Department of Pediatrics, New York Presbyterian Hospital, Weill Cornell Medical Center, New York, New York, USA.
Pediatr Res. 2012 Nov;72(5):495-501. doi: 10.1038/pr.2012.118. Epub 2012 Aug 27.
Receptor activator of nuclear factor-κB ligand (RANKL) inhibitors are being considered for use in children with osteogenesis imperfecta (OI). We sought to assess efficacy of two doses of a RANKL inhibitor, osteoprotegerin-immunoglobulin Fc segment complex (OPG-Fc), in a growing animal model of OI, the col1α2-deficient mouse (oim/oim) and its wild-type controls (+/+).
Treated mice showed runting and radiographic evidence of osteopetrosis with either high- (20 mg/kg twice weekly) or low-dose (1 mg/kg/week) OPG-Fc. Because of this adverse event, OPG-Fc treatment was halted, and the mice were killed or monitored for recovery with monthly radiographs and assessment of serum osteoclast activity (tartrate-resistant acid phosphatase 5b, TRACP-5b) until 25 wk of age.
Twelve weeks of OPG-Fc treatment resulted in radiographic and histologic osteopetrosis with no evidence of bone modeling and negative tartrate-resistant acid phosphatase staining, root dentin abnormalities, and TRACP-5b activity suppression. Signs of recovery appeared 4-8 wk post-treatment.
Both high- and low-dose OPG-Fc treatment resulted in osteopetrotic changes in infant mice, an outcome that was not seen in studies with the RANKL inhibitor RANK-immunoglobulin Fc segment complex (RANK-Fc) or in studies with older animals. Further investigations of RANKL inhibitors are necessary before their consideration for use in children.
核因子-κB 受体激活剂配体（RANKL）抑制剂正被考虑用于治疗成骨不全症（OI）患儿。我们旨在评估 RANKL 抑制剂骨保护素免疫球蛋白 Fc 段复合物（OPG-Fc）在成骨不全症的生长动物模型，即胶原α2 缺陷型小鼠（oim/oim）及其野生型对照（+/+）中的两种剂量的疗效。
用高剂量（20mg/kg，每周两次）或低剂量（1mg/kg/周）OPG-Fc 处理的小鼠表现出矮小和骨硬化的放射学证据。由于这种不良事件，停止了 OPG-Fc 治疗，并对小鼠进行了监测，每月拍摄 X 光片，并评估血清破骨细胞活性（抗酒石酸酸性磷酸酶 5b，TRACP-5b），直至 25 周龄。
12 周的 OPG-Fc 治疗导致放射学和组织学上的骨质硬化，没有骨建模的证据，抗酒石酸酸性磷酸酶染色阴性，根牙本质异常和 TRACP-5b 活性抑制。治疗后 4-8 周出现恢复迹象。
高剂量和低剂量的 OPG-Fc 治疗均导致幼鼠发生骨质硬化改变，而 RANKL 抑制剂 RANK 免疫球蛋白 Fc 段复合物（RANK-Fc）或老年动物研究中未见这种结果。在考虑将 RANKL 抑制剂用于儿童之前，需要对其进行进一步研究。
