Histomorphometric and biochemical characterization of bone following acute severe burns in children

Klein, Gordon L.; Herndon, David N.; Goodman, William G.; Langman, Craig B.; Phillips, William A.; Dickson, Ian; Eastell, Richard; Naylor, Kim; Maloney, Norma A.; Desai, M. H.; Benjamin, Debra A.; Alfrey, Allen C.

doi:10.1016/8756-3282(95)00279-1

Cited by 146 publications

(119 citation statements)

References 22 publications

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“…The effects of IL-1␤ were counteracted by the IL-1 receptor antagonist, indicating that the cytokine was acting via a specific IL-1 receptor on parathyroid cells. Circulating levels of IL-1␤ are elevated after severe burn injury, which is associated with severe abnormalities of bone and mineral metabolism (38). The use of a sheep model demonstrated that the hypocalcemia that follows severe burn injury is related to up-regulation of parathyroid gland CASR expression (22).…”

Section: Discussionmentioning

confidence: 99%

Calcium-sensing Receptor Gene Transcription Is Up-regulated by the Proinflammatory Cytokine, Interleukin-1β

Canaff¹,

Hendy

2005

Journal of Biological Chemistry

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The calcium-sensing receptor (CASR) in parathyroid, thyroid, and kidney is essential for calcium homeostasis. Hypocalcemia is common in critically ill patients having increased circulating proinflammatory cytokines, although the causes are unknown. We hypothesized that the cytokines increase CASR expression and reduce the set point for parathyroid hormone suppression by extracellular calcium, leading to hypocalcemia and hypoparathyroidism. Here, we show in vivo in the rat that parathyroid, thyroid, and kidney CASR mRNA and protein increased after injection of interleukin-1␤. This was associated with decreased circulating parathyroid hormone, calcium, and 1,25-dihydroxyvitamin D levels. Interleukin-1␤ stimulated endogenous CASR gene transcripts and transfected promoter reporter activity in human thyroid C-cells (TT cells) and kidney proximal tubule (HKC) cells. Cotransfection of NF-B proteins enhanced activity of the reporter constructs, whereas cotransfection with inhibitor-B or application of an NF-B nuclear localization sequence peptide abrogated responsiveness to cytokine or NF-B proteins. Mutagenesis of some, but not all, of the potential B elements in the 5 part of the CASR gene led to loss of responsiveness to cytokine. These elements conferred cytokine responsiveness to a heterologous promoter, and in electrophoretic mobility shift assays, NF-B complexes formed on the same three B elements. In summary, the CASR gene has several functional B elements that mediate its upregulation by proinflammatory cytokines and probably contribute to altered extracellular calcium homeostasis in the critically ill.

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Section: Discussionmentioning

confidence: 99%

Calcium-sensing Receptor Gene Transcription Is Up-regulated by the Proinflammatory Cytokine, Interleukin-1β

Canaff¹,

Hendy

2005

Journal of Biological Chemistry

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“…37,38 However, typically, a more chronic state of decreased bone resorption develops as a result of loss of cell signaling to osteoclast progenitors. 39 Decreased bone formation and resorption have also been observed in the setting of increased endogenous glucocorticoid production (eg, in burn injury in children 40 ). The effects of glucocorticoids on bone cells are summarized in Table 1.…”

Section: Glucocorticoid Effects On Bone Formation and Resorptionmentioning

confidence: 99%

Section: Osteoimmunology: the Interplay Between The Immune System Andmentioning

confidence: 99%

“…[44][45][46] It is notable that some studies of bone resorption markers in inflammatory conditions have shown increased resorption, 47 whereas another study demonstrated decreased resorption in the setting of increased endogenous cortisol. 40 It has been hypothesized that the number of osteoblasts are decreased to the point that RANKL production is reduced.In addition to detrimental effects on bone metabolism, inflammatory cytokines such as TNF-␣ and IL-1 also adversely affect whole-body protein and energy metabolism, which is similar to glucocorticoid effects. 48 Specifically, TNF-␣-induced activation of nuclear factor B inhibits skeletal-muscle differentiation by suppressing MyoD messenger RNA.…”

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confidence: 99%

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Glucocorticoid-Induced Osteoporosis in Children: Impact of the Underlying Disease

