Randomized Trial of Etelcalcetide for Cardiac Hypertrophy in Hemodialysis.

[Figure: see text].

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.

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.

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.

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.

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.

Effects of 1α-Calcidol (Alfacalcidol) on Microvascular Endothelial Function, Arterial Stiffness, and Blood Pressure in Type II Diabetic Nephropathy Patients.

OBJECTIVES: To determine the effects of six months alfacalcidol on microvascular endothelial function, arterial stiffness, and BP in DN patients. METHODS: Twenty-eight DN patients on alfacalcidol, 0.25 µg daily for six months were compared to 32 controls on conventional treatment. Measurements of microvascular endothelial function, arterial stiffness [AIx and PWV], hsCRP, and BP were performed; differences between baseline and six months treatment were evaluated. RESULTS: No difference was seen in microvascular endothelial function for both groups after six months. Improvement in CSBP (p = 0.027) with trends of improvement in AIx (p = 0.063), PWV (p = 0.075), and systolic BP (p = 0.088) were seen in the alfacalcidol group with no changes observed in controls. Subgroup analysis of alfacalcidol group showed that vitamin D-deficient patients had better response to treatment. hsCRP level remained unchanged in alfacalcidol group; significant increase was however seen in controls. CONCLUSION: Alfacalcidol did not have an effect on microvascular endothelial function in DN patients. Alfacalcidol significantly improved CSBP with trends of improvement in arterial stiffness and peripheral BP. Alfacalcidol appears to be more beneficial in vitamin D-deficient patients.

Analysis of bone metabolism during early stage and clinical benefits of early intervention with alendronate in patients with systemic rheumatic diseases treated with high-dose glucocorticoid: Early DIagnosis and Treatment of OsteopoRosis in Japan (EDITOR-J) study.

We conducted a prospective multicenter study to assess early changes in the dynamics of bone metabolism in patients with systemic connective tissue diseases following commencement of high-dose glucocorticoid therapy and the benefits of early treatment with bisphosphonate and vitamin D analogue. The subjects of this randomized controlled trial were 106 female patients with systemic connective tissue diseases treated for the first time with glucocorticoids at doses equivalent to prednisolone ≥20 mg/day (age ≥ 18 years). One week after initiation of glucocorticoid therapy, patients were randomly assigned to treatment with alfacalcidol at 1 µg/day (n = 33), alendronate 35 mg/week (n = 37), and alfacalcidol plus alendronate (n = 36). The primary endpoints were changes in lumbar spine bone density at 6 months of treatment and the frequency of bone fracture at 12 months. Commencement of glucocorticoid therapy was associated with a rapid and marked bone resorption within 1 week. The combination of alfacalcidol and alendronate administered after the first week of glucocorticoid therapy halted the pathological processes affecting bone metabolism, increased bone density, and reduced the incidence of bone fracture over a period of 12 months. Taken together, the use of the combination of alfacalcidol and alendronate improved bone metabolism, increased bone density, and significantly reduced the incidence of bone fracture during 1-year high-dose glucocorticoid therapy.

[FGF23 related hypophosphatemic rickets:current therapy and unresolved issues].

FGF23-related hypophosphatemic rickets is basically treated with active vitamin D and phosphorus. The treatment goals are to minimize bone deformity and improve adult height in children, and to relieve pain and decrease osteomalacia in adult. However, since they do not target the underlying molecular defect, bone deformity can worsen during growth and adult height is suboptimal restricted. Many adult patients suffer from enthesopathy leading to symptoms such as spinal cord compression and debilitating pain. At present, no treatment is effective in preventing or revenging this complication. The recently developed anti-FGF23 antibody may potentially be a more fundamental treatment.

Effect of Alfacalcidol on multiple sclerosis-related fatigue: A randomized, double-blind placebo-controlled study.

