Glucocorticoid use and osteonecrosis in chronic pediatric inflammatory diseases

描述(申请人提供)：糖皮质激素(GC)是广泛用于治疗许多慢性儿科炎症性疾病的药物。在被归因于GCs的许多毒性中，骨坏死(ON，也称为缺血性坏死)是较严重的毒性之一，在一些人中会导致严重的疼痛、残疾和手术关节置换的需要。尽管已经很久了 关于儿童白血病等疾病与大剂量GC暴露的关系，在更广泛的儿科人群中，与这些常用药物相关的ON风险仍未得到很好的了解。关于某些炎症性疾病是否独立于GC剂量影响ON的风险，以及这种联系是否随着年龄的变化而变化，仍然存在其他问题。拟议的项目旨在通过以下广泛目标扩大对GC使用和ON之间的关系的了解：1)研究不同的GC暴露模式如何影响儿童和青少年ON的发展；2)确定年龄和潜在的炎症性疾病是否改变了GC和ON之间的联系；3)对申请者进行药物流行病学方法方面的培训，将其应用于慢性炎症疾病的治疗；以及4)支持申请者作为独立的临床研究人员的发展。申请者将利用来自联合王国的大型医疗记录数据库来实现所述目标。该数据库包含广泛的人口统计学、医学和治疗信息，并已成功地用于先前的药物流行病学研究。有和没有GC暴露的队列将从患有各种炎症性疾病的儿童和青少年人群中聚集起来。通过一系列不同的模型来表示GC的使用，将通过COX比例风险回归来评估GC与新诊断的、临床明显的On之间的关联。然后，这些模型将被用作测试按年龄和疾病诊断进行效果修改的基础。如果合适，将进行分组分析。申请者将在一名高级研究员和一组参与的共同导师和合作者的指导下完成这些目标，作为持续参与严格临床研究培训计划的一部分。由于得到了 作为K23/K08奖项的一部分，申请者将发展和完善在抗炎和免疫抑制药物的药物流行病学方面进行进一步研究所需的技能。此外，该F32奖项支持的项目的结果将通过量化广泛处方药物导致的严重骨病风险，并通过评估可能改变这种风险的一些关键因素，为儿科的多个领域做出有价值的贡献。这项研究的见解可能最终导致未来更好的治疗、监测和预防策略。

DESCRIPTION (provided by applicant): Glucocorticoids (GCs) are widely used medications for many chronic pediatric inflammatory diseases. Among the many toxicities attributed to GCs, osteonecrosis (ON, also called avascular necrosis) is one of the more serious, leading in some individuals to severe pain, disability, and the need for surgical joint replacement. Despite a long described association with high-dose GC exposure for diseases such as pediatric leukemia, the risk for ON in association with these commonly used medications in the broader pediatric population is still not well understood. Additional questions remain about whether certain inflammatory diseases affect the risk of ON independent of GC dosage, and whether this association changes with age. The proposed project aims to expand understanding of the relationship between GC use and ON through the following broad objectives: 1) examine how different patterns of GC exposure affect the development of ON in children and adolescents; 2) determine whether age and underlying inflammatory disease modify the association between GCs and ON; 3) train the applicant in methods of pharmacoepidemiology as they apply to treatments of disorders of chronic inflammation; and 4) support the applicant's development as an independent clinical investigator. The applicant will leverage a large medical records database from the United Kingdom to achieve the stated objectives. This database contains extensive demographic, medical, and therapeutic information and has been used successfully for prior pharmacoepidemiologic research. Cohorts with and without GC exposure will be assembled from a population of children and adolescents with diverse inflammatory diseases. Through a series of different models to represent GC use, the association between GCs and newly diagnosed, clinically apparent ON will be evaluated through Cox proportional hazards regression. These models will then be used as a foundation to test for effect modification by age and disease diagnosis. If appropriate, subgroup analysis will be performed. The applicant will complete these objectives with the help of directed one-on-one mentoring from a senior investigator and a team of participating co-mentors and collaborators, as part of ongoing participation in a rigorous clinical research training program. As a result of the support from the NRSA, the applicant will develop and refine the skills necessary to conduct further research in the pharmacoepidemiology of antiinflammatory and immunosuppressant medications as part of a K23/K08 award. Moreover, the results of the project supported by this F32 award will contribute valuably to multiple fields of pediatrics, by quantifying the risk of serious bone diseae from a widely prescribed medication, and by evaluating some of the key factors that might modify this risk. Insights from this study may eventually lead to better strategies for treating, monitoring for, and preventing ON in the future.