Vectorized ferrocenes with estrogens and vitamin D2: synthesis, cytotoxic activity and docking studies†

PubMed Central

Vera, José; Gao, Li Ming; Santana, Alberto; Matta, Jaime

2015-01-01

Three ferrocene complexes vectorized with estrogens and vitamin D2 were synthesized and fully characterized by spectroscopic, electrochemical and computational methods. The synthesis of these esters was accomplished by reacting ferrocenoyl chloride with the corresponding ROH groups (R = ergocalciferol, estradiol, estrone). The cytotoxicity of these complexes in HT-29 colon cancer and MCF-7 breast cancer cell lines was investigated in vitro. Only ferrocenoyl 17β-hydroxy-estra-1,3,5(10)-trien-3-olate showed good cytotoxic activity in both cell lines, exceeding those of ferrocenium and ferrocene. In MCF-7, ferrocenoyl 17β-hydroxy-estra-1,3,5(10)-trien-3-olate exhibited remarkable IC50, in the low micromolar range. This may be attributed to the presence of the estradiol vector. Docking studies between alpha-estrogen receptor ligand binding site and ferrocenoyl 17β-hydroxy-estra-1,3,5(10)-trien-3-olate revealed some key hydrophobic interactions that might explain the cytotoxic activity of this ester. PMID:21850331

New shell crosslinked micelles from dextran with hydrophobic end groups and their interaction with bioactive molecules.

PubMed

Mocanu, Georgeta; Nichifor, Marieta; Stanciu, Magdalena C

2015-03-30

Micelles formed in aqueous solution by dextran with hydrophobic (alkyl) end-groups were stabilized through divinyl sulfone crosslinking of the dextran shell. The efficacy of the crosslinking reaction was influenced by the divinyl sulfone amount, the pH and micelle concentration. Crosslinked micelles with a moderate crosslinking degree were further functionalized by attachment of 10 and 17 moles% N-(2-hydroxypropyl)-N,N-dimethyl-N-benzylammonium chloride groups along the dextran chain. The size and shape of both crosslinked micelles and their cationic derivatives were analyzed by DLS and TEM. The prepared micelles were able to bind anionic diclofenac (60-370 mg/g), hydrophobic anionic indometacin (70-120 mg/g), and hydrophobic alpha-tocopherol (170-220 mg/g) or ergocalciferol (90-110 mg/g) by hydrophobic or/and electrostatic forces. The release experiments and the antioxidant activity of bound alpha-tocopherol highlighted the potential of the new nano-sized micelles mainly as carriers for prolonged and controlled delivery of hydrophobic drugs. Copyright © 2014 Elsevier Ltd. All rights reserved.

Study on vitamin D₂ stability in dried mushrooms during drying and storage.

PubMed

Sławińska, Aneta; Fornal, Emilia; Radzki, Wojciech; Skrzypczak, Katarzyna; Zalewska-Korona, Marta; Michalak-Majewska, Monika; Parfieniuk, Ewa; Stachniuk, Anna

2016-05-15

The main objective of this work was to determine the stability of vitamin D2 in dried mushrooms Agaricus bisporus, Pleurotus ostreatus and Lentinula edodes during storage, as well as to examine the possibility of inducing vitamin D2 production in dried mushrooms by UVB irradiation. After 1.5 year storage of dried mushrooms, the level of vitamin D2 in button mushrooms was found to be 6.90 μg/g dw, which is a 48.32% of initial level of vitamin D2. In the case of dried oyster and shiitake mushrooms there was a decrease to the level of 66.90% and 68.40%, respectively. It was determined that dried mushrooms can produce ergocalciferol under UVB irradiation. The highest content of vitamin D2 was observed in A. bisporus. Freeze-dried A. bisporus contained from 42.08 to 119.21 μg/g dw and hot-air dried mushrooms contained from 21.51 to 81.17 μg/g dw vitamin D2. Copyright © 2015 Elsevier Ltd. All rights reserved.

Excessive vitamin D content of a standard iron-deficient diet for rats.

PubMed

Triggs, S M; Bailey-Wood, R

1976-03-01

1. The observation that thyroid C cell hyperplasia occurred in rats given the iron-deficient diet described by McCall, Newman, O'Brien, Valberg & Witts (1962) prompted a closer study of the preparation and constituents of this diet. 2. It became apparent that there was a discrepancy between the amounts of fat-soluble vitamins in the dietary formulation reported and the supposed final content of the diet. A diet prepared as described by McCall et al. (1962) contains 1000 mug (40 000 i.u.) ergocalciferol and 10 mug (14 500 i.u.) retinyl palmitate/kg. 3. An experiment was designed to study the effect of Fe-deficient and Fe-supplemented, high-vitamin-D diets, and an Fe-supplemented, normal-vitamin-D diet, on thyroid C cell volume and serum calcium concentration. 4. Thyroid C cell volumes and serum Ca concentrations were significantly higher in both groups given excess vitamin D than in the group given the Fe-supplemented, normal-vitamin-D diet. It is evident therefore, that hypervitaminosis D was the cause of the morphological and biochemical changes found in rats given the McCall et al. (1962) diet.

Comprehensive profiling of carotenoids and fat-soluble vitamins in milk from different animal species by LC-DAD-MS/MS hyphenation.

PubMed

Gentili, Alessandra; Caretti, Fulvia; Bellante, Simona; Ventura, Salvatore; Canepari, Silvia; Curini, Roberta

2013-02-27

This paper describes a novel and efficient analytical method to define the profile of fat-soluble micronutrients in milk from different animal species. Overnight cold saponification was optimized as a simultaneous extraction procedure. Analytes were separated by nonaqueous reversed-phase (NARP) chromatography: carotenoids on a C(30) column and fat-soluble vitamins on a tandem C(18) column system. Besides 12 target analytes for which standards are available (all-trans-lutein, all-trans-zeaxanthin, all-trans-β-cryptoxanthin, all-trans-β-carotene, all-trans-retinol, α-tocopherol, γ-tocopherol, δ-tocopherol, ergocalciferol, cholecalciferol, phylloquinone, and menaquinone-4), the DAD-MS combined detection allowed the provisional identification of other carotenoids on the basis of the expected retention times, the absorbance spectra, and the mass spectrometric data. Retinol and α-tocopherol were the most abundant fat-soluble micronutrients and the only ones found in donkey's milk along with γ-tocopherol. Ewe's milk also proved to be a good source of vitamin K vitamers. Bovine milk showed a large variety of carotenoids that were absent in milk samples from other species with the only exception of all-trans-lutein and all-trans-zeaxanthin.

[Analysis of the Cochrane Review: Vitamin D supplementation for prevention of cancer in adults. Cochrane Database Syst Rev. 2014, 6:CD007469].

PubMed

Cardoso, André Torres; Nanji, Liliana; Costa, João; Vaz-Carneiro, António

2014-01-01

Vitamin D has been mentioned in the literature has a potentially important agent for preventing the development of tumors, namely breast, colon, prostate and ovary tumors. However, the currently available evidence on the subject is contradictory and inconclusive. In this Cochrane systematic review, patients taking supplemental vitamin D on its various forms (cholecalciferol, ergocalciferol, alfacalcidol or calcitriol), regardless the dose, duration and route of administration, were compared with placebo, healthy adults without any intervention or adults with a disease in a stable phase, non-related with vitamin D metabolism. The results showed that currently, there is no firm evidence that vitamin D supplementation increases or decreases the risk of cancer occurrence, mainly in elderly community-dwelling women. Though at risk of type I errors due to small samples and substantial dropout of participants during the trials, the administration of supplemental cholecalciferol led to a 12% (CI 95%: 2 a 22%) decreased in cancer mortality, while the administration of supplemental vitamin D decreased all-cause mortality by 7% (CI 95%: 2 a 12%). The combined administration of supplements of cholecalciferol and calcium induced an increased incidence of nephrolithiasis.

Comparison of non-vertebral fracture between minodronate and risedronate therapy in elderly female patients with Alzheimer disease.

PubMed

Sato, Y; Honda, Y; Iwamoto, J; Amano, N

2013-09-01

Minodronate is a nitrogen-containing bisphosphonate that is commercially available for the treatment of osteoporosis in Japan. Preclinical studies demonstrated that minodronate is at least 10 times more potent than alendronate in inhibiting bone resorption in vivo. A high incidence of fractures, particularly of the hip, represents an important problem in Alzheimer disease (AD) patients who are prone to falls and may have osteoporosis. A total of 256 elderly patients with AD were assigned to daily treatment with 1.0 mg of minodronate or a daily treatment with risedronate combined with daily 1000 IU ergocalciferol and 1200 mg elemental calcium, and followed up for 12 months. At baseline, patients of both groups showed low 25-hydroxyvitamin D with compensatory hyperparathyroidism. Non-vertebral fractures occurred in 5 patients in the minodronate group and 7 patients in the risedronate group (5 hip fractures; one fracture each at the distal forearm and pelvis). There was no difference in risk of hip fracture between the two groups (p=.70; odds ratio=0.8). The study medications were well tolerated with relatively few adverse events and were equivalent in reducing the risk of a fracture in elderly patients with AD.

Application of supercritical fluid chromatography coupled to mass spectrometry to the determination of fat-soluble vitamins in selected food products.

