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research-article2015
NCPXXX10.1177/0884533615587720Nutrition in Clinical PracticeMayes et al
Clinical Research
Investigation of Bone Health Subsequent to Vitamin D Supplementation in Children Following Burn Injury
Nutrition in Clinical Practice Volume 30 Number 6 December 2015 830–837 © 2015 American Society for Parenteral and Enteral Nutrition DOI: 10.1177/0884533615587720 ncp.sagepub.com hosted at online.sagepub.com
Theresa Mayes, RD, CSP, CCRC1,2; Michele M. Gottschlich, PhD, RD, CSP1,3,4; Jane Khoury, PhD5; and Richard J. Kagan, MD4,6
Abstract Background: The effect of supplemental vitamin D on fracture occurrence following burn injuries is unclear. The objective of this study was to evaluate postintervention incidence of fractures in children during the rehabilitative phase postburn (PB) following participation in a randomized clinical trial of vitamin D supplementation. Materials and Methods: Follow-up for fracture evaluation was obtained in 39 of 50 patients randomized to daily enteral vitamin D2, D3, or placebo throughout the acute burn course. Serum 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D, D2, D3, calcitonin, and bone alkaline phosphatase (BAP) measurements were obtained PB day 7, midpoint, discharge, and 1-year PB. Urinary calcium was obtained PB day 7 and midpoint. Dual-energy x-ray absorptiometry (DXA) was performed at discharge and 1-year PB. Results: Fractures were reported in 6 of 39 respondents. Four fractures occurred in the placebo group, 2 in the D2 group, and none in the D3 group. Serum vitamin D, calcitonin, BAP, and urinary calcium were similar between fracture groups. The group with fracture morbidity had larger burn size (83.8% ± 4.9% vs 53.0% ± 2.9%, P < .0001), greater full-thickness burn (69.7% ± 9.4% vs 39.4% ± 4.1%, P = .02), and increased incidence of inhalation injury (33% vs 6%, P = .04). Decreased bone mineral density z score was noted at discharge in the placebo fracture compared with no-fracture group (P < .05). Conclusion: This preliminary report suggests there may be benefit of vitamin D3 in reducing postdischarge fracture risk. Results reaffirm the importance of monitoring bone health in pediatric patients postburn. (Nutr Clin Pract. 2015;30:830-837)
Keywords burns; vitamin D; bone health; pediatrics; vitamin D deficiency; bone density; bone fractures
Background It is widely recognized that a serious burn injury is associated with loss of bone formation and a long-term reduction in bone density.1–9 Bone demineralization in the postburn period and the failure of burned children to gain bone mass during periods of growth heighten the risk for fractures. In fact, the incidence of fractures in the burned pediatric population has been well documented.1,10,11 In 1995, Klein et al1 reported a fracture incidence of approximately 12% in children within 17 months following discharge in patients with a >40% total body surface area (TBSA) burn injury. Fractures were noted in 10 patients, with 2 reported as axial (1 hip; 1 rib) and 8 documented as appendicular (of limb or digit, not specified). Eight years later, a 6% long bone fracture occurrence was described in acutely injured patients with >40% TBSA burns.10 Hypovitaminosis D has been documented during the postburn period.12–14 Multiple physiological roles are supported by vitamin D, including modulation of cell growth,15–17 neuromuscular18–21 and immune function,16,22–25 reduction of inflammation,26,27 and growing evidence of a role in the prevention and treatment of diabetes,28–30 cancer,31–35 and multiple sclerosis.36–40 However, vitamin D is most commonly known for its role in bone metabolism41–45 because it promotes calcium absorption and assists with hemodynamic concentration of calcium and phosphate, enabling bone mineralization.
The relationship of vitamin D to propensity toward fragility fractures following burn injury is unknown. Therefore, the primary objective of this study was to evaluate the occurrence of fractures in children who received different supplemental regimens consisting of vitamin D2, D3, or placebo during the acute postburn course. Evaluation of demographics, serum and urine bone markers, and bone density as related to fracture risk represented secondary analyses.
