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.
Objectives
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.
Search 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.
Selection criteria
We included randomised controlled trials (RCTs) comparing different interventions used to prevent or treat bone disease in children with CKD stages 2 to 5D.
Data collection and analysis
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.
Main 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 (I2 = 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.
Authors' 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.
PICO
Plain language summary
Interventions for metabolic bone disease in children with chronic kidney disease
Chronic kidney disease (CKD) resulting in reduced kidney function and the need for dialysis and kidney transplant is associated with abnormalities in serum 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 18 small randomised studies involving 576 children comparing different vitamin D compounds administered via different routes and frequencies and different phosphate binders. Only five studies reported growth rates and no differences were detected between treatments. Bone disease, as assessed by changes in PTH levels, was improved by all vitamin D preparations regardless of preparation or route or frequency of administration. Fewer episodes of high blood 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 randomised studies 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.
Authors' conclusions
Background
Description of the condition
Chronic kidney disease (CKD) causes disordered regulation of mineral metabolism (Wesseling‐Perry 2013). Because this disorder results in renal osteodystrophy and vascular and/or soft tissue calcification, the manifestations of the disorder are now known as chronic kidney disease mineral and bone disorder (CKD‐MBD) (Moe 2006). CKD‐MBD is defined as a systemic disorder of bone and mineral metabolism due to CKD and manifested by one or a combination of:
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abnormalities of calcium. phosphorus, parathyroid hormone (PTH) or vitamin D metabolism;
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abnormalities in bone turnover, mineralization, volume, linear growth or strength; and
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vascular or other soft tissue calcification.
In children CKD‐MBD may be associated with increased fracture rates, reduced linear growth, bony deformities and chronic pain. In a review of 890 children on peritoneal dialysis, 5% had limb deformities, 1.4% had bone pain and 1.5% had vascular calcification (Borzych 2010). Abnormalities of bone turnover, mineralization and volume in CKD‐MBD can be quantitated using bone histomorphometry. The predominant lesion noted on bone biopsy in children on dialysis is one of high bone turnover (in 57% to 100% of patients) with low turnover bone disease much less common (4% of patients) (Bakkaloglu 2010; Hodson 1982; Salusky 2005a). Abnormal skeletal mineralization is commonly associated with both high and low turnover bone disease in dialysis patients. Among children with CKD stages 2‐4, high turnover bone disease was seen in 29% of children with CKD stage 4 but was not seen in children with stage 2 disease and was uncommon in children with stage 3 disease (Wesseling‐Perry 2012; Hodson 1982). In contrast mineralization abnormalities occurred in 43% children with stage 2 CKD and in 86% of children with stage 4 CKD (Wesseling‐Perry 2012); these findings confirm previous findings in early stages of CKD (Hodson 1982). Low turnover bone disease is rare in children not on dialysis.
Although bone disease may not be evident on bone histology in early CKD and plasma levels of calcium and phosphorus are normal, increased levels of the hormone fibroblast growth factor 23 (FGF23) (Wesseling‐Perry 2013) increase renal phosphate excretion and inhibit 1α‐hydroxylase activity thus suppressing circulating levels of 1, 25 (OH)2D leading to increased levels of parathyroid hormone (PTH).
Bone biopsy is an invasive procedure and is now generally limited to research studies so that radiological and biochemical abnormalities are used as surrogate measures of bone disease in CKD‐MBD. Radiological diagnosis is insensitive and cannot distinguish low‐turnover or adynamic bone disease from the high turnover state of secondary hyperparathyroidism. Biochemical abnormalities of parathyroid hormone, serum calcium and phosphate levels are frequently used as markers of bone disease if outside of the recommended KDOQI or European guideline parameters (KDOQI 2005; Klaus 2006). Abnormalities of these values, suggestive of histological changes, have been demonstrated in 28% to 81% of children with CKD stages 2‐5 (Blaszak 2005; Seikaly 2003). These biochemical abnormalities have also been used to specifically diagnose low turnover bone disease. In 41 dialysed children (31 peritoneal dialysis), low turnover bone disease was diagnosed in 48% based on the presence of elevated serum calcium with parathyroid hormone (PTH) values below recommended levels (Avila‐Diaz 2006). PTH levels are most commonly used to monitor the effectiveness of therapy. However optimal target ranges are unclear in part because earlier PTH assays measured active and inactive PTH fragments and newer assays still show considerable variation between PTH assays.
In the absence of clinical symptoms and signs, it has been unclear until recently what impact CKD‐MBD has on the outcome for children with CKD. Recent data have demonstrated an increased risk of coronary arterial calcification in young adults on dialysis (Goodman 2000) while elevated levels of PTH and phosphate are independent risk factors for left ventricular hypertrophy (Bakkaloglu 2011). These factors have been associated with increased mortality in children and young adults with CKD.
Description of the intervention
Treatment of CKD‐MBD aims to normalise mineral metabolism and minimise progression of extraskeletal calcification by maintaining blood levels of calcium and phosphorus close to the normal range for age and maintaining PTH levels at levels considered to be appropriate for the stage of CKD. The mainstays of treatment are with phosphate binders (calcium or non‐calcium containing) and vitamin D metabolites (calcitriol, 1α‐hydroxyvitamin D, newer vitamin D analogues). Dietary measures are instituted to reduce phosphate intake while maintaining adequate calcium and vitamin D intake. Also calcium levels in the dialysis fluid can be manipulated to maintain normocalcaemia. New agents include calcimimetic agents (cinacalcet), which control secondary hyperparathyroidism. For medically unresponsive patients, parathyroidectomy may be required.
How the intervention might work
Early in the development of CKD, circulating levels of 1,25 (OH)2 vitamin D falls following suppression of the renal enzyme 1‐ɑ‐hydoxylase by FGF23, resulting in reduced calcium absorption from the gut and increased PTH levels (Wesseling‐Perry 2013). Increased PTH levels initially maintain serum calcium levels by increasing bone resorption and by stimulating 1‐ɑ‐hydoxylase activity. With further decline in glomerular filtration rate (GFR), phosphate levels rise. These lower calcium levels and further suppress renal enzyme 1‐ɑ‐hydoxylase levels so PTH levels rise further. PTH increases bone turnover leading to renal osteodystrophy. Therefore therapies which increase gut absorption of calcium, reduce phosphate levels and increase circulating levels of 1,25 (OH)2 vitamin D will reduce PTH levels. However both calcium‐containing phosphate binders and vitamin D metabolites may cause hypercalcaemia and elevated calcium‐phosphorus product and predispose to vascular and soft tissue calcification. Calcimimetic agents modulate the calcium sensitive receptor in parathyroid glands, increase intracellular calcium and decrease PTH release.
Why it is important to do this review
There are a large number of studies reporting the efficacy of various medications and dietary manipulations to prevent and treat CKD‐MBD in children and there is extensive clinical experience confirming that current treatment of CKD‐MBD has reduced the severity of bony deformities and fractures over the past few decades. However there remains considerable uncertainty in children about the vascular outcomes related to treatment or non‐treatment of CKD‐MBD. In addition because of the recognised severity of potential side‐effects and the uncertain efficacy of some of the therapeutic agents used to treat CKD‐MBD, it is appropriate to critically review the treatment options.
Objectives
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
Criteria for considering studies for this review
Types of studies
All randomised controlled trials (RCTs) and quasi‐RCTs (studies in which allocation to treatment was obtained by alternation, use of alternate medical records, date of birth or other predictable methods) examining treatments for the prevention and treatment of CKD‐MBD in children and adolescents were included.
Types of participants
Inclusion criteria
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Studies involving children with CKD stages 2 to 5D (glomerular filtration rate < 90 mL/min/1.73 m2)
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Childhood was defined according to the definitions applied in the included studies, but did not exceed 21 years of age.
Exclusion criteria
Studies of children with CKD secondary to primary tubulopathies, e.g. cystinosis, or with diseases known to directly affect bones e.g. primary hyperoxaluria, and studies in children following kidney transplant were excluded. However it is possible that individual children with the above disorders might be included within an eligible study but not specifically specified. Studies of recombinant human growth hormone in children with CKD were excluded as these are included in a separate Cochrane Review (Growth Hormone in children with chronic kidney disease) (Hodson 2012).
Types of interventions
Interventions considered for inclusion were as follows.
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Dietary
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Pharmacological ‐ specifically vitamin D or metabolites, calcimimetic and phosphate binding agents
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Surgical
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Herbal or alternative treatments
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Changes in dialysis prescription.
For each of these interventions the following comparisons were considered.
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Intervention versus placebo
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Intervention A versus intervention B
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Frequency and mode of administration (e.g. oral or intravenous (IV))
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Dose and duration of treatment.
Types of outcome measures
Primary outcomes
Patient‐centred outcome measures
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Growth
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Bone fractures
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Bone deformities
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Symptoms related to hypercalcaemia
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Parathyroidectomy
Secondary outcomes
Patient‐centred outcome measures
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Commencing dialysis treatment
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Dialysis‐related clinical events
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Parathyroidectomy.
Surrogate outcomes
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Change in bone histology
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Changes in radiological abnormalities
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Changes in PTH levels
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Changes in alkaline phosphatase (ALP) levels
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Changes in serum calcium, phosphorus and calcium‐phosphorus product
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Changes in FGF23 levels
Adverse events
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Vascular or extraosseous calcifications
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Deterioration of kidney function
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Hyperphosphataemia
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Hypercalcaemia
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Elevation of calcium‐phosphorus product
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Radiological deterioration of CKD‐MBD
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Development of adynamic bone disease on bone histomorphometry
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Hypertension or hypotension
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Aggravation of anaemia.
Search methods for identification of studies
Electronic searches
We searched the Cochrane Kidney and Transplant Specialised Register to 8 September 2015 through contact with the Trials Search Co‐ordinator using search terms relevant to this review. The Specialised Register contains studies identified from the following sources.
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Monthly searches of the Cochrane Central Register of Controlled Trials (CENTRAL)
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Weekly searches of MEDLINE OVID SP
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Handsearching of kidney‐related journals and the proceedings of major kidney conferences
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Searching of the current year of EMBASE OVID SP
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Weekly current awareness alerts for selected kidney journals
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Searches of the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov.
Studies contained in the Specialised Register are identified through search strategies for CENTRAL, MEDLINE, and EMBASE based on the scope of Cochrane Kidney and Transplant. Details of these strategies, as well as a list of handsearched journals, conference proceedings and current awareness alerts, are available in the Specialised Register section of information about the Cochrane Kidney and Transplant.
See Appendix 1 for search terms used in strategies for this review.
Searching other resources
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Reference lists of clinical practice guidelines review articles and relevant studies.
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Letters seeking information about unpublished or incomplete studies to investigators known to be involved in previous studies.
Data collection and analysis
Selection of studies
In the previous version of this review (Geary 2009) all electronically derived abstracts and study titles were assessed for subject relevance and methodological quality. All possible RCTs or quasi‐RCTs which were relevant were assigned specific topic keywords in Reference Manager and the full published paper was obtained for full assessment. The review was undertaken by four authors. The search strategy described was used to obtain titles and abstracts of studies that were relevant to the review. The titles and abstracts were screened independently by DG, EH and DH, who discarded studies that were not applicable. However studies and reviews that might include relevant data or information on studies were retained initially. Three authors independently assessed retrieved abstracts, and if necessary, the full text of these studies to determine which studies satisfied the inclusion criteria.