PubMed

Oberson, Jean-Marie; Campos-Giménez, Esther; Rivière, Johann; Martin, Frédéric

2018-06-01

In the present manuscript, we describe a fully optimized and validated method suitable to analyse nine compounds (retinyl acetate, retinyl palmitate, retinol, α-tocopherol, α-tocopheryl acetate, cholecalciferol, ergocalciferol, phylloquinone, menaquinone-4) representing the major contributors to the fat-soluble vitamin activity of selected food products (infant formulas, adult nutritionals, infant cereals and mixed meals). Sample preparation involves direct solvent extraction using enzyme-assisted matrix disintegration and methanolic protein precipitation. Direct injection of the extract allows quantification of vitamins A, E and K in only 7 min, while vitamin D is determined after fast derivatization of the extract. Separation is achieved by supercritical fluid chromatography and detection performed by tandem mass spectrometry in positive Atmospheric Pressure Chemical Ionization mode. Results on a Standard Reference Material (SRM 1849a Infant/Adult Nutritional) were not statistically different from reference values. Full validation of the method showed excellent overall performance. Average recovery rate was between 90 and 110% for all vitamins and matrixes. The methodology shows enhanced safety and reduced cost as compared with previously published methods, together with potential for application to more complex matrixes. The full procedure can be easily applied in control laboratories dramatically increasing sample throughput and reducing solvent consumption. Copyright © 2018 Elsevier B.V. All rights reserved.

Determination of target fat-soluble micronutrients in rainbow trout's muscle and liver tissues by liquid chromatography with diode array-tandem mass spectrometry detection.

PubMed

Pérez Fernández, Virginia; Ventura, Salvatore; Tomai, Pierpaolo; Curini, Roberta; Gentili, Alessandra

2017-03-01

This paper describes an analytical approach, based on LC-diode array detector-MS/MS (LC-DAD-MS/MS), for characterizing the fat-soluble micronutrient fraction in rainbow trout (Oncorhynchus mykiss). Two different procedures were applied to isolate the analytes from liver and muscle tissue: overnight cold saponification to hydrolyze bound forms and to simplify the analysis; matrix solid-phase dispersion to avoid artifacts and to maintain unaltered the naturally occurring forms. Analytes were separated on a C 30 analytical column by using a nonaqueous reversed mobile phase compatible with the atmospheric pressure chemical ionization. Compared to other works, the most relevant advantage of the here illustrated method is the large amount of information obtained with few analytical steps: nine fat-soluble vitamins (3,4-dehydroretinol, retinol, cholecalciferol, ergocalciferol, α-tocopherol, γ-tocopherol, δ-tocopherol, phylloquinone, and menaquinone-4) and eight carotenoids (all-trans-lutein, all-trans-astaxanthin, all-trans-zeaxanthin, all-trans-β-cryptoxanthin, all-trans-canthaxanthin, all-trans-ζ-carotene, all-trans-β-carotene, and all-trans-γ-carotene) were quantified after the method validation, while other untargeted carotenoids were tentatively identified by exploiting the identification power of the LC-DAD-MS/MS hyphenation. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Vitamin D2 Stability During the Refrigerated Storage of Ultraviolet B-Treated Cultivated Culinary-Medicinal Mushrooms.

PubMed

Slawinska, Aneta; Fornal, Emilia; Radzki, Wojciech; Jablonska-Rys, Ewa; Parfieniuk, Ewa

2017-01-01

The effects of ultraviolet B (UVB) irradiation on the synthesis of vitamin D2 and its stability during refrigerated storage was determined in fresh cultivated culinary-medicinal mushrooms (Agaricus bisporus, Pleurotus ostreatus, and Lentinus edodes) after harvest. The irradiated mushrooms were stored at 4°C for up to 10 days. The concentrations of vitamin D2 and ergosterol were determined using ultrahigh-performance liquid chromatography/tandem mass spectrometry. The cultivated mushrooms not treated with UVB were devoid of vitamin D2. After UVB irradiation, we obtained mushrooms with a large amount of ergocalciferol. A. bisporus showed the lowest vitamin D2 content (3.55 ± 0.11 μg D2/g dry weight); P. ostreatus contained 58.96 ± 1.15 μg D2/g dry weight, and L. edodes contained 29.46 ± 2.21 μg/g dry weight. During storage at 4°C, the amount of vitamin D2 was gradually decreased in P. ostreatus and L. edodes, whereas in A. bisporus vitamin D2 gradually increased until the sixth day, then decreased. Mushrooms exposed to UVB radiation contain a significant amount of vitamin D2 and are therefore an excellent food source of vitamin D.

Low Vitamin D Status: Definition, Prevalence, Consequences and Correction

PubMed Central

Binkley, Neil; Ramamurthy, Rekha; Krueger, Diane

2014-01-01

Vitamin D is obtained from cutaneous production when 7-dehydrocholesterol is converted to vitamin D3 (cholecalciferol) by ultraviolet B radiation or by oral intake of vitamin D2 (ergocalciferol) and D3. An individual's vitamin D status is best evaluated by measuring the circulating 25-hydroxyvitamin D [25(OH)D] concentration. Though controversy surrounds the definition of low vitamin D status, there is increasing agreement that the optimal circulating 25(OH)D level should be ~30-32 ng/ml or above. Using this definition, it has been is estimated that approximately three quarters of all adults in the United States are low. Classically, low vitamin D status has skeletal consequences such as osteomalacia/rickets. More recently, associations between low vitamin D status and increased risk for various non-skeletal morbidities have been recognized; whether all of these associations are causally related to low vitamin D status remains to be determined. To achieve optimal vitamin D status, daily intakes of at least 1000 IU or more of vitamin D are required. The risk of toxicity with “high” amounts of vitamin D intake is low. Substantial between-individual variability exists in response to the same administered vitamin D dose. When to monitor 25(OH)D levels has received little attention. Supplementation with vitamin D3 may be preferable to vitamin D2. PMID:20511052

Risedronate and ergocalciferol prevent hip fracture in elderly men with Parkinson disease.

PubMed

Sato, Yoshihiro; Honda, Yoshiaki; Iwamoto, Jun

2007-03-20

There is a high incidence of hip fractures in patients with Parkinson disease (PD). Bone mineral density (BMD) is decreased in patients with PD, correlating with the immobilization-induced bone resorption and hypovitaminosis D with compensatory hyperparathyroidism. To evaluate the effectiveness of risedronate, an inhibitor of bone resorption, on osteoporosis and the risk of hip fractures in elderly men with PD. This was a 2-year, randomized, double-blind, placebo-controlled trial. In a prospective study of patients with PD, 121 patients received a daily dose of 2.5 mg risedronate and vitamin D2 1,000 IU for 2 years, and the remaining 121 received placebo and vitamin D2 1,000 IU. Incidence of hip fractures was compared between the two groups. Nine patients sustained hip fractures in the placebo group, and three hip fractures occurred in the risedronate group. The relative risk of a hip fracture in the risedronate group vs the placebo group was 0.33 (95% CI, 0.09 to 1.20). BMD increased by 2.2% in the risedronate group and decreased by 2.9% in the placebo group (p < 0.0001). Urinary deoxypyridinoline, a bone resorption marker, decreased by 46.7% in the risedronate group and by 33.0% in the placebo group. Treatment with risedronate and vitamin D2 increases bone mineral density in elderly men with Parkinson disease and reduces the risk of hip fractures.

Prevalence and factors promoting the occurrence of vitamin D deficiency in the elderly.

PubMed

Wyskida, Magdalena; Wieczorowska-Tobis, Katarzyna; Chudek, Jerzy

2017-03-13

Vitamin D deficiency affects a large part of the population of elderly people, especially women, who live in moderate climate countries due to a reduced amount of vitamin D in the diet (small sea fish consumption) and reduced content of 7-dehydrocholesterol, which causes decreased skin synthesis. The lowest seasonal concentration of 25(OH)D3 is usually observed during winter and spring. Sun exposure influences 25(OH)D3 concentration more strongly in men than in women. Sociodemographic factors that increase the risk of vitamin D deficiency in the elderly include poor environmental conditions, low economic status, lower educational level, drug exposure (smoking), reduced physical activity, overall poor health and obesity, which causes reduced skin exposure to sunlight. The use of medications or supplements that contain vitamin D and staying in a nursing home that employ such supplementation are factors that prevent deficiency. Significant prevalence of diseases of the gastrointestinal tract may contribute to cholecalciferol and ergocalciferol malabsorption or impair their liver transformation. In addition, the high incidence of chronic kidney disease in old age reduces processing hydroxylation of vitamin D and the formation of active metabolites. Vitamin D deficiency can not only cause bone mineralization disorders, but also increase incidence of cardiovascular diseases, cancers, type 2 diabetes and depression. The aim of this study was to summarize current knowledge about the risk factors of vitamin D deficiency development in the elderly population.

Vitamin D in health and disease.

PubMed

Heaney, Robert P

2008-09-01

Vitamin D functions in the body through both an endocrine mechanism (regulation of calcium absorption) and an autocrine mechanism (facilitation of gene expression). The former acts through circulating calcitriol, whereas the latter, which accounts for more than 80% of the metabolic utilization of the vitamin each day, produces, uses, and degrades calcitriol exclusively intracellularly. In patients with end-stage kidney disease, the endocrine mechanism is effectively disabled; however, the autocrine mechanism is able to function normally so long as the patient has adequate serum levels of 25(OH)D, on which its function is absolutely dependent. For this reason, calcitriol and its analogs do not constitute adequate replacement in managing vitamin D needs of such patients. Optimal serum 25(OH)D levels are greater than 32 ng/mL (80 nmol/L). The consequences of low 25(OH)D status include increased risk of various chronic diseases, ranging from hypertension to diabetes to cancer. The safest and most economical way to ensure adequate vitamin D status is to use oral dosing of native vitamin D. (Both daily and intermittent regimens work well.) Serum 25(OH)D can be expected to rise by about 1 ng/mL (2.5 nmol/L) for every 100 IU of additional vitamin D each day. Recent data indicate that cholecalciferol (vitamin D(3)) is substantially more potent than ergocalciferol (vitamin D(2)) and that the safe upper intake level for vitamin D(3) is 10,000 IU/d.

