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1.
Combinations of Calcitriol with Anticancer Treatments for Breast Cancer: An Update.
Segovia-Mendoza, M, García-Quiroz, J, Díaz, L, García-Becerra, R
International journal of molecular sciences. 2021;(23)
Abstract
Preclinical, clinical, and epidemiological studies indicate that vitamin D3 (VD) deficiency is a risk factor for the development of breast cancer. Underlying mechanisms include the ability of calcitriol to induce cell differentiation, inhibit oncogenes expression, and modify different signaling pathways involved in the control of cell proliferation. In addition, calcitriol combined with different kinds of antineoplastic drugs has been demonstrated to enhance their beneficial effects in an additive or synergistic fashion. However, a recognized adjuvant regimen based on calcitriol for treating patients with breast cancer has not yet been fully established. Accordingly, in the present work, we review and discuss the preclinical and clinical studies about the combination of calcitriol with different oncological drugs, aiming to emphasize its main therapeutic benefits and opportunities for the treatment of this pathology.
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Influence of Seasonal Vitamin D Changes on Clinical Manifestations of Rheumatoid Arthritis and Systemic Sclerosis.
Cutolo, M, Soldano, S, Sulli, A, Smith, V, Gotelli, E
Frontiers in immunology. 2021;:683665
Abstract
Vitamin D [1,25(OH)2D-calcitriol] is basically a steroid hormone with pleiotropic biologic effects, and its impact on the regulation of immune system may influence several clinical conditions. Calcidiol (25OHD), as precursor of calcitriol, derives, for the most part (80%), from cutaneous cholesterol (7-dehydrocholesterol) under the action of UV-B (sunlight). Consequently, serum concentrations fluctuate during the year following the circannual rhythm of sun exposition. We will update about the available evidence regarding the complex influence of seasonal vitamin D changes on two different chronic connective tissue diseases, namely rheumatoid arthritis (RA) and systemic sclerosis (SSc). Notably, RA is an emblematic model of autoimmune disease with prevalent joint inflammatory features, while SSc is mainly an autoimmune progressive pro-fibrotic disease. However, in both conditions, low serum concentrations of 25OHD are involved in the pathogenesis of the diseases, and emerging data report their impact on clinical manifestations.
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Mortality in Hemodialysis Patients with COVID-19, the Effect of Paricalcitol or Calcimimetics.
Arenas Jimenez, MD, González-Parra, E, Riera, M, Rincón Bello, A, López-Herradón, A, Cao, H, Hurtado, S, Collado, S, Ribera, L, Barbosa, F, et al
Nutrients. 2021;(8)
Abstract
BACKGROUND In COVID-19 patients, low serum vitamin D (VD) levels have been associated with severe acute respiratory failure and poor prognosis. In regular hemodialysis (HD) patients, there is VD deficiency and markedly reduced calcitriol levels, which may predispose them to worse outcomes of COVID-19 infection. Some hemodialysis patients receive treatment with drugs for secondary hyperparathyroidism, which have well known pleiotropic effects beyond mineral metabolism. The aim of this study was to evaluate the impact of VD status and the administration of active vitamin D medications, used to treat secondary hyperparathyroidism, on survival in a cohort of COVID-19 positive HD patients. METHODS A cross-sectional retrospective observational study was conducted from 12 March to 21 May 2020 in 288 HD patients with positive PCR for SARS-CoV2. Patients were from 52 different centers in Spain. RESULTS The percent of HD patients with COVID-19 was 6.1% (288 out of 4743). Mortality rate was 28.4% (81/285). Three patients were lost to follow-up. Serum 25(OH)D (calcidiol) level was 17.1 [10.6-27.5] ng/mL and was not significantly associated to mortality (OR 0.99 (0.97-1.01), p = 0.4). Patients receiving active vitamin D medications (16/94 (17%) vs. 65/191(34%), p = 0.003), including calcimimetics (4/49 (8.2%) vs. 77/236 (32.6%), p = 0.001), paricalcitol or calcimimetics (19/117 (16.2%) vs. 62/168 (36.9%); p < 0.001), and also those on both paricalcitol and calcimimetics, to treat secondary hyperparathyroidism (SHPTH) (1/26 (3.8%) vs. 80/259 (30.9%), p < 0.001) showed a lower mortality rate than patients receiving no treatment with either drug. Multivariate Cox regression analysis confirmed this increased survival. CONCLUSIONS Our findings suggest that the use of paricalcitol, calcimimetics or the combination of both, seem to be associated with the improvement of survival in HD patients with COVID-19. No correlation was found between serum VD levels and prognosis or outcomes in HD patients with COVID-19. Prospective studies and clinical trials are needed to support these findings.
