One of only a few approved and available anabolic treatments for severe osteoporosis is daily injections of PTH (1-34). This drug has a specific dual action which can act either anabolically or catabolically depending on the type of administration, i.e. intermittent or continuous, respectively. In this paper, we present a mechanistic pharmacokinetic-pharmacodynamic model of the action of PTH in postmenopausal osteoporosis. This model accounts for anabolic and catabolic activities in bone remodelling under intermittent and continuous administration of PTH. The model predicts evolution of common bone biomarkers and bone volume fraction (BV/TV) over time. We compared the relative changes in BV/TV resulting from a daily injection of 20 [Formula: see text]g of PTH with experimental data from the literature. Simulation results indicate a site-specific bone gain of 8.66[Formula: see text] (9.4 ± 1.13[Formula: see text]) at the lumbar spine and 3.14[Formula: see text] (2.82 ± 0.72[Formula: see text]) at the femoral neck. Bone gain depends nonlinearly on the administered dose, being, respectively, 0.68[Formula: see text], 3.4[Formula: see text] and 6.16[Formula: see text] for a 10, 20 and 40 [Formula: see text]g PTH dose at the FN over 2 years. Simulations were performed also taking into account a bone mechanical disuse to reproduce elderly frail subjects. The results show that mechanical disuse ablates the effects of PTH and leads to a 1.08% reduction of bone gain at the FN over a 2-year treatment period for the 20 [Formula: see text]g of PTH. The developed model can simulate a range of pathological conditions and treatments in bones including different PTH doses, different mechanical loading environments and combinations. Consequently, the model can be used for testing and generating hypotheses related to synergistic action between PTH treatment and physical activity.

中文翻译：

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使用新的机制性PK-PD模型研究PTH治疗和绝经后骨质疏松症的机械负荷的联合作用。

对于重度骨质疏松症，仅有的几种获批且可用的合成代谢疗法之一是每天注射PTH（1-34）。该药物具有特定的双重作用，其可以根据给药类型，即分别是间歇的或连续的，来无代谢地或分解代谢地起作用。在本文中，我们提出了PTH在绝经后骨质疏松症中作用的机制药代动力学-药效学模型。该模型说明了在间歇性和连续性施用PTH的情况下，骨骼重塑中的合成代谢和分解代谢活动。该模型可预测常见骨生物标志物和骨体积分数（BV / TV）随时间的演变。我们将每日注射20 g [PTH]的PTH与文献中的实验数据相比较，得出BV / TV的相对变化。模拟结果表明，在腰椎骨的特定部位骨增益为8.66 [公式：参见文本]（9.4±1.13 [公式：参见文本]），而在腰椎为3.14 [公式：参见文本]（2.82±0.72 [公式：参见文本]） ）在股骨颈处。骨增益非线性地取决于给药剂量，分别为10、20和40时，分别为0.68 [配方：参见文本]，3.4 [配方：参见文本]和6.16 [配方：参见文本] g FN上的PTH剂量超过2年。进行模拟时还考虑了骨骼机械的废用，以重现年老体弱的受试者。结果表明，机械废料可消除PTH的影响，并在2年的20克PTH的治疗期内，使FN处的骨吸收减少1.08％。开发的模型可以模拟骨骼中的一系列病理状况和治疗方法，包括不同的PTH剂量，不同的机械负荷环境和组合。因此，该模型可用于测试和生成与PTH治疗和身体活动之间的协同作用有关的假设。