Extract-filter-shoot liquid chromatography with mass spectrometry for the analysis of vitamin D2 in a powdered supplement capsule and standard reference material 3280.

PubMed

Byrdwell, William Craig

2014-08-01

An "extract-filter-shoot" method for the analysis of vitamin D2, ergocalciferol, in a dry powdered dietary supplement capsule containing rice flour excipient and in a National Institute of Standards and Technology standard reference material 3280 is reported. Quantification of vitamin D2 was done by atmospheric pressure chemical ionization mass spectrometry using selected ion monitoring, two transitions of selected reaction monitoring, and extracted ion chromatograms from full scans. UV detection was used for the quantification of Vitamin D2 in the dry powder capsule, whereas interfering species rendered UV detection unreliable for standard reference material 3280. Average values for standard reference material 3280 ranged from 8.27 ± 0.58 to 8.33 ± 0.57 μg/g using internal standard calibration and response factor approaches, compared to the previous National Institute of Standards and Technology internal value for vitamin D2 of 8.78 ± 0.11 μg/g, and the recently updated reference value of 8.6 ± 2.6 μg/g. The powdered supplement capsule was found to contain 28.19 ± 0.35 to 28.67 ± 0.90 μg/capsule for a capsule labeled to contain 25.00 μg. The triacylglycerol composition of the rice flour excipient in the powdered supplement capsule determined by atmospheric pressure chemical ionization mass spectrometry is also reported. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Supercritical Fluid Chromatography with Photodiode Array Detection in the Determination of Fat-Soluble Vitamins in Hemp Seed Oil and Waste Fish Oil.

PubMed

Tyśkiewicz, Katarzyna; Gieysztor, Roman; Maziarczyk, Izabela; Hodurek, Paweł; Rój, Edward; Skalicka-Woźniak, Krystyna

2018-05-10

In the presented study for the first time a new, optimized, fast SFC (supercritical fluid chromatography) method was applied to separate in one run fat-soluble vitamins from waste fish oil, including cis -and tran s-retinyl palmitate, cis - and trans -retinyl acetate, retinol, α-tocopherol, β-tocopherol, γ‑tocopherol, δ-tocopherol, ergocalciferol (D₂), cholecalciferol (D₃), cis - and trans -phylloquinone (K₁) and menaquinone-4 (K₂-MK4). Vitamins were baseline separated on an Acquity UPC² (ultra performance convergence chromatography) HSS C18 SB (highly strength chemically modified silica) column within 13 min. The influence of the stationary phase, such as Torus 1-AA (1-aminoanthracene), Torus Diol (high density diol), Torus DEA (diethylamine), BEH (silica with no bonding), BEH-2EP (2-ethylpirydine), CSH Fluoro-Phenyl (silica with fluoro-phenyl groups), column temperature, flow rate and back pressure on the separation of the compounds was described. The application of the modified saponification procedure allowed us to increase concentration in the sample prepared for the analysis of γ‑tocopherol from less than 1% (wt %) to 14% for the first time. In addition, α‑tocopherol, γ‑tocopherol, δ‑tocopherol and retinol were identified in waste fish oil. Vitamin purification and analysis in waste fish oil are reported for the first time here. Due to the short time and effectiveness of the proposed method, it can be easily applied in industrial processes.

Extracts from Lentinula edodes (Shiitake) Edible Mushrooms Enriched with Vitamin D Exert an Anti-Inflammatory Hepatoprotective Effect.

PubMed

Drori, Ariel; Shabat, Yehudit; Ben Ya'acov, Ami; Danay, Ofer; Levanon, Dan; Zolotarov, Lidya; Ilan, Yaron

2016-04-01

Vitamin D has been known for its anti-inflammatory properties. Extracts derived from Lentinula edodes (Shiitake) edible mushroom exert an anti-inflammatory effect. These extracts contain high levels of ergosterol, which converts into ergocalciferol (vitamin D2) following exposure to ultraviolet light, followed by absorption and hydroxylation into the active form 25-hydroxyvitamin D [25(OH)D]. To determine the anti-inflammatory effect of overexpression of vitamin D in edible mushrooms, L. edodes mushrooms were exposed to ultraviolet-B light, freeze-dried, followed by measurement of vitamin D2 contents, in their dry weight. C57B1/6 mice were orally treated with vitamin D2-enriched or nonenriched mushroom extract prior and during concanavalin A-immune-mediated liver injury. Exposure to ultraviolet light increased vitamin D2 content in Shiitake edible mushrooms. Following feeding of vitamin D-enriched mushroom extracts to mice with immune-mediated hepatitis, a significant decrease in liver damage was noted. This was shown by a decrease in alanine aminotransferase and aspartate aminotransferase serum levels, a decrease in proportion of mice with severe liver injury, and by improvement in liver histology. These effects were associated with a decrease in serum interferon gamma levels. A synergistic effect was noted between the anti-inflammatory effect of the mushroom extracts and that of vitamin D. Oral administration of vitamin D-enriched L. edodes edible mushroom exerts a synergistic anti-inflammatory effect in the immune-mediated hepatitis. The data support its potential use as safe immunomodulatory adjuvant for the treatment of HCV and nonalcoholic steatohepatitis.

The First Intervention Study in Elder Self-Neglect: A Randomized Clinical Trial to Improve Vitamin D Levels

NASA Technical Reports Server (NTRS)

Burnett, Jason; Hochschild, Ann; Smith, Scott M.; Diamond, Pam; Stotts, Angela; Dyer, Carmel

2011-01-01

Despite high mortality rates, elder self-neglect is characterized by refusal of medical and social interventions. To date there have been no tested clinical interventions in elders who self-neglect. Previous research from the TEAM Institute has shown significantly low vitamin D levels in this population. This study aimed to determine the feasibility of a clinical intervention. Replacement of vitamin D was chosen because of its ease of administration and favorable safety profile. Methods: A randomized clinical trial using directly observed therapy of vitamin D was conducted using 50 elders, >65 years of age, with Adult Protective Services (APS) validated self-neglect. A staggered intervention with waiting controls was used to maximize statistical power. One-third (n=17) of the group was administered 50,000 IU vitamin D2 (ergocalciferol) monthly and the remainder (n=33) were administered 400 IU monthly. Serum 25-OH vitamin D was assessed at baseline and 5-months. Results: 69% agreed to participate in the study and of those n=40 (80%) remained at 5-months. At baseline, 12% (n=7) were deficient in vitamin D (<30nmol/L) and approximately 38% (n=22) had inadequate vitamin D levels (<50nmol/L). The baseline 25-OH vitamin D level was 59 nmol/L +25 (mean SD), and increased significantly to 72nmol/L +21 nmol/L at 5-months. Conclusion: These data are the first to provide evidence that clinical interventions are feasible in elders who self-neglect. The increase in vitamin D levels confirmed that the study personnel were able to successfully intervene community-dwelling elders with self-neglect. This study sets the precedent for future intervention and prevention studies

A patient with hypophosphatemia, a femoral fracture, and recurrent kidney stones: report of a novel mutation in SLC34A3.

PubMed

Page, Kathleen; Bergwitz, Clemens; Jaureguiberry, Graciana; Harinarayan, Chittari V; Insogna, Karl

2008-10-01

To determine if there was a genetic contribution to our patient's unusual clinical presentation of nephrolithiasis and nonhealing stress fracture. We describe a 31-year-old man who had rickets as a child and developed a femur insufficiency fracture and recurrent nephrolithiasis as an adult after moving to the United States from India. The patient's clinical course and results from radiographic and biochemical analyses are described. Analysis of the SLC34A3 gene was performed using genomic DNA samples from the patient and his family members. Before referral to the Yale Bone Center, the patient was treated with calcitriol, ergocalciferol, and phosphate. Changing therapy to phosphate alone led to clinical improvement. Genetic analysis revealed that the patient is a compound heterozygote for mutations in the SLC34A3 gene. On 1 allele, he has a previously described missense mutation in exon 7: c.575C>T (p.Ser192Leu). The other allele carries a novel nonsense mutation in exon 3: c.145C>T (p.Gln49X). One unaffected sibling is a carrier of the missense mutation and 1 sister with a history of flank pain is a carrier of the novel mutation. Hereditary hypophosphatemic rickets with hypercalciuria is a rare metabolic disorder associated with mutations in SLC34A3, the gene that encodes the renal sodium phosphate cotransporter NaPi-IIc. Although hypercalciuria is a distinguishing feature of the disease, nephrolithiasis is rarely described. The patient's atypical clinical presentation illustrates that both environmental and genetic factors potentially affect phenotypic expression of SLC34A3 mutations.

Vitamin D supplementation for the management of knee osteoarthritis: a systematic review of randomized controlled trials.

