An update on vitamin D signaling and cancer.

A low vitamin D status is associated with an increased risk of various cancers, such as of colon, breast, prostate and hematological cells. The biologically most active vitamin D metabolite 1α,25-dihydroxyvitamin D3 (1,25(OH)2D3) is a high affinity ligand of the transcription factor vitamin D receptor (VDR). 1,25(OH)2D3 induces via VDR changes to the epigenome of healthy and neoplastic cells and in this way influences their transcriptome. Ligand-activated VDR binds to more than 10,000 loci within the human genome and affects the transcription of some 1000 target genes in a large proportion of human tissues and cell types. From the evolutionary perspective, the prime role of vitamin D was probably the control of energy metabolism later shifting to modulate innate and adaptive immunity as well as to regulate calcium and bone homeostasis. Since rapidly growing immune and cancer cells both use the same pathways and genes for controlling their proliferation, differentiation and apoptosis, not surprisingly, vitamin D signaling changes these processes also in neoplastic cells. Thus, anti-cancer effects of vitamin D may derive from managing growth and differentiation in immunity. This review provides an update on the molecular basis of vitamin D signaling, i.e., the effects of 1,25(OH)2D3 on the epigenome and transcriptome, and its relationship to cancer prevention and therapy.

Plasma Levels of Bioactive Vitamin D and A5 Ligands Positively Correlate with Clinical Atopic Dermatitis Markers.

BACKGROUND: Over the past decade, several controversial studies described a relationship between vitamin D and atopic diseases. Low plasma vitamin D levels or even vitamin D deficiency was associated with an increased incidence of atopic disease, postulating that a higher dietary intake of vitamin D may be a beneficial strategy against atopic diseases such as atopic dermatitis (AD). OBJECTIVE: Our aim was to determine the relationship between plasma 25-hydroxyvitamin D3 (25(OH)D3) levels, the levels of the ligand of the vitamin D receptor (VDR) heterodimerization partner as well as the retinoid X receptor (RXR) and the active vitamin A5 derivative 9-cis-13,14-dihydroretinoic acid (9CDHRA) and AD severity. METHODS/RESULTS: Samples from AD patients (n = 20) and healthy volunteers (n = 20) were assessed. In our study, the frequently measured VDR ligand precursor 25(OH)D3 in addition to the VDR-ligand 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) and 9CDHRA displayed no different levels when compared with the plasma of AD patients and healthy volunteers. When performing further correlation studies focusing on AD patients, plasma 25(OH)D3 levels showed a negative correlation with eosinophils in blood (EOS) and SCORing Atopic Dermatitis (SCORAD) values, while 1,25(OH)2D3 and 9CDHRA levels correlated positively with plasma IgE, EOS, and SCORAD values. CONCLUSION: In consequence, the metabolic activation of vitamin D from 25(OH)D3 towards 1,25(OH)2D3 as well as the co-liganding of the RXR by 9CDHRA may be an important signalling mechanism, an important marker for AD development and severity as well as the basis for novel nutritional and pharmaceutical AD treatment options.

Decrease in serum calcitriol (but not free 25-hydroxyvitamin D) concentration in hip fracture healing.

OBJECTIVE: To assess the decrease in serum calcitriol concentrations after hip fracture. METHODS: Serum concentrations of calcitriol, 25(OH)D, parathyroid hormone (PTH), directly measured free 25(OH)D, and indices of bone formation were measured in elderly patients with hip fracture (HF) and patients with elective hip replacement (EHR) at admission and after 7 weeks. RESULTS: A total of 45 patients with HF and 17 patients with EHR completed this prospective study. Baseline serum calcitriol levels were ≤ 60 pmol/l in 26% of the HF patients. After 7 weeks, they significantly decreased (p < 0.001). In patients with EHR, serum calcitriol was within the reference range in all but one patient and did not change during the 7-week recovery phase. Seven weeks after HF, a significant positive relationship was observed between the change in calcitriol and serum 25(OH)D concentration (r = 0.385, p = 0.009) and free 25(OH)D (r = 0.296, p = 0.048), and a decrease in calcitriol during recovery was associated with a decrease in serum PTH (p = 0.038). Seven weeks after HF, changes in both serum PTH and serum 25(OH)D concentrations contributed to the prediction of changes in serum calcitriol (R2 = 0.190, p = 0.012). CONCLUSIONS: Unlike patients with EHR, subjects with HF had low serum 25(OH)D and low free 25(OH)D concentrations at admission, while their serum 1,25D levels were relatively elevated. Decreases in circulating calcitriol levels in the 7 weeks following hip surgery were associated with a resolution of secondary hyperparathyroidism and low availability of free 25(OH)D.