In this update, study titles and abstracts were reviewed by two authors. Full text articles of studies considered relevant were obtained and assessed for eligibility by the same authors.
Data extraction and management
A data abstraction form was devised to record details of data elements such as outcome measures, participants and intervention of each included study for the 2009 review. Only comparisons and outcomes which were pre‐specified in the protocol were included. For this review, data were abstracted by a single assessor and a sample was double checked.
For this update, data extraction and assessment of risk of bias were performed by two authors using standardised data abstraction forms. Disagreements not resolved by discussion between authors were referred to a third author. Studies reported in languages other than English were to be translated before data extraction, but no foreign language reports were identified. Where more than one report of a study was identified, data were extracted from all reports. Where there were discrepancies between reports, data from the primary source were used. Study authors were contacted for additional information about studies.
Assessment of risk of bias in included studies
Hard copies of studies were independently assessed for the methodological quality by two assessors for the 2010 review. Quality assessments were made for allocation concealment, blinding, description of withdrawals and drop‐outs, numbers lost to follow‐up, and whether intention‐to‐treat (ITT) analysis was possible.
In the 2014 update, the following terms were assessed using the risk of bias assessment tool (Higgins 2011) (see Appendix 2).
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Was there adequate sequence generation (selection bias) ?
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Was allocation adequately concealed (selection bias)?
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Was knowledge of the allocated interventions adequately prevented during the study?
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Participants and personnel (performance bias)
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Outcome assessors (detection bias)
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Were incomplete outcome data adequately addressed (attrition bias)?
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Are reports of the study free of suggestion of selective outcome reporting (reporting bias)?
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Was the study apparently free of other problems that could put it at a risk of bias?
Measures of treatment effect
For dichotomous outcomes (number of children with improved growth, radiological bone changes, improved bone histology) results were expressed as risk ratio (RR) with 95% confidence intervals (CI). For numbers of children experiencing adverse effects, risk difference (RD) with 95% CI was used. For continuous outcomes scales of measurement were used to assess the effects of treatment (levels of PTH, serum levels of calcium, phosphorus and calcium‐phosphorus product, and creatinine clearance (CrCl), the mean difference (MD) with 95% CI were calculated unless the scales were different; in this instance, standard mean difference (SMD) was used.
Unit of analysis issues
Data from the first phase of cross‐over RCTs could not be separated so results from cross‐over studies were reported qualitatively.
Dealing with missing data
We aimed to analyse available data in meta‐analyses using intention‐to‐treat (ITT) data. However, where ITT data were only available graphically or not provided and additional information could not be obtained from study authors, per‐protocol (PP) data were used in analyses.
Assessment of heterogeneity
Heterogeneity was analysed using a Chi2 test on N‐1 degrees of freedom, with an alpha of 0.05 used for statistical significance and with the I2 test (Higgins 2003). I2 values of 25%, 50% and 75% correspond to low, medium and high levels of heterogeneity respectively.
Assessment of reporting biases
Because of the few studies available for each intervention, it was not possible to use funnel plots to assess for the potential existence of small study bias (Higgins 2011).
Data synthesis
Data were pooled using a random‐effects model for dichotomous and continuous data.
Subgroup analysis and investigation of heterogeneity
We had planned subgroup analyses to examine certain between‐study differences in participants (age, stage of CKD, type of dialysis), interventions (agent, dose and duration of treatment) and risk of bias hypothesised to explain any observed heterogeneity of treatment effects but there were insufficient studies for these to be performed.
Sensitivity analysis
We wished to perform sensitivity analyses in order to explore the influence of the following factors on effect size.
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Repeating the analysis excluding unpublished studies
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Repeating the analysis taking account of risk of bias, as specified
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Repeating the analysis excluding any very long or large studies to establish how much they dominate the results
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Repeating the analysis excluding studies using the following filters: diagnostic criteria, language of publication, source of funding (industry versus other), and country.
However except for one analysis, the maximum number of studies included in any analysis was two so we were not able to carry out any sensitivity analyses.
Results
Description of studies
Results of the search
2009 review
In the 2009 review, of the 1137 titles and abstracts identified, 19 studies were identified for full text review. Of these 15 studies (26 reports) (Ardissino 2000; Eke 1983; GFRD Study 1990; Greenbaum 2005; Greenbaum 2007; Hodson 1985; Jones 1994; Klaus 1995; Mak 1985; Pieper 2006; Salusky 1991; Salusky 1998; Salusky 2005; Schmitt 2003; Watson 1988) involved the defined populations and addressed relevant interventions and were included in the review. A copy of the completed manuscript was provided before publication by Greenbaum 2007. Three studies were cross‐over studies (Jones 1994; Mak 1985; Pieper 2006), and one study (Klaus 1995) was available in abstract form only. Four studies (nine reports) were excluded for ineligible intervention (Ardissino 2000a), ineligible population (El Husseini 2004; Ferraris 2000) and uncertainty as to whether the study was an RCT (Bettinelli 1986). There was no disagreement between authors regarding inclusion of studies. The 2009 review included 15 studies (26 reports) with 472 children.
2015 update
For the 2015 update 47 new reports were identified (Figure 1). Of these, four reports were of three new studies (Gulati 2010; Rianthavorn 2013; Shroff 2012) and 38 reports were of seven previously included studies (Eke 1983; GFRD Study 1990; Greenbaum 2005; Salusky 1991; Salusky 1998; Salusky 2005; Watson 1988). The remaining five new reports were excluded. Two studies were excluded as the populations were ineligible (Choudhary 2014; Kim 2006b), and in one study (Witmer 1976) randomisation was unclear. The remaining three reports were from two previously excluded studies (Ardissino 2000a; Ferraris 2000).
Study flow diagram
Re‐evaluation of Ardissino 2000 and Schmitt 2003 indicated that the data in Schmitt 2003 represented a 12 month follow‐up of 29 prepubertal children treated in Ardissino 2000. For ease of identification, we have continued to report these studies as two studies.
To allow analyses of comparisons between calcitriol and doxercalciferol and for separate reporting of the comparison between sevelamer and calcium carbonate in this 2 x 2 longitudinal factorial study, we have divided Salusky 2005 into three studies (Salusky 2005; Salusky 2005a; Salusky 2005b). Salusky 2005 includes the groups treated with sevelamer or calcium carbonate irrespective of vitamin D preparation used. Salusky 2005a includes the two groups treated with doxercalciferol while Salusky 2005b includes the two groups treated with calcitriol.
Therefore the 2015 update included 18 studies (68 reports) with 576 enrolled children.
Included studies
The 18 included studies were divided into eight treatment comparisons (Figure 1).
Intraperitoneal calcitriol versus oral calcitriol
Two studies (40 enrolled; 40 evaluated) compared intraperitoneal compared with oral calcitriol. Children receiving continuous cycling or continuous ambulatory peritoneal dialysis were treated for 12 months (Salusky 1998) or 3 months (Jones 1994). The study by Jones 1994 was a cross‐over study and data could not be meta‐analysed.
Intermittent oral calcitriol versus daily oral calcitriol
Three studies (109 enrolled; 104 evaluated) compared intermittent oral administration of calcitriol with daily oral administration in children with CKD stages 2 to 5 for 8 to 10 weeks (Ardissino 2000), 12 months (Schmitt 2003), or from 2 to 36 weeks (Klaus 1995).
Different vitamin D preparations versus placebo/no specific treatment
Four studies (104 enrolled; 103 evaluated) compared different vitamin D preparations administered orally or IV with placebo/no specific treatment in CKD patients stages 3 and 4 (Eke 1983) and in patients receiving peritoneal or haemodialysis (Greenbaum 2005; Greenbaum 2007; Watson 1988).
Different vitamin D preparations
Two studies (106 enrolled; 97 evaluated) compared different vitamin D preparations. GFRD Study 1990 compared oral calcitriol with oral dihydrotachysterol in children with CKD stages 3 and 4 treated for 12 months. Hodson 1985 compared oral calcitriol with oral ergocalciferol in children on dialysis or CKD stages 2 to 4.
One study (60 enrolled; 51 evaluated) compared doxercalciferol (Salusky 2005a) and calcitriol (Salusky 2005b) in combination with either sevelamer or calcium carbonate. Comparisons were reported for vitamin D preparations irrespective of the phosphate binder given.
Ergocalciferol versus placebo/control
Two studies (67 enrolled; 60 evaluated) compared ergocalciferol with placebo/no specific treatment in patients with CKD stages 2 to 5D (Rianthavorn 2013; Shroff 2012). In Rianthavorn 2013 the primary outcome was reduction in the dose of erythrocyte‐stimulating agent (ESA).
Calcium carbonate versus aluminium hydroxide
Two studies (34 enrolled; 29 evaluated) compared calcium hydroxide with calcium carbonate in pre‐dialysis children (Mak 1985) or those receiving peritoneal dialysis (Salusky 1991).
Sevelamer versus calcium‐containing phosphate binders
Three studies (98 enrolled; 66 evaluated) compared sevelamer with calcium‐containing phosphate binders in children with CKD stages 2 to 4 (Gulati 2010) or receiving dialysis (Pieper 2006; Salusky 2005) compared the non‐calcium‐containing sevelamer with calcium carbonate (Salusky 2005) or calcium acetate (Gulati 2010; Pieper 2006). In Salusky 2005, children were also randomised to receive doxercalciferol or calcitriol. Factorial analysis provided no evidence of treatment interaction between the two sterols so comparisons were reported for phosphate binders irrespective of vitamin D sterol given.
No RCTs examining interventions with dietary changes, surgery, alterations in dialysis prescription or calcimimetic agents were identified.
Excluded studies
Seven studies were excluded (Ardissino 2000a; Bettinelli 1986; Choudhary 2014; El Husseini 2004; Ferraris 2000; Kim 2006b; Witmer 1976). One cross‐over study (Ardissino 2000a) in children with CKD examined calcium absorption only after oral or IV calcitriol. Two studies examined bone mineral density in kidney transplant patients treated with calcitonin, alendronate or 1α‐hydroxyvitamin D (El Husseini 2004) or with methylprednisolone or deflazacort (Ferraris 2000). Randomisation was unclear and data was no longer available in Witmer 1976.
Risk of bias in included studies
Methodological quality graph: review authors' judgements about each methodological quality item presented as percentages across all included studies
Risk of bias summary: review authors' judgements about each risk of bias item for each included study
Allocation
Sequence generation was deemed to be at low risk of bias in 12 studies (Ardissino 2000; GFRD Study 1990; Greenbaum 2005; Greenbaum 2007; Gulati 2010; Hodson 1985; Pieper 2006; Salusky 1998; Salusky 2005; Schmitt 2003; Shroff 2012; Watson 1988). One study was at high risk of bias as patients were randomised sequentially (Rianthavorn 2013). In the remaining five studies, the sequence generation methodology was unclear.
Allocation concealment was at low risk of bias in 11 studies (Ardissino 2000; GFRD Study 1990; Greenbaum 2005; Greenbaum 2007; Gulati 2010; Pieper 2006; Salusky 1998; Salusky 2005; Schmitt 2003; Shroff 2012; Watson 1988). Two studies (Hodson 1985; Rianthavorn 2013) were considered at high risk of bias. Allocation concealment methodology was unclear in the remaining five studies (Eke 1983; Jones 1994; Klaus 1995; Mak 1985; Salusky 1991).