PubMed

Hussain, Salman; Singh, Ambrish; Akhtar, Mohd; Najmi, Abul Kalam

2017-09-01

Conflicting evidence exists concerning the supplementation of vitamin D in knee osteoarthritis condition. This systematic literature review was done to explore the effects of vitamin D supplementation in the management of knee osteoarthritis. Electronic literature search was done in databases like PubMed ® , Embase ® , and Cochrane CENTRAL from inception to 6th July 2016. The quality of included Randomized Controlled Trials (RCTs) was assessed using Cochrane risk of bias tool. We considered change in Western Ontario and McMaster Universities (WOMAC) index, Visual Analog Scale (VAS) and Functional Pain Score (FPS) as the primary outcome measure. Change in tibial cartilage thickness, joint space width and safety profile was considered as secondary outcomes. Participants were randomized either to treatment or placebo group. Participants received cholecalciferol as an intervention through oral route in the dose range of 800-60,000 IU except in the one study where participants received ergocalciferol. All included RCTs showed a significant increase in serum vitamin D level in the treatment group compared to the placebo group at the end point. No significant reduction in pain and function was reported on WOMAC scale except in one study. No significant difference was reported for WOMAC stiffness in any study. VAS was assessed in three studies in which two showed statistically significant improvement in knee pain. Three of the RCTs reported safety data with one incidence of calculus ureteric and hip fracture found to be related to the drug. The study found evidence from RCTs to be insufficient to support the use of vitamin D supplementation for patients with knee osteoarthritis.

An investigation into the effects of excipient particle size, blending techniques and processing parameters on the homogeneity and content uniformity of a blend containing low-dose model drug

PubMed Central

Alyami, Hamad; Dahmash, Eman; Bowen, James

2017-01-01

Powder blend homogeneity is a critical attribute in formulation development of low dose and potent active pharmaceutical ingredients (API) yet a complex process with multiple contributing factors. Excipient characteristics play key role in efficient blending process and final product quality. In this work the effect of excipient type and properties, blending technique and processing time on content uniformity was investigated. Powder characteristics for three commonly used excipients (starch, pregelatinised starch and microcrystalline cellulose) were initially explored using laser diffraction particle size analyser, angle of repose for flowability, followed by thorough evaluations of surface topography employing scanning electron microscopy and interferometry. Blend homogeneity was evaluated based on content uniformity analysis of the model API, ergocalciferol, using a validated analytical technique. Flowability of powders were directly related to particle size and shape, while surface topography results revealed the relationship between surface roughness and ability of excipient with high surface roughness to lodge fine API particles within surface groves resulting in superior uniformity of content. Of the two blending techniques, geometric blending confirmed the ability to produce homogeneous blends at low dilution when processed for longer durations, whereas manual ordered blending failed to achieve compendial requirement for content uniformity despite mixing for 32 minutes. Employing the novel dry powder hybrid mixer device, developed at Aston University laboratory, results revealed the superiority of the device and enabled the production of homogenous blend irrespective of excipient type and particle size. Lower dilutions of the API (1% and 0.5% w/w) were examined using non-sieved excipients and the dry powder hybrid mixing device enabled the development of successful blends within compendial requirements and low relative standard deviation. PMID:28609454

An investigation into the effects of excipient particle size, blending techniques and processing parameters on the homogeneity and content uniformity of a blend containing low-dose model drug.

PubMed

Alyami, Hamad; Dahmash, Eman; Bowen, James; Mohammed, Afzal R

2017-01-01

Powder blend homogeneity is a critical attribute in formulation development of low dose and potent active pharmaceutical ingredients (API) yet a complex process with multiple contributing factors. Excipient characteristics play key role in efficient blending process and final product quality. In this work the effect of excipient type and properties, blending technique and processing time on content uniformity was investigated. Powder characteristics for three commonly used excipients (starch, pregelatinised starch and microcrystalline cellulose) were initially explored using laser diffraction particle size analyser, angle of repose for flowability, followed by thorough evaluations of surface topography employing scanning electron microscopy and interferometry. Blend homogeneity was evaluated based on content uniformity analysis of the model API, ergocalciferol, using a validated analytical technique. Flowability of powders were directly related to particle size and shape, while surface topography results revealed the relationship between surface roughness and ability of excipient with high surface roughness to lodge fine API particles within surface groves resulting in superior uniformity of content. Of the two blending techniques, geometric blending confirmed the ability to produce homogeneous blends at low dilution when processed for longer durations, whereas manual ordered blending failed to achieve compendial requirement for content uniformity despite mixing for 32 minutes. Employing the novel dry powder hybrid mixer device, developed at Aston University laboratory, results revealed the superiority of the device and enabled the production of homogenous blend irrespective of excipient type and particle size. Lower dilutions of the API (1% and 0.5% w/w) were examined using non-sieved excipients and the dry powder hybrid mixing device enabled the development of successful blends within compendial requirements and low relative standard deviation.

25-Hydroxyvitamin D as a Biomarker of Vitamin D Status and Its Modeling to Inform Strategies for Prevention of Vitamin D Deficiency within the Population.

PubMed

Cashman, Kevin D; van den Heuvel, Ellen Ghm; Schoemaker, Ruud Jw; Prévéraud, Damien P; Macdonald, Helen M; Arcot, Jayashree

2017-11-01

There is substantial evidence that the prevalence of vitamin D deficiency is unacceptably high in the population, and this requires action from a public health perspective. Circulating 25-hydroxyvitamin D [25(OH)D] is a robust and reliable marker of vitamin D status and has been used by numerous agencies in the establishment of vitamin D dietary requirements and for population surveillance of vitamin D deficiency or inadequacy. In a wider context, modeling of serum 25(OH)D data and its contributory sources, namely dietary vitamin D supply and UVB availability, can inform our understanding of population vitamin D status. The aim of this review is to provide the current status of knowledge in relation to modeling of such vitamin D-relevant data. We begin by highlighting the importance of the measurement of 25(OH)D and its standardization, both of which have led to new key data on the prevalence of vitamin D deficiency and inadequacy in North America and Europe. We then overview how state-of-the-art modeling can be used to inform our understanding of the potential effect of ergocalciferol and 25(OH)D on vitamin D intake estimates and how meteorological data on UVB availability, when coupled with other key data, can help predict population serum 25(OH)D concentration, even accounting for seasonal fluctuations, and lastly, how these in silico approaches can help inform policymakers on strategic options on addressing low vitamin D status through food-based approaches and supplementation. The potential of exemplar food-based solutions will be highlighted, as will the possibility of synergies between vitamin D and other dairy food-based micronutrients, in relation to vitamin D status and bone health. Lastly, we will briefly consider the interactions between season and vitamin D supplements on vitamin D status and health. © 2017 American Society for Nutrition.

Evaluation of a method based on liquid chromatography-diode array detector-tandem mass spectrometry for a rapid and comprehensive characterization of the fat-soluble vitamin and carotenoid profile of selected plant foods.

PubMed

Gentili, Alessandra; Caretti, Fulvia

2011-02-04

The feasibility of using reversed-phase liquid chromatography/diode array/tandem mass spectrometry (LC-DAD-MS/MS) for a rapid and comprehensive profiling of fat soluble vitamins and pigments in some foods of plant origin (maize flour, green and golden kiwi) was evaluated. The instrumental approach was planned for obtaining two main outcomes within the same chromatographic run: (i) the quantitative analysis of ten target analytes, whose standards are commercially available; (ii) the screening of pigments occurring in the selected matrices. The quantitative analysis was performed simultaneously for four carotenoids (lutein, zeaxanthin, β-cryptoxanthin, and β-carotene) and six compounds with fat-soluble activity (α-tocopherol, δ-tocopherol, γ-tocopherol, ergocalciferol, phylloquinone and menaquinone-4), separated on a C30 reversed-phase column and detected by atmospheric pressure chemical ionization (APCI) tandem mass spectrometry, operating in Selected Reaction Monitoring (SRM) mode. Extraction procedure was based on matrix solid-phase dispersion with recoveries of all compounds under study exceeding 78 and 60% from maize flour and kiwi, respectively. The method intra-day precision ranged between 3 and 7%, while the inter-day one was below 12%. The mild isolation conditions precluded artefacts creation, such as cis-isomerization phenomena for carotenoids. During the quantitative LC-SRM determination of the ten target analytes, the identification power of the diode array detector joined to that of the triple quadrupole (QqQ) allowed the tentatively identification of several pigments (chlorophylls and carotenoids), without the aid of standards, on the basis of: (i) the UV-vis spectra recorded in the range of 200-700nm; (ii) the expected retention time; (iii) the two SRM transitions, chosen for the target carotenoids but also common to many of isomeric carotenoids occurring in the selected foods. Copyright © 2010 Elsevier B.V. All rights reserved.

Circulating vitamin D concentration and age-related macular degeneration: Systematic review and meta-analysis.

PubMed

Annweiler, Cedric; Drouet, Morgane; Duval, Guillaume T; Paré, Pierre-Yves; Leruez, Stephanie; Dinomais, Mickael; Milea, Dan

2016-06-01

Vitamin D may be involved in ocular function in older adults, but there is no current consensus on a possible association between circulating concentrations of 25-hydroxyvitamin D (25OHD) and the occurrence of age-related macular degeneration (AMD). Our objective was to systematically review and quantitatively assess the association of circulating 25OHD concentration with AMD. A Medline search was conducted in November 2015, with no date limit, using the MeSH terms "Vitamin D" OR "Vitamin D deficiency" OR "Ergocalciferols" OR 'Cholecalciferol' combined with "Age-related macular degeneration" OR "Macular degeneration" OR "Retinal degeneration" OR "Macula lutea" OR "Retina". Fixed and random-effects meta-analyses were performed to compute (i) standard mean difference in 25OHD concentration between AMD and non-AMD patients; (ii) AMD risk according to circulating 25OHD concentration. Of the 243 retrieved studies, 11 observational studies-10 cross-sectional studies and 1 cohort study-met the selection criteria. The number of participants ranged from 65 to 17,045 (52-100% women), and the number with AMD ranged from 31 to 1440. Circulating 25OHD concentration was 15% lower in AMD compared with non-AMD on average. AMD was inversely associated with the highest 25OHD quintile compared with the lowest (summary odds ratio (OR)=0.83 [95%CI:0.71-0.97]), notably late AMD (summary OR=0.47 [95%CI:0.28-0.79]). Circulating 25OHD<50nmol/L was also associated with late-stage AMD (summary OR=2.18 [95%CI:1.34-3.56]), an association that did not persist when all categories of AMD were considered (summary OR=1.26 [95%CI:0.90-1.76]). In conclusion, this meta-analysis provides evidence that high 25OHD concentrations may be protective against AMD, and that 25OHD concentrations below 50nmol/L are associated with late AMD. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

25-hydroxy vitamin D deficiency following pediatric hematopoietic stem cell transplant.

