Denosumab 治療骨鬆與腫瘤骨轉移 中山醫學大學附設醫院藥劑科藥師林政仁 中山醫學大學醫學系助理教授曾思文 摘要 2010 (U.S. Food and Drug Administration FDA) denosumab Denosumab IgG2 RANKL RANKL RANK 2011 FDA denosumab denosumab osteoporosis skeletal-related events bone metastases 壹 前言 (World Health Organization, WHO) (BMD; bone mass density; bone mineral density; ) 2.5 1 kappa B (receptor activation of nuclear factor kappa B ligand RANKL) D e n o s u m a b G 2 (immunoglobulin G2 IgG2) RANKL (RANKL ) RANKL RANKL RANK (bone resorption) 2 貳 目前的研究重點一 停經後婦女骨質疏鬆症 ( 一 ) 停經後婦女骨質疏鬆症有兩重要試驗 1. 2009 FREEDOM 3 denosumab 60 mg 6 361000 46 THE JOURNAL OF TAIWAN PHARMACY Vol.29 No.2 Jun. 30 2013
Denosumab mg D60-90 T -4-2.5 3 12 5 ( SERM) tibolone calcitonin calcitriold 12 ng/ml 7, 8 6 8 72.3 5.2 36 82% 68% 40% 20% 2. 2009 4 denosumab ( 660 mg) alendronate (70 mg) 1189 T -2.5 500 mg D 400 IU 12 (trodranter) 12 denosumab alendronate (3.5% vs 2.6%, p < 0.0001) denosumab alendronate (0.6%) (1%) (1.1%) (0.6%) (p < 0.0001) 二 預防骨骼相關事件 Denosumab FDA (skeletal-related events, SREs) ( 一 ) 轉移性乳癌有兩重要試驗 1. ( ) 5 denosumab 13 N-telopeptide ( creatinine [untx/ Cr]) UNTx SREs 255 denosumab 4 30 mg (n = 42)4 120 mg (n = 42) 4 180 mg (n = 43)12 60 mg (N = 42) 12 180 mg (N = 43) 43 (zoledronic acid, pamidronate, or ibandronate) D 25 untx > 65% > 65% SRE ( 57 ) 292 Jun. 30 2013 藥學雜誌第 115 冊 47
deno- sumab denosumab untx4 120 mg untx 95% untx 90% denosumab 74% > 65% untx 63% > 65% untx denosumab 1329 SRE denosumab 9% 16% SREs denosumab denosumab denosumab 4 120 mg 2. 6 denosumab zoledronic acid SREs 500 mg D 400 IU D e n o s u m a b 1, 0 2 6 zoledronic acid 1020Denosumab 4 120 mg zoledronic acid 4 4 mg 34 SREs denosumab zoledronic acid 18% (P =0.01) Zoledronic acid 26.5 denosumab SREs denosumab zoledronic acid23% (P = 0.001) ( ) zoledronic acid denosumab ( 二 ) 轉移性前列腺癌 denosumab 120 mg zoledronic acid 4 mg SRE 7,8 denosumab 18% SRE (P =0.008) Zoledronic acid 17.1 denosumab 20.7 SREs denosumab zoledronic acid18% (P = 0.004) untx denosumab denosumab (12.8% vs. 5.8%) ( 三 ) 其他轉移性癌症與多發性骨髓瘤 9 denosumab 120 mg (886 ) zoledronic acid 4 mg (890 ) SRE denosumab 16% SRE (P =0.0007) SREs 48 THE JOURNAL OF TAIWAN PHARMACY Vol.29 No.2 Jun. 30 2013
Denosumab denosumab 21% 126% FDA denosumab SREs 參 結論 Denosumab FDA denosumab SREs () denosumab () denosumab denosumab denosumab ( ) denosumab 表一 Denosumab 簡介 Denosumab RANKL IgG2 Denosumab 147 kda ( ) denosumab 60 mg denosumab 120 mg 1000 mgd 400-800 IU (ClCr <30/ ) C Denosumab / ( ) 表二 Denosumab 與 Zoledronic acid 第三期隨機試驗之比較 SREs ( ) NR v 26.4 (HR,0.82; 95% CI, 0.71 to 0.95; P=0.01) 20.7 v 17.1 (HR 0.82 ; 95% CI: 0.71 to 0.95; p =0.008) ( ) 20.6 vs 16.3 (HR, 0.84; 95% CI, 0.71 to 0.98; P =0.0007). SREs rate ratio, 0.77; 95% CI, 0.66 to 0.89; P= 0.001. HR 0.82 ; 95% CI: 0.71, 0.94 ; p = 0.004. rate ratio, 0.90; 95% CI, 0.77 to 1.04; P=0.14 HR, 0.95; 95% CI, 0.81 to 1.11; P=0.49. HR 1.03 ; 95% CI: 0.91, 1.17 ; p = 0.65. HR,1.00;95%CI, 0.89 to 1.11; P=0.93. HR 1.06; 95% CI: 0.95, 1.18; p = 0.30. HR, 0.95; 95% CI, 0.83 to HR, 1.00; 95% CI, 1.08; P 0.43) 0.89 to 1.12; P=1.0 HR 0.79, 95% CI, 0.65 to 0.95) HR 2.26 (95% CI, 1.13 to 4.50) Abbreviations: SREs, skeletal-related events; HR, hazard ratio; AEs, adverse effects; NSCLC, non small-cell lung cancer; NR, not reached. 292 Jun. 30 2013 藥學雜誌第 115 冊 49
