Medicine › Pathology and Forensic Medicine

Vitamin D Research Studies

Works Count: 74073

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Description

This cluster of papers focuses on the evaluation, treatment, and prevention of vitamin D deficiency, as well as its impact on various health outcomes such as bone health, cancer, cardiovascular disease, and the immune system. The papers also cover topics like supplementation, epidemiology, genetic determinants, and the role of vitamin D in specific conditions like diabetes and multiple sclerosis.

Keywords

Vitamin D; Deficiency; Supplementation; Health; Bone; Cancer; Cardiovascular Disease; Immune System; Meta-analysis; Clinical Practice Guideline

Hypovitaminosis D is associated with insulin resistance and β cell dysfunction

2004-05-01

Ken C. Chiu , Audrey Y. Chu , Vay Liang W. Go +1 more

Vitamin D Metabolism, Mechanism of Action, and Clinical Applications

2014-02-13

Daniel D. Bikle

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Prediction of bone density from vitamin D receptor alleles

1994-01-20

Nigel A. Morrison , Jian Qi , Akifumi Tokita +5 more

Vitamin D signalling pathways in cancer: potential for anticancer therapeutics

2007-08-24

Kristin K. Deeb , Donald L. Trump , Candace S. Johnson

Distribution of the Vitamin D receptor and 1α-hydroxylase in human brain

2004-10-05

Darryl W. Eyles , Steven A. Smith , Robert T. Kinobe +2 more

Vitamin D and Human Health: Lessons from Vitamin D Receptor Null Mice

2008-10-01

Roger Bouillon , Geert Carmeliet , Lieve Verlinden +6 more

Abstract The vitamin D endocrine system is essential for calcium and bone homeostasis. The precise mode of action and the full spectrum of activities of the vitamin D hormone, 1,25-dihydroxyvitamin … Abstract The vitamin D endocrine system is essential for calcium and bone homeostasis. The precise mode of action and the full spectrum of activities of the vitamin D hormone, 1,25-dihydroxyvitamin D [1,25-(OH)2D], can now be better evaluated by critical analysis of mice with engineered deletion of the vitamin D receptor (VDR). Absence of a functional VDR or the key activating enzyme, 25-OHD-1α-hydroxylase (CYP27B1), in mice creates a bone and growth plate phenotype that mimics humans with the same congenital disease or severe vitamin D deficiency. The intestine is the key target for the VDR because high calcium intake, or selective VDR rescue in the intestine, restores a normal bone and growth plate phenotype. The VDR is nearly ubiquitously expressed, and almost all cells respond to 1,25-(OH)2D exposure; about 3% of the mouse or human genome is regulated, directly and/or indirectly, by the vitamin D endocrine system, suggesting a more widespread function. VDR-deficient mice, but not vitamin D- or 1α-hydroxylase-deficient mice, and man develop total alopecia, indicating that the function of the VDR and its ligand is not fully overlapping. The immune system of VDR- or vitamin D-deficient mice is grossly normal but shows increased sensitivity to autoimmune diseases such as inflammatory bowel disease or type 1 diabetes after exposure to predisposing factors. VDR-deficient mice do not have a spontaneous increase in cancer but are more prone to oncogene- or chemocarcinogen-induced tumors. They also develop high renin hypertension, cardiac hypertrophy, and increased thrombogenicity. Vitamin D deficiency in humans is associated with increased prevalence of diseases, as predicted by the VDR null phenotype. Prospective vitamin D supplementation studies with multiple noncalcemic endpoints are needed to define the benefits of an optimal vitamin D status.

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High Prevalence of Vitamin D Inadequacy and Implications for Health

2006-03-01

Michael F. Holick

The Nuclear Vitamin D Receptor: Biological and Molecular Regulatory Properties Revealed