Modulation of Intestinal Phosphate Transport in Young Goats Fed a Low Phosphorus Diet.

The intestinal absorption of phosphate (Pi) takes place transcellularly through the active NaPi-cotransporters type IIb (NaPiIIb) and III (PiT1 and PiT2) and paracellularly by diffusion through tight junction (TJ) proteins. The localisation along the intestines and the regulation of Pi absorption differ between species and are not fully understood. It is known that 1,25-dihydroxy-vitamin D3 (1,25-(OH)2D3) and phosphorus (P) depletion modulate intestinal Pi absorption in vertebrates in different ways. In addition to the apical uptake into the enterocytes, there are uncertainties regarding the basolateral excretion of Pi. Functional ex vivo experiments in Ussing chambers and molecular studies of small intestinal epithelia were carried out on P-deficient goats in order to elucidate the transepithelial Pi route in the intestine as well as the underlying mechanisms of its regulation and the proteins, which may be involved. The dietary P reduction had no effect on the duodenal and ileal Pi transport rate in growing goats. The ileal PiT1 and PiT2 mRNA expressions increased significantly, while the ileal PiT1 protein expression, the mid jejunal claudin-2 mRNA expression and the serum 1,25-(OH)2D3 levels were significantly reduced. These results advance the state of knowledge concerning the complex mechanisms of the Pi homeostasis in vertebrates.

Autophagy efficacy and vitamin D status: Population effects.

Toll-like receptor (TLR) 2/1 signalling is linked to autophagy through transcriptional actions of the 1,25-dihydroxyvitamin D3 (1,25(OH)2D3)-vitamin D receptor (VDR) complex. Population-specific effects have been reported for TLR2/1-VDR signalling. We hypothesized that population effects extend to autophagy and are influenced by vitamin D status. Serum 25(OH)D3 of healthy South Africans (Black individuals n = 10, White individuals n = 10) was quantified by LC-MS/MS. Primary monocytes-macrophages were supplemented in vitro with 1,25(OH)2D3 and stimulated with the lipoprotein Pam3CysSerLys4. TLR2, VDR, hCAP18, Beclin1, LC3-IIB, cytokines and CYP24A1 mRNA were quantified by flow cytometry and RT-qPCR, respectively. Black individuals showed significantly lower overall cumulative LC3-IIB (P < 0.010), but higher Beclin1, VDR, IL6 and TNFA (P < 0.050) than White individuals. 1,25(OH)2D3 enhanced autophagic flux in monocytes-macrophages from Black individuals upon TLR2/1 stimulation and strengthened autophagy in 25(OH)D3 deficient individuals (independent cohort, n = 20). These findings support population-directed vitamin D supplementation.

Balancing Altered Calcium Metabolism with Bone Health in Sarcoidosis.

Abnormal calcium metabolism in sarcoidosis patients can lead to hypercalcemia, hypercalciuria, and kidney stones. Hypercalcemia in sarcoidosis is usually due to increased activity of 1α-hydroxylase in macrophages of pulmonary granulomata, resulting in low levels of 25-hydroxyvitamin D and high levels of calcitriol. Vitamin D supplementation may be dangerous for some sarcoidosis patients and is recommended only for those with decreased 25-hydroxyvitamin D and reduced or normal calcitriol level. Diagnosis, treatment of osteoporosis, and maintenance of bone health are complex issues for sarcoidosis patients. An approach to diagnosis and treatment of bone fragility is presented.

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.

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.

Continuous Renal Replacement Therapy Might Mask Immobilization-Induced Hypercalcemia in Critically Ill Patients.

