Drake Matthew T, Farr Joshua N
Division of Endocrinology, Metabolism, Nutrition and Diabetes, Department of Medicine, Mayo Clinic, Rochester, Minnesota, USA.
Curr Opin Rheumatol. 2014 Jul;26(4):447-52. doi: 10.1097/BOR.0000000000000073.
Recent data suggest that inhibitors of sclerostin, an osteocyte-produced Wnt signaling pathway antagonist, can stimulate bone formation. This review provides rationale and summarizes recent evidence supporting this novel approach to skeletal anabolism.
Data from numerous preclinical models in rodents and monkeys consistently demonstrate that antisclerostin monoclonal antibody (Scl-Ab) treatment leads to improvements in bone mass and strength, as well as enhanced fracture repair. Delivery of Scl-Ab therapy either subcutaneously or intravenously in phase 1 and 2 human clinical trials demonstrates short-term anabolic responses in excess of those seen with teriparatide, the only currently available anabolic skeletal agent. Gains have been primarily at central (spine and hips) versus peripheral (wrist) sites. Strikingly, Scl-Ab treatment appears to both stimulate bone formation and inhibit bone resorption in humans. If proven, Scl-Ab would be the first pharmacologic agent with such dual properties. Data on fractures are not yet available.
Scl-Ab therapy represents a novel pharmacologic approach to skeletal anabolism. Although many questions remain before Scl-Ab treatment can be introduced into clinical practice, phase 3 human clinical trials are currently underway and could provide the necessary data to bring this exciting class of skeletal anabolic agents to patient care.
近期数据表明，骨细胞产生的Wnt信号通路拮抗剂硬化蛋白的抑制剂可刺激骨形成。本综述阐述了原理，并总结了支持这种新型骨骼合成代谢方法的近期证据。
来自啮齿动物和猴子的大量临床前模型的数据一致表明，抗硬化蛋白单克隆抗体（Scl-Ab）治疗可改善骨量和骨强度，并增强骨折修复。在1期和2期人体临床试验中，皮下或静脉注射Scl-Ab疗法显示出的短期合成代谢反应超过了目前唯一可用的合成代谢骨骼药物特立帕肽。骨量增加主要发生在中轴部位（脊柱和髋部）而非外周部位（腕部）。引人注目的是，Scl-Ab治疗似乎既能刺激人体骨形成，又能抑制骨吸收。如果得到证实，Scl-Ab将成为首个具有这种双重特性的药物。目前尚无关于骨折的数据。
Scl-Ab疗法代表了一种新型的骨骼合成代谢药理学方法。尽管在Scl-Ab治疗能够引入临床实践之前仍有许多问题有待解决，但目前3期人体临床试验正在进行，可能会提供必要的数据，将这类令人兴奋的骨骼合成代谢药物应用于患者治疗。