1998-03-01

Mark R. Haussler , G. Kerr Whitfield , Carol A. Haussler +5 more

In the decade since the vitamin D receptor (VDR) was cloned1 and recognized as a member of the superfamily of nuclear receptors that regulate gene expression in a ligand-dependent manner,2, … In the decade since the vitamin D receptor (VDR) was cloned1 and recognized as a member of the superfamily of nuclear receptors that regulate gene expression in a ligand-dependent manner,2, 3 the central role of VDR in the biology of vitamin D action has been illuminated and is being defined at the molecular level. Following renal production as the hormonal metabolite of vitamin D, 1α,25-dihydroxyvitamin D3 (1,25(OH)2D3) functions as the ligand for VDR, with the hormone–receptor complex inducing calcemic and phosphatemic effects that result in normal bone mineralization and remodeling. VDR not only mediates the action of 1,25(OH)2D3 in calcium/phosphate translocating tissues, primarily intestine, but also elicits a myriad of apparent bioactivities in other major cell systems in the organism, including immune, neural, epithelial, and endocrine. The scope of this review will be limited to highlighting the actions of 1,25(OH)2D3 mediated by nuclear VDR and discussing new developments in the structure/function analysis of the receptor, including the phenotype of VDR knockout mice and the biochemical classification of patients with point mutations in the receptor. These new advances, along with other recent research, will be interpreted to update our understanding of the molecular role of VDR, ranging from characterization of its natural gene and clinically significant polymorphisms, through its DNA contact sites and protein partners, to novel ligand analogs that hold the promise of influencing VDR conformation in a therapeutically beneficial fashion. The traditional action of vitamin D, via its 1,25(OH)2D3 hormonal metabolite, is to effect calcium and phosphate homeostasis to ensure the deposition of bone mineral (summarized in Fig. 1A). 1,25(OH)2D3 stimulates intestinal calcium and phosphate absorption, bone calcium and phosphate resorption, and renal calcium and phosphate reabsorption, thus increasing the blood Ca•PO4 ion product. Failure to achieve normal bone mineral accretion by these mechanisms leads to rachitic syndromes. Nutritional rickets, caused by the simultaneous deprivation of sunlight exposure4 and dietary vitamin D, was ameliorated in classic experiments by administration of this fat soluble vitamin (reviewed in Ref. 5). Subsequently, it was recognized that the pathways comprising the metabolic activation of the vitamin to its hormonal form and consequent functions of the hormone in target tissues (Fig. 1) present additional steps where defects directly elicit vitamin D–resistant rachitic syndromes. Two such disorders involve the inadequate bioactivation of 25-hydroxyvitamin D3 (25(OH)D3), a constitutively produced intermediary metabolite, to 1,25- (OH)2D3. This step is catalyzed by the 1α-OHase enzyme in kidney (Fig. 1A). Chronic renal failure results in renal rickets and secondary hyperparathyroidism when compromised renal mass reduces 1α-OHase activity,6 whereas pseudo–vitamin D–deficiency rickets (PDDR) involves a specific hereditary defect in the gene coding for the 1α-OHase enzyme.7 The latter conclusion has been verified by the recent cloning of cDNAs for the rat8 and mouse9 1α-OHase P450 and the pinpointing of the human 1α-OHase gene to a chromosomal locus coincident with PDDR.8 Interestingly, the 1α-OHase/PDDR locus maps rather closely to the VDR gene on chromosome 12 in the 12q13–14 region,7 a proximity that may be relevant to the evolution and control of the vitamin D ligand–receptor system. Calcemic and phosphatemic biological actions of vitamin D in mammals. (A) Effects of vitamin D and its metabolites to ensure skeletal integrity, especially when calcium is limiting. (Central open box) Vitamin D3, obtained from diet or derived from sunlight-initiated photobiogenesis in skin, is converted via two hydroxylation reactions to the 1,25(OH)2D3 hormonal form that circulates in blood. The final step in bioactivation of vitamin to hormone is catalyzed by the renal 1α-OHase when stimulated by PTH under conditions of low calcium. (Lower portion) Integrated actions of the 1,25(OH)2D3 metabolite, via binding to the intracellular VDR, to control calcium homeostasis in bone, intestine, kidney, and parathyroid as explained in the text. (Top left) Action of 1,25(OH)2D3–VDR in skin cell differentiation. (Top center) Conversion of 1,25(OH)2D3 or the preceding 25(OH)D3 metabolite to 24-hydroxylated forms in response to 1,25(OH)2D3–VDR induction of the 24-OHase gene. This conversion serves to initiate catabolism of the vitamin D molecule, but may also produce 24-hydroxylated metabolites with novel hormonal activity with respect to chondrocyte differentiation and bone mineralization (see text). (B) The vitamin D bioactivation-phosphate homeostatic loop: proposed novel roles for phosphatonin, the PEX gene product, and NPT2. (Left and lower portion) Under normal physiologic conditions, low PO4 enhances the synthesis of 1,25(OH)2D3, which then acts through VDR to effect phosphate reclamation by suppressing PTH as well as inducing NPT2 and PEX gene expression. NPT2 acts directly to reabsorb PO4, while the PEX enzyme eliminates phosphatonin. (Top right) Tumor-induced osteomalacia and XLH each elicit increased phosphatonin, an uncharacterized phosphaturic hormone that is postulated to inhibit both NPT2 and the 1α-OHase, to cause severe phosphate wasting. Clinical and molecular genetic data from the last decade have provided unequivocal evidence for the obligatory role of VDR in mediating the action of vitamin D. Familial target tissue insensitivity to 1,25(OH)2D3, known as hereditary hypocalcemic vitamin D–resistant rickets (HVDRR), is an autosomal recessive disorder resulting in a phenotype characterized by severe bowing of the lower extremities, short stature, and often alopecia.10 In virtually all cases, the cause of this syndrome has been shown to be a defect in the gene encoding human VDR (hVDR) (reviewed in Refs. 10-13), although potential exceptions have been described.14, 15 The fact that the phenotype of HVDRR patients, excluding alopecia, mimics classic nutritional rickets indicates that 1,25(OH)2D3-liganded VDR not only executes all of the bone mineral homeostatic actions of 1,25(OH)2D3 but suggests that VDR itself also participates in the normal hair growth cycle in skin. Recently, VDR knockout mice have been created by two groups,16, 17 revealing apparently normal heterozygotes but homozygotes that display a phenotype very similar to HVDRR, including the progressive development of alopecia over 4–7 weeks of age. At various intervals after birth (differing somewhat between the two studies), VDR null mice acquired low bone mass, hypocalcemia, hypophosphatemia, hyperparathyroidism, and 10-fold elevated 1,25(OH)2D3, coincident with extremely low 24,25(OH)2D3. Affected homozygotes died within 15 weeks16 or exhibited near normal survival rates for up to 6 months.17 The differing survival times may be related to diet or environmental variations, since ablation of exon II/first zinc finger16 or exon III/second zinc finger17 should produce equivalent functional consequences of VDR gene knockout. Despite a lack of VDR throughout early development, VDR null mice are born phenotypically normal, exhibiting symptoms of rickets/osteomalacia and secondary hyperparathyroidism primarily after weaning.16 This observation suggests that the vitamin D endocrine system is principally required for maintaining bone mineral homeostasis when the organism is deprived of a consistent and plentiful supply of calcium, such as occurs after weaning in mammals, after hatching in birds, or after leaving the aqueous environment in the case of amphibians.18 In addition to the data reported in their abstract, Demay and coworkers19 also presented preliminary results describing the prevention of many, but not all, of the phenotypic effects of VDR knockout by means of a "rescue diet," consisting of high levels of lactose, calcium, and phosphate. By manipulating blood calcium and phosphate levels in this manner, parathyroid hormone (PTH) was normalized and bone mineralization was greatly improved in the VDR knockout animals, to a degree that the histology of the growth plate was indistinguishable from that of normal littermates. However, alopecia and skin abnormalities, such as dermal cysts, persisted in the VDR null mice on the rescue diet, intimating that VDR plays an indispensable role in hair and skin development independent of bone mineral homeostasis. That normalizing circulating mineral concentrations via dietary intervention in VDR knockout mice prevents the rachitic phenotype is consistent with results in HVDRR patients whose bone abnormalities are resolved by frequent therapy with overnight intravenous calcium infusions.20, 21 Thus, the generation of VDR null mice and the reversal of their bone abnormalities by diet dramatizes the concept that the major physiologic effect of 1,25(OH)2D3 is on intestinal absorption of calcium and phosphate, although certain calcium regulating end-points such as depressed renal calbindin-D9k mRNA expression in kidney are not corrected when VDR null mice are maintained on the rescue diet (M. Demay et al., unpublished results). Moreover, in another preliminary study, Kato and colleagues22 found that, when utilizing the coculture system of Suda and coworkers,23 osteoblasts/stromal cells from VDR knockout mice will not support 1,25(OH)2D3-induced osteoclastogenesis of normal spleen cells, whereas the reverse experiment (normal osteoblasts/stromal cells and VDR null mouse spleen cells) results in the production of osteoclasts upon exposure of the coculture to 1,25(OH)2D3. Therefore, as depicted in Fig. 1(A), VDR appears to be essential for 1,25(OH)2D3 to elicit a paracrine signal from osteoblasts, which in turn facilitates osteoclast differentiation, at least in vitro. However, the fact that VDR null mice curiously possess normal, or even increased numbers of osteoclasts16 suggests that other osteoclast-activating factors, such as PTH or interleukin-1 (IL-1), can still support osteoclastogenesis in the absence of functional VDR. Superimposed upon its pivotal role in controlling bone mineral transport and differentiation in hair follicles, another function of the 1,25(OH)2D3–VDR complex is to govern the level of the renal 1,25(OH)2D3 hormone by feedback regulation of its biosynthesis and by induction of a key catabolic enzyme. 1,25(OH)2D3 appears to effect a short feedback loop (Fig. 1A) to repress the 1α-OHase enzyme,24 and is also a potent suppressor of the synthesis and secretion of PTH,25 the primary tropic hormone stimulating the 1α-OHase (Fig. 1).26 The mechanism whereby 1,25(OH)2D3 curtails PTH production involves a VDR-mediated silencing of PTH gene transcription.27-29 Based upon preliminary data from dietarily rescued VDR null mice, excess calcium is able to adequately control PTH secretion and parathyroid cell growth, suggesting that the role of 1,25(OH)2D3 in these processes is cooperative with physiologic calcium levels but can be overridden in situations of calcium abundance. Turnover of 1,25(OH)2D3 is accomplished via several catabolic routes,30, 31 with 24-hydroxylation initiating the apparent primary pathway for elimination of vitamin D metabolites. The 24-OHase enzyme is markedly enhanced by 1,25(OH)2D3 through a VDR-dependent mechanism (Fig. 1A), a phenomenon predominating in kidney but also occurring in all 1,25(OH)2D3 target cells.32, 33 The dependency of 24-OHase activity on VDR action is emphasized by the extremely low levels of 24-hydroxylated metabolites found in VDR null mice, as discussed above.16 Both the 25(OH)D3 precursor and the 1,25(OH)2D3 hormone serve as effective substrates for the 24-OHase enzyme, rendering the latter capable of catalyzing a potent attenuation of active vitamin D metabolite concentrations. In fact, homozygous 24-OHase null mice34 display reduced 1,25(OH)2D3 clearance, with the F1 progeny exhibiting signs of vitamin D intoxication, such as calcified kidneys. Interestingly, the F1 progeny also have defective intramembranous ossification. The failure of bones such as the calvaria and mandible to calcify in this situation could be a developmental consequence of excess 1,25(OH)2D3. Another possibility is that a 24-hydroxylated D-metabolite(s) is required for some aspect of cartilage or bone formation (Fig. 1A),35-38 perhaps via pharmacokinetic interactions with 1,25(OH)2D3 or through an uncharacterized novel receptor for the 24-hydroxylated metabolite. Other than negative feedback on PTH synthesis and secretion27, 39 to suppress this phosphaturic hormone, how does the 1,25(OH)2D3–VDR complex influence phosphate metabolism to maintain the Ca•PO4 ion product? One mechanism seems to be the primary induction of phosphate translocating proteins in kidney and perhaps intestine (Fig. 1). An example is the renal sodium–phosphate cotransporter-2 (NPT2) (Fig. 1B),40, 41 a likely 1,25(OH)2D3-induced protein because its gene contains a vitamin D responsive element (VDRE) in the promoter region (see below). It is also well established that hypophosphatemia stimulates the 1α-OHase (Fig. 1B) to elevate circulating 1,25(OH)2D3 levels.26 However, circulating 1,25(OH)2D3 is inappropriately low for the prevailing phosphate concentrations in patients with X-linked hypophosphatemic rickets (XLH),42 a dominant familial disorder of renal phosphate wasting. Importantly, such patients can be cured with a therapeutic combination of oral phosphate and 1,25(OH)2D3.43 The defective gene responsible for XLH has been identified as PEX, or phosphate-regulating gene with homologies to endopeptidases located on the X-chromosome.44 Further, there exists a significant number of cases of tumor-induced osteomalacia, an acquired disorder that closely resembles the phosphate wasting of XLH and is characterized by low circulating 1,25(OH)2D3.45 Finally, renal cross-transplantation46 and parabiosis47 studies in normal and genetically hypophosphatemic mice demonstrate that a novel uncharacterized phosphaturic hormone is present in the circulation. Taken together, these observations argue strongly that the XLH and tumor-induced osteomalacia syndromes are both caused by excess amounts of this novel humoral factor, which is distinct from PTH and has been named phosphatonin (Fig. 1B).48, 49 Like PTH, phosphatonin is presumably a potent inactivator of NPT2 (Fig. 1B), but in contrast to PTH, this newly recognized factor apparently also inhibits the 1α-OHase, thus suppressing 1,25(OH)2D3. As depicted in Fig. 1(B), the normal role of the PEX gene product is postulated to be the proteolytic inactivation of this phosphaturic principle, such that inactivating PEX mutations in XLH elicit the appearance of abnormally high circulating levels of phosphatonin.44 In the case of