Denosumab与破骨细胞RANKL/RANK通路
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摘要
Denosumab(狄诺塞麦)是一种人工合成、完全人源化、可与RNAKL结合的单克隆抗体(IgG2抗体),对人源RANKL具有很高的亲和力和特异性~([1]),具有较好的骨吸收抑制作用,是以破骨细胞RANKL/RANK信号调控通路为靶点的骨质疏松靶向治疗药物,并可降低恶性肿瘤骨转移患者骨骼相关事件(SRE)的发生、延缓骨痛的进展。本文综述了狄诺塞麦抑制骨吸收的生理作用机制,狄诺塞麦治疗骨质疏松和恶性肿瘤骨转移的研究进展,为狄诺塞麦在临床的应用提供更好的循证医学证据。
Denosumab was a humanized monoclonal antibody that specifically binding to RNAKL, and had a good bone resorption inhibitory effect. It was a osteoporosis targeted therapy drug, which targeted at the RANKL/RANK signaling pathway of osteoclasts, could reduce the occurrence of bone-related events(SRE) in patients with malignant bone metastases and delay the progression of bone pain. This article reviewed the physiological mechanism of denosumab inhibiting bone resorption, and the research progress of denosumab in the treatment of osteoporosis and malignant tumor bone metastasis.It could provide better evidence-based medical evidence for the clinical application of denosumab.
Denosumab was a humanized monoclonal antibody that specifically binding to RNAKL, and had a good bone resorption inhibitory effect. It was a osteoporosis targeted therapy drug, which targeted at the RANKL/RANK signaling pathway of osteoclasts, could reduce the occurrence of bone-related events(SRE) in patients with malignant bone metastases and delay the progression of bone pain. This article reviewed the physiological mechanism of denosumab inhibiting bone resorption, and the research progress of denosumab in the treatment of osteoporosis and malignant tumor bone metastasis.It could provide better evidence-based medical evidence for the clinical application of denosumab.
引文
[1] Narayanan P. Denosumab: a comprehensive review[J]. South Asian J Cancer, 2013, 2(4): 272-277.
[2] 车路阳, 刘长振, 黄鹏. RANKL/RANK/OPG 通路及其相关药物狄诺塞麦治疗骨质疏松的研究进展[J].世界最新医学信息文摘, 2017, 17(34):43-46.
[3] Iranikhah M, Wilborn TW, Wensel TM, et al. Denosumab for the prevention of skeletal-related events in patients with bone metastasis from solid tumor[J]. Pharmacotherapy, 2012, 32(3):274-284.
[4] 吕芳, 李梅. 骨质疏松症靶向治疗药物[J]. 中华骨质疏松和骨矿盐疾病杂志, 2017, 10(6):566-571.
[5] Lacey DL, Boyle WJ, Simonet WS, et al. Bench to bedside: elucidation of the OPG-RANK-RANKL pathway and the development of denosumab [J]. Nat Rav D drug Discov,2012,11: 401-419.
[6] Eastell R, Christiansen C, Grauer A, et al.Effects of denosumab on bone turnver markers in postmenopausal osteoporosis [J]. J Bone Miner Res, 2011, 26(3): 530-537.
[7] Chen Q, Hu C, Liu Y, et al. Pharmacokinetics, pharmacodynamics, safety, and tolerability of single-dose denosumab in healthy Chinese volunteers: A randomized, single-blind, placebo-controlled study [J]. PLoS One, 2018, 13(6):e0197984.
[8] Kostenuik PJ, Smith SY, Jolette J, et al.Decreased bone remodeling and porosity are associated with improved bone strength in ovariectomized cynomolgus monkeys treated with denosumab, a fully human RANKL antibody[J].Bone, 2011, 49(2): 151-61.
[9] Scott LJ. Denosumab: a review of its use in postmenopausal women with osteoporosis[J]. Drugs Aging, 2014, 31(7):555-576.
