Randomized Trial of Etelcalcetide for Cardiac Hypertrophy in Hemodialysis.

[Figure: see text].

Alfacalcidol improves the growth velocity in children with vitamin D deficiency/insufficiency: A single center retrospective cohort study.

OBJECTIVES: To investigate the growth velocity-improving effects of vitamin D replacement therapy in pediatric patients diagnosed with vitamin D deficiency and insufficiency. STUDY DESIGN: A retrospective cohort study was conducted in 34 pediatric patients diagnosed with vitamin D deficiency/insufficiency. Based on the clinical findings, the subjects were divided into two groups: a bowed leg (BL) group and a non-bowed leg (non-BL) group. After the initiation of alfacalcidol, the standard deviation score (SDS) of their heights, weights and growth velocities in each group were monitored. RESULTS: The median age at the first visit was significantly lesser in the BL group (1.58 years old [interquartile range (IQR): 1.33, 2.17]) than that in the non-BL group (3.00 years old [IQR: 2.33, 3.67]). On the contrary, the SDS for height was significantly lower in the non-BL group (-2.27 [IQR: -2.63, -1.94]) than that in the BL group (-1.37 [IQR: -1.91, -1.07]). One-year treatment with alfacalcidol showed significant improvements in both height SDSs and growth velocity SDSs not only in the BL group but also in the non-BL group. CONCLUSIONS: The current study revealed that vitamin D replacement therapy improved the growth rate in children with vitamin D deficiency/insufficiency, regardless of the presence of BL. This study emphasizes the importance of assessing the vitamin D status in children with poor growth rates and suggests that alfacalcidol could be a valid option for the treatment of short stature.

Five-year Estimated Glomerular Filtration Rate in Patients With Hypoparathyroidism Treated With and Without rhPTH(1-84).

CONTEXT: Chronic hypoparathyroidism (HypoPT) is conventionally managed with oral calcium and active vitamin D. Recombinant human parathyroid hormone (1-84) (rhPTH[1-84]) is a therapy targeting the pathophysiology of HypoPT by replacing parathyroid hormone. OBJECTIVE: To compare changes in the estimated glomerular filtration rate (eGFR) in patients with chronic HypoPT receiving or not receiving rhPTH(1-84) during a 5-year period. DESIGN/SETTING: A retrospective analysis of patients with chronic HypoPT treated with or without rhPTH(1-84). PATIENTS: Sixty-nine patients with chronic HypoPT from 4 open-label, long-term trials (NCT00732615, NCT01268098, NCT01297309, and NCT02910466) composed the rhPTH(1-84) cohort and 53 patients with chronic HypoPT not receiving rhPTH(1-84) from the Geisinger Healthcare Database (01/2004-06/2016) composed the historical control cohort. INTERVENTIONS: The rhPTH(1-84) cohort (N = 69) received rhPTH(1-84) therapy; the historical control cohort (N = 53) did not receive rhPTH(1-84). MAIN OUTCOME MEASURES: Changes in eGFR from baseline during a 5-year follow-up were examined in multivariate regression analyses. RESULTS: At baseline, demographic characteristics and eGFR were similar between cohorts, though the proportions with diabetes and cardiac disorders were lower in the rhPTH(1-84) cohort. At the end of follow-up, mean eGFR increased by 2.8 mL/min/1.73 m2 in the rhPTH(1-84) cohort, while mean eGFR fell by 8.0 mL/min/1.73 m2 in the control cohort. In the adjusted model, the difference in the annual eGFR change between the rhPTH(1-84) cohort and the control cohort was 1.7 mL/min/1.73 m2 per year (P = 0.009). CONCLUSIONS: Estimated glomerular filtration rate was preserved for over 5 years among patients with chronic HypoPT receiving rhPTH(1-84) treatment, contrasting with an eGFR decline among those not receiving rhPTH(1-84).

Rotational and translational osteotomy for treatment of severe deformity in hypophosphatemic rickets: A case report.

RATIONALE: Hypophosphatemic rickets (HR) is a rare hereditary disease characterized by hypophosphatemia, defects in bone mineralization, and rickets, and surgical intervention is warranted for the patient of severe skeletal deformity. PATIENT CONCERNS: Here we report a case of an 11-year-old boy who presented with severe varus deformities of the bilateral lower extremities and was associated with uncoordinated gait with multiple unintentional falls onto ground resulting in fractures of lower extremities. DIAGNOSES: He was diagnosed as HR caused by genetic mutations in the phosphate-regulating endopeptidase homologue. Based on his family history and laboratory tests, including high serum alkaline phosphatase, high urinary phosphorus, hypophosphatemia, and normal serum calcium level, the patient was diagnosed with this disorder. INTERVENTIONS: Rotational and translational osteotomy was performed to redress the severe varus deformity and readjust the malalignment of the lower extremity. OUTCOMES: Right after the surgery, the alignment in the left lower extremity was readjusted, and his appearance seemed normal. Combined with rehabilitation and pharmacological intervention, including oral intake of phosphate and alphacalcidol, the bone healed uneventfully. After the second surgery of a similar procedure on the right femur, the patient was able to walk almost like a normal teenager. LESSONS: This case proposed a novel technique to treat severe varus or valgus deformity of the lower extremity. HR is a rare disease, and it is important to stress its recognition to avoid delay of diagnosis and surgical intervention if necessary.