tumor-induced osteomalacia, the tumor appears to produce phosphatonin ectopically. Thus, as illustrated in Fig. 1(B), the PEX/phosphatonin system could participate in a novel regulatory loop for maintaining normal phosphate homeostasis, which becomes deranged in XLH, or when tumors directly secrete phosphatonin. Another role of 1,25(OH)2D3/VDR in phosphate control is postulated to be the induction of PEX gene expression (Fig. 1B), thus creating an additional strategy for protection by 1,25(OH)2D3 against hypophosphatemia. Indeed, the PEX gene appears to possess a VDRE based upon Southwestern analysis of the relevant yeast artificial chromosome.50 The present hypothesis is that a low phosphate level triggers an increase in circulating 1,25(OH)2D3, which in turn augments the PEX gene product to destroy phosphatonin, constituting a novel phosphate homeostatic loop that is overwhelmed when high levels of phosphatonin diminish 1,25(OH)2D3 synthesis and inhibit NPT2. This concept is consistent with the relatively depressed 1,25(OH)2D3 levels observed either in patients with tumor-induced osteomalacia or in kindreds with XLH caused by inactivating PEX mutations. Given the present indications that phosphatonin represents a pathophysiologically relevant phosphaturic hormone that regulates vitamin D bioactivation, its characterization at the chemical level is eagerly anticipated. As summarized in Table 1, the potential actions of 1,25(OH)2D3 via its nuclear VDR extend far beyond the bone mineral homeostasis realm pictured in Fig. 1. The following three independent methodologies have been employed to provide evidence that 1,25(OH)2D3 functions in a diverse array of cells: autoradiographic localization of the ligand following administration to vitamin D–deficient animals, immunohistochemical detection of VDR in the nucleus of target cells, and responsiveness of specific cell types in culture to 1,25(OH)2D3 and its active analogs. In many cases, these data are coupled to biological responses or to loss of function in VDR null mice, in vivo, for instance in the maintenance of insulin secretion by 1,25(OH)2D3,51 the uterine hypoplasia reported in VDR knockout female mice apparently caused by suboptimal ovarian estrogen production,16 and the exploitation of the prodifferentiation/antiproliferative actions of 1,25(OH)2D3 in the treatment of psoriasis.52 One major neoclassical target for 1,25(OH)2D3 is the immune system (reviewed in Ref. 53), with the suppression of IL-1 to IL-6 and interferon-γ constituting prominent in vitro 1,25(OH)2D3 effects mediated by VDR (Table 1). Moreover, in vivo immunomodulatory actions of the hormone also have been documented (reviewed in Ref. 54), such as reduced macrophage and lymphocyte function in vitamin D–deficient rats.55 1,25(OH)2D3 functions as a general suppressor of the immune system, especially of T-helper cells (subset type 1), suggesting that analogs of vitamin D might be useful therapeutic agents in procedures such as organ transplants56 or in the treatment of autoimmune disorders.57 In addition, 1,25(OH)2D3 is thought to play an important role in the differentiation of cells in the hematopoietic lineage. Several illustrations of this action have been reported, including differentiation of a human promyelocytic leukemia cell line (HL-60) into macrophage-like cells,58, 59 and the development of osteoclasts in bone from colony forming unit–granulocyte/macrophage precursors (see Ref. 53 and references therein). Many of these effects of 1,25(OH)2D3–VDR, although of potential therapeutic significance, may be biologically redundant with other immune modulators, perhaps offering survival advantages. The tentative conclusion of redundant immunoregulation is based upon the normal immune profile of VDR null mice at 7 weeks of age,16 but it is reasonable to hypothesize that the potential immunomodulatory power of 1,25(OH)2D3–VDR could become more significant during pathophysiological stress situations or under conditions of senescence. Other apparent sites of action for 1,25(OH)2D3 and VDR include the central nervous system (CNS) (Table 1), where one of the outcomes is immunosuppression. For example, 1,25(OH)2D3 treatment elicits a partial improvement of symptoms in rodents with developing experimental allergic encephalomyelitis.60, 61 Moreover, 1,25(OH)2D3 also has been shown to induce expression of the following neurotrophic hormones or their mRNAs: glial cell-derived neurotrophic factor (a protein that may be important in protecting certain types of neural tissue from degenerative processes),62 leukemia inhibitory factor (a widely distributed protein in the brain with neurotrophic activity),63 neurotrophin-3 mRNA (in primary astrocytes),64 and nerve growth factor (both in primary newborn astrocytes65 and in the hippocampus and cortex of the adult rat66). Furthermore, the activity of cholinergic acetyltransferase is elevated in specific brain regions in response to 1,25(OH)2D3 administration.67 In some neurons, analogous to the antiapoptotic effect of calbindin-D28k in lymphocytes,68 the induction of calbindins by 1,25(OH)2D3 may protect against cell death in the face of repetitive calcium transients,69 and in fact the expression of calbindin-D28k mRNA is decreased in the hippocampus of Alzheimer's patients as assessed by in situ hybridization.70, 71 Taken together, these observations not only imply a modulatory role for VDR in neural cell growth and differentiation but also intimate a possible role for 1,25(OH)2D3 in therapeutic intervention for neurodegenerative disorders. Similarly, 1,25(OH)2D3 appears to affect dramatically the maturation and functions of certain normal and neoplastic epithelial cells (Table 1). As discussed above, VDR plays a key role in the hair growth cycle, an action related to the ability of 1,25(OH)2D3 to stimulate the differentiation of keratinocytes (Table 1). Also, the proliferation of a number of epithelially derived cancer cells (e.g., mammary, prostate, and colon) is inhibited in culture by 1,25(OH)2D3, with some cells being directed toward a more differentiated phenotype. This effect in neoplastic cells may be related to the reported ability of liganded VDR to arrest cells at the G1 stage by influencing cell cycle regulatory proteins, such as p21 and p27, to control cell growth transcription factors such as c-myc and c-fos, or to elicit apoptosis by down-regulating Bcl-2 (Table 1 and references therein). Therefore, the 1,25(OH)2D3 hormone seems to resemble its nutritionally derived, lipophilic ligand cousins, vitamin A and thyroid hormone, in possessing the ability to influence the program of cell development as well as to evoke classic metabolic and growth regulatory effects. 1,25(OH)2D3 also reportedly affects several major endocrine processes, such as TRH/TSH action and pancreatic insulin secretion (Table 1). However, only further investigations of VDR null mice and other transgenic strategies, such as tissue-specific expression of a dominant negative VDR, will allow us to sort out which of the putative neoclassical effects of 1,25(OH)2D3 mediated by VDR are biologically relevant. At this early juncture, of those sites enumerated in Table 1, only the skin/hair growth cycle and ovarian/uterine systems appear to be markedly affected in the VDR null mouse. However, the limited phenotype of VDR knockout mice does not preclude 1,25(OH)2D3 and its analogs from being valuable as biological response modifiers useful in the treatment of hyperproliferative disorders, autoimmunity, and CNS deterioration, as well as traditional maladies of calcium and phosphorus metabolism such as renal osteodystrophy, hypoparathyroidism, and osteoporosis. The recently characterized gene encoding hVDR (Fig. 2A),72 previously localized to chromosome 12,73 is similar to other nuclear receptor genes74 in that each of the two zinc fingers is encoded by separate exons (II and III), and the 5′ end of the gene exhibits some complexity in the form of alternate splice and/or translation start sites. For hVDR, alternate splicing of three exons (IA–IC) encoding portions of the 5′ untranslated region generates at least three mRNA variants,72 while the presence of a polymorphic sequence in exon II determines the presence or absence of an alternative translation start site (see discussion of FokI polymorphism below).72 A unique feature of the hVDR gene is the presence of an additional exon (V) that is not found in other nuclear receptor genes (Fig. 2A)72; it resides near the center of the gene and encodes residues 155–194 in hVDR. This region of the VDR protein is more expansive than the corresponding segment in other nuclear receptors, suggesting that the VDR may have acquired a novel exon of unknown function as it diverged evolutionarily from other nuclear receptor genes.72 Schematic view of genomic and deduced amino acid sequences for hVDR, displaying known natural variations. (A) The hVDR chromosomal gene, containing a total of 11 exons, three of which (IA, IB, and IC) encode 5′ UTR region and are variably present in VDR transcripts.72 Several polymorphic variants, including a FokI site in exon II, and a cluster of linked sites near or in exon IX, are discussed in the text. (B) Schematized linear amino acid sequence of hVDR, highlighting functional domains as currently understood from mutagenesis analysis. ⊕ signifies a cluster of five basic amino acids in the intervening sequence between the two zinc fingers. Two reported sites of modulatory serine phosphorylation at serine-51 and serine-208 are indicated by S51 and S208, respectively. Known natural point mutations in human patients with the HVDRR syndrome are indicated by single-letter abbreviations (e.g., G33D is a glycine to aspartate substitution at position 33). X refers to a premature stop codon, while f indicates a frame-shift mutation, leading to premature termination. Point mutants from positions 33–80 are defective in DNA binding, and all X and f mutants can neither bind hormone nor heterodimerize with RXR. Other point mutations in the C-terminal half of the receptor (from positions 259–391) display defects in either hormone-binding or heterodimer formation with RXR (or both) as discussed in the text. One of the most intriguing, yet controversial, areas of bone-related genetic research in the past few years has been the discovery of common polymorphisms in the hVDR gene and their potential relationship to bone mineral density (BMD) and the pathophysiology of osteoporosis, hyperparathyroidism, and cancers of the breast and prostate. Morrison, Eisman, and colleagues75 first reported that VDR alleles could predict BMD, contending that the occurrence of a BsmI restriction site (Fig. 2A, denoted b) in the intron separating exons VIII and IX of the gene (Fig. 2A) is associated with enhanced lumbar spine BMD. Conversely, the absence of the BsmI site (denoted B) in VDR was correlated with low BMD. In a population of Australian twins of Irish ancestry, Morrison et al.75 concluded that the VDR genotype (b vs. B) accounted for up to 75% of the genetic component of BMD, although a correction/partial retraction of this report appeared recently.76 Numerous subsequent studies with other population samples have found more modest,77, 78 little if any,79-82 and even conflicting associations83 of the B versus b alleles with BMD. A meta-analytic approach84 that incorporated the results of 16 VDR polymorphic studies revealed a 1.5–2.5% decrease in BMD associated with BB (versus bb) homozygotes, far less dramatic than the 12% effect originally proposed.75 Additional studies have also suggested a trend toward lower bone mass with the B allele,85-88 but it has become clear that other confounding factors, such as age, estrogen status, ethnicity, and calcium intake, must be accounted for to reveal the true impact, if any, of this VDR polymorphism on BMD. Further evaluation of the VDR gene has revealed a cluster of linked polymorphisms in the 3′ portion of the VDR gene (Fig. 2A),89 including the aforementioned BsmI site, a nearby ApaI site (in the same intron), and a silent mutation within codon 352 of the ninth exon that alters a TaqI site. These VDR polymorphisms have been linked not only to variations in bone-specific parameters but also to a higher occurrence of sporadic primary hyperparathyroidism in patients with the b allele,90 as well as to prostate cancer, which possesses a particularly strong association with the T allele (lack of the TaqI site).91 However, given that none of these polymorphisms change the encoded VDR protein in any way, the explanation for these findings has been unclear. Recently, an additional genetic variation in the hVDR gene was found in the form of a microsatellite poly(A) repeat in the 3′ UTR, approximately 1 kb upstream of the poly(A) tail (Fig. 2A). Multiple (≥12) allelic variants of this microsatellite were detected and classified into two groupings, long (L) and short (S), based upon the length of the repeat.92, 93 The L grouping (linked to T; see Fig. 2A) exhibits a strong association with prostate cancer incidence93 but displays a contrasting protective effect against breast cancer.94 It is still not established whether this poly(A) microsatellite is the functionally relevant locus, although by analogy to short tandem repeats in other genes95 the length of the repeat may affect a crucial parameter, such as mRNA stability. Alternatively, the poly(A) microsatellite may be tightly linked to yet another site which is the true functional locus. Regardless of which scenario is correct, a complicating factor in interpreting earlier findings using the BsmI, TaqI, or ApaI polymorphic restriction sites is that the linkage is imperfect between these restriction sites and the L versus S groupings, such that some ethnic groups exhibit a very tight linkage (thus displaying a clear correlation between BMD and the BsmI site), while in others (e.g., African-Americans) the presence of the BsmI or TaqI site is not a good predictor of the L versus S genotype,92 leading to a loss of functional correlation between BsmI or TaqI and BMD. Nonetheless, the study of the poly(A) microsatellite sequence may have brought us closer to a functional understanding of VDR genetic diversity, while also providing a partial explanation for the variability in association of BsmI or TaqI genotypes with BMD and hyperproliferative disorders. Near the 5′ end of the hVDR gene, a FokI restriction endonuclease site has been identified,96, 97 the presence of which (denoted f) dictates that the 427-residue, M1 isoform of VDR is expressed (so named because it contains an ATG methionine translational start site corresponding to codon #1). An evolutionarily more recent polymorphism (Fig. 3),98 or neomorph, has been reported in which both the FokI restriction site and the ATG codon #1 are changed, causing an alternative 424-residue isoform of the receptor to be translated. The F neomorph, encoding M4 hVDR (for initiation of translation at the fourth codon) already constitutes approximately 65% of VDR allel

