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1.
Vitamin D Metabolism Is Dysregulated in Asthma and Chronic Obstructive Pulmonary Disease.
Jolliffe, DA, Stefanidis, C, Wang, Z, Kermani, NZ, Dimitrov, V, White, JH, McDonough, JE, Janssens, W, Pfeffer, P, Griffiths, CJ, et al
American journal of respiratory and critical care medicine. 2020;(3):371-382
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Abstract
Rationale: Vitamin D deficiency is common in patients with asthma and chronic obstructive pulmonary disease (COPD). Low 25-hydroxyvitamin D (25[OH]D) levels may represent a cause or a consequence of these conditions.Objectives: To determine whether vitamin D metabolism is altered in asthma or COPD.Methods: We conducted a longitudinal study in 186 adults to determine whether the 25(OH)D response to six oral doses of 3 mg vitamin D3, administered over 1 year, differed between those with asthma or COPD versus control subjects. Serum concentrations of vitamin D3, 25(OH)D3, and 1α,25-dihydroxyvitamin D3 (1α,25[OH]2D3) were determined presupplementation and postsupplementation in 93 adults with asthma, COPD, or neither condition, and metabolite-to-parent compound molar ratios were compared between groups to estimate hydroxylase activity. Additionally, we analyzed 14 datasets to compare expression of 1α,25(OH)2D3-inducible gene expression signatures in clinical samples taken from adults with asthma or COPD versus control subjects.Measurements and Main Results: The mean postsupplementation 25(OH)D increase in participants with asthma (20.9 nmol/L) and COPD (21.5 nmol/L) was lower than in control subjects (39.8 nmol/L; P = 0.001). Compared with control subjects, patients with asthma and COPD had lower molar ratios of 25(OH)D3-to-vitamin D3 and higher molar ratios of 1α,25(OH)2D3-to-25(OH)D3 both presupplementation and postsupplementation (P ≤ 0.005). Intergroup differences in 1α,25(OH)2D3-inducible gene expression signatures were modest and variable if statistically significant.Conclusions: Attenuation of the 25(OH)D response to vitamin D supplementation in asthma and COPD associated with reduced molar ratios of 25(OH)D3-to-vitamin D3 and increased molar ratios of 1α,25(OH)2D3-to-25(OH)D3 in serum, suggesting that vitamin D metabolism is dysregulated in these conditions.
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Calciotropic and phosphotropic hormones in fetal and neonatal bone development.
Ryan, BA, Kovacs, CS
Seminars in fetal & neonatal medicine. 2020;(1):101062
Abstract
There are remarkable differences in bone and mineral metabolism between the fetus and adult. The fetal mineral supply is from active transport across the placenta. Calcium, phosphorus, and magnesium circulate at higher levels in the fetus compared to the mother. These high concentrations enable the skeleton to accrete required minerals before birth. Known key regulators in the adult include parathyroid hormone (PTH), calcitriol, fibroblast growth factor-23, calcitonin, and the sex steroids. But during fetal life, PTH plays a lesser role while the others appear to be unimportant. Instead, PTH-related protein (PTHrP) plays a critical role. After birth, serum calcium falls and phosphorus rises, which trigger an increase in PTH and a subsequent rise in calcitriol. The intestines become the main source of mineral supply while the kidneys reabsorb filtered minerals. This striking developmental switch is triggered by loss of the placenta, onset of breathing, and the drop in serum calcium.
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Vitamin D and the insulin-like growth factor system: Implications for colorectal neoplasia.
