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Comparison of Paricalcitol and Calcitriol in Dialysis Patients With Secondary Hyperparathyroidism: A Meta-Analysis of Randomized Controlled Studies.
Zhang, T, Ju, H, Chen, H, Wen, W
Therapeutic apheresis and dialysis : official peer-reviewed journal of the International Society for Apheresis, the Japanese Society for Apheresis, the Japanese Society for Dialysis Therapy. 2019;(1):73-79
Abstract
Paricalcitol and calcitriol are widely used for the treatment of secondary hyperparathyroidism in dialysis patients. We conducted a systematic review and meta-analysis to compare the efficacy and safety of paricalcitol and calcitriol for secondary hyperparathyroidism in dialysis patients. PubMed, EMbase, Web of Science, EBSCO, and Cochrane library databases were systematically searched. Randomized controlled trials (RCT) assessing the efficacy of paricalcitol and calcitriol for secondary hyperparathyroidism in dialysis patients are included. Two investigators independently searched articles, extracted data, and assessed the quality of included studies. Meta-analysis was carried out using the random-effect model. Six randomized controlled trials are included in the meta-analysis. Overall, compared with calcitriol treatment for secondary hyperparathyroidism in dialysis patients, paricalcitol treatment has comparable ≥50% reduction of parathyroid hormone (risk ratio [RR] = 1.33; 95% CI = 0.93-1.91; P = 0.12), calcium concentration (standard mean difference [Std. MD] = -0.21; 95% CI = -0.94 to 0.52; P = 0.58), phosphate concentration (Std. MD = -0.17; 95% CI = -0.58 to 0.24; P = 0.42), calcium phosphate (Std. MD = -0.08; 95% CI = -0.49-0.34; P = 0.71), alkaline phosphatase (Std. MD = -0.21; 95% CI = -0.73-0.31; P = 0.43), hypercalcemia (RR = 1.43; 95% CI = 0.51 to 3.98; P = 0.49), adverse events (RR = 0.79; 95% CI = 0.42-1.49; P = 0.47), and serious adverse events (RR = 0.78; 95% CI = 0.47-1.30; P = 0.33). Paricalcitol and calcitriol result in similar ≥50% reduction of parathyroid hormone, calcium concentration, phosphate concentration, calcium phosphate, alkaline phosphatase, hypercalcemia, adverse events, and serious adverse events for secondary hyperparathyroidism in dialysis patients.
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Differential Effects of Oral Boluses of Vitamin D2 vs Vitamin D3 on Vitamin D Metabolism: A Randomized Controlled Trial.
Martineau, AR, Thummel, KE, Wang, Z, Jolliffe, DA, Boucher, BJ, Griffin, SJ, Forouhi, NG, Hitman, GA
The Journal of clinical endocrinology and metabolism. 2019;(12):5831-5839
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Abstract
CONTEXT Vitamin D2 and vitamin D3 have been hypothesized to exert differential effects on vitamin D metabolism. OBJECTIVE To compare the influence of administering vitamin D2 vs vitamin D3 on metabolism of vitamin D3. METHODS We measured baseline and 4-month serum concentrations of vitamin D3, 25-hydroxyvitamin D3 [25(OH)D3], 25-hydroxyvitamin D2, 24R,25-dihydroxyvitamin D3 [24R,25(OH)2D3], 1α,25-dihydroxyvitamin D3 [1α,25(OH)2D3], and 4β,25-dihydroxyvitamin D3 [4β,25(OH)2D3] in 52 adults randomized to receive a total of four oral bolus doses of 2.5 mg vitamin D2 (n = 28) or vitamin D3 (n = 24) over four months. Metabolite-to-parent compound ratios were calculated to estimate hydroxylase activity. Pairwise before vs after comparisons were made to evaluate effects of vitamin D2 and vitamin D3 on metabolism of vitamin D. Mean postsupplementation metabolite-to-parent ratios were then compared between groups. RESULTS Vitamin D2 was less effective than vitamin D3 in elevating total serum 25(OH)D concentration. Vitamin D2 suppressed mean four-month serum concentrations of 25(OH)D3, 24R,25(OH)2D3, 1α,25(OH)2D3, and 4β,25(OH)2D3 and mean ratios of 25(OH)D3 to D3 and 1α,25(OH)2D3 to 25(OH)D3, while increasing the mean ratio of 24R,25(OH)2D3 to 25(OH)D3. Vitamin D3 increased mean four-month serum concentrations of 25(OH)D3, 24R,25(OH)2D3, 1α,25(OH)2D3, and 4β,25(OH)2D3 and the mean ratio of 24R,25(OH)2D3 to 25(OH)D3. Participants receiving vitamin D2 had lower mean postsupplementation ratios of 25(OH)D3 to vitamin D3 and 1α,25(OH)2D3 to 25(OH)D3 than those receiving vitamin D3. Mean postsupplementation ratios of 24R,25(OH)2D3 to 25(OH)D3 and 4β,25(OH)2D3 to 25(OH)D3 did not differ between groups. CONCLUSIONS Bolus-dose vitamin D2 is less effective than bolus-dose vitamin D3 in elevating total serum 25(OH)D concentration. Administration of vitamin D2 reduces 25-hydroxylation of vitamin D3 and 1-α hydroxylation of 25(OH)D3, while increasing 24R-hydroxylation of 25(OH)D3.
