We previously found that in children recovering from burns of approximately 40% TBSA, disturbances in bone metabolism result in long-term deficits in bone mineral density (BMD) which will result in decreased peak bone mass and increase the risks of later fracture. Measurement of indirect indices of bone turnover suggest disturbances in bone protein and mineral anabolism and also bone remodeling, all important processes in bone growth. However no direct kinetic measurement of these processes have been made. Our general hypothesis is that adequate bone growth and mineralization are unlikely to occur unless bone collagen synthesis occurs normally and that in burned children these processes are slowed or arrested. To test this we will examine bone mineral turnover and collagen synthesis using non- radioactive, stable isotope tracer methodology. We will use 42Ca and 44 Ca, to probe bone accretion and resorption and 13C and 15N proline (applied in a novel flooding dose protocol) for assay of collagen synthesis, which has never before been applied to the study of bone in children. We will begin our studies by comparing differences in bone metabolism, composition and histomorphometry between children recovering from major burn injury and normal children studied during admission for a elective orthopedic reconstructive surgery, for conditions (e.g. sclerosis) unlikely to have a major impact upon bone metabolism. The prediction is that in the burned children bone synthesis and bone calcium turnover are depressed, features which correlate with measures of indirect indices of bone collagen and mineral metabolism (e.g. serum C- terminal Type 1 (I) pro-collagen peptide, osteocalcin. parathyroid hormone and urinary deoxypyridinoline excretion). Having obtained this baseline information we intend to test three therapeutic interventions (i.e. growth hormone administration, participation in a weight-bearing exercise program, and inhibition of cortisol secretion by ketoconazole administration). The results will not only provide insights into the mechanisms impairing bone growth in previously burned children, but should also help to identify new therapeutic targets; they may possibly benefit the influence the design and implementation of rehabilitation programs. Furthermore, the new knowledge could help us understand the underlying pathology involved in osteopenia in children and osteoporosis in adults.
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