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Influence of Season and Latitude on the Cutaneous Synthesis of Vitamin D3: Exposure to Winter Sunlight in Boston and Edmonton Will Not Promote Vitamin D3Synthesis in Human Skin*

1988-08-01

Ann R. Webb , Loren Kline , Michael F. Holick

Sunlight has long been recognized as a major provider of vitamin D for humans; radiation in the UVB (290-315 nm) portion of the solar spectrum photolyzes 7-dehydrocholesterol in the skin … Sunlight has long been recognized as a major provider of vitamin D for humans; radiation in the UVB (290-315 nm) portion of the solar spectrum photolyzes 7-dehydrocholesterol in the skin to previtamin D3, which, in turn, is converted by a thermal process to vitamin D3. Latitude and season affect both the quantity and quality of solar radiation reaching the earth's surface, especially in the UVB region of the spectrum, but little is known about how these influence the ability of sunlight to synthesize vitamin D3 in skin. A model has been developed to evaluate the effect of seasonal and latitudinal changes on the potential of sunlight to initiate cutaneous production of vitamin D3. Human skin or [3 alpha-3H]7-dehydrocholesterol exposed to sunlight on cloudless days in Boston (42.2 degrees N) from November through February produced no previtamin D3. In Edmonton (52 degrees N) this ineffective winter period extended from October through March. Further south (34 degrees N and 18 degrees N), sunlight effectively photoconverted 7-dehydrocholesterol to previtamin D3 in the middle of winter. These results quantify the dramatic influence of changes in solar UVB radiation on cutaneous vitamin D3 synthesis and indicate the latitudinal increase in the length of the "vitamin D winter" during which dietary supplementation of the vitamin may be advisable.

