Development of computational models of bone formation and resorption to predict changes in bone in preclinical intervention studies.

我们希望开发计算机程序来测试骨骼疾病的新疗法，以减少动物试验并加速研究进展。包括关节炎、骨关节炎和骨质疏松症在内的肌肉骨骼疾病是影响英国工作相关疾病的最普遍原因，占全科医生咨询的三分之一。受这些疾病影响的患者往往行动不便，导致孤立和生活质量差。尽管在治疗这些疾病方面取得了巨大进展，但仍有很多人对这些治疗没有很好的反应。因此，这些病人需要新的治疗方法。任何新药在用于人体之前都需要在动物身上进行试验。这不仅是为了看看药物是否安全，也是为了了解它们是否有效。在此过程中，需要成群的老鼠来测试每个剂量或给药时间，并且必须在确定药物对骨骼的影响之前杀死老鼠。这需要进行多次实验，而且非常费力、昂贵和耗时。更重要的是，它可能需要使用许多动物，因为需要测试几个条件，例如需要服用多少药物才能看到效果，服用多长时间，多长时间。另一个重要的问题是，有时很难知道老鼠对病人病情的预测有多准确。这是因为我们从未能够对它们进行适当的比较。要做到这一点，我们需要取一些骨头碎片进行分析。我们可以在老鼠身上取骨样本，但在病人身上就不那么简单了，因为即使取极小的样本也可能是一个令人不快的过程，如果是为了研究目的，实际上只能在极少数志愿者身上做。该项目旨在通过创建能够预测药物如何起作用、需要多少以及持续多长时间的计算机程序来克服这些问题。类似的程序也正在开发中，以预测患者的反应，因此可以在人类和小鼠之间进行比较。这样，当必须测试一种新药时，我们可以先使用计算机程序，然后确定最佳剂量和给药时间，只在一小群动物中进行测试，以验证计算机预测的准确性。为了创建计算机程序，我们将首先通过服用一种药物来收集数据，这种药物已知可以使骨骼发育良好，并且已经用于患有骨质疏松症的患者；给老鼠注射不同剂量和不同时间的药物，然后从两方面分析对骨量和强度的影响。一种是用传统的方法观察几个不同的时间点，另一种是使用一种新的设备，称为体内微计算机断层扫描（microCT）扫描仪，它能够在一段时间内观察同一只老鼠的骨骼，而不需要杀死它。该设备与患者使用的DEXA扫描非常相似。我们将新方法与传统方法进行比较，以确保新方法的性能与传统方法相同或更好。这些数据将被用来生成一个方程来模拟骨骼是如何形成的，这样当需要测试一种新药时，我们就可以用这个方程来预测它的效果。通过同时采用新的设备-体内微ct和这个方程，我们将减少使用的小鼠数量，并且得出的数据将更加精确，因为它们是在同一只小鼠中测量的。此外，我们可以在人类身上建立类似的程序，并在小鼠预测患者反应时更好地比较两者的理解。

We want to develop computer programs to test new therapies for diseases of bone to reduce animal testing and accelerate research progress. Musculoskeletal disease including arthritis, osteoarthritis and osteoporosis are the most prevalent cause of work-related disease affecting the UK and account for one third of GP consultations. Patients affected by these conditions have often reduced mobility, leading to isolation and poor quality of life. Despite excellent progress in the care of these conditions there are still high numbers of people, who do not respond to these treatments very well. New cures are therefore required for these patients.Any new drug needs to be tested on animals before it can be used in people. This is not only to see if the drugs are safe but also to understand whether they are efficacious. When doing this, groups of mice are needed to test each individual dose or time of administration and the mice have to be killed before the effect of the drug on bone can be determined. This can take many experiments, and is very laborious, expensive and time consuming. More importantly, it may require the use of many animals as several conditions need to be tested, such as how much drug needs to be administered to see a benefit, for how long and how often. Another important problem is that sometimes it is difficult to know how well the mouse will predict what will happen in patients. This is because we have never been able to compare them properly. To do that, we need to take pieces of bone for analysis. We can take bone samples in mice but this is less straightforward in patients because even taking extremely small samples can be an unpleasant procedure and if done for research purposes can only be practically done in very small numbers of volunteers. This project aims to overcome these problems by creating computer programs able to predict how a drug may work, how much is needed and for how long. Similar programs are being created to predict responses in patients, so comparisons between human and mice can be made. In this way when a new drug will have to be tested, we can use the computer program first and then determine the best dose and time of administration to be tested only in a small group of animals to verify the accuracy of the computer prediction. To create the computer program we will collect data first by taking a drug which is known to build bone well and is already used in patients affected by osteoporosis; giving it to mice at different doses and for different times and then analysing the effects on bone mass, and strength in two ways. One in the traditional way of looking at several different time points, and one uses a new piece of equipment, called an in vivo microcomputed tomography (microCT) scanner, which is capable of looking at the bones in the same mouse over a period of time, without the need to kill it. This equipment is very similar to the DEXA scan used in patients. We will compare the new method with the traditional one to ensure the new method performs in the same way or better than the traditional one. The data will be used to generate an equation which will model how bone is formed so that when a new drug needs to be tested we will be able to use this equation to predict how good this will be. By adopting both the new equipment - in vivo microCT and this equation we will reduce the number of mice used, and the data derived will be more precise because they have been measured in the same mouse. Moreover, we can build similar programs in humans and compare the two understanding better when mice will predict patients' response.