參考資料 : 1. National Osteoporosis Foundation. Clinician's Guide to Prevention and Treatment of Osteoporosis. Washington, DC: National Osteoporosis Foundation; 2010. 2. Prolia 3. Cummings SR, San Martin J, McClung MR, et al: Denosumab for prevention of fractures in postmenopausal women with osteoporosis. N Engl J Med. 2009;361:756-765. 4. Brown JP, Prince RL, Deal C, et al: Comparison of the effect of denosumab and alendronate on BMD and biochemical markers of bone turnover in postmenopausal women with low bone mass: a randomized, blinded, phase 3 trial. J Bone Miner Res. 2009;24:153-161. 5. Lipton A, Steger GG, Figueroa J, et al: Randomized active controlled phase II study of denosumab efficacy and safety in patients with breast cancer-related bone metastases. J Clin Oncol. 2007;25:4431-4437. 6. Stopeck A, Lipton A, Body JJ, et al: Denosumab compared with Zoledronic acid for the treatment of bone metastases in patients with advanced breast cancer: a randomized, double-blind study. J Clin Oncol. 2010;28:5132-5139. 7. Fizazi K, Carducci MA, Smith MR, et al: A randomized phase III trial of denosumab versus Zoledronic acid in patients with bone metastases from castration-resistant prostate cancer. Presented at: American Society of Clinical Oncology; June 4 8, 2010; Chicago, IL. 8. Fizazi K, Bosserman L, Gao G, Skacel T, Markus R. Denosumab treatment of prostate cancer with bone metastases and increased urine N-telopeptide levels after therapy with intravenous bisphosphonates: results of a randomized phase II trial. J Urol. 2009;182:509-516. 9. David H. Henry, Luis Costa, Francois Goldwasser, et al: Randomized, double-blind Study of Denosumab versus Zoledronic acid in the treatment of bone metastases in patients with advanced cancer (excluding breast and prostate cancer) or multiple myeloma. J Clin Oncol. 2011;29:1125-1132. Denosumab for Treatment of Osteoporosis and Bone Metastases Zheng-Ren Lin 1, Szu-Wen Tseng 2 Department of Pharmacy, Chung Shan Medical University Hospital 1 School of Medicine, Chung Shan Medical University 2 Abstract Denosumab has been approved for treating high fracture risk of osteoporosis in postmenopausal women by the U.S. Food and Drug Administration (FDA) in 2010. It is a drug of entirely new mechanism. Denosumab is a human IgG2 monoclonal antibody that inhibits the binding of receptor activation of nuclear factor kappa B ligand (RANKL) to RANK receptors located on the surface of osteoclasts and their precursor cells. This inactivation prevents the formation, function, and survival of osteoclasts, and then reduces bone resorption, allowing for growth in cortical and trabecular bone. An improvement in BMD (bone mass density) has been demonstrated with the use of denosumab. In 2011, FDA also approved denosumab for prevention of skeletal-related events in bone metastases from solid tumors. 50 THE JOURNAL OF TAIWAN PHARMACY Vol.29 No.2 Jun. 30 2013