Prevalence of Vitamin D Insufficiency in an Adult Normal Population

1997-09-01

M C Chapuy , Paul Preziosi , M. Maamer +4 more

Intake of vitamin D and risk of type 1 diabetes: a birth-cohort study

2001-11-01

Elina Hyppönen , Esa Läärä , Antti Reunanen +2 more

Estimation of optimal serum concentrations of 25-hydroxyvitamin D for multiple health outcomes

2006-07-01

Heike A. Bischoff‐Ferrari , Edward L. Giovannucci , Walter C. Willett +2 more

Calcium plus Vitamin D Supplementation and the Risk of Fractures

2006-02-15

Rebecca D. Jackson , Andrea Z. LaCroix , Margery Gass +7 more

The efficacy of calcium with vitamin D supplementation for preventing hip and other fractures in healthy postmenopausal women remains equivocal.We recruited 36,282 postmenopausal women, 50 to 79 years of age, … The efficacy of calcium with vitamin D supplementation for preventing hip and other fractures in healthy postmenopausal women remains equivocal.We recruited 36,282 postmenopausal women, 50 to 79 years of age, who were already enrolled in a Women's Health Initiative (WHI) clinical trial. We randomly assigned participants to receive 1000 mg of elemental [corrected] calcium as calcium carbonate with 400 IU of vitamin D3 daily or placebo. Fractures were ascertained for an average follow-up period of 7.0 years. Bone density was measured at three WHI centers.Hip bone density was 1.06 percent higher in the calcium plus vitamin D group than in the placebo group (P<0.01). Intention-to-treat analysis indicated that participants receiving calcium plus vitamin D supplementation had a hazard ratio of 0.88 for hip fracture (95 percent confidence interval, 0.72 to 1.08), 0.90 for clinical spine fracture (0.74 to 1.10), and 0.96 for total fractures (0.91 to 1.02). The risk of renal calculi increased with calcium plus vitamin D (hazard ratio, 1.17; 95 percent confidence interval, 1.02 to 1.34). Censoring data from women when they ceased to adhere to the study medication reduced the hazard ratio for hip fracture to 0.71 (95 percent confidence interval, 0.52 to 0.97). Effects did not vary significantly according to prerandomization serum vitamin D levels.Among healthy postmenopausal women, calcium with vitamin D supplementation resulted in a small but significant improvement in hip bone density, did not significantly reduce hip fracture, and increased the risk of kidney stones. (ClinicalTrials.gov number, NCT00000611.).

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Vitamin D Status: Measurement, Interpretation, and Clinical Application

2008-03-12

Michael F. Holick

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Guidelines for the management of asymptomatic primary hyperparathyroidism: summary statement from the third international workshop.

2009-02-01

John P. Bilezikian , Aliya Khan , John T. Potts

Asymptomatic primary hyperparathyroidism (PHPT) is a common clinical problem. The purpose of this report is to guide the use of diagnostics and management for this condition in clinical practice.Interested professional … Asymptomatic primary hyperparathyroidism (PHPT) is a common clinical problem. The purpose of this report is to guide the use of diagnostics and management for this condition in clinical practice.Interested professional societies selected representatives for the consensus committee and provided funding for a one-day meeting. A subgroup of this committee set the program and developed key questions for review. Consensus was established at a closed meeting that followed and at subsequent discussions.Each question was addressed by a relevant literature search (on PubMed), and the data were presented for discussion at the group meeting.Consensus was achieved by a group meeting. Statements were prepared and reviewed by all authors who represented the Planning Committee and the participating professional societies.

Global vitamin D status and determinants of hypovitaminosis D

2009-06-18

Ambrish Mithal , D. A. Wahl , J.‐P. Bonjour +7 more

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Vitamin D Deficiency in Children and Its Management: Review of Current Knowledge and Recommendations

2008-08-01

Madhusmita Misra , Danièle Pacaud , Anna Petryk +2 more

Given the recent spate of reports of vitamin D deficiency, there is a need to reexamine our understanding of natural and other sources of vitamin D, as well as mechanisms … Given the recent spate of reports of vitamin D deficiency, there is a need to reexamine our understanding of natural and other sources of vitamin D, as well as mechanisms whereby vitamin D synthesis and intake can be optimized. This state-of-the-art report from the Drug and Therapeutics Committee of the Lawson Wilkins Pediatric Endocrine Society was aimed to perform this task and also reviews recommendations for sun exposure and vitamin D intake and possible caveats associated with these recommendations.

Resurrection of vitamin D deficiency and rickets

2006-08-01

Michael F. Holick

The epidemic scourge of rickets in the 19th century was caused by vitamin D deficiency due to inadequate sun exposure and resulted in growth retardation, muscle weakness, skeletal deformities, hypocalcemia, … The epidemic scourge of rickets in the 19th century was caused by vitamin D deficiency due to inadequate sun exposure and resulted in growth retardation, muscle weakness, skeletal deformities, hypocalcemia, tetany, and seizures. The encouragement of sensible sun exposure and the fortification of milk with vitamin D resulted in almost complete eradication of the disease. Vitamin D (where D represents D2 or D3) is biologically inert and metabolized in the liver to 25-hydroxyvitamin D [25(OH)D], the major circulating form of vitamin D that is used to determine vitamin D status. 25(OH)D is activated in the kidneys to 1,25-dihydroxyvitamin D [1,25(OH)2D], which regulates calcium, phosphorus, and bone metabolism. Vitamin D deficiency has again become an epidemic in children, and rickets has become a global health issue. In addition to vitamin D deficiency, calcium deficiency and acquired and inherited disorders of vitamin D, calcium, and phosphorus metabolism cause rickets. This review summarizes the role of vitamin D in the prevention of rickets and its importance in the overall health and welfare of infants and children.

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Vitamin D Deficiency and Risk of Cardiovascular Disease

2008-01-08

Thomas J. Wang , Michael J. Pencina , Sarah L. Booth +7 more

Background— Vitamin D receptors have a broad tissue distribution that includes vascular smooth muscle, endothelium, and cardiomyocytes. A growing body of evidence suggests that vitamin D deficiency may adversely affect … Background— Vitamin D receptors have a broad tissue distribution that includes vascular smooth muscle, endothelium, and cardiomyocytes. A growing body of evidence suggests that vitamin D deficiency may adversely affect the cardiovascular system, but data from longitudinal studies are lacking. Methods and Results— We studied 1739 Framingham Offspring Study participants (mean age 59 years; 55% women; all white) without prior cardiovascular disease. Vitamin D status was assessed by measuring 25-dihydroxyvitamin D (25-OH D) levels. Prespecified thresholds were used to characterize varying degrees of 25-OH D deficiency (<15 ng/mL, <10 ng/mL). Multivariable Cox regression models were adjusted for conventional risk factors. Overall, 28% of individuals had levels <15 ng/mL, and 9% had levels <10 ng/mL. During a mean follow-up of 5.4 years, 120 individuals developed a first cardiovascular event. Individuals with 25-OH D <15 ng/mL had a multivariable-adjusted hazard ratio of 1.62 (95% confidence interval 1.11 to 2.36, P =0.01) for incident cardiovascular events compared with those with 25-OH D ≥15 ng/mL. This effect was evident in participants with hypertension (hazard ratio 2.13, 95% confidence interval 1.30 to 3.48) but not in those without hypertension (hazard ratio 1.04, 95% confidence interval 0.55 to 1.96). There was a graded increase in cardiovascular risk across categories of 25-OH D, with multivariable-adjusted hazard ratios of 1.53 (95% confidence interval 1.00 to 2.36) for levels 10 to <15 ng/mL and 1.80 (95% confidence interval 1.05 to 3.08) for levels <10 ng/mL ( P for linear trend=0.01). Further adjustment for C-reactive protein, physical activity, or vitamin use did not affect the findings. Conclusions— Vitamin D deficiency is associated with incident cardiovascular disease. Further clinical and experimental studies may be warranted to determine whether correction of vitamin D deficiency could contribute to the prevention of cardiovascular disease.

