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  • br Acknowledgments The authors would like to thank Sarah Mac

    2019-05-09


    Acknowledgments The authors would like to thank Sarah Mack for technical assistance with the histology and IHC. We would also like to acknowledge Dr. Gregory Dieudonne in the Department of Musculoskeletal Radiology, University of Rochester Medical Center for advice and assistance in manuscript writing; Dr. Houjing Huang in the Department of Hygiene and Statistics, Zunyi Medical University for advice and assistance in statistic analysis; Dr. Zhengyuan Xian in the Department of Radiology, First Affiliated Hospital of Zunyi Medical University for advice in CT scan protocol and image analysis. National Nature Science Foundation of China award NSFC81260280/H0606, the Orthopaedic Research and Education Foundation, the National Institutes of Health PHS awards AR061307 and AR54041, and University of Rochester Wilmot Cancer Center in USA. This work was supported by research grants from the National Nature Science Foundation of China award NSFC81260280, the Orthopaedic Research and Education Foundation, the National Institutes of Health PHS awards AR061307 and AR54041, and University of Rochester Wilmot Cancer Center in USA.
    Introduction Osteonecrosis of the jaw (ONJ) emerged as a well-known devastating side effect of parenteral bisphosphonate therapy since the widespread use of biphosphonates to reduce skeletal related events (SRE) [1]. Biphosphonates are commonly used every three to four weeks with around 14–48% reduction of SRE occurrence and ONJ occurrence in 1.2–3.8% despite preventive measures [2–5]. Although the positive results of 4 different trials, the use of biyearly biphosphonates regimens to reduce AIBL is NOT approved [6–9]. This spaced interval of six months achieved an increase in median bone mineral density of 2.7–4.3% in the lumbar spine and 1.6–1.7% in the hip when used in post-menopausal women receiving adjuvant hormonal aromatase inhibitor [7,8]. However, the risk of developing ONJ with the bi-annually regimen of zoledronic histone deacetylase inhibitors is not well recognized.
    Material and methods
    Results The upfront biyearly regimen of zoledronic acid significantly increased bone mineral density (BMD) in postmenopausal women receiving aromatase inhibitors for early breast cancer [6–9]. The Z-FAST trial enrolled 602 postmenopausal women with early hormone receptor-positive breast cancer receiving adjuvant letrozole [6]. Patients were randomized equally to receive upfront or delayed zoledronic acid with a 4mg intravenous regimen every 6 months for 5 years. The investigators reported two cases of ONJ in the upfront group during the 60 months follow-up. However, an ONJ adjudication committee deemed one of the cases inconsistent with ONJ and the other one indeterminate because of insufficient information [6]. The ZO-FAST trial recruited 1065 postmenopausal women receiving adjuvant letrozole that were randomly assigned to immediate zoledronic acid with a regimen of 4mg every 6 months for 5 years, or delayed administration initiated at fracture occurrence or on-study BMD decrease. A total of nine potential ONJ events from seven patients were reported in this study after 60 months follow up. Each event was independently adjudicated by an external panel that confirmed ONJ occurrence in three cases, deemed possible for insufficient data in two cases, and excluded the remaining cases [7]. Therefore, in the ZO-FAST trial, ONJ occurred in 0.28–0.47%. In the E-ZO-FAST trial, 527 postmenopausal women receiving aromatase inhibitors were randomized to either immediate or delayed zoledronic acid treatment, at 4mg every 6 months. Two reported cases of ONJ of the immediate zoledronic acid group were confirmed by the adjudication committee. At diagnosis, patients had received 3 and 6 doses of zoledronic acid. Treatment was discontinued in both patients but ONJ only resolved in one patient [8]. Accordingly, the E-ZO-FAST trial report ONJ in 0.38%. Finally, the ABCSG-12 trial is the largest study recruiting 1803 patients with early breast cancer receiving zoledronic acid 4mg intravenously every 6 months. There were no confirmed cases of ONJ during a follow up of 84 months [9]. All these studies are summarized in the Table 1.