Cochrane review: Interventions for bone disease in children with chronic kidney disease

Abstract

BackgroundBone 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.ObjectivesTo investigate the benefits and harms of interventions for preventing and treating bone disease in children with CKD.Search strategyThe Cochrane Renal Group's specialised register, the Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, reference lists and abstracts were searched without language restriction.Selection criteriaRandomised controlled trials (RCTs) comparing different interventions used to prevent or treat bone disease in children with CKD stages 2‐5D compared with placebo, no treatment or other agents were included. Studies examining different routes or frequency of treatment were also included.Data collection and analysisData were extracted by two authors. The random‐effects model was used and results were reported as risk ratios or risk differences for dichotomous outcomes and mean differences for continuous outcomes with 95% confidence intervals.Main resultsFifteen RCTs (369 children) were identified. Compared with oral calcitriol, intraperitoneal calcitriol significantly reduced the level of serum parathyroid hormone (PTH) but there were no significant differences in bone histology or other biochemical measures (2 RCTs). There were no significant differences detected in growth, PTH, serum calcium or phosphorus between daily versus intermittent calcitriol (3 RCTs). Vitamin D therapy significantly reduced PTH levels compared with placebo or no treatment. The number of children with hypercalcaemia did not differ significantly between groups (4 RCTs). No significant differences were detected in growth rates, bone histology or biochemical parameters between calcitriol and either dihydrotachysterol or ergocalciferol (2 RCTs). Though fewer episodes of hypercalcaemia were reported with sevelamer, no significant differences were detected in serum calcium, phosphorus and PTH levels between calcium‐containing phosphate binders and either aluminium hydroxide or sevelamer (4 RCTs).Authors' conclusionsBone 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 have been demonstrated. Though fewer episodes of high calcium levels occurred with the non calcium‐containing 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 RCTs were small with few data available on patient‐centred outcomes (growth, bone deformities) and limited data on biochemical parameters resulting in considerable imprecision of results thus limiting the applicability to care of children with CKD.Plain Language SummaryInterventions for bone disease in children with chronic kidney diseaseChronic kidney disease (CKD) resulting in reduced kidney function and the need for dialysis and kidney transplant is associated with abnormalities in blood calcium and phosphorus levels leading to high levels of the parathyroid hormone (PTH) and to bone disease. This may result in bone deformities, bone pain, fractures and reduced growth rates. Commonly used treatments (Vitamin D compounds and phosphate binders) aim to prevent or correct these outcomes. However these treatments may raise levels of blood calcium, allow calcium and phosphorus deposition in blood vessels and lead to early cardiovascular disease, which is known to be a problem in adults with CKD. This review identified only 15 small RCTs involving 369 children comparing different vitamin D compounds, different routes and frequencies of administration of vitamin D compounds and different phosphate binders. Only five RCTs reported on growth rates and no differences were detected between treatments. Renal bone disease, as assessed by changes in PTH levels, was improved by all vitamin D preparations regardless of preparation used or the route or frequency of administration. Fewer episodes of high blood calcium levels and lower overall serum calcium levels occurred with the non calcium‐containing binder, sevelamer, compared with calcium‐containing binders. As newer treatments for renal bone disease are developed, comparisons with the current standard therapies will be required in well designed RCTs in children using outcome measures including those of direct clinical relevance to children and their families such as rates of growth, reduction in bone fractures and bone pain and reduction in calcification in blood vessels.

Commentary on ‘Interventions for bone disease in children with chronic kidney disease’

“…Secondly, the review confirms the safety of non-calcium based phosphate binders in avoiding high blood calcium levels although there was no difference in phosphate control or in bone formation rate (15). Only one study has looked at the growth as an outcome measure and shown that there was no difference in height standard deviation score between children treated with intraperitoneal vs oral calcitriol (15).…”

“…In contrast, a recent meta-analysis of vitamin D therapy in CKD has concluded that Vitamin D compounds do not consistently reduce PTH levels, and beneficial effects on patient-level outcomes are unproven (16). Secondly, the review confirms the safety of non-calcium based phosphate binders in avoiding high blood calcium levels although there was no difference in phosphate control or in bone formation rate (15). Only one study has looked at the growth as an outcome measure and shown that there was no difference in height standard deviation score between children treated with intraperitoneal vs oral calcitriol (15).…”

“…The review does conclusively show that calcitriol therapy administered by oral or intraperitoneal route and in any dosing frequency reduces PTH levels (15). In contrast, a recent meta-analysis of vitamin D therapy in CKD has concluded that Vitamin D compounds do not consistently reduce PTH levels, and beneficial effects on patient-level outcomes are unproven (16).…”

“…In the face of these difficulties, Geary et al present a systematic review that includes 15 randomised controlled trials in 369 children with stage 2-5 CKD making 5 treatment comparisons between vitamin D and phosphate binder therapy (15). All studies are small, have variable doses and routes of administration and rely predominantly on surrogate end-points, in particular PTH.…”

“…. .few data available on patient-centred outcomes and limited data on biochemical parameters resulting in considerable imprecision of results and limiting the applicability to care of children with CKD' (15).…”