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Effect of Treating Vitamin D Deficiency in Uncontrolled Type 2 Diabetes: A Randomized, Placebo-Controlled Study.
Lo, MC, Abushamat, L, Mramba, LK
American journal of therapeutics. 2019;(4):e441-e451
Abstract
BACKGROUND Literature increasingly supports the inverse relationship of vitamin D (VitD) level and type 2 diabetes (T2DM). Proposed protective mechanisms of VitD include its anti-inflammatory effects, increased insulin secretion via pancreatic β-cell stimulation, and downregulation of parathyroid hormone levels. Interventional studies show mixed results of VitD therapy in prediabetic patients with VitD deficiency or diabetic patients with normal VitD levels. STUDY QUESTION Does high-dose VitD replacement improve glycemic control and microalbuminuria (MAU) in uncontrolled T2DM and concurrent VitD deficiency? STUDY DESIGN This placebo-controlled, double-blinded study randomized 30 subjects aged 30-65 years with an elevated HbA1c level of 7.5%-10% and a low total 25-hydroxyvitamin-D value of <20 ng/mL to either placebo (n = 16) or ergocalciferol 50,000 IU (n = 14) once weekly for 8 weeks then once monthly for 4 months. MEASURES AND OUTCOMES Primary outcome was difference in HbA1c from baseline to month 6 between the VitD-intervention group and the placebo-controlled group. Secondary end points were differences in total 25-hydroxyvitamin-D and MAU. Paired t tests and linear mixed-effects models were used for statistical analysis. RESULTS No significant differences were seen in HbA1c or MAU between baseline versus postintervention visits within the placebo group (HbA1c: 8.4% ± 0.2 vs. 8.1% ± 0.3, P = 0.088; MAU: 94.1 mg/g ± 43.9 vs. 45.9 mg/g ± 20.2, P = 0.152) and the intervention group (HbA1c: 8.8% ± 0.3 vs. 8.7% ± 0.4, P = 0.692; MAU: 167.8 mg/g ± 70.1 vs. 108.5 mg/g ± 39.9, P = 0.356). The difference between placebo-slope and intervention-slope was nonsignificant for MAU (β = -0.1 mg/g ± 0.4, P = 0.835) but was significant for total 25-hydroxyvitamin-D (β = 11.7 ng/mL ± 2.5, P ≤ 0.001). Greater HbA1c reduction occurred unexpectedly in the placebo group ((Equation is included in full-text article.)= -0.4% ± 0.2) than in the intervention group ((Equation is included in full-text article.)= -0.2% ± 0.4), although the difference in slopes was not significant (β = 0.2% ± 0.4, P = 0.640). CONCLUSIONS Our proof-of-concept study found no benefit of high-dose VitD therapy in glycemic control and MAU in uncontrolled T2DM and VitD deficiency. Post hoc analyses raise concerns for high-dose VitD therapy to delay glycemic improvement. Large-scale interventional trials are much needed in this patient population to substantiate our findings and elucidate VitD's mechanisms on glucose metabolism.
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Changes in microparticle profiles by vitamin D receptor activation in chronic kidney disease - a randomized trial.
