PDF(Pubmed)
Abstract：
Radium 223 (Ra-223) is an α-emitting bone-homing radiopharmaceutical that targets tumor-induced osteoblasts and is used to reduce bone pain and prolong overall survival in men with bone-metastatic, castrate-resistant prostate cancer. However, increased fracture risk in skeletal sites with no bone metastasis has been observed in patients treated with Ra-223. Both luciferase- or green fluorescence protein (GFP)-labeled osteoblast reporter mice were used to monitor the effect of Ra-223 on resident osteoblasts and normal bone structure. Upon Ra-223 treatment, 70% of resident osteoblasts were reduced within 2 days, and the osteoblast reduction lasted for at least 18 weeks without detectable recovery, as measured by in vivo bioluminescent imaging. In GFP-labeled osteoblast reporter mice, Ra-223 mainly reduced osteoblasts localized in the trabecular bone areas; the osteoblasts in the growth plates were less affected. Micro-computed tomography analyses showed that Ra-223 significantly reduced bone mineral density and bone microstructure in the trabecular area of femurs but not in the cortical bone. Tumor-induced bone was generated by inoculating osteogenic TRAMP-BMP4 prostate cancer cells into the mouse femurs; Ra-223 treatment significantly reduced tumor-induced osteoblasts. Our study shows that Ra-223 affects bone structures that are not involved in bone metastasis. Strategies that improve bone health may reduce fracture risk in patients receiving Ra-223.
摘要：
镭223（Ra-223）是一种α发射的骨归巢放射性药物，靶向肿瘤诱导的成骨细胞，用于减轻骨转移男性的骨痛和延长整体生存期。去势抵抗前列腺癌.然而,在接受Ra-223治疗的患者中，观察到没有骨转移的骨骼部位骨折风险增加。荧光素酶或绿色荧光蛋白（GFP）标记的成骨细胞报告小鼠均用于监测Ra-223对常驻成骨细胞和正常骨结构的影响。Ra-223处理后，70%的常驻成骨细胞在2天内减少，成骨细胞减少持续了至少18周，没有可检测到的恢复，通过体内生物发光成像测量。在GFP标记的成骨细胞报告小鼠中，Ra-223主要减少位于小梁骨区的成骨细胞；生长板中的成骨细胞受影响较小。显微计算机断层扫描分析显示，Ra-223显着降低了股骨小梁区域的骨矿物质密度和骨微结构，但未降低皮质骨。通过将成骨TRAMP-BMP4前列腺癌细胞接种到小鼠股骨中来产生肿瘤诱导的骨;Ra-223处理显著减少了肿瘤诱导的成骨细胞。我们的研究表明，Ra-223会影响与骨转移无关的骨骼结构。改善骨骼健康的策略可以降低接受Ra-223的患者的骨折风险。