PubMed

Duncan, Christine N; Vrooman, Lynda; Apfelbaum, Erin M; Whitley, Katherine; Bechard, Lori; Lehmann, Leslie E

2011-05-01

Children may be at increased risk for vitamin D deficiency following HSCT because of lack of sun exposure, the recommended use of sunscreen, dietary insufficiency, malabsorption, and the use of certain medications. We prospectively assessed the prevalence of and risk factors for 25-hydroxy (25-OH) vitamin D deficiency in 67 patients transplanted at our institution. 25-OH vitamin D levels were checked during 3 separate 4-week periods in the spring, autumn, and winter. Subjects were <2 years following transplant and/or being treated for chronic graft-versus-host disease (cGVHD). Levels less than 20 ng/mL were considered deficient, and those less than 30 ng/mL were considered insufficient. The mean 25-OH vitamin D level was 22.8 ng/mL (range: 7-46.2). A total of 80.6% (confidence interval [CI] 69.1%-89.3%) of patients had a level less than the lower limit of the institutional normal range. The deficiency rate was 37.3% (CI 25.8%-50%). The mean parathyroid hormone (PTH) level was 77.5 (SD = 80.5). There was no correlation between 25-OH vitamin D and PTH levels. We evaluated potential risk factors for 25-OH vitamin D deficiency including age, season of testing, sun exposure, sunscreen use, use of steroid or calcineurin inhibitor, race, and dairy intake. In multivariate logistic regression, only older age was found to be a risk factor for deficiency (P = .004). Patients with deficient levels were treated with 50,000 IU of ergocalciferol once weekly for 6 weeks. A postrepletion 25-OH level was available for 22 patients. The majority of repleted patients had a normal posttreatment level (63.6%). The postsupplementation level corrected into the insufficient range for 31.8% of patients and 4.6% remained deficient. Vitamin D insufficiency and deficiency are common following HSCT. Further investigation into potential risk factors and the appropriate supplementation for these patients is warranted. Copyright © 2011 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

Hip fracture risk in relation to vitamin D supplementation and serum 25-hydroxyvitamin D levels: a systematic review and meta-analysis of randomised controlled trials and observational studies

PubMed Central

2010-01-01

Background Vitamin D supplementation for fracture prevention is widespread despite conflicting interpretation of relevant randomised controlled trial (RCT) evidence. This study summarises quantitatively the current evidence from RCTs and observational studies regarding vitamin D, parathyroid hormone (PTH) and hip fracture risk. Methods We undertook separate meta-analyses of RCTs examining vitamin D supplementation and hip fracture, and observational studies of serum vitamin D status (25-hydroxyvitamin D (25(OH)D) level), PTH and hip fracture. Results from RCTs were combined using the reported hazard ratios/relative risks (RR). Results from case-control studies were combined using the ratio of 25(OH)D and PTH measurements of hip fracture cases compared with controls. Original published studies of vitamin D, PTH and hip fracture were identified through PubMed and Web of Science databases, searches of reference lists and forward citations of key papers. Results The seven eligible RCTs identified showed no significant difference in hip fracture risk in those randomised to cholecalciferol or ergocalciferol supplementation versus placebo/control (RR = 1.13[95%CI 0.98-1.29]; 801 cases), with no significant difference between trials of <800 IU/day and ≥800 IU/day. The 17 identified case-control studies found 33% lower serum 25(OH)D levels in cases compared to controls, based on 1903 cases. This difference was significantly greater in studies with population-based compared to hospital-based controls (χ21 (heterogeneity) = 51.02, p < 0.001) and significant heterogeneity was present overall (χ216 (heterogeneity) = 137.9, p < 0.001). Serum PTH levels in hip fracture cases did not differ significantly from controls, based on ten case-control studies with 905 cases (χ29 (heterogeneity) = 149.68, p < 0.001). Conclusions Neither higher nor lower dose vitamin D supplementation prevented hip fracture. Randomised and observational data on vitamin D and hip fracture appear to differ. The reason for this is unclear; one possible explanation is uncontrolled confounding in observational studies. Post-fracture PTH levels are unrelated to hip fracture risk. PMID:20540727

a Study of the Synchrotron Laue Method for Quantitative Crystal Structure Analysis.

NASA Astrophysics Data System (ADS)

Gomez de Anderez, Dora M.

1990-01-01

Available from UMI in association with The British Library. Quantitative crystal structure analyses have been carried out on small molecule crystals using synchrotron radiation and the Laue method. A variety of single crystal structure determinations and associated refinements are used and compared with the monochromatic analyses. The new molecular structure of 7-amino-5-bromo -4-methyl-2-oxo-1,2,3,4-tetrahidro-1, 6 -naphthyridine-8-carbonitrile (C_{10 }H_9ON_4 Br.H_2O) has been determined, first using monochromatic Mo Kalpha radiation and a four-circle diffractometer, then using synchrotron Laue diffraction photography. The structure refinements showed a R-factor of 4.97 and 14.0% for the Mo Kalpha and Laue data respectively. The molecular structure of (S)-2-chloro-2-fluoro-N-((S)-1-phenylethyl) ethanamide, (C_{10}H _{11}ClFNO), has been determined using the same crystal throughout for X-ray monochromatic analyses (Mo Kalpha and Cu K alpha) followed by synchrotron Laue data collection. The Laue and monochromatic data compare favourably. The R -factors (on F) were 6.23, 6.45 and 8.19% for the Mo K alpha, Cu Kalpha and Laue data sets respectively. The molecular structure of 3-(5-hydroxy-3-methyl-1-phenylpyrazol-4-yl)-1,3-diphenyl -prop- 2-en-1-one, (C_{25 }H_{20}N _2O_2) has been determined using the synchrotron Laue method. The results compare very well with Mo Kalpha monochromatic data. The R-factors (on F) were 4.60 and 5.29% for Mo Kalpha and Laue analysis respectively. The Laue method is assessed in locating the 20 hydrogen atoms in this structure. The structure analysis of the benzil compound ((C_6H_5 O.CO_2)) is carried out using the synchrotron Laue method firstly at room temperature and secondly at low temperature -114 ^circC. The structure shows an R-factor (on F) of 13.06% and 6.85% for each data set respectively. The synchrotron Laue method was used to collect data for ergocalciferol (Vitamin D_2). The same crystal was also used to record oscillation data with the synchrotron radiation monochromatic beam. A new molecular structure of (Dinitrato-(N,N ^'-dimethylethylene-diamine)copper(II)) has been determined using Mo Kalpha radiation on a four circle diffractometer. The refinement resulted in an R-factor (on F) of 4.06%.

A Study of the Synchrotron Laue Method for Quantitative Crystal Structure Analysis

NASA Astrophysics Data System (ADS)

Gomez de Anderez, Dora M.

1990-01-01

Quantitative crystal structure analyses have been carried out on small molecule crystals using synchrotron radiation and the Laue method. A variety of single crystal structure determinations and associated refinements are used and compared with the monochromatic analyses. The new molecular structure of 7-amino-5-bromo -4-methyl-2-oxo-1,2,3,4 -tetrahidro-1,6 -naphthyridine-8-carbonitrile (C_{10 }H_9ON_4 BrcdotH_2O) has been determined, first using monochromatic Mo K alpha radiation and a four-circle diffractometer, then using synchrotron Laue diffraction photography. The structure refinements showed an R-factor of 4.97 and 14.0% for the Mo Kalpha and Laue data respectively. The molecular structure of (S)-2-chloro-2-fluoro-N-((S)-1-phenylethyl) ethanamide, (C_{10}H _{11}ClFNO), has been determined using the same crystal throughout for X-ray monochromatic analyses (Mo Kalpha and Cu K alpha) followed by synchrotron Laue data collection. The Laue and monochromatic data compare favourably. The R -factors (on F) were 6.23, 6.45 and 8.19% for the Mo K alpha, Cu Kalpha and Laue data sets respectively. The molecular structure of 3-(5-hydroxy-3-methyl-1-phenylpyrazol-4-yl)-1,3-diphenyl -prop-2-en-1-one, (C_{25}H _{20}N_2 O_2) has been determined using the synchrotron Laue method. The results compare very well with Mo Kalpha monochromatic data. The R-factors (on F) were 4.60 and 5.29% for Mo Kalpha and Laue analyses respectively. The Laue method is assessed in locating the 20 hydrogen atoms in this structure. The structure analyses of the benzil compound ((C_6H_5 OcdotCO_2)) is carried out using the synchrotron Laue method firstly at room temperature and secondly at low temperature. The structure shows an R-factor (on F) of 13.06% and 6.85% for each data set respectively. The synchrotron Laue method was used to collect data for ergocalciferol (Vitamin D_2). The same crystal was also used to record oscillation data with the synchrotron radiation monochromatic beam. A new molecular structure of (Dinitrato-(N,N ^'-dimethylethylene-diamine)copper(II)) has been determined using Mo Kalpha radiation on a four circle diffractometer. The refinement resulted in an R-factor (on F) of 4.06%.

