Department of Clinical Pharmacokinetics and Pharmacodynamics, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan.
Development Planning, Clinical Development Center, Asahi Kasei Pharma Corporation, Chiyoda-ku, Tokyo, Japan.
J Clin Pharmacol. 2021 May;61(5):606-613. doi: 10.1002/jcph.1774. Epub 2020 Nov 1.
The prevention of fractures is the ultimate goal of osteoporosis treatments. To achieve this objective, developing a method to predict fracture risk in the early stage of osteoporosis treatment would be clinically useful. This study aimed to develop a mathematical model quantifying the long-term fracture risk after 2 annual doses of 5 mg of once-yearly administered zoledronic acid or placebo based on the short-term measurement of bone turnover markers or bone mineral density (BMD). The data used in this analysis were obtained from a randomized, placebo-controlled, double-blind, 2-year study of zoledronic acid that included 656 patients with primary osteoporosis. Two-year individual bone resorption marker (tartrate-resistant acid phosphatase 5b [TRACP-5b]) and lumbar spine (L2-L4) BMD profiles were simulated using baseline values and short-term measurements (at 3 months for TRACP-5b and 6 months for BMD) according to the pharmacodynamic model. A new parametric time-to-event model was developed to describe the risk of clinical fractures. Fracture risk was estimated using TRACP-5b or BMD and the number of baseline vertebral fractures. As a result, the fracture risk during the 2 years was successfully predicted using TRACP-5b or BMD. The 90% prediction intervals well covered the observed fracture profiles in both models. Therefore, TRACP-5b or BMD is useful to predict the fracture risk of patients with osteoporosis, and TRACP-5b would be more useful because it is an earlier marker. Importantly, the developed model allows clinicians to inform patients of their predicted response at the initial stage of zoledronic acid treatment.
预防骨折是骨质疏松症治疗的最终目标。为了实现这一目标，开发一种方法来预测骨质疏松症治疗早期的骨折风险将具有临床意义。本研究旨在开发一种数学模型，该模型基于短期骨转换标志物或骨密度（BMD）测量来量化在接受每年一次 5mg 唑来膦酸治疗 2 年后的长期骨折风险。本分析中使用的数据来自一项为期 2 年的随机、安慰剂对照、双盲、唑来膦酸研究，该研究纳入了 656 例原发性骨质疏松症患者。根据药效动力学模型，使用基线值和短期测量值（TRACP-5b 为 3 个月，BMD 为 6 个月）模拟 2 年个体骨吸收标志物（抗酒石酸酸性磷酸酶 5b [TRACP-5b]）和腰椎（L2-L4）BMD 曲线。开发了一种新的参数时变模型来描述临床骨折的风险。使用 TRACP-5b 或 BMD 和基线椎体骨折数量来估计骨折风险。结果，成功地使用 TRACP-5b 或 BMD 预测了 2 年内的骨折风险。在两个模型中，90%预测区间都很好地覆盖了观察到的骨折曲线。因此，TRACP-5b 或 BMD 可用于预测骨质疏松症患者的骨折风险，TRACP-5b 更有用，因为它是更早的标志物。重要的是，开发的模型允许临床医生在唑来膦酸治疗的初始阶段告知患者他们的预测反应。
