Clinical Kidney Journal, 2021, vol. 14, no. 10, 2177–2186 doi: 10.1093/ckj/sfab035 Advance Access Publication Date: 5 February 2021 Original Article Clinical Kidney Journal Downloaded from https://academic.oup.com/ckj/article/14/10/2177/6129095 by Fundacio Biblioteca Josep Laporte user on 22 December 2022 ORIGINAL ARTICLE Impact of nutritional vitamin D supplementation on parathyroid hormone and 25-hydroxyvitamin D levels in non-dialysis chronic kidney disease: a meta-analysis Jordi Bover1, Joel Gunnarsson2, Philipp Csomor3, Edelgard Kaiser3, Giuseppe Cianciolo4 and Rosa Lauppe2 1 Fundació Puigvert, Servicio de Nefrologı́a, IIB Sant Pau, REDinREN, Barcelona, Spain, 2Quantify Research, Stockholm, Sweden, 3Vifor Pharma, Glattbrugg, Switzerland and 4Nephrology Dialysis and Kidney Transplantation Unit, IRCCS, Azienda Ospedaliero-Universitaria di Bologna, S. Orsola Malpighi Hospital, Bologna, Italy Correspondence to: Joel Gunnarsson; E-mail: joel.gunnarsson@quantifyresearch.com ABSTRACT Background. Secondary hyperparathyroidism (SHPT) is a common and major complication in chronic kidney disease (CKD), reflecting the increase of parathyroid hormone (PTH) in response to reduced vitamin D signalling and hypocalcaemia. This meta-analysis evaluated the impact of nutritional vitamin D (NVD) (cholecalciferol or ergocalciferol) on SHPT-related biomarkers. Methods. A systematic literature search was performed in PubMed to identify relevant randomized control trials to be included in the meta-analysis. Fixed- and random-effects models were used to pool study-level results. Effects were studied within NVD study arms and relative to control groups (placebo/no treatment); the former in order to identify the effect of actively altering biomarkers levels. Results. Reductions in PTH from supplementation with NVD were small when observed within the NVD study arms (pooled reduction: 10.5 pg/mL) and larger when compared with placebo/no treatment (pooled reduction: 49.7 pg/mL). NVD supplementation increased levels of 25-hydroxyvitamin D [25(OH)D] in both analyses (increase within NVD study arm: 20.6 ng/mL, increase versus placebo/no treatment: 26.9 ng/mL). While small and statistically non-significant changes in phosphate and fibroblast growth factor 23 were observed, NVD supplementation caused calcium levels to increase when compared with placebo/no treatment (increase: 0.23 mg/dL). Conclusions. Our results suggest that supplementation with NVD can be used to increase 25(OH)D to a certain extent, while the potential of NVD to actively reduce PTH in non-dialysis-CKD patients with SHPT is limited. Received: 8.9.2020; Editorial decision: 11.01.2021 C The Author(s) 2021. Published by Oxford University Press on behalf of ERA-EDTA. V This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/ licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com 2177 2178 | J. Bover et al. Keywords: meta-analysis, non-dialysis chronic kidney disease, PTH, secondary hyperparathyroidism, vitamin D supplementation INTRODUCTION locally to the vitamin D receptor [15]. However, it is unknown whether the level of 1a-hydroxylase activity in parathyroid Secondary hyperparathyroidism (SHPT) is a common and major glands is able to produce adequate amounts of 1,25(OH)2D to af- complication in chronic kidney disease (CKD), and is frequent in Downloaded from https://academic.oup.com/ckj/article/14/10/2177/6129095 by Fundacio Biblioteca Josep Laporte user on 22 December 2022 fect PTH secretion. both patients with non-dialysis CKD (ND-CKD) and patients New evidence suggests that the increases in 25(OH)D levels requiring dialysis [1, 2]. SHPT is characterized by the increase of able to induce meaningful reductions in PTH in ND-CKD are parathyroid hormone (PTH) in response to reduced vitamin D higher than previously thought. In a secondary analysis of two signalling and hypocalcaemia induced by phosphate retention large randomized controlled trials (RCTs), Strugnell et al. [16] and/or fibroblast growth factor 23 (FGF23) increase as a conse- identified a 50.8 ng/mL threshold of 25(OH)D for significant PTH quence of decreasing kidney function. Prolonged parathyroid reductions while observing that gradual elevation of 25(OH)D to gland stimulation leads to parathyroid hyperplasia with a pro- 92.5 ng/mL was not associated with significant adverse changes gressive decrease in number and sensitivity of the vitamin D, in safety parameters. In a large sampled cross-sectional study, calcium-sensing and FGF23 receptors, ultimately resulting in se- Ennis et al. [17] found indications that optimal levels of 25(OH)D vere and uncontrolled SHPT. If left untreated, SHPT can cause were in a similar range. bone and cardiovascular disease and result in increased rates of A recent study indicates that the potential of NVD supple- fractures, vascular calcification, morbidity and mortality in CKD mentation to lower high PTH may be limited in CKD patients patients [3–5]. SHPT has also been associated with a faster CKD [18]. The authors found that PTH reductions in patients receiv- progression [5]. ing supplementation with cholecalciferol were minor, but that The mainstays of early treatment of SHPT are the reduction these reductions appeared substantial when compared with the of PTH by limiting phosphate load and an increase in vitamin D, placebo group, in which PTH levels increased over the study while at the same time trying to avoid adverse changes in period. parameters such as calcium, phosphate and FGF23. Phosphate In this