[Vitamin D, determinant of bone and extrabone health. Importance of vitamin D supplementation in milk and dairy products].

PubMed

Navarro Valverde, Cristina; Quesada Gómez, José Manuel

2015-04-07

Vitamin D is obtained mainly from ultraviolet irradiation of 7-dehydrocholesterol in the skin to form cholecalciferol (vitamin D3), and minimally from diet, unless vitamin D fortified food is taken, mainly enriched milk. In some countries, vitamin D is added to diet as ergocalciferol (vitamin D2). In the liver, vitamin D3 is hydroxylated to form 25-hydroxyvitamin D3 (marker of body nutritional status of vitamin D). Subsequently, in the kidney, 25OHD3 is hydroxylated to form 1,25-dihydroxyvitamin D3 (1,25(OH)2D3). By VDR stimulation, (1,25)OH)2D3 controls calcium homeostasis and bone health and, what is more, many other cells and tissues including skin, muscle, cardiovascular and immune systems as well as glucose homeostasis. Thus, about 3% of the human genome is regulated by this hormone. Association and recent intervention studies describe beneficial effects on bone, cardiovascular disease, hypertension, diabetes mellitus type 2,colorectal cancer, breast cancer, multiple sclerosis, immune function inflammation etc. A minimum target for public health should be to achieve serum 25OHD levels above 20 ng/ml to ensure optimum status for bone health. However, levels above 30 ng/ml should be reached to achieve other health goals. Paradoxically, inadequacy (or even deficiency) in vitamin D levels is highly prevalent in children and youth in Spain. This deficit persists in adults, as well as in postmenopausal women (osteoporotic or not) and the elderly (especially amongst those institutionalized). Seasonal variation barely normalizes serum 25OHD levels after summer-autumn. Treated postmenopausal osteoporotic women also show high prevalence of inadequate levels of vitamin D, a major contributor to antiresortive treatments failure. A normalization of serum vitamin D enables diet to provide the calcium necessary to achieve a good bone health and an adequate response to antiresortive drugs. Given the difficulty to get adequate levels of vitamin D by UV irradiation and diet, a proper supplementation of milk with vitamin D is an attractive chance and a challenge for Public Health of Spain and the European Union. It has provided excellent results in the US, Canada, Northern Europe Countries, etc. Copyright AULA MEDICA EDICIONES 2014. Published by AULA MEDICA. All rights reserved.

Supplemental vitamin D and calcium in the management of African Americans with heart failure having hypovitaminosis D.

PubMed

Zia, Ayhan A; Komolafe, Babatunde O; Moten, Marriyam; Ahokas, Robert A; McGee, Jesse E; William Rosenberg, E; Bhattacharya, Syamal K; Weber, Karl T

2011-02-01

A dyshomeostasis of macro- and micronutrients, including vitamin D and oxidative stress, are common pathophysiologic features in patients with congestive heart failure (CHF). In African Americans (AA) with CHF, reductions in plasma 25(OH)D are of moderate-to-marked severity (<20 ng/mL) and may be accompanied by ionized hypocalcemia with compensatory increases in serum parathyroid hormone (PTH). The management of hypovitaminosis D in AA with CHF has not been established. Herein, a 14-week regimen: an initial 8 weeks of oral ergocalciferol (50,000 IU once weekly); followed by a 6-week maintenance phase of cholecalciferol (1400 IU daily); and a CaCO₃ (1000 mg daily) supplement given throughout was designed and tested. Fourteen AA patients having a dilated (idiopathic) cardiomyopathy with reduced ejection fraction (EF, <35%) were enrolled: all completed the initial 8-week course; and 12 complied with the full 14 weeks. At baseline, 8 and/or 14 weeks, serum 25(OH)D and PTH; serum 8-isoprostane, a biomarker of lipid peroxidation, and echocardiographic EF were monitored. Reduced 25(OH)D at entry (14.4 ± 1.3 ng/mL) was improved (P < 0.05) in all patients at 8 weeks (30.7 ± 3.2 ng/mL) and sustained (P < 0.05) at 14 weeks (30.9 ± 2.8 ng/mL). Serum PTH, abnormally increased in 5 patients at baseline (104.8 ± 8.2 pg/mL), was reduced at 8 and 14 weeks (74.4 ± 18.3 and 73.8 ± 13.0 pg/mL, respectively). Plasma 8-isoprostane at entry (136.1 ± 8.8 pg/mL) was reduced at 14 weeks (117.8 ± 7.8 pg/mL; P < 0.05), whereas baseline EF (24.3 ± 1.7%) was improved (31.3 ± 4.3%; P < 0.05). Thus, the 14-week course of supplemental vitamin D and CaCO₃ led to healthy 25(OH)D levels in AA with heart failure having vitamin D deficiency of moderate-to-marked severity. Albeit a small patient population, the findings suggest that this regimen may attenuate the accompanying secondary hyperparathyroidism and oxidative stress and improve ventricular function.

Fall prevention with supplemental and active forms of vitamin D: a meta-analysis of randomised controlled trials.

PubMed

Bischoff-Ferrari, H A; Dawson-Hughes, B; Staehelin, H B; Orav, J E; Stuck, A E; Theiler, R; Wong, J B; Egli, A; Kiel, D P; Henschkowski, J

2009-10-01

To test the efficacy of supplemental vitamin D and active forms of vitamin D with or without calcium in preventing falls among older individuals. We searched Medline, the Cochrane central register of controlled trials, BIOSIS, and Embase up to August 2008 for relevant articles. Further studies were identified by consulting clinical experts, bibliographies, and abstracts. We contacted authors for additional data when necessary. Review methods Only double blind randomised controlled trials of older individuals (mean age 65 years or older) receiving a defined oral dose of supplemental vitamin D (vitamin D(3) (cholecalciferol) or vitamin D(2) (ergocalciferol)) or an active form of vitamin D (1alpha-hydroxyvitamin D(3) (1alpha-hydroxycalciferol) or 1,25-dihydroxyvitamin D(3) (1,25-dihydroxycholecalciferol)) and with sufficiently specified fall assessment were considered for inclusion. Eight randomised controlled trials (n=2426) of supplemental vitamin D met our inclusion criteria. Heterogeneity among trials was observed for dose of vitamin D (700-1000 IU/day v 200-600 IU/day; P=0.02) and achieved 25-hydroxyvitamin D(3) concentration (25(OH)D concentration: <60 nmol/l v >or=60 nmol/l; P=0.005). High dose supplemental vitamin D reduced fall risk by 19% (pooled relative risk (RR) 0.81, 95% CI 0.71 to 0.92; n=1921 from seven trials), whereas achieved serum 25(OH)D concentrations of 60 nmol/l or more resulted in a 23% fall reduction (pooled RR 0.77, 95% CI 0.65 to 0.90). Falls were not notably reduced by low dose supplemental vitamin D (pooled RR 1.10, 95% CI 0.89 to 1.35; n=505 from two trials) or by achieved serum 25-hydroxyvitamin D concentrations of less than 60 nmol/l (pooled RR 1.35, 95% CI 0.98 to 1.84). Two randomised controlled trials (n=624) of active forms of vitamin D met our inclusion criteria. Active forms of vitamin D reduced fall risk by 22% (pooled RR 0.78, 95% CI 0.64 to 0.94). Supplemental vitamin D in a dose of 700-1000 IU a day reduced the risk of falling among older individuals by 19% and to a similar degree as active forms of vitamin D. Doses of supplemental vitamin D of less than 700 IU or serum 25-hydroxyvitamin D concentrations of less than 60 nmol/l may not reduce the risk of falling among older individuals.

Fall prevention with supplemental and active forms of vitamin D: a meta-analysis of randomised controlled trials

PubMed Central

Dawson-Hughes, B; Staehelin, H B; Orav, J E; Stuck, A E; Theiler, R; Wong, J B; Egli, A; Kiel, D P; Henschkowski, J

2009-01-01

Objective To test the efficacy of supplemental vitamin D and active forms of vitamin D with or without calcium in preventing falls among older individuals. Data sources We searched Medline, the Cochrane central register of controlled trials, BIOSIS, and Embase up to August 2008 for relevant articles. Further studies were identified by consulting clinical experts, bibliographies, and abstracts. We contacted authors for additional data when necessary. Review methods Only double blind randomised controlled trials of older individuals (mean age 65 years or older) receiving a defined oral dose of supplemental vitamin D (vitamin D3 (cholecalciferol) or vitamin D2 (ergocalciferol)) or an active form of vitamin D (1α-hydroxyvitamin D3 (1α-hydroxycalciferol) or 1,25-dihydroxyvitamin D3 (1,25-dihydroxycholecalciferol)) and with sufficiently specified fall assessment were considered for inclusion. Results Eight randomised controlled trials (n=2426) of supplemental vitamin D met our inclusion criteria. Heterogeneity among trials was observed for dose of vitamin D (700-1000 IU/day v 200-600 IU/day; P=0.02) and achieved 25-hydroxyvitamin D3 concentration (25(OH)D concentration: <60 nmol/l v ≥60 nmol/l; P=0.005). High dose supplemental vitamin D reduced fall risk by 19% (pooled relative risk (RR) 0.81, 95% CI 0.71 to 0.92; n=1921 from seven trials), whereas achieved serum 25(OH)D concentrations of 60 nmol/l or more resulted in a 23% fall reduction (pooled RR 0.77, 95% CI 0.65 to 0.90). Falls were not notably reduced by low dose supplemental vitamin D (pooled RR 1.10, 95% CI 0.89 to 1.35; n=505 from two trials) or by achieved serum 25-hydroxyvitamin D concentrations of less than 60 nmol/l (pooled RR 1.35, 95% CI 0.98 to 1.84). Two randomised controlled trials (n=624) of active forms of vitamin D met our inclusion criteria. Active forms of vitamin D reduced fall risk by 22% (pooled RR 0.78, 95% CI 0.64 to 0.94). Conclusions Supplemental vitamin D in a dose of 700-1000 IU a day reduced the risk of falling among older individuals by 19% and to a similar degree as active forms of vitamin D. Doses of supplemental vitamin D of less than 700 IU or serum 25-hydroxyvitamin D concentrations of less than 60 nmol/l may not reduce the risk of falling among older individuals. PMID:19797342

Vitamin D in Real and Simulated Weightlessness: Implications for Earth

NASA Technical Reports Server (NTRS)

Rice, Barbara L.; Zwart, Sara R.; Smith, Scott M.

