Division of Cancer, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, Hammersmith Hospital Campus, London W12 0NN, UK.
Nat Rev Clin Oncol. 2011 Jun;8(6):357-68. doi: 10.1038/nrclinonc.2011.67. Epub 2011 May 10.
Metastatic bone disease (MBD) in advanced-stage cancer increases the risk of intractable bone pain, pathological skeletal fracture, spinal-cord compression and decreased survival. The disease manifestation course during MBD is largely driven by homotypic and heterotypic cellular interactions between invading tumor cells, osteoblasts and osteoclasts. The outcome is a sustained vicious cycle of bone matrix remodeling. Osteoclast-mediated bone degradation and subsequent bone loss are the hallmarks of secondary bone metastases from most solid tumors. An additional complication in prostate cancer is the predominance of osteosclerotic lesions typified by inappropriate bone production. Successful therapeutic strategies for the treatment of osteolytic MBD include the administration of intravenous bisphosphonates or subcutaneous inhibitors of receptor activator of nuclear factor κB ligand (RANKL). Inhibitors of SRC and cABL kinases and cathepsin K are under clinical investigation as potential anti-osteolytics. In contrast to the rapid progress being made in the development of anti-osteolytic therapies, the treatment of osteosclerotic MBD remains restricted to palliative radiotherapy for symptomatic solitary lesions and systemic taxane-based chemotherapy for widespread multiple lesions. This Review discusses the complex pathology of bone lesions in metastatic castration-resistant prostate cancer and focuses on new therapeutic strategies and targets that are emerging in preclinical studies.
晚期癌症的转移性骨病 (MBD) 增加了难治性骨痛、病理性骨骨折、脊髓压迫和降低生存率的风险。MBD 过程中的疾病表现主要是由侵袭性肿瘤细胞、成骨细胞和破骨细胞之间的同型和异型细胞相互作用驱动的。结果是骨基质重塑的持续恶性循环。破骨细胞介导的骨降解和随后的骨丢失是大多数实体瘤继发骨转移的标志。前列腺癌的另一个并发症是骨硬化病变为主，其特征是不适当的骨生成。治疗溶骨性 MBD 的成功治疗策略包括静脉注射双膦酸盐或核因子 κB 配体 (RANKL) 受体激活抑制剂的皮下给药。Src 和 cABL 激酶以及组织蛋白酶 K 的抑制剂作为潜在的抗骨吸收剂正在临床研究中。与抗溶骨性治疗的快速发展形成鲜明对比的是，MBD 的治疗仍然局限于有症状的单一病变的姑息性放疗和广泛的多发性病变的基于紫杉醇的全身化疗。本综述讨论了转移性去势抵抗性前列腺癌中骨病变的复杂病理学，并重点介绍了正在临床前研究中出现的新的治疗策略和靶点。