analysis, we re-assess the topic of NVD supplementa- load and low levels of calcifediol [25-hydroxyvitamin D, hereaf- tion to target SHPT in ND-CKD by synthesizing results from the ter 25(OH)D] and calcitriol [1,25-dihydroxyvitamin D, hereafter growing body of evidence from RCTs using meta-analytic meth- 1,25(OH)2D] are considered critical factors in the onset and pro- ods. Specifically, the objective of this analysis was to investigate gression of SHPT [1, 6] and the prevalence of vitamin D insuffi- the effectiveness of NVD supplementation to actively lower PTH ciency or deficiency is higher among patients with kidney and raise vitamin D in ND-CKD patients with elevated PTH lev- disease compared with the general population [7–9]. els. To be able to distinguish between an actual decrease of PTH 25(OH)D is hydroxylated to 1,25(OH)2D by the enzyme 1a-hy- and relative lower levels we measured the effects of NVD sup- droxylase (CYP27B1) in several tissues in addition to the kidney. plementation on PTH and 25(OH)D in two ways: as changes be- The 1,25(OH)2D synthesized in extrarenal tissues mainly per- fore versus after NVD supplementation limited to the patients forms autocrine or paracrine cell-specific roles. Furthermore, that received NVD (without comparison with a control group) in contrast to that originating from the kidney, extrarenal pro- and as changes in biomarker levels compared with control duction of 1,25(OH)2D does not significantly contribute to the groups comprising placebo or untreated patients. circulating pool of 1,25(OH)2D [6, 8–10]. Secondary objectives included investigating the ability of To address deficiency of vitamin D in the CKD population, NVD to raise levels of 25(OH)D above clinically meaningful existing clinical guidelines recommend supplementation with thresholds and evaluating the effects of supplementation with nutritional vitamin D (NVD), i.e. cholecalciferol or ergocalciferol, NVD on the safety-related biomarkers calcium, phosphate and although clinical benefits from such supplementation have not FGF23. been verified, especially in patients with ND-CKD for the treat- ment of e.g. SHPT [11, 12]. At the same time, routine use of ac- tive vitamin D and active vitamin D analogues is no longer MATERIALS AND METHODS recommended in earlier stages of CKD after having been shown Study selection and data extraction to increase calcium, phosphate and FGF23, and increase the risk of hypercalcaemia in recent trials [11, 13, 14]. Instead, these To identify articles for inclusion in the meta-analysis, a system- agents should be reserved for severe and progressive SHPT in atic literature review was conducted in PubMed according to CKD Stages 4–5 [11]. Preferred Reporting Items for Systematic reviews and Meta- Definition of an effective treatment strategy of SHPT in ND- Analyses (PRISMA) guidelines [19]. A publication was included CKD, starting from NVD, is further complicated by several fac- in the meta-analysis if it presented results from an RCT that tors: (i) there is no consensus on vitamin D status assessment evaluated one or both of the NVD supplements ergocalciferol and what constitutes adequate or toxic levels of vitamin D in and cholecalciferol, and had a study population of at least 20 ND-CKD patients; (ii) there is no agreement about target levels adult (18þ years) patients with documented ND-CKD. All stages of PTH in ND-CKD; and (iii) the interrelationship between PTH of the study selection and data extraction were performed inde- and vitamin D is not fully understood [11, 12]. pendently by two reviewers. The pathways involved in the PTH-lowering effect of NVD The main results extracted from the included studies supplementation are unclear. Parathyroid glands have been were changes in absolute values of the biomarkers PTH, shown to express 1a-hydroxylase, so suggesting a possible auto- 25(OH)D, calcium, phosphate and FGF23 from start to end of the crine mechanism where circulating 25(OH)D can be converted study periods for the patient groups in the study. We contacted to 1,25(OH)2D within parathyroid cells which in turn binds authors of publications where results were reported as median Meta-analysis of vitamin D supplementation | 2179 and interquartile ranges (IQRs) to obtain corresponding mean Of the 14 studies, 7 included a placebo group [18, 21, 24–28] and standard deviations (SDs). Still, median results for PTH and two included a control group receiving no treatment [29, from two publications had to be used [20, 21]. The IQRs reported 30]. The five remaining studies [20, 31–34] included only study in these publications were converted to SDs by dividing the arms that received an active intervention, and no study arms range of the IQRs by 1.35 [22]. receiving placebo-treatment or no treatment. Thus, they were excluded from the analyses where the outcome was compared with placebo/no treatment. One study [25] reported all results Outcomes as geometric means. Only median values were available for PTH Downloaded from https://academic.oup.com/ckj/article/14/10/2177/6129095 by Fundacio Biblioteca Josep Laporte user on 22 December 2022 The main treatment outcomes in this study were changes in ab- in two studies [20, 21]. Table 1 presents characteristics for the solute values of the biomarkers PTH and 25(OH)D. included studies and patient groups. Treatment outcomes were measured in two different ways. First, the outcomes were measured as the change in biomarker Quality of evidence values from baseline to end of study within