{"paper_id":"230b2965-6ebd-4d95-b94e-ccf63794b259","body_text":"Abstract\nSummary\nIncident vertebral fractures and lumbar spine bone mineral density (BMD) were assessed in the 12 months following glucocorticoid initiation in 65 children with nephrotic syndrome. The incidence of vertebral fractures was low at 12 months (6 %) and most patients demonstrated recovery in BMD Z-scores by this time point.\nIntroduction\nVertebral fracture (VF) incidence following glucocorticoid (GC) initiation has not been previously reported in pediatric nephrotic syndrome.\nMethods\nVF was assessed on radiographs (Genant method); lumbar spine bone mineral density (LS BMD) was evaluated by dual-energy X-ray absorptiometry.\nResults\nSixty-five children were followed to 12 months post-GC initiation (median age, 5.4 years; range, 2.3–17.9). Three of 54 children with radiographs (6 %; 95 % confidence interval (CI), 2–15 %) had incident VF at 1 year. The mean LS BMD Z-score was below the healthy average at baseline (mean ± standard deviation (SD), −0.5 ± 1.1; p = 0.001) and at 3 months (−0.6 ± 1.1; p < 0.001), but not at 6 months (−0.3 ± 1.3; p = 0.066) or 12 months (−0.3 ± 1.2; p = 0.066). Mixed effect modeling showed a significant increase in LS BMD Z-scores between 3 and 12 months (0.22 SD; 95 % CI, 0.08 to 0.36; p = 0.003). A subgroup (N = 16; 25 %) had LS BMD Z-scores that were ≤−1.0 at 12 months. In these children, each additional 1,000 mg/m2 of GC received in the first 3 months was associated with a decrease in LS BMD Z-score by 0.39 at 12 months (95 % CI, −0.71 to −0.07; p = 0.017).\nConclusions\nThe incidence of VF at 1 year was low and LS BMD Z-scores improved by 12 months in the majority. Twenty-five percent of children had LS BMD Z-scores ≤−1.0 at 12 months. In these children, LS BMD Z-scores were inversely associated with early GC exposure, despite similar GC exposure compared to the rest of the cohort.\nSimilar content being viewed by others\nAbbreviations\n- BMD:\n-\nBone mineral density\n- CI:\n-\nConfidence interval\n- GFR:\n-\nGlomerular filtration rate\n- GC:\n-\nGlucucorticoid\n- IQR:\n-\nInterquartile range\n- LS:\n-\nLumbar spine\n- NS:\n-\nNephrotic syndrome\n- SD:\n-\nStandard deviation\n- VF:\n-\nVertebral fracture\nReferences\nHodson EM, Knight JF, Willis NS, Craig JC (2001) Corticosteroid therapy for nephrotic syndrome in children. Cochrane Database Syst Rev 2\nTarshish P, Tobin JN, Bernstein J, Edelmann CM Jr (1997) Prognostic significance of the early course of minimal change nephrotic syndrome: report of the International Study of Kidney Disease in Children. J Am Soc Nephrol 8:769–776\nCanalis E, Mazziotti G, Giustina A, Bilezikian JP (2007) Glucocorticoid-induced osteoporosis: pathophysiology and therapy. Osteoporos Int 18:1319–1328\nWeinstein RS (2012) Glucocorticoid-induced osteoporosis and osteonecrosis. Endocrinol Metab Clin North Am 41:595–611\nvan Staa TP, Cooper C, Leufkens HG, Bishop N (2003) Children and the risk of fractures caused by oral corticosteroids. J Bone Miner Res 18:913–918\nRodd C, Lang B, Ramsay T et al (2012) Incident vertebral fractures among children with rheumatic disorders 12 months after glucocorticoid initiation: a national observational study. Arthritis Care Res 64:122–131\nNakhla M, Scuccimarri R, Duffy KN, Chedeville G, Campillo S, Duffy CM, Azouz EM, Shenouda N, Sharma AK, Rodd C (2009) Prevalence of vertebral fractures in children with chronic rheumatic diseases at risk for osteopenia. J Pediatr 154:438–443\nVaronos S, Ansell BM, Reeve J (1987) Vertebral