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Prevention of Rickets and Vitamin D Deficiency in Infants, Children, and Adolescents

2008-10-31

Carol L. Wagner , Frank R. Greer

Rickets in infants attributable to inadequate vitamin D intake and decreased exposure to sunlight continues to be reported in the United States. There are also concerns for vitamin D deficiency … Rickets in infants attributable to inadequate vitamin D intake and decreased exposure to sunlight continues to be reported in the United States. There are also concerns for vitamin D deficiency in older children and adolescents. Because there are limited natural dietary sources of vitamin D and adequate sunshine exposure for the cutaneous synthesis of vitamin D is not easily determined for a given individual and may increase the risk of skin cancer, the recommendations to ensure adequate vitamin D status have been revised to include all infants, including those who are exclusively breastfed and older children and adolescents. It is now recommended that all infants and children, including adolescents, have a minimum daily intake of 400 IU of vitamin D beginning soon after birth. The current recommendation replaces the previous recommendation of a minimum daily intake of 200 IU/day of vitamin D supplementation beginning in the first 2 months after birth and continuing through adolescence. These revised guidelines for vitamin D intake for healthy infants, children, and adolescents are based on evidence from new clinical trials and the historical precedence of safely giving 400 IU of vitamin D per day in the pediatric and adolescent population. New evidence supports a potential role for vitamin D in maintaining innate immunity and preventing diseases such as diabetes and cancer. The new data may eventually refine what constitutes vitamin D sufficiency or deficiency.

Human serum 25-hydroxycholecalciferol response to extended oral dosing with cholecalciferol

2003-01-01

Robert P. Heaney , K. Michael Davies , Tai C. Chen +2 more

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Estimates of optimal vitamin D status

2005-03-17

Bess Dawson‐Hughes , Robert P. Heaney , Michael F. Holick +3 more

Sunlight and vitamin D for bone health and prevention of autoimmune diseases, cancers, and cardiovascular disease

2004-12-01

Michael F. Holick

1,25-Dihydroxyvitamin D3 is a negative endocrine regulator of the renin-angiotensin system

2002-07-15

Yan Chun Li , Juan Kong , Minjie Wei +3 more

Inappropriate activation of the renin-angiotensin system, which plays a central role in the regulation of blood pressure, electrolyte, and volume homeostasis, may represent a major risk factor for hypertension, heart … Inappropriate activation of the renin-angiotensin system, which plays a central role in the regulation of blood pressure, electrolyte, and volume homeostasis, may represent a major risk factor for hypertension, heart attack, and stroke. Mounting evidence from clinical studies has demonstrated an inverse relationship between circulating vitamin D levels and the blood pressure and/or plasma renin activity, but the mechanism is not understood. We show here that renin expression and plasma angiotensin II production were increased severalfold in vitamin D receptor-null (VDR-null) mice, leading to hypertension, cardiac hypertrophy, and increased water intake. However, the salt- and volume-sensing mechanisms that control renin synthesis are still intact in the mutant mice. In wild-type mice, inhibition of 1,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)] synthesis also led to an increase in renin expression, whereas 1,25(OH)(2)D(3) injection led to renin suppression. We found that vitamin D regulation of renin expression was independent of calcium metabolism and that 1,25(OH)(2)D(3) markedly suppressed renin transcription by a VDR-mediated mechanism in cell cultures. Hence, 1,25(OH)(2)D(3) is a novel negative endocrine regulator of the renin-angiotensin system. Its apparent critical role in electrolytes, volume, and blood pressure homeostasis suggests that vitamin D analogues could help prevent or ameliorate hypertension.

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Genetics and biology of vitamin D receptor polymorphisms

2004-07-23

André G. Uitterlinden , Yue Fang , Joyce B. J. van Meurs +2 more

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Vitamin D: A millenium perspective

2003-01-06

Michael F. Holick

Abstract Vitamin D is one of the oldest hormones that have been made in the earliest life forms for over 750 million years. Phytoplankton, zooplankton, and most plants and animals … Abstract Vitamin D is one of the oldest hormones that have been made in the earliest life forms for over 750 million years. Phytoplankton, zooplankton, and most plants and animals that are exposed to sunlight have the capacity to make vitamin D. Vitamin D is critically important for the development, growth, and maintenance of a healthy skeleton from birth until death. The major function of vitamin D is to maintain calcium homeostasis. It accomplishes this by increasing the efficiency of the intestine to absorb dietary calcium. When there is inadequate calcium in the diet to satisfy the body's calcium requirement, vitamin D communicates to the osteoblasts that signal osteoclast precursors to mature and dissolve the calcium stored in the bone. Vitamin D is metabolized in the liver and then in the kidney to 1,25‐dihydroxyvitamin D [1,25(OH) 2 D]. 1,25(OH) 2 D receptors (VDR) are present not only in the intestine and bone, but in a wide variety of other tissues, including the brain, heart, stomach, pancreas, activated T and B lymphocytes, skin, gonads, etc. 1,25(OH) 2 D is one of the most potent substances to inhibit proliferation of both normal and hyperproliferative cells and induce them to mature. It is also recognized that a wide variety of tissues, including colon, prostate, breast, and skin have the enzymatic machinery to produce 1,25(OH) 2 D. 1,25(OH) 2 D and its analogs have been developed for treating the hyperproliferative disease psoriasis. Vitamin D deficiency is a major unrecognized health problem. Not only does it cause rickets in children, osteomalacia and osteoporosis in adults, but may have long lasting effects. Chronic vitamin D deficiency may have serious adverse consequences, including increased risk of hypertension, multiple sclerosis, cancers of the colon, prostate, breast, and ovary, and type 1 diabetes. There needs to be a better appreciation of the importance of vitamin D for overall health and well being. J. Cell. Biochem. 88: 296–307, 2003. © 2002 Wiley‐Liss, Inc.

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Vitamin D and calcium supplementation reduces cancer risk: results of a randomized trial

2007-06-01

Joan M. Lappe , Dianne Travers‐Gustafson , K. Michael Davies +2 more

Vitamin D Deficiency

2007-07-18

Michael F. Holick

Once foods in the United States were fortified with vitamin D, rickets appeared to have been conquered, and many considered major health problems from vitamin D deficiency resolved. But vitamin … Once foods in the United States were fortified with vitamin D, rickets appeared to have been conquered, and many considered major health problems from vitamin D deficiency resolved. But vitamin D deficiency is common. This review considers the role of vitamin D in skeletal and nonskeletal health and suggests strategies for the prevention and treatment of vitamin D deficiency.

Toll-Like Receptor Triggering of a Vitamin D-Mediated Human Antimicrobial Response

2006-02-24

Philip T. Liu , Steffen Stenger , Huiying Li +7 more

In innate immune responses, activation of Toll-like receptors (TLRs) triggers direct antimicrobial activity against intracellular bacteria, which in murine, but not human, monocytes and macrophages is mediated principally by nitric … In innate immune responses, activation of Toll-like receptors (TLRs) triggers direct antimicrobial activity against intracellular bacteria, which in murine, but not human, monocytes and macrophages is mediated principally by nitric oxide. We report here that TLR activation of human macrophages up-regulated expression of the vitamin D receptor and the vitamin D-1-hydroxylase genes, leading to induction of the antimicrobial peptide cathelicidin and killing of intracellular Mycobacterium tuberculosis. We also observed that sera from African-American individuals, known to have increased susceptibility to tuberculosis, had low 25-hydroxyvitamin D and were inefficient in supporting cathelicidin messenger RNA induction. These data support a link between TLRs and vitamin D-mediated innate immunity and suggest that differences in ability of human populations to produce vitamin D may contribute to susceptibility to microbial infection.