Lundwall, K, Mörtberg, J, Mobarrez, F, Jacobson, SH, Jörneskog, G, Spaak, J
BMC nephrology. 2019;(1):290
Abstract
BACKGROUND Microparticles (MPs) are biomarkers and mediators of disease through their expression of surface receptors, reflecting activation or stress in their parent cells. Endothelial markers, ICAM-1 and VCAM-1, are implicated in atherosclerosis and associated with cardiovascular risk. Chronic kidney disease (CKD) patients have endothelial dysfunction and high levels of endothelial derived MPs. Vitamin D treatment has been reported to ameliorate endothelial function in CKD patients. We aimed to examine cell specific MP profiles and concentrations of MPs expressing the atherosclerotic markers ICAM-1 and VCAM-1 after treatment with paricalcitol in patients with CKD stage 3-4. METHODS Sub-study of the previously reported SOLID trial where 36 patients were randomly assigned to placebo, 1 or 2 μg paricalcitol, for 12 weeks. MPs were measured by flow cytometry after labelling with antibodies against endothelial (CD62E), platelet (CD62P, CD41, CD154) leukocyte (CD45) and vascular (CD54, CD106) markers. RESULTS Patients had a mean age of 65 years with a mean eGFR of 40 mL/min/1.73m2. Concentrations of ICAM-1 positive MPs were significantly reduced by treatment (repeated measures ANOVA p = 0.04). Repeated measures MANOVA of concentrations of endothelial, platelet and leukocyte MPs showed sustained levels in the 2 μg treatment group (p = 0.85) but a decline in the 1 μg (p = 0.04) and placebo groups (p = 0.005). CONCLUSIONS Treatment with paricalcitol reduces concentrations of ICAM-1 positive MPs. This is accompanied by sustained concentrations of all cell specific MPs in the 2 μg group, and decreasing concentrations in the other groups, possibly due to a more healthy and reactive endothelium with paricalcitol treatment.
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Vitamin D receptor activation raises soluble thrombomodulin levels in chronic kidney disease patients: a double blind, randomized trial.
D'arrigo, G, Pizzini, P, Cutrupi, S, Tripepi, R, Tripepi, G, Mallamaci, F, Zoccali, C
Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association. 2019;(5):819-824
Abstract
BACKGROUND Thrombomodulin (TM) is a proteoglycan highly represented in the endothelial glycocalix that regulates the haemostasis and the endothelial response to inflammation. High soluble TM levels underlie a lower risk for coronary heart disease in population studies. Activation of vitamin D receptor (VDR) upregulates TM, but the effect of this intervention on soluble TM has never been tested in chronic kidney disease (CKD) patients. METHODS We performed a post hoc analysis of a 12 weeks double blind, randomized, placebo-controlled trial testing the effect of VDR activation by paricalcitol (PCT) on endothelium-dependent flow-mediated vasodilatation (FMD) in the forearm (ClinicalTrials.gov identifier: NCT01680198). Circulating TM was measured in the whole CKD population [88 patients: PCT n = 44; placebo n = 44] that took part into this trial. RESULTS Soluble TM at baseline was inversely related to the glomerular filtration rate (r = -0.65, P < 0.001) and to FMD (Spearman's ρ = -0.29, P = 0.01). Alongside the expected effects on bone mineral biomarkers, PCT produced a consistent rise (P = 0.005) in TM levels, from a median value of 8446.0 pg/mL [interquartile range (IQR): 6227.8-10 910.8 pg/mL] to 9127.5 pg/mL (6393.0-11 287.3 pg/mL) while placebo had no effect (between-groups difference P = 0.008). TM levels re-approached baseline values 2 weeks after stopping PCT. TM changes across the trial paralleled simultaneous changes in FMD. CONCLUSIONS VDR activation by PCT raises TM levels and FMD and such effects are rapidly reversible after stopping the treatment. The TM rise induced by PCT is a possible mechanism whereby improvement in endothelial function by VDR activation may favourably impact upon vascular health in CKD patients.
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Use of Paricalcitol as Adjunctive Therapy to Renin-Angiotensin-Aldosterone System Inhibition for Diabetic Nephropathy: A Systematic Review of the Literature.