the study arm re- ceiving NVD (‘difference within the NVD study arm’). When The outcome of changes in PTH within the NVD study arms was expressed this way, biomarker changes in control groups did assessed to be of moderate quality, due to the large number of not have an influence on the results, aiming to capture the po- studies available for inclusion and moderate levels of heteroge- tential of NVD to actively increase or decrease the biomarkers in neity in the study level results. The two outcomes of change in patients receiving supplementation. Second, the outcomes PTH versus placebo/no treatment and the outcome of change in were measured as the difference in biomarker values at base- 25(OH)D within the NVD study arms were assessed to be of low quality, given a moderate number of available studies and sub- line and end of the study in the study arms receiving NVD rela- stantial amounts of heterogeneity in the study level results, re- tive to the study arms receiving placebo treatment or no spectively. Finally, the outcome of changes in 25(OH)D versus treatment (‘difference versus placebo/no treatment’). When de- placebo/no treatment was evaluated to be of very low quality fined this way, changes in biomarker levels in both the NVD because of the moderate number of articles available for inclu- study arms and the placebo/no treatment arms contributed to sion and the substantial levels of heterogeneity in study-level the measured effect. results. Funnel plots for the four outcomes are shown in The ability of NVD to raise levels of 25(OH)D above certain Supplementary data, Figure S1 in the Supplementary Materials. thresholds was assessed using the end-of-study 25(OH)D levels in the NVD study arms. Values for PTH and FGF23 were transformed to picograms Results on PTH per millilitre (pg/mL), 25(OH)D to nanograms per millilitre (ng/ When estimated as the difference from baseline to end of study mL), and calcium and phosphate to milligrams per decilitre within the NVD study arm, the pooled difference in PTH in the (mg/dL). NVD study arms was 10.5 pg/mL [95% confidence interval (CI) 16.3 to 4.7] from the fixed-effects model and 12.8 pg/mL Quality of evidence (95% CI 21.5 to 4.1) from the random-effects model (Figure 2). When instead compared versus placebo/no treatment, the The quality of the evidence for the outcomes on PTH and pooled difference in PTH was larger: 49.7 pg/mL (95% CI 70.2 25(OH)D was assessed to be of high, moderate, low or very low to 29.3) from the fixed-effects model and 52.4 pg/mL (95% CI quality using the methodology of the Grades of 85.3 to 19.6) from the random-effects model (Figure 3). Recommendation, Assessment, Development and Evaluation (GRADE) Working Group [23]. Results on 25(OH)D The pooled increase in 25(OH)D in within the NVD-study arms Statistical analysis was 20.6 ng/mL (95% CI 19.6–21.7) from the fixed-effects model Fixed- and random-effects models were used to combine study- and 25.8 ng/mL (95% CI 20.3–31.4) from the random-effects level results into overall, pooled effects. Inverse variance model (Figure 4). The pooled increases in 25(OH)D were similar weighting was applied in the fixed-effects model and the when compared versus placebo/no treatment, with a pooled in- weighting of study level results in the random-effects model crease of 26.8 ng/mL (95% CI 24.4–29.3) from the fixed-effects was based on the DerSimonian and Laird method. model and 27.8 ng/mL (95% CI 18.1–37.4) from the random- Sensitivity analyses were performed where studies with a effects model (Figure 5). When compared with placebo/no treat- high assessed risk of bias and publications reporting results ment, the sizes of study level results on 25(OH)D varied consid- other than mean measures were excluded. Meta-regressions us- erably, ranging from 8.9 ng/mL [30] to 55.4 ng/mL [28]. At the end ing variables related to patient and study characteristics were of the study periods, the average levels of 25(OH)D in the NVD performed to explore possible sources of heterogeneity in the study arms was >30 ng/mL in all but two studies [30, 34] and results. All analyses were performed in Stata version 16. >50 ng/mL in five of the included studies [18, 21, 28, 29, 31] (Supplementary data, Table S1 in the Supplementary Materials). RESULTS Sensitivity analyses and meta-regressions Study selection and patient characteristics Sensitivity analyses that excluded publications with a high The initial search was conducted on 3 January 2019 and yielded assessed risk of bias and publications reporting non-mean a total of 952 hits. Fourteen of the identified studies fulfilled the results (median or geometric mean) showed similar results as inclusion criteria and evaluated at least one NVD, and were for the main analyses (Supplementary data, Figures S2–S5). hence included in the meta-analysis. Figure 1 shows the step- Meta-regression indicated that PTH reductions are larger wise identification of publications for the meta-analysis. in studies where baseline values of 25(OH)D are lower, with a 2180 | J. Bover et al. 952 articles identified and screened 885 articles excluded 67 full-text articles Downloaded from https://academic.oup.com/ckj/article/14/10/2177/6129095 by Fundacio Biblioteca Josep Laporte user on 22 December 2022 assessed for eligibility 23 full-text articles excluded: Selection process of the • Relevant results from trial reported in systematic literature review other articles (n = 12) • Insufficiently large patient group (n = 4) • Non-relevant patient group (n = 4) • No relevant results reported (n = 3) 44 articles included in systematic literature review 30 articles excluded that did not evaluate NVD 14 articles that evaluated NVD Articles utilized in meta-analysis 9 articles included in 14 articles included in analyses of changes analyses of changes versus placebo/no within the NVD study treatment arms FIGURE 1: Study selection. 