Effects of dietary calcium and phosphorus levels and supplementation of 25-hydroxycholecalciferol on performance and bone properties of broiler starters.

To investigate effects of dietary calcium (Ca) and phosphorus (P) levels and 25-hydroxycholecalciferol (25OHD3) supplementation on performance and bone properties of broiler starters, 224 male Arbor Acre broilers were used in a 21-d trial. Broilers were allotted to one of four treatments in a 2 × 2 factorial arrangement including diets either normal or low in Ca and P, which were further supplemented or not with 69 µg 25OHD3/kg feed. Feeding low Ca and P diets significantly reduced performance of boilers and decreased ash, Ca, P and hydroxyproline contents in tibias and femurs (p < 0.05). Ultimate load, bending moment, stiffness and energy to fail were decreased (p < 0.05) in broilers fed diets deficient in Ca and P. Addition of 25OHD3 did not influence performance but significantly increased serum 25OHD3 levels. Furthermore, the addition of 25OHD3 caused an increased tibial and femoral bone density and femoral hydroxyproline content (p < 0.05), increased bending moment in tibias (p < 0.05), and enhanced ultimate load and bending moment in femurs (p < 0.05). No significant interactions were observed for bone properties. Overall, feeding 25OHD3 at 69 µg/kg feed to broilers had no effect on growth performance but partly improved bone biochemical and biomechanical properties of broiler starters.

Co-targeting of endothelin-A and vitamin D receptors: a novel strategy to ameliorate cisplatin-induced nephrotoxicity.

BACKGROUND: Although modulation of the vitamin D receptor (VDR) and endothelin-A receptor (ETAR) has previously been reported to offer renoprotection against cisplatin-induced nephrotoxicity, the possible interaction between the ET-1 and vitamin D pathways remains obscure. Therefore, the present study addressed the possible interaction between these signalling pathways using BQ-123 (a selective ETAR blocker) and alfacalcidol (a vitamin D3 analogue) separately or in combination. METHODS: Male Sprague-Dawley rats were divided into the following groups: control (DMSO orally), cisplatin (single dose of 6 mg/kg ip; nephrotoxicity model), cisplatin + BQ-123 (1 mg/kg BQ-123 ip 1 h before and 1 day after cisplatin), cisplatin + alfacalcidol (50 ng/kg alfacalcidol orally 5 days before and 14 days after cisplatin), and cisplatin + BQ-123+alfacalcidol. Nephrotoxicity was evaluated 96 h and 14 days following cisplatin administration. RESULTS: Both BQ-123 and alfacalcidol counteracted cisplatin-induced nephrotoxic changes. Specifically, they reduced serum creatinine and urea levels; renal tumour necrosis factor-alpha (TNF-α), transforming growth factor-beta1 (TGF-ß1), and phosphorylated nuclear factor-kappa B (pNF-κB) content; and caspase-3 activity. They downregulated ET-1 and ETAR expression and ameliorated cisplatin-induced acute tubular necrosis. In addition, the treatments have increased VDR and endothelin-B receptor (ETBR) expression; however, BQ-123 did not affect ETBR. The effect of the combination regimen surpassed that of each drug alone. CONCLUSION: These findings highlight the potential cross-talk between vitamin D and ET-1 pathways and pave the way for future preclinical/clinical studies to explore further mechanisms involved in this cross-talk.

25-Hydroxyvitamin D serum levels in rheumatic female patients in southeast Spain: The paradigm of daily optimal sunshine levels and inadequate vitamin D status / Concentraciones séricas de 25-hidroxivitamina D en mujeres reumáticas del sureste de España: el paradigma de los niveles diarios óptimos de luz solar y la insuficiencia de vitamina D

Background: Almeria is a region in southeast Spain with optimal sunlight levels, along with low pluvial and pollution rates. If exposure to sunlight is sufficient to maintain adequate levels of vitamin D (25OHD), this population should display high serum levels. Objectives: To describe 25OHD serum status in women from Almeria and evaluate the impact of long sunlight exposure along the seasons on 25OHD. Methods: Cross-sectional study, performed in women consecutively recruited from an outpatient rheumatology clinic. Serum levels of 25OHD were assessed in all patients and evaluated according to age (<48 yrs, 48-53 yrs, 54-60 yrs and >60 yrs), season, and presence or absence of menopause. Clinical and laboratory variables that could affect status of vitamin D were also considered. Results: The sample included 319 Caucasian female patients. Mean 25OHD were 30.2ng/ml with 195 (61.1%) exhibiting 25OHD inadequate serum levels. Season had a significant effect on 25OHD levels, with autumn being the season in which 25OHD serum levels remained well above 30ng/ml in all age bands, and winter the season with more levels of insufficiency. Menopause did not modify 25OH serum levels. Women whose age was below 48 and over 60 had inadequate levels of 25OHD during summer. Conclusions: Optimal levels of sunlight could not overcome the problem of inadequate 25OHD serum levels, particularly in elderly and young female population. Vitamin D supplementation may be recommended predominantly in winter and summer in this population