[10] Keaveny TM, McClung MR, Genant HK, et al. Femoral and vertebral strength improvements in postmenopausal women with osteoporosis treated with denosumab[J]. J Bone Miner Res, 2014, 29: 158-165.
[11] Suzuki T, Nakamura Y, Kamimura M, et al. Denosumab significantly improves lumbar spine bone mineral density more in treatment-na?ve than in long-term bisphosphonate-treated patients[J]. Bone Rep, 2018, 8:110-114.
[12] Wolverton D, Elliott DP. Evaluating the evidence behind treating osteoporosis in the oldest adults[J]. Consult Pharm, 2018, 33(6): 308-316.
[13] Dempster DW, Brown JP, Fahrleitner-Pammer A, et al. Effects of long-term denosumab on bone histomorphometry and mineralization in women with postmenopausal osteoporosis [J]. J Clin Endocrinol Metab, 2018,103(7): 2498-2509.
[14] Suzuki T, Nakamura Y, Kato H, et al. Determination of serum bone-related minerals during denosumab treatment in osteoporosis patients with rheumatoid arthritis: Mineral change by denosumab in osteoporosis with rheumatoid arthritis[J].Clin Nutr ESPEN, 2018, 26:53-56.
[15] Bone HG, Wagman RB, Brandi ML, et al. 10 years of denosumab treatment in postmenopausal women with osteoporosis: results from the phase 3 randomised FREEDOM trial and open-label extension[J]. Lancet Diabetes Endocrinol, 2017, 5(7): 513-523.
[16] Coleman RE. Metastatic bone disease: clinical features,pathophysiology and treatment strategies [J]. Cancer Treat Rev, 2015, 27(3): 165-176.
[17] 赵蔚.狄诺塞麦治疗恶性肿瘤骨转移机制及进展[D]. 重庆医科大学附属第一医院.2015.
[18] 罗静, 何宇, 周蕾蕾,等. 狄诺塞麦在乳腺癌中的应用[J]. 华西医学, 2011, 26(7): 1003-1005.
[19] von Moos R, Body JJ, Rider A, et al. Bone-targeted agent treatment patterns and the impact of bone metastases on patients with advanced breast cancer in real-world practice in six European countries[J]. J Bone Oncol, 2017, 11: 1-9.
[20] Hegemann M, Bedke J, Stenzl A, et al. Denosumab treatment in the management of patients with advanced prostate cancer: clinical evidence and experience[J]. Ther Adv Urol, 2017, 9(3-4): 81-88
[21] James N, Sydes M, Clarke N, et al. Addition of docetaxel, zoledronic acid, or both to first-line long-term hormone therapy in prostate cancer (STAMPEDE): survival results from an adaptive, multiarm, multistage, platform randomised controlled trial[J]. Lancet, 2015, 387: 1163-1177.
[22] Raje N, Roodman GD, Willenbacher W, et al. A cost-effectiveness analysis of denosumab for the prevention of skeletal-related events in patients with multiple myeloma in the United States of America[J]. J Med Econ, 2018, 21(5): 525-536.
[2] 车路阳, 刘长振, 黄鹏. RANKL/RANK/OPG 通路及其相关药物狄诺塞麦治疗骨质疏松的研究进展[J].世界最新医学信息文摘, 2017, 17(34):43-46.
[3] Iranikhah M, Wilborn TW, Wensel TM, et al. Denosumab for the prevention of skeletal-related events in patients with bone metastasis from solid tumor[J]. Pharmacotherapy, 2012, 32(3):274-284.
[4] 吕芳, 李梅. 骨质疏松症靶向治疗药物[J]. 中华骨质疏松和骨矿盐疾病杂志, 2017, 10(6):566-571.
[5] Lacey DL, Boyle WJ, Simonet WS, et al. Bench to bedside: elucidation of the OPG-RANK-RANKL pathway and the development of denosumab [J]. Nat Rav D drug Discov,2012,11: 401-419.