From 1Department of Nutrition, Shriners Hospitals for Children, Cincinnati, Ohio; 2Division of Nutrition Therapy, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio; 3Department of Research, Shriners Hospitals for Children, Cincinnati, Ohio; 4Department of Surgery, University of Cincinnati College of Medicine, Cincinnati, Ohio; 5Division of Biostatistics and Epidemiology, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio; and 6Department of Surgery, Shriners Hospitals for Children, Cincinnati, Ohio. Financial disclosure: None declared. This article originally appeared online on May 29, 2015. Corresponding Author: Theresa Mayes, RD, CSP, CCRC, Cincinnati Children’s Hospital Medical Center, Division of Nutrition Therapy, 3333 Burnet Ave, Cincinnati, OH 45229, USA. Email: [email protected]
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Materials and Methods This protocol was approved by the University of Cincinnati Human Research Institutional Review Board. A secondary analysis of fracture incidence was conducted in 39 of 50 patients available for follow-up fracture evaluation. These 39 patients had a mean burn size of 58%, mean full-thickness injury of 44%, and mean age of 7.4 years, ranging between 0.7 and 18 years. All were previously enrolled in a randomized vitamin D supplementation trial. The details of the study design and the effect of intervention on vitamin D biomarkers have been published separately.14 In brief, patients were randomized to receive 100 IU/kg/d enteral vitamin D2, D3, or placebo during their acute burn course. Serum 25-hydroxyvitamin vitamin D (D25), 1,25-dihydroxyvitamin D (D1,25), D2 and D3 metabolites, calcitonin, and bone alkaline phosphatase (BAP) were examined at baseline (postburn day 7), midpoint of hospital stay (estimated by 1 day per percent burn divided by 2), date of acute discharge, and 1-year after discharge to examine the association of intervention to longterm bone health. Baseline and midpoint 24-hour urinary calcium, as well as total body dual-energy x-ray absorptiometry (DXA) assessment using pediatric software (version 11.2.1, Hologic, Bedford, MA) and a QDR-Delphi S DXA scanner (Hologic, Bedford, MA) of bone density performed at acute discharge and at 1 year after discharge, represented additional independent variables. Beginning 22 months after enrollment of the final study patient,14 attempts (3 phone calls maximum) were made to contact the parent or primary caregiver of each study participant to ascertain the incidence of long bone fracture since the acute injury. Fracture outcome was differentiated between the vitamin D2, D3, and placebo supplementation groups. Demographics, biochemical markers, and bone density z scores were compared between the positive and negative fracture groups.
Data Analysis Data were managed and analyzed using SAS version 9.3 (SAS Institute, Cary NC). Continuous variables were initially examined for distributional properties. If there was evidence of deviation from the assumption of normality, either an appropriate transformation was used for analysis or an equivalent nonparametric analysis was used. A t test was used to compare age %, TBSA, % full-thickness burn, and postburn day of admission between fracture groups; Fisher exact test was used for sex, race, and inhalation injury comparisons. The vitamin D metabolites calcitonin, bone alkaline phosphatase, and urinary calcium were log transformed for analysis; geometric means with 95% confidence intervals (CIs) are reported. A generalized linear model was used for examining differences in change over time between fracture groups with a Tukey-Kramer adjustment to examine differences at each time point. Mean ± standard
Supplementation Received Placebo (n = 13) Vitamin D2 (n = 13) Vitamin D3 (n = 13)
No. (%) Patients With Fracture 4 (31) 2 (15) 0 (0)
a
Overall P value using Fisher exact test was .13.