Antecedentes: Almería es una región del sureste de España con un grado óptimo de luz solar, junto con bajas tasas de contaminación y lluvia. Si la exposición a la luz solar es suficiente para mantener niveles adecuados de vitamina D (25OHD), esta población debería presentar concentraciones séricas altas. Objetivos: Describir los valores séricos de 25OHD en mujeres de Almería y evaluar el efecto de la exposición prolongada a la luz solar sobre la 25OHD a lo largo de las distintas estaciones. Métodos: Estudio transversal en mujeres reclutadas consecutivamente en una consulta externa de reumatología. Se determinaron las concentraciones séricas de 25OHD en todas las pacientes y se valoraron en función de la edad (< 48 años, 48-53 años, 54-60 años y > 60 años), la estación y la presencia o ausencia de menopausia. También se tuvieron en cuenta las variables clínicas y analíticas que pudieran afectar al estado de la vitamina D. Resultados: La muestra incluyó 319 mujeres de raza blanca. El valor medio de 25OHD fue de 30,2 ng/ml, y 195 (61,1%) mostraron concentraciones séricas inadecuadas de 25OHD. La estación tenía un efecto importante en las concentraciones de 25OHD, y el otoño era la estación en la que los valores séricos de 25OHD se mantenían bastante por encima de 30 ng/ml en todas las franjas de edad, y el invierno la estación con más grado de insuficiencia. La menopausia no modificaba las concentraciones séricas de 25OH. Las mujeres menores de 48 años y mayores de 60 años tenían niveles insuficientes de 25OHD durante el verano. Conclusión: La luz solar óptima no podía superar el problema de la insuficiencia de las concentraciones séricas de 25OHD, sobre todo en las poblaciones de mujeres mayores y jóvenes. Pueden recomendarse suplementos de vitamina D predominantemente en invierno y en verano en esta población

Auditing the Efficacy and Safety of Alfacalcidol and Calcium Therapy in Idiopathic Hypoparathyroidism.

CONTEXT: Patients with hypoparathyroidism are treated with vitamin D and calcium. PTH is an emerging option because of its physiological action. It is important to assess the efficacy and shortcomings of conventional therapy. OBJECTIVE: We assessed the efficacy and safety of alfacalcidol in a large cohort of patients with idiopathic hypoparathyroidism (IH) and identified a subset who could be treated without oral calcium. DESIGN AND SETTING: Observational study at tertiary care center. SUBJECTS AND METHODS: We assessed 92 patients with IH who were receiving alfacalcidol and oral calcium to maintain an optimal serum total calcium level of 8.0 to 8.5 mg/dL during routine follow-up. Patients with suboptimal control were provided free medicines and followed up frequently. Oral calcium and alfacalcidol doses were titrated sequentially to determine the minimum doses for optimal calcium control. Serum phosphate level, 1,25-dihydroxyvitamin D, fractional excretion of phosphorus (FEPh), and hypercalciuria (urine calcium-to-creatinine ratio, >0.2) were assessed at each step of titration. RESULTS: Only 38% of patients had optimal calcium control during routine follow-up. With good compliance, all achieved optimal serum calcium and 1,25-dihydroxyvitamin D levels and 43% of patients could stop taking oral calcium. Hyperphosphatemia, hypercalciuria, and low FEPh persisted at all stages of therapy. Serum phosphorus levels normalized when the serum calcium level increased to 9.9 mg/dL, but this level of serum total calcium was associated with hypercalciuria in 90% of patients. CONCLUSION: Alfacalcidol is effective in achieving calcemic control in IH. Calcemic control without oral calcium was achieved in 43% of patients receiving alfacalcidol. However, optimal calcium control was associated with hyperphosphatemia and hypercalciuria in most patients.

Activated vitamin D3 formulations can be safely used as concomitant medication for prevention of denosumab-induced hypocalcemia in women with postmenopausal osteoporosis.

