DataSheet1_Clinical Data for Parametrization of In Silico Bone Models Incorporating Cell-Cytokine Dynamics: A Systematic Review of Literature.pdf

In silico simulations aim to provide fast, inexpensive, and ethical alternatives to years of costly experimentation on animals and humans for studying bone remodeling, its deregulation during osteoporosis and the effect of therapeutics. Within the varied spectrum of in silico modeling techniques, bone cell population dynamics and agent-based multiphysics simulations have recently emerged as useful tools to simulate the effect of specific signaling pathways. In these models, parameters for cell and cytokine behavior are set based on experimental values found in literature; however, their use is currently limited by the lack of clinical in vivo data on cell numbers and their behavior as well as cytokine concentrations, diffusion, decay and reaction rates. Further, the settings used for these parameters vary across research groups, prohibiting effective cross-comparisons. This review summarizes and evaluates the clinical trial literature that can serve as input or validation for in silico models of bone remodeling incorporating cells and cytokine dynamics in post-menopausal women in treatment, and control scenarios. The GRADE system was used to determine the level of confidence in the reported data, and areas lacking in reported measures such as binding site occupancy, reaction rates and cell proliferation, differentiation and apoptosis rates were highlighted as targets for further research. We propose a consensus for the range of values that can be used for the cell and cytokine settings related to the RANKL-RANK-OPG, TGF-β and sclerostin pathways and a Levels of Evidence-based method to estimate parameters missing from clinical trial literature.

硅基模拟（in silico simulation）旨在为研究骨重塑、骨质疏松症中的骨重塑失调以及治疗手段效果的长期昂贵动物与人体实验，提供快速、低成本且符合伦理的替代方案。在多样的硅基模拟建模技术中，骨细胞群体动力学与基于智能体的多物理场模拟近期已成为模拟特定信号通路效应的有效工具。在这类模型中，细胞与细胞因子（cytokine）的行为参数均基于文献中的实验值设定，但目前其应用受限于缺乏关于细胞数量、行为以及细胞因子浓度、扩散、降解与反应速率的临床体内数据。此外，各研究团队采用的参数设置各不相同，阻碍了有效的跨组比较。本综述总结并评估了可作为绝经后女性骨重塑硅基模型（整合细胞与细胞因子动力学）输入或验证依据的临床试验文献，此类模型覆盖治疗组与对照组场景。本研究采用GRADE系统（GRADE system）确定所报道数据的置信等级，并指出了报道指标中存在缺失的领域，如结合位点占有率、反应速率以及细胞增殖、分化与凋亡速率，将其列为后续研究的目标。我们针对与RANKL-RANK-OPG、转化生长因子β（TGF-β）及骨硬化蛋白（sclerostin）通路相关的细胞与细胞因子参数设置范围提出了共识，并提出了一种基于证据等级的方法，用以估算临床试验文献中缺失的参数。