error is presented unless otherwise noted. A P value of 19,000 elderly individuals.65 Understandably, an elderly individual is considerably different from a pediatric burn
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patient; however, the similarity between groups as far as vitamin D provision affecting bone health and thus fracture risk cannot be negated. Given the multitude of factors in the acute and rehabilitative phases of burn injury that predispose burn patients to bone demineralization and that no fracture(s) occurred in the patients receiving vitamin D3, the recommendation for vitamin D3 supplementation during the acute phase of burn injury is supported. Furthermore, continued provision into the rehabilitative phase of injury seems intuitive; however, questions regarding the method(s) of best practice for delivery, including dose and length of treatment in the postdischarge phase, remain unanswered. In addition, the impact of simultaneous calcium and vitamin D supplementation in the postburn period requires study. Collective data from 7 major randomized trials suggest that given together, calcium and vitamin D have a greater effect on fracture prevention than vitamin D alone. Data for this review were collected in a nonburned, aging population but offer an additional intriguing area of study in burns.66 Calcitonin is a hormone secreted by the thyroid gland that inhibits bone resorption by osteoclasts.67,68 Reduced serum levels are associated with decreased bone density. Due to its antiresorptive function, calcitonin supplementation has been used to manage osteoporotic disorders.8,68,69 Akcay et al70 applied this concept in burns comparing the impact of calcitonin, growth hormone, or placebo administration on urinary deoxypyridinoline (DPD), an accepted marker of collagen breakdown71,72 contributing to the integrity of bone. The authors report significantly improved DPD levels in the group supplemented with calcitonin, therefore proposing a relationship between calcitonin supplementation and diminished bone loss following burns. In our study, serum calcitonin levels were similarly low in both the fracture and nonfracture groups (Table 3). Improvement in levels in either group was not clinically appreciated with advancing time postburn. This trend supports our earlier report of low calcitonin levels in patients a mean of 7 years postburn73 and supports Dolecek and collegues,8 who include calcitonin supplementation as a therapeutic possibility to assist with bone health in the extended postburn period. Serum BAP is a marker of bone turnover.74–76 A high serum level indicates excessive bone demineralization and, therefore, a greater risk of fracture. Urinary calcium losses increase with bone degradation as well. Despite fracture occurrence, participants in our study demonstrated similar BAP and urinary calcium levels at the studied time points (Table 3). Interestingly, measurements of BAP were considerably higher than normal in both the fracture and no-fracture groups, further suggestive of bone demineralization in the postburn period. A limitation in sample size was observed at various time points of comparison, coupled with large variability among the indices noted in Table 3, both of which could affect power to differentiate significance between groups. However, given the consistent lack of statistical differences in calcitonin, BAP, and urinary
calcium between the fracture and no-fracture groups, these bone markers appear to be unreliable predictors of fracture risk postburn. This study supports previous reports from our institution that there is an association between burn size and presence of inhalation injury and vitamin D status.12 This finding aligns with the documented metabolic response to injury, that being, as burn size increases, so does the catabolic impact of injury and extent of nutrient loss via the open wound. The impact of inhalation injury on vitamin D metabolism, as well as possibly requirement, is intriguing and supports increasing documentation of the role of vitamin D in inflammation.26,27 Interestingly, emerging preclinical trials report the role of vitamin D as an anti-inflammatory agent for treatment of lung injury.77,78 However, from the reported data herein, it is difficult to tease out the unique impact of inhalation injury on vitamin D and fracture status as all patients with inhalation injury had concomitant large burns. Derived from the noninvasive DXA measurement, BMD z score is recommended for the diagnosis of low bone mass in children. Using pediatric software, measurements are compared with the bone density of an age- and sex-matched reference population.79 In adults, BMD z score is used to assess future risk of fracture80,81; however, this concept has not been proven in the pediatric population.79,82 Using z score, Klein and colleagues1 report a long-term reduction in bone mass in burned children. The authors note that 31% of the 16 children studied with moderate burns (between 15% and 36% TBSA) and 60% of the 52 children reviewed with severe burns (≥40% TBSA) demonstrated a mean z score for bone mass at ≤–1 standard deviation (SD) approximately 5 years postburn. In the severely burned classification, 27% of the patients had a BMD z score of ≤–2 SD. In our current study, differences in the BMD z scores between the fracture (–1.4 ± 0.5 SD) and no-fracture (-0.5 ± 0.2 SD) groups at discharge nearly met statistical significance, with a P value of .06. Little improvement in BMD z score was seen in either group at 1 year after discharge (Table 4). When differentiated by fracture and supplementation group, the DXA results not surprisingly revealed decreased bone density in the fracture group at discharge, suggesting that a z score of at least 1 standard deviation from the mean for the patients’ age, sex, and ethnicity may represent a threshold for heightened fracture risk postburn (Table 5). No differences in serum vitamin D parameters based on supplementation distinction between fracture groups were noted (Table 5). In addition, no relationship between D25 and D1,25 levels at any stage in the acute phase or at 1 year postburn was found to correlate with fracture risk (Figure 1). Limitations to this study exist in that neither vitamin D levels nor nutrient intake data were available at the time of fracture. The medical literature supports a relationship between serum vitamin D levels and intake at the time of injury occurrence. A systematic review of 8 studies with a total of 2634 military personnel who sustained stress fractures reported
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decreased D25 levels at the time of stress fracture diagnosis (3 of the 8 studies) or at the time of entry into basic training (5 of the 8 studies).83 In another study, stress fracture risk was associated with decreased vitamin D intake in female athletes 9 to 15 years of age.84–90 Furthermore, while studies in aged populations have also demonstrated low serum vitamin D levels at the time of fracture,85 this concept is not generally supported via routine check of vitamin D status in many subsets of clinical practice at risk for fractures.91 In addition, we identify the small sample of patients as a limitation to this research and recognize that with any survey type of study, there will be patients who do not respond to invitation. In this study, 11 of the 50 patients did not respond to our prompts for information for unknown reasons. Finally, we note that follow-up fracture information was per verbal report from a parent or primary caregiver. Imaging reports were not available.