collapse in juvenile chronic arthritis: its relationship with glucocorticoid therapy. Calcif Tissue Int 41:75–78\nFeber J, Gaboury I, Ni A et al (2012) Skeletal findings in children recently initiating glucocorticoids for the treatment of nephrotic syndrome. Osteoporos Int 23:751–760\nFujita T, Satomura A, Hidaka M, Ohsawa I, Endo M, Ohi H (2000) Acute alteration in bone mineral density and biochemical markers for bone metabolism in nephrotic patients receiving high-dose glucocorticoid and one-cycle etidronate therapy. Calcif Tissue Int 66:195–199\nLeonard MB, Feldman HI, Shults J, Zemel BS, Foster BJ, Stallings VA (2004) Long-term, high-dose glucocorticoids and bone mineral content in childhood glucocorticoid-sensitive nephrotic syndrome. N Engl J Med 351:868–875\nSbrocchi AM, Rauch F, Matzinger M, Feber J, Ward LM (2011) Vertebral fractures despite normal spine bone mineral density in a boy with nephrotic syndrome. Pediatr Nephrol 26:139–142\nHalton J, Gaboury I, Grant R et al (2009) Advanced vertebral fracture among newly diagnosed children with acute lymphoblastic leukemia: results of the Canadian Steroid-Associated Osteoporosis in the Pediatric Population (STOPP) research program. J Bone Miner Res 24:1326–1334\nInternational Study of kidney Disease in Children (1981) The primary nephrotic syndrome in children. Identification of patients with minimal change nephrotic syndrome from initial response to prednisone. A report of the International Study of Kidney Disease in Children. J Pediatr 98:561–564\nInstitute of Medicine (1997) Dietary reference intakes for calcium, phosphorus, magnesium, vitamin D, fluoride. National Academy Press, Washington\nGbadegesin R, Smoyer WE (2008) Nephrotic syndrome. In: Geary DF, Schaefer F (eds) Comprehensive pediatric nephrology. Elsevier, New York\nSchwartz GJ, Munoz A, Schneider MF, Mak RH, Kaskel F, Warady BA, Furth SL (2009) New equations to estimate GFR in children with CKD. J Am Soc Nephrol 20:629–637\nMarshall WA, Tanner JM (1969) Variations in pattern of pubertal changes in girls. Arch Dis Child 44:291–303\nMarshall WA, Tanner JM (1970) Variations in the pattern of pubertal changes in boys. Arch Dis Child 45:13–23\nOgden CL, Kuczmarski RJ, Flegal KM, Mei Z, Guo S, Wei R, Grummer-Strawn LM, Curtin LR, Roche AF, Johnson CL (2002) Centers for Disease Control and Prevention 2000 growth charts for the United States: improvements to the 1977 National Center for Health Statistics version. Pediatrics 109:45–60\nWorld Health Organization Multicentre Growth Reference Study Group (2006) WHO child growth standards: length/height-for-age, weight-for-age, weight-for-length, weight-for-height and body mass index-for-age: methods and development. World Health Organization, Geneva, pp 229–300\nMusgrave KO, Giambalvo L, Leclerc HL, Cook RA, Rosen CJ (1989) Validation of a quantitative food frequency questionnaire for rapid assessment of dietary calcium intake. J Am Diet Assoc 89:1484–1488\nHay J (1997) Development and validation of the Habitual Activity Estimation Scale (HAES). Children and Exercise XIX II:125–129\nWells GD, Wilkes DL, Schneiderman-Walker J, Elmi M, Tullis E, Lands LC, Ratjen F, Coates AL (2008) Reliability and validity of the habitual activity estimation scale (HAES) in patients with cystic fibrosis. Pediatr Pulmonol 43:345–353\nvan Staa TP, Leufkens HG, Cooper C (2002) The epidemiology of corticosteroid-induced osteoporosis: a meta-analysis. Osteoporos Int 13:777–787\nCurtis JR, Westfall AO, Allison J, Bijlsma JW, Freeman A, George V, Kovac SH, Spettell