Blinding
Four studies were blinded and considered to be at low risk of bias for performance bias ( GFRD Study 1990; Greenbaum 2005; Greenbaum 2007; Shroff 2012). Blinding was unclear in one study, which was reported to be double‐blinded but did not clarify how this was achieved (Eke 1983). The remaining thirteen studies were not blinded and were considered at high risk of performance bias.
Since the primary outcomes (PTH level, bone mineralization) in all studies were based on laboratory assessment, and unlikely to be influenced by blinding, all included studies were considered to be at low risk of detection bias.
Incomplete outcome data
Nine studies were considered at low risk of attrition bias (Eke 1983; Greenbaum 2005; Greenbaum 2007; Gulati 2010; Jones 1994; Mak 1985; Rianthavorn 2013; Shroff 2012; Watson 1988). Seven studies were considered at high risk of attrition bias with more than 15% loss to follow‐up or exclusion from analysis (Ardissino 2000; GFRD Study 1990; Hodson 1985; Pieper 2006; Salusky 1991; Salusky 2005; Schmitt 2003). In the remaining two studies attrition bias was considered unclear (Klaus 1995; Salusky 1998). Loss to follow‐up or exclusion resulted commonly when children on dialysis underwent kidney transplant. Other reasons for exclusion were non‐adherence to treatment, protocol violation or withdrawal by families or physicians.
Selective reporting
Studies were considered to be at high risk of reporting bias if they did not provide data on final or change in PTH, calcium, phosphorus, calcium‐phosphorus product or ALP levels, bone histology, patient centred outcomes such as fractures or growth, adverse events such as hypercalcaemia or all‐cause mortality. Seven studies were considered at high risk of reporting bias (Eke 1983; GFRD Study 1990; Jones 1994; Klaus 1995; Mak 1985; Pieper 2006; Salusky 2005). The remaining 11 studies were considered to be at low risk of reporting bias.
Other potential sources of bias
Eleven studies appeared to be free of other potential sources of bias (Ardissino 2000; Eke 1983; GFRD Study 1990; Gulati 2010; Hodson 1985; Mak 1985; Salusky 1991; Salusky 1998; Salusky 2005; Schmitt 2003; Shroff 2012). Five studies were funded by industry and considered at high risk of bias (Greenbaum 2005; Greenbaum 2007; Jones 1994; Pieper 2006; Watson 1988). In the remaining two studies, it was unclear whether the study was free of other potential sources of bias (Klaus 1995; Rianthavorn 2013).
Effects of interventions
Intraperitoneal versus oral calcitriol
Two studies investigated this comparison (Salusky 1998; Jones 1994) (Table 1). The first study (Jones 1994) compared IP with oral calcitriol in a cross‐over study including seven children and reported that mean height standard deviation score (SDS) did not differ between groups at the end of the study. The data for each part of the cross‐over could not be separated.
| Outcome | Summary estimateb | ||
| Abnormal bone biopsy | Not reported | 12/16c versus 12/17d | RR 1.06 (0.70 to 1.61) |
| Adynamic bone disease | Not reported | 7/16 versus 5/17 | RR 1.49 (0.59 to 3.74) |
| Osteitis fibrosa | Not reported | 2/16 versus 6/17 | RR 0.35 (0.08 to 1.51) |
| Mixed/mild disease | Not reported | 3/16 versus 7/17 | RR 0.46 (0.14 to 1.46) |
| Normal/reduced bone formation rate | Not reported | 11/16 versus 11/17 | RR 1.06 (0.66 to 1.72) |
| Bone formation rate (µm2/mm2/d) | Not reported | 297 ± 472 versus 586 ± 973 | MD ‐289.00 (‐806.13 to 228.13) |
| PTH (pg/mL) | No significant difference | 169 ± 228 versus 670 ± 400 | MD ‐501.00 (‐721.54 to ‐280.46) |
| Maximum serum calcium (mg/dL) | Not reported | 10.4 ± 2 versus 9.7 ± 1.64 | MD 0.70 (‐0.55 to 1.95) |
| Hypercalcaemic patients | 0/7 versus 0/7 | 8/16 versus 5/17 | RD 0.21 (‐0.12 to 0.53) |
| Hypophosphataemic patients | Not reported | 2/16 versus 3/17 | RD ‐0.05 (‐0.29 to 0.19) |
| Peritonitis episodes/patient‐month | 1/ 11 versus 1/11 | 1/12 versus 1/10 | RD 0.01 (‐0.24 to 0.26) |
| Height SDS | ‐2.26 (‐4.5 to ‐1.61) versus ‐2.33 (‐4.27 to ‐1.43) (end) | Not reported | Not calculated |
a Cross‐over study
b Summary estimate (RR, RD, MD) and 95% CI; cross‐over studies excluded
c Experimental intervention
d Comparative intervention
PTH ‐ parathyroid hormone; SDS ‐ standard deviation score
Salusky 1998 reported no significant differences in the number of children overall with abnormal bone histology (Analysis 1.1.1 (1 study, 33 children): RR 1.06, 95% CI 0.70 to 1.61), the number with adynamic bone disease (Analysis 1.1.2 (1 study, 33 children): RR 1.49, 95% CI 0.59 to 3.74), osteitis fibrosa (Analysis 1.1.3 (1 study, 33 children): RR 0.35, 95% CI 0.08 to 1.51), mixed or mild disease (Analysis 1.1.4 (1 study, 33 children): RR 0.46, 95% CI 0.14 to 1.46) or normal/reduced bone formation rates (Analysis 1.1.5 (1 study, 33 children): RR 1.06, 95% CI 0.66 to 1.72).
Salusky 1998 reported bone formation rates did not differ significantly between treatment groups (Analysis 1.2 (1 study, 33 children): MD ‐289.00 μm2/mm2/d, 95% CI ‐806.13 to 228.13).
Jones 1994 (cross‐over RCT) reported that no significant differences were found in PTH levels, the number of children with hypercalcaemia and the number of peritonitis episodes between groups (Table 1). Salusky 1998. reported mean PTH levels were significantly lower with IP calcitriol compared with oral (Analysis 1.3 (1 study, 33 children): MD ‐501.00 pg/mL, 95% CI ‐721.54 to ‐280.46).
Salusky 1998 reported maximum serum calcium levels (Analysis 1.4 (1 study, 33 children): MD 0.70 mg/dL, 95% CI ‐0.55 to 1.95) and the number of children with hypercalcaemia (Analysis 1.5.1 (1 study, 33 children): RD 0.21, 95% CI ‐0.12 to 0.53) or hyperphosphataemia (Analysis 1.5.2 (1 study, 33 children): RD ‐0.05, 95% CI ‐0.29 to 0.19) did not differ between treatment groups. The number of peritonitis episodes/patient‐month did not differ between treatment groups (Analysis 1.6 (1 study, 33 children): RD 0.01, 95% CI ‐0.24 to 0.26).
Intermittent oral versus daily oral calcitriol
Three parallel studies (104 evaluated children) compared intermittent oral with daily oral calcitriol (Ardissino 2000; Klaus 1995; Schmitt 2003) (Table 2).
| Outcome | Summary estimate a | |||
| % fall PTH | 13.7 ± 46.7b versus 19.2 ± 57.8c | Not reported | 58 ± 26 versus 64 ± 22 | MD ‐5.83 (‐21.49 to 9.83) |
| Number with fall in PTH | 21/30 versus 23/29 | "median PTH fell in both groups" | Not reported | RR 0.88 (0.65 to 1.19) |
| Mean integrated PTH (pg/mL) | Not reported | Not reported | 285 ± 213 versus 343 ± 171 | MD ‐58.00 (‐212.55 to 96.55) |
| CrCl (mL/min/1.73 m2) | 22 ± 13 versus 22 ± 11(end) | Not reported | ‐1.6 ± 4.0 versus 3.1± 4.8 (change) | MD 0.50 (‐5.72 to 6.72) |
| Change in height SDS | Not reported | Not reported | ‐0.05 ± 0.52 versus ‐0.18 ± 0.34 | MD 0.13 (‐0.22 to 0.48) |
| Hypercalcaemic patients | 1/30 versus 1/29 | 2/12 versus 3/9 | No difference in number of episodes | RD ‐0.02 (‐0.17 to 0.13) |
| Hypophosphataemic patients | 0/30 versus 1/29 | Not reported | No difference in number of episodes | RD 0.03 (‐0.06 to 0.12) |
a Summary estimate (RR, RD, MD) and 95%
b Experimental intervention
c Comparative intervention
CrCl ‐ creatinine clearance; PTH ‐ parathyroid hormone; SDS ‐ standard deviation score
Schmitt 2003 reported no significant difference in change in mean height SDS (Analysis 2.1 (1 study, 24 children): MD 0.13, 95% CI ‐0.22 to 0.48). No significant differences between treatment routes were found for any surrogate biochemical outcome.
Ardissino 2000 and Schmitt 2003 reported no significant differences in the fall in PTH levels at 8 weeks (Analysis 2.2.1 (Ardissino 2000, 59 children): MD ‐5.50%, 95% CI ‐32.37 to 21.37) and 12 months (Analysis 2.2,2 (Schmitt 2003, 48 children): MD ‐6.00%, 95% CI ‐25.27 to 13.27), the number with reduction in PTH (Analysis 2.3 (Ardissino 2000, 59 children): RR 0.88, 95% CI 0.65 to 1.19) and the mean integrated PTH levels (Analysis 2.4 (Schmitt 2003, 24 children): MD ‐58.00 pg/mL, 95% CI ‐212.55 to 96.55). In Klaus 1995, median (range) PTH levels fell significantly in both treatment groups with no differences between treatment groups (Table 2).
There were no significant differences in CrCl at eight weeks (Analysis 2.5.1 (Ardissino 2000, 59 children): MD 0.50 mL/min/1.73 m2, 95% CI ‐5.72 to 6.72) or 12 months (Analysis 2.5.2 (Schmitt 2003, 24 children): MD 1.50 mL/min/1.73 m2, 95% CI ‐2.04 to 5.04,), or in numbers with hypercalcaemia (Analysis 2.6.1 (2 studies, 80 children): RD ‐0.02, 95% CI ‐0.17 to 0.13; I2 = 19%) or hyperphosphataemia (Analysis 2.6.2 (Ardissino 2000, 59 children): RD 0.03, 95% CI ‐0.06 to 0.12). Schmitt 2003 reported no difference in the number of episodes of hypercalcaemia or hyperphosphataemia between the treatment groups.