Schuster, A, Al-Makki, A, Shepler, B
Clinical therapeutics. 2019;(11):2416-2423
Abstract
PURPOSE Diabetic nephropathy (DN) is a major complication of diabetes. Paricalcitol is a vitamin D analog that is typically used for secondary hyperparathyroidism in patients with chronic kidney disease but may have some beneficial effect on DN. This review evaluates the effect of paricalcitol in combination with renin-angiotensin-aldosterone system inhibitor therapy in managing DN. METHODS A literature search was conducted of PubMed and ClinicalTrials.gov. Limits were set to include only clinical trials in humans written in English. The search terms used were paricalcitol and diabetic nephropathy. The following outcomes of kidney function and damage as well as adverse drug events were assessed and included: 24-h urine albumin excretion, serum phosphorus and calcium concentrations, urinary albumin excretion rates, estimated glomerular filtration rate, and markers of inflammation and endothelial function. FINDINGS Four studies with a total of 389 patients were identified for review through the process described above. Two of the 6 studies provide evidence of the effect of paricalcitol on DN by way of reduction in urine albumin to creatinine ratio and urinary albumin excretion rate when compared with placebo. One study reported an increase in serum phosphorous, 1 study observed a decrease in estimated glomerular filtration rate, and 1 study reported no effect on inflammatory markers or endothelial function. IMPLICATIONS The number of clinical trials examining the effect of paricalcitol in DN is small. The studies that have been completed enrolled <300 patients. Paricalcitol can reduce protein in the urine, but there is no compelling evidence that it preserves kidney function.
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Feasibility of intervention in elder self-neglecters: Setting the stage for future research.
Lee, JL, Burnett, J, Xia, R, Smith, SM, Dyer, CB
Journal of elder abuse & neglect. 2018;(3):223-235
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Abstract
OBJECTIVES Interventions are critical to improving clinical outcomes in elder self-neglecters. This study assessed feasibility of a randomized controlled trial of oral vitamin D in Adult Protective Services-substantiated self-neglect clients ≥65 years. METHODS Participants were directly observed to consume ergocalciferol 50,000 IU (treatment) or ergocalciferol 400 IU (control), once a month, for 10 months. For months 6-10, half the control group randomly crossed into the treatment group (crossover). Intervention feasibility was measured by number of potential participants who agreed to participate and by retention rates during the study. RESULTS Ninety-four referrals were received and 59 (63%) agreed to participate. Forty-nine participants were enrolled after prescreening and 35 completed the two-phase trial for a 72% retention rate. The participants' average age was 75.2 ± 6.8 years, mainly female (59%), African-American (47%), and living alone (41%). DISCUSSION Despite assumptions that self-neglecters are resistant to care, we have successfully conducted the first clinical intervention in this vulnerable population.
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The effect of vitamin D2 supplementation on muscle strength in early postmenopausal women: a randomized, double-blind, placebo-controlled trial.
Suebthawinkul, C, Panyakhamlerd, K, Yotnuengnit, P, Suwan, A, Chaiyasit, N, Taechakraichana, N
Climacteric : the journal of the International Menopause Society. 2018;(5):491-497
Abstract
BACKGROUND Low serum 25-hydroxyvitamin D [25(OH)D] has been shown to be associated with low muscle mass and loss of muscle strength, resulting in increased disability and frailty in older men and women. Vitamin D deficiency is common in postmenopausal women. The primary objective of the present study was to evaluate the effects of vitamin D supplementation on muscle strength in early postmenopausal women. The effects of vitamin D2 supplementation on muscle mass and muscle cross-sectional area (CSA) were secondarily investigated. METHODS A 12-week, prospective, randomized, double-blind, placebo-controlled trial was conducted in early postmenopausal women (45-60 years old) with vitamin D deficiency (serum 25(OH)D < 20 ng/ml). A total of 88 subjects were randomized into group I: vitamin D2 supplement 40 000 IU/week (n = 44), or group II: placebo (n = 44). Serum 25(OH)D level, muscle strength, muscle mass and muscle CSA were assessed at baseline and 12 weeks after the supplementation. RESULTS After 12 weeks of supplementation, 70% of women in group I achieved a sufficient level of serum 25(OH)D (>30 ng/ml). There were significant differences in changes of serum 25(OH)D levels between the two groups (p < 0.05). Muscle strength and muscle CSA in group I increased significantly after 12 weeks (p = 0.015, 0.045, respectively). However, there were no significant differences in the mean changes of muscle strength, muscle mass and muscle CSA between the two groups (p = 0.16, 0.89, 0.84, respectively). CONCLUSION In this study, we found no obvious effect of vitamin D supplementation on the changes in muscle strength, muscle mass and muscle CSA when compared to placebo. However, there were significant changes in muscle strength and muscle CSA from baseline in the vitamin D supplementation group.
