Glucocorticoids and Bone Mineral Content in the Childhood Nephrotic Syndrome
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《新英格兰医药杂志》
To the Editor: Leonard et al. (Aug. 26 issue)1 report that the use of glucocorticoids does not appear to be associated with deficits in bone mineral content in children with the nephrotic syndrome — results that differ from ours.2 An important observation was a lower bone mineral content at the spine after correction for the body-mass index. The earliest changes of glucocorticoid-induced bone loss are indeed seen in the lumbar spine because of its high bone mineral content. We would also be interested to know the correlation between the bone mineral content and glucocorticoid dose, since doses varied widely. There is also no information on the dietary calcium intake in the report by Leonard et al. In our study, both calcium intake and the glucocorticoid dose were important predictors of bone mineral density.2 It is unlikely that our results were confounded by height, since we used the height for age for comparison. The effect of sex on bone mineral density becomes important only after the age of 16 years,3 and only three children were in that age group. Glucocorticoids do seem to have adverse skeletal effects, even in the nephrotic syndrome.2,4,5
Sanjeev Gulati, D.M.
Kiran Gulati, M.D.
McMaster University
Hamilton, ON L8N 3Z5, Canada
References
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.
Gulati S, Godbole M, Singh U, Gulati K, Srivastava A. Are children with idiopathic nephrotic syndrome at risk for metabolic bone disease? Am J Kidney Dis 2003;41:1163-1169.
Faulkner RA, Bailey DA, Drinkwater DT, McKay HA, Arnold C, Wilkinson AA. Bone densitometry in Canadian children 8-17 years of age. Calcif Tissue Int 1996;59:344-351.
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.
Mittal SK, Dash SC, Tiwari SC, Agarwal SK, Saxena S, Fishbane S. Bone histology in patients with nephrotic syndrome and normal renal function. Kidney Int 1999;55:1912-1919.
To the Editor: Intermittent treatment with long-term, high-dose glucocorticoids may result in high whole-body bone mineral content and normal spinal bone mineral content in children.1 In addition to a high body-mass index,1 poor bone-material properties could also play an important role. First, bone stiffness in growing children is low as compared with that in adults. Second, glucocorticoids may impair bone-material properties.2 Bone strain generated by biomechanical loading is a pivotal factor that influences bone mineral content,3 and impairment of bone-material properties could induce bone mineral gain through an increase in bone strain from loading.4 When weight-bearing activity is maintained, an increase in the body-mass index and impairment of bone-material properties could synergistically increase bone mineral content in the weight-bearing skeleton. In contrast, such an increase in bone mineral content would not be observed in non–weight-bearing bones, suggesting that these bones become fragile as a result of poor bone-material properties. This is consistent with a recent report that the incidence of humerus fracture is high whereas hip or vertebral fractures occur very rarely in children treated with oral corticosteroids.5
Toshihiro Sugiyama, M.D., Ph.D.
Hiroshi Tanaka, M.D., Ph.D.
Toshihiko Taguchi, M.D., Ph.D.
Yamaguchi University School of Medicine
Yamaguchi 755-8505, Japan
toshihiro.sugiyama@chive.ocn.ne.jp
References
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.
Sugiyama T, Kawai S. Quantitative ultrasound, skeletal quality, and fracture risk. Lancet 2004;363:1076-1077.
Ehrlich PJ, Lanyon LE. Mechanical strain and bone cell function: a review. Osteoporos Int 2002;13:688-700.
Sugiyama T, Taguchi T, Kawai S. Adaptation of bone to mechanical loads. Lancet 2002;359:1160-1160.
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.
To the Editor: Leonard et al. report the relative preservation of bone mineral content in children with the nephrotic syndrome who were treated with prednisone. Prednisone is an intrinsically inactive glucocorticoid that requires conversion to prednisolone by the 11-hydroxysteroid dehydrogenase type 1 (11-HSD1) enzyme to achieve biologic activity. This conversion occurs not only in the liver but also in adipose tissue and osteoblasts. In healthy adults, the degree of suppression of osteoblast function seen with prednisolone is predicted by 11-HSD1 activity.1 Local glucocorticoid generation thus appears to play a major role in the effect of glucocorticoids on osteoblasts. In cultured human osteoblasts, 11-HSD1 activity increases with the donor's age and in response to inflammatory cytokines.2,3 The relative preservation of bone content reported by Leonard et al. is thus likely to be a consequence of the limited exposure of osteoblasts to active glucocorticoids in this young population with limited inflammatory disease. Since this enzyme system handles other synthetic steroids differently,4 it is important that the authors' conclusions not be extrapolated to other therapeutic glucocorticoids.
