Periodontal disease and bisphosphonates induce osteonecrosis of the jaws in the rat

Abstract

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.

Severe compromise of preosteoblasts in a surgical mouse model of bisphosphonate-associated osteonecrosis of the jaw

“…The variable reproduction of osteonecrotic-like changes have been also reported in different murine models of ONJ and seems to be associated with the degree of surgical trauma (Marino et al 2011). Otherwise, empty lacunae, the other key feature in human and experimental osteonecrotic diseases (Okazaki et al 2009;Aghaloo et al 2011), were recognized widely in the bone sequestra and selectively in the superficial layer of submucosal bone in the alveolar socket. Interestingly, the number of empty lacunae in the submucosal bone significantly increased after long-term treatment, suggesting that this finding may be associated with the cumulative doses fixed in the alveolar bone.…”

“…Otherwise, empty lacunae, the other key feature in human and experimental osteonecrotic diseases (Okazaki et al 2009;Aghaloo et al 2011), were recognized widely in the bone sequestra and selectively in the superficial layer of submucosal bone in the alveolar socket.…”

Teriparatide and the treatment of bisphosphonate-related osteonecrosis of the jaw: a rat model

“…22 It was shown that, especially in the mandible, with progression of the severity of the BRONJ lesion, formation of new periostal bone increases. 20,22,23 In a periodontal disease induced BRONJ rat model, Aghaloo et al 24 reported increased periosteal new bone formation and wider alveolar bone on microCT images. Intermittent parathyroid hormone administration was also shown to induce an increase in alveolar bone formation in rats.…”

The Effect of Bisphosphonates and Low-Dose Doxcycline Therapy in Diabetics With Periodontitis: A Review

“…BRONJ in patients taking oral BPs for osteoporosis is rare, estimated at 0.001% to 0.1%. 78 The pathogenesis of BRONJ is not completely defined, but currently, two main hypothesis explain the mechanism for the complication of BP therapy. The first explains the pathology in terms of the osteoclastic-inhibiting effect of this class of drug on the cessation of bone remodelling and bone turnover.…”