Conclusion In conclusion, the occurrence of postdischarge fracture was associated with placebo or D2 treatment during the acute postburn period and also decreased BMD z score at acute hospital discharge. Interestingly, there was no evidence of a relationship between serum vitamin D, calcitonin, BAP, and urinary calcium and fracture. Although we were unable to prove a cause-effect relationship of vitamin D intake to fractures due to possible confounding variables such as burn size, depth of burn, and inhalation injury, the results reaffirm the negative impact of burns on bone health. Because no fractures occurred in the D3-supplemented group, it is speculated that vitamin D3 provision during the acute postburn period may offer a protective benefit against fractures in children; however, the small sample size makes this impossible to demonstrate statistically.
Applicability of Research to Practice Our research confirms an existing gap in knowledge regarding best practice methods for postburn fracture prevention. The high morbidity and cost associated with fractures make the results of this study sufficiently compelling to routinely monitor vitamin D status in acute burn patients and give consideration to supplement provision. Vitamin D trials are required to test various doses of vitamin D as well as to determine whether exogenous calcium adds value to fracture prevention. Additional research is needed to further delineate vitamin D3 requirements acutely, during the rehabilitation phase, and possibly for years postinjury. Furthermore, the impact of inhalation injury on vitamin D metabolism and requirements postburn also requires further attention. Finally, until it manifests as a fracture, deterioration of bone status is a clinically silent disorder postburn. To implement appropriate preventative measures, differentiating the mechanisms involved in bone demineralization is worthy of continued study. This study serves to draw attention to the need for intervention strategies
that foster bone health in both the acute and rehabilitative phases of burn injury. Research is needed to develop therapies (eg, exercise regimens, pharmacological interventions, biochemical monitors, and nutrition advancements) that will serve to improve/sustain bone mineralization throughout the postburn continuum.
Acknowledgments The authors wish to recognize the contributions of Lois Cone, RT (R), ARRT; Chris Allgeier, DTR; and Carmen Brunner, RD, for their invaluable assistance toward the completion of this study.
Statement of Authorship T. Mayes and M. M. Gottschlich contributed to the conception/ design of the research; T. Mayes, M. M. Gottschlich, J. Khoury, and R. J. Kagan contributed to the acquisition, analysis, or interpretation of the data; T. Mayes drafted the manuscript; T. Mayes, M. M. Gottschlich, J. Khoury, and R. J. Kagan critically revised the manuscript; and T. Mayes, M. M. Gottschlich, J. Khoury, and R. J. Kagan agree to be fully accountable for ensuring the integrity and accuracy of the work. All authors read and approved the final manuscript.
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78. Zosky GR, Berry LJ, Elliott G, et al. Vitamin D deficiency causes deficits in lung function and alters lung structure. J Respir Crit Care Med. 2011;183:1336-1343. 79. Specker B, Schoenau E. Quantitative bone analysis in children: current methods and recommendations. J Pediatr. 2005;146:726-731. 80. Huang C, Ross P, Wasnich RD. Short-term and long-term fracture prediction by bone mass measurements: a prospective study. J Bone Miner Res. 1998;13:107-113. 81. Cummings SR, Black DM, Nevitt MC, et al. The study of osteoporotic fractures research group: bone densitometry at various sites for prediction of hip fractures. Lancet. 1993;341:72-75. 82. Gafni R, Baron J. Overdiagnosis of osteoporosis in children due to misinterpretation of dual-energy x-ray absorptiometry (DEXA). J Pediatr. 2004;144:253-257. 83. Dao D, Sodhi S, Tabasinejad R, et al. Serum 25-hydroxyvitamin D levels and stress fractures in military personnel [published online November 4, 2014]. Am J Sports Med. 84. Harrison L. Lower stress fracture risk in girls linked to vitamin D intake. Arch Pediatr Adolesc Med. 2012;166:595-600. 85. Pieper CF, Colon-Emeric C, Caminis J, et al. Distribution and correlates of serum 25-hydroxyvitamin D levels in a sample of patients with hip fracture. Am J Geriatr Pharmacother. 2007;5:335-340. 86. Bischoff-Ferrari HA, Can U, Staehelin HB, et al. Severe vitamin D deficiency in Swiss hip fracture patients. Bone. 2008;42:597-602. 