Immobilization and prolonged bed rest are harmful to the skeleton, which suffers increased resorption, and contribute to reducing survival rates among patients in critical care units. We report a patient who presented hypercalcemia 10 days after continuous venovenous hemofiltration has ended. Investigative tests showed an increase of serum C-terminal telopeptide of type I collagen (CTx), with suppressed parathormone and calcitriol. Denosumab was administered with a significant response, decreasing ionized calcium and CTx levels. The calcium infusion rate during dialysis procedures, used for citrate anticoagulation compensation, has progressively decreased, suggesting that endogenous calcium was taking part in the citrate chelation. In this report, we highlight the challenges in early diagnosis of immobilization-induced hypercalcemia among patients who are on continuous renal replacement therapy undergoing citrate anticoagulation.

Association of vitamin D and FGF23 with serum ferritin in hypoparathyroid thalassemia: a case control study.

BACKGROUND: FGF23 controls serum l,25(OH)2D3 levels and phosphate homeostasis. This study evaluates the effects of ferritin on intact PTH, FGF23, and l,25(OH)2D3 in patients with major thalassemia. It also evaluates FGF23 changes in patients with hypoparathyroidism to clarify the interaction between FGF23 and PTH in the absence of proper PTH functioning in human. METHODS: In this case-control study, 25 major-beta thalassemia patients with hypoparathyroidism were age- and gender-matched with major-beta thalassemia patients having normal parathyroid function. Biochemical studies assessed the serum calcium, albumin, phosphorus, alkaline phosphatase, PTH, FGF23, 25(OH) D, 1,25(OH)2D3, ferritin, and the fractional excretion of phosphorous. RESULTS: FGF23 was higher in the patients with hypoparathyroidism than the controls (P = 0.002). The fractional excretion of phosphorous was lower in patients with hypoparathyroidism, despite the high level of FGF23 (P = 0.001). There was a correlation between serum 1,25(OH)2D3 and FGF23 with ferritin in the controls (P = < 0.001and P = < 0.001, respectively). CONCLUSIONS: The present study showed a strong positive correlation between serum ferritin and levels of FGF23 and 1,25(OH)2D3. We hypothesized that ferritin could have a stimulatory effect on the production of 1,25(OH)2D3. Moreover, a rise in FGF23 in patients with thalassemia, might be either associated with the stimulating effect of PTH and 1,25(OH)2D3, or directly related to the stimulating effect of ferritin.

Evaluation of vitamin D3 metabolites in Callithrix jacchus (common marmoset).

Vitamin D3 (cholecalciferol) is endogenously produced in the skin of primates when exposed to the appropriate wavelengths of ultraviolet light (UV-B). Common marmosets (Callithrix jacchus) maintained indoors require dietary provision of vitamin D3 due to lack of sunlight exposure. The minimum dietary vitamin D3 requirement and the maximum amount of vitamin D3 that can be metabolized by marmosets is unknown. Observations of metabolic bone disease and gastrointestinal malabsorption have led to wide variation in dietary vitamin D3 provision amongst research institutions, with resulting variation in circulating 25-hydroxyvitamin D3 (25(OH)D3 ), the accepted marker for vitamin D sufficiency/deficiency. Multiple studies have reported serum 25(OH)D3 in captive marmosets, but 25(OH)D3 is not the final product of vitamin D3 metabolism. In addition to serum 25(OH)D3, we measured the most physiologically active metabolite, 1,25-dihydroxyvitamin D3 (1,25(OH)2 D3 ), and the less well understood metabolite, 24,25-dihydroxyvitamin D3 (24,25(OH)2 D3 ) to characterize the marmoset's ability to metabolize dietary vitamin D3 . We present vitamin D3 metabolite and related serum chemistry value colony reference ranges in marmosets provided diets with 26,367 (Colony A, N = 113) or 8,888 (Colony B, N = 52) international units (IU) of dietary vitamin D3 per kilogram of dry matter. Colony A marmosets had higher serum 25(OH)D3 (426 ng/ml [SD 200] vs. 215 ng/ml [SD 113]) and 24,25(OH)2 D3 (53 ng/ml [SD 35] vs. 7 ng/ml [SD 5]). There was no difference in serum 1,25(OH)2 D3 between the colonies. Serum 1,25(OH)2 D3 increased and 25(OH)D3 decreased with age, but the effect was weak. Marmosets tightly regulate metabolism of dietary vitamin D3 into the active metabolite 1,25(OH)2 D3 ; excess 25(OH)D3 is metabolized into 24,25(OH)2 D3 . This ability explains the tolerance of high levels of dietary vitamin D3 by marmosets, however, our data suggest that these high dietary levels are not required.