Active vitamin D preparations versus placebo or no specific treatment
Four parallel studies compared active vitamin D preparations (calcitriol, paricalcitol, 1α‐hydroxyvitamin D) with placebo or no specific treatment (Table 3) (Eke 1983; Greenbaum 2005; Greenbaum 2007; Watson 1988). None of the studies reported any data for patient‐centred outcomes.
| Outcomes | Summary estimatea | ||||
| Number with abnormal bone histology | 7/8b versus 2/7c | Not reported | Not reported | Reduced osteoid, bone formation and | RR 0.17 (0.03 to 1.16) |
| PTH (pmol/L) | No difference | Not reported | Not reported | 18 ± 15 versus 73 ± 32 | MD ‐55.00 (‐83.03 to ‐26.97) |
| Elevated PTH | Not reported | Not reported | Not reported | 1/6 versus 6/6 | RR 0.17 (0.03 to 1.00) |
| Number with 30% fall in PTH | Not reported | 11/21 versus 5/26 | 9/15 versus 3/14 | Not reported | RR 2.75 (1.39 to 5.47) |
| Change in PTH (pg/mL) | Not reported | ‐193 ± 637 versus 10 ± 347 | ‐164 versus +238 | Not reported | MD ‐203.00 (‐506.34 to 100.34) |
| Hypercalcaemic patients | 0/8 versus 0/7 | 5/21 versus 0/26 | 0/15 versus 0/14 | 3/6 versus 2/6 | RD 0.08 (‐0.08 to 0.24) |
| Ca x P > 7.5 mg2/dL2 | Not reported | 8/21 versus 1/26 | Not reported | Not reported | RD 0.34 (0.12 to 0.56) |
| Phosphorus > 6.5 mg/dL x 2 | Not reported | 15/21 versus 12/26 | Not reported | Not reported | RD 0.25 (‐0.02 to 0.52) |
| Change in serum calcium (mg/dL) | No difference | 0.38 ± 0.6 versus 0.08 ± 0.66 | 0.00 ± 1.01 versus 0.29 ± 1.01 | No difference | MD ‐0.10 (‐0.45 to 0.65) |
| Change in Ca x P (mg2/dL2) | Not reported | 4.7 ± 12.4 versus 0.6 ± 14.8 | ‐1.35 ± 14.1 versus 3.21 ± 14.1 | Not reported | MD ‐0.45 (‐7.94 to 8.83) |
| Change in serum phosphorus (mg/dL) | No difference | 0.23 ± 1.33 versus 0.00 ± 1.68 | ‐0.15 ± 1.35 versus 0.18 ± 1.35 | No difference | MD ‐0.01 (‐0.66 to 0.63) |
| Change in bone ALP (U/L) | No difference | ‐4.5 ± 67 versus 43.2 ± 66 | Not reported | Not reported | MD ‐47.70 (‐88.54 to ‐6.86) |
a Summary estimate (RR, RD, MD) and 95% CI
b Experimental intervention
c Comparative intervention
ALP ‐ alkaline phosphatase; Ca x P ‐ calcium‐phosphorus product; PTH ‐ parathyroid hormone
Two parallel studies (28 children) compared 1α‐hydroxyvitamin D with no specific treatment (Eke 1983; Watson 1988). Though only 1/8 children treated with 1α‐hydroxyvitamin D versus 5/7 not treated had abnormal bone histology at the end of treatment, the difference was not significant due to small numbers (Analysis 3.1 (Eke 1983, 15 patients): RR 0.17, 95% CI 0.03 to 1.16). This study reported no significant difference in PTH levels at the end of the study (Table 3). Watson 1988 reported children treated with 1α‐hydroxyvitamin D showed reduced osteoid volume and both the number of children with PTH levels above the normal range of 3 to 25 pmol/L (Analysis 3.2 (12 children): RR 0.23, 95% CI 0.06 to 0.97) and the mean PTH levels (Analysis 3.3 (12 children): MD ‐55.00 pmol/L, 95% CI ‐83.03 to ‐26.97) were significantly lower in treated children compared with controls.
Two parallel studies (57 children) compared IV calcitriol (Greenbaum 2005) or IV paricalcitol (Greenbaum 2007) given three times/week with placebo. IV vitamin D preparations (calcitriol or paricalcitol) significantly increased the number of children who achieved a 30% fall in PTH levels on at least two occasions during the study (Analysis 3.4 (2 studies, 76 children): RR 2.75, 95% CI 1.39 to 5.47; I2 = 0%). However changes in mean PTH levels during treatment were not significantly different in children treated with IV calcitriol compared with placebo (Analysis 3.5 (1 study, 47 children): MD ‐203.00 pg/mL, 95% CI ‐506.34 to 100.34). An analysis of mean PTH levels following paricalcitol therapy was not possible as standard deviations were not provided.
Overall there was no significant difference in the risk of hypercalcaemia with vitamin D preparations compared with placebo/no specific treatment (Analysis 3.6 (4 studies, 103 children): RD 0.08, 95% CI ‐0.08 to 0.24; I2 = 55%). However there was heterogeneity with one study showing a significantly greater risk of hypercalcaemia in children treated with IV calcitriol. Following IV calcitriol, the number of children with elevated serum calcium‐phosphorus products (Analysis 3.7 (Greenbaum 2005, 47 children): RD 0.34, 95% CI 0.12 to 0.56) was increased compared with placebo while there was no significant difference in number with hyperphosphataemia (Analysis 3.8 (Greenbaum 2005, 47 children): RD 0.25, 95% CI ‐0.02 to 0.52). Mean changes in levels of serum calcium (Analysis 3.9.1 (2 studies, 76 children): MD 0.10 mg/dL, 95% CI ‐0.45 to 0.65; I2 = 50%), serum calcium‐phosphorus product (Analysis 3.9.2 (2 studies. 76 children): MD 0.45 mg2/dL2, 95% CI ‐7.94 to 8.83; I2 = 42%) and serum phosphorus (Analysis 3.9.3 (2 studies, 76 children): MD ‐0.01 mg/dL, 95% CI ‐0.66 to 0.63; I2 = 0%) did not differ between children treated with IV calcitriol or paricalcitol and placebo. Bone ALP was significantly reduced following IV calcitriol (Analysis 3.9.4 (Greenbaum 2005, 41 children): MD ‐47.70 µg/L, 95% CI ‐88.54 to ‐6.86). In the studies of 1α‐hydroxyvitamin D no differences were reported in mean serum calcium or phosphorus levels at the end of treatment but only graphical data or data without standard deviations were provided (Table 3).
Calcitriol versus dihydrotachysterol or ergocalciferol
One study (82 children) compared the effect of calcitriol and dihydrotachysterol on growth, GFR and the number of episodes of hypercalcaemia (GFRD Study 1990). Data on growth and GFR were reported as changes in slopes of growth rates so were not amenable to meta‐analysis. Growth rates did not differ between treatment groups. GFR fell during treatment in both groups but there was no difference between groups. There was no significant difference in the number of episodes of hypercalcaemia between groups (Table 4).
| Outcome | Doxercalciferol treatment | Calcitriol treatment | Summary estimatea | ||
| PTH (pg/mL) | Not reported | 0.87 ± 0.44b versus 1.35 ± 0.89c | Graphical data only | Graphical data only | MD ‐0.48 (‐1.23 to 0.27) |
| Number with Improved histology | Not reported | 7/8 versus 4/7 | Not reported | Not reported | RR 1.53 (0.77 to 3.06) |
| Height velocity ≥ expected | Positive growth scores with both treatments | 1/8 versus 4/7 | Not reported | Not reported | RR 0.22 (0.03 to 1.53) |
| Hypercalcaemic patients | No difference in number of episodes | 6/8 versus 3/7 | 17 in sevelamer treatedb versus | 17 in sevelamer treatedb versus | RR 1.75 (0.68 to 4.50) |
| GFR (mL/min/1.73 m2) | Fell in both groups | Not reported | Peritoneal dialysis patients | Peritoneal dialysis patients | Not calculated |
| Calcium (mmol/L) | Not reported | 2.63 ± 0.10 versus 2.45 ± 0.20 | Graphical data only | Graphical data only | MD 0.18 (0.01 to 0.35) |
| Phosphorus (mmol/L) | Not reported | 1.59 ± 0.30 versus 1.93 ± 0.47 | Graphical data only | Graphical data only | MD ‐0.34 (‐0.76 to 0.08) |
| ALP (U/L) | Not reported | 169 ± 58 versus 208 ± 84 | Graphical data only | Graphical data only | MD ‐39.00 (‐116.63 to 38.63) |
| Bone formation rate (µm3/µm2/d) | Not reported | Not reported | 60 ± 97 versus 53 ± 100 | 62 ± 201 versus 45 ± 73 | MD 10.29 (‐53.07 to 73.65) |
| Osteoid volume (%) | Not reported | Not reported | 11.1 ± 19.8 versus 10.8 ± 10.4 | 8.2 ± 20.1 versus 8.9 ± 14.3 | MD ‐0.16 (‐9.16 to 8.83) |
| Eroded bone surface (%) | Not reported | Not reported | 7.9 ± 9.7 versus 7.3 ± 15.6 | 8.6 ± 12.8 versus 7.7 ± 11.6 | MD 0.76 (‐6.16 to 7.71) |
| Bone volume (%) | Not reported | Not reported | 29.9 ± 17.3 versus 28.2 ± 15.9 | 30.3 ± 44.5 versus 26 ± 24.9 | MD 2.19 (‐9.12 to 13.91) |
a Summary estimate (RR, RD, MD) and 95% CI
b Experimental intervention
c Comparative intervention
ALP ‐ alkaline phosphatase; GFR ‐ glomerular filtration rate; PTH ‐ parathyroid hormone
Hodson 1985 compared calcitriol with ergocalciferol and found no significant differences between treatments in the number with height velocity ≥ expected (Analysis 4.1 (15 children): RR 0.22, 95% CI 0.03 to 1.53), in the number with improved bone histology (Analysis 4.2 (15 children): RR 1.53, 95% CI 0.77 to 3.06) and in final PTH levels (Analysis 4.3 (15 children): MD ‐0.48 ng/mL, 95% CI ‐1.23 to 0.27). The number of children with hypercalcaemia did not differ between groups (Analysis 4.4 (15 children): RR 1.75, 95% CI 0.68 to 4.50). The mean levels of serum calcium (Analysis 4.5.1 (15 children): MD 0.18 mmol/L, 95% CI 0.01 to 0.35), serum phosphorus (Analysis 4.5.2 (15 children): MD ‐0.34 mmol/L, 95% CI ‐0.76 to 0.08) and serum ALP (Analysis 4.5.3 (15 children): MD ‐39.00 U/L, 95% CI ‐116.63 to 38.63) at the end of the study did not differ between groups.
Ergocalciferol (replacement doses) versus placebo or no treatment
Two studies (Rianthavorn 2013; Shroff 2012) compared ergocalciferol in patients with CKD and vitamin D deficiency. Fewer children treated with ergocalciferol developed secondary hyperparathyroidism but the difference was not significant due to small patient numbers (Analysis 5.1 (Shroff 2012, 40 children): RR 0.33, 95% CI 0.11 to 1.05). However the time to development of hyperparathyroidism was significantly longer in children treated with ergocalciferol compared with placebo (hazard ratio 0.30, 95% CI 0.09‐0.93) (Shroff 2012). There were no significant differences between treatment groups in final PTH (Analysis 5.2 (Rianthavorn 2013, 20 children): MD ‐1.16 pg/mL, 95% CI ‐1.04 to 0.71), phosphorus levels (Analysis 5.4 (2 studies, 60 children): MD ‐0.29 mg/dL, 95% CI ‐0.96 to 0.39; I2 = 0%) and final calcium (Analysis 5.3 (2 studies, 60 children): MD 0.26 mg/dL, 95% CI ‐0.28 to 0.81; I2 = 42%). Vitamin D (1,25 (OH)) levels (Analysis 5.5 (Shroff 2012, 40 children): MD 27.00 pmol/L, 95%CI 17.35 to 36.65) were significantly higher in the treatment group compared to control group though the differences were not clinically important. Both studies reported no adverse effects related to ergocalciferol and no child developed hypercalcaemia.