1 ng/mL increase in baseline 25(OH)D corresponding with an when compared with changes in study arms receiving placebo approximate 1.9 pg/mL lower reduction in PTH (Panel b of treatment or no treatment, as PTH in the comparison groups of- Supplementary data, Figure S6; P ¼ 0.035). Meta-regressions us- ten increased further. This indicates that NVD might be effec- ing the other covariates mean age, percent of female partici- tive in preventing further increases in PTH but less effective in pants, baseline values of eGFR, baseline values of PTH, assessed reducing PTH in patients with significantly increased levels. risk of bias and study length yielded no definite conclusion as to Supplementation with cholecalciferol and ergocalciferol whether any of these characteristics explain the heterogeneity raised levels of 25(OH)D in all analyses, but large variations in found in the study level results (Supplementary data, Figures S6 the sizes of the study level effects make precise gauging of a and S7). true overall effect size difficult. Analyses of end-of-study values of 25(OH)D indicate that NVD can likely be used to raise 25(OH)D >30 ng/mL, while there is limited potential to raise 25(OH)D Results on calcium, phosphate and FGF23 above the approximate threshold of 50 ng/mL, which might be Supplementation with NVD significantly increased levels of cal- necessary for clinically meaningful PTH responses in CKD cium versus placebo/no treatment, with a pooled increase of patients as suggested by Strugnell et al. [16] and Ennis et al. [17]. 0.23 mg/dL (95% CI 0.12–0.34 mg/dL) from the fixed-effects Indeed, there are studies showing that increasing 25(OH)D model and 0.24 mg/dL (95% CI 0.08–0.40 mg/dL) from the levels above such thresholds can be achieved by providing calci- random-effects model (Supplementary data, Figure S8). Versus fediol in a slow and gradual manner, which can be achieved placebo/no treatment, there were no statistically significant with an extended-release formulation of calcifediol (ERC). ERC effects found on levels of phosphate or FGF23 (Supplementary is indicated for the treatment of SHPT in CKD Stages 3 and 4 data, Figures S9 and S10) from supplementation with NVD. patients and vitamin D insufficiency or deficiency and has been Incidence rates of hypercalcaemia and hyperphosphataemia shown to gradually raise serum 25(OH)D, resulting in progres- were rarely reported in the included publications and were low sive but physiologically controlled increases in serum levels of when reported. 1,25(OH)2D and sustained reductions in PTH levels without signs of any clinically relevant increases in serum phosphate and calcium [11, 16, 35]. DISCUSSION Additional analyses showed statistically significant We performed a meta-analysis on the effects of supplementa- increases in calcium from supplementation with NVD versus tion with NVD on several biomarkers in patients with ND-CKD, placebo/no treatment. The observed effects on phosphate using evidence identified in a systematic review of RCTs. The and FGF23 were minimal and incidences of hypercalcaemia results showed that supplementation with the NVD cholecalcif- and hyperphosphataemia were very low, corroborating the erol and ergocalciferol caused only marginal PTH reductions in findings of limited toxicity from high levels of 25(OH)D in the NVD study arms. Differences in PTH were more pronounced Strugnell et al. [16]. Table 1. Selected studies and patient characteristics Baseline eGFR Baseline Baseline Study Risk of Number of Percentage (mL/min/ PTH 25(OH)D References length bias Study arms Dose patients Age (years) of female 1.73 m2) (pg/mL) (ng/mL) Panel A: Studies comparing NVD versus placebo or no treatment (used in analyses of change versus placebo/no treatment and in analyses of changes in NVD study arms) Alvarez et al. 52 weeks Moderate Cholecalciferol 50 000 IU/week first 12 weeks, 50 000 IU/ 22 63.2 9.1 62.5 89.1 26.7 [24] every other week rest of study (approximate average weekly dose of 30 800 IU) Placebo NA 24 62.6 8.3 61.2 78.2 32.1 Chandra et al. 12 weeks High Cholecalciferol 50 000 IU/week 17 62.2 60 33.3 288.9a 17.3a [25] Placebo NA 17 59.5 60 29.8 290.5a 18.6a Dogan et al. 4 weeks High Cholecalciferol 300 000 IU/month (only one treatment) 20 51 18 36.3 368 8.5f [30] (approximate average weekly dose of 75 000 IU) No treatment NA 20 47 18 34.6 273 6.8f Dreyer et al. 26 weeks High Ergocalciferol 50 000 IU/week first month, 50 000 IU/ 20 45.8 39.1 33 102.8 NA [26] month remaining 5 months (approximate average weekly dose of 18 300 IU) Placebo NA 18 48.8 26.3 38.7 118.9 NA Gravesen et al. 6 weeks High Ergocalciferol 50 000 IU/week 26 NA NA 20.1 180.1 25 [29] No treatment NA 17 NA NA 20.9 166.252 23.72 Kumar et al. 16 weeks Moderate Cholecalciferol 300 000 IU/month (only two treatments) 60 43.2 29 35.8 139b 13.4 [27] (approximate average weekly dose of 75 000 IU) Placebo NA 60 45.2 32 34.6 146b 13.2 Marckmann 8 weeks Moderate Cholecalciferol 40 000 IU/week 13 71b,c 27b,c 32b,c 79.2b 15.7b et al. [28]d Placebo NA 12 68b,c 23b,c 29b,c 119.8b 11.4b Petchey et al. 26 weeks Moderate Cholecalciferol 2000 IU/day (approximate average weekly 13 65 46 39 84.9b 38 [21] dose of 14 000 IU) Placebo NA 15 67 13 41 103.7b 35.2 Westerberg 12 weeks Low Cholecalciferol 8000 IU/day (approximate average weekly 48 62.6 44 32 102.8 23 et al. [18] dose of 56 000 IU) Placebo NA 49 64 20 29.5 123.5 22.7 Summary Approximate average weekly dose 471 52.5 32.9 35.7 158.7 20.7 Panel A: 45 448 IU (sum) (average) (average) (average) (average) (average) Panel B: Studies investigating an NVD compared with another NVD or a non-relevant comparator (used only in analysis of changes in NVD study arms) Kendrick et al. 26 weeks Very low Cholecalciferol 4000 IU/day first month, 2000 IU/day 64 58 30 33.5 99.5c 23 Meta-analysis of vitamin D supplementation [20] remaining 5 months (approximate | average weekly dose of 16 200 IU) Calcitriole 0.25 lg/day first month, 0.5 lg/day months 64 59 36 32.8 93.8c 21.7 2–6 (if no episode of hypercalcaemia) 2181 (continued) Downloaded from https://academic.oup.com/ckj/article/14/10/2177/6129095 by Fundacio Biblioteca Josep Laporte user on 22 December 2022 2182 Table 1. (continued) Baseline eGFR Baseline Baseline | J. Bover et al. Study Risk of Number of Percentage (mL/min/ PTH 25(OH)D References length bias Study arms Dose patients Age (years) of female 1.73 m2) (pg/mL) (ng/mL) Kovesdy et al. 16 weeks Moderate Ergocalciferol Dosed according to baseline 25(OH)D lev- 40 67.6 0 30.9 175 17.2 (2012) [34] els (as recommended by KDOQI) (aver- age weekly dose not available) Paricalcitole 1 lg/day 40 69.3 2 32.1 168 16.3 Moe et al. [33] 13 weeks High Cholecalciferol 4000 IU/day first month, 2000 IU/day 22 62 54 29.6 109 14 remaining months (approximate average weekly dose of 18 300 IU) Doxercalciferole 0.5 lg/day 25 65 36 36.4 106 15.1 Wetmore et al. 12 weeks Moderate Ergocalciferol 50 000 IU/week 22 59.4 47.6 37.5 149 20.5 [31] Cholecalciferol 50 000 IU/week 22 56.7 65 42.5 76.6 20.9 Zhang et al. Mean Moderate Ergocalciferol 50 000 IU/week first 3 months, maintained 104 57.4 28.8 41.6 109.7 15.14 [32] follow-up at 50 000 IU/month according to 144 weeks 25(OH)D levels (approximate average weekly dose of 50 000 IU) Calcitriole 0.25 lg/day (dose adjusted in response to 100 56.3 34 42.9 89.5 14.9 changes in 25(OH)D, Ca, P and PTH) Summary Approximate average weekly dose 503 (sum) 61.1 32.4 36.0 117.6 17.9 Panel B: 33 615 IU (average) (average) (average) (average) (average) Summary all Approximate average weekly dose 974 (sum) 55.8 32.7 35.8 144.0 19.6 studies: 41 807 IU (average) (average) (average) (average) (average) a Numbers refer to geometric mean value. b Numbers refer to median values. c Numbers include measures for the full population of both dialysis and ND patients included in the study. d In the publication by Marckmann et al., only median value changes are reported, however, mean value changes for both PTH and 25(OH)D were obtained from the authors via e-mail, and as such, the results presented in the Results sections below refer to mean values and not median values. e The values from these comparator arms will not be used in any of the analyses performed in this meta-analysis. f In the publication by Dogan et al., values are reported as pg/mL of calcidiol. No change in the estimated values or conversion of units has been made for these values in any of the analyses performed on 25(OH)D. NA, not applicable; KDOQI, Kidney Disease Outcomes Quality Initiative; Ca, calcium; P, phosphorus. Downloaded from https://academic.oup.com/ckj/article/14/10/2177/6129095 by Fundacio Biblioteca Josep Laporte user on 22 December 2022 Meta-analysis of vitamin D supplementation | 2183 Author (year) ES (95% CI) % weight (I–V) Cholecalciferol Alvarez (2012) –13.70 (–33.02, 5.62) 9.02 Chandra (2008) –88.40 (–200.30, 23.50) 0.27 Dogan (2008) –89.00 (–203.18, 25.18) 0.26 Kendrick (2017) 3.00 (–12.95, 18.95) 13.24 Kumar (2017) –53.37 (–81.89, –24.85) 4.14 Marckmann (2012) –43.38 (–70.03, –16.72) 4.74 Downloaded from https://academic.oup.com/ckj/article/14/10/2177/6129095 by Fundacio Biblioteca Josep Laporte user on 22 December 2022 Moe (2010) –12.00 (–33.16, 9.16) 7.52 Petchey (2013) 9.43 (–33.16, 52.02) 1.86 Westerberg (2018) –3.77 (–18.38, 10.84) 15.77 Wetmore (2016) –15.30 (–29.72, –0.88) 16.20 I–V subtotal (I2 = 60.4%, p = 0.007) –12.84 (–19.63, –6.05) 73.02 D+L subtotal –16.88 (–29.15, –4.60) Ergocalciferol Dreyer (2014) –5.60 (–41.83, 30.63) 2.57 Gravesen (2013) –12.26 (–63.25, 38.73) 1.30 Kovesdy (2012) –9.00 (–38.37, 20.37) 3.90 Wetmore (2016) 2.30 (–13.70, 18.30) 13.15 Zhang (2016) –13.20 (–36.75, 10.35) 6.07 I–V subtotal (I2 = 0.0%, p = 0.844) –4.27 (–15.44, 6.90) 26.98 D+L subtotal –4.27 (–15.44, 6.90) Heterogeneity between groups: p = 0.199 I–V overall (I2 = 45.6%, p = 0.028) –10.53 (–16.33, –4.72) 100.00 D+L overall –12.78 (–21.50, –4.07) –203 0 203 FIGURE 2: Changes in PTH (pg/mL) from baseline to end of study in the NVD study arms. ES, effect size. Author (year) Comparator WMD (95% CI) % weight (I–V) Cholecalciferol Chandra (2008) Placebo –67.60 (–238.20, 103.00) 1.43 Dogan (2008) No treatment –104.00 (–251.97, 43.97) 1.91 Kumar (2017) Placebo –100.73 (–150.17, –51.29) 17.08 Marckmann (2012) Placebo –103.73 (–155.42, –52.04) 15.63 Petchey (2013) Placebo 0.00 (–78.63, 78.63) 6.75 Westerberg (2018) Placebo –23.58 (–56.28, 9.13) 39.03 I–V subtotal (I2 = 60.2%, p = 0.028) –55.69 (–78.27, –33.10) 81.83 D+L subtotal –62.97 (–105.89, –20.05) Ergocalciferol Dreyer (2014) Placebo –22.50 (–84.81, 39.81) 10.75 Gravesen (2013) No treatment –23.58 (–98.59, 51.44) 7.42 I–V subtotal (I2 = 0.0%, p = 0.983) –22.94 (–70.87, 24.99) 18.17 D+L subtotal –22.94 (–70.87, 24.99) Heterogeneity between groups: p = 0.226 I–V overall (I2 = 50.1%, p = 0.051) –49.74 (–70.17, –29.30) 100.00 D+L overall –52.43 (–85.30, –19.55) -252 0 252 FIGURE 3: Changes in PTH (pg/mL) from NVD supplementation versus placebo/no treatment. WMD, weighted mean difference. Previous meta-analyses on vitamin D supplementation in et al. [35] included six observational studies and two RCTs that CKD were not planned to study solely ND-CKD patients and reported results for patients with ND-CKD. The pooled results lacked sufficient statistical power from RCTs to draw any strong from the observational evidence in patients with ND-CKD show conclusions for the cohort of patients with ND-CKD. Kandula an increase of 19 ng/mL in 25(OH)D and a 26 pg/mL reduction in 2184 | J. Bover et al. Author (year) ES (95% CI) % weight (I–V) Cholecalciferol Alvarez (2012) 13.60 (7.43, 19.77) 2.81 Chandra (2008) 32.10 (18.69, 45.51) 0.59 Dogan (2008) 9.30 (0.43, 18.17) 1.36 Kendrick (2017) 11.80 (9.51, 14.09) 20.28 Kumar (2017) 24.87 (21.86, 27.89) 11.74 Marckmann (2012) 53.32 (45.47, 61.17) 1.73 Downloaded from https://academic.oup.com/ckj/article/14/10/2177/6129095 by Fundacio Biblioteca Josep Laporte user on 22 December 2022 Moe (2010) 23.20 (19.24, 27.16) 6.80 Petchey (2013) 20.40 (12.70, 28.10) 1.80 Westerberg (2018) 41.64 (36.55, 46.73) 4.12 Wetmore (2016) 45.00 (38.11, 51.89) 2.25 I–V subtotal (I2 = 96.5%, p = 0.000) 21.70 (20.29, 23.12) 53.48 D+L subtotal 27.37 (19.08, 35.67) Ergocalciferol Gravesen (2013) 26.44 (14.13, 38.75) 0.70 Kovesdy (2012) 11.80 (9.15, 14.45) 15.16 Wetmore (2016) 30.70 (24.31, 37.09) 2.61 Zhang (2016) 22.22 (20.27, 24.17) 28.04 I–V subtotal (I2 = 94.3%, p = 0.000) 19.36 (17.85, 20.88) 46.52 D+L subtotal 22.08 (14.07, 30.09) Heterogeneity between groups: p = 0.027 I–V overall (I2 = 95.9%, p = 0.000) 20.62 (19.58, 21.65) 100.00 D+L overall 25.87 (20.30, 31.44) –61.2 0 61.2 FIGURE 4: Changes in 25(OH)D (ng/mL) from baseline to end of study in the NVD study arms, ES, effect size. Author (year) Comparator WMD (95% CI) % weight (I–V) Cholecalciferol Alvarez (2012) Placebo 14.50 (7.21, 21.79) 11.13 Chandra (2008) Placebo 31.20 (16.44, 45.96) 2.71 Dogan (2008) No treatment 8.90 (–0.33, 18.13) 6.94 Kumar (2017) Placebo 23.36 (19.77, 26.96) 45.77 Marckmann (2012) Placebo 55.40 (46.44, 64.36) 7.36 Petchey (2013) Placebo 23.20 (13.17, 33.23) 5.87 Westerberg (2018) Placebo 39.76 (33.94, 45.58) 17.44 I–V Subtotal (I = 93.2%, p = 0.000) 26.89 (24.43, 29.36) 97.22 D+L Subtotal 27.99 (17.48, 38.49) Ergocalciferol Gravesen (2013) No treatment 26.00 (11.43, 40.57) 2.78 I–V Subtotal (I = .%, p = .) 2 26.00 (11.43, 40.57) 2.78 D+L Subtotal 26.00 (11.43, 40.57) Heterogeneity between groups: p = 0.906 I–V Overall (I2 = 92.0%, p = 0.000) 26.87 (24.44, 29.30) 100.00 D+L Overall 27.77 (18.11, 37.42) –64.4 0 64.4 FIGURE 5: Changes in 25(OH)D (ng/mL) from NVD supplementation versus placebo/no treatment. WMD, weighted mean difference. Meta-analysis of vitamin D supplementation | 2185 PTH from supplementation with NVD, while the pooled results potentially incomparable effect estimates distort the overall from the two RCTs comprising ND-CKD patients are not results. reported separately. Additionally, large variations in effect sizes at the study level In a more recent meta-analysis, Agarwal and Georgianos [36] caused moderate to high levels of heterogeneity in all out- identified four RCTs that evaluated vitamin D supplementation comes, thereby making it difficult to draw any conclusions on in ND-CKD. In an erratum to the original article, the authors what the true effect sizes may be. To investigate this heteroge- present statistically significant pooled increases in 25(OH)D neity, meta-regressions were performed using a broad set of ranging from 12 to 21 ng/mL (depending on the model used) and covariates relating patients and study characteristics, but Downloaded from https://academic.oup.com/ckj/article/14/10/2177/6129095 by Fundacio Biblioteca Josep Laporte user on 22 December 2022 statistically significant lowering of PTH when compared with yielded no conclusive results on what underlying characteris- placebo ranging from 62 to 58 pg/mL from supplementation tics may cause the heterogeneous results. As such, uncertainty with NVD. Nonetheless, the substantial heterogeneity in study- regarding the variation in effect sizes remains. Furthermore, in- level effects and the low number of studies and patients in- vestigation of any long-term effects is prohibited by the rela- cluded in the analysis lead the authors to conclude that recom- tively short study durations (average approximate 6 months) in mendations to use NVD in ND-CKD are not justified based on the included studies. Measures of uncertainty are also inherent their evidence. in the biomarker outcomes analysed in this study, e.g. due to While confirming the conclusions that vitamin D supple- seasonal variability and variation over test assays. In particular, mentation can increase levels of 25(OH)D compared with pla- PTH is known to have a wide variance within patients over rela- cebo or no treatment as presented in Kandula et al. [35] and tively short time spans. Therefore, repeated measurements at Agarwal and Georgianos [36], the present meta-analysis pro- the end-of-studies might yield a more reliable effect measure. vides evidence that levels of 25(OH)D tend to increase in To our knowledge, however, the effects of NVD on the