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Effect of one time high dose "stoss therapy" of vitamin D on glucose homeostasis in high risk obese adolescents.
Brar, PC, Contreras, M, Fan, X, Visavachaipan, N
Archives of endocrinology and metabolism. 2018;(2):193-200
Abstract
OBJECTIVE To study the effect of using a one time high dose "stoss therapy" of vitamin D2 (ergocalciferol: VD2) on indices of insulin sensitivity {whole body sensitivity index: WBISI} and secretion {insulinogenic index: IGI} measured during an oral glucose tolerance test (OGTT) in obese adolescents with VDD (25 OHD; serum metabolite of vit D: < 30 ng/dL). SUBJECTS AND METHODS In a randomized placebo controlled cross over design 20 obese adolescents with vitamin D deficiency (VDD) had baseline OGTT. Arm A received one time high dose 300,000 IU of ergocalciferol and Arm B received placebo. After 6 weeks the adolescents were reassigned to Arm A if they were in Arm B and vice versa. 25OHD, calcium, parathyroid hormone, comprehensive metabolic panel, urine calcium creatinine ratio were measured at each study visit. OGTTs to assess indices of sensitivity and secretion were done at baseline, 6 weeks and 12 weeks respectively. RESULTS Adolescents were obese and insulin resistant (mean ± SD: mean age = 15.1 ± 1.9 years; BMI: 32.7 ± 9.8; homeostatic model of insulin resistance: HOMA-IR: 4.2 ± 2.8). Stoss therapy with VD2 increased 25OHD from baseline (16.7 ± 2.9 to 19.5 ± 4.5; p = 0.0029) when compared to the placebo. WBISI (2.8 ± 1.9) showed a trend towards improvement in Rx group (p = 0.0577) after adjustment for covariates. IGI (3 ± 2.2) showed an improvement in both Rx and placebo groups. CONCLUSIONS Our study demonstrated that using a high dose of VD2 (300,000 IU) did not have any beneficial effect on insulin sensitivity (whole body sensitivity index {WBISI}) and secretory indices (insulinogenic index {IGI}) in obese adolescents. High dose "stoss therapy" of VD2 did not appear to have any beneficial effect on glucose homeostasis on obese adolescents.
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Treatment Effect of Ergocalciferol on Bone Metabolism Indexes and Parathyroid Hormone in Hemodialysis Patients.
Bashardoust, B, Zakeri, A, Fouladi, N, Izadi, Z, Hosseini, F
Iranian journal of kidney diseases. 2018;(6):359-363
Abstract
INTRODUCTION Vitamin D deficiency is a common problem in end-stage renal disease patients under hemodialysis. Both active and nutritional vitamin D supplementation have been recommended for its treatment. In this study we aimed to evaluate the effects of treatment with ergocalciferol on bone metabolism indexes in hemodialysis patients. MATERIALS AND METHODS In a randomized controlled trial, 40 hemodialysis patients were randomly allocated to the intervention (n = 20) and placebo (n = 20) groups. During the study, 4 patients in the placebo and 1 in the intervention group were excluded. Patients received calcitriol, 0.25 mg/d, with ergocalciferol, 50 000 IU, or placebo weekly for 3 months. Serum levels of 25-hydroxyvitamin D, calcium, parathyroid hormone, and alkaline phosphatase were measured before and after treatment. RESULTS 25-hydroxyvitamin D levels were significantly improved in the intervention group (12.00 ± 4.90 ng/mL versus 29.89 ± 9.48 ng/mL, P < .001), but the placebo group had no improvement (14.23 ± 7.62 ng/mL versus 13.87 ± 8.04 ng/mL, P > .05). There was no significant changes in serum calcium, parathyroid hormone, or alkaline phosphatase levels in each group. Eight patients (42.1%) in the intervention compared to zero cases in the placebo group had normal 25-hydroxyvitamin D levels after treatment (P = .004). No cases of hypercalcemia were seen in the studied patients. CONCLUSIONS Treatment with ergocalciferol could significantly improve vitamin D deficiency with no significant effects of serum calcium or parathyroid hormone levels.