Phosphate binders: calcium carbonate versus aluminium hydroxide
Two studies (Salusky 1991 (parallel study); Mak 1985 (cross‐over study) compared calcium carbonate with aluminium hydroxide as phosphate binders (Table 5). Salusky 1991 reported no significant difference in mean final height SDS between treatments (Analysis 6.1 (17 children): MD ‐0.86 SDS, 95% CI ‐2.24 to 0.52). The number with abnormal bone biopsies at the end of treatment was significantly lower in children treated with calcium carbonate compared with aluminium hydroxide (Analysis 6.2 (17 children): RR 0.35, 95% CI 0.13 to 0.95). Bone aluminium levels (Analysis 6.3 (17 children): MD ‐1.00 mg/kg dry weight, 95% CI ‐12.29 to 10.29), final PTH levels (Analysis 6.4 (17 children): MD ‐187.00 mL‐eq/L, 95% CI ‐1089.25 to 715.25) and final ALP (Analysis 6.5 (17 children): MD 21.00 U/L, 95% CI ‐216.62 to 258.62) did not differ significantly between groups. The number with hypercalcaemia did not differ between groups (Analysis 6.6 (17 children): RD 0.31, 95% CI ‐0.14 to 0.77). In the cross‐over study by Mak 1985 (12 children), results were not reported separately for each group. PTH levels normalised in both treatment groups. Serum calcium and phosphorus levels did not differ between groups. Plasma aluminium levels were significantly higher at the end of aluminium treatment compared with calcium carbonate treatment. Results of bone histology (overall no change), GFR (improved) and growth velocity SDS (improved) were not reported separately for treatment groups.
| Outcome | Summary estimateb | ||
| Abnormal bone biopsy | 4 improved, 5 no change, 2 worse | 3/10 versus 6/7 | RR 0.35 (0.13 to 0.95) |
| Bone aluminium (mg/kg) | Not reported | 9 ± 9.5 versus 10 ± 13 | MD ‐1.00 (‐12.29 to 10.29) |
| PTH levels (mL‐eq/L) | Normalised with both treatments | 731 ± 1062c versus 918 ± 833d | MD ‐‐187.00 (‐1089.25 to 715.25) |
| ALP (IU/L) | Not reported | 259 ± 231 versus 328 ± 256 | MD 21.00 (‐216.62 to 258.62) |
| Hypercalcaemic patients | Not reported | 6/10 versus 2/7 | RD 0.31 (‐0.14 to 0.77) |
| GFR (mL/min/1.73 m2) | 21 (SE 4; beginning) versus 23 (SE 5; end) | Peritoneal dialysis patients | Not calculated |
| Height SDS | Not reported | ‐2.73 ± 1.55 versus ‐1.92 ± 1.33 (end) | MD ‐0.86 (‐2.44 to 0.52) |
| Growth velocity SDS for chronological age | ‐0.82 (SE 0.31) increased to +0.31 (SE 0.39) P < 0.01 | Not reported | Not calculated |
| Plasma aluminium (µ/dL) | 3.0 ± 2.1 versus 9.0 ± 4.5 | Not reported | Not calculated |
a Cross‐over study
b Summary estimate (RR, RD, MD) and 95% CI; cross‐over studies excluded
c Experimental intervention
d Comparative intervention
ALP ‐ alkaline phosphatase; GFR ‐ glomerular filtration rate; PTH ‐ parathyroid hormone; SDS ‐ standard deviation score
Phosphate binders: sevelamer compared with calcium carbonate or calcium acetate
Two parallel group (Gulati 2010; Salusky 2005) and one cross‐over study (Pieper 2006) compared sevelamer with calcium carbonate or calcium acetate (Table 6). No study reported any patient‐centred outcomes. There were no significant differences in the final PTH levels (Analysis 7.1 ( 2 studies, 48 children): MD 51.92 pg/mL, 95% CI ‐77.53 to 181.36; I2 = 34%), final ALP levels (Analysis 7.2 (2 studies, 48 children): MD 90.48 IU/L, 95% CI ‐139.38 to 320.35; I2 = 30%), mean serum calcium‐phosphorus product (Analysis 7.3 (2 studies, 48 children): MD ‐1.12 mg2/dL2, 95% CI, ‐5.88 to 3.64; I2 = 0%), mean serum calcium levels (Analysis 7.4 (2 studies, 48 children): MD ‐0.40 mg/dL, 95% CI ‐1.16 to 0.36; I2 = 59%) or mean serum phosphorus levels (Analysis 7.5 (2 studies, 48 children): MD 0.17 mg/dL, 95% CI 0.37 to 0.71; I2 = 0%) between groups.
| Outcome | Summary estimateb | |||
| PTH (pg/mL) | 165 ± 45 versus 144 ± 34 (final) | ‐7 ± 196 versus ‐43 ± 270 (change) | 562 ± 403c versus 369 ± 344d (final) | MD 51.92 (‐77.53 to 181.36) |
| ALP (U/L) | 1352 ± 500 versus1018 ± 557 (final) | 70 ± 108 versus 34 ± 127 (change) | 254 ± 155 versus 220 ± 157 (final) | MD 90.48 (‐139.38 to 320.35) |
| Hypercalcaemic patients | 0/10 versus 0/9 | 1/32 versus 6/30 periods of calcitriol | 5 episodes versus 22 episodes | Not calculated |
| Ca x P (mg2/dL2) | 51.2 ± 8.4 versus 49.4 ± 12.9 | ‐1.37 ± 1.4 versus ‐1.12 ± 1.25 (change) | 51 ± 7.4 versus 53 ± 7.5 | MD ‐1.12 (‐5.9 to 3.64) |
| Calcium (mg/dL) | 8.6 ± 1 versus 8.5 ± 1 | ‐0.2 ± 0.7 versus 0.4 ± 1.0 (change) | 8.9 ± 0.8 versus 9.6 ± 0.4 | MD ‐0.4 (‐1.16 to ‐0.36) |
| Phosphorus (mg/dL) | 6.2 ± 0.4 versus 5.8 ± 1.7 | ‐1.5 ± 1.6 versus ‐1.7 ± 1.7 (change) | 5.6 ± 1.2 versus 5.5 ± 0.4 | MD 0.17 (‐0.37 to 0.71) |
a Cross‐over study
b Summary estimate (RR, RD, MD) and 95% CI; cross‐over studies excluded
c Experimental intervention
d Comparative intervention
ALP ‐ alkaline phosphatase; Ca x P ‐ calcium‐phosphorus product; PTH ‐ parathyroid hormone
Salusky 2005 reported bone histology parameters of bone formation rates, % fall in bone formation rates, eroded perimeter, osteoid seam width, and bone area did not differ between treatments (Analysis 7.6). Osteoid area (Analysis 7.6.4 (1 study, 29 children); MD 4.20%, 95% CI 0.99 to 7.41) and osteoid perimeter (Analysis 7.6.5 (1 study, 29 children): MD 13.00%, 95% CI 3.81 to 22.19) were significantly higher in sevelamer treated children but the differences were of no clinical significance. In the cross‐over study by Pieper 2006 the change in PTH levels and serum ALP did not differ between groups. Similarly the change in mean serum calcium‐phosphorus product, serum calcium and serum phosphorus levels did not differ between therapy groups. Salusky 2005 reported 22 episodes of hypercalcaemia with calcium carbonate compared with five in children receiving sevelamer while Pieper 2006 reported six episodes of hypercalcaemia with calcium carbonate compared with one in children receiving sevelamer. No hypercalcaemic episodes were reported by Gulati 2010.
Calcitriol versus doxercalciferol
Salusky 2005a and Salusky 2005b compared doxercalciferol plus calcium carbonate or sevelamer to calcitriol plus calcium carbonate or sevelamer (Table 4). Bone histology parameters of bone formation rate (Analysis 8.1.1 (51 children): MD 10.29 µm3/µm2/d, 95% CI ‐53.07 to 73.65), percentage eroded bone (Analysis 8.1.2 (51 children): MD 0.76%, 95% CI ‐6.19 to 7.71), percentage osteoid volume (Analysis 8.1.3 ( 51 children): MD ‐0.16%, 95% CI ‐9.16 to 8.83), percentage osteoid surface (Analysis 8.1.4 (51 children): MD 1.04%, 95% CI ‐29.63 to 31.71), osteoid maturation time (Analysis 8.1.5 (51 children): MD 0.82 days, 95% CI ‐14.41 to 16.05) and percentage bone volume (Analysis 8.1.6 (51 children): MD 2.19%, 95% CI ‐9.82 to 13.91) did not differ significantly between treatment groups. Final levels of PTH, calcium, phosphorus, serum alkaline phosphatase (ALP) and FGF23 did not differ between groups (data only shown graphically in study reports). Values of PTH and ALP fell significantly while values of FGF23 rose significantly with either vitamin D preparation. No differences in episodes of hypercalcaemia were seen between the two vitamin D therapies.
Outcomes not reported
No studies reported fractures, bone deformities, need for parathyroidectomy, dialysis‐related events, symptoms related to hypercalcaemia or vascular/extra osseous calcification.
Discussion
Summary of main results
We were only able to identify 18 RCTs of all interventions used for CKD‐MBD in children over a period of 30 years. All identified studies examined phosphate binders or vitamin D sterols. No studies specifically examining dietary or surgical interventions, changes in dialysis prescription or calcimimetics were identified. Six studies of treatment of CKD‐MBD involved phosphate binders (aluminium hydroxide) or vitamin D sterols (ergocalciferol, dihydrotachysterol) or routes of administration (intraperitoneal) which are no longer used or are uncommonly used in current clinical practice except for the small doses of ergocalciferol recommended for children with CKD and low 25 hydroxyvitamin D levels (KDOQI 2009). There were few data to assist clinicians with the prevention of complications of renal bone disease since the only patient‐centred‐outcome reported was growth. This was reported in five studies (GFRD Study 1990; Hodson 1985; Jones 1994; Salusky 1991; Schmitt 2003) with no significant differences identified between treatments.
Treatment with calcitriol by both intraperitoneal and oral routes was effective in improving bone histology (Salusky 1998) but growth rates did not differ between routes (Jones 1994). The number of hypercalcaemic episodes did not differ between treatment routes although intraperitoneal calcitriol lowered PTH levels significantly more than oral calcitriol (Salusky 1998). However both treatments used intermittently and in high dose increased the number of children with adynamic bone disease (Salusky 1998). Intraperitoneal calcitriol is no longer recommended.
No differences in height SDS, PTH levels and frequency of hypercalcaemia were found between oral daily or oral intermittent calcitriol therapy (Ardissino 2000; Klaus 1995; Schmitt 2003). Oral intermittent therapy is no longer recommended.
Vitamin D sterols given orally or IV resulted in reduced PTH levels compared with placebo or no specific treatment. Hypercalcaemic episodes were more common with IV calcitriol in one study (Greenbaum 2005). Increased risk of hypercalcaemia was not reported with 1α‐hydroxyvitamin D or paricalcitol. Qualitative description of bone histology indicated improvement in children treated with vitamin D sterols (Eke 1983; Watson 1988).
No significant differences in growth rates (GFRD Study 1990; Hodson 1985) or bone histology (Salusky 2005a; Salusky 2005b) were detected in studies comparing different vitamin D sterols.
Two studies (Rianthavorn 2013; Shroff 2012) compared ergocalciferol in patients with CKD and vitamin D deficiency. Although there was no significant difference in the number of children, who developed secondary hyperparathyroidism, the development of secondary hyperparathyroidism was significantly delayed while calcium levels were significantly increased with ergocalciferol compared with placebo.