bio- patients receiving NVD supplementation, eliminating potential markers are evaluated by a single measurement in the included concerns that previously published results are driven by reduc- studies, which could contribute to the heterogeneity observed tions in 25(OH)D in comparator groups. in the study-level results. Concerning the effects of NVD on levels of PTH, our findings This meta-analysis presents, to the best of our knowledge, indicate statistically significant reductions in PTH from NVD the most comprehensive evidence to date regarding the effects supplementation in all analyses. Nonetheless, our dual analy- ses of effects as compared with placebo/no treatment and of the from supplementation with NVD on the biomarkers PTH and effects in the NVD study arms show that only a small part of the 25(OH)D in ND-CKD patients based on the randomized clinical difference versus placebo/no treatment can be attributed to PTH evidence. Our novel approach of separating the effects com- decreases in patients receiving NVD. The analyses of changes in pared with study arms receiving placebo or no treatment and PTH within the NVD study arms show a statistically significant the effects within the NVD study arms shines a new light on the but low reduction in PTH, which might be of limited benefit for underlying mechanisms of vitamin D supplementation in ND- patients that suffer from elevated levels of PTH or SHPT. The CKD. Our results suggest that supplementation with NVD in benefits from supplementation with NVD on PTH levels may patients with ND-CKD is probably useful in raising low levels of therefore be interpreted as stemming largely from an avoidance 25(OH)D. However, the increase in 25(OH)D levels is often not of further elevations in PTH levels, rather than actively lowering sufficiently large to induce PTH-lowering effects and to mean- PTH. Supplementation with NVD might consequently be of ingfully reduce levels of PTH in patients with SHPT. more use to patients that are early in the development of SHPT, while being limited in efficacy for patients with more advanced SUPPLEMENTARY DATA SHPT and elevated levels of PTH. In a recent study, Westerberg et al. [18] reached a similar conclusion after observing marginal Supplementary data are available at ckj online. PTH reductions from NVD supplementation and increases in PTH in placebo-treated patients. In their study, however, base- CONFLICT OF INTEREST STATEMENT line values of PTH and share of patients in CKD Stage 4 were higher in the placebo arm than in the NVD arm (P-value be- J.G. and R.L. are employees of Quantify Research, P.C. and E.K. tween groups ¼ 0.09 for both PTH and CKD stage distribution), are employees of Vifor Pharma. J.B. reports personal fees from indicating that patients in the placebo-arm had more pro- several pharmaceutical companies. G.C. has nothing to disclose. gressed SHPT at baseline and were prone to additional PTH Medical writing assistance was utilized in this manuscript and increases. Additionally, a meta-regression indicated that PTH was funded by Vifor Fresenius Medical Care Renal Pharma. reductions are larger in studies where baseline values of 25(OH)D are lower, seemingly reflecting a lack of impact from NVD on PTH in patients with less severe vitamin D insuffi- DATA AVAILABILITY STATEMENT ciency. The results from this meta-regression should be inter- The data underlying this article will be shared on reasonable re- preted with some caution, however, as the correlation is driven quest to the corresponding author. to a large degree by two studies with a high risk of bias [25, 30] and two studies with a moderate risk of bias [27, 28]. The present analysis is not without limitations. At the study REFERENCES level, limitations stem from a combination of occasional lack of 1. Cunningham J, Locatelli F, Rodriguez M. Secondary hyper- transparency in study designs, non-blinding of treatment allo- parathyroidism: pathogenesis, disease progression, and cation and non-standard reporting of effects, reducing the reli- therapeutic options. Clin J Am Soc Nephrol 2011; 6: 913–921 ability of the pooled effects. For this reason, sensitivity analyses 2. Scialla JJ, Astor BC, Isakova T et al. Mineral metabolites and were performed using a subset of more comparable and higher- CKD progression in African Americans. J Am Soc Nephrol quality studies, which gave no indication that low-quality and 2013; 24: 125–135 2186 | J. Bover et al. 3. Nigwekar SU, Tamez H, Thadhani RI. Vitamin D and chronic 21. Petchey WG, Hickman IJ, Prins JB et al. Vitamin D does not kidney disease-mineral bone disease (CKD-MBD). Bonekey improve the metabolic health of patients with chronic kid- Rep 2014; 3: 498 ney disease stage 3-4: a randomized controlled trial. 4. Geng S, Kuang Z, Peissig PL et al. Parathyroid hormone inde- Nephrology (Carlton) 2013; 18: 26–35 pendently predicts fracture, vascular events, and death in 22. Higgins JPT, Green S. Cochrane Handbook for Systematic patients with stage 3 and 4 chronic kidney disease. Reviews of Interventions. Hoboken, NJ: Wiley, 2011 Osteoporos Int 2019; 30: 2019–2025 23. Schünemann H , Guyatt G, Oxman A (eds); GRADE Working 5. Schumock GT, Andress DL, Marx SE et al. Association of sec- Group. Handbook for Grading the Quality of Evidence and the Downloaded from https://academic.oup.com/ckj/article/14/10/2177/6129095 by Fundacio Biblioteca Josep Laporte user on 22 December 2022 ondary hyperparathyroidism with CKD progression, health Strength of Recommendations Using the GRADE Approach care costs and survival in diabetic predialysis CKD patients. (updated October 2013). 