CONTEXT: Fatigue is one of the most common and disabling symptoms of multiple sclerosis (MS); however, there is no medication that has been approved specifically to treat MS-related fatigue. OBJECTIVE: We aimed to evaluate the effect of vitamin D analogue, Alfacalcidol, on MS-related fatigue. DESIGN, SETTINGS, PARTICIPANTS: This was a randomized, double-blind, parallel group, placebo-controlled trial in patients with clinically definite MS by McDonald criteria conducted in a single university-affiliated medical center in Israel. Randomly selected patients from the Sheba MS Registry computerized database (N=600) were assessed using the self-report Fatigue Severity Scale (FSS). Patients with clinically meaningful fatigue (N=259) were further assessed for trial eligibility, and MS patients with significant fatigue (N=158; 61%, 118 females, mean age 41.1 ± 9.2 years and mean disease duration of 6.2 ± 5.5 years) were included in the study and randomized to receive treatment or placebo. INTERVENTION: Alfacalcidol (1 mcg/d, N=80) or placebo (N=78) was administered for six consecutive months. MAIN OUTCOME MEASURE: The primary endpoint of the study was the change between Alfacalcidol and placebo-treated patients in the Fatigue Impact Scale (FIS) score; the cut-off point for improvement was defined as 30% decrease. All analyses followed the intention-to-treat principle and were performed for all participants based on the group they were randomly allocated regardless of whether or not they dropped out. RESULTS: Alfacalcidol decreased the mean relative FIS score as compared with placebo (-41.6% vs. -27.4%, p=0.007, respectively). This advantage was further emphasized when the modified FIS (MFIS) relative change was calculated. Quality of Life (QoL) improved in Alfacalcidol-treated patients as compared with placebo in the RAYS psychological (p=0.033) and social (p=0.043) sub-scales. The Alfacalcidol-treated group had reduced number of relapses (p=0.006) and higher proportion of relapse-free patients (p=0.007). Reduction of relapses by Alfacalcidol became significant at 4 months of treatment, was sustained at 6 months and decayed 2 months after drug discontinuation. Alfacalcidol treatment was safe and no serious adverse events were recorded. CONCLUSION: Alfacalcidol is a safe and effective treatment strategy to decrease fatigue and improve QoL in patients with MS.

Randomized study comparing vitamin D3 and 1α-Hydroxyvitamin D3 in combination with pegylated interferon/ribavirin therapy for chronic hepatitis C.

BACKGROUND AND AIM: An intention-to-treat prospective randomized study was carried out to compare the potentiation of antiviral efficacies between cholecalciferol, non-activated vitamin D3 supplement, and alfacalcidol, activated 1α-Hydroxyvitamin D3 [1α (OH)-vitamin D3]. METHODS: Chronic hepatitis patients with genotype 1b hepatitis C virus (HCV) infection showing serum HCV-RNA levels greater than 5 Log IU/mL received oral administration of cholecalciferol (2000 IU/day) or alfacalcidol (0.5 µg/day) for 4 weeks, and then they were given pegylated interferon (Peg-IFN)-α2a plus ribavirin therapy in combination with either vitamin D3 for 48 or 72 weeks according to the response-guided manner. RESULTS: A total of 36 patients were evaluated. Serum 25-hydroxyvitamin D3 [25(OH)-D3] levels were increased only in patients in the cholecalciferol group during the lead-in vitamin D administration, and the levels at 4 weeks were higher in these patients than in those in the alfacalcidol group (P < 0.001), while serum 1α,25-dihydroxyvitamin D3 [1α,25(OH)2 -D3] levels were not different between both groups. Rapid virological response was obtained in six (33%) patients in the cholecalciferol group; the ratio was higher than that in the alfacalcidol group (one patient; 6%, P < 0.05). Serum HCV-RNA level decline at 4 weeks of combined Peg-IFN-α2a plus ribavirin therapy compared with the baseline levels were greater in the cholecalciferol group (4.6 Log IU/mL) than in the alfacalcidol group (3.5 Log IU/mL) (P < 0.05), when four patients showing null response to the therapy was excluded. However, both complete early virological response and sustained viral response rates were not different between both groups. CONCLUSION: Cholecalciferol produced superior potentiation of the antiviral activity than alfacalcidol only during the initial periods of combined Peg-IFN-α2a plus ribavirin therapy through upregulation of serum 25(OH)-D3 levels.

