Bare-Bones Fact — Children Are Not Small Adults
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《新英格兰医药杂志》
Diagnostic and therapeutic guidelines used for children are commonly extrapolated from studies conducted in adults. There are potential dangers in assuming that children will have the same response to disease or therapy as adults, given important physiological differences. For example, it is reasonable to question whether glucocorticoid excess will have the same skeletal effects in adults as in a growing child. Glucocorticoids are thought to threaten bone health through a number of mechanisms.1 They reduce bone formation by inhibiting the number and function of bone-building osteoblasts. Glucocorticoids also contribute to bone loss by stimulating calciuresis and impairing the intestinal absorption of calcium by inhibiting the action of vitamin D. The reduction in available calcium stimulates the release of parathyroid hormone, leading to bone resorption. Glucocorticoids can also reduce the production of sex steroids by inhibiting gonadotropins.1
Glucocorticoids contribute to bone loss and fragility-induced fractures in adults.2,3 Thirty to 50 percent of adults who receive more than 5 mg of prednisone daily have measurable decreases in bone mineral density that are evident within the first six months of treatment. The incidence of fractures increases as much as a factor of five at the spine and a factor of two at nonvertebral sites in users of glucocorticoids.3 The risk of bone loss and fracture varies with the daily and cumulative dose of glucocorticoids, age, menopausal status, and risk factors related to the underlying disease.3
The skeletal risks associated with glucocorticoid therapy in children and adolescents are less well established. Low bone mass has been observed in small cohorts of young patients treated with glucocorticoids for various chronic diseases.4 Because of their small samples, these studies lacked the statistical power to provide reliable estimates of the incidence of fracture. However, a recent case–control study involving more than 20,000 children receiving systemic glucocorticoids found an increased risk of fracture.5 During a mean follow-up period of 2.7 years, the adjusted odds ratio for fracture was 1.32 (95 percent confidence interval, 1.03 to 1.69) among children who received four or more courses of oral glucocorticoids (mean duration, 6.4 days), as compared with controls.
The study by Leonard et al. in this issue of the Journal6 examines the skeletal effects of glucocorticoid therapy in a homogeneous group of children with glucocorticoid-sensitive nephrotic syndrome. The effects of prednisone on the bones of these young subjects were not confounded by risk factors of immobilization, malnutrition, chronic inflammation, or cytokine excess. The children had received an average of 23,000 mg of prednisone over a mean of 4.4 years, three times as much as the daily dose of 5 mg that represents the adult threshold for bone loss. Despite long-term glucocorticoid therapy, the bone mineral content of the lumbar spine and whole body was similar among children with the nephrotic syndrome and controls, after adjustment for age, sex, bone area, maturity (Tanner stage), and race. Children with the nephrotic syndrome had a lower bone mineral content than the controls only after correction for body-mass index and only at the spine.
These data challenge the assumption that long-term glucocorticoid therapy inevitably leads to bone loss. Although this finding is reassuring, the limitations of the study leave many questions unanswered. The data are cross-sectional, making it impossible to exclude the possibility of bone loss or decreased rates of mineral accrual in individual patients. Furthermore, bone mass was the only measure of skeletal health evaluated, and it was assessed by means of dual-energy x-ray absorptiometry. Bone strength is influenced not only by mass but also by bone geometry, bone quality, and material properties that are not captured by dual-energy x-ray absorptiometry.7 There is reason to be concerned about bone geometry in children who receive glucocorticoids because their bone size is reduced. Leonard et al. observed that patients with the nephrotic syndrome were shorter than controls; their shorter bones were also probably narrower. Since resistance to fracture from bending forces is proportional to the radius to the fourth power, even a minor decrease in bone diameter could reduce bone strength.8 Bone quality and material properties are more difficult to quantify, but they are influenced by rates of bone resorption and formation.7 Bone turnover can be assessed with the use of biochemical markers and bone histomorphometry.7 When bone histomorphometry was analyzed in eight children with nonazotemic nephrotic syndrome, those receiving the highest doses of prednisone had reduced rates of bone formation, whereas trabecular microarchitecture was preserved.9
Further studies are needed to resolve these questions. Magnetic resonance imaging or quantitative computed tomography could better define the effects of glucocorticoids on bone geometry and on cortical as compared with trabecular bone. Bone histomorphometry and assessments of biochemical bone markers could shed light on glucocorticoid-induced changes in microarchitecture and turnover. However, these laboratory studies are proxy markers of bone health whose value in predicting fractures in children is uncertain. Among adults, current and prior exposure to corticosteroids confers an increased risk of fracture beyond that predicted on the basis of bone mineral density.10 The ultimate concern for the pediatrician is the effect of glucocorticoids on peak bone mass and the lifetime risk of fracture. We need to identify all skeletal risk factors associated with the spectrum of chronic childhood disease. Years of careful observation will be needed to define the natural history of bone fragility in these disorders.