Mark S. Cooper, Ph.D.
Paul M. Stewart, F.R.C.P.
University of Birmingham
Birmingham B15 2TT, United Kingdom
p.m.stewart@bham.ac.uk
References
Cooper MS, Blumsohn A, Goddard PE, et al. 11Beta-hydroxysteroid dehydrogenase type 1 activity predicts the effects of glucocorticoids on bone. J Clin Endocrinol Metab 2003;88:3874-3877.
Cooper MS, Rabbitt EH, Goddard PE, Bartlett WA, Hewison M, Stewart PM. Osteoblastic 11beta-hydroxysteroid dehydrogenase type 1 activity increases with age and glucocorticoid exposure. J Bone Miner Res 2002;17:979-986.
Cooper MS, Bujalska I, Rabbitt E, et al. Modulation of 11beta-hydroxysteroid dehydrogenase isozymes by proinflammatory cytokines in osteoblasts: an autocrine switch from glucocorticoid inactivation to activation. J Bone Miner Res 2001;16:1037-1044.
Diederich S, Eigendorff E, Burkhardt P, et al. 11Beta-hydroxysteroid dehydrogenase types 1 and 2: an important pharmacokinetic determinant for the activity of synthetic mineralo- and glucocorticoids. J Clin Endocrinol Metab 2002;87:5695-5701.
The authors reply: Whereas we reported that glucocorticoid therapy was not associated with significant reductions in bone mineral content at the lumbar spine, adjusted for bone area, age, sex, degree of maturation, and race, in the childhood nephrotic syndrome, Gulati et al. reported significant deficits in spine-area bone mineral density.1 We suggested in our article that their use of sex-nonspecific reference data resulted in the overdiagnoses of osteoporosis in their cohort, which had a predominance of males (83 percent). In their letter, Gulati and Gulati respond that "the effect of sex on bone mineral density becomes important only after the age of 16 years," and they cite a report by Faulkner et al. In fact, Faulkner et al. reported that bone mineral density of the spine was significantly greater in girls in the age range of 8 to 17 years,2 a finding attributable to the earlier onset of puberty in girls, which is associated with a marked increase in bone accretion. As Faulkner et al. stated, "shifting the male curve about two years to the left (which would approximately align the males and females on a maturity status) negates the gender differences in childhood." Furthermore, our comparison of reference data on spinal bone mineral density in the assessment of children 9 to 15 years of age showed that the use of sex-specific reference data resulted in the diagnoses of osteoporosis in 10 percent of boys, whereas application of the sex-nonspecific data used by Gulati et al. resulted in the diagnosis of osteoporosis in 44 percent of the same subjects.3
The study by Gulati et al. included children with glucocorticoid-resistant nephrotic syndrome, whereas ours was limited to children with glucocorticoid-sensitive nephrotic syndrome in remission. Persistent nephrosis may result in urinary losses of vitamin D and osteomalacia, independently of the effects of glucocorticoid. Gulati and Gulati cite two reports of abnormal histologic findings in bone in patients with the nephrotic syndrome.4,5 Both studies included subjects in relapse, and histologic studies showed osteomalacia consistent with vitamin D insufficiency. Therefore, we do not believe there is convincing evidence of glucocorticoid-induced bone loss in the childhood nephrotic syndrome.
We agree with Drs. Cooper and Stewart that our findings may not be generalizable to other therapeutic glucocorticoid preparations. However, prednisone is the most widely used systemic glucocorticoid for the treatment of pediatric conditions.
We agree that glucocorticoids may have effects on bone material and quality that are not captured by bone mineral content. Although the greater bone mineral content in children with glucocorticoid-induced obesity may reflect an adaptive response to increased strain in poor-quality bone, we would note that the increased bone mineral content associated with obesity was indistinguishable between obese children with the nephrotic syndrome and obese controls.
Mary B. Leonard, M.D., M.S.C.E.
Babette S. Zemel, Ph.D.
Virginia A. Stallings, M.D.
Children's Hospital of Philadelphia
Philadelphia, PA 19104
leonard@email.chop.edu
References
Gulati S, Godbole M, Singh U, Gulati K, Srivastava A. Are children with idiopathic nephrotic syndrome at risk for metabolic bone disease? Am J Kidney Dis 2003;41:1163-1169.
Faulkner RA, Bailey DA, Drinkwater DT, McKay HA, Arnold C, Wilkinson AA. Bone densitometry in Canadian children 8-17 years of age. Calcif Tissue Int 1996;59:344-351.