Efficacy of raloxifene hydrochloride for the prevention of health care problems in patients who undergo surgery for endometrial cancer: a multicenter randomized clinical trial.

OBJECTIVE: Removal of the ovaries is common during surgery for endometrial cancer. However, because loss of the ovaries can cause several health problems in patients, strategies for the prevention of such problems need to be established. Hence, we decided to conduct a multicenter randomized clinical trial to assess the effect of raloxifene on bone mineral density (BMD), bone metabolism, and the lipid profile of patients who had undergone surgery for patients with endometrial cancer. MATERIALS AND METHODS: Patients with endometrial cancer were enrolled after treatment. The participants were randomized into 2 groups: group 1 included 39 women who received alfacalcidol (1 µg/d) alone and group 2 included 37 women who received alfacalcidol and the test drug, raloxifene hydrochloride, at a dose of 60 mg/d. The BMD of lumbar spine and femoral neck, serum bone markers, as well as lipid profile parameters were evaluated at enrollment as well as 6, 12, and 24 months after the enrollment. The primary efficacy end point was the percentage change from baseline to 24 months in lumbar spine (L2-L4) and femoral neck BMD. RESULTS: Sixty-four women completed the 24-month study. At 24 months, the lumbar and femoral neck BMDs were significantly increased in group 2 compared with group 1 (3.5% vs -0.8% and 2.3% vs -2.8%, respectively). In group 2, low-density lipoprotein-cholesterol levels were significantly reduced by 13.6% and serum N-terminal telopeptide of type I collagen as well as bone-specific alkaline phosphatase values were significantly reduced by 16.7% and 25.7%, respectively. The patients who received adjuvant therapy for endometrial cancer showed a significantly higher response to raloxifene (5.8% vs 1.9%). Recurrence was detected in 2 (2.6%) patients in group 1. No severe adverse events were noted in any patient during the study period. CONCLUSIONS: Raloxifene exerts positive effects on BMD, bone metabolism, and lipid profile parameters and could provide an improved therapeutic option for patients with endometrial cancer.

Effects on calcium homeostasis of changing PTH replacement therapy of postoperative hypoparathyroidism from intact PTH to teriparatide: a case series.

The objective of this study was to assess the effect on calcium homeostasis of changing PTH replacement therapy (PTH-RT) from intact PTH (PTH(1-84)) to teriparatide (PTH(1-34)). This study is a consecutive case series. All patients with postoperative hypoparathyroidism who changed medication from PTH(1-84) (100 µg) to PTH(1-34) (20 µg) were included. Plasma ionized calcium, daily dose of 1α-hydroxylated-vitamin D metabolites alfacalcidol, calcium, TSH and PTH was collected. Eight patients (women = 88%) with a mean age of 54 ± 12 years and a duration of hypoPT of 13 ± 6 years were included. Before initiation of PTH(1-84), the mean daily dose of alfacalcidol was 1.9 ± 1.1 µg/d and calcium supplements were 1,550 ± 705 mg. Alfacalcidol dose was reduced with 88 ± 29% (p < 0.01) after 6 months of PTH(1-84) treatment and terminated in six patients. Calcium levels were reduced with 78 ± 36% (p = 0.02) to 273 ± 353 mg/d and stopped in five patients. Six patients received 100 µg PTH(1-84) daily, the seventh 2 out of 3 days and the last every second day. When changing from PTH(1-84) to PTH(1-34), plasma ionized calcium initially dropped and the demand for supplements increased. Alfacalcidol was resumed in five patients; mean daily dose increased to 1.50 ± 1.56 µg/d, (p = 0.02) and calcium increased to 329 ± 368 mg/d, (p = 0.72). Five patients received 20 µg PTH(1-34) a day, two patients twice-a-day and one 20/40 µg/d alternately. Compared with PTH(1-34), PTH(1-84) has a longer plasma half-life and a higher calcemic response. We have shown a need for higher doses of alfacalcidol and calcium supplements to maintain normal serum calcium when treated with PTH(1-34) compared to PTH(1-84) and in some a need for more than one daily PTH(1-34) dose.