2006-01-01

Vitamin D deficiency has reemerged as a public health concern in the United States. It is also a concern for astronauts because spacecraft are shielded from ultraviolet light, leaving diet as the sole source of vitamin D. We report here the findings from four studies: one evaluation of astronauts before and after 4- to 6-month missions to the International Space Station, and the other three from a ground-based analog for space flight, long-term bed rest. For the space flight study, blood samples were collected before the flight and within hours of landing after it. Crewmembers (n = 11) were provided vitamin D supplements (as cholecalciferol (10 g/d) throughout the mission. The average number of vitamin D supplements reported to be consumed per week was 5.7 plus or minus 4.0. The vitamin D status indicator serum 25-hydroxycholecalciferol was 25% less after landing (48 plus or minus 20) than before flight (63 plus or minus 16) (P less than 0.01). A series of three studies was undertaken to evaluate nutritional changes during and after 60 or 90 days of -6 deg. head-down-tilt bed rest. A total of 11 subjects (8 M, 3 F; age 26-55 y) participated in the studies. Blood and urine were collected twice before bed rest and once per month during bed rest. During bed rest the average dietary intake of vitamin D for the three studies was 4.84 plus or minus 0.16 (study 1), 6.24 plus or minus 0.81 (study 2), and 7.16 plus or minus 1.40 (study 3) micrograms/day. In study 1 only, subjects were given a daily supplement of 10 g vitamin D (as ergocalciferol). Data were analyzed using repeated-measures ANOVA. In the first study, 7 days after the end of the bed rest, serum 25-hydroxycholecalciferol was 30% less than it was before bed rest (p less than 0.05). In the second and third studies, during or after bed rest the serum 25-hydroxycholecalciferol concentration was not significantly different from its concentration before bed rest. These data demonstrate that vitamin D intake is critical for individuals not exposed to the sun. Although we studied astronauts and healthy subjects in bed rest, the implications of our results also apply to people living in northern latitudes and others who receive little exposure to sunlight, such as elderly people who seldom go outdoors. The inability of supplements to maintain vitamin D status is also an important finding, and highlights the need for careful food selection to ensure adequate vitamin D intake.

Vitamin D supplementation for prevention of mortality in adults.

PubMed

Bjelakovic, Goran; Gluud, Lise Lotte; Nikolova, Dimitrinka; Whitfield, Kate; Wetterslev, Jørn; Simonetti, Rosa G; Bjelakovic, Marija; Gluud, Christian

2011-07-06

The available evidence on vitamin D and mortality is inconclusive. To assess the beneficial and harmful effects of vitamin D for prevention of mortality in adults. We searched The Cochrane Library, MEDLINE, EMBASE, LILACS, the Science Citation Index Expanded, and Conference Proceedings Citation Index-Science (to January 2011). We scanned bibliographies of relevant publications and asked experts and pharmaceutical companies for additional trials. We included randomised trials that compared vitamin D at any dose, duration, and route of administration versus placebo or no intervention. Vitamin D could have been administered as supplemental vitamin D (vitamin D(3) (cholecalciferol) or vitamin D(2) (ergocalciferol)) or an active form of vitamin D (1α-hydroxyvitamin D (alfacalcidol) or 1,25-dihydroxyvitamin D (calcitriol)). Six authors extracted data independently. Random-effects and fixed-effect model meta-analyses were conducted. For dichotomous outcomes, we calculated the risk ratios (RR). To account for trials with zero events, meta-analyses of dichotomous data were repeated using risk differences (RD) and empirical continuity corrections. Risk of bias was considered in order to minimise risk of systematic errors. Trial sequential analyses were conducted to minimise the risk of random errors. Fifty randomised trials with 94,148 participants provided data for the mortality analyses. Most trials included elderly women (older than 70 years). Vitamin D was administered for a median of two years. More than one half of the trials had a low risk of bias. Overall, vitamin D decreased mortality (RR 0.97, 95% confidence interval (CI) 0.94 to 1.00, I(2) = 0%). When the different forms of vitamin D were assessed separately, only vitamin D(3) decreased mortality significantly (RR 0.94, 95% CI 0.91 to 0.98, I(2) = 0%; 74,789 participants, 32 trials) whereas vitamin D(2), alfacalcidol, or calcitriol did not. Trial sequential analysis supported our finding regarding vitamin D(3), corresponding to 161 individuals treated to prevent one additional death. Vitamin D(3) combined with calcium increased the risk of nephrolithiasis (RR 1.17, 95% CI 1.02 to 1.34, I(2) = 0%). Alfacalcidol and calcitriol increased the risk of hypercalcaemia (RR 3.18, 95% CI 1.17 to 8.68, I(2) = 17%). Data on health-related quality of life and health economics were inconclusive. Vitamin D in the form of vitamin D(3) seems to decrease mortality in predominantly elderly women who are mainly in institutions and dependent care. Vitamin D(2), alfacalcidol, and calcitriol had no statistically significant effect on mortality. Vitamin D(3) combined with calcium significantly increased nephrolithiasis. Both alfacalcidol and calcitriol significantly increased hypercalcaemia.

Differential effects of vitamin D2 and D3 supplements on 25-hydroxyvitamin D level are dose, sex, and time dependent: a randomized controlled trial.

PubMed

Hammami, Muhammad M; Yusuf, Ahmed

2017-02-24

Vitamin D (D) supplements are indispensable for its world-wide deficiency. Controversy continues on ergocalciferol (D2) and cholecalciferol (D3) relative potency as well as on dosing-schedule and sex role in raising 25-hydroxy D (25(OH)D) level, the best indicator of D status. We randomized 279 adults to daily D2, D3, D2/D3, or placebo; 2-weekly D2 or D3; or 4-weekly D2 or D3 (250,000 IU over/140 days). Randomization sequence, stratified by body-mass-index (BMI) and sex, was concealed from study coordinators and participants who were then blinded to capsules' content. D2, D3, 25(OH)D2, and 25(OH)D3 Serum levels were determined blindly on days 0,1,2,3,4,7,14, and 2-weekly thereafter by high performance liquid chromatography assay. The results of 269 participants were available for analysis. Primary endpoint was area-under-the-curve (AUC) of 25(OH)D (25(OH)D2 + 25(OH)D3) adjusted for sex, BMI, and baseline 25(OH)D level. Mean(SD) age was 33.0(8.5) year, 41% were males, and 85% completed follow-up. Baseline 25(OH)D level was 39.8(11.9) and increased by 3.3(11.6) and 28.6(16.3) nmol/L, in the placebo and active-treatment groups, respectively. AUC from day 0 to 140 (AUC 140 ) of 25(OH)D was 40% (D3 daily) to 55% (D3 2-weekly) higher with active-treatment than placebo (p < 0.001). 25(OH)D2 AUC 140 was higher in daily than 2-weekly (17%, p = 0.006) and 4-weekly (20%, p = 0.001) D2-treated groups. 25(OH)D3 AUC 140 was lower in daily than 2-weekly (11%, p = 0.002) and 4-weekly D3-treated groups (10%, p = 0.008). In D2-treated groups, there was 16.4 nmol/L decrease in 25(OH)D3 level that correlated (p < 0.001) with 25(OH)D2 level increase (r = 0.48) and baseline 25(OH)D level (r = 0.58), in one participant with measurable baseline 25(OH)D2 level, D3 caused a similar decrease in 25(OH)D2 level, while in the D2/D3-treated group, 25(OH)D3 level didn't increase. Incremental AUC from day 0 to 7 (AUC 7 ) of D3 and 25(OH)D3 in D3-treated groups were 118-243% higher and 31-39% lower, respectively, than incremental AUC 7 of D2 and 25(OH)D2 in D2-treated groups. Incremental AUC 7 of D3 and 25(OH)D3 in D3-treated groups and D2 and 25(OH)D2 in D2-treated groups were higher in females than males (55, 13, 64, and 28%, respectively). Baseline 25(OH)D level predicted response to D2 and D3 (p < 0.001), whereas, BMI was significant predictor only for early response to D2. Effects of D2 and D3 supplements on 25 (OH)D level may be dosing-schedule and sex-dependent. D2-associated reduction in 25(OH)D3 level may be related to total 25(OH)D level rather than being D2-specific. D2 may be 25-hydroxylated faster than D3. ClinicalTrial.gov identifier: NCT01170494 (registered July 25, 2010).