87. LeBoff MS, Kohlmeier L, Hurwitz S, et al. Occult vitamin D deficiency in postmenopausal U.S. women with acute hip fracture. JAMA. 1999;281:1505-1511. 88. Gallacher SJ, McQuillian C, Harkness M, et al. Prevalence of vitamin D inadequacy in Scottish adults with non-vertebral fragility fractures. Curr Med Res Opin. 2005;21:1355-1361. 89. Moniz C, Dew T, Dixon T. Prevalence of vitamin D inadequacy in osteoporotic hip fracture patients in London. Curr Med Res Opin. 2005;21:1891-1894. 90. Looker AC, Mussolino ME. Serum 25-hydroxyvitamin D and hip fracture risk in older U.S. white adults. J Bone Miner Res. 2008;23:143-150. 91. Isenor JE, Ensom MH. Is there a role for therapeutic drug monitoring of vitamin D level as a surrogate marker for fracture risk? Pharmacotherapy. 2010;30:254-264.
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research-article2015
NCPXXX10.1177/0884533615587720Nutrition in Clinical PracticeMayes et al
Clinical Research
Investigation of Bone Health Subsequent to Vitamin D Supplementation in Children Following Burn Injury
Nutrition in Clinical Practice Volume 30 Number 6 December 2015 830–837 © 2015 American Society for Parenteral and Enteral Nutrition DOI: 10.1177/0884533615587720 ncp.sagepub.com hosted at online.sagepub.com
Theresa Mayes, RD, CSP, CCRC1,2; Michele M. Gottschlich, PhD, RD, CSP1,3,4; Jane Khoury, PhD5; and Richard J. Kagan, MD4,6
Abstract Background: The effect of supplemental vitamin D on fracture occurrence following burn injuries is unclear. The objective of this study was to evaluate postintervention incidence of fractures in children during the rehabilitative phase postburn (PB) following participation in a randomized clinical trial of vitamin D supplementation. Materials and Methods: Follow-up for fracture evaluation was obtained in 39 of 50 patients randomized to daily enteral vitamin D2, D3, or placebo throughout the acute burn course. Serum 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D, D2, D3, calcitonin, and bone alkaline phosphatase (BAP) measurements were obtained PB day 7, midpoint, discharge, and 1-year PB. Urinary calcium was obtained PB day 7 and midpoint. Dual-energy x-ray absorptiometry (DXA) was performed at discharge and 1-year PB. Results: Fractures were reported in 6 of 39 respondents. Four fractures occurred in the placebo group, 2 in the D2 group, and none in the D3 group. Serum vitamin D, calcitonin, BAP, and urinary calcium were similar between fracture groups. The group with fracture morbidity had larger burn size (83.8% ± 4.9% vs 53.0% ± 2.9%, P < .0001), greater full-thickness burn (69.7% ± 9.4% vs 39.4% ± 4.1%, P = .02), and increased incidence of inhalation injury (33% vs 6%, P = .04). Decreased bone mineral density z score was noted at discharge in the placebo fracture compared with no-fracture group (P < .05). Conclusion: This preliminary report suggests there may be benefit of vitamin D3 in reducing postdischarge fracture risk. Results reaffirm the importance of monitoring bone health in pediatric patients postburn. (Nutr Clin Pract. 2015;30:830-837)
Keywords burns; vitamin D; bone health; pediatrics; vitamin D deficiency; bone density; bone fractures
Background It is widely recognized that a serious burn injury is associated with loss of bone formation and a long-term reduction in bone density.1–9 Bone demineralization in the postburn period and the failure of burned children to gain bone mass during periods of growth heighten the risk for fractures. In fact, the incidence of fractures in the burned pediatric population has been well documented.1,10,11 In 1995, Klein et al1 reported a fracture incidence of approximately 12% in children within 17 months following discharge in patients with a >40% total body surface area (TBSA) burn injury. Fractures were noted in 10 patients, with 2 reported as axial (1 hip; 1 rib) and 8 documented as appendicular (of limb or digit, not specified). Eight years later, a 6% long bone fracture occurrence was described in acutely injured patients with >40% TBSA burns.10 Hypovitaminosis D has been documented during the postburn period.12–14 Multiple physiological roles are supported by vitamin D, including modulation of cell growth,15–17 neuromuscular18–21 and immune function,16,22–25 reduction of inflammation,26,27 and growing evidence of a role in the prevention and treatment of diabetes,28–30 cancer,31–35 and multiple sclerosis.36–40 However, vitamin D is most commonly known for its role in bone metabolism41–45 because it promotes calcium absorption and assists with hemodynamic concentration of calcium and phosphate, enabling bone mineralization.
