Glucocorticoid use and osteonecrosis in chronic pediatric inflammatory diseases

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.