title: Interventions for metabolic bone disease in children with chronic kidney disease.
abstract: BACKGROUND
  Bone disease is common in children with chronic kidney disease (CKD) and when untreated may result in bone deformities, bone pain, fractures and reduced growth rates. This is an update of a review first published in 2010.
  
  
  OBJECTIVE
  This review aimed to examine the benefits (improved growth rates, reduced risk of bone fractures and deformities, reduction in PTH levels) and harms (hypercalcaemia, blood vessel calcification, deterioration in kidney function) of interventions (including vitamin D preparations and phosphate binders) for the prevention and treatment of metabolic bone disease in children with CKD.
  
  
  METHODS
  We searched the Cochrane Kidney and Transplant Specialised Register to 8 September 2015 through contact with the Trial's Search Co-ordinator using search terms relevant for this review.
  
  
  METHODS
  We included randomised controlled trials (RCTs) comparing different interventions used to prevent or treat bone disease in children with CKD stages 2 to 5D.
  
  
  METHODS
  Data were assessed for study eligibility, risk of bias and extracted independently by two authors. Results were reported as risk ratios (RR) or risk differences (RD) with 95% confidence intervals (CI) for dichotomous outcomes. For continuous outcomes the mean difference (MD) or standardised mean difference (SMD) with 95% confidence intervals (CI) was used. Statistical analyses were performed using the random-effects model.
  
  
  RESULTS
  This review included 18 studies (576 children); three new studies were added for this update. Adequate sequence generation and allocation concealment were reported in 12 and 11 studies respectively. Only four studies reported blinding of children, investigators or outcome assessors. Nine studies were at low risk of attrition bias and 12 studies were at low risk of selective reporting bias.Eight different interventions were compared. Two studies compared intraperitoneal (IP) with oral calcitriol. PTH levels were significantly lower with IP compared with oral calcitriol (1 study: MD -501.00 pg/mL, 95% CI -721.54 to -280.46) but the number of children with abnormal bone histology did not differ between treatments. Three studies compared intermittent with daily oral calcitriol. The change in mean height SDS (1 study: MD 0.13, 95% CI -0.22 to 0.48) and the percentage fall in parathyroid hormone (PTH) levels at eight weeks (1 study: MD -5.50%, 95% CI -32.37 to 21.37) and 12 months (1 study: MD -6.00% 95% CI -25.27 to 13.27) did not differ between treatments.Four studies compared active vitamin D preparations (calcitriol, paricalcitol, 1α-hydroxyvitamin D) with placebo or no specific treatment. One study reported vitamin D preparations significantly reduced PTH levels (-55.00 pmol/L, 95% CI -83.03 to -26.97). There was no significant difference in hypercalcaemia risk with vitamin D preparations compared with placebo or no specific treatment (4 studies, 103 children: RD 0.08 mg/dL, 95% CI -0.08 to 0.24). However, there was heterogeneity (I(2) = 55%) with one study showing a significantly greater risk of hypercalcaemia with intravenous (IV) calcitriol administration. Two studies (97 children) compared calcitriol with other vitamin D preparations and both found no significant differences in growth between preparations.Two studies compared ergocalciferol in patients with CKD and vitamin D deficiency. Elevated PTH levels developed significantly later in ergocalciferol treated children (1 study: hazard ratio 0.30, 95% CI 0.09 to 0.93) though the number with elevated PTH levels did not differ between groups (1 study, 40 children: RR 0.33, 95% CI 0.11 to 1.05).Two studies compared calcium carbonate with aluminium hydroxide as phosphate binders. One study (17 children: MD -0.86 SDS, 95% CI -2.24 to 0.52) reported no significant difference in mean final height SDS between treatments. Three studies compared sevelamer with calcium-containing phosphate binders. There were no significant differences in the final calcium, phosphorus or PTH levels between binders. More episodes of hypercalcaemia occurred with calcium-containing binders. One study reported no significant differences between calcitriol and doxercalciferol in bone histology or biochemical parameters.
  
  
  CONCLUSIONS
  Bone disease, assessed by changes in PTH levels, is improved by all vitamin D preparations. However, no consistent differences between routes of administration, frequencies of dosing or vitamin D preparations were demonstrated. Although fewer episodes of high calcium levels occurred with the non-calcium-containing phosphate binder, sevelamer, compared with calcium-containing binders, there were no differences in serum phosphorus and calcium overall and phosphorus values were reduced to similar extents. All studies were small with few data available on patient-centred outcomes (growth, bone deformities) and limited data on biochemical parameters or bone histology resulting in considerable imprecision of results thus limiting the applicability to the care of children with CKD.
authors.affiliation: Department of Nephrology, The Children's Hospital at Westmead, Locked Bag 4001, Westmead, NSW, Australia, 2145.
authors.forename: Deirdre
authors.initials: D
authors.lastname: Hahn
authors.forename: Elisabeth M
authors.initials: EM
authors.lastname: Hodson
authors.forename: Jonathan C
authors.initials: JC
authors.lastname: Craig
mesh_terms: D000536:Aluminum Hydroxide / Q000627:therapeutic use; D050071:Bone Density Conservation Agents / Q000627:therapeutic use*; D001851:Bone Diseases, Metabolic / Q000097:blood / Q000188:drug therapy* / Q000209:etiology; D002117:Calcitriol / Q000627:therapeutic use; D002118:Calcium / Q000097:blood; D002119:Calcium Carbonate / Q000627:therapeutic use; D002648:Child; D002908:Chronic Disease; D004872:Ergocalciferols / Q000627:therapeutic use; D006801:Humans; D007674:Kidney Diseases / Q000150:complications*; D010281:Parathyroid Hormone / Q000097:blood; D010758:Phosphorus / Q000097:blood; D011073:Polyamines / Q000627:therapeutic use; D016032:Randomized Controlled Trials as Topic; D000069603:Sevelamer / Q000627:therapeutic use; D014807:Vitamin D / Q000627:therapeutic use
chemical_list: D050071:Bone Density Conservation Agents; D004872:Ergocalciferols; D010281:Parathyroid Hormone; D011073:Polyamines; D014807:Vitamin D; D010758:Phosphorus; D000536:Aluminum Hydroxide; D000069603:Sevelamer; D002117:Calcitriol; D002119:Calcium Carbonate; D002118:Calcium