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Evidence supporting a role of glucocorticoids in short-term bone loss in burned children
Gordon L Klein1, Lin Xiang Bi, Donald J Sherrard
1Department of Pediatrics, Children's Hospital, University of Texas Medical Branch, 301 University Boulevard, Galveston, TX 77555-0352, USA. gklein@utmb.edu
Insights
Severe pediatric burns cause acute bone loss, potentially due to high cortisol. Studies show reduced osteoblasts and impaired bone formation markers in burn patients, suggesting a glucocorticoid effect on bone health.
Area of Science:
- Pediatric endocrinology
- Skeletal biology
- Burn trauma research
Background:
- Severe burns in children (>40% total body surface area) are associated with acute bone loss.
- The underlying mechanisms contributing to this bone loss remain unclear.
- Endogenous glucocorticoid production is a potential factor influencing bone metabolism post-burn.
Purpose of the Study:
- To investigate the role of elevated endogenous glucocorticoids in pediatric burn-induced bone loss.
- To examine characteristics of corticosteroid-induced bone loss in pediatric burn patients.
- To assess markers of osteoblast differentiation and glucocorticoid receptor expression in burn survivors.
Main Methods:
- Bone histomorphometry was performed on 14 pediatric burn patients.
- Gene expression analysis (RT-PCR) for glucocorticoid receptor, collagen, and alkaline phosphatase was conducted.
- Marrow stromal cell cultures were used to evaluate osteoblast differentiation markers.
Main Results:
- Histomorphometry revealed reduced osteoblast and osteoid surfaces, with fewer detectable osteoblasts and decreased resorptive surfaces.
- A significant decrease in type-1 collagen mRNA was observed in burn patients compared to controls.
- Burn cell cultures showed reduced expression of osteoblast differentiation markers, including core-binding factor a1, bone morphogenetic protein-2, type-I collagen, and alkaline phosphatase.
Conclusions:
- Elevated urinary free cortisol excretion in burn patients suggests increased endogenous glucocorticoid activity.
- The observed low osteoblast number and reduced markers of osteoblast differentiation are consistent with acute glucocorticoid toxicity.
- These findings support a significant role for glucocorticoids in the pathogenesis of acute bone loss following severe pediatric burns.
Abstract:
Children burned > or =40% total body surface area suffer acute bone loss. The reason(s) for this is uncertain. In order to determine whether high endogenous glucocorticoid production can contribute to the bone loss, we sequentially studied a total of 14 pediatric burn patients for bone histomorphometry; 7 of these patients and 4 controls were studied for characteristics of corticosteroid-induced bone loss, including decreased osteoblasts and down-regulation of the glucocorticoid receptor in bone. We then studied 4 of the burn patients and three controls for a decrease in markers of osteoblast differentiation, another feature of glucocorticoid toxicity. Bone biopsies were taken from each of the 14 burn patients a mean of 3 weeks post-burn. Histomorphometry was performed on one specimen ( n=7) and either glucocorticoid and mineralocorticoid receptor, collagen and alkaline phosphatase expression by RT-PCR ( n=7) or marrow stromal cell culture ( n=4) on the other. Patients were permitted a maximum of two biopsies for study. One biopsy was obtained intra-operatively from normal subjects during elective iliac crest alveolar bone grafting and compared with burn specimens for glucocorticoid receptors and marrow stromal cell culture. A 24 h urine specimen was obtained for free cortisol ( n=7). Histomorphometry revealed low osteoblast and osteoid surfaces and few detectable osteoblasts. Resorptive surfaces were also reduced. Glucocorticoid receptor alpha mRNA (GRalpha) was not decreased; however, there was a trend toward inverse relationships between urine free cortisol and GRalpha and type-1 collagen mRNA, r=-0.61 and -0.64, respectively, and a significantly lower mRNA for type-1 collagen in bone in burn vs control patients by the median test, lambda(2)=7.6 ( p<0.01). Markers of osteoblast differentiation, core-binding factor (cbf)a1, bone morphogenetic protein (BMP)-2, type-I collagen, and alkaline phosphatase were reduced in burn cell cultures compared with controls ( p<0.05). The eightfold elevation of urinary free cortisol excretion, low osteoblast number, decreased resorptive surface, and reduced markers of osteoblast differentiation are all consistent with an acute glucocorticoid effect on bone.
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