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DISCUSSION
Advances in burn care over the past several decades have dramatically decreased mortality, [37] leading to multiple challenges in long-term care of the burned victim, ranging from wound healing and hypertrophic scarring to physical disabilities and psychosocial difficulties. Burns covering over 30% TBSA are associated with a continuous hypermetabolic response that lasts for 2 years following the initial insult. [2, 21–22, 35] This was confirmed by our study, in which the control group showed a dramatic increase in REE during the convalescent period that remained above normal levels for as long as 18 months after burn. The present study revealed clear differences in the percent of predicted REE between oxandrolone and control patients up to 6 months after burn injury, indicating a sustained attenuation of the hypermetabolic state by oxandrolone. In this study, we have demonstrated that this prolonged attenuation of the hypermetabolic response is accompanied by long-term improvements in total body BMC and increased height velocity in massively burned children.
Severe burn is associated with marked retardation of linear growth and abnormal bone loss in the pediatric population. [38–39] Since the beginning of the 1960s, oxandrolone has been safely administered to pediatric patients with growth retardation. In 1965, a randomized controlled trial conducted by Ray and colleagues revealed that children with Down’s syndrome exhibited significant improvements in height after oxandrolone treatment for 1 and 2 years at a dose of 0.5 and 0.25 mg/kg respectively. [7, 9] In 1965, Danowski reported that administration of 10–40 mg oxandrolone for 13–37 months induced a two-fold acceleration in height in children 3–17 years old who were below the third percentile for height. [6, 10] The use of oxandrolone in patients with Turner’s syndrome as an adjunctive therapy to prevent constitutional growth delay has been well described. A randomized, double blind, placebo-controlled trial following a large cohort of girls with Turner’s syndrome receiving growth hormone over a 10-year period showed that 0.05 mg/kg/day oxandrolone improved final height in these individuals. [8]
In this study, we were interested in examining the patients with growth arrest, as seen by height velocities below normal limits. Our data showed that a much larger percentage of patients with significant growth arrest were present in the control group than in the oxandrolone group (48 vs. 8%, P<0.01), similar results were found at the second year post burn (32 vs. 7%) (P<0.05).
We have previously shown that oxandrolone significantly improved growth in severely burned children after 1 year of treatment, with this increase maintained a full year after discontinuation of therapy. [18] This finding is supported by the current study, which revealed that oxandrolone-treated patients went from their baseline height percentile to higher ones, while control patients exhibited a loss in height percentile. This was more pronounced in children who were 7–18 years of age at the time of the burn injury, with oxandrolone-treated children in this age range having a significantly increased percent change in height percentiles for up to 4 years post burn. Importantly, these increases in height were associated with improvements in BMC, as assessed by DEXA. This study was not powered to determine ultimate height in these severely burned children. Therefore, a larger study in a larger group of individuals to look at ultimate stature is necessary.
Bone loss occurs quickly following a severe burn, as manifested by an approximate 2% loss of total body BMC by 2 months post burn, increasing to about 3.5% by 6 months, with lumbar spine BMC falling about 8% and remaining low for up to 24 months post burn. [39] The recovery of bone from the catabolic effects of burn injury occurs relatively slowly. In previous studies of small groups of children, we have shown that a significant increase in BMC occurs at 12 months post burn. [17–18] Our study extends these observations by showing that oxandrolone continues to increase BMC for up to 5 years. In this study, we have provided evidence of a gradual increment in bone mass that reaches and remains significant after 2 years post injury. We speculate that this long-term increase in BMC results from the significant increase in IGF-1 levels as well as the protective effect of oxandrolone during the first year after burn, where ongoing stress and inflammation results in increased endogenous glucocorticoid production, abnormal calcium metabolism, and resorptive cytokine stimulation. The normal circulating levels of the chief binding protein for IGF-1, IGFBP3, could suggest an increase in IGFBP5, the main binding protein that transports IGF-1 to bone. [40] Interestingly, this effect is most pronounced in patients who were 7–18 years old at the time of the burn. This 2-year peak in BMC and height seen in oxandrolone-treated patients represents the beginning of the pre-pubertal growth spurt. The temporal aspect of changes in height percentiles seen here suggests that oxandrolone stimulates rather than impairs epiphyseal cartilage proliferation, possibly triggering ossification at these sites. In vitro, oxandrolone can up regulate the androgen receptor and concomitantly stimulate human osteoblasts to produce a significant but modest increase in type I collagen, alkaline phosphatase, and osteocalcin. These data suggest that there may be a weak direct effect of oxandrolone on osteoblasts. [41] However, burn victims have little to no osteoblastic activity from 14 days post burn to 1 year post burn. [42–44] As previously reported, oxandrolone had little to no effect on BMD. [17] However, the addition of exercise to oxandrolone therapy led to a significant increase in BMC concomitantly with an increase in LBM. This finding, as well as the finding that oxandrolone stimulates IGF-1, suggests that an increase in LBM brought about by oxandrolone and exercise could increase skeletal loading and in this particular setting, further increasing bone formation and BMC.