Leonard MB, Propert KJ, Zemel BS, Stallings VA, Feldman HI. Discrepancies in pediatric bone mineral density reference data: potential for misdiagnosis of osteopenia. J Pediatr 1999;135:182-188.
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.
Mittal SK, Dash SC, Tiwari SC, Agarwal SK, Saxena S, Fishbane S. Bone histology in patients with nephrotic syndrome and normal renal function. Kidney Int 1999;55:1912-1919.
Sanjeev Gulati, D.M.
Kiran Gulati, M.D.
McMaster University
Hamilton, ON L8N 3Z5, Canada
References
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.
Gulati S, Godbole M, Singh U, Gulati K, Srivastava A. Are children with idiopathic nephrotic syndrome at risk for metabolic bone disease? Am J Kidney Dis 2003;41:1163-1169.
Faulkner RA, Bailey DA, Drinkwater DT, McKay HA, Arnold C, Wilkinson AA. Bone densitometry in Canadian children 8-17 years of age. Calcif Tissue Int 1996;59:344-351.
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.
Mittal SK, Dash SC, Tiwari SC, Agarwal SK, Saxena S, Fishbane S. Bone histology in patients with nephrotic syndrome and normal renal function. Kidney Int 1999;55:1912-1919.
To the Editor: Intermittent treatment with long-term, high-dose glucocorticoids may result in high whole-body bone mineral content and normal spinal bone mineral content in children.1 In addition to a high body-mass index,1 poor bone-material properties could also play an important role. First, bone stiffness in growing children is low as compared with that in adults. Second, glucocorticoids may impair bone-material properties.2 Bone strain generated by biomechanical loading is a pivotal factor that influences bone mineral content,3 and impairment of bone-material properties could induce bone mineral gain through an increase in bone strain from loading.4 When weight-bearing activity is maintained, an increase in the body-mass index and impairment of bone-material properties could synergistically increase bone mineral content in the weight-bearing skeleton. In contrast, such an increase in bone mineral content would not be observed in non–weight-bearing bones, suggesting that these bones become fragile as a result of poor bone-material properties. This is consistent with a recent report that the incidence of humerus fracture is high whereas hip or vertebral fractures occur very rarely in children treated with oral corticosteroids.5
Toshihiro Sugiyama, M.D., Ph.D.
Hiroshi Tanaka, M.D., Ph.D.
Toshihiko Taguchi, M.D., Ph.D.
Yamaguchi University School of Medicine
Yamaguchi 755-8505, Japan
toshihiro.sugiyama@chive.ocn.ne.jp
References
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.
Sugiyama T, Kawai S. Quantitative ultrasound, skeletal quality, and fracture risk. Lancet 2004;363:1076-1077.
Ehrlich PJ, Lanyon LE. Mechanical strain and bone cell function: a review. Osteoporos Int 2002;13:688-700.
Sugiyama T, Taguchi T, Kawai S. Adaptation of bone to mechanical loads. Lancet 2002;359:1160-1160.
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.
To the Editor: Leonard et al. report the relative preservation of bone mineral content in children with the nephrotic syndrome who were treated with prednisone. Prednisone is an intrinsically inactive glucocorticoid that requires conversion to prednisolone by the 11-hydroxysteroid dehydrogenase type 1 (11-HSD1) enzyme to achieve biologic activity. This conversion occurs not only in the liver but also in adipose tissue and osteoblasts. In healthy adults, the degree of suppression of osteoblast function seen with prednisolone is predicted by 11-HSD1 activity.1 Local glucocorticoid generation thus appears to play a major role in the effect of glucocorticoids on osteoblasts. In cultured human osteoblasts, 11-HSD1 activity increases with the donor's age and in response to inflammatory cytokines.2,3 The relative preservation of bone content reported by Leonard et al. is thus likely to be a consequence of the limited exposure of osteoblasts to active glucocorticoids in this young population with limited inflammatory disease. Since this enzyme system handles other synthetic steroids differently,4 it is important that the authors' conclusions not be extrapolated to other therapeutic glucocorticoids.
Mark S. Cooper, Ph.D.
Paul M. Stewart, F.R.C.P.
University of Birmingham
Birmingham B15 2TT, United Kingdom
p.m.stewart@bham.ac.uk
References
Cooper MS, Blumsohn A, Goddard PE, et al. 11Beta-hydroxysteroid dehydrogenase type 1 activity predicts the effects of glucocorticoids on bone. J Clin Endocrinol Metab 2003;88:3874-3877.
