Division of Hematology-Oncology, Massachusetts General Hospital Cancer Center, Massachusetts General Hospital, 55 Fruit Street, Yawkey 7E, Boston, MA 02114, USA.
J Clin Oncol. 2011 Sep 20;29(27):3705-14. doi: 10.1200/JCO.2010.34.4994. Epub 2011 Aug 22.
Skeletal morbidity is a prominent burden to men with advanced prostate cancer throughout the natural history of the disease. Bone metastases can cause pain and greatly elevate the risk for fractures and other structural complications. Distinct from the problem of metastases, treatment-related osteoporosis and associated fragility fractures are potential complications of androgen-deprivation therapy. Bone-targeted therapies for prostate cancer have therefore been the focus of considerable research and drug development efforts. The osteoclast is a validated therapeutic target in the management of prostate cancer. Osteoclast inhibition with zoledronic acid (a bisphosphonate) or with denosumab (a monoclonal antibody to RANK ligand) reduces risk for skeletal events in men with castration-resistant prostate cancer metastatic to bone. Osteoclast inhibition with any of several bisphosphonates improves bone mineral density, a surrogate for osteoporotic fracture risk. Denosumab and toremifene (a selective estrogen receptor modulator) have each been shown to reduce osteoporotic fracture risk among men receiving androgen-deprivation therapy. Beta-emitting radiopharmaceuticals reduce pain due to metastatic disease. Investigations involving alpha-emitting radium-223, endothelin-A receptor antagonists atrasentan and zibotentan, proto-oncogene tyrosine-protein kinase (SRC) inhibitor dasatinib, and tyrosine kinase inhibitor cabozantinib (XL184) are ongoing in clinical trials and are also discussed.
骨骼相关并发症是晚期前列腺癌患者的一个主要负担，贯穿于疾病的整个自然病程。骨转移可引起疼痛，并大大增加骨折和其他结构并发症的风险。与转移问题不同，治疗相关的骨质疏松症和相关的脆性骨折是雄激素剥夺治疗的潜在并发症。因此，针对前列腺癌的骨骼靶向治疗一直是大量研究和药物开发努力的重点。破骨细胞是治疗前列腺癌的一个经过验证的治疗靶点。用唑来膦酸（双膦酸盐）或地舒单抗（针对 RANK 配体的单克隆抗体）抑制破骨细胞可降低去势抵抗性前列腺癌骨转移患者发生骨骼相关事件的风险。几种双膦酸盐中的任何一种抑制破骨细胞均可改善骨密度，这是骨质疏松性骨折风险的替代指标。地舒单抗和托瑞米芬（一种选择性雌激素受体调节剂）均已被证明可降低接受雄激素剥夺治疗的男性发生骨质疏松性骨折的风险。β发射放射性药物可缓解转移性疾病引起的疼痛。正在临床试验中进行涉及α发射镭-223、内皮素 A 受体拮抗剂 atrasentan 和 zibotentan、原癌基因酪氨酸蛋白激酶（Src）抑制剂 dasatinib 以及酪氨酸激酶抑制剂 cabozantinib（XL184）的研究，本文也对其进行了讨论。