Vitamin D supplementation for prevention of cancer in adults.

BACKGROUND: The evidence on whether vitamin D supplementation is effective in decreasing cancers is contradictory. OBJECTIVES: To assess the beneficial and harmful effects of vitamin D supplementation for prevention of cancer in adults. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, LILACS, Science Citation Index Expanded, and the Conference Proceedings Citation Index-Science to February 2014. We scanned bibliographies of relevant publications and asked experts and pharmaceutical companies for additional trials. SELECTION CRITERIA: We included randomised trials that compared vitamin D at any dose, duration, and route of administration versus placebo or no intervention in adults who were healthy or were recruited among the general population, or diagnosed with a specific disease. 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), or 1,25-dihydroxyvitamin D (calcitriol)). DATA COLLECTION AND ANALYSIS: Two review authors extracted data independently. We conducted random-effects and fixed-effect model meta-analyses. For dichotomous outcomes, we calculated the risk ratios (RRs). We considered risk of bias in order to assess the risk of systematic errors. We conducted trial sequential analyses to assess the risk of random errors. MAIN RESULTS: Eighteen randomised trials with 50,623 participants provided data for the analyses. All trials came from high-income countries. Most of the trials had a high risk of bias, mainly for-profit bias. Most trials included elderly community-dwelling women (aged 47 to 97 years). Vitamin D was administered for a weighted mean of six years. Fourteen trials tested vitamin D3, one trial tested vitamin D2, and three trials tested calcitriol supplementation. Cancer occurrence was observed in 1927/25,275 (7.6%) recipients of vitamin D versus 1943/25,348 (7.7%) recipients of control interventions (RR 1.00 (95% confidence interval (CI) 0.94 to 1.06); P = 0.88; I² = 0%; 18 trials; 50,623 participants; moderate quality evidence according to the GRADE instrument). Trial sequential analysis (TSA) of the 18 vitamin D trials shows that the futility area is reached after the 10th trial, allowing us to conclude that a possible intervention effect, if any, is lower than a 5% relative risk reduction. We did not observe substantial differences in the effect of vitamin D on cancer in subgroup analyses of trials at low risk of bias compared to trials at high risk of bias; of trials with no risk of for-profit bias compared to trials with risk of for-profit bias; of trials assessing primary prevention compared to trials assessing secondary prevention; of trials including participants with vitamin D levels below 20 ng/mL at entry compared to trials including participants with vitamin D levels of 20 ng/mL or more at entry; or of trials using concomitant calcium supplementation compared to trials without calcium. Vitamin D decreased all-cause mortality (1854/24,846 (7.5%) versus 2007/25,020 (8.0%); RR 0.93 (95% CI 0.88 to 0.98); P = 0.009; I² = 0%; 15 trials; 49,866 participants; moderate quality evidence), but TSA indicates that this finding could be due to random errors. Cancer occurrence was observed in 1918/24,908 (7.7%) recipients of vitamin D3 versus 1933/24,983 (7.7%) in recipients of control interventions (RR 1.00 (95% CI 0.94 to 1.06); P = 0.88; I² = 0%; 14 trials; 49,891 participants; moderate quality evidence). TSA of the vitamin D3 trials shows that the futility area is reached after the 10th trial, allowing us to conclude that a possible intervention effect, if any, is lower than a 5% relative risk reduction. Vitamin D3 decreased cancer mortality (558/22,286 (2.5%) versus 634/22,206 (2.8%); RR 0.88 (95% CI 0.78 to 0.98); P = 0.02; I² = 0%; 4 trials; 44,492 participants; low quality evidence), but TSA indicates that this finding could be due to random errors. Vitamin D3 combined with calcium increased nephrolithiasis (RR 1.17 (95% CI 1.03 to 1.34); P = 0.02; I² = 0%; 3 trials; 42,753 participants; moderate quality evidence). TSA, however, indicates that this finding could be due to random errors. We did not find any data on health-related quality of life or health economics in the randomised trials included in this review. AUTHORS' CONCLUSIONS: There is currently no firm evidence that vitamin D supplementation decreases or increases cancer occurrence in predominantly elderly community-dwelling women. Vitamin D3 supplementation decreased cancer mortality and vitamin D supplementation decreased all-cause mortality, but these estimates are at risk of type I errors due to the fact that too few participants were examined, and to risks of attrition bias originating from substantial dropout of participants. Combined vitamin D3 and calcium supplements increased nephrolithiasis, whereas it remains unclear from the included trials whether vitamin D3, calcium, or both were responsible for this effect. We need more trials on vitamin D supplementation, assessing the benefits and harms among younger participants, men, and people with low vitamin D status, and assessing longer duration of treatments as well as higher dosages of vitamin D. Follow-up of all participants is necessary to reduce attrition bias.