Molecular evidence of role of vitamin D deficiency in various extraskeletal diseases.

BACKGROUND: Role of vitamin D is not only limited to skeletal system but various other systems of the body, such as immune system, endocrine system, and cardiopulmonary system. MATERIALS AND METHODS: It is supported by the confirmations of systems-wide expression of vitamin D receptor (VDR), endocrinal effect of calcitriol, and its role in immune responses. RESULTS: Expression of VDR in various systems, immunoregulatory and hormonal response of vitamin D and deficiency of vitamin D may establish various pathologies in the body. CONCLUSION: This review provides molecular evidence of relation of vitamin D with extra skeletal.

Anomalous bone changes in ovariectomized type 2 diabetic rats: inappropriately low bone turnover with bone loss in an estrogen-deficient condition.

Estrogen deprivation accelerates bone resorption, leading to imbalance of bone remodeling and osteoporosis in postmenopausal women. In the elderly, type 2 diabetes mellitus (T2DM) frequently coexists as an independent factor of bone loss. However, little is known about the skeletal changes in a combined condition of estrogen deficiency and T2DM. Herein, we performed ovariectomy (OVX) in nonobese Goto-Kakizaki (GK) T2DM rats to examine changes associated with calcium and phosphate metabolism and bone microstructures and strength. As expected, wild-type (WT) rats subjected to ovariectomy (OVX-WT) had low trabecular bone volume and serum calcium with increased dynamic histomorphometric and serum bone markers, consistent with the high turnover state. T2DM in GK rats also led to low trabecular volume and serum calcium. However, the dynamic histomorphometric markers of bone remodeling were unaffected in these GK rats, indicating the distinct mechanism of T2DM-induced bone loss. Interestingly, OVX-GK rats were found to have anomalous and unique changes in bone turnover-related parameters, i.e., decreased osteoblast and osteoclast surfaces with lower COOH-terminal telopeptide of type I collagen levels compared with OVX-WT rats. Furthermore, the levels of calciotropic hormones, i.e., parathyroid hormone and 1,25(OH)2D3, were significantly decreased in OVX-GK rats. Although the OVX-induced bone loss did not further worsen in GK rats, a three-point bending test indicated that OVX-GK bones exhibited a decrease in bone elasticity. In conclusion, T2DM and estrogen deficiency both led to microstructural bone loss, the appearance of which did not differ from each factor alone. Nevertheless, the combination worsened the integrity and suppressed the turnover, which might eventually result in adynamic bone disease.

Association among plasma 1,25(OH)2 D, ratio of 1,25(OH)2 D to 25(OH)D, and prostate cancer aggressiveness.