Leonard

2007

Pediatrics

110

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Glucocorticoids inhibit osteoblasts through multiple mechanisms, which results in significant reductions in bone formation. The growing skeleton may be especially vulnerable to adverse glucocorticoid effects on bone formation, which could possibly compromise trabecular and cortical bone accretion. Although decreased bone mineral density has been described in various pediatric disorders that require glucocorticoids, and a population-based study reported increased fracture risk in children who require Ͼ4 courses of glucocorticoids, some of the detrimental bone effects attributed to glucocorticoids may be caused by the underlying inflammatory disease. For example, inflammatory cytokines that are elevated in chronic disease, such as tumor necrosis factor ␣, suppress bone formation and promote bone resorption through mechanisms similar to glucocorticoid-induced osteoporosis. Summarized in this review are changes in bone density and dimensions during growth, the effects of glucocorticoids and cytokines on bone cells, the potential confounding effects of the underlying inflammatory-disease process, and the challenges in interpreting dual-energy x-ray absorptiometry results in children with altered growth and development in the setting of glucocorticoid therapy. Two recent studies of children treated with chronic glucocorticoids highlight the differences in the effect of underlying disease, as well as the importance of associated alterations in growth and development. S166LEONARD by guest on May 10, 2018 http://pediatrics.aappublications.org/ Downloaded from D URING CHILDHOOD AND adolescence, skeletal development is characterized by gender-, maturation-, and race-specific increases in cortical dimensions and trabecular density. The 2000 National Institutes of Health Osteoporosis Prevention, Diagnosis, and Therapy Consensus Development Conference identified bone accrual during childhood as a critical determinant of lifelong skeletal health. The authors of the resulting consensus statement 1 specifically called for research to determine the impact of chronic diseases and glucocorticoid therapy on bone accrual in children.Glucocorticoid-induced osteoporosis (GIO) is the most common cause of secondary osteoporosis in adults and is the result of profound effects of glucocorticoids on bone cells. 2 Glucocorticoids inhibit osteoblastogenesis and promote osteoblast apoptosis, which results in significant reductions in bone formation. 3 Studies in adults have demonstrated that glucocorticoids cause rapid, dose-dependent bone loss and increased fracture risk. 4 The growing skeleton may be especially vulnerable to adverse glucocorticoid effects on bone formation, which could possibly compromise trabecular and cortical bone accretion.Glucocorticoids are used in myriad pediatric diseases. Decreased bone mineral density (BMD) has been described in various pediatric disorders that require glucocorticoids, including asthma, juvenile rheumatoid arthritis, inflammatory bowel disease, systemic lupus erythematosus, and organ trans...

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“…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.…”

Section: Introductionmentioning

confidence: 99%

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

Przkora

Herndon

Sherrard

et al. 2007

Bone

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We have previously shown that pamidronate, when given within ten days of burn injury, preserves lumbar spine bone mineral content from admission to discharge in 6-8 weeks and at six months increases both lumbar spine and total body bone mineral content (BMC) over placebo. We followed patients unblinded after 6 months every 3 months up to 2 years post-burn to see if the effects of pamidronate were sustained. Additionally, we assessed bone remodeling at one year post-burn by iliac crest bone biopsy. We enrolled 57 subjects who were initially randomized to pamidronate (n=32) and placebo (n=25). After 2 yr, 21 subjects (pamidronate=8, placebo=13) remained. Analysis of bone densitometry by dual energy x-ray absorptiometry revealed an effect of both treatment (p<0.012 for total body BMC, p<0.001 for lumbar spine BMC, p<0.014 for lumbar spine bone area and p<0.003 for lumbar spine bone density (BMD)) and time (p<0.0003 on total body BMC, p<0.001 on lumbar spine BMC, p<0.001 on lumbar spine bone area, and no significant difference on lumbar spine BMD). There was no interaction between treatment and time. Results for bone histomorphometry revealed no effect of treatment on either static or dynamic parameters but did show an effect of time on osteoid area (p=0.004, surface p<0.001, and width, p<0.001). We conclude that acute administration of pamidronate resulted in sustained therapeutic effect on bone and that this type of administration may serve as a useful adjunct to other therapies in the preservation and augmentation of bone mass following severe burns.

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Histomorphometric and biochemical characterization of bone following acute severe burns in children

Cited by 146 publications

References 22 publications

Calcium-sensing Receptor Gene Transcription Is Up-regulated by the Proinflammatory Cytokine, Interleukin-1β

Calcium-sensing Receptor Gene Transcription Is Up-regulated by the Proinflammatory Cytokine, Interleukin-1β

Glucocorticoid-Induced Osteoporosis in Children: Impact of the Underlying Disease

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

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