Comparison of oral and intravenous alfacalcidol in chronic hemodialysis patients.

BACKGROUND: Activated vitamin D is the mainstay of treatment for secondary hyperparathyroidism (SHPT) in chronic hemodialysis patients. However, the optimal route of administration is still debated. The aim of our study was to compare efficacy of oral vs intravenous (IV) administration of alfacalcidol in hemodialysis. A secondary objective was to determine the cost-effectiveness advantage of oral administration. METHODS: Eighty-eight chronic hemodialysis patients receiving IV alfacalcidol three times a week were included in the study. All were switched to the same dose of alfacalcidol given orally three times a week during the hemodialysis session. A budget impact analysis was performed. RESULTS: Mean patient age was 64 years old and 43% were males. The mean alfacalcidol dose administered was 2.1 µg three times a week. After three months, serum parathormone (PTH) levels decreased from 80 to 59 pmol/L (p = 0.001) and total serum calcium levels increased from 2.34 to 2.40 mmol/L (p = 0.002). After six months, total serum calcium levels were still significantly higher. Alfacalcidol dosage was significantly decreased during study period; the mean reduction was 0.44 µg per dose. Finally, oral administration was associated with an annual cost reduction of 197 678$CAN and an annual nursing time reduction of 25 days. CONCLUSION: Our findings support that switching IV to oral administration of alfacalcidol during hemodialysis sessions may lead to a similar control of SHPT with lower doses of activated vitamin D. This is a good strategy for optimizing compliance and may allow a dose reduction because of a greater efficacy to suppress PTH. Oral administration also has significant cost-effectiveness advantages.

Zoledronic acid in combination with alfacalcidol has additive effects on trabecular microarchitecture and mechanical properties in osteopenic ovariectomized rats.