The relationship of vitamin D to propensity toward fragility fractures following burn injury is unknown. Therefore, the primary objective of this study was to evaluate the occurrence of fractures in children who received different supplemental regimens consisting of vitamin D2, D3, or placebo during the acute postburn course. Evaluation of demographics, serum and urine bone markers, and bone density as related to fracture risk represented secondary analyses.
From 1Department of Nutrition, Shriners Hospitals for Children, Cincinnati, Ohio; 2Division of Nutrition Therapy, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio; 3Department of Research, Shriners Hospitals for Children, Cincinnati, Ohio; 4Department of Surgery, University of Cincinnati College of Medicine, Cincinnati, Ohio; 5Division of Biostatistics and Epidemiology, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio; and 6Department of Surgery, Shriners Hospitals for Children, Cincinnati, Ohio. Financial disclosure: None declared. This article originally appeared online on May 29, 2015. Corresponding Author: Theresa Mayes, RD, CSP, CCRC, Cincinnati Children’s Hospital Medical Center, Division of Nutrition Therapy, 3333 Burnet Ave, Cincinnati, OH 45229, USA. Email: [email protected]
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Materials and Methods This protocol was approved by the University of Cincinnati Human Research Institutional Review Board. A secondary analysis of fracture incidence was conducted in 39 of 50 patients available for follow-up fracture evaluation. These 39 patients had a mean burn size of 58%, mean full-thickness injury of 44%, and mean age of 7.4 years, ranging between 0.7 and 18 years. All were previously enrolled in a randomized vitamin D supplementation trial. The details of the study design and the effect of intervention on vitamin D biomarkers have been published separately.14 In brief, patients were randomized to receive 100 IU/kg/d enteral vitamin D2, D3, or placebo during their acute burn course. Serum 25-hydroxyvitamin vitamin D (D25), 1,25-dihydroxyvitamin D (D1,25), D2 and D3 metabolites, calcitonin, and bone alkaline phosphatase (BAP) were examined at baseline (postburn day 7), midpoint of hospital stay (estimated by 1 day per percent burn divided by 2), date of acute discharge, and 1-year after discharge to examine the association of intervention to longterm bone health. Baseline and midpoint 24-hour urinary calcium, as well as total body dual-energy x-ray absorptiometry (DXA) assessment using pediatric software (version 11.2.1, Hologic, Bedford, MA) and a QDR-Delphi S DXA scanner (Hologic, Bedford, MA) of bone density performed at acute discharge and at 1 year after discharge, represented additional independent variables. Beginning 22 months after enrollment of the final study patient,14 attempts (3 phone calls maximum) were made to contact the parent or primary caregiver of each study participant to ascertain the incidence of long bone fracture since the acute injury. Fracture outcome was differentiated between the vitamin D2, D3, and placebo supplementation groups. Demographics, biochemical markers, and bone density z scores were compared between the positive and negative fracture groups.
Data Analysis Data were managed and analyzed using SAS version 9.3 (SAS Institute, Cary NC). Continuous variables were initially examined for distributional properties. If there was evidence of deviation from the assumption of normality, either an appropriate transformation was used for analysis or an equivalent nonparametric analysis was used. A t test was used to compare age %, TBSA, % full-thickness burn, and postburn day of admission between fracture groups; Fisher exact test was used for sex, race, and inhalation injury comparisons. The vitamin D metabolites calcitonin, bone alkaline phosphatase, and urinary calcium were log transformed for analysis; geometric means with 95% confidence intervals (CIs) are reported. A generalized linear model was used for examining differences in change over time between fracture groups with a Tukey-Kramer adjustment to examine differences at each time point. Mean ± standard
Supplementation Received Placebo (n = 13) Vitamin D2 (n = 13) Vitamin D3 (n = 13)
No. (%) Patients With Fracture 4 (31) 2 (15) 0 (0)
a
Overall P value using Fisher exact test was .13.