BACKGROUND: African-American (AA) men tend to present with more aggressive prostate cancer (Gleason score >7) than European-American (EA) men. Vitamin D and its metabolites are implicated in prostate cancer biology with vitamin D deficiency, indicated by its metabolite levels in serum or plasma, usually observed in AA men. OBJECTIVE: To determine if 1, 25-dihydroxy vitamin D3 [1,25(OH)2 D] plasma levels in AA and EA prostate cancer patients alter the risk of having aggressive prostate cancer. DESIGN: Research subjects from the North Carolina-Louisiana Prostate Cancer Project (AA n = 435 and EA n = 532) were included. Plasma metabolites 1,25(OH)2 D and 25-hydroxyvitamin D3 [25(OH)D] were measured using liquid chromatography with tandem mass spectrophotometry. Research subjects were classified into low (Gleason sum < 7, stage T1-T2, and Prostate-specific antigen (PSA) < 9 ng/mL) or high (Gleason sum > 8 or Gleason sum = 7 with 4 + 3, or PSA > 20 ng/mL, or Gleason sum = 7 and stage T3-T4) aggressive disease. RESULTS: Research subjects in the second and third tertiles of plasma levels of 1, 25(OH)2 D had lower odds of high aggressive prostate cancer (AA [ORT2vsT1 : 0.66, 95%CI: 0.39-1.12; ORT3vsT1 : 0.83, 95%CI: 0.49-1.41] and EA [ORT2vsT1 : 0.68, 95%CI: 0.41-1.11; ORT3vsT1 : 0.67, 95%CI: 0.40-1.11]) compared with the first tertile, though confidence intervals included the null. Greater 1,25(OH)2 D/25(OH)D molar ratios were associated with lower odds of high aggressive prostate cancer more evidently in AA (ORQ4vsQ1 : 0.45, CI: 0.24-0.82) than in EA (ORQ4vsQ1 : 0.64, CI: 0.35-1.17) research subjects. CONCLUSIONS: The 1,25(OH)2 D/25(OH)D molar ratio was associated with decreased risk of high aggressive prostate cancer in AA men, and possibly in EA men. Further studies analyzing vitamin D polymorphisms, vitamin D binding protein levels, and prostatic levels of these metabolites may be useful. These studies may provide a better understanding of the vitamin D pathway and its biological role underlying health disparities in prostate cancer.

Diagnosis, Pathophysiology and Management of Hypercalcemia in Malignancy: A Review of the Literature.

Hypercalcemia of malignancy is the most common life-threatening metabolic disorder in patients with advanced stage cancers and is a sign of poor prognosis. It usually presents with markedly elevated calcium level and is severely symptomatic. It is associated with hematological malignancies, such as multiple myeloma, non-Hodgkin lymphoma, leukemias and solid cancers, particularly renal and breast carcinomas as well as squamous cell carcinomas of any organ. Several mechanisms have been implicated in the development of hypercalcemia of malignancy amongst them the osteolytic related hypercalcemia, parathyroid hormone-related peptide (PTHrP) mediated hypercalcemia, extrarenal 1,25 dixydroxyvitamin D (calcitriol) mediated hypercalcemia and parathyroid hormone (PTH) related hypercalcemia either ectopic in origin or in patients with parathyroid carcinoma. Clinical history and and physical examination could point towards the correct diagnosis confirmed by the above-mentioned biochemical mediators of hypercalcemia. Early diagnosis and treatment lowering calcium levels in the blood can improve symptoms and the quality of life of these patients and avoid delays for further antitumor therapy.

High-serum phosphate and parathyroid hormone distinctly regulate bone loss and vascular calcification in experimental chronic kidney disease.

BACKGROUND: In chronic kidney disease (CKD), increases in serum phosphate and parathyroid hormone (PTH) aggravate vascular calcification (VC) and bone loss. This study was designed to discriminate high phosphorus (HP) and PTH contribution to VC and bone loss. METHODS: Nephrectomized rats fed a HP diet underwent either sham operation or parathyroidectomy and PTH 1-34 supplementation to normalize serum PTH. RESULTS: In uraemic rats fed a HP diet, parathyroidectomy with serum PTH 1-34 supplementation resulted in (i) reduced aortic calcium (80%) by attenuating osteogenic differentiation (higher α-actin; reduced Runx2 and BMP2) and increasing the Wnt inhibitor Sclerostin, despite a similar degree of hyperphosphataemia, renal damage and serum Klotho; (ii) prevention of bone loss mostly by attenuating bone resorption and increases in Wnt inhibitors; and (iii) a 70% decrease in serum calcitriol levels despite significantly reduced serum Fgf23, calcium and renal 24-hydroxylase, which questions that Fgf23 is the main regulator of renal calcitriol production. Significantly, when vascular smooth muscle cells (VSMCs) were exposed exclusively to high phosphate and calcium, high PTH enhanced while low PTH attenuated calcium deposition through parathyroid hormone 1 receptor (PTH1R) signalling. CONCLUSIONS: In hyperphosphataemic CKD, a defective suppression of high PTH exacerbates HP-mediated osteogenic VSMC differentiation and reduces vascular levels of anti-calcifying sclerostin.