Vitamin D treatment improves levels of sexual hormones, metabolic parameters and erectile function in middle-aged vitamin D deficient men.

PubMed

Canguven, Onder; Talib, Raidh A; El Ansari, Walid; Yassin, Dany-Jan; Al Naimi, Abdullah

2017-03-01

The associations between serum vitamin D (VD), serum testosterone (TT) and metabolic syndrome are complex and with limited published research, particularly on the effects of VD treatment on sexual hormones, erectile function and the metabolic syndrome. This study assessed whether a monthly high dose VD treatment for 12 months in VD deficient middle-aged men was associated with: changes in levels of sexual hormones, improvement of diabetes control and metabolic syndrome components, better erectile function [International Index of Erectile Function (IIEF)-5 questionnaire]; and changes in a prostate marker. Descriptive research of a prospective study, conducted between October 2014 and September 2015, 102 male patients ≥35 [(±SD: 53.2 ± 10.5), (range 35-64)] years with deficient serum VD level (<30 ng/mL) were included in the study. Participants were followed up for one year, with monitoring at 3-, 6-, 9- and 12-months. At the initial baseline visit, a complete medical examination was conducted, and blood was drawn for laboratory tests for above biochemical and hormonal variables under examination. Participants received an initial VD (Ergocalciferol; oral solution 600 000 IU/1.5 ml), and followed a VD treatment regime thereafter. At the four follow up visits (3, 6, 9 and 12 months), blood was collected, and patients' erectile function was evaluated by IIEF-5 questionnaire. During the follow up visits, all the biochemical and hormonal (TT, estradiol and luteinizing hormones, HbA1c, serum lipids profile) were assessed, and patients' erectile function was evaluated by IIEF-5 questionnaire. Patients' mean age was 53.2 ± 10.4 years. Serum VD exhibited significant increments (p <0.001) from baseline (15.16 ± 4.64 ng/mL), to 3 (31.90 ± 15.99 ng/mL), 6 (37.23 ± 12.42 ng/mL), 9 (44.88 ± 14.49 ng/mL) and 12 months (48.54 ± 11.62 ng/mL), and there was significant stepladder increases in both serum TT level (12.46 ± 3.30 to 15.99 ± 1.84 nmol/L) and erectile function scores (13.88 ± 3.96 to 20.25 ± 3.24) (p <0.001 for both). We also observed significant stepladder decreases in estradiol (87.90 ± 27.16 to 69.85 ± 14.80 pmol/L, p = 0.001), PTH (from 58.52 ± 28.99 to 38.33 ± 19.44 pg/mL, p <0.001) and HbA1c levels (7.41 ± 2.85 to 6.66 ± 1.67%, p = 0.001). Mean BMI significantly decreased from 33.91 ± 6.67 to 33.14 ± 6.35 kg/m 2 (p = 0.001); and PSA values significantly increased from 0.59 ± 0.30 to 0.82 ± 0.39 ng/mL (p <0.001) at the end of the 12 months' follow-up. There were no changes in LH levels. This study demonstrated that VD treatment improves testosterone levels, metabolic syndrome and erectile function in middle-aged men. More randomized placebo-controlled interventional trials of VD treatment in patients with the metabolic syndrome and low TT could assist in uncovering the putative roles of VD.

Vitamin D supplementation for prevention of cancer in adults.

PubMed

Bjelakovic, Goran; Gluud, Lise Lotte; Nikolova, Dimitrinka; Whitfield, Kate; Krstic, Goran; Wetterslev, Jørn; Gluud, Christian

2014-06-23

The evidence on whether vitamin D supplementation is effective in decreasing cancers is contradictory. To assess the beneficial and harmful effects of vitamin D supplementation for prevention of cancer in adults. 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. 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)). 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. 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. 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.

Vitamin D supplementation for prevention of mortality in adults.

PubMed

Bjelakovic, Goran; Gluud, Lise Lotte; Nikolova, Dimitrinka; Whitfield, Kate; Wetterslev, Jørn; Simonetti, Rosa G; Bjelakovic, Marija; Gluud, Christian

2014-01-10

Available evidence on the effects of vitamin D on mortality has been inconclusive. In a recent systematic review, we found evidence that vitamin D3 may decrease mortality in mostly elderly women. The present systematic review updates and reassesses the benefits and harms of vitamin D supplementation used in primary and secondary prophylaxis of mortality. To assess the beneficial and harmful effects of vitamin D supplementation for prevention of mortality in healthy adults and adults in a stable phase of disease. We searched The Cochrane Library, MEDLINE, EMBASE, LILACS, the Science Citation Index-Expanded and Conference Proceedings Citation Index-Science (all up to February 2012). We checked references of included trials and pharmaceutical companies for unidentified relevant trials. Randomised trials that compared any type of vitamin D in any dose with any duration and route of administration versus placebo or no intervention in adult participants. Participants could have been recruited from the general population or from patients diagnosed with a disease in a stable phase. Vitamin D could have been administered as supplemental vitamin D (vitamin D3 (cholecalciferol) or vitamin D2 (ergocalciferol)) or as an active form of vitamin D (1α-hydroxyvitamin D (alfacalcidol) or 1,25-dihydroxyvitamin D (calcitriol)). Six review authors extracted data independently. Random-effects and fixed-effect meta-analyses were conducted. For dichotomous outcomes, we calculated the risk ratios (RRs). To account for trials with zero events, we performed meta-analyses of dichotomous data using risk differences (RDs) and empirical continuity corrections. We used published data and data obtained by contacting trial authors.To minimise the risk of systematic error, we assessed the risk of bias of the included trials. Trial sequential analyses controlled the risk of random errors possibly caused by cumulative meta-analyses. We identified 159 randomised clinical trials. Ninety-four trials reported no mortality, and nine trials reported mortality but did not report in which intervention group the mortality occurred. Accordingly, 56 randomised trials with 95,286 participants provided usable data on mortality. The age of participants ranged from 18 to 107 years. Most trials included women older than 70 years. The mean proportion of women was 77%. Forty-eight of the trials randomly assigned 94,491 healthy participants. Of these, four trials included healthy volunteers, nine trials included postmenopausal women and 35 trials included older people living on their own or in institutional care. The remaining eight trials randomly assigned 795 participants with neurological, cardiovascular, respiratory or rheumatoid diseases. Vitamin D was administered for a weighted mean of 4.4 years. More than half of the trials had a low risk of bias. All trials were conducted in high-income countries. Forty-five trials (80%) reported the baseline vitamin D status of participants based on serum 25-hydroxyvitamin D levels. Participants in 19 trials had vitamin D adequacy (at or above 20 ng/mL). Participants in the remaining 26 trials had vitamin D insufficiency (less than 20 ng/mL).Vitamin D decreased mortality in all 56 trials analysed together (5,920/47,472 (12.5%) vs 6,077/47,814 (12.7%); RR 0.97 (95% confidence interval (CI) 0.94 to 0.99); P = 0.02; I(2) = 0%). More than 8% of participants dropped out. 'Worst-best case' and 'best-worst case' scenario analyses demonstrated that vitamin D could be associated with a dramatic increase or decrease in mortality. When different forms of vitamin D were assessed in separate analyses, only vitamin D3 decreased mortality (4,153/37,817 (11.0%) vs 4,340/38,110 (11.4%); RR 0.94 (95% CI 0.91 to 0.98); P = 0.002; I(2) = 0%; 75,927 participants; 38 trials). Vitamin D2, alfacalcidol and calcitriol did not significantly affect mortality. A subgroup analysis of trials at high risk of bias suggested that vitamin D2 may even increase mortality, but this finding could be due to random errors. Trial sequential analysis supported our finding regarding vitamin D3, with the cumulative Z-score breaking the trial sequential monitoring boundary for benefit, corresponding to 150 people treated over five years to prevent one additional death. We did not observe any statistically significant differences in the effect of vitamin D on mortality in subgroup analyses of trials at low risk of bias compared with trials at high risk of bias; of trials using placebo compared with trials using no intervention in the control group; of trials with no risk of industry bias compared with trials with risk of industry bias; of trials assessing primary prevention compared with trials assessing secondary prevention; of trials including participants with vitamin D level below 20 ng/mL at entry compared with trials including participants with vitamin D levels equal to or greater than 20 ng/mL at entry; of trials including ambulatory participants compared with trials including institutionalised participants; of trials using concomitant calcium supplementation compared with trials without calcium; of trials using a dose below 800 IU per day compared with trials using doses above 800 IU per day; and of trials including only women compared with trials including both sexes or only men. Vitamin D3 statistically significantly decreased cancer mortality (RR 0.88 (95% CI 0.78 to 0.98); P = 0.02; I(2) = 0%; 44,492 participants; 4 trials). Vitamin D3 combined with calcium increased the risk of nephrolithiasis (RR 1.17 (95% CI 1.02 to 1.34); P = 0.02; I(2) = 0%; 42,876 participants; 4 trials). Alfacalcidol and calcitriol increased the risk of hypercalcaemia (RR 3.18 (95% CI 1.17 to 8.68); P = 0.02; I(2) = 17%; 710 participants; 3 trials). Vitamin D3 seemed to decrease mortality in elderly people living independently or in institutional care. Vitamin D2, alfacalcidol and calcitriol had no statistically significant beneficial effects on mortality. Vitamin D3 combined with calcium increased nephrolithiasis. Both alfacalcidol and calcitriol increased hypercalcaemia. Because of risks of attrition bias originating from substantial dropout of participants and of outcome reporting bias due to a number of trials not reporting on mortality, as well as a number of other weaknesses in our evidence, further placebo-controlled randomised trials seem warranted.