Ciulei, G, Orasan, OH, Coste, SC, Cozma, A, Negrean, V, Procopciuc, LM
European journal of clinical investigation. 2020;(9):e13265
Abstract
Epidemiological studies have strongly associated lower levels of vitamin D and its metabolites with an increased risk of colorectal cancer (CRC). The action of calcitriol, the active metabolite of vitamin D, is mediated by the vitamin D receptor (VDR) that is present in most tissues. In advanced CRC, VDR expression is lowered. Calcitriol has several antineoplastic effects in CRC: it promotes the G1-phase cycle arrest, lowers vascular endothelial growth factor (VEGF) synthesis and acts on tumour stromal fibroblasts to limit cell migration and angiogenesis. Hyperinsulinemia and insulin-like growth factors (IGFs) have been implicated in the pathophysiology of CRC. IGF-1 and IGFBP-3 have been the most studied components of the IGF system. Only 1% of the total serum IGF-1 is free and bioactive, and 80% of it binds to IGFBP-3. IGF-1 and its receptor IGF-1R are known to induce cell proliferation. Both IGF-1 and IGFBP-3 can favour angiogenesis by increasing the transcription of the VEGF gene. A high serum IGF-1/IGFBP-3 ratio is associated with increased risk for CRC. VDR is a transcription factor for the IGFBP-3 gene, and IGF-1 can increase calcitriol synthesis. Studies examining the effect of vitamin D treatment on serum IGF-1 and IGFBP-3 have not been in agreement since different populations, dosages and intervention periods have been used. New vitamin D treatment studies that examine CRC should take in account confounding factors such as obesity or VDR genotypes.
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Effect of calcitriol combined with sevelamer carbonate on serum parathyroid hormone in patients with chronic renal failure.
Zheng, H, Liu, Z
Cellular and molecular biology (Noisy-le-Grand, France). 2020;(2):31-35
Abstract
This study aimed to observe and analyze the effect of calcitriol combined with sevelamer carbonate on serum parathyroid hormone in patients with chronic renal failure. This study included 180 patients who had been treated for chronic renal failure in our hospital were enrolled as research objects. The patients were randomly divided into two groups: a research group and a control group, each containing 90 cases. The research group was treated with calcitriol combined with sevelamer carbonate, and the control group was treated with calcitriol alone. The therapeutic effects of the two groups were observed and analyzed by SPSS 21. Comparing the levels of blood indexes (Ca, Cr, P, ALP, iPTH, TC, TG, LDL-C, HDL-C) of the two groups showed no significant difference between the two groups, P <0.05. Our results have the effect of different treatment regimens, the improvement effect of various blood indicators in the research group was significantly better than the control group, p<0.05. We concluded that the combined therapy of calcitriol and sevelamer carbonate in chronic renal failure patients can significantly improve the therapeutic effect, and at the same time actively improve the serum parathyroid hormone level, which is a treatment model that can be popularized and applied.
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Vitamin D Status and Pregnancy Complications: Serum 1,25-di-hydroxyl-Vitamin D and its Ratio to 25-hydroxy-Vitamin D are Superior Biomarkers than 25-hydroxy-Vitamin D.
Albahlol, IA, Almaeen, AH, Alduraywish, AA, Dar, UF, El-Metwally, TH
International journal of medical sciences. 2020;(18):3039-3048
Abstract
Vitamin D (VitD) deficiency during pregnancy has been associated with adverse neonatal outcomes and increased risk of late pregnancy complications. We planned to correlate serum VitD biomarkers; 25-hydroxyvitamin D (25-OH-VitD) and 1,25-dihydroxyvitamin D (1,25-diOH-VitD) levels; and their ratio with the frequency of feto-maternal pregnancy complications. A prospective cross-sectional case-control study was conducted at Aljouf Maternity and Children Hospital, Sakaka, Saudi Arabia, during the period of September 1, 2017 to September 30, 2019. 322 pregnant women were stratified into 2 groups: controls (110 cases) and complicated group (212 cases). The later comprised severe preeclamptic toxemia associated with intrauterine growth restriction (58 cases), gestational diabetes mellitus (GDM; 82 cases), abortion (26 cases), undisturbed ectopic pregnancy (16 cases), premature rupture of membranes (PROM; 14 cases), and, inevitable preterm labour (16 cases). After clinical assessment, peripheral blood samples were collected. Serum biomarkers were measured using specific immunoassays. The direct 1,25-diOH-VitD/25-OH-VitD ratio was calculated. Serum 25-OH-VitD indicated widely spreading VitD deficiency among participants with significantly higher levels in controls vs. GDM subgroup only. 1,25-diOH-VitD levels and the ratio were markedly reduced in the six complicated subgroups vs. controls, with non-significant differences amongst the complicated subgroups. ROC analysis showed very high sensitivity and specificity, to differentiate patients from controls, only for 1,25-diOH-VitD (AUC = 0.965; 0.947 - 0.983, p <0.001) followed by the ratio but not 25-OH-VitD. In conclusions, 25-OH-VitD did not show significant changes except for GDM. 1,25-diOH-VitD levels and the ratio showed strong associations with pregnancy complications. Serum 1,25-di-OH-VitD and its ratio to 25-OH-VitD are more reliable and physiologically relevant biomarkers for VitD status in pregnancy.
