BISPHOSPHONATE BONE QUALITY IN WOMEN WITH BREAST CANCER

描述（由申请人提供）：双膦酸盐可降低乳腺癌女性骨转移的发生率，但生存数据不一致。因此，西南肿瘤组正在进行一项为期3年的临床研究，招募6,000名妇女，随机接受氯膦酸盐、伊班膦酸盐或唑来膦酸盐治疗，以确定高剂量的这些双膦酸盐是否可以预防骨转移并改善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2至10倍，高剂量双膦酸盐对这些女性骨骼健康的影响尚不确定。动物研究表明，高剂量的双膦酸盐会导致骨的微损伤积累和异常的材料特性。乳腺癌研究提供了一个特殊的机会，以评估双膦酸盐诱导的骨质量和骨生理学的变化在人类。假设高剂量双膦酸盐治疗将导致骨吸收和形成的深度抑制，矿化密度增加和骨的内在韧性降低。对于该提议，90名绝经前女性的子集将在双膦酸盐治疗前后接受四环素标记的髂嵴骨活检、双能X射线吸收法骨密度测量和骨转换的血清生化标志物。将使用微型计算机断层扫描测量骨骼的结构参数，包括连接性、骨体积和皮质厚度。压缩中的生物力学测试将确定刚度（杨氏模量）、屈服点、韧性和强度。骨表面的组织形态测量将允许计算骨形成速率和激活频率。矿化密度将使用背散射电子成像测量。27名妇女的一个子集将通过18-氟化物PET扫描进行骨骼中氟化物沉积的动力学分析。研究结果将提供有关高剂量双膦酸盐对人体骨骼影响的有价值的信息。

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.