骨转移在超过90％的睾丸切除后的前列腺癌患者中发展，是骨微环境和肿瘤细胞之间复杂相互作用的结果。既往的去势疗法（ADT）已知会导致骨丢失，以及预防骨骼并发症的抗吸收类药物zoledronic acid（ZA），可能会影响这些相互作用以及骨髓中分散的肿瘤细胞（DTC）的生长。因此，在人类前列腺癌的自发性转移异种移植瘤模型中进一步优化，以模拟常见的接受ADT（去势）和原发肿瘤切除的临床情况。分析了这些干预措施及其与ZA治疗的单独或联合作用对细胞转移到骨髓和其他远处部位的影响。使用人类特异性Alu-qPCR，生物发光成像（BLI）和免疫组织化学等方法量化了转移负荷。此外，通过静态组织形态学和血清参数评估了骨重塑。 NSG和SCID小鼠之间的初步比较分析表明，NSG小鼠中皮下PC-3异种移植瘤的自发性系统转移明显增强。原发肿瘤的切除和因此延长的观察期导致尸检时较高的总转移细胞负荷，而肿瘤生长本身会导致显著的骨丢失，手术去势进一步加剧了这种状况。此外，去势小鼠的骨转移负荷明显高于未去势的小鼠。每周用ZA治疗小鼠完全防止了去势和肿瘤引起的骨丢失，但对骨转移负荷没有影响。相反，BLI测定的总肺转移负载显着降低了。这些发现为未来研究提供了基础，以探讨ZA在不仅预防骨骼并发症，还在减少对其他器官的转移方面的作用。版权所有©2023年Elsevier Inc.

Bone metastases develop in >90 % of patients with castration-resistant prostate cancer (PCa) through complex interactions between the bone microenvironment and tumor cells. Previous androgen-deprivation therapy (ADT), which is known to cause bone loss, as well as anti-resorptive agents such as zoledronic acid (ZA), used to prevent skeletal complications, may influence these interactions and thereby the growth of disseminated tumor cells (DTC) in the bone marrow (BM). Here, a spontaneously metastatic xenograft tumor model of human PCa was further optimized to mimic the common clinical situation of ADT (castration) combined with primary tumor resection in vivo. The effects of these interventions, alone or in combination with ZA treatment, on tumor cell dissemination to the BM and other distant sites were analyzed. Metastatic burden was quantified by human-specific Alu-qPCR, bioluminescence imaging (BLI), and immunohistochemistry. Further, bone remodeling was assessed by static histomorphometry and serum parameters. Initial comparative analysis between NSG and SCID mice showed that spontaneous systemic dissemination of subcutaneous PC-3 xenograft tumors was considerably enhanced in NSG mice. Primary tumor resection and thereby prolonged observational periods resulted in a higher overall metastatic cell load at necropsy and tumor growth alone caused significant bone loss, which was further augmented by surgical castration. In addition, castrated mice showed a strong trend towards higher bone metastasis loads. Weekly treatment of mice with ZA completely prevented castration- and tumor-induced bone loss but had no effect on bone metastasis burden. Conversely, the total lung metastasis load as determined by BLI was significantly decreased upon ZA treatment. These findings provide a basis for future research on the role of ZA not only in preventing skeletal complications but also in reducing metastasis to other organs.Copyright © 2023. Published by Elsevier Inc.