2013; https://gradepro.org/cite/ Nephron Clin Pract 2009; 113: c54–c61 24. Alvarez JA, Law J, Coakley KE et al. High-dose cholecalciferol 6. Lishmanov A, Dorairajan S, Pak Y et al. Elevated serum para- reduces parathyroid hormone in patients with early chronic thyroid hormone is a cardiovascular risk factor in moderate kidney disease: a pilot, randomized, double-blind, placebo- chronic kidney disease. Int Urol Nephrol 2012; 44: 541–547 controlled trial. Am J Clin Nutr 2012; 96: 672–679 7. Doorenbos CR, van den Born J, Navis G et al. Possible reno- 25. Chandra P, Binongo JNG, Ziegler TR et al. Cholecalciferol (vi- protection by vitamin D in chronic renal disease: beyond tamin D3) therapy and vitamin D insufficiency in patients mineral metabolism. Nat Rev Nephrol 2009; 5: 691–700 with chronic kidney disease: a randomized controlled pilot 8. Holick MF. Vitamin D deficiency. N Engl J Med 2007; 357: study. Endocr Pract 2008; 14: 10–17 266–281 26. Dreyer G, Tucker AT, Harwood SM et al. Ergocalciferol and 9. Jean G, Souberbielle JC, Chazot C. Vitamin D in chronic kid- microcirculatory function in chronic kidney disease and ney disease and dialysis patients. Nutrients 2017; 9: 328 10. Dusso AS, Brown AJ, Slatopolsky E. Vitamin D. Am J Physiol concomitant vitamin d deficiency: an exploratory, double Renal Physiol 2005; 289: F8–F28 blind, randomised controlled trial. PLoS One 2014; 9: e99461 11. Kidney Disease: Improving Global Outcomes (KDIGO). 27. Kumar V, Yadav AK, Lal A et al. A randomized trial of vitamin Clinical Practice Guideline Update for the Diagnosis, Evaluation, D supplementation on vascular function in CKD. J Am Soc Prevention, and Treatment of Chronic Kidney Disease–Mineral and Nephrol 2017; 28: 3100–3108 Bone Disorder (CKD-MBD). Kidney Int Suppl 2017; 7: 1–59 28. Marckmann P, Agerskov H, Thineshkumar S et al. 12. Kidney Disease: Improving Global Outcomes (KDIGO). Randomized controlled trial of cholecalciferol supplementa- KDIGO clinical practice guideline for the diagnosis, evalua- tion in chronic kidney disease patients with hypovitamino- tion, prevention, and treatment of Chronic Kidney Disease- sis D. Nephrol Dial Transplant 2012; 27: 3523–3531 Mineral and Bone Disorder (CKD-MBD). Kidney Int Suppl 2009; 29. Gravesen E, Hofman-Bang J, Lewin E et al. Ergocalciferol 113: S1–S130 treatment and aspects of mineral homeostasis in patients 13. Thadhani R, Appelbaum E, Pritchett Y et al. Vitamin D ther- with chronic kidney disease stage 4–5. Scand J Clin Lab Invest apy and cardiac structure and function in patients with 2013; 73: 107–116 chronic kidney disease: the PRIMO randomized controlled 30. Dogan E, Erkoc R, Sayarlioglu H et al. Effect of depot oral cho- trial. JAMA 2012; 307: 674–684 lecalciferol treatment on secondary hyperparathyroidism in 14. Wang AYM, Fang F, Chan J et al. Effect of paricalcitol on left stage 3 and stage 4 chronic kidney diseases patients. Ren Fail ventricular mass and function in CKD–the OPERA trial. J Am 2008; 30: 407–410 Soc Nephrol 2014; 25: 175–186 31. Wetmore JB, Kimber C, Mahnken JD et al. Cholecalciferol v. 15. Segersten U, Correa P, Hewison M et al. 25-hydroxyvitamin ergocalciferol for 25-hydroxyvitamin D (25(OH)D) repletion D(3)-1alpha-hydroxylase expression in normal and patho- in chronic kidney disease: a randomised clinical trial. Br J logical parathyroid glands. J Clin Endocrinol Metab 2002; 87: Nutr 2016; 116: 2074–2081 2967–2972 32. Zhang D, Li H, Yin D et al. Ergocalciferol versus calcitriol for 16. Strugnell SA, Sprague SM, Ashfaq A et al. Rationale for rais- controlling chronic kidney disease mineral bone disorder in ing current clinical practice guideline target for serum 25- stage 3 to 5 CKD: a randomized controlled trial. Eur J hydroxyvitamin D in chronic kidney disease. Am J Nephrol Pharmacol 2016; 789: 127–133 2019; 49: 284–293 33. Moe SM, Saifullah A, LaClair RE et al. A randomized trial of 17. Ennis JL, Worcester EM, Coe FL et al. Current recommended cholecalciferol versus doxercalciferol for lowering parathy- 25-hydroxyvitamin D targets for chronic kidney disease roid hormone in chronic kidney disease. Clin J Am Soc Nephrol management may be too low. J Nephrol 2016; 29: 63–70 2010; 5: 299–306 18. Westerberg PA, Sterner G, Ljunggren Ö et al. High doses of 34. Kovesdy CP, Lu JL, Malakauskas SM et al. Paricalcitol versus cholecalciferol alleviate the progression of hyperparathy- roidism in patients with CKD Stages 3–4: results of a 12- ergocalciferol for secondary hyperparathyroidism in CKD week double-blind, randomized, controlled study. Nephrol stages 3 and 4: a randomized controlled trial. Am J Kidney Dis Dial Transplant 2018; 33: 466–471 2012; 59: 58–66 19. Moher D, Shamseer L, Clarke M et al.; PRISMA-P Group. 35. Kandula P, Dobre M, Schold JD et al. Vitamin D supplementa- Preferred reporting items for systematic review and meta- tion in chronic kidney disease: a systematic review and analysis protocols (PRISMA-P) 2015 statement. Syst Rev 2015; meta-analysis of observational studies and randomized 4: 1 controlled trials. Clin J Am Soc Nephrol 2011; 6: 50–62 20. Kendrick J, Andrews E, You Z et al. Cholecalciferol, calcitriol, 36. Agarwal R, Georgianos PI. Con: Nutritional vitamin D re- and vascular function in CKD: a randomized, bouble-blind placement in chronic kidney disease and end-stage renal trial. Clin J Am Soc Nephrol 2017; 12: 1438–1446 disease. Nephrol Dial Transplant 2016; 31: 706–713