AIM: Denosumab prevents osteoporosis by potently inhibiting bone resorption, but requires oral therapy with calcium and vitamin D preparations to prevent the side effects of hypocalcemia. Generally, a combination drug containing calcium, natural vitamin D, and magnesium is used. However, if activated vitamin D has been used before the initiation of denosumab therapy, continued use of activated vitamin D is not uncommon. This study aimed to evaluate the combination vitamin D preparation, alfacalcidol, and eldecalcitol on the therapeutic effect on denosumab therapy, the preventive effect on hypocalcemia, and the effect on renal function, to determine the optimal choice of concomitant medication. METHODS: This is a retrospective and single-center study. Among 39 patients who had used denosumab (60 mg dose) for at least 12 months between November 2013 and October 2015, those who used the combination medication concomitantly as the standard treatment, those who used alfacalcidol concomitantly, and those who used eldecalcitol concomitantly were compared. RESULTS: Denosumab therapy markedly increased lumbar spine and femoral neck bone densities at 12 months in the three groups, showing no particular difference in the rate of increase of bone density. The three groups had marked decreases in bone metabolism markers, but had no intergroup differences. No hypocalcemia, hypercalcemia, or obvious renal dysfunction occurred over 12 months. CONCLUSION: This study indicates that the use of activated vitamin D preparations, as concomitant medications with denosumab therapy, is appropriate considering the therapeutic efficacy of denosumab, prevention of hypocalcemia, and influence on renal function.

Interactive effects of calcium and top-dressed 25-hydroxy vitamin D3 on egg production, egg shell quality, and bones attributes in aged Lohmann LSL-lite layers1.

Calcium and vitamin D are critical in attenuating metabolic Ca insufficiency often observed in older hens. We investigated interactive effects of dietary Ca and top-dressed 25-hydroxy vitamin D3 (25OHD3) on egg production, eggshell quality (thickness, EST, and breaking strength, ESBS), serum Ca, kidney, liver, and bones attributes in 74-wk old Lohmann LSL-lite layers. A total of 4 levels of Ca (3.0, 3.5, 4.0, and 4.5%) and 3 levels of 25OHD3 (0, 69, and 138 µg/kg) were tested. All diets had basal level of 3,300 IU of vitamin D3/kg, were allocated to 84 individually housed hens (n = 7), and fed to 81 wk of age. Dual-energy X-ray absorptiometry was used to measure bone mineral content (BMC) and density (BMD) in left ulna, femur, and tibia at week 74 (13 spare birds, baseline) and week 81. Birds fed diets containing 3.0, 3.5, 4.0, and 4.5% Ca consumed 3.4, 4.1, 4.2, and 4.8 Ca g/b/d. Interaction (P < 0.05) between Ca and 25OHD3 was such that 25OHD3 linearly increased egg weight and percentage of eggs graded as jumbo (≥70 g) at 3.0, 3.5, and 4.5% Ca levels. There was no interaction (P > 0.05) between Ca and 25OHD3 on the rest of the parameters. Calcium increased EST and ESBS quadratically (P < 0.05), EST increased with Ca intake up to 4.1 g of Ca/b/d whereas Ca intakes (3.4 and 4.8 g of Ca/b/d) had poor ESBS relative to intermediate Ca intakes. Kidney ash concentration increased linearly (P = 009) with Ca intake. However, BMC and BMD in ulna, tibia, and femur declined (P < 0.05) at week 81 relative to baseline. In conclusion, top dressed 25OHD3 linearly increased egg weight at various Ca intakes with no negative effect on eggshell quality or bone attributes. Feeding 4.1 to 4.2 g of Ca/b/d improved eggshell quality, however, higher intake deteriorated eggshell quality and increased renal ash accumulation with no benefit on skeletal integrity.

Effect of Alfacalcidol on Inflammatory markers and T Cell Subsets in Elderly with Frailty Syndrome: a Double Blind Randomized Controlled Trial.

BACKGROUND: Alphacalcidol, a vitamin D analog, shows immune regulatory potency as it works on the macrophage and T cell to control inflammation and T cell dysregulation in elderly. None has been known about its effect on elderly with various states of frailty syndrome, which have different level of chronic low grade inflammation. This study aimed to determine the effect of alphacalcidol on inflammatory cytokines (IL-6, IL-10, g-IFN ) and T cell subsets (CD4/CD8 ratio and CD8+ CD28-) of elderly with various stages of frailty syndrome. METHODS: from January to July 2017, a double blind randomized controlled trial (RCT) with allocation concealment, involving 110 elderly subjects from Geriatric Outpatient Clinic Cipto Mangunkusumo Hospital Jakarta, was conducted to measure the effect of 0.5 mcg alphacalcidol administration for 90 days to inflammatory cytokines (IL-6, IL-10, g-IFN) from PBMC culture supernatant, as well as CD4/CD8 and CD8+CD28- percentage using flow cytometry. Statistical analysis using SPSS version 20 was performed with t-test to measure mean difference. RESULTS: of 110 subjects involved in the RCT consisting of 27 fit, 27 pre-frail  and 56 frail elderly, 25(OH)D serum level was found to be as low as 25.59 (12.2) ng/ml in alphacalcidol group and 28.27 (10.4) ng/ml in placebo group. Alphacalcidol did not decrease IL-6 (p=0.4) and g- IFN (p=0.001), but it increased IL-10 (p=0,005) and decreased IL6/IL10 ratio (p=0.008). Alphacalcidol increased CD4/CD8 ratio from 2.68 (SD 2.45) to 3.2 (SD 2.9); p=0.001 and decreased CD8+ CD28- percentage from 5.1 (SD 3.96) to 2.5 (1.5); p<0.001. Sub group analysis showed similar patterns in all frailty states. CONCLUSION: Alphacalcidol improves immune senescence by acting as anti-inflammatory agent through increased IL-10 and decreased IL6/IL-10 ratio and also improves cellular immunity through increased CD4/CD8 ratio and decreased CD8+ CD28- subset in elderly. This effect is not influenced by frailty state.