Overall we found that phosphate binders (aluminium hydroxide, calcium carbonate or acetate and sevelamer) had indistinguishable effects in lowering serum phosphorus, reducing PTH and on mean height SDS but that hypercalcaemia was more common with calcium‐containing binders (Gulati 2010; Mak 1985; Pieper 2006; Salusky 1991; Salusky 2005). One study suggested that bone histology remained abnormal less commonly in calcium carbonate treated children compared with those treated with aluminium hydroxide (Salusky 1991).
Overall completeness and applicability of evidence
There were significant gaps between the interventions and outcomes that we had planned to study in this systematic review and the available data. In particular, no study provided data on patient‐centred outcomes such as fractures, deformities and bone pain with only three studies providing numerical data on changes in height. The majority of studies only provided surrogate biochemical outcomes of PTH, serum ALP, calcium and phosphorus levels with a few early studies also reporting on radiological changes. We did not identify any studies, which considered non‐pharmacological or surgical interventions or any studies, which evaluated calcimimetic agents in children.
There were many limitations in the available data which precluded combining results across studies in meta‐analyses in many cases. Criteria for diagnosis of CKD‐MBD varied between studies. As well as variation in the interventions examined, there was variation on outcomes reported and in how the outcomes were measured. Many studies reported the point estimate of the results but not the SD or 95% CI. The cross‐over studies only presented the combined data for both arms, rather than each arm separately, and so could not be included in the meta‐analyses. Some inconsistencies in outcome reporting are inevitable when comparing studies published in different eras. Early studies tended to focus only on the incidence of hypercalcaemia as an adverse consequence of both vitamin D and phosphate binders whereas more recent studies included hyperphosphataemia and elevated serum calcium‐phosphorus product, since recognition of the adverse consequences of these parameters. Similarly, reporting of radiological abnormalities was a common outcome measure historically which has now largely been discarded. The relevance of certain outcome measures has changed over time. For example, measurements of plasma or bone aluminium levels, which were of relevance when aluminium hydroxide was used as a phosphate binder is no longer relevant.
Bone histomorphometry has been considered the reference standard to assess treatment efficacy in this setting, but only two of 18 included studies (Salusky 1998; Salusky 2005; Salusky 2005a; Salusky 2005b) provided adequate and comparable bone biopsy data making the value of bone histomorphometry in assessing treatment response difficult to assess in this systematic review. In addition, bone histomorphometry of trabecular bone does not reflect the effects of CKD on cortical bone. CKD reduces cortical bone volume and alters its architecture increasing the risk of fractures in long bones.
Though a surrogate measure, reduction in PTH levels is the most commonly used measure of efficacy of therapies in CKD‐MBD. However in the reported studies there was considerable variation in the way in which PTH levels were measured. PTH values were variably reported as end of study mean or median values, percentage fall in PTH, the number of children with a fall in PTH levels, the mean integrated PTH value, the mean change in PTH levels during the study and the number of children with two consecutive falls of ≥ 30% in PTH values. The potential for outcomes reporting bias is high when children are reported as having a successful outcome if their PTH value has fallen by an apparently arbitrary proportion at any time during the study period, rather than reporting whether the benefit was transient, or sustained, or what the primary outcome measure was. Also, the comparison of PTH values between studies is limited because different PTH assays have been used in different studies reflecting the variations in PTH assays over the past 30 years (Wesseling‐Perry 2013).
Comparisons of new therapeutic agents or a new method for their administration against placebo are of little clinical relevance if alternative agents are already recognised as successfully treating the disorder. Such a comparison was described in four studies. Two of these studies (Eke 1983; Watson 1988) were published in the 1980s when alternative successful treatments for renal bone disease were not confirmed. However two recently published studies reported that IV calcitriol (Greenbaum 2005) or IV paricalcitol (Greenbaum 2007) reduce PTH values more effectively than placebo. These results are not remarkable because it is generally agreed that vitamin D analogues are beneficial for biochemical abnormalities associated with CKD‐MBD. Of more relevance to the clinician would be knowing whether IV calcitriol or IV paricalcitol are associated with improvements in patient‐centred outcomes such as improved growth rates as well as fewer episodes of hypercalcaemia and reduction in PTH levels compared with oral calcitriol. In studies evaluating newer agents, or alternative modes of administration, it is important to compare a new agent, or its mode of administration with agents considered to represent the current standard of care using patient‐centred outcomes as the primary outcomes.
Quality of the evidence
Included studies were commonly reported incompletely and were of poor methodological quality, although this may reflect pre‐2001 CONSORT (Consolidated Standards of Reporting Trials) practices (www.consort‐statement.org). Sequence generation and allocation concealment was adequate in 12 and 11 of 18 studies respectively. Four studies reported blinding of participants, investigators or outcome assessors. All studies were considered at low risk of detection bias because they measured laboratory‐based outcomes unlikely to be influenced by lack of blinding. Seven studies reported loss of follow‐up or exclusion from data analysis (attrition bias) exceeding 10% and six studies were at high risk of selective reporting bias. Absence of allocation concealment, blinding and intention‐to‐treat analysis tends to lead to an over‐estimate of the observed treatment effects (Schulz 1995; Wood 2008). Many studies were too small to detect any differences between treatments even if differences did exist. Several studies provided outcome data qualitatively as normal or not statistically different without providing the numeric results. Although this under‐reporting of data was more common in the earlier studies, it was still evident in the most recent studies (Figure 3).
Studies included small numbers of patients. Few studies used the same interventions and/or reported outcomes in the same way so therefore they could not be combined in the meta‐analyses. Therefore there were insufficient data to create summary of findings tables.
Potential biases in the review process
Since the study was commenced, the literature search has been run several times up to September 2015 making it unlikely that any studies have been missed. However 40% of study reports in the Cochrane Kidney and Transplant Specialised Register have been identified by handsearching of conference proceedings so it remains possible that further studies of therapies for CKD‐MBD in children will be identified as conference proceedings from different congresses are searched.
The inability to include any data from cross‐over studies in meta‐analyses may have resulted in bias towards the results from parallel studies. However results from cross‐over studies have been included in the additional tables as well as being referred to in the text (Table 1; Table 2; Table 3; Table 4; Table 5; Table 6).
Agreements and disagreements with other studies or reviews
Systematic reviews evaluating the use of vitamin D compounds in adults identified similar limitations to their review as we did (Palmer 2009a; Palmer 2009b). In particular few studies reported patient‐centred outcomes, few studies compared the newer vitamin D preparations with established ones and for each comparison there were limited numbers of studies and patients limiting the conclusions that could be drawn. While established vitamin D preparations (calcitriol,1α‐hydroxyvitamin D) were not demonstrated to reduce PTH levels significantly, there was considerable heterogeneity in the analyses. Newer vitamin D preparations including paricalcitol significantly reduced mean PTH levels. All vitamin D preparations increased the risk of hypercalcaemia compared with placebo. The authors concluded that the value of vitamin D therapy on important clinical outcomes in patients with CKD remains uncertain.
In a systematic review of nutritional vitamin D compounds of four RCTs (90 participants), which included both dialysis and non‐dialysis CKD patients, the PTH levels decreased significantly with vitamin D therapy (Kandula 2011).
Two systematic reviews (Navaneethan 2011; Tonelli 2007), comparing sevelamer with calcium‐containing phosphate binders, identified no differences between binders for all‐cause mortality or cardiovascular mortality. Following sevelamer treatment the risk of hypercalcaemia was reduced and serum calcium levels were lower. However serum phosphate levels were higher and levels of serum calcium‐phosphorus product did not differ. End of treatment PTH levels were significantly higher with sevelamer compared with calcium salts (Navaneethan 2011).
As in our review, the primary outcomes reported in these systematic reviews were surrogate biochemical markers rather than patient‐centred outcomes so that the clinical value of vitamin D compounds or non‐calcium‐containing phosphate binders in patients with CKD remains uncertain.
Study flow diagram
Methodological quality graph: review authors' judgements about each methodological quality item presented as percentages across all included studies
Risk of bias summary: review authors' judgements about each risk of bias item for each included study
Comparison 1 Intraperitoneal versus oral calcitriol, Outcome 1 Bone disease on bone histology.
Comparison 1 Intraperitoneal versus oral calcitriol, Outcome 2 Bone formation rate.
Comparison 1 Intraperitoneal versus oral calcitriol, Outcome 3 PTH.
Comparison 1 Intraperitoneal versus oral calcitriol, Outcome 4 Maximum calcium level.
Comparison 1 Intraperitoneal versus oral calcitriol, Outcome 5 Adverse events.
Comparison 1 Intraperitoneal versus oral calcitriol, Outcome 6 Peritonitis episodes/patient‐months.
Comparison 2 Intermittent versus daily oral calcitriol, Outcome 1 Change in height SDS at 12 months.
Comparison 2 Intermittent versus daily oral calcitriol, Outcome 2 Fall in PTH.
Comparison 2 Intermittent versus daily oral calcitriol, Outcome 3 Number with fall in PTH at 8 weeks.
Comparison 2 Intermittent versus daily oral calcitriol, Outcome 4 Mean integrated PTH at 12 months.
Comparison 2 Intermittent versus daily oral calcitriol, Outcome 5 Kidney function.
Comparison 2 Intermittent versus daily oral calcitriol, Outcome 6 Adverse events.
Comparison 3 Vitamin D preparations versus placebo/no treatment, Outcome 1 Abnormal bone histology.
Comparison 3 Vitamin D preparations versus placebo/no treatment, Outcome 2 Elevated PTH.
Comparison 3 Vitamin D preparations versus placebo/no treatment, Outcome 3 PTH.
Comparison 3 Vitamin D preparations versus placebo/no treatment, Outcome 4 Number with 30% fall in PTH on two occasions.
Comparison 3 Vitamin D preparations versus placebo/no treatment, Outcome 5 Change in PTH with IV calcitriol.
Comparison 3 Vitamin D preparations versus placebo/no treatment, Outcome 6 Hypercalcaemia.
Comparison 3 Vitamin D preparations versus placebo/no treatment, Outcome 7 Calcium‐phosphorus product > 7.5 mg²/dL².
Comparison 3 Vitamin D preparations versus placebo/no treatment, Outcome 8 Phosphorus > 6.5 mg/dL.
Comparison 3 Vitamin D preparations versus placebo/no treatment, Outcome 9 Change in biochemical values.
Comparison 4 Calcitriol versus ergocalciferol, Outcome 1 Height velocity ≥ expected.
Comparison 4 Calcitriol versus ergocalciferol, Outcome 2 Improved bone histology.
Comparison 4 Calcitriol versus ergocalciferol, Outcome 3 PTH.
Comparison 4 Calcitriol versus ergocalciferol, Outcome 4 Hypercalcaemia.
Comparison 4 Calcitriol versus ergocalciferol, Outcome 5 Biochemical values.
Comparison 5 Ergocalciferol versus placebo/no treatment, Outcome 1 Number developing hyperparathyroidism.
Comparison 5 Ergocalciferol versus placebo/no treatment, Outcome 2 PTH.
Comparison 5 Ergocalciferol versus placebo/no treatment, Outcome 3 Calcium.
Comparison 5 Ergocalciferol versus placebo/no treatment, Outcome 4 Phosphorus.