BACKGROUND: We conducted the present study to investigate the therapeutic effects of the antiresorptive agent zoledronic acid (ZOL), alone and in combination with alfacalcidol (ALF), in a rat model of postmenopausal osteoporosis. METHODS: Female Wistar rats were ovariectomized (OVX) or sham-operated at 3 months of age. Twelve weeks post surgery, rats were randomized into six groups: (1) sham + vehicle, (2) OVX + vehicle, (3) OVX + ZOL (100 µg/kg, i.v. single dose), (4) OVX + ZOL (50 µg/kg, i.v. single dose), (5) OVX + ALF (0.5 µg/kg, oral gauge daily) and (6) OVX + ZOL (50 µg/kg, i.v. single dose) + ALF (0.5 µg/kg, oral gauge daily) for 12 weeks. After treatment, we evaluated the mechanical properties of the lumbar vertebra and femoral mid-shaft. Femurs were also tested for bone density, porosity and trabecular micro-architecture. Biochemical markers in serum and urine were also determined. RESULTS: With respect to improvement in the mechanical strength of the lumbar spine and the femoral mid-shaft, the combination treatment of ZOL and ALF was more effective than each administered as a monotherapy. Moreover, combination therapy using ZOL and ALF preserved the trabecular micro-architecture and cortical bone porosity. Furthermore, the combination treatment of ZOL and ALF corrected the decrease in serum calcium and increase in serum alkaline phosphatase and the tartarate-resistant acid phosphatase level better than single-drug therapy using ZOL or ALF in OVX rats. In addition, the combination treatment of ZOL and ALF corrected the increase in urine calcium, phosphorous and creatinine levels better than single-drug therapy using ZOL or ALF in OVX rats. CONCLUSIONS: These data suggest that the combination treatment of ZOL and ALF has a therapeutic advantage over each monotherapy for the treatment of osteoporosis.

[Experience with active vitamin D metabolites in phosphorus-calcium metabolic disorders in patients with predialysis chronic kidney disease].

AIM: To evaluate the efficacy and safety of alfacalcidol and paracalcitol used to correct impaired phosphorus-calcium metabolism (PCM) in patients with predialysis chronic kidney disease (CKD). SUBJECTS AND METHODS: Examinations were made in 128 patients with Stages III-V CKD, including 89 (69.5%) patients with chronic glomerulonephritis, 30 (23.4%) with chronic tubulointerstitial nephritis, and 9 (7.1%) with hypertensive nephrosclerosis. Impaired PCM was detected in 90 (70.3%) of the examined patients. According to the pattern of the previous therapy, all the 90 CKD patients with PCM disorders were divided into 3 groups: 1) 32 patients with Stages IIIB-V CKD who had taken oral alfacalcidol 0.25 microg/day; 2) 28 patients with Stages IIIB-V CKD who had used oral paricalcitol 1 microg/day; 3) 30 patients with Stages IIIB-V CKD who had not received, as self- motivated, active vitamin D metabolites at the predialysis stage. RESULTS: Alfacalcidol and paricalcitol were quite satisfactorily tolerated by the patients. After 3 months of initiation of the use of these agents, Groups 1 and 2 patients with predialysis CKD and baseline elevated blood intact parathyroid hormone (iPTH) levels could not only achieve, but also maintain target blood iPTH levels. In the patients taking paricalcitol, the urinary protein level decreased more promptly; moreover, by the end of month 6 the reduction in blood pressure (BP) was more significant than in those using alfacalcidol (p < 0.05). Comparison of the effects of angiotensin-converting enzyme inhibitors in combination with alfacalcidol or paricalcitol on BP changes and left ventricular mass index indicated that the most pronounced positive changes occurred when angiotensin-converting enzyme inhibitors were used in combination with paricalcitol. CONCLUSION: The use of paricalcitol in predialysis CKD with PTH hyperproduction results in not only normalization of the levels of both PTH and osseous isoenzyme of alkaline phosphatase, but also in significantly reduced daily proteinuria and regression of left ventricular hypertrophy and chronic heart failure.

A Health Technology Assessment Based on Chinese Guideline: Active Vitamin D and Its Analogs in the Treatment of Osteoporosis.