Effects of activated vitamin D, alfacalcidol, and low-intensity aerobic exercise on osteopenia and muscle atrophy in type 2 diabetes mellitus model rats.

Diabetes mellitus causes secondary osteoporosis and muscle atrophy. The ability of alfacalcidol (ALF) and exercise (Exe) to inhibit osteoporosis and muscle atrophy in type 2 diabetes mellitus (T2DM) model rats was examined. Twenty-week-old Otsuka Long-Evans Tokushima Fatty rats were randomized to ALF (orally 0.1 µg/kg/day), Exe (treadmill exercise at 10 m/min, 60 min/day, 5 days/week), Comb (ALF and Exe), and Cont (T2DM control treated with vehicle and no exercise) groups (n = 8-10 per group). Sedentary Long-Evans Tokushima Otsuka rats were used as a non-hyperphagic control. After treatment for 2 or 6 weeks, blood glucose (BG) levels, cross-sectional area (CSA) of tibialis anterior muscle fibers, femoral bone mineral density (BMD), and relative quantities of muscle anabolic markers (Pax7, MyoD, and myogenin) and catabolic markers (Atrogin-1, MuRF1, and REDD1) of the soleus muscle assessed by real-time polymerase chain reaction assays were measured. Exe and Comb treatments for 6 weeks decreased BG levels compared with those of the Cont group. ALF, Exe, and Comb treatments for 2 and 6 weeks recovered the CSA compared with that of the Cont group. ALF and Comb treatments for 6 weeks increased femoral BMDs compared with those of the Cont group. After 2 weeks of treatment, Comb treatment increased MyoD expression and decreased MuRF1 expression. ALF or Exe monotherapy significantly decreased Atrogin-1 or MuRF1 expression after 2 weeks of treatment, respectively. After 6 weeks of treatment, ALF and Comb treatments decreased Atrogin-1 and REDD1. These results demonstrate that a combination of ALF and Exe improved CSA from the early phase of treatment by stimulating skeletal muscle differentiation and suppressing muscle catabolic genes. Improvements in BG, BMD, and CSA were observed as long-term effects of the combination therapy. Continued suppression of muscle catabolic genes was observed as a background to these effects.

1α-Hydroxycholecalciferol improves the growth performance and up-regulates the mRNA expression of vitamin D receptor in the small intestine and kidney of broiler chickens.

1α-Hydroxycholecalciferol (1α-OH-D3) is a vitamin D derivative. The objective of this study was to evaluate the effects of 1α-OH-D3 on the growth and the mRNA expression of vitamin D receptor (VDR) in the small intestine and kidney of chickens. A total of 240 males of one-day-old Ross 308 broilers was randomly assigned to 4 treatments with 5 replicates of 12 birds per replicate. Three levels of 1α-OH-D3 (1.25, 2.5, and 5 µg/kg) were added to a basal diet containing 0.50% calcium (Ca), 0.25% non-phytate phosphorus (NPP), and without supplemental cholecalciferol (vitamin D3). The control diet contained 1.00% Ca, 0.45% NPP, and 25 µg/kg cholecalciferol. Dietary 1α-OH-D3 levels linearly improved the average daily feed intake (ADFI), average daily gain (ADG), femur and tibia mineralization, and plasma Ca concentration, and retained Ca and total phosphorus (tP) amounts in broilers from 1 to 21 d of age (P < 0.05). In addition, 1α-OH-D3 also linearly up-regulated the mRNA expression levels of VDR in the duodenum as well as those of VDR and sodium-phosphate cotransporter NaPi-IIa and NaPi-IIc in the kidney of broilers (P < 0.05). However, 1α-OH-D3 did not affect the mRNA levels of 25-hydroxylase in the liver or NaPi-IIb in the duodenum (P > 0.05). No differences were observed in the ADFI, ADG, bone length, plasma mineral concentration, retained tP amount, or the mRNA levels of the above genes (except for VDR in the kidney) between the birds fed the diet with 5 µg/kg 1α-OH-D3 and the birds fed the control diet (P > 0.05). By contrast, the weight, ash weight, ash percentage, and Ca percentage of the bone, retained Ca amount, and the mRNA level of VDR in the kidney were lower in the birds fed the diet with 5 µg/kg 1α-OH-D3 than in the birds fed the control diet (P < 0.05). These data indicate that 1α-OH-D3 up-regulates the gene expression of VDR in the small intestine and kidney at the transcriptional level, thereby improving the growth performance and bone mineralization of broiler chickens from 1 to 21 d of age.

