(taken from the application) The R03 candidate has made outstanding progress in the K08 study entitled """"""""Glucocorticoid (GC)-Induced Osteoporosis in Childhood Nephrosis"""""""" (1 K08 DK02523-03). She has enrolled 124 children with nephrotic syndrome (NS) and 150 healthy controls. In the course of these studies, she has identified important limitations of dual energy x-ray absorptiometry (DXA) in the assessment of bone mineralization in children with chronic disease. Although DXA is a widely accepted tool, DXA integrates bone mass in a projected area, prohibiting discrete assessment of cortical and trabecular structure and density. Studies of GC effects in adults have emphasized trabecular sites. However, growth is characterized by rapid expansion of cortical bone, a major determinant of bone strength. In addition, muscle contraction stimulates cortical modeling and children with decreased muscle strength have decreased cortical thickness. A recent animal study underscores the impact of GC on the growing skeleton: young rats treated with GC exhibited severe impairment of cortical expansion and trabecular mineralization. The recent availability of peripheral quantitative computed tomography (pQCT) substantially improves the assessment of bone mineralization. This method quantitates trabecular and cortical bone material properties and architecture, integrating these data to estimate bone strength. The NS subjects studied to date exhibit decreased height and increased adiposity in the setting of substantial GC exposure. However, standard DXA measures failed to demonstrate osteopenia in these subjects. The application of newer volumetric DXA techniques revealed decreased trabecular density in NS. Despite this advance, cortical structure and density could not be addressed due to the limitations of DXA. Therefore, we now propose expanding the current K08 protocol to included pQCT measures of bone structure and strength, and isometric dynamometric measures of muscle strength in the NS subjects and 200 additional healthy controls enrolled in our on-going K08 study. The primary hypotheses are that pQCT and dynamometry will describe more accurately the unique effects of GC on the growing skeleton, and that children with chronic GC therapy will exhibit cortical thinning and decreased muscle strength. The relative contributions of decreased muscle strength, and trabecular and cortical mineralization defects in children with GC-induced osteopenia will have important therapeutic implications. This proposed expansion of the K08 will provide the applicant with an effective springboard to a career as a fully independent investigator.