error is presented unless otherwise noted. A P value of 19,000 elderly individuals.65 Understandably, an elderly individual is considerably different from a pediatric burn
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patient; however, the similarity between groups as far as vitamin D provision affecting bone health and thus fracture risk cannot be negated. Given the multitude of factors in the acute and rehabilitative phases of burn injury that predispose burn patients to bone demineralization and that no fracture(s) occurred in the patients receiving vitamin D3, the recommendation for vitamin D3 supplementation during the acute phase of burn injury is supported. Furthermore, continued provision into the rehabilitative phase of injury seems intuitive; however, questions regarding the method(s) of best practice for delivery, including dose and length of treatment in the postdischarge phase, remain unanswered. In addition, the impact of simultaneous calcium and vitamin D supplementation in the postburn period requires study. Collective data from 7 major randomized trials suggest that given together, calcium and vitamin D have a greater effect on fracture prevention than vitamin D alone. Data for this review were collected in a nonburned, aging population but offer an additional intriguing area of study in burns.66 Calcitonin is a hormone secreted by the thyroid gland that inhibits bone resorption by osteoclasts.67,68 Reduced serum levels are associated with decreased bone density. Due to its antiresorptive function, calcitonin supplementation has been used to manage osteoporotic disorders.8,68,69 Akcay et al70 applied this concept in burns comparing the impact of calcitonin, growth hormone, or placebo administration on urinary deoxypyridinoline (DPD), an accepted marker of collagen breakdown71,72 contributing to the integrity of bone. The authors report significantly improved DPD levels in the group supplemented with calcitonin, therefore proposing a relationship between calcitonin supplementation and diminished bone loss following burns. In our study, serum calcitonin levels were similarly low in both the fracture and nonfracture groups (Table 3). Improvement in levels in either group was not clinically appreciated with advancing time postburn. This trend supports our earlier report of low calcitonin levels in patients a mean of 7 years postburn73 and supports Dolecek and collegues,8 who include calcitonin supplementation as a therapeutic possibility to assist with bone health in the extended postburn period. Serum BAP is a marker of bone turnover.74–76 A high serum level indicates excessive bone demineralization and, therefore, a greater risk of fracture. Urinary calcium losses increase with bone degradation as well. Despite fracture occurrence, participants in our study demonstrated similar BAP and urinary calcium levels at the studied time points (Table 3). Interestingly, measurements of BAP were considerably higher than normal in both the fracture and no-fracture groups, further suggestive of bone demineralization in the postburn period. A limitation in sample size was observed at various time points of comparison, coupled with large variability among the indices noted in Table 3, both of which could affect power to differentiate significance between groups. However, given the consistent lack of statistical differences in calcitonin, BAP, and urinary
calcium between the fracture and no-fracture groups, these bone markers appear to be unreliable predictors of fracture risk postburn. This study supports previous reports from our institution that there is an association between burn size and presence of inhalation injury and vitamin D status.12 This finding aligns with the documented metabolic response to injury, that being, as burn size increases, so does the catabolic impact of injury and extent of nutrient loss via the open wound. The impact of inhalation injury on vitamin D metabolism, as well as possibly requirement, is intriguing and supports increasing documentation of the role of vitamin D in inflammation.26,27 Interestingly, emerging preclinical trials report the role of vitamin D as an anti-inflammatory agent for treatment of lung injury.77,78 However, from the reported data herein, it is difficult to tease out the unique impact of inhalation injury on vitamin D and fracture status as all patients with inhalation injury had concomitant large burns. Derived from the noninvasive DXA measurement, BMD z score is recommended for the diagnosis of low bone mass in children. Using pediatric software, measurements are compared with the bone density of an age- and sex-matched reference population.79 In adults, BMD z score is used to assess future risk of fracture80,81; however, this concept has not been proven in the pediatric population.79,82 Using z score, Klein and colleagues1 report a long-term reduction in bone mass in burned children. The authors note that 31% of the 16 children studied with moderate burns (between 15% and 36% TBSA) and 60% of the 52 children reviewed with severe burns (≥40% TBSA) demonstrated a mean z score for bone mass at ≤–1 standard deviation (SD) approximately 5 years postburn. In the severely burned classification, 27% of the patients had a BMD z score of ≤–2 SD. In our current study, differences in the BMD z scores between the fracture (–1.4 ± 0.5 SD) and