Changes in bone metabolism after gastric cancer surgery in male patients: a prospective observational study.

BACKGROUND: Several retrospective studies have shown that bone disorders occur after gastric cancer surgery. This study was designed to prospectively evaluate the changes in bone metabolism after gastrectomy for gastric cancer. METHODS: We prospectively enrolled 39 men with early gastric cancer who underwent gastrectomy. We excluded women to avoid the effects of menopause. We employed dual energy X-ray absorptiometry (DEXA) to measure bone mineral density (BMD) of the lumbar spine. DEXA was performed before and 1 and 2 years after surgery. The serum levels of alkaline phosphatase (ALP), 1,25-dihydroxy vitamin D [1,25(OH)2VD], 25-hydroxy vitamin D [25(OH)VD], and estradiol were measured before surgery and every 3 months until 2 years after surgery. RESULTS: DEXA revealed that BMD significantly decreased by 0.036 ± 0.033 g/cm2 12 months after gastrectomy (P < 0.001) and by 0.046 ± 0.040 g/cm2 24 months after gastrectomy (P < 0.001). The serum ALP level significantly increased by 38.31 ± 103.8 IU/L 24 months after surgery (P = 0.013). The serum 25(OH)VD level significantly decreased by 4.88 ± 6.42 ng/ml 24 months after surgery (P < 0.001), whereas the serum 1,25(OH)2VD levels were consistently in the normal range. The serum estradiol level significantly increased by 2.94 ± 7.49 pg/ml 12 months after gastrectomy (P = 0.035). A lower preoperative body mass index (BMI) significantly correlated with the reduction in BMD 12 months after surgery; the correlation coefficient was 0.37 (P = 0.025). CONCLUSIONS: This study showed that a significant decrease in BMD was observed for up to 24 months after gastrectomy, not only 12 months.

The effect of prolactin itself and in combination with estrogen on bone mineral density in female rats.

Estrogen deficiency induced by hyperprolactinemia can reduce bone mineral density. Hyperprolactinemia through other mechanisms other than estrogen deficiency, with direct effect on the bone might cause bone loss in women. The present study evaluated the effect of prolactin itself and in combination with estrogen on bone mineral density of female rats. This study was performed on 50 adult female rats divided into five groups; included (a) Sham, (b) Ovariectomized rats; and (c-e) included ovariectomized rats were given prolactin alone, prolactin + estradiol and estradiol, respectively. Bone mineral density (BMD) and vitamin D metabolism parameters were checked in all groups before and after the study. There was no significant difference in baseline values of these parameters. Estradiol could increase 1,25(OH)2D3 and PTH levels and decrease serum ALP level. In addition, Prolactin could increase serum 1,25(OH)2D3 and ALP levels and decrease tibia BMD significantly without any change in PTH level. Combination of estradiol and prolactin could increase serum 1,25(OH)2D3 and PTH and tibia BMD compared with OVX group. Combination of estradiol and prolactin could significantly increase tibia BMD, in ovariectomized rats. We hypothesized that this combination could improve bone loss secondary to hyperprolactinemia by elevated PTH.

Correlation of Vitamin D3 (Calcitriol) Serum Concentrations with Vitamin B12 and Folic Acid in Women Undergoing in vitro Fertilisation/Intracytoplasmatic Sperm Injection.