Stimulation of intestinal calcium absorption by orally administrated vitamin D3 compounds: a prospective open-label randomized trial in osteoporosis.

Intestinal fractional calcium absorption (FCA) was assessed before and after vitamin D3 treatment. Serum 1,25(OH)2D concentration was significantly increased by plain vitamin D3 and reduced by eldecalcitol. The 1α hydroxyl calcidiol and eldecalcitol treatments increased FCA, which may be induced through direct stimulation of vitamin D receptors in the intestine. INTRODUCTION: To assess the effects of vitamin D3 compounds on intestinal FCA and calcium-regulating hormones in post-menopausal osteoporosis, a randomized open-label prospective study was conducted. METHODS: Forty eligible patients were allocated randomly into four groups: eldecalcitol (ELD; 0.75 µg/day), 1α hydroxyl calcidiol (ALF; 1 µg/day), plain vitamin D3 (800 IU/day), and control. Before and after the 4-week treatment, intestinal FCA was estimated by using a double isotope method, and serum concentrations of calcium-regulating hormones and a bone turnover marker were measured. RESULTS: The baseline FCA value of the participants was 21.5 ± 7.9% (mean ± SD) and was significantly correlated with serum 1,25(OH)2D (calcitriol) concentration. After the treatment, the FCA significantly increased by 59.5% (95% CI, 41.6 to 77.4%) in the ELD group and by 45.9% (27.9 to 63.8%) in the ALF group, whereas no significant change in the plain vitamin D3 group was found. Unlike the baseline FCA, post-treatment FCA exhibited no significant correlation with serum calcitriol concentration. Parathyroid hormone levels were suppressed by ALF and plain vitamin D3 but were sustained in the ELD and control groups. Serum calcitriol tended to be suppressed by ELD, whereas plain vitamin D3 treatment increased both serum 25(OH)D and calcitriol concentrations. CONCLUSION: These findings suggest that oral administration of vitamin D3 analogues (ALF and ELD) stimulates FCA but plain vitamin D3 does not. Those effects of vitamin D3 compounds on FCA were independent of serum calcitriol concentration, suggesting that ALF and ELD may directly stimulate intestinal vitamin D receptors.

Vitamin D supplementation for chronic liver diseases in adults.

