BISPHOSPHONATE BONE QUALITY IN WOMEN WITH BREAST CANCER

描述（由申请人提供）：双膦酸盐可能降低乳腺癌女性骨转移的发生率，但生存数据不一致。因此，西南肿瘤小组正在开展一项为期3年的临床方案，随机招募6000名妇女，随机分配氯膦酸盐、依邦膦酸盐或唑来膦酸盐，以确定高剂量的双膦酸盐是否能预防骨转移并提高乳腺癌妇女的生存率。剂量是用于治疗骨质疏松症的剂量的两到十倍，高剂量双膦酸盐对这些妇女骨骼健康的影响尚不确定。动物研究表明，高剂量双膦酸盐引起骨微损伤积累和材料特性异常。乳腺癌研究提供了一个特殊的机会来评估双膦酸盐引起的人类骨质量和骨生理的变化。假设高剂量双膦酸盐治疗会导致骨吸收和形成的严重抑制，矿化密度增加，骨的内在韧性下降。在本研究中，90名绝经前妇女将接受四环素标记的髂骨活检，双x线吸收仪测量骨密度，以及双膦酸盐治疗前后骨转换的血清生化标志物。骨将用微型计算机断层扫描测量结构参数，包括连通性、骨体积和皮质厚度。压缩生物力学测试将确定刚度（杨氏模量）、屈服点、韧性和强度。骨表面的组织形态学测量将允许计算骨形成率和激活频率。矿化密度将用背散射电子成像测量。27名妇女将接受18-氟化物PET扫描对骨骼中氟化物沉积的动力学分析。研究结果将为高剂量双膦酸盐对人体骨骼的影响提供有价值的信息。

DESCRIPTION (provided by applicant): Bisphosphonates may reduce the incidence of bone metastases in women with breast cancer, but survival data are inconsistent. The Southwest Oncology Group is therefore conducting a 3 year clinical protocol enrolling 6,000 women with randomization to clodronate, ibandronate or zoledronate to determine whether high doses of these bisphosphonates can prevent bone metastases and improve survival in women with breast cancer. The doses are two to ten times greater than those used to treat osteoporosis, and the effects of high-dose bisphosphonates on the bone health in these women are uncertain. Animal studies have shown that high-dose bisphosphonates caused microdamage accumulation and abnormal material properties of the bone. The breast cancer study provides an exceptional opportunity to evaluate bisphosphonate-induced changes in bone quality and bone physiology in humans. The hypothesis is that high-dose bisphosphonate therapy will result in profound depression of bone resorption and formation, increased mineralization density and decreased intrinsic toughness of the bone. For this proposal, a subset of 90 premenopausal women will undergo tetracycline-labeled iliac crest bone biopsies, bone density measurements by dual x ray absorptimetry and serum biochemical markers of bone turnover before and after bisphosphonate treatment. The bone will be measured with micro-computed tomography for structural parameters including connectivity, bone volume, and cortical thickness. Biomechanical testing in compression will determine the stiffness (Young's modulus), yield point, toughness and strength. Histomorphometric measurements of bone surfaces will allow calculations of bone formation rates and activation frequency. Mineralization density will be measured using backscattered electron imaging. A subset of 27 women will undergo kinetic analysis of fluoride deposition in bone by 18-Fluoride PET scans. Results of the study will provide valuable information about skeletal effects of high-dose bisphosphonates in humans.