This paper introduces a theoretical framework for the study of the efficacy of romosozumab, a humanized monoclonal antibody targeting sclerostin for the treatment of osteoporosis. We developed a comprehensive mechanistic pharmacokinetic-pharmacodynamic (PK-PD) model of the effect of drug treatment on bone remodeling in postmenopausal osteoporosis (PMO). We utilized a one-compartment PK model to represent subcutaneous injections of romosozumab and subsequent absorption into serum. The PD model is based on a recently-developed bone cell population model describing the bone remodeling process at the tissue scale. The latter accounts for mechanical feedback via incorporating nitric oxide (NO) and sclerostin (Scl) as biochemical feedback molecules. Utilizing a competitive binding model, where Wnt and Scl compete for binding to LRP5/6, allows to regulate anabolic bone remodeling responses. Here, we extended this model with respect to romosozumab binding to sclerostin. For the currently approved monthly injections of 210 mg, the model predicted a 6.59%, 10.38% and 15.25% increase in BMD at the lumbar spine after 6, 12 and 24 months, respectively. These results are in good agreement with the data reported in the literature. Our model is also able to distinguish the bone-site specific drug effects. For instance, at the femoral neck, our model predicts a BMD increase of 3.85% after 12 months of 210 mg injections, which is consistent with literature observations. Finally, our simulations indicate rapid bone loss after treatment discontinuation, indicating that some additional interventions such as use of bisphosphonates are required to maintain bone.

中文翻译：

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romosozumab 治疗绝经后骨质疏松症的疗效评估：骨重塑机械 PK-PD 机械恒压模型的结果

本文介绍了研究 romosozumab 疗效的理论框架，romosozumab 是一种靶向硬化素的人源化单克隆抗体，用于治疗骨质疏松症。我们开发了药物治疗对绝经后骨质疏松症 (PMO) 骨重建影响的综合机械药代动力学-药效学 (PK-PD) 模型。我们利用单室 PK 模型来表示 romosozumab 的皮下注射和随后的血清吸收。PD 模型基于最近开发的骨细胞群模型，描述了组织尺度的骨重塑过程。后者通过结合一氧化氮 (NO) 和硬化蛋白 (Scl) 作为生化反馈分子来解释机械反馈。利用竞争性结合模型，其中 Wnt 和 Scl 竞争与 LRP5/6 的结合，允许调节合成代谢骨重塑反应。在这里，我们扩展了关于 romosozumab 与硬化蛋白结合的模型。对于目前批准的每月注射 210 毫克，该模型预测腰椎 BMD 在 6、12 和 24 个月后分别增加 6.59%、10.38% 和 15.25%。这些结果与文献报道的数据非常吻合。我们的模型还能够区分骨部位特定的药物作用。例如，在股骨颈，我们的模型预测注射 210 毫克 12 个月后 BMD 增加 3.85%，这与文献观察结果一致。最后，我们的模拟表明治疗中断后骨质会迅速流失，这表明需要一些额外的干预措施，例如使用双膦酸盐来维持骨骼。