Comparison 5 Ergocalciferol versus placebo/no treatment, Outcome 5 End 1.25(OH)D3 levels.
Comparison 6 Calcium carbonate versus aluminium hydroxide, Outcome 1 Height SDS.
Comparison 6 Calcium carbonate versus aluminium hydroxide, Outcome 2 Abnormal bone biopsy.
Comparison 6 Calcium carbonate versus aluminium hydroxide, Outcome 3 Bone aluminium.
Comparison 6 Calcium carbonate versus aluminium hydroxide, Outcome 4 PTH.
Comparison 6 Calcium carbonate versus aluminium hydroxide, Outcome 5 ALP.
Comparison 6 Calcium carbonate versus aluminium hydroxide, Outcome 6 Hypercalcaemia.
Comparison 7 Sevelamer versus calcium‐containing phosphate binders, Outcome 1 PTH.
Comparison 7 Sevelamer versus calcium‐containing phosphate binders, Outcome 2 ALP.
Comparison 7 Sevelamer versus calcium‐containing phosphate binders, Outcome 3 Calcium‐phosphorus product.
Comparison 7 Sevelamer versus calcium‐containing phosphate binders, Outcome 4 Calcium.
Comparison 7 Sevelamer versus calcium‐containing phosphate binders, Outcome 5 Phosphorus.
Comparison 7 Sevelamer versus calcium‐containing phosphate binders, Outcome 6 Bone histomorphometry.
Comparison 8 Calcitriol versus doxercalciferol, Outcome 1 Bone histomorphometry.
| Outcome | Summary estimateb | ||
| Abnormal bone biopsy | Not reported | 12/16c versus 12/17d | RR 1.06 (0.70 to 1.61) |
| Adynamic bone disease | Not reported | 7/16 versus 5/17 | RR 1.49 (0.59 to 3.74) |
| Osteitis fibrosa | Not reported | 2/16 versus 6/17 | RR 0.35 (0.08 to 1.51) |
| Mixed/mild disease | Not reported | 3/16 versus 7/17 | RR 0.46 (0.14 to 1.46) |
| Normal/reduced bone formation rate | Not reported | 11/16 versus 11/17 | RR 1.06 (0.66 to 1.72) |
| Bone formation rate (µm2/mm2/d) | Not reported | 297 ± 472 versus 586 ± 973 | MD ‐289.00 (‐806.13 to 228.13) |
| PTH (pg/mL) | No significant difference | 169 ± 228 versus 670 ± 400 | MD ‐501.00 (‐721.54 to ‐280.46) |
| Maximum serum calcium (mg/dL) | Not reported | 10.4 ± 2 versus 9.7 ± 1.64 | MD 0.70 (‐0.55 to 1.95) |
| Hypercalcaemic patients | 0/7 versus 0/7 | 8/16 versus 5/17 | RD 0.21 (‐0.12 to 0.53) |
| Hypophosphataemic patients | Not reported | 2/16 versus 3/17 | RD ‐0.05 (‐0.29 to 0.19) |
| Peritonitis episodes/patient‐month | 1/ 11 versus 1/11 | 1/12 versus 1/10 | RD 0.01 (‐0.24 to 0.26) |
| Height SDS | ‐2.26 (‐4.5 to ‐1.61) versus ‐2.33 (‐4.27 to ‐1.43) (end) | Not reported | Not calculated |
| a Cross‐over study b Summary estimate (RR, RD, MD) and 95% CI; cross‐over studies excluded c Experimental intervention d Comparative intervention PTH ‐ parathyroid hormone; SDS ‐ standard deviation score | |||
| Outcome | Summary estimate a | |||
| % fall PTH | 13.7 ± 46.7b versus 19.2 ± 57.8c | Not reported | 58 ± 26 versus 64 ± 22 | MD ‐5.83 (‐21.49 to 9.83) |
| Number with fall in PTH | 21/30 versus 23/29 | "median PTH fell in both groups" | Not reported | RR 0.88 (0.65 to 1.19) |
| Mean integrated PTH (pg/mL) | Not reported | Not reported | 285 ± 213 versus 343 ± 171 | MD ‐58.00 (‐212.55 to 96.55) |
| CrCl (mL/min/1.73 m2) | 22 ± 13 versus 22 ± 11(end) | Not reported | ‐1.6 ± 4.0 versus 3.1± 4.8 (change) | MD 0.50 (‐5.72 to 6.72) |
| Change in height SDS | Not reported | Not reported | ‐0.05 ± 0.52 versus ‐0.18 ± 0.34 | MD 0.13 (‐0.22 to 0.48) |
| Hypercalcaemic patients | 1/30 versus 1/29 | 2/12 versus 3/9 | No difference in number of episodes | RD ‐0.02 (‐0.17 to 0.13) |
| Hypophosphataemic patients | 0/30 versus 1/29 | Not reported | No difference in number of episodes | RD 0.03 (‐0.06 to 0.12) |
| a Summary estimate (RR, RD, MD) and 95% b Experimental intervention c Comparative intervention CrCl ‐ creatinine clearance; PTH ‐ parathyroid hormone; SDS ‐ standard deviation score | ||||
| Outcomes | Summary estimatea | ||||
| Number with abnormal bone histology | 7/8b versus 2/7c | Not reported | Not reported | Reduced osteoid, bone formation and | RR 0.17 (0.03 to 1.16) |
| PTH (pmol/L) | No difference | Not reported | Not reported | 18 ± 15 versus 73 ± 32 | MD ‐55.00 (‐83.03 to ‐26.97) |
| Elevated PTH | Not reported | Not reported | Not reported | 1/6 versus 6/6 | RR 0.17 (0.03 to 1.00) |
| Number with 30% fall in PTH | Not reported | 11/21 versus 5/26 | 9/15 versus 3/14 | Not reported | RR 2.75 (1.39 to 5.47) |
| Change in PTH (pg/mL) | Not reported | ‐193 ± 637 versus 10 ± 347 | ‐164 versus +238 | Not reported | MD ‐203.00 (‐506.34 to 100.34) |
| Hypercalcaemic patients | 0/8 versus 0/7 | 5/21 versus 0/26 | 0/15 versus 0/14 | 3/6 versus 2/6 | RD 0.08 (‐0.08 to 0.24) |
| Ca x P > 7.5 mg2/dL2 | Not reported | 8/21 versus 1/26 | Not reported | Not reported | RD 0.34 (0.12 to 0.56) |
| Phosphorus > 6.5 mg/dL x 2 | Not reported | 15/21 versus 12/26 | Not reported | Not reported | RD 0.25 (‐0.02 to 0.52) |
| Change in serum calcium (mg/dL) | No difference | 0.38 ± 0.6 versus 0.08 ± 0.66 | 0.00 ± 1.01 versus 0.29 ± 1.01 | No difference | MD ‐0.10 (‐0.45 to 0.65) |
| Change in Ca x P (mg2/dL2) | Not reported | 4.7 ± 12.4 versus 0.6 ± 14.8 | ‐1.35 ± 14.1 versus 3.21 ± 14.1 | Not reported | MD ‐0.45 (‐7.94 to 8.83) |
| Change in serum phosphorus (mg/dL) | No difference | 0.23 ± 1.33 versus 0.00 ± 1.68 | ‐0.15 ± 1.35 versus 0.18 ± 1.35 | No difference | MD ‐0.01 (‐0.66 to 0.63) |
| Change in bone ALP (U/L) | No difference | ‐4.5 ± 67 versus 43.2 ± 66 | Not reported | Not reported | MD ‐47.70 (‐88.54 to ‐6.86) |
| a Summary estimate (RR, RD, MD) and 95% CI b Experimental intervention c Comparative intervention ALP ‐ alkaline phosphatase; Ca x P ‐ calcium‐phosphorus product; PTH ‐ parathyroid hormone | |||||
| Outcome | Doxercalciferol treatment | Calcitriol treatment | Summary estimatea | ||
| PTH (pg/mL) | Not reported | 0.87 ± 0.44b versus 1.35 ± 0.89c | Graphical data only | Graphical data only | MD ‐0.48 (‐1.23 to 0.27) |
| Number with Improved histology | Not reported | 7/8 versus 4/7 | Not reported | Not reported | RR 1.53 (0.77 to 3.06) |
| Height velocity ≥ expected | Positive growth scores with both treatments | 1/8 versus 4/7 | Not reported | Not reported | RR 0.22 (0.03 to 1.53) |
| Hypercalcaemic patients | No difference in number of episodes | 6/8 versus 3/7 | 17 in sevelamer treatedb versus | 17 in sevelamer treatedb versus | RR 1.75 (0.68 to 4.50) |
| GFR (mL/min/1.73 m2) | Fell in both groups | Not reported | Peritoneal dialysis patients | Peritoneal dialysis patients | Not calculated |
| Calcium (mmol/L) | Not reported | 2.63 ± 0.10 versus 2.45 ± 0.20 | Graphical data only | Graphical data only | MD 0.18 (0.01 to 0.35) |
| Phosphorus (mmol/L) | Not reported | 1.59 ± 0.30 versus 1.93 ± 0.47 | Graphical data only | Graphical data only | MD ‐0.34 (‐0.76 to 0.08) |
| ALP (U/L) | Not reported | 169 ± 58 versus 208 ± 84 | Graphical data only | Graphical data only | MD ‐39.00 (‐116.63 to 38.63) |
| Bone formation rate (µm3/µm2/d) | Not reported | Not reported | 60 ± 97 versus 53 ± 100 | 62 ± 201 versus 45 ± 73 | MD 10.29 (‐53.07 to 73.65) |
| Osteoid volume (%) | Not reported | Not reported | 11.1 ± 19.8 versus 10.8 ± 10.4 | 8.2 ± 20.1 versus 8.9 ± 14.3 | MD ‐0.16 (‐9.16 to 8.83) |
| Eroded bone surface (%) | Not reported | Not reported | 7.9 ± 9.7 versus 7.3 ± 15.6 | 8.6 ± 12.8 versus 7.7 ± 11.6 | MD 0.76 (‐6.16 to 7.71) |
| Bone volume (%) | Not reported | Not reported | 29.9 ± 17.3 versus 28.2 ± 15.9 | 30.3 ± 44.5 versus 26 ± 24.9 | MD 2.19 (‐9.12 to 13.91) |
| a Summary estimate (RR, RD, MD) and 95% CI b Experimental intervention c Comparative intervention ALP ‐ alkaline phosphatase; GFR ‐ glomerular filtration rate; PTH ‐ parathyroid hormone | |||||
| Outcome | Summary estimateb | ||
| Abnormal bone biopsy | 4 improved, 5 no change, 2 worse | 3/10 versus 6/7 | RR 0.35 (0.13 to 0.95) |
| Bone aluminium (mg/kg) | Not reported | 9 ± 9.5 versus 10 ± 13 | MD ‐1.00 (‐12.29 to 10.29) |
| PTH levels (mL‐eq/L) | Normalised with both treatments | 731 ± 1062c versus 918 ± 833d | MD ‐‐187.00 (‐1089.25 to 715.25) |
| ALP (IU/L) | Not reported | 259 ± 231 versus 328 ± 256 | MD 21.00 (‐216.62 to 258.62) |
| Hypercalcaemic patients | Not reported | 6/10 versus 2/7 | RD 0.31 (‐0.14 to 0.77) |
| GFR (mL/min/1.73 m2) | 21 (SE 4; beginning) versus 23 (SE 5; end) | Peritoneal dialysis patients | Not calculated |
| Height SDS | Not reported | ‐2.73 ± 1.55 versus ‐1.92 ± 1.33 (end) | MD ‐0.86 (‐2.44 to 0.52) |
| Growth velocity SDS for chronological age | ‐0.82 (SE 0.31) increased to +0.31 (SE 0.39) P < 0.01 | Not reported | Not calculated |
| Plasma aluminium (µ/dL) | 3.0 ± 2.1 versus 9.0 ± 4.5 | Not reported | Not calculated |
| a Cross‐over study b Summary estimate (RR, RD, MD) and 95% CI; cross‐over studies excluded c Experimental intervention d Comparative intervention ALP ‐ alkaline phosphatase; GFR ‐ glomerular filtration rate; PTH ‐ parathyroid hormone; SDS ‐ standard deviation score | |||
| Outcome | Summary estimateb | |||
| PTH (pg/mL) | 165 ± 45 versus 144 ± 34 (final) | ‐7 ± 196 versus ‐43 ± 270 (change) | 562 ± 403c versus 369 ± 344d (final) | MD 51.92 (‐77.53 to 181.36) |