CM, Saag KG (2006) Population-based assessment of adverse events associated with long-term glucocorticoid use. Arthritis Rheum 55:420–426\nDubner SE, Shults J, Baldassano RN, Zemel BS, Thayu M, Burnham JM, Herskovitz RM, Howard KM, Leonard MB (2009) Longitudinal assessment of bone density and structure in an incident cohort of children with Crohn's disease. Gastroenterology 136:123–130\nGenant HK, Wu CY, van Kuijk C, Nevitt MC (1993) Vertebral fracture assessment using a semiquantitative technique. J Bone Miner Res 8:1137–1148\nKeats TE, Smith TH (1977) An atlas of normal developmental anatomy, 2nd edn. Year Book of Medical Publishers, Chicago\nGaca AM, Barnhart HX, Bisset GS 3rd (2010) Evaluation of wedging of lower thoracic and upper lumbar vertebral bodies in the pediatric population. AJR Am J Roentgenol 194:516–520\nWebber CE, Beaumont LF, Morrison J, Sala A, Barr RD (2007) Age-predicted values for lumbar spine, proximal femur, and whole-body bone mineral density: results from a population of normal children aged 3 to 18 years. Can Assoc Radiol J 58:37–45\nNewcombe RG (1998) Two-sided confidence intervals for the single proportion: comparison of seven methods. Stat Med 17:857–872\nGoulding A, Cannan R, Williams SM, Gold EJ, Taylor RW, Lewis-Barned NJ (1998) Bone mineral density in girls with forearm fractures. J Bone Miner Res 13:143–148\nAlos N, Grant RM, Ramsay T et al (2012) High incidence of vertebral fractures in children with acute lymphoblastic leukemia 12 months after the initiation of therapy. J Clin Oncol 30:2760–2767\nBurnham JM (2012) Inflammatory diseases and bone health in children. Curr Opin Rheumatol 24:548–553\nBak M, Serdaroglu E, Guclu R (2006) Prophylactic calcium and vitamin D treatments in steroid-treated children with nephrotic syndrome. Pediatr Nephrol 21:350–354\nJia D, O'Brien CA, Stewart SA, Manolagas SC, Weinstein RS (2006) Glucocorticoids act directly on osteoclasts to increase their life span and reduce bone density. Endocrinology 147:5592–5599\nDalle Carbonare L, Bertoldo F, Valenti MT, Zenari S, Zanatta M, Sella S, Giannini S, Cascio VL (2005) Histomorphometric analysis of glucocorticoid-induced osteoporosis. Micron 36:645–652\nGulati S, Sharma RK, Gulati K, Singh U, Srivastava A (2005) Longitudinal follow-up of bone mineral density in children with nephrotic syndrome and the role of calcium and vitamin D supplements. Nephrol Dial Transplant 20:1598–1603\nHegarty J, Mughal MZ, Adams J, Webb NJ (2005) Reduced bone mineral density in adults treated with high-dose corticosteroids for childhood nephrotic syndrome. Kidney Int 68:2304–2309\nWetzsteon RJ, Shults J, Zemel BS, Gupta PU, Burnham JM, Herskovitz RM, Howard KM, Leonard MB (2009) Divergent effects of glucocorticoids on cortical and trabecular compartment BMD in childhood nephrotic syndrome. J Bone Miner Res 24:503–513\nTsampalieros A, Gupta P, Denburg MR, Shults J, Zemel BS, Mostoufi-Moab S, Wetzsteon RJ, Herskovitz RM, Whitehead KM, Leonard MB (2013) Glucocorticoid effects on changes in bone mineral density and cortical structure in childhood nephrotic syndrome. J Bone Miner Res 28:480–488\nOstalska-Nowicka D, Zachwieja J, Nowicki M, Kaczmarek E, Siwinska A, Witt M (2005) Vascular endothelial growth factor (VEGF-C1)-dependent inflammatory response of podocytes in nephrotic syndrome glomerulopathies in children: an immunohistochemical approach. Histopathology 46:176–183\nAcknowledgments\nThis study was primarily funded by an operating grant from the Canadian Institutes for Health Research (FRN 64285). Additional funding for this work has been provided to Dr. Leanne Ward by the Canadian Institutes for Health Research New Investigator Program, the Canadian Child Health Clinician Scientist Career Enhancement Program, a University of Ottawa Research Chair Award and the CHEO Departments of Pediatrics and Surgery. This work was also supported by the Children's Hospital of Eastern Ontario Research Institute and the University of Alberta Women and Children's Health Research Institute.