no-fracture (-0.5 ± 0.2 SD) groups at discharge nearly met statistical significance, with a P value of .06. Little improvement in BMD z score was seen in either group at 1 year after discharge (Table 4). When differentiated by fracture and supplementation group, the DXA results not surprisingly revealed decreased bone density in the fracture group at discharge, suggesting that a z score of at least 1 standard deviation from the mean for the patients’ age, sex, and ethnicity may represent a threshold for heightened fracture risk postburn (Table 5). No differences in serum vitamin D parameters based on supplementation distinction between fracture groups were noted (Table 5). In addition, no relationship between D25 and D1,25 levels at any stage in the acute phase or at 1 year postburn was found to correlate with fracture risk (Figure 1). Limitations to this study exist in that neither vitamin D levels nor nutrient intake data were available at the time of fracture. The medical literature supports a relationship between serum vitamin D levels and intake at the time of injury occurrence. A systematic review of 8 studies with a total of 2634 military personnel who sustained stress fractures reported
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decreased D25 levels at the time of stress fracture diagnosis (3 of the 8 studies) or at the time of entry into basic training (5 of the 8 studies).83 In another study, stress fracture risk was associated with decreased vitamin D intake in female athletes 9 to 15 years of age.84–90 Furthermore, while studies in aged populations have also demonstrated low serum vitamin D levels at the time of fracture,85 this concept is not generally supported via routine check of vitamin D status in many subsets of clinical practice at risk for fractures.91 In addition, we identify the small sample of patients as a limitation to this research and recognize that with any survey type of study, there will be patients who do not respond to invitation. In this study, 11 of the 50 patients did not respond to our prompts for information for unknown reasons. Finally, we note that follow-up fracture information was per verbal report from a parent or primary caregiver. Imaging reports were not available.
Conclusion In conclusion, the occurrence of postdischarge fracture was associated with placebo or D2 treatment during the acute postburn period and also decreased BMD z score at acute hospital discharge. Interestingly, there was no evidence of a relationship between serum vitamin D, calcitonin, BAP, and urinary calcium and fracture. Although we were unable to prove a cause-effect relationship of vitamin D intake to fractures due to possible confounding variables such as burn size, depth of burn, and inhalation injury, the results reaffirm the negative impact of burns on bone health. Because no fractures occurred in the D3-supplemented group, it is speculated that vitamin D3 provision during the acute postburn period may offer a protective benefit against fractures in children; however, the small sample size makes this impossible to demonstrate statistically.
Applicability of Research to Practice Our research confirms an existing gap in knowledge regarding best practice methods for postburn fracture prevention. The high morbidity and cost associated with fractures make the results of this study sufficiently compelling to routinely monitor vitamin D status in acute burn patients and give consideration to supplement provision. Vitamin D trials are required to test various doses of vitamin D as well as to determine whether exogenous calcium adds value to fracture prevention. Additional research is needed to further delineate vitamin D3 requirements acutely, during the rehabilitation phase, and possibly for years postinjury. Furthermore, the impact of inhalation injury on vitamin D metabolism and requirements postburn also requires further attention. Finally, until it manifests as a fracture, deterioration of bone status is a clinically silent disorder postburn. To implement appropriate preventative measures, differentiating the mechanisms involved in bone demineralization is worthy of continued study. This study serves to draw attention to the need for intervention strategies
that foster bone health in both the acute and rehabilitative phases of burn injury. Research is needed to develop therapies (eg, exercise regimens, pharmacological interventions, biochemical monitors, and nutrition advancements) that will serve to improve/sustain bone mineralization throughout the postburn continuum.
Acknowledgments The authors wish to recognize the contributions of Lois Cone, RT (R), ARRT; Chris Allgeier, DTR; and Carmen Brunner, RD, for their invaluable assistance toward the completion of this study.
Statement of Authorship T. Mayes and M. M. Gottschlich contributed to the conception/ design of the research; T. Mayes, M. M. Gottschlich, J. Khoury, and R. J. Kagan contributed to the acquisition, analysis, or interpretation of the data; T. Mayes drafted the manuscript; T. Mayes, M. M. Gottschlich, J. Khoury, and R. J. Kagan critically revised the manuscript; and T. Mayes, M. M. Gottschlich, J. Khoury, and R. J. Kagan agree to be fully accountable for ensuring the integrity and accuracy of the work. All authors read and approved the final manuscript.
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