Cooper MS, Rabbitt EH, Goddard PE, Bartlett WA, Hewison M, Stewart PM. Osteoblastic 11beta-hydroxysteroid dehydrogenase type 1 activity increases with age and glucocorticoid exposure. J Bone Miner Res 2002;17:979-986.
Cooper MS, Bujalska I, Rabbitt E, et al. Modulation of 11beta-hydroxysteroid dehydrogenase isozymes by proinflammatory cytokines in osteoblasts: an autocrine switch from glucocorticoid inactivation to activation. J Bone Miner Res 2001;16:1037-1044.
Diederich S, Eigendorff E, Burkhardt P, et al. 11Beta-hydroxysteroid dehydrogenase types 1 and 2: an important pharmacokinetic determinant for the activity of synthetic mineralo- and glucocorticoids. J Clin Endocrinol Metab 2002;87:5695-5701.
The authors reply: Whereas we reported that glucocorticoid therapy was not associated with significant reductions in bone mineral content at the lumbar spine, adjusted for bone area, age, sex, degree of maturation, and race, in the childhood nephrotic syndrome, Gulati et al. reported significant deficits in spine-area bone mineral density.1 We suggested in our article that their use of sex-nonspecific reference data resulted in the overdiagnoses of osteoporosis in their cohort, which had a predominance of males (83 percent). In their letter, Gulati and Gulati respond that "the effect of sex on bone mineral density becomes important only after the age of 16 years," and they cite a report by Faulkner et al. In fact, Faulkner et al. reported that bone mineral density of the spine was significantly greater in girls in the age range of 8 to 17 years,2 a finding attributable to the earlier onset of puberty in girls, which is associated with a marked increase in bone accretion. As Faulkner et al. stated, "shifting the male curve about two years to the left (which would approximately align the males and females on a maturity status) negates the gender differences in childhood." Furthermore, our comparison of reference data on spinal bone mineral density in the assessment of children 9 to 15 years of age showed that the use of sex-specific reference data resulted in the diagnoses of osteoporosis in 10 percent of boys, whereas application of the sex-nonspecific data used by Gulati et al. resulted in the diagnosis of osteoporosis in 44 percent of the same subjects.3
The study by Gulati et al. included children with glucocorticoid-resistant nephrotic syndrome, whereas ours was limited to children with glucocorticoid-sensitive nephrotic syndrome in remission. Persistent nephrosis may result in urinary losses of vitamin D and osteomalacia, independently of the effects of glucocorticoid. Gulati and Gulati cite two reports of abnormal histologic findings in bone in patients with the nephrotic syndrome.4,5 Both studies included subjects in relapse, and histologic studies showed osteomalacia consistent with vitamin D insufficiency. Therefore, we do not believe there is convincing evidence of glucocorticoid-induced bone loss in the childhood nephrotic syndrome.
We agree with Drs. Cooper and Stewart that our findings may not be generalizable to other therapeutic glucocorticoid preparations. However, prednisone is the most widely used systemic glucocorticoid for the treatment of pediatric conditions.
We agree that glucocorticoids may have effects on bone material and quality that are not captured by bone mineral content. Although the greater bone mineral content in children with glucocorticoid-induced obesity may reflect an adaptive response to increased strain in poor-quality bone, we would note that the increased bone mineral content associated with obesity was indistinguishable between obese children with the nephrotic syndrome and obese controls.
Mary B. Leonard, M.D., M.S.C.E.
Babette S. Zemel, Ph.D.
Virginia A. Stallings, M.D.
Children's Hospital of Philadelphia
Philadelphia, PA 19104
leonard@email.chop.edu
References
Gulati S, Godbole M, Singh U, Gulati K, Srivastava A. Are children with idiopathic nephrotic syndrome at risk for metabolic bone disease? Am J Kidney Dis 2003;41:1163-1169.
Faulkner RA, Bailey DA, Drinkwater DT, McKay HA, Arnold C, Wilkinson AA. Bone densitometry in Canadian children 8-17 years of age. Calcif Tissue Int 1996;59:344-351.
Leonard MB, Propert KJ, Zemel BS, Stallings VA, Feldman HI. Discrepancies in pediatric bone mineral density reference data: potential for misdiagnosis of osteopenia. J Pediatr 1999;135:182-188.
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.
Mittal SK, Dash SC, Tiwari SC, Agarwal SK, Saxena S, Fishbane S. Bone histology in patients with nephrotic syndrome and normal renal function. Kidney Int 1999;55:1912-1919.