Until more definitive information becomes available, what is the best approach to children requiring long-term treatment with glucocorticoids? We need to improve our methods of identifying children with poor bone health. The interpretation of bone densitometric analyses in growing children is very challenging, and errors abound when the results of dual-energy x-ray absorptiometry are interpreted by those unfamiliar with these complexities. More than half the children referred for a trial of treatment for osteoporosis diagnosed on the basis of dual-energy absorptiometry were found to have normal bone mineral density after their scans were reviewed by experts.11 The most common error in the interpretation of the scans was the use of a T score, which compares the child's bone mineral density with reference standards for adults, rather than a z score, which uses age-matched norms. Even if z scores are used, however, the diagnosis of osteoporosis in a child or adolescent cannot be based on bone mineral density alone.12
To preserve bone health, all disease-related risk factors, such as undernutrition, immobilization, sex steroid or growth hormone deficiency, and inflammation, must be addressed. Such simple measures as ensuring the adequacy of vitamin D stores and daily calcium intake are often overlooked in children with chronic illnesses.13
Finally, we cannot assume that drugs used to treat osteoporosis in adults are appropriate for use in children. Bisphosphonates have been established as effective in preventing and treating glucocorticoid-induced osteoporosis in adults,14 but these agents have neither been licensed for use nor adequately studied in children. Although observational studies suggest that pamidronate reduces fractures and increases bone density in children, we need randomized, controlled trials to establish the safety, efficacy, and optimal dose of bisphosphonates for use in children.15
The stakes with respect to preventing and treating the adverse skeletal effects of glucocorticoids and chronic disease are even greater for children than for adults. Failure to do so compromises the gains in bone mass and geometry during childhood and adolescence that contribute to a robust adult skeleton. However, the risks of misdiagnosis and inappropriate treatment are also greater for children. Children are not simply small adults.
Dr. Bachrach reports having received consulting fees and a grant from Pfizer, consulting fees from Novartis, and lecture fees from Genentech.
Source Information
From the Division of Pediatric Endocrinology, Stanford University Medical Center, Stanford, Calif.
References
Canalis E, Giustina A. Glucocorticoid-induced osteoporosis: summary of a workshop. J Clin Endocrinol Metab 2001;86:5681-5685.
Van Staa TP, Leufkens HG, Cooper C. The epidemiology of corticosteroid-induced osteoporosis: a meta-analysis. Osteoporos Int 2002;13:777-787.
Sambrook PN. Corticosteroid osteoporosis: practical implications of recent trials. J Bone Miner Res 2000;15:1645-1649.
Bachrach LK. Osteoporosis in childhood and adolescence. In: Marcus R, Feldman D, Kelsey J, eds Osteoporosis. 2nd ed. Vol. 2. San Diego, Calif.: Academic Press, 2001:151-93.
Van Staa TP, Cooper C, Leufkens HGM, Bishop N. Children and the risk of fractures caused by oral corticosteroids. J Bone Miner Res 2003;18:913-918.
Leonard MB, Feldman HI, Shults J, Zemel BS, Foster BJ, Stallings VA. Long-term, high-dose glucocorticoids and bone mineral content in childhood glucocorticoid-sensitive nephrotic syndrome. N Engl J Med 2004;351:868-875.
Heaney RP. Is the paradigm shifting? Bone 2003;33:457-465.
Orwell ES. Toward an expanded understanding of the role of the periosteum in skeletal health. J Bone Miner Res 2003;18:949-954.
Freundlich M, Jofe M, Goodman WG, Salusky IB. Bone histology in steroid-treated children with non-azotemic nephrotic syndrome. Pediatr Nephrol 2004;19:400-407.
Kanis JA, Johansson H, Oden A, et al. A meta-analysis of prior corticosteroid use and fracture risk. J Bone Miner Res 2004;19:893-899.
Gafni RI, Baron J. Overdiagnosis of osteoporosis in children due to misinterpretation of dual-energy x-ray absorptiometry (DEXA). J Pediatr 2004;144:253-257.
Writing Group for the ISCD Position Development Conference. Diagnosis of osteoporosis in men, premenopausal women, and children. J Clin Densitom 2004;7:17-26.
Sentongo TA, Semaeo EJ, Stettler N, Piccoli DA, Stallings VA, Zemel BS. Vitamin D status in children, adolescents, and young adults with Crohn disease. Am J Clin Nutr 2002;76:1077-1081.