Objective: To quantitatively assess all dosage forms of three active vitamin D and its analogs, namely, calcitriol, alfacalcidol, and eldecalcitol, to provide a basis for the selection of active vitamin D and its analogs in hospitals. Methods: In this study, three active vitamin D and its analogs were evaluated by quantitative scoring in five dimensions, including pharmaceutical properties (28 points), efficacy (27 points), safety (25 points), economy (10 points), and other attributes (10 points). Results: The final scores of quantitative assessment for the selection of alfacalcidol soft capsules, calcitriol soft capsules I, calcitriol soft capsules II, alfacalcidol tablets, alfacalcidol capsules, alfacalcidol oral drops, calcitriol injection, and eldecalcitol soft capsules were 73.17, 72.06, 71.52, 71.29, 69.62, 68.86, 65.60, 64.05 points. Conclusion: Based on the scoring results, alfacalcidol soft capsules, calcitriol soft capsules I, calcitriol soft capsules II, alfacalcidol tablets can be entered into the medication list of medical institutions as strongly recommended drugs. This study offers guidance on selecting and using active vitamin D and its analogs in hospitals, with consideration for the patient's needs.

Associations of dietary calcium, vitamin D, milk intakes, and 25-hydroxyvitamin D with bone mass in Spanish adolescents: the HELENA study.

Adequate nutrition is needed for the accrual of bone mass during the pre- and postpubertal growth periods. This study aimed to examine the associations between dietary calcium, vitamin D (calciferol), and milk intakes and 25-hydroxyvitamin D [25(OH)D] status and bone mineral content (BMC) and bone mineral density (BMD) in Spanish adolescents, aged 12.5-17.5 years, participating in the Healthy Lifestyle in Europe by Nutrition in Adolescence Cross-Sectional Study (HELENA-CSS). Bone mass was measured with dual-energy X-ray absorptiometry and diet via 2 nonconsecutive 24-h dietary recalls (n=227; 48% males). A random subsample of 101 adolescents (46% males) had available measures of 25(OH)D. Multiple linear regression was applied. Significant adjusted associations were observed in males, among milk intakes and BMC and BMD. Also in males, whole-body, head, and right arm BMD were positively related to calcium intakes. In females, 25(OH)D was positively related among others to whole-body, subtotal, and left and right arm BMC and BMD. It could be speculated that diet is not a limiting factor of bone mass development in this group of healthy adolescents, and further research on the effect of other factors in addition to diet in a larger sample should be undertaken.

Sevelamer hydrochloride binds phosphate released from phytate in chicks fed 1α-hydroxy cholecalciferol.

OBJECTIVE: Hyperphosphatemia in animal models of human renal disease has been linked to increased risk of death. Phosphate binders (e.g., sevelamer hydrochloride) and plant-based, low phosphate diets are used to reduce dietary phosphate load; however, animal models show that treatment with active forms of vitamin D(3) (e.g., calcitriol, a renal disease therapy) renders plant phytate phosphate available for absorption. Using an established chick model, the effectiveness of sevelamer in preventing the apparent absorption of liberated phytate phosphate during active vitamin D use was investigated in two separate experiments. DESIGN: One-day-old chicks were fed ad libitum a basal diet containing deficient levels of inorganic phosphate (0.13%), but adequate in total phosphate (0.40%, 0.23% as phytate phosphate), with or without the inclusion of sevelamer hydrochloride (a phosphate binder), available inorganic phosphate, or active vitamin D as 1α-(OH) D(3). MAIN OUTCOME MEASURES: Plasma phosphate (mg/dL), total bone ash (%), and weight gain (g). RESULTS: Adding inorganic phosphate (0.36%) or 1α-(OH) D(3) increased plasma phosphate 49% and 48%, respectively (P < .0001), and bone ash 23% and 19%, respectively (P < .001). The addition of 1% sevelamer to the basal diet with added inorganic phosphate or 1α-(OH) D(3) significantly decreased plasma phosphate by 28% and 20%, respectively (P < .01). CONCLUSION: Active vitamin D increased the availability of phytate phosphate for intestinal absorption in an animal model; however, sevelamer effectively reduced the availability of phosphate liberated from phytate. These data imply that sevelamer has phytate phosphate binding efficacy.