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Enhanced Antiproliferative Effect of Combined Treatment with Calcitriol and All-Trans Retinoic Acid in Relation to Vitamin D Receptor and Retinoic Acid Receptor α Expression in Osteosarcoma Cell Lines.
Paukovcekova, S, Valik, D, Sterba, J, Veselska, R
International journal of molecular sciences. 2020;(18)
Abstract
The main objective of this study was to analyze changes in the antiproliferative effect of vitamin D3, in the form of calcitriol and calcidiol, via its combined application with all-trans retinoic acid (ATRA) in osteosarcoma cell lines. The response to treatment with calcitriol and calcidiol alone was specific for each cell line. Nevertheless, we observed an enhanced effect of combined treatment with ATRA and calcitriol in the majority of the cell lines. Although the levels of respective nuclear receptors did not correlate with the sensitivity of cells to these drugs, vitamin D receptor (VDR) upregulation induced by ATRA was found in cell lines that were the most sensitive to the combined treatment. In addition, all these cell lines showed high endogenous levels of retinoic acid receptor α (RARα). Our study confirmed that the combination of calcitriol and ATRA can achieve enhanced antiproliferative effects in human osteosarcoma cell lines in vitro. Moreover, we provide the first evidence that ATRA is able to upregulate VDR expression in human osteosarcoma cells. According to our results, the endogenous levels of RARα and VDR could be used as a predictor of possible synergy between ATRA and calcitriol in osteosarcoma cells.
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Sarcoidosis and calcium homeostasis disturbances-Do we know where we stand?
Gwadera, Ł, Białas, AJ, Iwański, MA, Górski, P, Piotrowski, WJ
Chronic respiratory disease. 2019;:1479973119878713
Abstract
The majority of cases involving hypercalcemia in the setting of sarcoidosis are explained by the overproduction of calcitriol by activated macrophages. Vitamin D takes part in the regulation of granuloma formation. However, using vitamin D metabolites to assess the activity of the disease is still problematic, and its usefulness is disputable. In some cases, though, a calcium metabolism disorder could be a valuable tool (i.e. as a marker of extrathoracic sarcoidosis). Although sarcoidosis does not cause a decrease in bone mineral density, increased incidence of vertebral deformities is noted. Despite increasing knowledge about calcium homeostasis disorders in patients with sarcoidosis, there is still a need for clear guidelines regarding calcium and vitamin D supplementation in these patients.
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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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9.
Vitamin D and Calcium for the Prevention of Fracture: A Systematic Review and Meta-analysis.
Yao, P, Bennett, D, Mafham, M, Lin, X, Chen, Z, Armitage, J, Clarke, R
JAMA network open. 2019;(12):e1917789
Abstract
IMPORTANCE Vitamin D and calcium supplements are recommended for the prevention of fracture, but previous randomized clinical trials (RCTs) have reported conflicting results, with uncertainty about optimal doses and regimens for supplementation and their overall effectiveness. OBJECTIVE To assess the risks of fracture associated with differences in concentrations of 25-hydroxyvitamin D (25[OH]D) in observational studies and the risks of fracture associated with supplementation with vitamin D alone or in combination with calcium in RCTs. DATA SOURCES PubMed, EMBASE, Cochrane Library, and other RCT databases were searched from database inception until December 31, 2018. Searches were performed between July 2018 and December 2018. STUDY SELECTION Observational studies involving at least 200 fracture cases and RCTs enrolling at least 500 participants and reporting at least 10 incident fractures were included. Randomized clinical trials compared vitamin D or vitamin D and calcium with control. DATA EXTRACTION AND SYNTHESIS Two researchers independently extracted data according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines and assessed possible bias. Rate ratios (RRs) were estimated using fixed-effects meta-analysis. Data extraction and synthesis took place between July 2018 and June 2019. MAIN OUTCOMES AND MEASURES Any fracture and hip fracture. RESULTS In a meta-analysis of 11 observational studies (39 141 participants, 6278 fractures, 2367 hip fractures), each increase of 10.0 ng/mL (ie, 25 nmol/L) in 25 (OH)D concentration was associated with an adjusted RR for any fracture of 0.93 (95% CI, 0.89-0.96) and an adjusted RR for hip fracture of 0.80 (95% CI, 0.75-0.86). A meta-analysis of 11 RCTs (34 243 participants, 2843 fractures, 740 hip fractures) of vitamin D supplementation alone (daily or intermittent dose of 400-30 000 IU, yielding a median difference in 25[OH]D concentration of 8.4 ng/mL) did not find a reduced risk of any fracture (RR, 1.06; 95% CI, 0.98-1.14) or hip fracture (RR, 1.14; 95% CI, 0.98-1.32), but these trials were constrained by infrequent intermittent dosing, low daily doses of vitamin D, or an inadequate number of participants. In contrast, a meta-analysis of 6 RCTs (49 282 participants, 5449 fractures, 730 hip fractures) of combined supplementation with vitamin D (daily doses of 400-800 IU, yielding a median difference in 25[OH]D concentration of 9.2 ng/mL) and calcium (daily doses of 1000-1200 mg) found a 6% reduced risk of any fracture (RR, 0.94; 95% CI, 0.89-0.99) and a 16% reduced risk of hip fracture (RR, 0.84; 95% CI, 0.72-0.97). CONCLUSIONS AND RELEVANCE In this systematic review and meta-analysis, neither intermittent nor daily dosing with standard doses of vitamin D alone was associated with reduced risk of fracture, but daily supplementation with both vitamin D and calcium was a more promising strategy.
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Vitamin D inhibits pro-inflammatory cytokines in the airways of cystic fibrosis patients infected by Pseudomonas aeruginosa- pilot study.
Olszowiec-Chlebna, M, Koniarek-Maniecka, A, Brzozowska, A, Błauż, A, Rychlik, B, Stelmach, I
Italian journal of pediatrics. 2019;(1):41
Abstract
BACKGROUND Vitamin D plays an important role in inflammatory responses after antigen exposure. Interleukin-23 (Il-23) promotes Il-17-dependent inflammation during Pseudomonas aeruginosa (P. aeruginosa) pulmonary infection. We aimed to compare the ability of calcitriol and cholecalciferol to modulate the inflammatory response of the CF airways infected with P. aeruginosa. METHODS This was a randomized, placebo-controlled, double-blind, cross-over trial. Twenty-three patients with CF (aged 6-19), chronically infected by P. aeruginosa were randomly assigned to: calcitriol group receiving 1,25(OH)2D 0,5 mcg daily or cholecalciferol group receiving cholecalciferol 1000 IU daily for three months. The levels of Il-23 and Il-17A in the exhaled breath concentrate (EBC) were measured. Calcium-phosphorus balance was also evaluated (serum concentration of calcium, phosphorus, 25OHD, parathormone (PTH) and calcium/creatinine ratio in urine). Data were analyzed using means of Stata/Special Edition, release 14.2. A level of P < 0.05 was considered statistically significant. RESULTS The level of Il-17A in EBC significantly decreased in calcitriol group from 0,475 pg/mL (± SD 0,515 pg/mL) to 0,384 pg/mL (± SD 0,429 pg/mL) (p = 0,008); there was no change in cholecalciferol group (p = 0,074). The level of Il-23 in EBC did not significantly change in calcitriol group (p = 0,086); there was significant decrease in cholecalciferol group from 8,90 pg/mL (± SD 4,07 pg/mL) to 7,33 pg/mL (± SD 3,88 pg/mL) (p = 0,001). In calcitriol group serum phosphorus and PTH significantly decreased (p = 0,021 and p = 0,019 respectively), the concentration of calcium significantly increased (p = 0,001); there were no changes in cholecalciferol group. CONCLUSIONS Both analogs of vitamin D revealed their anti-inflammatory effect and reduced the level of Il-17A and Il-23 in the airway of CF patients with chronic P. aeruginosa infection. We observed improvement in calcium-phosphorus metabolism after supplementation with calcitriol, without adverse effects. It is recommended to use vitamin D in CF patients.