文章：

在胫骨内前列腺癌小鼠模型中，唑来膦酸预防镭-223、醋酸阿比特龙和泼尼松联合治疗引起的骨吸收

Zoledronic Acid Prevents Bone Resorption Caused by the Combination of Radium-223, Abiraterone Acetate, and Prednisone in an Intratibial Prostate Cancer Mouse Model

原文发布日期：15 August 2023

DOI: 10.3390/cancers15164115

类型: Article

开放获取: 是

英文摘要：

An increased risk of non-pathological fractures in patients with prostate cancer and bone metastases has been associated with combination treatment with radium-223, abiraterone, and prednisone/prednisolone in the absence of bone-protecting agents. Here, we investigated possible mechanisms leading to this outcome using an intratibial LNCaP model mimicking prostate cancer bone metastases. Male NOD.scid mice were inoculated intratibially with LNCaP prostate cancer cells and treated with vehicle, radium-223, abiraterone, prednisone, zoledronic acid, or their combinations for 28 days. Serum TRACP 5b and PSA levels were measured. Bone structure, quality, and formation rate of non-tumor-bearing and tumor-bearing tibiae were analyzed by microCT, 3-point bending assay, and dynamic histomorphometry, respectively. Radium-223 incorporation into bone was also measured. Radium-223/abiraterone/prednisone combination treatment induced a transient increase in bone resorption indicated by elevated TRACP 5b levels, which was inhibited by concurrent treatment with zoledronic acid. Furthermore, radium-223/abiraterone/prednisone combination reduced periosteal and trabecular new bone formation and the number of osteoblasts, but bone structure or biomechanical quality were not affected. The abiraterone/prednisone treatment decreased radium-223 incorporation into tumor-bearing bone, possibly explaining the lack of additional antitumor efficacy. In conclusion, radium-223/abiraterone/prednisone combination increased bone resorption, which may have been one of the mechanisms leading to an increased fracture risk in patients with mCRPC.

摘要翻译： 

前列腺癌骨转移患者发生非病理性骨折风险增加，与在缺乏骨保护剂的情况下联合使用镭-223、阿比特龙和泼尼松/泼尼松龙相关。本研究通过模拟前列腺癌骨转移的胫骨内LNCaP模型，探讨导致这一结果的潜在机制。雄性NOD.scid小鼠胫骨内接种LNCaP前列腺癌细胞后，分别接受载体对照、镭-223、阿比特龙、泼尼松、唑来膦酸或其联合治疗28天。检测血清TRACP 5b和PSA水平，分别通过显微CT、三点弯曲试验和动态组织形态计量学分析非荷瘤及荷瘤胫骨的骨结构、骨质量和骨形成率，并测定镭-223在骨组织中的沉积量。结果显示，镭-223/阿比特龙/泼尼松联合治疗引起TRACP 5b水平升高，表明骨吸收出现短暂性增强，而同时使用唑来膦酸可抑制此现象。此外，该联合方案降低了骨膜和骨小梁的新骨形成量及成骨细胞数量，但未影响骨结构或生物力学质量。阿比特龙/泼尼松治疗减少了镭-223在荷瘤骨中的沉积，这可能是联合方案未能增强抗肿瘤疗效的原因。综上所述，镭-223/阿比特龙/泼尼松联合治疗增强了骨吸收作用，这可能是导致转移性去势抵抗性前列腺癌患者骨折风险增加的机制之一。

原文链接：

Zoledronic Acid Prevents Bone Resorption Caused by the Combination of Radium-223, Abiraterone Acetate, and Prednisone in an Intratibial Prostate Cancer Mouse Model