Calvo-Gallego José L, Pivonka Peter, Ruiz-Lozano Rocío, Martínez-Reina Javier
Departamento de Ingeniería Mecánica y Fabricación, Universidad de Sevilla, Seville, Spain.
School of Mechanical, Medical and Process Engineering, Queensland University of Technology, Brisbane, QLD, Australia.
Front Bioeng Biotechnol. 2022 Aug 17;10:940620. doi: 10.3389/fbioe.2022.940620. eCollection 2022.
Alendronate is the most widely used drug for postmenopausal osteoporosis (PMO). It inhibits bone resorption, affecting osteoclasts. Pharmacokinetics (PK) and pharmacodynamics (PD) of alendronate have been widely studied, but few mathematical models exist to simulate its effect. In this work, we have developed a PK model for alendronate, valid for short- and long-term treatments, and a mechanistic PK-PD model for the treatment of PMO to predict bone density gain (BDG) at the hip and lumbar spine. According to our results, at least three compartments are required in the PK model to predict the effect of alendronate in both the short and long terms. Clinical data of a 2-year treatment of alendronate, reproduced by our PK-PD model, demonstrate that bone response is site specific (hip: 7% BDG, lumbar spine: 4% BDG). We identified that this BDG is mainly due to an increase in tissue mineralization and a decrease in porosity. The difference in BDG between sites is linked to the different loading and dependence of the released alendronate on the bone-specific surface and porosity. Osteoclast population diminishes quickly within the first month of alendronate treatment. Osteoblast population lags behind but also falls due to coupling of resorption and formation. Two dosing regimens were studied (70 mg weekly and 10 mg daily), and both showed very similar BDG evolution, indicating that alendronate accumulates quickly in bone and saturates. The proposed PK-PD model could provide a valuable tool to analyze the effect of alendronate and to design patient-specific treatments, including drug combinations.
阿仑膦酸钠是治疗绝经后骨质疏松症（PMO）最常用的药物。它通过影响破骨细胞来抑制骨吸收。阿仑膦酸钠的药代动力学（PK）和药效学（PD）已得到广泛研究，但用于模拟其效果的数学模型却很少。在这项研究中，我们建立了一个适用于短期和长期治疗的阿仑膦酸钠PK模型，以及一个用于治疗PMO的机制性PK-PD模型，以预测髋部和腰椎的骨密度增加（BDG）。根据我们的结果，PK模型中至少需要三个房室来预测阿仑膦酸钠在短期和长期的效果。我们的PK-PD模型重现的阿仑膦酸钠2年治疗临床数据表明，骨反应具有部位特异性（髋部：BDG为7%，腰椎：BDG为4%）。我们发现这种BDG主要是由于组织矿化增加和孔隙率降低。不同部位BDG的差异与释放的阿仑膦酸钠对骨特异性表面和孔隙率的不同负载及依赖性有关。在阿仑膦酸钠治疗的第一个月内，破骨细胞数量迅速减少。成骨细胞数量滞后但也因吸收与形成的耦合而减少。研究了两种给药方案（每周70毫克和每日10毫克），两者显示出非常相似的BDG变化，表明阿仑膦酸钠在骨中迅速蓄积并达到饱和。所提出的PK-PD模型可为分析阿仑膦酸钠的效果和设计个性化治疗方案（包括药物联合）提供有价值工具。
