Two Doses of Sclerostin Antibody in Cynomolgus Monkeys Increases Bone Formation, Bone Mineral Density, and Bone Strength
Two Doses of Sclerostin Antibody in Cynomolgus Monkeys Increases Bone Formation, Bone Mineral Density, and Bone Strength
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DOI：
10.1002/jbmr.14
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发表时间：
2010-05-01
影响因子：
6.2
通讯作者：
Paszty, Chris
中科院分区：
文献类型：
--
作者：
Ominsky, Michael S.;Vlasseros, Fay;Paszty, Chris
骨重建合成代谢药物的发展治疗骨相关疾病一直是一个长期的目标。人类和小鼠的遗传研究表明，分泌的硬化蛋白是骨形成的关键负调节因子。最近，在啮齿类动物研究中，给药硬化蛋白中和单克隆抗体表明，硬化蛋白的药物抑制导致骨形成、骨量和骨强度增加。为了探讨硬核蛋白在灵长类动物中的抑制作用，我们给雌性食蟹猴注射了人源化的硬核蛋白中和单克隆抗体（scll - abiv）。以3、10和30 mg/kg的剂量水平皮下注射Scl-AbIV，每月两次，研究在2个月时终止。Scl-AbIV治疗具有明显的合成代谢作用，在骨小梁、骨膜、皮质内和皮质内表面的骨形成有明显的剂量依赖性增加。骨密度测定显示，Scl-AbIV治疗增加了骨形成，导致几个骨骼部位（即股骨颈、桡骨干骺端和胫骨干骺端）的骨矿物质含量（BMC）和/或骨矿物质密度（BMD）显著增加。这些增加，以基线变化百分比表示，比车辆处理组高出11至29个百分点。此外，在最高剂量组中，腰椎的骨小梁厚度和骨强度显著增加。总之，在这项短期猴子研究中取得的显着的成骨效果表明，对于骨折愈合和骨质疏松症等可能需要增加骨形成的医疗条件，抑制硬化蛋白代表了一种有希望的新治疗方法。(C) 2010年美国骨与矿物研究学会。
The development of bone-rebuilding anabolic agents for treating bone-related conditions has been a long-standing goal. Genetic studies in humans and mice have shown that the secreted protein sclerostin is a key negative regulator of bone formation. More recently, administration of sclerostin-neutralizing monoclonal antibodies in rodent studies has shown that pharmacologic inhibition of sclerostin results in increased bone formation, bone mass, and bone strength. To explore the effects of sclerostin inhibition in primates, we administered a humanized sclerostin-neutralizing monoclonal antibody (Scl-AbIV) to gonad-intact female cynomolgus monkeys. Two once-monthly subcutaneous injections of Scl-AbIV were administered at three dose levels (3, 10, and 30 mg/kg), with study termination at 2 months. Scl-AbIV treatment had clear anabolic effects, with marked dose-dependent increases in bone formation on trabecular, periosteal, endocortical, and intracortical surfaces. Bone densitometry showed that the increases in bone formation with Scl-AbIV treatment resulted in significant increases in bone mineral content (BMC) and/or bone mineral density (BMD) at several skeletal sites (ie, femoral neck, radial metaphysis, and tibial metaphysis). These increases, expressed as percent changes from baseline were 11 to 29 percentage points higher than those found in the vehicle-treated group. Additionally, significant increases in trabecular thickness and bone strength were found at the lumbar vertebrae in the highest-dose group. Taken together, the marked bone-building effects achieved in this short-term monkey study suggest that sclerostin inhibition represents a promising new therapeutic approach for medical conditions where increases in bone formation might be desirable, such as in fracture healing and osteoporosis. (C) 2010 American Society for Bone and Mineral Research.