\nThe Canadian STOPP Consortium would like to thank the following individuals: The children and their families who participated in the study and without whom the STOPP study would not have been possible. Research Associates who managed the study at the co-ordinating center (the Children's Hospital of Eastern Ontario Ottawa, Ontario): Elizabeth Sykes (STOPP Project Manager), Maya Scharke (STOPP Data Analyst and Database Manager), Monica Tomiak (Statistical Analyses), Victor Konji (STOPP Publications and Presentations Committee Liaison and hand morphometry measurements), Steve Anderson (Children's Hospital of Eastern Ontario Pediatric Bone Health Program Research Manager), Catherine Riddell (STOPP National Study Monitor); Research Associates who took care of the patients from the following institutions: Alberta Children's Hospital, Calgary, Alberta: Eileen Pyra; British Columbia Children's Hospital, Vancouver British Columbia: Terry Viczko, Sandy Hwang, Angelyne Sarmiento; Children's Hospital of Eastern Ontario, Ottawa, Ontario: Heather Cosgrove, Josie MacLennan, Catherine Riddell; Children's Hospital, London Health Sciences Centre, London, Ontario: Leila MacBean, Mala Ramu; McMaster Children's Hospital, Hamilton, Ontario: Susan Docherty-Skippen; IWK Health Center, Halifax, Nova Scotia: Aleasha Warner; Montréal Children's Hospital, Montréal, Québec: Diane Laforte, Maritza Laprise, Ste. Justine Hospital, Montréal, Québec: Claude Belleville, Natacha Gaulin Marion; Stollery Children's Hospital, Edmonton, Alberta: Ronda Blasco, Amanda Mullins, Toronto Hospital for Sick Children, Toronto, Ontario: Michele Petrovic; Winnipeg Children's Hospital, Winnipeg, Manitoba: Dan Catte, Erika Bloomfield. The Research Nurses, Support Staff and all the STOPP collaborators from the various Divisions of Nephrology, Oncology, Rheumatology and Radiology who have contributed to the care of the children enrolled in the study.\nFunding\nPrimary funding source: The Canadian Institutes of Health Research Operating Grants Program (FRN 64285). Additional Funding Sources: The Canadian Child Health Clinician Scientist Program; The Canadian Institutes for Health Research New Investigator Program; The Children's Hospital of Eastern Ontario Research Institute, University of Ottawa; The Women and Children's Health Research Institute, University of Alberta\nConflicts of interest\nDr. Leanne M. Ward has been a consultant to Novartis Pharmaceuticals Corporation, Merck Sharpe & Dohme Corp. and Amgen Inc. in the last 2 years. All other authors have no conflict of interest to declare.