Serum 25-Hydroxyvitamin D Levels and Risk of Multiple Sclerosis

2006-12-19

Kassandra L. Munger , Lynn I. Levin , Bruce W. Hollis +2 more

Epidemiological and experimental evidence suggests that high levels of vitamin D, a potent immunomodulator, may decrease the risk of multiple sclerosis. There are no prospective studies addressing this hypothesis.To examine … Epidemiological and experimental evidence suggests that high levels of vitamin D, a potent immunomodulator, may decrease the risk of multiple sclerosis. There are no prospective studies addressing this hypothesis.To examine whether levels of 25-hydroxyvitamin D are associated with risk of multiple sclerosis.Prospective, nested case-control study among more than 7 million US military personnel who have serum samples stored in the Department of Defense Serum Repository. Multiple sclerosis cases were identified through Army and Navy physical disability databases for 1992 through 2004, and diagnoses were confirmed by medical record review. Each case (n = 257) was matched to 2 controls by age, sex, race/ethnicity, and dates of blood collection. Vitamin D status was estimated by averaging 25-hydroxyvitamin D levels of 2 or more serum samples collected before the date of initial multiple sclerosis symptoms.Odds ratios of multiple sclerosis associated with continuous or categorical levels (quantiles or a priori-defined categories) of serum 25-hydroxyvitamin D within each racial/ethnic group.Among whites (148 cases, 296 controls), the risk of multiple sclerosis significantly decreased with increasing levels of 25-hydroxyvitamin D (odds ratio [OR] for a 50-nmol/L increase in 25-hydroxyvitamin D, 0.59; 95% confidence interval, 0.36-0.97). In categorical analyses using the lowest quintile (<63.3 nmol/L) as the reference, the ORs for each subsequent quintile were 0.57, 0.57, 0.74, and 0.38 (P = .02 for trend across quintiles). Only the OR for the highest quintile, corresponding to 25-hydroxyvitamin D levels higher than 99.1 nmol/L, was significantly different from 1.00 (OR, 0.38; 95% confidence interval, 0.19-0.75; P = .006). The inverse relation with multiple sclerosis risk was particularly strong for 25-hydroxyvitamin D levels measured before age 20 years. Among blacks and Hispanics (109 cases, 218 controls), who had lower 25-hydroxyvitamin D levels than whites, no significant associations between vitamin D and multiple sclerosis risk were found.The results of our study suggest that high circulating levels of vitamin D are associated with a lower risk of multiple sclerosis.

The 2011 Report on Dietary Reference Intakes for Calcium and Vitamin D from the Institute of Medicine: What Clinicians Need to Know

2010-12-01

A. Catharine Ross , JoAnn E. Manson , Steven A. Abrams +7 more

This article summarizes the new 2011 report on dietary requirements for calcium and vitamin D from the Institute of Medicine (IOM). An IOM Committee charged with determining the population needs … This article summarizes the new 2011 report on dietary requirements for calcium and vitamin D from the Institute of Medicine (IOM). An IOM Committee charged with determining the population needs for these nutrients in North America conducted a comprehensive review of the evidence for both skeletal and extraskeletal outcomes. The Committee concluded that available scientific evidence supports a key role of calcium and vitamin D in skeletal health, consistent with a cause-and-effect relationship and providing a sound basis for determination of intake requirements. For extraskeletal outcomes, including cancer, cardiovascular disease, diabetes, and autoimmune disorders, the evidence was inconsistent, inconclusive as to causality, and insufficient to inform nutritional requirements. Randomized clinical trial evidence for extraskeletal outcomes was limited and generally uninformative. Based on bone health, Recommended Dietary Allowances (RDAs; covering requirements of ≥97.5% of the population) for calcium range from 700 to 1300 mg/d for life-stage groups at least 1 yr of age. For vitamin D, RDAs of 600 IU/d for ages 1-70 yr and 800 IU/d for ages 71 yr and older, corresponding to a serum 25-hydroxyvitamin D level of at least 20 ng/ml (50 nmol/liter), meet the requirements of at least 97.5% of the population. RDAs for vitamin D were derived based on conditions of minimal sun exposure due to wide variability in vitamin D synthesis from ultraviolet light and the risks of skin cancer. Higher values were not consistently associated with greater benefit, and for some outcomes U-shaped associations were observed, with risks at both low and high levels. The Committee concluded that the prevalence of vitamin D inadequacy in North America has been overestimated. Urgent research and clinical priorities were identified, including reassessment of laboratory ranges for 25-hydroxyvitamin D, to avoid problems of both undertreatment and overtreatment.

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The Role of Vitamin D and Calcium in Type 2 Diabetes. A Systematic Review and Meta-Analysis

2007-03-28

Anastassios G. Pittas , Joseph Lau , Frank B. Hu +1 more

Abstract Context: Altered vitamin D and calcium homeostasis may play a role in the development of type 2 diabetes mellitus (type 2 DM). Evidence Acquisition and Analyses: MEDLINE review was … Abstract Context: Altered vitamin D and calcium homeostasis may play a role in the development of type 2 diabetes mellitus (type 2 DM). Evidence Acquisition and Analyses: MEDLINE review was conducted through January 2007 for observational studies and clinical trials in adults with outcomes related to glucose homeostasis. When data were available to combine, meta-analyses were performed, and summary odds ratios (OR) are presented. Evidence Synthesis: Observational studies show a relatively consistent association between low vitamin D status, calcium or dairy intake, and prevalent type 2 DM or metabolic syndrome [OR (95% confidence interval): type 2 DM prevalence, 0.36 (0.16–0.80) among nonblacks for highest vs. lowest 25-hydroxyvitamin D; metabolic syndrome prevalence, 0.71 (0.57–0.89) for highest vs. lowest dairy intake]. There are also inverse associations with incident type 2 DM or metabolic syndrome [OR (95% confidence interval): type 2 DM incidence, 0.82 (0.72–0.93) for highest vs. lowest combined vitamin D and calcium intake; 0.86 (0.79–0.93) for highest vs. lowest dairy intake]. Evidence from trials with vitamin D and/or calcium supplementation suggests that combined vitamin D and calcium supplementation may have a role in the prevention of type 2 DM only in populations at high risk (i.e. glucose intolerance). The available evidence is limited because most observational studies are cross-sectional and did not adjust for important confounders, whereas intervention studies were short in duration, included few subjects, used a variety of formulations of vitamin D and calcium, or did post hoc analyses. Conclusions: Vitamin D and calcium insufficiency may negatively influence glycemia, whereas combined supplementation with both nutrients may be beneficial in optimizing glucose metabolism.

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Vitamin D Deficiency and Secondary Hyperparathyroidism in the Elderly: Consequences for Bone Loss and Fractures and Therapeutic Implications

2001-08-01

Paul Lips

Vitamin D deficiency is common in the elderly, especially in the housebound and in geriatric patients. The establishment of strict diagnostic criteria is hampered by differences in assay methods for … Vitamin D deficiency is common in the elderly, especially in the housebound and in geriatric patients. The establishment of strict diagnostic criteria is hampered by differences in assay methods for 25-hydroxyvitamin D. The synthesis of vitamin D3 in the skin under influence of UV light decreases with aging due to insufficient sunlight exposure, and a decreased functional capacity of the skin. The diet contains a minor part of the vitamin D requirement. Vitamin D deficiency in the elderly is less common in the United States than elsewhere due to the fortification of milk and use of supplements. Deficiency in vitamin D causes secondary hyperparathyroidism, high bone turnover, bone loss, mineralization defects, and hip and other fractures. Less certain consequences include myopathy and falls. A diet low in calcium may cause an increased turnover of vitamin D metabolites and thereby aggravate vitamin D deficiency. Prevention is feasible by UV light exposure, food fortification, and supplements. Vitamin D3 supplementation causes a decrease of the serum PTH concentration, a decrease of bone turnover, and an increase of bone mineral density. Vitamin D3 and calcium may decrease the incidence of hip and other peripheral fractures in nursing home residents. Vitamin D3 is recommended in housebound elderly, and it may be cost-effective in hip fracture prevention in selected risk groups.

