Berenson J R, Vescio R A, Rosen L S, VonTeichert J M, Woo M, Swift R, Savage A, Givant E, Hupkes M, Harvey H, Lipton A
Division of Hematology and Oncology, Cedars-Sinai Medical Center, Los Angeles, California 90048, USA.
Clin Cancer Res. 2001 Mar;7(3):478-85.
Bisphosphonates are potent inhibitors of bone resorption and provide a therapeutic benefit for patients with bone metastases. Zoledronic acid is a highly potent, nitrogen-containing bisphosphonate. In the present trial, we assessed the safety and tolerability of increasing doses of zoledronic acid and its effects on urinary markers of bone resorption in cancer patients with bone metastases. Fifty-nine cancer patients with bone metastases were enrolled sequentially into one of 8 treatment groups in the core protocol. Each patient received a 5-min i.v. infusion of 0.1, 0.2, 0.4, 0.8, 1.5, 2, 4, or 8 mg zoledronic acid monthly for 3 months. Patients were monitored for clinical findings, adverse events, electrocardiograms, markers of bone resorption, as well as routine hematology, blood chemistries, and urinalysis. Thirty patients who demonstrated a radiographic response to treatment or stable disease in the core protocol were enrolled in a humanitarian extension protocol and continued to receive monthly infusions. Zoledronic acid was well tolerated at all dose levels. Adverse events reported by >10% of patients included skeletal pain, nausea, fatigue, upper respiratory tract infection, constipation, headache, diarrhea, and fever. Three patients in the core protocol and one patient in the extension protocol experienced grade 3 skeletal pain, "flu-like" symptoms, or hypophosphatemia, which were possibly related to treatment; all recovered completely. Adverse events were reported with similar frequency across all of the dosage groups. Zoledronic acid resulted in sustained, dose-dependent decreases in urinary markers of bone resorption. Zoledronic acid was safe and well tolerated and demonstrated potent inhibition of bone resorption.
双膦酸盐是骨吸收的强效抑制剂，对骨转移患者具有治疗益处。唑来膦酸是一种高效的含氮双膦酸盐。在本试验中，我们评估了递增剂量的唑来膦酸在骨转移癌患者中的安全性和耐受性及其对骨吸收尿标志物的影响。59例骨转移癌患者按顺序纳入核心方案的8个治疗组之一。每位患者每月接受一次5分钟的静脉输注，分别给予0.1、0.2、0.4、0.8、1.5、2、4或8mg唑来膦酸，共3个月。对患者进行临床检查、不良事件、心电图、骨吸收标志物以及常规血液学、血液化学和尿液分析监测。30例在核心方案中对治疗有影像学反应或病情稳定的患者纳入人道主义扩展方案，并继续接受每月一次的输注。唑来膦酸在所有剂量水平下耐受性良好。超过10%的患者报告的不良事件包括骨痛、恶心、疲劳、上呼吸道感染、便秘、头痛、腹泻和发热。核心方案中有3例患者和扩展方案中有1例患者出现3级骨痛、“流感样”症状或低磷血症，可能与治疗有关；所有患者均完全康复。所有剂量组报告的不良事件频率相似。唑来膦酸导致骨吸收尿标志物持续、剂量依赖性降低。唑来膦酸安全且耐受性良好，并显示出对骨吸收的强效抑制作用。
