Mineral and bone metabolism after burns
Key Points
- Severe burns cause rapid bone loss through glucocorticoid-mediated osteoblast apoptosis, cytokine-driven PTH suppression, and chronic vitamin D deficiency [1][2][3]
- Burned skin synthesizes vitamin D at only 20-25% of normal capacity, making supplementation the only means to ensure vitamin D sufficiency [2]
- Patients with burns greater than 40% TBSA should be monitored for bone mineral density loss and are at increased fracture risk [3]
- Acute pamidronate administration may help preserve bone mass in severely burned children [10]
- Vitamin D supplementation corrects hypovitaminosis D and may improve muscle strength but has not yet demonstrated bone density improvement in burn patients [9]
Overview
Severe burn injury produces profound disturbances in mineral and bone metabolism that lead to rapid bone loss, increased fracture risk, and prolonged musculoskeletal morbidity [1][2]. The mechanisms are multifactorial: the stress response generates endogenous glucocorticoids that cause osteoblast apoptosis and suppress bone formation; the inflammatory response produces cytokines that disrupt calcium homeostasis; and the injured skin loses the capacity to synthesize vitamin D normally [1][2]. Klein has been the leading investigator in this field, establishing through a series of studies that postburn bone loss is rapid, sustained, and mediated by a unique pathophysiology distinct from other forms of osteoporosis [1][2][3].
Pathophysiology of bone loss
Glucocorticoid-mediated osteoblast suppression
The stress response to burn injury produces large amounts of endogenous glucocorticoids that decrease osteoblasts on the mineralization surface of bone and inhibit differentiation of marrow stromal cells into osteoblasts [1]. This reduces bone formation and, because osteoblasts are required for osteoclastogenesis through RANK ligand production, also blocks normal bone resorption pathways, resulting in a state of low bone turnover with net bone loss [1].
Cytokine-mediated calcium dysregulation
The inflammatory response generates cytokines including interleukin-1beta and interleukin-6, which upregulate the calcium-sensing receptor (CaSR) on parathyroid gland chief cells [1][5]. This upregulation lowers the serum calcium set point required to suppress parathyroid hormone (PTH) production, resulting in hypocalcemic hypoparathyroidism and urinary calcium wasting [1][2]. Hendy and Canaff reviewed the role of the CaSR as both a promoter of and responder to inflammation, with proinflammatory cytokines acting through defined response elements in the CaSR gene promoters to decrease serum PTH and 1,25-dihydroxyvitamin D levels [5].
Vitamin D deficiency
Burn-injured skin, both scarred areas and normal-appearing adjacent skin, converts 7-dehydrocholesterol to previtamin D3 at a rate that is only 20 to 25% of normal skin [2]. Circulating levels of 25-hydroxyvitamin D are chronically low in burn patients [2][6]. Klein described a pathologic cascade: burn injury gives rise to calcium wasting, failure of bone to take up excessive calcium released during acute bone resorption, and vitamin D insufficiency to frank deficiency [2]. The resulting deficiency of 1,25-dihydroxyvitamin D may contribute to derepression of renin production, elevated angiotensin II levels, and insulin resistance [1].
Clinical manifestations
Bone mineral density loss
Wray et al. studied 41 pediatric burn patients (mean 53.1% TBSA) and found that decreased 25-hydroxycholecalciferol and 1,25-dihydroxycholecalciferol levels correlated with serum calcium and phosphorus abnormalities [7]. During the initial week of hospitalization, there was no correlation between vitamin D and other variables, possibly due to burn shock effects, but after the first week vitamin D significantly affected phosphorus homeostasis [7].
Terzi and Guven studied 25 male patients more than one year postburn (greater than 30% TBSA) and found significantly lower femoral neck z scores, bone mineral density values, 25(OH) vitamin D3, and bone-specific ALP compared with controls [8]. A negative correlation between Modified Vancouver Scar Scale Score and vitamin D levels was identified, suggesting that patients with more severe scarring are at highest risk for vitamin D deficiency [8].
Fracture risk
Klein summarized that bone loss occurs quickly following a severe burn, is sustained, and increases the risk of postburn fracture [3]. Patients with burns greater than 40% TBSA should be monitored for bone loss [3].
