Gordon L. Klein

The Management of Acute Bone Loss in Severe Catabolism due to Burn Injury

Reduced bone formation has been documented in both children and adults following burn injury of > or = 40% total body surface area. In children, reduced bone formation and hypercalciuria may be the underlying causes of acute and sustained reduction in bone mineral density. The possible consequences of this reduction are an increase in extrapolated annual fracture incidence and reduced peak bone mass. Excessive endogenous glucocorticoid production, immobilization, bone marrow suppression, and magnesium depletion are all postulated as underlying causes. The most promising potential management agent is recombinant human growth hormone, which can stimulate bone formation via production of insulin-like growth factor I(IGF-I) and its associated binding protein, IGFBP-3, which correlates with bone mineral density in adults. Long-term treatment may be necessary to see a positive effect on bone formation and bone density. Correcting any detected magnesium depletion, and exercise as tolerated, are two other management strategies that might improve bone formation in this population.

Pamidronate attenuates muscle loss after pediatric burn injury.

Children who are burned >40% total body surface area lose significant quantities of both bone and muscle mass because of acute bone resorption, inflammation, and endogenous glucocorticoid production, which result in negative nitrogen balance. Because administration of the bisphosphonate pamidronate within 10 days of the burn injury completely prevents the bone loss, we asked whether muscle protein balance was altered by the preservation of bone. We reviewed the results from 17 burned pediatric subjects previously enrolled in a double‐blind randomized controlled study of pamidronate in the prevention of post‐burn bone loss and who were concurrently evaluated for muscle protein synthesis and breakdown by stable isotope infusion studies during the acute hospitalization. We found a significantly lower fractional protein synthesis rate (FSR) in the pamidronate group and a correspondingly lower rate of appearance of the amino acid tracer in venous blood, suggesting lower muscle protein turnover. Moreover, net protein balance (synthesis minus breakdown) was positive in the subjects receiving pamidronate and negative in those receiving placebo. Muscle fiber diameter was significantly greater in the pamidronate subjects and leg strength at 9 months post‐burn was not different between subjects who received pamidronate and normal physically fit age‐matched children studied in our lab. Leg strength in burned subjects who served as controls tended to be weaker, although not significantly so. If substantiated by a larger study, these results suggest that bone may have a paracrine mechanism to preserve muscle and this finding may have implications for the treatment of sarcopenia in the elderly.

The effect of burn on serum concentrations of sclerostin and FGF23

Severe burn results in acute bone resorption followed by an adynamic state, most likely due to changes brought about by the inflammatory and glucocorticoid responses to the injury. There is a consequent increase in annual extrapolated fracture incidence in children. While osteoblasts have been reported to disappear from the bone surface and stem cell differentiation into osteoblasts is impaired, the effect of burns on osteocyte function is unknown. We measured serum concentrations of two osteocyte proteins, sclerostin and fibroblast growth factor (FGF)-23 between 6 and 60 days post-burn in pediatric patients, ages 5-18 years who had participated in a randomized controlled double-blind study of acute administration of pamidronate to prevent the resorptive bone loss. While FGF-23 was undetectable in all samples, the plot of sclerostin concentration versus time post-burn yielded a statistically significant difference between slopes, -2.5 in the placebo control group and +3.5 in the group receiving pamidronate, p=0.016 by ANCOVA. The FGF23 data suggest that osteocytes may be apoptotic, although the sclerostin data may indicate partial preservation of osteocyte function in subjects receiving pamidronate or an ectopic source of sclerostin.

Calcemic response to burns differs between adults and children: A review of the literature

Objectives The calcemic and parathyroid hormone (PTH) responses to severe burn injury appear to differ between children and adults. In our limited studies children exhibited hypocalcemic hypoparathyroidism consistent with up-regulation of the parathyroid calcium-sensing receptor (CaSR) while adults did not, suggesting a developmental cutoff in cytokine-mediated up-regulation of the CaSR. This difference may be clinically important as published studies indicate that extracellular calcium (Ca) may stimulate the inflammatory response. The aim of this study was to examine the existing literature on burns to see if the differences between pediatric and adult calcemic and PTH responses to burn supported our findings providing stronger evidence to support this developmental difference. Methods We reviewed the National Library of Medicine database using the terms burns, PTH and ionized calcium and found 9 articles from 8 different medical centers; one was eliminated due to mixing of adults and children. Results There were 245 burn patients reported from the literature, 178 pediatric and 67 adults. The data are mostly consistent with our reported findings. Of the 10 pediatric patients with severe burns that we studied, mean ionized Ca concentration was below the lower limit of normal of 1.10 mM. The 67 adult burn patients reported in the literature had a mean blood ionized Ca concentration that was within the adult normal range or was lower than normal but with secondary hyperparathyroidism. Moreover, serum PTH concentrations were uniformly low in the 178 children in the burn literature but normal or mildly elevated in the 67 adults. Conclusions These results support the hypothesis that the difference between pediatric and adult victims is consistent with an age-related CaSR response to cytokine stimulation and may be consistent with a lower level of inflammation in children. Ionized Ca and PTH might serve as possible therapeutic targets to lower the inflammatory response in burn victims.