Low Dose of Bisphosphonate Enhances Sclerostin Antibody-Induced Trabecular Bone Mass Gains in Brtl/+ Osteogenesis Imperfecta Mouse Model.
Low Dose of Bisphosphonate Enhances Sclerostin Antibody-Induced Trabecular Bone Mass Gains in Brtl/+ Osteogenesis Imperfecta Mouse Model.
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DOI：
10.1002/jbmr.3421
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发表时间：
2018-07
期刊：
影响因子：
--
通讯作者：
Kozloff KM
中科院分区：
文献类型：
--
作者：
Olvera D;Stolzenfeld R;Marini JC;Caird MS;Kozloff KM
骨生成障碍（OI）是一种遗传性疾病，其特征是骨质量改变和骨重建不平衡，导致骨骼骨折，这在儿童时期最为突出。OI的治疗重点是恢复儿童骨密度和结构，以恢复功能强度，从而降低脆性。虽然抗吸收剂如双膦酸盐（BP）是目前治疗OI最常见的干预措施，但许多研究已显示硬化蛋白抗体（SclAb）在OI小鼠模型中诱导骨量增加和降低脆性方面的疗效。在本研究中，在col1a1上携带引起OI的Gly→Cys突变的小鼠的骨生长过程中评价了BP和SclAb同时使用的影响。单剂量抗吸收BP通过保留原代骨小梁（否则将重塑）增加新骨形成表面的可用性，促进SclAb的合成代谢作用。BP和SclAb同时给药的慢性效应显示，累积周期在骨小梁质量和椎体硬度方面具有协同增益，表明两种治疗组合具有明显优势。通过单独SclAb，皮质的质量和强度增加，与BP的存在无关。总之，这些临床前结果支持了以下科学假设，即最低限度的抗吸收治疗可以在骨骼生长的早期阶段放大SclAb的作用，以进一步改善骨结构和刚度，这对OI儿童是有益的结果。
Osteogenesis imperfecta (OI) is a genetic disorder characterized by altered bone quality and imbalanced bone remodeling, leading to skeletal fractures which are most prominent during childhood. Treatments for OI have focused on restoring pediatric bone density and architecture to recover functional strength and consequently reduce fragility. Though antiresorptive agents like bisphosphonates (BP) are currently the most common intervention for the treatment of OI, a number of studies have shown efficacy of sclerostin antibody (SclAb) in inducing gains in bone mass and reducing fragility in OI mouse models. In this study, the effects of the concurrent use of BP and SclAb were evaluated during bone growth in a mouse harboring an OI-causing Gly→Cys mutation on col1a1. A single dose of antiresorptive BP facilitated the anabolic action of SclAb by increasing availability of surfaces for new bone formation via retention of primary trabeculae that would otherwise be remodeled. Chronic effects of concurrent administration of BP and SclAb revealed that accumulating cycles conferred synergistic gains in trabecular mass and vertebral stiffness, suggesting a distinct advantage of both therapies combined. Cortical gains in mass and strength occurred through SclAb alone, independent of presence of BP. In conclusion, these preclinical results support the scientific hypothesis that minimal antiresorptive treatment can amplify the effects of SclAb during early stages of skeletal growth to further improve bone structure and rigidity, a beneficial outcome for children with OI.
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