| ALP (U/L) | 1352 ± 500 versus1018 ± 557 (final) | 70 ± 108 versus 34 ± 127 (change) | 254 ± 155 versus 220 ± 157 (final) | MD 90.48 (‐139.38 to 320.35) |
| Hypercalcaemic patients | 0/10 versus 0/9 | 1/32 versus 6/30 periods of calcitriol | 5 episodes versus 22 episodes | Not calculated |
| Ca x P (mg2/dL2) | 51.2 ± 8.4 versus 49.4 ± 12.9 | ‐1.37 ± 1.4 versus ‐1.12 ± 1.25 (change) | 51 ± 7.4 versus 53 ± 7.5 | MD ‐1.12 (‐5.9 to 3.64) |
| Calcium (mg/dL) | 8.6 ± 1 versus 8.5 ± 1 | ‐0.2 ± 0.7 versus 0.4 ± 1.0 (change) | 8.9 ± 0.8 versus 9.6 ± 0.4 | MD ‐0.4 (‐1.16 to ‐0.36) |
| Phosphorus (mg/dL) | 6.2 ± 0.4 versus 5.8 ± 1.7 | ‐1.5 ± 1.6 versus ‐1.7 ± 1.7 (change) | 5.6 ± 1.2 versus 5.5 ± 0.4 | MD 0.17 (‐0.37 to 0.71) |
| a Cross‐over study b Summary estimate (RR, RD, MD) and 95% CI; cross‐over studies excluded c Experimental intervention d Comparative intervention ALP ‐ alkaline phosphatase; Ca x P ‐ calcium‐phosphorus product; PTH ‐ parathyroid hormone | ||||
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Bone disease on bone histology Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 1.1 Abnormal bone histology | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 1.2 Adynamic bone disease | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 1.3 Osteitis fibrosa | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 1.4 Mixed or mild bone disease | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 1.5 Normal or reduced bone formation | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 2 Bone formation rate Show forest plot | 1 | Mean Difference (IV, Random, 95% CI) | Totals not selected | |
| 3 PTH Show forest plot | 1 | Mean Difference (IV, Random, 95% CI) | Totals not selected | |
| 4 Maximum calcium level Show forest plot | 1 | Mean Difference (IV, Random, 95% CI) | Totals not selected | |
| 5 Adverse events Show forest plot | 1 | Risk Difference (M‐H, Random, 95% CI) | Totals not selected | |
| 5.1 Calcium > 11 mg/dL | 1 | Risk Difference (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 5.2 Phosphate > 7.0 mg/dL | 1 | Risk Difference (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 6 Peritonitis episodes/patient‐months Show forest plot | 1 | Risk Difference (M‐H, Random, 95% CI) | Totals not selected | |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Change in height SDS at 12 months Show forest plot | 1 | Mean Difference (IV, Random, 95% CI) | Totals not selected | |
| 2 Fall in PTH Show forest plot | 2 | Mean Difference (IV, Random, 95% CI) | Totals not selected | |
| 2.1 8 weeks | 1 | Mean Difference (IV, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 2.2 12 months | 1 | Mean Difference (IV, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 3 Number with fall in PTH at 8 weeks Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 4 Mean integrated PTH at 12 months Show forest plot | 1 | Mean Difference (IV, Random, 95% CI) | Totals not selected | |
| 5 Kidney function Show forest plot | 2 | Mean Difference (IV, Random, 95% CI) | Totals not selected | |
| 5.1 Final CrCl at 8 weeks [mL/min/1.73 m2] | 1 | Mean Difference (IV, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 5.2 Change in CrCl at 12 months [mL/min/1.73 m2] | 1 | Mean Difference (IV, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 6 Adverse events Show forest plot | 2 | Risk Difference (M‐H, Random, 95% CI) | Subtotals only | |
| 6.1 Calcium > 11.5 mg/dL | 2 | 80 | Risk Difference (M‐H, Random, 95% CI) | ‐0.02 [‐0.17, 0.13] |
| 6.2 Phosphorus > 7.5 mg/dL | 1 | 59 | Risk Difference (M‐H, Random, 95% CI) | 0.03 [‐0.06, 0.12] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Abnormal bone histology Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 2 Elevated PTH Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 3 PTH Show forest plot | 1 | Mean Difference (IV, Random, 95% CI) | Totals not selected | |
| 4 Number with 30% fall in PTH on two occasions Show forest plot | 2 | 76 | Risk Ratio (M‐H, Random, 95% CI) | 2.75 [1.39, 5.47] |
| 5 Change in PTH with IV calcitriol Show forest plot | 1 | Mean Difference (IV, Random, 95% CI) | Totals not selected | |
| 6 Hypercalcaemia Show forest plot | 4 | 103 | Risk Difference (M‐H, Random, 95% CI) | 0.08 [‐0.08, 0.24] |
| 7 Calcium‐phosphorus product > 7.5 mg²/dL² Show forest plot | 1 | Risk Difference (M‐H, Random, 95% CI) | Totals not selected | |
| 8 Phosphorus > 6.5 mg/dL Show forest plot | 1 | Risk Difference (M‐H, Random, 95% CI) | Totals not selected | |
| 9 Change in biochemical values Show forest plot | 2 | Mean Difference (IV, Random, 95% CI) | Subtotals only | |
| 9.1 Calcium [mg/dL] | 2 | 76 | Mean Difference (IV, Random, 95% CI) | 0.10 [‐0.45, 0.65] |
| 9.2 Calcium‐phosphorus product [mg2/dL2] | 2 | 76 | Mean Difference (IV, Random, 95% CI) | 0.45 [‐7.94, 8.83] |
| 9.3 Phosphorus [mg/dL] | 2 | 76 | Mean Difference (IV, Random, 95% CI) | ‐0.01 [‐0.66, 0.63] |
| 9.4 Bone ALP [µg/L] | 1 | 41 | Mean Difference (IV, Random, 95% CI) | ‐47.7 [‐88.54, ‐6.86] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Height velocity ≥ expected Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 2 Improved bone histology Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 3 PTH Show forest plot | 1 | Mean Difference (IV, Random, 95% CI) | Totals not selected | |
| 4 Hypercalcaemia Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 5 Biochemical values Show forest plot | 1 | Mean Difference (IV, Random, 95% CI) | Totals not selected | |
| 5.1 Calcium [mmol/L] | 1 | Mean Difference (IV, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 5.2 Phosphorus [mmol/L] | 1 | Mean Difference (IV, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 5.3 ALP [U/L] | 1 | Mean Difference (IV, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Number developing hyperparathyroidism Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 2 PTH Show forest plot | 1 | Mean Difference (IV, Random, 95% CI) | Totals not selected | |
| 3 Calcium Show forest plot | 2 | 60 | Mean Difference (IV, Random, 95% CI) | 0.26 [‐0.28, 0.81] |
| 4 Phosphorus Show forest plot | 2 | 60 | Mean Difference (IV, Random, 95% CI) | ‐0.29 [‐0.96, 0.39] |
| 5 End 1.25(OH)D3 levels Show forest plot | 1 | Mean Difference (IV, Random, 95% CI) | Totals not selected | |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Height SDS Show forest plot | 1 | Mean Difference (IV, Random, 95% CI) | Totals not selected | |
| 2 Abnormal bone biopsy Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 3 Bone aluminium Show forest plot | 1 | Mean Difference (IV, Random, 95% CI) | Totals not selected | |
| 4 PTH Show forest plot | 1 | Mean Difference (IV, Random, 95% CI) | Totals not selected | |
| 5 ALP Show forest plot | 1 | Mean Difference (IV, Random, 95% CI) | Totals not selected | |
| 6 Hypercalcaemia Show forest plot | 1 | Risk Difference (M‐H, Random, 95% CI) | Totals not selected | |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 PTH Show forest plot | 2 | 48 | Mean Difference (IV, Random, 95% CI) | 51.92 [‐77.53, 181.36] |
| 2 ALP Show forest plot | 2 | 48 | Mean Difference (IV, Random, 95% CI) | 90.48 [‐139.38, 320.35] |
| 3 Calcium‐phosphorus product Show forest plot | 2 | 48 | Mean Difference (IV, Random, 95% CI) | ‐1.12 [‐5.88, 3.64] |
| 4 Calcium Show forest plot | 2 | 48 | Mean Difference (IV, Random, 95% CI) | ‐0.40 [‐1.16, 0.36] |
| 5 Phosphorus Show forest plot | 2 | 48 | Mean Difference (IV, Random, 95% CI) | 0.17 [‐0.37, 0.71] |
| 6 Bone histomorphometry Show forest plot | 1 | Mean Difference (IV, Random, 95% CI) | Totals not selected | |
| 6.1 Bone formation rate [µm3/mm2/d] | 1 | Mean Difference (IV, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 6.2 Fall in bone formation rate [%] | 1 | Mean Difference (IV, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 6.3 Eroded perimeter [%] | 1 | Mean Difference (IV, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 6.4 Osteoid area [%] | 1 | Mean Difference (IV, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 6.5 Osteoid perimeter [%] | 1 | Mean Difference (IV, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 6.6 Osteoid seam width [µm] | 1 | Mean Difference (IV, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 6.7 Bone area [%] | 1 | Mean Difference (IV, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Bone histomorphometry Show forest plot | 2 | Mean Difference (IV, Random, 95% CI) | Subtotals only | |
| 1.1 Bone formation rate [µm3/µm2/d] | 2 | 51 | Mean Difference (IV, Random, 95% CI) | 10.29 [‐53.07, 73.65] |
| 1.2 Eroded bone surface [%] | 2 | 51 | Mean Difference (IV, Random, 95% CI) | 0.76 [‐6.19, 7.71] |
| 1.3 Osteoid volume [%] | 2 | 51 | Mean Difference (IV, Random, 95% CI) | ‐0.16 [‐9.16, 8.83] |
| 1.4 Osteoid surface [%] | 2 | 51 | Mean Difference (IV, Random, 95% CI) | 1.04 [‐29.63, 31.71] |
| 1.5 Osteoid maturation time [days] | 2 | 51 | Mean Difference (IV, Random, 95% CI) | 0.82 [‐14.41, 16.05] |
| 1.6 Bone volume [%] | 2 | 51 | Mean Difference (IV, Random, 95% CI) | 2.19 [‐9.52, 13.91] |