Severe burns accelerate catabolism of skeletal muscle. Previous studies have clearly shown that short-term oxandrolone treatment during the acute phase significantly increases LBM and net balance of muscle protein. [1, 13–15] Oxandrolone appears to achieve these effects by enhancing the efficiency of muscle protein synthesis. [1, 15] In previous studies, we have shown an improved net deposition of leg muscle protein through increased amino acid utilization after 6 months of oxandrolone treatment, [16] and significant improvement in LBM after 1 year of oxandrolone treatment.[17–18] Here, we found only a trend (P<0.06) toward improved LBM throughout the time studied.
The combination of a 12-week exercise program with oxandrolone therapy increased LBM to levels above that seen with oxandrolone therapy alone. Significant effects on muscle strength (measured by peak torque) were recorded only in the oxandrolone and exercise group. These results agree with our previous finding that combining exercise with oxandrolone produces more significant effects on LBM and weight gain. [19] The current findings are notable in that they show that the benefits of exercise are maintained for years after burn injury. In contrast, exercise seems to have little or no effect in BMC. This in agreement with a previous study where we evaluated the long-term effect of growth hormone, and found no effect in BMC in patients who participated in a similar exercise program. [45]
Oxandrolone and exercise probably affect body composition through different mechanisms. As already mentioned, oxandrolone likely increases total body BMC through IGF-1. However, the failure of oxandrolone and exercise to increase IGF-1 to significantly greater levels than oxandrolone alone suggests that the exercise effect is not mediated by IGF-1. The increase in LBM with exercise and oxandrolone suggests that the increase in BMC is secondary to increased skeletal loading, an effect different from that of IGF-1.
Assessment of cardiac function revealed that the oxandrolone group exhibited significant decreases in CO, percent predicted CO, percent predicted HR, and RPP at 1 year post burn as well as significant decreases in percent predicted CO and HR at 2 years post burn compared with the control group. These findings provide new evidence in favor of a more efficient utilization of energy by the myocardium of patients who received oxandrolone. Interestingly, these findings coincide with the increases seen in height and BMC during the same time period, suggesting that an attenuation of the hypermetabolic response occurred in oxandrolone-treated patients while the controls remained hypermetabolic. Considering the marked contributions by the heart to the overall daily energy expenditure, we speculate that the effect exerted by oxandrolone on cardiac physiology could explain the decrease in percent predicted REE as measured by indirect calorimetry. Additional studies are needed to further elucidate the mechanism by which oxandrolone decreases REE.
Special attention has been given to sex as a predictor of outcome following injury. Controversies have arisen regarding whether administration of androgens or estrogens can positively impact outcomes. Differential effects of sex hormones on immunity, organ function, and cellular response have been reported and continue to be extensively investigated. [46–50] We found that the effect of oxandrolone on height velocity was the same in females and in the overall group. The positive effect in girls persists alongside that seen in boys.
Assessment of safety showed that there were no long-lasting deleterious effects associated with oxandrolone use in our patients. Three female patients with perineal burns developed clitoral hood edema, and this condition was resolved within 3 months of discontinuation of treatment. Although we previously reported an elevation of AST and ALT between 17 and 40 days post burn in patients treated with oxandrolone, here we show that there are no long-term elevations in these markers. Bone age was not affected; premature closure of the epiphyses was not found. Anxiety, pain and mood disorders were not different between the groups. Taken together, this data indicate that oxandrolone can be safely used in severely burned children.
In conclusion, our findings provide strong evidence that oxandrolone is efficacious in attenuating the hypermetabolism elicited by burn injury, significantly improving the long-term recovery of severely burned children in height, bone mineral content, and muscle strength. This, taken with the safety profile of this drug, supports the use of oxandrolone as an adjunct therapy to the current standard of burn care.
