唑来膦酸治疗实体瘤骨转移或多发性骨髓瘤中重度骨痛的Ⅲ期临床研究

Phase Ⅲ clinical study of zoledronic acid in the treatment of pain induced by bone metastasis from solid tumor or multiple myeloma

目的评价唑来膦酸治疗实体瘤骨转移或多发性骨髓瘤引起的中重度骨痛的效果和安全性。方法采用随机、双盲、双模拟、多中心的实验设计方法。将228例实体瘤骨转移或多发性骨髓瘤引起中重度骨痛[视觉模拟评分（VAS）〉50mm]的患者随机分为唑来膦酸组（116例）和帕米膦酸二钠组（112例），分别接受静脉输注唑来膦酸（4mg）或帕米膦酸二钠（90mg）的单剂量治疗。检测唑来膦酸对疼痛及尿液中Ⅰ型胶原交联氨基末端肽（NTX）／肌酐（Cr）、Ⅰ型胶原交联羧基末端肽（CTX）／Cr的影响，并观察不良反应，评价其安全性。结果228例患者中202例完成试验，其中唑来膦酸组104例，膦酸二钠组98例。用药后两组VAS评分逐渐下降，唑来膦酸组第8、15、22、28天对基线的平均变化百分比分别为-11．77％、-24．60％、-28．50％和-32．37％，帕米膦酸二钠组则分别为-10．87％、-21、06％、-25．67％和-31．26％，两组各时间点相对基线变化的百分比均有统计学意义（均P≤0．0001），但两组间相对基线变化的百分比差异无统计学意义（P=0.6587）。用药后两组尿NTX／Cr均快速下降，第8天降到最低点，与基线相比，唑来膦酸组用药后第28天的变化百分比中位值为-36．9％（P=0.0002），帕米膦酸二钠为-32．1％（P=0．0018），两组间差异无统计学意义（P=0．7922）。用药后两组尿CTX／Cr均快速下降，第8天时降到最低点，与基线相比，唑来膦酸组用药后第28天变化百分比中位值为-63．2％（P〈0．0001），帕米膦酸二钠组为-47．9％（P〈0.0001），两组间差异无统计学意义（P=0.834）。唑来膦酸和帕米膦酸二钠组中常见的不良反应为发热（19．0％和31．3％）、呕吐（6．0％和8．9％）、恶心（4．3％和4．5％）、乏力（3．4％和2．7％）、便秘（2．6％和1．8％）、低钙血症（5．2％和3．6％），均未出现血肌酐值升高。结论4mg唑来膦酸单剂量治疗中国人实体瘤骨转移或多发性骨髓瘤，在缓解骨痛和降低骨吸收标记物方面与帕米膦酸二钠同样有效，患者耐受性好。

Objective To evaluate the efficacy and safety of zoledronic acid in the treatment of bone pain in patients with bone metastasis from solid tumor or multiple myeloma. Methods A randomized, double-bland, double-simulated and multi-center phase Ⅲ clinical trail with pamidronate as control was conducted. Patients with moderate to severe bone pain（ VAS 〉 50 mm） induced by solid tumor or multiple myeloma were randomized to receive intravenous zoledronic acid 4 mg or pamidronate 90 mg. Then the change of VAS and urinary NTX/Cr and CTX/Cr were observed in two groups. Results From July 2005 to September 2006, 228 patients with bone pain induced by bone metastasis from 15 cancer centers were randomize into two groups ： 116 patients in zoledronic acid group and 112 patients in pamidronate group. The VAS value was decreased gradually after treatment in these two groups. Significant improvement in bone pain after treatment were observed both in zoledronic acid group and the control group when compared with baseline VAS on D8 （ - 11.77% vs. - 10.87% ）, D15 （ - 24.60% vs. - 21,06% ） and D28 （ - 32.37% vs. -31.26% ） （ P≤0. 0001 ）, but no significant difference existed between two groups （P = 0. 6587）. Compared with baseline, urine NTX/Cr and CTX/Cr level were decreased rapidly after treatment in both groups, the nadir was on D8, the median decreased on D28, which was - 36. 9% vs. - 32. 1% for NTX/Cr （P = 0. 7922） and - 63.2% vs. - 47.9% for CTX/Cr （P = 0. 834）. The frequently observed adverse events were pyrexia （19.0% vs. 31.3% ）, vomiting（6.0% vs. 8.9% ）, nausea（4.3% vs. 4.5% ）, fatigue（3.4% vs. 2.7% ） and constipation（2.6% vs. 1.8% ） in the two groups. Compared with baseline, the serum creatinine level was not significantly increased throughout the study. Conclusion Intravenous injection of 4 mg zoledronic acid can significantly reduce bone pain and bone resorption marker in urine in the Chinese patients with bone metastasis from solid tumor or multiple myeloma, which is tolerable and also comparable to pamidronate in the efficacy and safety.