Sambrook PN, Kotowicz M, Nash P, et al. Prevention and treatment of glucocorticoid-induced osteoporosis: a comparison of calcitriol, vitamin D plus calcium, and alendronate plus calcium. J Bone Miner Res 2003;18:919-924.
Batch JA, Couper JJ, Rodda C, Cowell CT, Zacharin M. Use of bisphosphonate therapy for osteoporosis in childhood and adolescence. J Paediatr Child Health 2003;39:88-92.(Laura K. Bachrach, M.D.)
Glucocorticoids contribute to bone loss and fragility-induced fractures in adults.2,3 Thirty to 50 percent of adults who receive more than 5 mg of prednisone daily have measurable decreases in bone mineral density that are evident within the first six months of treatment. The incidence of fractures increases as much as a factor of five at the spine and a factor of two at nonvertebral sites in users of glucocorticoids.3 The risk of bone loss and fracture varies with the daily and cumulative dose of glucocorticoids, age, menopausal status, and risk factors related to the underlying disease.3
The skeletal risks associated with glucocorticoid therapy in children and adolescents are less well established. Low bone mass has been observed in small cohorts of young patients treated with glucocorticoids for various chronic diseases.4 Because of their small samples, these studies lacked the statistical power to provide reliable estimates of the incidence of fracture. However, a recent case–control study involving more than 20,000 children receiving systemic glucocorticoids found an increased risk of fracture.5 During a mean follow-up period of 2.7 years, the adjusted odds ratio for fracture was 1.32 (95 percent confidence interval, 1.03 to 1.69) among children who received four or more courses of oral glucocorticoids (mean duration, 6.4 days), as compared with controls.
The study by Leonard et al. in this issue of the Journal6 examines the skeletal effects of glucocorticoid therapy in a homogeneous group of children with glucocorticoid-sensitive nephrotic syndrome. The effects of prednisone on the bones of these young subjects were not confounded by risk factors of immobilization, malnutrition, chronic inflammation, or cytokine excess. The children had received an average of 23,000 mg of prednisone over a mean of 4.4 years, three times as much as the daily dose of 5 mg that represents the adult threshold for bone loss. Despite long-term glucocorticoid therapy, the bone mineral content of the lumbar spine and whole body was similar among children with the nephrotic syndrome and controls, after adjustment for age, sex, bone area, maturity (Tanner stage), and race. Children with the nephrotic syndrome had a lower bone mineral content than the controls only after correction for body-mass index and only at the spine.
These data challenge the assumption that long-term glucocorticoid therapy inevitably leads to bone loss. Although this finding is reassuring, the limitations of the study leave many questions unanswered. The data are cross-sectional, making it impossible to exclude the possibility of bone loss or decreased rates of mineral accrual in individual patients. Furthermore, bone mass was the only measure of skeletal health evaluated, and it was assessed by means of dual-energy x-ray absorptiometry. Bone strength is influenced not only by mass but also by bone geometry, bone quality, and material properties that are not captured by dual-energy x-ray absorptiometry.7 There is reason to be concerned about bone geometry in children who receive glucocorticoids because their bone size is reduced. Leonard et al. observed that patients with the nephrotic syndrome were shorter than controls; their shorter bones were also probably narrower. Since resistance to fracture from bending forces is proportional to the radius to the fourth power, even a minor decrease in bone diameter could reduce bone strength.8 Bone quality and material properties are more difficult to quantify, but they are influenced by rates of bone resorption and formation.7 Bone turnover can be assessed with the use of biochemical markers and bone histomorphometry.7 When bone histomorphometry was analyzed in eight children with nonazotemic nephrotic syndrome, those receiving the highest doses of prednisone had reduced rates of bone formation, whereas trabecular microarchitecture was preserved.9
Further studies are needed to resolve these questions. Magnetic resonance imaging or quantitative computed tomography could better define the effects of glucocorticoids on bone geometry and on cortical as compared with trabecular bone. Bone histomorphometry and assessments of biochemical bone markers could shed light on glucocorticoid-induced changes in microarchitecture and turnover. However, these laboratory studies are proxy markers of bone health whose value in predicting fractures in children is uncertain. Among adults, current and prior exposure to corticosteroids confers an increased risk of fracture beyond that predicted on the basis of bone mineral density.10 The ultimate concern for the pediatrician is the effect of glucocorticoids on peak bone mass and the lifetime risk of fracture. We need to identify all skeletal risk factors associated with the spectrum of chronic childhood disease. Years of careful observation will be needed to define the natural history of bone fragility in these disorders.