DISCUSSION
Advances in burn care over the past several decades have dramatically decreased mortality, [37] leading to multiple challenges in long-term care of the burned victim, ranging from wound healing and hypertrophic scarring to physical disabilities and psychosocial difficulties. Burns covering over 30% TBSA are associated with a continuous hypermetabolic response that lasts for 2 years following the initial insult. [2, 21–22, 35] This was confirmed by our study, in which the control group showed a dramatic increase in REE during the convalescent period that remained above normal levels for as long as 18 months after burn. The present study revealed clear differences in the percent of predicted REE between oxandrolone and control patients up to 6 months after burn injury, indicating a sustained attenuation of the hypermetabolic state by oxandrolone. In this study, we have demonstrated that this prolonged attenuation of the hypermetabolic response is accompanied by long-term improvements in total body BMC and increased height velocity in massively burned children.
Severe burn is associated with marked retardation of linear growth and abnormal bone loss in the pediatric population. [38–39] Since the beginning of the 1960s, oxandrolone has been safely administered to pediatric patients with growth retardation. In 1965, a randomized controlled trial conducted by Ray and colleagues revealed that children with Down’s syndrome exhibited significant improvements in height after oxandrolone treatment for 1 and 2 years at a dose of 0.5 and 0.25 mg/kg respectively. [7, 9] In 1965, Danowski reported that administration of 10–40 mg oxandrolone for 13–37 months induced a two-fold acceleration in height in children 3–17 years old who were below the third percentile for height. [6, 10] The use of oxandrolone in patients with Turner’s syndrome as an adjunctive therapy to prevent constitutional growth delay has been well described. A randomized, double blind, placebo-controlled trial following a large cohort of girls with Turner’s syndrome receiving growth hormone over a 10-year period showed that 0.05 mg/kg/day oxandrolone improved final height in these individuals. [8]
In this study, we were interested in examining the patients with growth arrest, as seen by height velocities below normal limits. Our data showed that a much larger percentage of patients with significant growth arrest were present in the control group than in the oxandrolone group (48 vs. 8%, P<0.01), similar results were found at the second year post burn (32 vs. 7%) (P<0.05).
We have previously shown that oxandrolone significantly improved growth in severely burned children after 1 year of treatment, with this increase maintained a full year after discontinuation of therapy. [18] This finding is supported by the current study, which revealed that oxandrolone-treated patients went from their baseline height percentile to higher ones, while control patients exhibited a loss in height percentile. This was more pronounced in children who were 7–18 years of age at the time of the burn injury, with oxandrolone-treated children in this age range having a significantly increased percent change in height percentiles for up to 4 years post burn. Importantly, these increases in height were associated with improvements in BMC, as assessed by DEXA. This study was not powered to determine ultimate height in these severely burned children. Therefore, a larger study in a larger group of individuals to look at ultimate stature is necessary.
Bone loss occurs quickly following a severe burn, as manifested by an approximate 2% loss of total body BMC by 2 months post burn, increasing to about 3.5% by 6 months, with lumbar spine BMC falling about 8% and remaining low for up to 24 months post burn. [39] The recovery of bone from the catabolic effects of burn injury occurs relatively slowly. In previous studies of small groups of children, we have shown that a significant increase in BMC occurs at 12 months post burn. [17–18] Our study extends these observations by showing that oxandrolone continues to increase BMC for up to 5 years. In this study, we have provided evidence of a gradual increment in bone mass that reaches and remains significant after 2 years post injury. We speculate that this long-term increase in BMC results from the significant increase in IGF-1 levels as well as the protective effect of oxandrolone during the first year after burn, where ongoing stress and inflammation results in increased endogenous glucocorticoid production, abnormal calcium metabolism, and resorptive cytokine stimulation. The normal circulating levels of the chief binding protein for IGF-1, IGFBP3, could suggest an increase in IGFBP5, the main binding protein that transports IGF-1 to bone. [40] Interestingly, this effect is most pronounced in patients who were 7–18 years old at the time of the burn. This 2-year peak in BMC and height seen in oxandrolone-treated patients represents the beginning of the pre-pubertal growth spurt. The temporal aspect of changes in height percentiles seen here suggests that oxandrolone stimulates rather than impairs epiphyseal cartilage proliferation, possibly triggering ossification at these sites. In vitro, oxandrolone can up regulate the androgen receptor and concomitantly stimulate human osteoblasts to produce a significant but modest increase in type I collagen, alkaline phosphatase, and osteocalcin. These data suggest that there may be a weak direct effect of oxandrolone on osteoblasts. [41] However, burn victims have little to no osteoblastic activity from 14 days post burn to 1 year post burn. [42–44] As previously reported, oxandrolone had little to no effect on BMD. [17] However, the addition of exercise to oxandrolone therapy led to a significant increase in BMC concomitantly with an increase in LBM. This finding, as well as the finding that oxandrolone stimulates IGF-1, suggests that an increase in LBM brought about by oxandrolone and exercise could increase skeletal loading and in this particular setting, further increasing bone formation and BMC.