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The use of bone turnover markers for monitoring the treatment of osteoporosis in postmenopausal females undergoing total knee arthroplasty: a prospective randomized study.
Ma, R, Wu, M, Li, Y, Wang, J, Yang, P, Chen, Y, Wang, W, Song, J, Wang, K
Journal of orthopaedic surgery and research. 2021;(1):195
Abstract
BACKGROUND Osteoporosis (OP) and osteoarthritis (OA) commonly coexist in postmenopausal females. The decrease in bone density and increase in bone resorption in postmenopausal females with OP may consequently affect the surgical outcome of total knee arthroplasty (TKA). However, clinicians often ignore monitoring the treatment of OP in the perioperative management of TKA. Bone turnover marker (BTM) can timely and accurately reflect bone metabolism to monitor the treatment of OP. The purpose of this study was to investigate the effect of BTM monitoring to guide the treatment of OP in postmenopausal females undergoing TKA. METHODS Postmenopausal females with OP who underwent primary unilateral TKA were randomly divided into two groups (monitoring group and control group), given oral medication (alendronate, calcitriol, and calcium), and followed for 1 year. In the monitoring group, serum BTMs (C-telopeptide of type I collagen (CTX-I), N-terminal propeptide of type I procollagen (PINP), and 25(OH)D) were assessed preoperatively and repeated postoperatively; alendronate was withdrawn when CTX-I and PINP reached the reference interval; and calcitriol and calcium were withdrawn when 25(OH)D reached the reference interval. In the control group, oral medication was implemented for a uniform duration of 3 months. During the 1-year follow-up, the mean maximum total point motion (MTPM) of the tibial component, bone mineral density (BMD), visual analog scale (VAS) score, range of motion, and Oxford Knee Score (OKS) score were obtained. RESULTS In the monitoring group, BTM monitoring prolonged the medication duration, but did not cause more adverse reactions than in the control group. The mean MTPM values at 6 m and 12 m in the monitoring group were lower than those in the control group, and the BMD at 12 m in the monitoring group was significantly higher than that in the control group. Patients in the monitoring group had lower VAS scores at 6 m and higher OKS scores at 6 m and 12 m than those in the control group. CONCLUSION In postmenopausal females with osteoporosis undergoing primary TKA, the application of BTM monitoring to guide the treatment of osteoporosis can enhance bone density, maintain prosthesis stability, and improve surgical outcome. TRIAL REGISTRATION ChiCTR ChiCTR-INR-17010495 . Registered on 22 January 2017.
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The efficacy of calcitriol treatment in non-alcoholic fatty liver patients with different genotypes of vitamin D receptor FokI polymorphism.
Yaghooti, H, Ghanavati, F, Seyedian, SS, Cheraghian, B, Mohammadtaghvaei, N
BMC pharmacology & toxicology. 2021;(1):18
Abstract
BACKGROUND Vitamin D deficiency is prevalent in patients with non-alcoholic fatty liver disease (NAFLD), but there are debates on the usefulness of vitamin D treatment. The interindividual variations in response may be due to different genetic backgrounds. The present study evaluated the efficacy of calcitriol treatment in NAFLD patients with regard to the vitamin D receptor (VDR) genotypes of FokI polymorphism. METHODS The study was conducted on 128 NAFLD patients randomly divided into two groups and were subjected to intervention with 0.25 mcg calcitriol/day or placebo for 4 months, while anthropometric parameters, glycemic status, lipid profiles, inflammatory markers, liver enzymes, and fatty liver indices were measured. The ARMS-PCR method was used to genotype the VDR FokI polymorphism. RESULTS Calcitriol treatments along with weight loss and diet recommendations decreased the liver enzymes (AST, ALT, and ALP, p < 0.001 for all) and fatty liver indices (HSI, p < 0.01 and APRI, p < 0.001), compared to the baseline. But when the calcitriol effects were compared to the placebo group, only ALP decrease remained significant (17.5 IU. P = 0.02). The prevalent FokI variants in our population were FF (53.1%) and Ff genotype (45.3%). No significant interaction of FokI variants to the calcitriol effects was found except for ALP. The decrease in the ALP activity was higher in calcitriol-received patients with the Ff genotype (p = 0.05). CONCLUSIONS The FF and Ff variants of VDR FokI polymorphism did not interact with the effects of calcitriol on fatty liver, but the ALP was more responsive in subjects with the Ff variant. IRCT REGISTRATION NUMBER IRCT2017053034222N1 Registration date: 2017-06-28 - Retrospectively registered, https://en.irct.ir/trial/26203.
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6.
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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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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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.