DMD, Department of Oral and Maxillofacial Surgery, University Medical Center Hamburg Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany.
Anticancer Res. 2013 Sep;33(9):3917-24.
Since its first description by Marx in 2003, the etiology of bisphosphonate-related osteonecrosis of the jaw (BRONJ) is the subject of numerous scientific discussions for oral and maxillofacial surgeons. Many retrospective studies on its etiology and pathogenesis have been carried out to explain pathological mechanisms; most of them just take a close look at the issue of dosage and application. Recently, attempts have been made, to identify co-factors which might promote the development of BRONJ.
The present study is based on data of 169 patients with osseous metastatic malignancies. All patients received intravenous bisphosphonate therapy. On the basis of medical history, malignancy, and primary treatment, the modality of bisphosphonate therapy, and existing comorbidities and medication were analyzed. The role of immunosuppressive drugs, influence of underlying diseases, and general factors such as age and gender were examined. The predictability of necrotic involvement, influenced by the underlying malignancy and its specific therapy, e.g. radiation and cytostatic therapy were analyzed and statistically evaluated.
A total of 8.9% (n=15) of patients developed BRONJ. The average time between diagnosis of malignancy and BRONJ was 80 months. Nine patients suffered from breast cancer, five had prostate cancer and one renal cancer. Separation into stage and histological subtype did not show any significant correlation, nor did age or gender, to the occurrence of BRONJ. However statistical analysis did show a significant correlation concerning monocytostatic (p=0.0215) and triple-cytostatic therapy (p=0.0137). The majority of patients with BRONJ (60%) received a bisphosphonate therapy including zoledronate. Single application with one bisphosphonate was administered in 28 cases; 44 patients had a medical history of different use of bisphosphonate. Concomitant medication did not suggest possible correlation, nor did accompanying diseases, arterial hypertension (33.33%) or arterial microcirculatory disturbances (20%).
The evaluation of our results is pioneering. The influence of cytostatics and combined therapy of cytotoxic drugs on the pathogenesis of BRONJ is demonstrated here statistically. We confirmed a drug- and dose-dependent occurrence of BRONJ. Further prospective studies should be performed to elucidate the role of tissue perfusion and oxygen saturation, and the influence of immunosuppressive drugs in relation to the occurrence of BRONJ, as well as on wound healing of initial lesions.
自 2003 年 Marx 首次描述以来，双膦酸盐相关性下颌骨坏死（BRONJ）的病因一直是口腔颌面外科医生讨论的热点。许多关于其病因和发病机制的回顾性研究试图解释病理机制；其中大多数只是密切关注剂量和应用问题。最近，有人试图寻找可能促进 BRONJ 发展的共同因素。
本研究基于 169 例骨转移恶性肿瘤患者的数据。所有患者均接受静脉双膦酸盐治疗。根据病史、恶性肿瘤和初始治疗，分析双膦酸盐治疗方式以及并存疾病和用药情况。研究了免疫抑制药物的作用、基础疾病的影响以及年龄和性别等一般因素。检查了基础恶性肿瘤及其特定治疗（如放疗和细胞毒性治疗）对坏死累及的预测性，并进行了统计评估。
共有 8.9%（n=15）的患者发生 BRONJ。从恶性肿瘤诊断到 BRONJ 的平均时间为 80 个月。9 例患者患有乳腺癌，5 例患者患有前列腺癌，1 例患者患有肾癌。分期和组织学亚型的分离没有显示出任何显著的相关性，年龄或性别也与 BRONJ 的发生没有相关性。然而，统计分析确实显示了单核细胞抑制剂（p=0.0215）和三细胞毒性治疗（p=0.0137）之间存在显著相关性。大多数 BRONJ 患者（60%）接受唑来膦酸盐治疗。28 例患者单次应用一种双膦酸盐；44 例患者有不同双膦酸盐应用史。同时用药并未提示可能存在相关性，伴随疾病（33.33%）或动脉微循环障碍（20%）也没有相关性。
我们的评估具有开创性。统计学显示，细胞毒性药物和联合细胞毒性药物治疗对 BRONJ 发病机制的影响。我们证实 BRONJ 的发生与药物和剂量有关。应进一步进行前瞻性研究，以阐明组织灌注和氧饱和度的作用，以及免疫抑制药物在 BRONJ 发生以及初始病变愈合中的作用。