Severe burns accelerate catabolism of skeletal muscle. Previous studies have clearly shown that short-term oxandrolone treatment during the acute phase significantly increases LBM and net balance of muscle protein. [1, 13–15] Oxandrolone appears to achieve these effects by enhancing the efficiency of muscle protein synthesis. [1, 15] In previous studies, we have shown an improved net deposition of leg muscle protein through increased amino acid utilization after 6 months of oxandrolone treatment, [16] and significant improvement in LBM after 1 year of oxandrolone treatment.[17–18] Here, we found only a trend (P<0.06) toward improved LBM throughout the time studied.
The combination of a 12-week exercise program with oxandrolone therapy increased LBM to levels above that seen with oxandrolone therapy alone. Significant effects on muscle strength (measured by peak torque) were recorded only in the oxandrolone and exercise group. These results agree with our previous finding that combining exercise with oxandrolone produces more significant effects on LBM and weight gain. [19] The current findings are notable in that they show that the benefits of exercise are maintained for years after burn injury. In contrast, exercise seems to have little or no effect in BMC. This in agreement with a previous study where we evaluated the long-term effect of growth hormone, and found no effect in BMC in patients who participated in a similar exercise program. [45]
Oxandrolone and exercise probably affect body composition through different mechanisms. As already mentioned, oxandrolone likely increases total body BMC through IGF-1. However, the failure of oxandrolone and exercise to increase IGF-1 to significantly greater levels than oxandrolone alone suggests that the exercise effect is not mediated by IGF-1. The increase in LBM with exercise and oxandrolone suggests that the increase in BMC is secondary to increased skeletal loading, an effect different from that of IGF-1.
Assessment of cardiac function revealed that the oxandrolone group exhibited significant decreases in CO, percent predicted CO, percent predicted HR, and RPP at 1 year post burn as well as significant decreases in percent predicted CO and HR at 2 years post burn compared with the control group. These findings provide new evidence in favor of a more efficient utilization of energy by the myocardium of patients who received oxandrolone. Interestingly, these findings coincide with the increases seen in height and BMC during the same time period, suggesting that an attenuation of the hypermetabolic response occurred in oxandrolone-treated patients while the controls remained hypermetabolic. Considering the marked contributions by the heart to the overall daily energy expenditure, we speculate that the effect exerted by oxandrolone on cardiac physiology could explain the decrease in percent predicted REE as measured by indirect calorimetry. Additional studies are needed to further elucidate the mechanism by which oxandrolone decreases REE.
Special attention has been given to sex as a predictor of outcome following injury. Controversies have arisen regarding whether administration of androgens or estrogens can positively impact outcomes. Differential effects of sex hormones on immunity, organ function, and cellular response have been reported and continue to be extensively investigated. [46–50] We found that the effect of oxandrolone on height velocity was the same in females and in the overall group. The positive effect in girls persists alongside that seen in boys.
Assessment of safety showed that there were no long-lasting deleterious effects associated with oxandrolone use in our patients. Three female patients with perineal burns developed clitoral hood edema, and this condition was resolved within 3 months of discontinuation of treatment. Although we previously reported an elevation of AST and ALT between 17 and 40 days post burn in patients treated with oxandrolone, here we show that there are no long-term elevations in these markers. Bone age was not affected; premature closure of the epiphyses was not found. Anxiety, pain and mood disorders were not different between the groups. Taken together, this data indicate that oxandrolone can be safely used in severely burned children.
In conclusion, our findings provide strong evidence that oxandrolone is efficacious in attenuating the hypermetabolism elicited by burn injury, significantly improving the long-term recovery of severely burned children in height, bone mineral content, and muscle strength. This, taken with the safety profile of this drug, supports the use of oxandrolone as an adjunct therapy to the current standard of burn care.