Treatment strategies
Vitamin D supplementation
Rech et al. reviewed vitamin D in burn-injured patients and found that low 25(OH)D levels were observed in nearly all pediatric and most adult burn patients [6]. The preferred vitamin D dose, formulation, and route of administration remain unknown, and there is limited data on the impact of vitamin D status on clinical outcomes [6].
Rousseau et al. conducted a pilot randomized controlled trial of cholecalciferol supplementation (200,000 IU quarterly intramuscular injection) with optimized calcium intake in 15 adults with burns dating 2 to 5 years prior [9]. After one year, calcidiol levels significantly increased in the supplemented group (to 40 ng/mL). The supplementation improved quadriceps strength at high velocity but did not significantly change bone mineral density [9]. Notably, 66% of all patients had vitamin D deficiency and 53% (including 3 men under age 40) were osteopenic at inclusion [9].
Bisphosphonates
Klein et al. conducted a randomized, double-blind, placebo-controlled study of acute intravenous pamidronate administration in 43 children with burns greater than 40% TBSA [10]. At discharge, lumbar spine bone mineral content was significantly higher in the pamidronate group (P < 0.005), and by 6 months postburn, total body bone mineral content was also significantly higher (P < 0.05) [10]. Pamidronate did not exacerbate hypocalcemia [10]. The proposed mechanism was inhibition of glucocorticoid-induced apoptosis of osteoblasts and osteocytes [10].
Bone metabolism monitoring
Schryver et al. reviewed 11 randomized, placebo-controlled, prospective clinical trials evaluating the impact of severe burns on markers of bone formation and bone metabolism in pediatric patients [4]. The clinical utility of individual biomarkers (osteocalcin, sclerostin, bone morphogenetic protein-2, type I collagen markers) remains uncertain for acute burn care decision-making [4].
Controversies and Evidence Gaps
Optimal vitamin D supplementation regimens (dose, formulation, route, duration) for burn patients are not established [6]. Whether vitamin D supplementation can prevent or reverse postburn bone loss when initiated early is unknown. The long-term efficacy of bisphosphonates in preventing postburn fractures has not been established in large trials. Most evidence comes from pediatric populations; adult burn bone metabolism data are limited. The interaction between anabolic agents (oxandrolone, growth hormone) and bone metabolism in burns needs further characterization. Whether exercise programs during rehabilitation can attenuate postburn bone loss independent of pharmacologic intervention is not established. The role of calcium supplementation timing and dosing in the context of cytokine-mediated CaSR upregulation is poorly understood.
References
[1] Klein GL. "The interaction between burn injury and vitamin D metabolism and consequences for the patient." Curr Clin Pharmacol 2008;3:204-210. PMID: 18781907 [2] Klein GL. "Burns: where has all the calcium (and vitamin D) gone?" Adv Nutr 2011;2:457-462. PMID: 22332088 [3] Klein GL. "Burn-induced bone loss: importance, mechanisms, and management." J Burns Wounds 2006;5:e5. PMID: 16921418 [4] Schryver E et al. "Bone metabolism in pediatric burned patients: A review." Burns 2018;44:1863-1869. PMID: 30077487 [5] Hendy GN et al. "Calcium-sensing receptor, proinflammatory cytokines and calcium homeostasis." Semin Cell Dev Biol 2016;49:37-43. PMID: 26612442 [6] Rech MA et al. "Vitamin D in burn-injured patients." Burns 2019;45:32-41. PMID: 29776863 [7] Wray CJ et al. "The 2002 Moyer Award. Metabolic effects of vitamin D on serum calcium, magnesium, and phosphorus in pediatric burn patients." J Burn Care Rehabil 2002;23:416-423. PMID: 12432318 [8] Terzi R et al. "Bone Mineral Density After Burn Injury and Its Relation to the Characteristics of Scar Tissue." J Burn Care Res 2016;37:e263-e267. PMID: 25882515 [9] Rousseau AF et al. "Effects of cholecalciferol supplementation and optimized calcium intakes on vitamin D status, muscle strength and bone health: a one-year pilot randomized controlled trial in adults with severe burns." Burns 2015;41:317-325. PMID: 25239849 [10] Klein GL et al. "The efficacy of acute administration of pamidronate on the conservation of bone mass following severe burn injury in children: a double-blind, randomized, controlled study." Osteoporos Int 2005;16:631-635. PMID: 15452689