Until more definitive information becomes available, what is the best approach to children requiring long-term treatment with glucocorticoids? We need to improve our methods of identifying children with poor bone health. The interpretation of bone densitometric analyses in growing children is very challenging, and errors abound when the results of dual-energy x-ray absorptiometry are interpreted by those unfamiliar with these complexities. More than half the children referred for a trial of treatment for osteoporosis diagnosed on the basis of dual-energy absorptiometry were found to have normal bone mineral density after their scans were reviewed by experts.11 The most common error in the interpretation of the scans was the use of a T score, which compares the child's bone mineral density with reference standards for adults, rather than a z score, which uses age-matched norms. Even if z scores are used, however, the diagnosis of osteoporosis in a child or adolescent cannot be based on bone mineral density alone.12
To preserve bone health, all disease-related risk factors, such as undernutrition, immobilization, sex steroid or growth hormone deficiency, and inflammation, must be addressed. Such simple measures as ensuring the adequacy of vitamin D stores and daily calcium intake are often overlooked in children with chronic illnesses.13
Finally, we cannot assume that drugs used to treat osteoporosis in adults are appropriate for use in children. Bisphosphonates have been established as effective in preventing and treating glucocorticoid-induced osteoporosis in adults,14 but these agents have neither been licensed for use nor adequately studied in children. Although observational studies suggest that pamidronate reduces fractures and increases bone density in children, we need randomized, controlled trials to establish the safety, efficacy, and optimal dose of bisphosphonates for use in children.15
The stakes with respect to preventing and treating the adverse skeletal effects of glucocorticoids and chronic disease are even greater for children than for adults. Failure to do so compromises the gains in bone mass and geometry during childhood and adolescence that contribute to a robust adult skeleton. However, the risks of misdiagnosis and inappropriate treatment are also greater for children. Children are not simply small adults.
Dr. Bachrach reports having received consulting fees and a grant from Pfizer, consulting fees from Novartis, and lecture fees from Genentech.
Source Information
From the Division of Pediatric Endocrinology, Stanford University Medical Center, Stanford, Calif.
References
Canalis E, Giustina A. Glucocorticoid-induced osteoporosis: summary of a workshop. J Clin Endocrinol Metab 2001;86:5681-5685.
Van Staa TP, Leufkens HG, Cooper C. The epidemiology of corticosteroid-induced osteoporosis: a meta-analysis. Osteoporos Int 2002;13:777-787.
Sambrook PN. Corticosteroid osteoporosis: practical implications of recent trials. J Bone Miner Res 2000;15:1645-1649.
Bachrach LK. Osteoporosis in childhood and adolescence. In: Marcus R, Feldman D, Kelsey J, eds Osteoporosis. 2nd ed. Vol. 2. San Diego, Calif.: Academic Press, 2001:151-93.
Van Staa TP, Cooper C, Leufkens HGM, Bishop N. Children and the risk of fractures caused by oral corticosteroids. J Bone Miner Res 2003;18:913-918.
Leonard MB, Feldman HI, Shults J, Zemel BS, Foster BJ, Stallings VA. Long-term, high-dose glucocorticoids and bone mineral content in childhood glucocorticoid-sensitive nephrotic syndrome. N Engl J Med 2004;351:868-875.
Heaney RP. Is the paradigm shifting? Bone 2003;33:457-465.
Orwell ES. Toward an expanded understanding of the role of the periosteum in skeletal health. J Bone Miner Res 2003;18:949-954.
Freundlich M, Jofe M, Goodman WG, Salusky IB. Bone histology in steroid-treated children with non-azotemic nephrotic syndrome. Pediatr Nephrol 2004;19:400-407.
Kanis JA, Johansson H, Oden A, et al. A meta-analysis of prior corticosteroid use and fracture risk. J Bone Miner Res 2004;19:893-899.
Gafni RI, Baron J. Overdiagnosis of osteoporosis in children due to misinterpretation of dual-energy x-ray absorptiometry (DEXA). J Pediatr 2004;144:253-257.
Writing Group for the ISCD Position Development Conference. Diagnosis of osteoporosis in men, premenopausal women, and children. J Clin Densitom 2004;7:17-26.
Sentongo TA, Semaeo EJ, Stettler N, Piccoli DA, Stallings VA, Zemel BS. Vitamin D status in children, adolescents, and young adults with Crohn disease. Am J Clin Nutr 2002;76:1077-1081.
Sambrook PN, Kotowicz M, Nash P, et al. Prevention and treatment of glucocorticoid-induced osteoporosis: a comparison of calcitriol, vitamin D plus calcium, and alendronate plus calcium. J Bone Miner Res 2003;18:919-924.
Batch JA, Couper JJ, Rodda C, Cowell CT, Zacharin M. Use of bisphosphonate therapy for osteoporosis in childhood and adolescence. J Paediatr Child Health 2003;39:88-92.(Laura K. Bachrach, M.D.)