BACKGROUND: Vitamin D deficiency is often reported in people with chronic liver diseases. Therefore, improving vitamin D status could have a beneficial effect on people with chronic liver diseases. OBJECTIVES: To assess the beneficial and harmful effects of vitamin D supplementation in people with chronic liver diseases. SEARCH METHODS: We searched The Cochrane Hepato-Biliary Group Controlled Trials Register, Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, Science Citation Index Expanded, and Conference Proceedings Citation Index - Science. We also searched databases of ongoing trials and the World Health Organization International Clinical Trials Registry Platform. We scanned bibliographies of relevant publications and asked experts and pharmaceutical companies for additional trials. All searches were up to January 2017. SELECTION CRITERIA: Randomised clinical trials that compared vitamin D at any dose, duration, and route of administration versus placebo or no intervention in adults with chronic liver diseases. Vitamin D could have been administered as supplemental vitamin D (vitamin D3 (cholecalciferol) or vitamin D2 (ergocalciferol)), or an active form of vitamin D (1α-hydroxyvitamin D (alfacalcidol), 25-hydroxyvitamin D (calcidiol), or 1,25-dihydroxyvitamin D (calcitriol)). DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by The Cochrane Collaboration. We contacted authors of the trials to ask for missing information. We conducted random-effects and fixed-effect meta-analyses. For dichotomous outcomes, we calculated risk ratios (RRs), and for continuous outcomes, we calculated mean differences (MD), both with 95% confidence intervals (CI) and Trial Sequential Analyses-adjusted CIs. We calculated Peto odds ratio (OR) for rare events. We considered risk of bias in domains to assess the risk of systematic errors. We conducted Trial Sequential Analyses to control the risk of random errors. We assessed the quality of the evidence with GRADE. MAIN RESULTS: We included 15 randomised clinical trials with 1034 participants randomised. All trials had a parallel group design. Nine trials were conducted in high-income countries and six trials in middle-income countries. All trials were at high risk of bias. Six trials included participants with chronic hepatitis C, four trials included participants with liver cirrhosis, four trials included participants with non-alcoholic fatty liver disease, and one trial included liver transplant recipients. All included trials reported the baseline vitamin D status of participants. Participants in six trials had baseline 25-hydroxyvitamin D levels at or above vitamin D adequacy (20 ng/mL), while participants in the remaining nine trials were vitamin D insufficient (less than 20 ng/mL). All trials administered vitamin D orally. Mean duration of vitamin D supplementation was 0.5 years and follow-up was 0.6 years. Eleven trials (831 participants; 40% women; mean age 52 years) tested vitamin D3, one trial (18 men; mean age 61 years) with three intervention groups tested vitamin D2 and 25-dihydroxyvitamin D in separate groups, and three trials (185 participants; 55% women; mean age 55 years) tested 1,25-dihydroxyvitamin D. Seven trials used placebo, and eight trials used no intervention in the control group.The effect of vitamin D on all-cause mortality at the end of follow-up is uncertain because the results were imprecise (Peto OR 0.70, 95% CI 0.09 to 5.38; I2 = 32%; 15 trials; 1034 participants; very low quality evidence). Trial Sequential Analysis on all-cause mortality was performed based on a mortality rate in the control group of 10%, a relative risk reduction of 28% in the experimental intervention group, a type I error of 2.5%, and type II error of 10% (90% power). There was no diversity. The required information size was 6396 participants. The cumulative Z-curve did not cross the trial sequential monitoring boundary for benefit or harm after the 15th trial, and the Trial Sequential Analyses-adjusted CI was 0.00 to 2534.The effect of vitamin D on liver-related mortality (RR 1.62, 95% CI 0.08 to 34.66; 1 trial; 18 participants) and on serious adverse events such as hypercalcaemia (RR 5.00, 95% CI 0.25 to 100.8; 1 trial; 76 participants), myocardial infarction (RR 0.75, 95% CI 0.08 to 6.81; 2 trials; 86 participants), and thyroiditis (RR 0.33 95% CI 0.01 to 7.91; 1 trial; 68 participants) is uncertain because the results were imprecise. The evidence on all these outcomes is of very low quality. The effect of vitamin D3 on non-serious adverse events such as glossitis (RR 3.70, 95% CI 0.16 to 87.6; 1 trial; 65 participants; very low quality of evidence) is uncertain because the result was imprecise.Due to few data, we did not conduct Trial Sequential Analysis on liver-related mortality, and serious and non-serious adverse events.We found no data on liver-related morbidity and health-related quality of life in the randomised trials included in this review. AUTHORS' CONCLUSIONS: We are uncertain as to whether vitamin D supplements in the form of vitamin D3, vitamin D2, 1,25-dihydroxyvitamin D, or 25-dihydroxyvitamin D have important effect on all-cause mortality, liver-related mortality, or on serious or non-serious adverse events because the results were imprecise. There is no evidence on the effect of vitamin D supplementation on liver-related morbidity and health-related quality of life. Our conclusions are based on few trials with an insufficient number of participants and on lack of data on clinically important outcomes. In addition, the analysed trials are at high risk of bias with significant intertrial heterogeneity. The overall quality of evidence is very low.

[Alphacalcidol combined with dexamethasone for reducing pulmonary fibrosis in mice and its mechanism].

Objective To study the effect of alphacalcidol and dexamethasone on pulmonary fibrosis and its mechanism. Methods Forty C57BL/6 mice were randomly divided into five groups: normal control group, pulmonary fibrosis group, alphacalcidol group, dexamethasone group, dexamethasone combined with alphacalcidol group. The normal control group was given 0.5 µL/g normal saline by one-time intratracheal injection as well as 0.2 mL normal saline by daily intragastric infusion. The other groups received 0.5 µL/g bleomycin solution by one-time intratracheal injection; besides, the pulmonary fibrosis group were subjected to 0.2 mL normal saline gavage; the dexamethasone group were treated with dexamethasone [0.5 mg/ (kg.d)] orally; the alphacalcidol group received intragastric infusion of alphacalcidol [0.5 µg/ (kg.d)]; and the dexamethasone plus alphacalcidol group was given dexamethasone [0.5 mg/ (kg.d)] mixed with alphacalcidol [0.5 µg/ (kg.d)] orally. Then they were killed after 21 days. The pathological changes of lung tissues was observed using HE and Masson staining. The serum was collected to detect hydroxyproline (Hyp) values. Bronchoalveolar lavage fluid (BALF) was collected for cell counting. ELISA was performed to examine interleukin 1 beta (IL-1ß), IL-6, tumor necrosis factor alpha (TNF-α) and transforming growth factor beta 1 (TGF-ß1) in supernatants. Results In the alphacalcidol combined with dexamethasone group, IL-1ß, IL-6, TNF-α and TGF-ß1, cell count, Sazpiel score, Hyp values were lower than those in the other groups except for the control group, and the alveolar inflammation and fibrin deposition were also lower than those in the other groups except for the control group. Conclusion The curative effect of alphacalcidol combined with dexamethasone on pulmonary fibrosis is better than either dexamethasone or alphacalcidol alone, and the mechanism may be related to the inhibition of TGF-ß1 and inflammatory factors.

