Recker Robert R, Benson Charles T, Matsumoto Toshio, Bolognese Michael A, Robins Deborah A, Alam Jahangir, Chiang Alan Y, Hu Leijun, Krege John H, Sowa Hideaki, Mitlak Bruce H, Myers Stephen L
Osteoporosis Research Center, Creighton University, Omaha, NE, USA.
J Bone Miner Res. 2015 Feb;30(2):216-24. doi: 10.1002/jbmr.2351.
Sclerostin, a SOST protein secreted by osteocytes, negatively regulates formation of mineralized bone matrix and bone mass. We report the results of a randomized, double-blind, placebo-controlled multicenter phase 2 clinical trial of blosozumab, a humanized monoclonal antibody targeted against sclerostin, in postmenopausal women with low bone mineral density (BMD). Postmenopausal women with a lumbar spine T-score -2.0 to -3.5, inclusive, were randomized to subcutaneous blosozumab 180 mg every 4 weeks (Q4W), 180 mg every 2 weeks (Q2W), 270 mg Q2W, or matching placebo for 1 year, with calcium and vitamin D. Serial measurements of spine and hip BMD and biochemical markers of bone turnover were performed. Overall, 120 women were enrolled in the study (mean age 65.8 years, mean lumbar spine T-score -2.8). Blosozumab treatment resulted in statistically significant dose-related increases in spine, femoral neck, and total hip BMD as compared with placebo. In the highest dose group, BMD increases from baseline reached 17.7% at the spine, and 6.2% at the total hip. Biochemical markers of bone formation increased rapidly during blosozumab treatment, and trended toward pretreatment levels by study end. However, bone specific alkaline phosphatase remained higher than placebo at study end in the highest-dose group. CTx, a biochemical marker of bone resorption, decreased early in blosozumab treatment to a concentration less than that of the placebo group by 2 weeks, and remained reduced throughout blosozumab treatment. Mild injection site reactions were reported more frequently with blosozumab than placebo. In conclusion, treatment of postmenopausal women with an antibody targeted against sclerostin resulted in substantial increases in spine and hip BMD. These results support further study of blosozumab as a potential anabolic therapy for osteoporosis.
硬化素是一种由骨细胞分泌的SOST蛋白，对矿化骨基质的形成和骨量起负向调节作用。我们报告了一项在低骨密度（BMD）的绝经后女性中进行的关于布洛索单抗（一种靶向硬化素的人源化单克隆抗体）的随机、双盲、安慰剂对照多中心2期临床试验结果。腰椎T值在-2.0至-3.5（含）之间的绝经后女性被随机分为皮下注射布洛索单抗组，每4周注射180mg（Q4W）、每2周注射180mg（Q2W）、每2周注射270mg（Q2W），或匹配的安慰剂组，为期1年，并补充钙和维生素D。对脊柱和髋部的BMD以及骨转换的生化标志物进行了系列测量。总体而言，120名女性参与了该研究（平均年龄65.8岁，平均腰椎T值-2.8）。与安慰剂相比，布洛索单抗治疗导致脊柱、股骨颈和全髋部的BMD出现具有统计学意义的剂量相关增加。在最高剂量组中，脊柱的BMD从基线增加达到17.7%，全髋部增加6.2%。在布洛索单抗治疗期间，骨形成的生化标志物迅速增加，并在研究结束时趋向于治疗前水平。然而，在最高剂量组中，研究结束时骨特异性碱性磷酸酶仍高于安慰剂组。骨吸收的生化标志物CTx在布洛索单抗治疗早期降至低于安慰剂组的浓度，并在整个布洛索单抗治疗期间持续降低。与安慰剂相比，布洛索单抗更频繁地报告有轻度注射部位反应。总之，用靶向硬化素的抗体治疗绝经后女性可使脊柱和髋部的BMD大幅增加。这些结果支持进一步研究布洛索单抗作为骨质疏松症的潜在合成代谢疗法。
