Skeletal findings in the first 12 months following initiation of glucocorticoid therapy for pediatric nephrotic syndrome

Summary Incident 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.

Vertebral fracture (VF) incidence following glucocorticoid (GC) initiation has not been previously reported in pediatric nephrotic syndrome.

VF was assessed on radiographs (Genant method); lumbar spine bone mineral density (LS BMD) was evaluated by dual-energy X-ray absorptiometry.

Sixty-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).

The 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. Similar content being viewed by others Abbreviations - BMD: - Bone mineral density - CI: - Confidence interval - GFR: - Glomerular filtration rate - GC: - Glucucorticoid - IQR: - Interquartile range - LS: - Lumbar spine - NS: - Nephrotic syndrome - SD: - Standard deviation - VF: - Vertebral fracture

Hodson EM, Knight JF, Willis NS, Craig JC (2001) Corticosteroid therapy for nephrotic syndrome in children. Cochrane Database Syst Rev 2 Tarshish 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 Canalis E, Mazziotti G, Giustina A, Bilezikian JP (2007) Glucocorticoid-induced osteoporosis: pathophysiology and therapy. Osteoporos Int 18:1319–1328 Weinstein RS (2012) Glucocorticoid-induced osteoporosis and osteonecrosis. Endocrinol Metab Clin North Am 41:595–611 van 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 Rodd 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 Nakhla 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 Varonos S, Ansell BM, Reeve J (1987) Vertebral collapse in juvenile chronic arthritis: its relationship with glucocorticoid therapy. Calcif Tissue Int 41:75–78 Feber 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 Fujita 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 Leonard 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 Sbrocchi 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 Halton 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 International 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 Institute of Medicine (1997) Dietary reference intakes for calcium, phosphorus, magnesium, vitamin D, fluoride. National Academy Press, Washington Gbadegesin R, Smoyer WE (2008) Nephrotic syndrome. In: Geary DF, Schaefer F (eds) Comprehensive pediatric nephrology. Elsevier, New York Schwartz 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 Marshall WA, Tanner JM (1969) Variations in pattern of pubertal changes in girls. Arch Dis Child 44:291–303 Marshall WA, Tanner JM (1970) Variations in the pattern of pubertal changes in boys. Arch Dis Child 45:13–23 Ogden 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 World 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 Musgrave 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 Hay J (1997) Development and validation of the Habitual Activity Estimation Scale (HAES). Children and Exercise XIX II:125–129 Wells 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 van Staa TP, Leufkens HG, Cooper C (2002) The epidemiology of corticosteroid-induced osteoporosis: a meta-analysis. Osteoporos Int 13:777–787 Curtis 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 Dubner 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 Genant HK, Wu CY, van Kuijk C, Nevitt MC (1993) Vertebral fracture assessment using a semiquantitative technique. J Bone Miner Res 8:1137–1148 Keats TE, Smith TH (1977) An atlas of normal developmental anatomy, 2nd edn. Year Book of Medical Publishers, Chicago Gaca 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 Webber 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 Newcombe RG (1998) Two-sided confidence intervals for the single proportion: comparison of seven methods. Stat Med 17:857–872 Goulding 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 Alos 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 Burnham JM (2012) Inflammatory diseases and bone health in children. Curr Opin Rheumatol 24:548–553 Bak M, Serdaroglu E, Guclu R (2006) Prophylactic calcium and vitamin D treatments in steroid-treated children with nephrotic syndrome. Pediatr Nephrol 21:350–354 Jia 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 Dalle 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 Gulati 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 Hegarty 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 Wetzsteon 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 Tsampalieros 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 Ostalska-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 Acknowledgments This 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. The 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. Funding Primary 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 Conflicts of interest Dr. 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. Author information Authors and Affiliations Consortia Corresponding author Additional information The Canadian STeroid-associated Osteoporosis in the Pediatric Population (STOPP) Consortium (a pan-Canadian, pediatric bone health working group) #Principal investigator; *Executive Committee Member; §Publications and Presentations Committee Member Coordinating center Children'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) Ottawa Hospital Research Institute, Ottawa Methods Centre Ottawa, Ontario: David Moher*§ (Research Methods), Tim Ramsay (Statistical Analyses) Participating centers Alberta Children's Hospital, Calgary, Alberta: David Stephure (Site Principal Investigator), Reinhard Kloiber (Radiology), Victor Lewis (Oncology), Julian Midgley (Nephrology), Paivi Miettunen (Rheumatology) British Columbia Children's Hospital, Vancouver, British Columbia: David Cabral* (Site Principal Investigator), David B. Dix (Oncology), Kristin Houghton (Rheumatology), Helen R. Nadel (Radiology) British Columbia Women's and Children's Hospital and Health Sciences Center, Vancouver, British Columbia: Brian C. Lentle§ (Radiology) Brock University, Faculty of Applied Health Sciences, St. Catharines, Ontario: John Hay§ (Physical Activity Measurements) Children'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) IWK Health Center, Halifax, Nova Scotia: Elizabeth Cummings (Site Principal Investigator), Conrad Fernandez (Oncology), Adam M. Huber§ (Rheumatology), Bianca Lang*§ (Rheumatology), Kathy O'Brien (Radiology) McMaster 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), Montréal Children's Hospital, Montréal, Québec: Celia Rodd§ (Site Principal Investigator), Sharon Abish (Oncology), Lorraine Bell (Nephrology), Rosie Scuccimarri (Rheumatology) Shriners Hospital for Children, Montréal, Québec: Frank Rauch*§ (Co-Chair, Publications and Presentations Committee and Ancillary Studies Committee), Francis Glorieux* Ste. Justine Hospital, Montréal, Québec: Nathalie Alos* (Site Principal Investigator), Josée Dubois (Radiology), Caroline Laverdière (Oncology), Véronique Phan (Nephrology), Claire Saint-Cyr (Rheumatology) Stollery 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) Toronto Hospital for Sick Children, Toronto, Ontario: Ronald Grant* (Site Principal Investigator), Martin Charron (Radiology), Diane Hebert (Nephrology) Université de Sherbrooke, Department of family medicine, Sherbrooke, Québec: Isabelle Gaboury*§ (Biostatistics) Winnipeg Children's Hospital, Winnipeg, Manitoba: Shayne Taback§ (Site Principal Investigator), Tom Blydt-Hansen (Nephrology), Sara Israels (Oncology), Kiem Oen (Rheumatology), Martin Reed (Radiology) Rights and permissions About this article Cite this article Phan, 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 Received: Accepted: Published: Issue date: DOI: https://doi.org/10.1007/s00198-013-2466-7