BACKGROUND: The important role of vitamin D3 in human health is well recognized. In this study, we measured serum concentrations of vitamin D3, vitamin B12 and B9 (folic acid) in 410 women undergoing in vitro fertilisation (IVF)/intracytoplasmatic sperm injection (ICSI) with dedicated focus on 3-month changes in consideration of patients' BMI. METHODS: Patients were of European origin and did not take any supplementation of D3. In preparing for pregnancy, patients took ≥4 weeks 400 µg folic acid combined with 9 µg vitamin B12 and 150 µg iodide as recommended. RESULTS: We found a significant 3-month quartile change of D3 serum concentrations (p < 0.0001) with maximum levels in autumn and lowest in spring. D3 correlated significantly with B12 (p = 0.035, ρ = 0.102) and folic acid (p < 0.0001, ρ = 0.191). BMIs however showed a negative correlation with B12 (p = 0.031, ρ = -0.105) and folic acid (p = 0.012, ρ = -0.125). CONCLUSIONS: Our results suggest a model in which the sun exposure during summer months enables storage of D3 followed by a slow release as a major factor to maintain D3 levels throughout the year. Finally, our data indicate that B12 and folic acid uptake might be influenced by vitamin D receptor and D3, where D3 and the BMI appear to have an indirect relationship - via B12 and folic acid.

Effectiveness of Vitamin D Supplementation in the Management of Multiple Sclerosis: A Systematic Review.

OBJECTIVE: to examine the extent of effect vitamin D in Multiple Sclerosis (MS) on pathology and symptoms. METHODS: A literature search was performed in November 2018 (CRD42018103615). Eligibility criteria: randomised control trials in English from 2012 to 2018; a clinical diagnosis of MS; interventions containing vitamin D supplementation (vitamin D3 or calcitriol) in disease activity compared to a control/placebo; improvement in: serum 25(OH)D, relapse rates, disability status by Expanded Disability Status Scale (EDSS) scores, cytokine profile, quality of life, mobility, T2 lesion load and new T2 or T1 Gd enhancing lesions, safety and adverse effects. Risk of bias was evaluated. RESULTS: Ten studies were selected. The study size ranged from 40 to 94 people. All studies evaluated the use of vitamin D supplementation (ranging from 10 to 98,000 IU), comparing to a placebo or low dose vitamin D. The duration of the intervention ranged from 12 to 96 weeks. One trial found a significant effect on EDSS score, three demonstrated a significant change in serum cytokines level, one found benefits to current enhancing lesions and three studies evaluating the safety and tolerability of vitamin D reported no serious adverse events. Disease measures improved to a greater extent overall in those with lower baseline serum 25(OH)D levels. CONCLUSIONS: As shown in 3 out of 10 studies, improvement in disease measures may be more apparent in those with lower baseline vitamin D levels.

In vivo evidence for an interplay of FGF23/Klotho/PTH axis on the phosphate handling in renal proximal tubules.

Phosphate homeostasis is primarily maintained in the renal proximal tubules, where the expression of sodium/phosphate cotransporters (Npt2a and Npt2c) is modified by the endocrine actions of both fibroblast growth factor 23 (FGF23) and parathyroid hormone (PTH). However, the specific contribution of each regulatory pathway in the proximal tubules has not been fully elucidated in vivo. We have previously demonstrated that proximal tubule-specific deletion of the FGF23 coreceptor Klotho results in mild hyperphosphatemia with little to no change in serum levels of FGF23, 1,25(OH)2D3, and PTH. In the present study, we characterized mice in which the PTH receptor PTH1R was specifically deleted from the proximal tubules, either alone or in combination with Klotho ( PT-PTH1R-/- and PT-PTH1R/KL-/-, respectively). PT-PTH1R-/- mice showed significant increases in serum FGF23 and PTH levels, whereas serum phosphate levels were maintained in the normal range, and Npt2a and Npt2c expression in brush border membrane (BBM) did not change compared with control mice. In contrast, PT-PTH1R/KL-/- mice displayed hyperphosphatemia and an increased abundance of Npt2a and Npt2c in the renal BBM, along with increased circulating FGF23 levels. While serum calcium was normal, 1,25(OH)2D3 levels were significantly decreased, leading to extremely high levels of PTH. Collectively, mice with a deletion of PTH1R alone in proximal tubules results in only minor changes in phosphate regulation, whereas deletion of both PTH1R and Klotho leads to a severe disturbance, including hyperphosphatemia with increased sodium/phosphate cotransporter expression in BBM. These results suggest an important interplay between the PTH/PTH1R and FGF23/Klotho pathways to affect renal phosphate handling in the proximal tubules.