Antiproliferative Effects of 1α-OH-vitD3 in Malignant Melanoma: Potential Therapeutic implications.

Early detection and surgery represent the mainstay of treatment for superficial melanoma, but for high risk lesions (Breslow's thickness >0.75 mm) an effective adjuvant therapy is lacking. Vitamin D insufficiency plays a relevant role in cancer biology. The biological effects of 1α hydroxycholecalciferol on experimental melanoma models were investigated. 105 melanoma patients were checked for 25-hydroxycholecalciferol (circulating vitamin D) serum levels. Human derived melanoma cell lines and in vivo xenografts were used for studying 1α-hydroxycholecalciferol-mediated biological effects on cell proliferation and tumor growth. 99 out of 105 (94%) melanoma patients had insufficient 25-hydroxycholecalciferol serum levels. Interestingly among the six with vitamin D in the normal range, five had a diagnosis of in situ/microinvasive melanoma. Treatment with 1α-hydroxycholecalciferol induced antiproliferative effects on melanoma cells in vitro and in vivo, modulating the expression of cell cycle key regulatory molecules. Cell cycle arrest in G1 or G2 phase was invariably observed in vitamin D treated melanoma cells. The antiproliferative activity induced by 1α-hydroxycholecalciferol in experimental melanoma models, together with the discovery of insufficient 25-hydroxycholecalciferol serum levels in melanoma patients, provide the rationale for using vitamin D in melanoma adjuvant therapy, alone or in association with other therapeutic options.

A Case of Vitamin-D-Dependent Rickets Type 1A with Normal 1,25-Dihydroxyvitamin D Caused by Two Novel Mutations of the CYP27B1 Gene.

BACKGROUND: Vitamin-D-dependent rickets 1A (VDDR-1A) is caused by mutations of the renal CYP27B1 gene and is a rare form of rickets. Herein, we report a 20-month-old toddler who presented with inability to walk and failure to thrive. The clinical, biochemical and radiological findings were consistent with a diagnosis of rickets, specifically of the genetic type due to increased 25-OH vitamin D stores. METHODS AND RESULTS: Our patient was a compound heterozygote with 2 novel mutations: c.242G>A(p.Gly81Glu) and c.1144C>G (p.Pro382Ala) in the CYP27B1 gene. Analysis of both mutations with in silico models predicted a deleterious effect on 25-OH vitamin D 1α-hydroxylase function. Interestingly, the levels of 1,25-(OH)2 vitamin D were within normal limits. Our patient was initiated on 1α-hydroxyvitamin D (alfacalcidol) and supplemental calcium. Monitoring of bone metabolism showed a normalization of all bone metabolism serum indices after 3 months of therapy and, thereafter, only alfacalcidol was given at a maintenance dose. The clinical follow-up showed a dramatic improvement in musculoskeletal activity, and the patient regained acceleration in height and weight appropriate for his age. CONCLUSION: This rare case report of VDDR-1A with normal levels of 1,25-(OH)2 vitamin D enhances our awareness for this type of rickets in clinical practice.

Conversion of oral alfacalcidol to oral calcitriol in the treatment of secondary hyperparathyroidism in chronic hemodialysis patients.

PURPOSE: The optimal vitamin D3 therapy for the treatment of secondary hyperparathyroidism (SHPT) in chronic hemodialysis patients is still controversial. Recent studies suggest that uremia in end-stage renal disease is associated with enzymatic hepatic dysfunction altering 25-hydroxylation of vitamin D3. The goal of our study was to compare the efficacy of calcitriol, the fully hydroxylated active form of vitamin D3, to alfacalcidol which needs 25-hydroxylation to be effective, for the treatment of SHPT in chronic hemodialysis patients. METHODS: We retrospectively reviewed 45 chronic hemodialysis patients who were switched from oral alfacalcidol to oral calcitriol for the treatment of SHPT. Parathyroid hormone (PTH), serum calcium and serum phosphorus levels were compared pre- and post-conversion using paired Student's t tests. RESULTS: The mean dose of active vitamin D3 decreased from 3.50 mcg/week at baseline to 2.86 mcg (P < 0001) after the switch from alfacalcidol to calcitriol. PTH significantly decreased from 94.4 to 82.6 pmol/L (-11.8 pmol/L, P = 0.02). The mean corrected calcium increased from 2.17 to 2.25 mmol/L (+0.08 mmol/L, P < 0.001) without any clinically significant hypercalcemia, and phosphorus levels were stable. Results were similar in a subgroup of patients (n = 17) for whom the medication was administrated during the hemodialysis session, ensuring a complete compliance. CONCLUSIONS: According to our study, calcitriol in equal dosage is more effective than alfacalcidol in lowering serum PTH level in chronic hemodialysis patients. This suggests that calcitriol may be the optimal active vitamin D3 for the treatment of SHPT in chronic hemodialysis patients.