Preclinical development of agents for the treatment of osteoporosis
Preclinical development of agents for the treatment of osteoporosis
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DOI：
10.1177/019262339902700126
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发表时间：
1999-01-01
影响因子：
1.5
通讯作者：
Hartke, JR
中科院分区：
文献类型：
--
作者：
Hartke, JR
由于临床试验的高成本和长时间框架，动物模型在鉴定和选择用于治疗骨质疏松症的药剂中起着至关重要的作用。在项目早期使用动物模型的重点是建立有效性，而在项目后期使用动物模型来检查骨安全性。更具体地说，动物模型用于获得骨骼作用机制的信息，检查多个骨骼部位（轴向和非轴向），并检查高于人类使用剂量的影响。动物模型还可以预测替代标记物在临床试验中的有用性，如骨形成和骨吸收标记物以及骨密度。使用替代标志物预防骨折的危害通过高剂量的氟化物给药来强调，这可以增加骨密度（被认为是骨折保护的强预测因子），同时不能防止骨折。雌激素缺乏模型最常用于模拟女性绝经后骨丢失;这些模型的特征在于骨转换增加和负骨平衡。在动物模型中给予新疗法的时机可以帮助确定该药物是否在预防骨质疏松症或治疗已确定的骨质疏松症方面更有效。用于测量骨量或体积的新方法侵入性更小，需要更短的采集时间，并且具有增强的分辨率，从而增加了关于结构变化和骨沉积特定部位的知识。最后，从动物模型中测量骨的生物力学强度可用于预测在临床试验中对骨折率的保护作用。当与其他方法结合使用时，动物模型可以大大增加我们对骨质疏松症病理生理学的理解，并可以加速新疗法的开发。
Because of the high cost and long time frame of clinical testing, animal models play a crucial role in the identification and selection of agents for the treatment of osteoporosis. The use of animal models early in a program focuses on the establishment of efficacy, while animal models used later in a program to examine bone safety. More specifically, animal models are used to gain information on the skeletal mechanism of action, to examine multiple skeletal sites (axial and appendicular), and to examine the effects of higher doses than will be used in humans. Animal models also predict the usefulness of surrogate markers in clinical trials, such as formation and resorption markers, as well as bone density. The hazard of using surrogate markers for fracture prevention is highlighted by high dose fluoride administration, which can increase bone density (considered a strong predictor of fracture protection) while not protecting against fractures. Estrogen-deficient models are most commonly used to mimic the postmenopausal bone loss in women; these models are characterized by increased bone turnover and a negative bone balance. The timing of the administration of the new therapy in animal models can help determine whether the agent will be more effective in the prevention of osteoporosis or in the treatment of established osteoporosis. New methods for the measurement of bone mass or Volume are less invasive, require shorter acquisition time, and have enhanced resolution, resulting in increased knowledge concerning architectural changes and specific sites of bone deposition. Finally, the measurement of biomechanical strength of bones from animal models can be used to predict protective effects on fracture rates in clinical trials. When used in combination with other methods, animal models can greatly increase our understanding of the pathophysiology of osteoporosis and can expedite the development of new therapies.