN) in a long-term study. 9 However, studies using lower dosages of Bps showed only a transient impairment of alveolar socket healing after tooth extractions.…”

“…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.…”

Collagen sponge and rhBMP-2 improve socket healing in rats treated with zoledronic acid

“…2 This has a significant influence on the patients' quality of life, 3 although a small percentage of patients develop osteonecrosis of the jaw spontaneously. 4,5 Osteonecrosis of the jaw associated with antiresorptive agents has also been named antiresorptive agent-related osteonecrosis of the jaw (ARONJ). 6 There is Declaration of Interests: The authors certify that they have no commercial or associative interest that represents a conflict of interest in connection with the manuscript.…”