We previously found that in children recovering from burns of >40% TBSA, disturbances in bone metabolism result in long-term deficits in bone mineral density (BMD) which result in decreased peak bone mass and increase the risks of later fracture. Measurements we made of indirect indices of bone turnover suggest disturbances in bone protein and mineral anabolism and re-modeling, all important processes in bone growth. However, no direct kinetic measurements of these processes have been made either in burned children or in children in whom bone growth would be expected to be normal. 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. We wish to compare 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. scoliosis) unlikely to have a major impact upon bone metabolism. The present application only concerns studies in normal children since we already have IRB approval for the studies in burned children (IRB 92-304). However in order to interpret the results and to gain insights into normal bone physiology currently lacking, we need information on the bone growth in metabolically normal children. In a separate, but related study we wish to examine discover the effects of acute burn injury and recovery on collagen metabolism of unburned skin, and of scar tissue. We therefore wish to sample some skin (~2g) at the margin of the wound made during elective orthopedic surgery to provide samples of unburned, normal skin, analysis. The analysis of this skin will enable us to make comparisons with samples from burned children, to discover what differences if any exist in their respective skin collagen metabolism. Our general hypothesis is that, in burned children, bone (and unburned skin) collagen synthesis and bone calcium turnover are depressed. To test this we will examine bone mineral turnover and collagen synthesis using non-radioactive, stable isotope tracer methodology. We will use Ca, to probe bone mineral accretion and stable tracer amino acids including C6 Phenylalanine, N proline and C proline (applied in a novel flooding dose protocol developed by us) for assay of skin and bone protein, particularly collagen synthesis, which has never before been applied to the study of skin or bone in children. We also wish to examine the relationships of these dynamic measure of bone metabolism 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). The results will provide new information concerning normal human bone collagen and calcium metabolism during growth, an area in which information is almost non-existent. In addition it should allow us to gain insights into the mechanisms impairing bone growth in previously burned children, which may help us to identify new therapeutic targets, thereby possibly benefitting the influence, 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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