\nAuthor information\nAuthors and Affiliations\nConsortia\nCorresponding author\nAdditional information\nThe Canadian STeroid-associated Osteoporosis in the Pediatric Population (STOPP) Consortium (a pan-Canadian, pediatric bone health working group)\n#Principal investigator; *Executive Committee Member; §Publications and Presentations Committee Member\nCoordinating center\nChildren's Hospital of Eastern Ontario, Ottawa, Ontario: Leanne M. Ward#*§ (Study Principal Investigator), Janusz Feber*§ (Nephrology), Jacqueline Halton*§ (Oncology), Roman Jurencak (Rheumatology), MaryAnn Matzinger (Radiology, Central Radiograph Analyses), Johannes Roth (Rheumatology), Nazih Shenouda§ (Radiology, Central Radiograph Analyses)\nOttawa Hospital Research Institute, Ottawa Methods Centre Ottawa, Ontario: David Moher*§ (Research Methods), Tim Ramsay (Statistical Analyses)\nParticipating centers\nAlberta Children's Hospital, Calgary, Alberta: David Stephure (Site Principal Investigator), Reinhard Kloiber (Radiology), Victor Lewis (Oncology), Julian Midgley (Nephrology), Paivi Miettunen (Rheumatology)\nBritish Columbia Children's Hospital, Vancouver, British Columbia: David Cabral* (Site Principal Investigator), David B. Dix (Oncology), Kristin Houghton (Rheumatology), Helen R. Nadel (Radiology)\nBritish Columbia Women's and Children's Hospital and Health Sciences Center, Vancouver, British Columbia: Brian C. Lentle§ (Radiology)\nBrock University, Faculty of Applied Health Sciences, St. Catharines, Ontario: John Hay§ (Physical Activity Measurements)\nChildren's Hospital, London Health Sciences Centre, University of Western Ontario, London, Ontario: Robert Stein (Site Principal Investigator), Elizabeth Cairney (Oncology), Cheril Clarson (Bone Health), Guido Filler (Nephrology) §, Joanne Grimmer (Nephrology), Keith Sparrow (Radiology)\nIWK Health Center, Halifax, Nova Scotia: Elizabeth Cummings (Site Principal Investigator), Conrad Fernandez (Oncology), Adam M. Huber§ (Rheumatology), Bianca Lang*§ (Rheumatology), Kathy O'Brien (Radiology)\nMcMaster Children's Hospital, Hamilton, Ontario: Stephanie Atkinson*§ (Site Principal Investigator), Steve Arora (Nephrology), Ronald Barr§ (Oncology), Craig Coblentz (Radiology), Peter B. Dent (Rheumatology), Maggie Larche (Rheumatology), Colin Webber* (Radiology),\nMontréal Children's Hospital, Montréal, Québec: Celia Rodd§ (Site Principal Investigator), Sharon Abish (Oncology), Lorraine Bell (Nephrology), Rosie Scuccimarri (Rheumatology)\nShriners Hospital for Children, Montréal, Québec: Frank Rauch*§ (Co-Chair, Publications and Presentations Committee and Ancillary Studies Committee), Francis Glorieux*\nSte. Justine Hospital, Montréal, Québec: Nathalie Alos* (Site Principal Investigator), Josée Dubois (Radiology), Caroline Laverdière (Oncology), Véronique Phan (Nephrology), Claire Saint-Cyr (Rheumatology)\nStollery Children's Hospital, Edmonton, Alberta: Robert Couch* (Site Principal Investigator), Janet Ellsworth (Rheumatology), Claire LeBlanc (Rheumatology), Maury Pinsk (Nephrology), Kerry Siminoski§ (Radiology), Beverly Wilson (Oncology)\nToronto Hospital for Sick Children, Toronto, Ontario: Ronald Grant* (Site Principal Investigator), Martin Charron (Radiology), Diane Hebert (Nephrology)\nUniversité de Sherbrooke, Department of family medicine, Sherbrooke, Québec: Isabelle Gaboury*§ (Biostatistics)\nWinnipeg Children's Hospital, Winnipeg, Manitoba: Shayne Taback§ (Site Principal Investigator), Tom Blydt-Hansen (Nephrology), Sara Israels (Oncology), Kiem Oen (Rheumatology), Martin Reed (Radiology)\nRights and permissions\nAbout this article\nCite this article\nPhan, V., Blydt-Hansen, T., Feber, J. et al. Skeletal findings in the first 12 months following initiation of glucocorticoid therapy for pediatric nephrotic syndrome. Osteoporos Int 25, 627–637 (2014). https://doi.org/10.1007/s00198-013-2466-7\nReceived:\nAccepted:\nPublished:\nIssue date:\nDOI: https://doi.org/10.1007/s00198-013-2466-7","source_license":"CC0","license_restricted":false}