Abstract
Necrotic bone exposure in the oral cavity has recently been reported in patients treated with nitrogen-containing bisphosphonates as part of their therapeutic regimen for multiple myeloma or metastatic cancers to bone. It has been postulated that systemic conditions associated with cancer patients combined with tooth extraction may increase the risk of osteonecrosis of the jaw (ONJ). The objective of this study was to establish an animal model of bisphosphonate-related ONJ by testing the combination of these risk factors. The generation of ONJ lesions in rats resembling human disease was achieved under the confluence of intravenous injection of zoledronate (ZOL; 35 µg/kg every 2 weeks), maxillary molar extraction, and vitamin D deficiency [VitD(−)]. The prevalence of ONJ in the VitD(−)/ZOL group was 66.7%, which was significantly higher (p < .05, Fisher exact test) than the control (0%), VitD(−) (0%), and ZOL alone (14.3%) groups. Similar to human patients, rat ONJ lesions prolonged the oral exposure of necrotic bone sequestra and were uniquely associated with pseudoepitheliomatous hyperplasia. The number of terminal deoxynucleotidyl transferase–mediated deoxyuridine triphosphate–biotin nick-end label–positive (TUNEL+) osteoclasts significantly increased on the surface of post–tooth extraction alveolar bone of the VitD(−)/ZOL group, where sustained inflammation was depicted by [18F]fluorodeoxyglucose micro-positron emission tomography (µPET). ONJ lesions were found to be associated with dense accumulation of mixed inflammatory/immune cells. These cells, composed of neutrophils and lymphocytes, appeared to juxtapose apoptotic osteoclasts. It is suggested that the pathophysiologic mechanism(s) underpinning ONJ may involve the interaction between bisphosphonates and compromised vitamin D functions in the realm of skeletal homeostasis and innate immunity. © 2010 American Society for Bone and Mineral Research.
Highlights
Nitrogen-containing bisphosphonates (BPs), synthetic analogues of pyrophosphate, are effective in treatment of hypercalcemia of malignancy, osteolytic lesions in multiple myeloma, and bone metastases from solid tumors, including breast cancer and hormone-independent prostate cancer.[1]. Serious complications are relatively rare but include acute systemic inflammatory reaction, renal failure, and electrolyte imbalance.[2] a new concern is raised by the recent reports of osteonecrosis of the jaw (ONJ) in patients treated with these drugs.[3,4,5] Estimates of the cumulative incidence of ONJ from retrospective case reports and reviews[5,6,7,8] are as high as 10% among patients treated with BP intravenous infusions
The American Society for Bone and Mineral Research (ASBMR) Task Force proposed the provisional case definition of ONJ as an area of exposed bone in the maxillofacial region that did not heal within 8 weeks in a patient who had been exposed to BPs.[10]. ONJ typically is described as a failure of wound healing in the oral
Most ONJ lesions are observed in patients presenting a primary diagnosis of multiple myeloma or breast cancer.[5,9,14] A survey of multiple myeloma patients revealed that 40% had vitamin D deficiency ( 36 nmol/L) and 35% had vitamin D insufficiency (36 to 75 nmol/L).(15) Vitamin D insufficiency (< 50 nmol/L) was reported for 30.2% of breast cancer patients.[16] the vitamin D status of ONJ patients has not been established,(17,18) the high-risk populations for ONJ appear to overlap with those with inadequate vitamin D levels
Summary
Nitrogen-containing bisphosphonates (BPs), synthetic analogues of pyrophosphate, are effective in treatment of hypercalcemia of malignancy, osteolytic lesions in multiple myeloma, and bone metastases from solid tumors, including breast cancer and hormone-independent prostate cancer.[1] Serious complications are relatively rare (ranging from 0.1% to 1.8%) but include acute systemic inflammatory reaction, renal failure, and electrolyte imbalance.[2] a new concern is raised by the recent reports of osteonecrosis of the jaw (ONJ) in patients treated with these drugs.[3,4,5] Estimates of the cumulative incidence of ONJ from retrospective case reports and reviews[5,6,7,8] are as high as 10% among patients treated with BP intravenous infusions. The implication of a role for vitamin D in ONJ is further seen in a prospective clinical study reporting that patients who exhibited significantly elevated serum levels of immunoreactive parathyroid hormone (iPTH) (likely owing to vitamin D insufficiency) prior to and throughout BP treatment eventually developed ONJ. It was found that ONJ lesions developed most frequently in rats with all three risk factors
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