Evidence supporting a role of glucocorticoids in short-term bone loss in burned children

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.

Urinary Cortisol and Catecholamine Excretion after Burn Injury in Children

“…The exact cause of the hypermetabolic response is still inadequately understood and the biochemical pathways poorly defined. We know that there is a marked increase in stress hormones including glucocorticoids and catecholamines (14,27). This initial increase is due to stimulation of the HPA axis which should, under normal conditions, be controlled via negative feedback by the products of adrenal stimulation.…”

“…Little is know about the magnitude of the change in hormone production or how and when the levels return to normal. One study involving 14 pediatric patients showed an 8-fold increase in cortisol levels after severe thermal injury and linked this to a marked decrease in type I collagen and bone formation, together with a lack of detectable surface osteoblasts and a reduction in biochemical markers of osteoblast differentiation (14). The purpose of this study was to determine, in a large clinical prospective trial, the acute and long-term pattern of urine cortisol and catecholamine expression in severely burned children.…”

The Pathophysiologic Response to Severe Burn Injury.

“…Using labeled tetracycline, they determined bone turnover rates and found that burned patients have almost no bone formation and synthesis. [76][77][78][79][80][81][82] We did not determine bone turnover rates in this study, however, the biochemical markers that we determined indicate that bone metabolism is dysfunctional very early postburn indicating another target for therapeutic intervention. In a recent study, pamidronate 81 was shown to improve bone metabolism during the acute phase and long-term phase postburn.…”

“…63,69,[72][73][74][75] Another striking finding was that osteocalcin and parathyroid hormone were drastically decreased immediately after burn and remained decreased during the acute phase postburn. Klein and colleagues [76][77][78][79][80][81][82] published extensively on bone metabolism postburn. They showed that burned children have decreased BMC and BMD.…”

Pamidronate preserves bone mass for at least 2 years following acute administration for pediatric burn injury

“…Imbalances in hormone and vitamin metabolism such as an eightfold increase in glucocorticoids, hypoparathyroidism resulting in urinary calcium wasting, and a persisting vitamin D deficiency are responsible for a reduction in bone mass as well as bone mineral density in these children. [3][4][5][6][7][8][9] The clinical consequences of these alterations are an increased fracture risk, a reduction in growth velocity, and finally, a likely but unproven reduction in peak bone mass. 2 Therapeutic approaches have been shown to attenuate and increase bone mass after burn in pediatric patients.…”