Skeletal Health and Bone Marrow Composition in Adolescents with Crohn’s Disease

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Project Summary Children with Crohn’s disease (CD) often have low bone mineral density (BMD) and altered bone structure, resulting in increased skeletal fragility. While bone formation is compromised in pediatric and adolescent patients at diagnosis with CD, the factors mediating these disease-related complications remain poorly understood and represent a critical opportunity to identify proactive measures and therapies for young patients with CD. The majority of bone mass is acquired by late adolescence through the acceleration of bone turnover, including bone formation and resorption. A failure to achieve peak bone mass increases the lifetime risk of osteoporosis. Hematopoietic (red) bone marrow converts to lipid-rich (yellow) marrow during normal skeletal development in healthy children and adolescents. Conditions that accelerate the conversion of premature red to yellow marrow - and possibly its reversibility - are central to the deficits in bone health in youth with CD. The presence of increased marrow fat in adolescents and adults is associated with reduced biomechanical strength, with implications for fracture risk. In other pediatric diseases, the hormonal milieu can alter mesenchymal stem cells to differentiate preferentially into adipocytes over osteoblasts, compromising osteogenesis. We will examine adolescents with newly-diagnosed CD at baseline and one year later to evaluate the impact of CD inflammatory activity on marrow fat, BMD, bone turnover markers, and to correlate with peripheral blood immune parameters. This project is a prospective, longitudinal, case-control study with the following aims: (1) Using magnetic resonance imaging (MRI), dual-energy x-ray absorptiometry (DXA), and peripheral quantitative computed tomography (pQCT), evaluate bone marrow composition, areal and volumetric BMD in adolescents with newly- diagnosed CD and compare to healthy matched controls; (2) Examine changes in marrow fat and BMD at one year after diagnosis, across patients with CD versus in healthy matched controls, and investigate the associations between marrow fat, BMD, and body composition; and (3) To evaluate the mechanism of compromised bone formation in patients with CD, we will investigate bone turnover markers and immune cellular/molecular parameters and their associations with BMD and marrow fat. Dr. Gordon’s career goal is to become an independent clinical researcher, applying state-of-the-art research methods to clinically relevant problems in pediatric bone health. During the K23 award, Dr. Gordon will acquire the requisite skills in clinical and translational investigation through a combination of formal didactic coursework, attendance at seminars and conferences, personalized mentoring, and hands-on research experience in the supportive environment of Boston Children’s Hospital and Harvard Medical School. She will be mentored by leading investigators in the fields of inflammatory bowel disease and bone and mineral metabolism. In summary, this study will utilize state-of-the-art tools to investigate novel mechanisms of disease in an understudied population, and serve as a basis for developing Dr. Gordon’s career as an independent physician scientist.