Body Jean-Jacques, Facon Thierry, Coleman Robert E, Lipton Allan, Geurs Filip, Fan Michelle, Holloway Donna, Peterson Mark C, Bekker Pirow J
Department of Medicine, Institut Jules Bordet, Brussels, Belgium.
Clin Cancer Res. 2006 Feb 15;12(4):1221-8. doi: 10.1158/1078-0432.CCR-05-1933.
Receptor activator of nuclear factor-kappaB ligand (RANKL) is essential for the differentiation, function, and survival of osteoclasts, which play a key role in establishment and propagation of skeletal disease in patients with multiple myeloma or bone metastases as well as many other skeletal diseases. Denosumab (AMG 162), a fully human monoclonal antibody to RANKL, was developed to treat patients with skeletal diseases.
This was a randomized, double-blind, double-dummy, active-controlled, multicenter study to determine the safety and efficacy of denosumab in patients with breast cancer (n = 29) or multiple myeloma (n = 25) with radiologically confirmed bone lesions. Patients received a single dose of either denosumab (0.1, 0.3, 1.0, or 3.0 mg/kg s.c.) or pamidronate (90 mg i.v.). Bone antiresorptive effect was assessed by changes in urinary and serum N-telopeptide levels. Pharmacokinetics of denosumab also were assessed.
Following a single s.c. dose of denosumab, levels of urinary and serum N-telopeptide decreased within 1 day, and this decrease lasted through 84 days at the higher denosumab doses. Pamidronate also decreased bone turnover, but the effect diminished progressively through follow-up. Denosumab injections were well tolerated. Mean half-lives of denosumab were 33.3 and 46.3 days for the two highest dosages.
A single s.c. dose of denosumab given to patients with multiple myeloma or bone metastases from breast cancer was well tolerated and reduced bone resorption for at least 84 days. The decrease in bone turnover markers was similar in magnitude but more sustained than with i.v. pamidronate.
核因子κB受体活化因子配体（RANKL）对于破骨细胞的分化、功能及存活至关重要，而破骨细胞在多发性骨髓瘤或骨转移患者以及许多其他骨骼疾病的骨骼疾病发生和发展中起关键作用。地诺单抗（AMG 162）是一种针对RANKL的全人单克隆抗体，用于治疗骨骼疾病患者。
这是一项随机、双盲、双模拟、活性对照、多中心研究，旨在确定地诺单抗在经放射学证实有骨病变的乳腺癌患者（n = 29）或多发性骨髓瘤患者（n = 25）中的安全性和疗效。患者接受单剂量的地诺单抗（0.1、0.3、1.0或3.0 mg/kg皮下注射）或帕米膦酸盐（90 mg静脉注射）。通过尿和血清N-端肽水平的变化评估骨抗吸收作用。还评估了地诺单抗的药代动力学。
单次皮下注射地诺单抗后，尿和血清N-端肽水平在1天内下降，且在较高地诺单抗剂量下这种下降持续至84天。帕米膦酸盐也降低了骨转换，但随着随访其作用逐渐减弱。地诺单抗注射耐受性良好。两种最高剂量地诺单抗的平均半衰期分别为33.3天和46.3天。
单次皮下注射地诺单抗给予多发性骨髓瘤或乳腺癌骨转移患者耐受性良好，且至少84天减少了骨吸收。骨转换标志物的下降幅度相似，但比静脉注射帕米膦酸盐更持久。