[6] Eastell R, Christiansen C, Grauer A, et al.Effects of denosumab on bone turnver markers in postmenopausal osteoporosis [J]. J Bone Miner Res, 2011, 26(3): 530-537.
[7] Chen Q, Hu C, Liu Y, et al. Pharmacokinetics, pharmacodynamics, safety, and tolerability of single-dose denosumab in healthy Chinese volunteers: A randomized, single-blind, placebo-controlled study [J]. PLoS One, 2018, 13(6):e0197984.
[8] Kostenuik PJ, Smith SY, Jolette J, et al.Decreased bone remodeling and porosity are associated with improved bone strength in ovariectomized cynomolgus monkeys treated with denosumab, a fully human RANKL antibody[J].Bone, 2011, 49(2): 151-61.
[9] Scott LJ. Denosumab: a review of its use in postmenopausal women with osteoporosis[J]. Drugs Aging, 2014, 31(7):555-576.
[10] Keaveny TM, McClung MR, Genant HK, et al. Femoral and vertebral strength improvements in postmenopausal women with osteoporosis treated with denosumab[J]. J Bone Miner Res, 2014, 29: 158-165.
[11] Suzuki T, Nakamura Y, Kamimura M, et al. Denosumab significantly improves lumbar spine bone mineral density more in treatment-na?ve than in long-term bisphosphonate-treated patients[J]. Bone Rep, 2018, 8:110-114.
[12] Wolverton D, Elliott DP. Evaluating the evidence behind treating osteoporosis in the oldest adults[J]. Consult Pharm, 2018, 33(6): 308-316.
[13] Dempster DW, Brown JP, Fahrleitner-Pammer A, et al. Effects of long-term denosumab on bone histomorphometry and mineralization in women with postmenopausal osteoporosis [J]. J Clin Endocrinol Metab, 2018,103(7): 2498-2509.
[14] Suzuki T, Nakamura Y, Kato H, et al. Determination of serum bone-related minerals during denosumab treatment in osteoporosis patients with rheumatoid arthritis: Mineral change by denosumab in osteoporosis with rheumatoid arthritis[J].Clin Nutr ESPEN, 2018, 26:53-56.
[15] Bone HG, Wagman RB, Brandi ML, et al. 10 years of denosumab treatment in postmenopausal women with osteoporosis: results from the phase 3 randomised FREEDOM trial and open-label extension[J]. Lancet Diabetes Endocrinol, 2017, 5(7): 513-523.
[16] Coleman RE. Metastatic bone disease: clinical features,pathophysiology and treatment strategies [J]. Cancer Treat Rev, 2015, 27(3): 165-176.
[17] 赵蔚.狄诺塞麦治疗恶性肿瘤骨转移机制及进展[D]. 重庆医科大学附属第一医院.2015.
[18] 罗静, 何宇, 周蕾蕾,等. 狄诺塞麦在乳腺癌中的应用[J]. 华西医学, 2011, 26(7): 1003-1005.
[19] von Moos R, Body JJ, Rider A, et al. Bone-targeted agent treatment patterns and the impact of bone metastases on patients with advanced breast cancer in real-world practice in six European countries[J]. J Bone Oncol, 2017, 11: 1-9.
[20] Hegemann M, Bedke J, Stenzl A, et al. Denosumab treatment in the management of patients with advanced prostate cancer: clinical evidence and experience[J]. Ther Adv Urol, 2017, 9(3-4): 81-88
[21] James N, Sydes M, Clarke N, et al. Addition of docetaxel, zoledronic acid, or both to first-line long-term hormone therapy in prostate cancer (STAMPEDE): survival results from an adaptive, multiarm, multistage, platform randomised controlled trial[J]. Lancet, 2015, 387: 1163-1177.
[22] Raje N, Roodman GD, Willenbacher W, et al. A cost-effectiveness analysis of denosumab for the prevention of skeletal-related events in patients with multiple myeloma in the United States of America[J]. J Med Econ, 2018, 21(5): 525-536.
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