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Vitamin D supplementation, 25-hydroxyvitamin D concentrations, and safety

1999-05-01

Reinhold Vieth

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Vitamin D: importance in the prevention of cancers, type 1 diabetes, heart disease, and osteoporosis

2004-03-01

Michael F. Holick

Overview of general physiologic features and functions of vitamin D

2004-12-01

Hector F. DeLuca

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Fracture Prevention With Vitamin D Supplementation

2005-05-10

Heike A. Bischoff‐Ferrari , Walter C. Willett , John B. Wong +3 more

The role and dose of oral vitamin D supplementation in nonvertebral fracture prevention have not been well established.To estimate the effectiveness of vitamin D supplementation in preventing hip and nonvertebral … The role and dose of oral vitamin D supplementation in nonvertebral fracture prevention have not been well established.To estimate the effectiveness of vitamin D supplementation in preventing hip and nonvertebral fractures in older persons.A systematic review of English and non-English articles using MEDLINE and the Cochrane Controlled Trials Register (1960-2005), and EMBASE (1991-2005). Additional studies were identified by contacting clinical experts and searching bibliographies and abstracts presented at the American Society for Bone and Mineral Research (1995-2004). Search terms included randomized controlled trial (RCT), controlled clinical trial, random allocation, double-blind method, cholecalciferol, ergocalciferol, 25-hydroxyvitamin D, fractures, humans, elderly, falls, and bone density.Only double-blind RCTs of oral vitamin D supplementation (cholecalciferol, ergocalciferol) with or without calcium supplementation vs calcium supplementation or placebo in older persons (> or =60 years) that examined hip or nonvertebral fractures were included.Independent extraction of articles by 2 authors using predefined data fields, including study quality indicators.All pooled analyses were based on random-effects models. Five RCTs for hip fracture (n = 9294) and 7 RCTs for nonvertebral fracture risk (n = 9820) met our inclusion criteria. All trials used cholecalciferol. Heterogeneity among studies for both hip and nonvertebral fracture prevention was observed, which disappeared after pooling RCTs with low-dose (400 IU/d) and higher-dose vitamin D (700-800 IU/d), separately. A vitamin D dose of 700 to 800 IU/d reduced the relative risk (RR) of hip fracture by 26% (3 RCTs with 5572 persons; pooled RR, 0.74; 95% confidence interval [CI], 0.61-0.88) and any nonvertebral fracture by 23% (5 RCTs with 6098 persons; pooled RR, 0.77; 95% CI, 0.68-0.87) vs calcium or placebo. No significant benefit was observed for RCTs with 400 IU/d vitamin D (2 RCTs with 3722 persons; pooled RR for hip fracture, 1.15; 95% CI, 0.88-1.50; and pooled RR for any nonvertebral fracture, 1.03; 95% CI, 0.86-1.24).Oral vitamin D supplementation between 700 to 800 IU/d appears to reduce the risk of hip and any nonvertebral fractures in ambulatory or institutionalized elderly persons. An oral vitamin D dose of 400 IU/d is not sufficient for fracture prevention.

Effect of Vitamin D on Falls

2004-04-27

Heike A. Bischoff‐Ferrari , Bess Dawson‐Hughes , Walter C. Willett +4 more

Falls among elderly individuals occur frequently, increase with age, and lead to substantial morbidity and mortality. The role of vitamin D in preventing falls among elderly people has not been … Falls among elderly individuals occur frequently, increase with age, and lead to substantial morbidity and mortality. The role of vitamin D in preventing falls among elderly people has not been well established.To assess the effectiveness of vitamin D in preventing an older person from falling.MEDLINE and the Cochrane Controlled Trials Register from January 1960 to February 2004, EMBASE from January 1991 to February 2004, clinical experts, bibliographies, and abstracts. Search terms included trial terms: randomized-controlled trial or controlled-clinical trial or random-allocation or double-blind method, or single-blind method or uncontrolled-trials with vitamin D terms: cholecalciferol or hydroxycholecalciferols or calcifediol or dihydroxycholecalciferols or calcitriol or vitamin D/aa[analogs & derivates] or ergocalciferol or vitamin D/bl[blood]; and with accidental falls or falls, and humans.We included only double-blind randomized, controlled trials (RCTs) of vitamin D in elderly populations (mean age, 60 years) that examined falls resulting from low trauma for which the method of fall ascertainment and definition of falls were defined explicitly. Studies including patients in unstable health states were excluded. Five of 38 identified studies were included in the primary analysis and 5 other studies were included in a sensitivity analysis.Independent extraction by 3 authors using predefined data fields including study quality indicators.Based on 5 RCTs involving 1237 participants, vitamin D reduced the corrected odds ratio (OR) of falling by 22% (corrected OR, 0.78; 95% confidence interval [CI], 0.64-0.92) compared with patients receiving calcium or placebo. From the pooled risk difference, the number needed to treat (NNT) was 15 (95% CI, 8-53), or equivalently 15 patients would need to be treated with vitamin D to prevent 1 person from falling. The inclusion of 5 additional studies, involving 10 001 participants, in a sensitivity analysis resulted in a smaller but still significant effect size (corrected RR, 0.87; 95% CI, 0.80-0.96). Subgroup analyses suggested that the effect size was independent of calcium supplementation, type of vitamin D, duration of therapy, and sex, but reduced sample sizes made the results statistically nonsignificant for calcium supplementation, cholecalciferol, and among men.Vitamin D supplementation appears to reduce the risk of falls among ambulatory or institutionalized older individuals with stable health by more than 20%. Further studies examining the effect of alternative types of vitamin D and their doses, the role of calcium supplementation, and effects in men should be considered.

Evaluation, Treatment, and Prevention of Vitamin D Deficiency: an Endocrine Society Clinical Practice Guideline

2011-06-07

Michael F. Holick , Neil Binkley , Heike A. Bischoff‐Ferrari +5 more

The objective was to provide guidelines to clinicians for the evaluation, treatment, and prevention of vitamin D deficiency with an emphasis on the care of patients who are at risk … The objective was to provide guidelines to clinicians for the evaluation, treatment, and prevention of vitamin D deficiency with an emphasis on the care of patients who are at risk for deficiency. The Task Force was composed of a Chair, six additional experts, and a methodologist. The Task Force received no corporate funding or remuneration. Consensus was guided by systematic reviews of evidence and discussions during several conference calls and e-mail communications. The draft prepared by the Task Force was reviewed successively by The Endocrine Society's Clinical Guidelines Subcommittee, Clinical Affairs Core Committee, and cosponsoring associations, and it was posted on The Endocrine Society web site for member review. At each stage of review, the Task Force received written comments and incorporated needed changes. Considering that vitamin D deficiency is very common in all age groups and that few foods contain vitamin D, the Task Force recommended supplementation at suggested daily intake and tolerable upper limit levels, depending on age and clinical circumstances. The Task Force also suggested the measurement of serum 25-hydroxyvitamin D level by a reliable assay as the initial diagnostic test in patients at risk for deficiency. Treatment with either vitamin D2 or vitamin D3 was recommended for deficient patients. At the present time, there is not sufficient evidence to recommend screening individuals who are not at risk for deficiency or to prescribe vitamin D to attain the noncalcemic benefit for cardiovascular protection.

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Decreased bioavailability of vitamin D in obesity

2000-09-01

Jacobo Wortsman , Lois Y. Matsuoka , Tai C. Chen +2 more

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Common genetic determinants of vitamin D insufficiency: a genome-wide association study

2010-06-11

Thomas J. Wang , Feng Zhang , J. Brent Richards +7 more

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Vitamin D deficiency: a worldwide problem with health consequences

2008-04-01

Michael F. Holick , Tai C. Chen

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Annual High-Dose Oral Vitamin D and Falls and Fractures in Older Women

2010-05-11

Kerrie M. Sanders , Amanda L. Stuart , Elizabeth Williamson +4 more

Improving vitamin D status may be an important modifiable risk factor to reduce falls and fractures; however, adherence to daily supplementation is typically poor.To determine whether a single annual dose … Improving vitamin D status may be an important modifiable risk factor to reduce falls and fractures; however, adherence to daily supplementation is typically poor.To determine whether a single annual dose of 500,000 IU of cholecalciferol administered orally to older women in autumn or winter would improve adherence and reduce the risk of falls and fracture.A double-blind, placebo-controlled trial of 2256 community-dwelling women, aged 70 years or older, considered to be at high risk of fracture were recruited from June 2003 to June 2005 and were randomly assigned to receive cholecalciferol or placebo each autumn to winter for 3 to 5 years. The study concluded in 2008.500,000 IU of cholecalciferol or placebo.Falls and fractures were ascertained using monthly calendars; details were confirmed by telephone interview. Fractures were radiologically confirmed. In a substudy, 137 randomly selected participants underwent serial blood sampling for 25-hydroxycholecalciferol and parathyroid hormone levels.Women in the cholecalciferol (vitamin D) group had 171 fractures vs 135 in the placebo group; 837 women in the vitamin D group fell 2892 times (rate, 83.4 per 100 person-years) while 769 women in the placebo group fell 2512 times (rate, 72.7 per 100 person-years; incidence rate ratio [RR], 1.15; 95% confidence interval [CI], 1.02-1.30; P = .03). The incidence RR for fracture in the vitamin D group was 1.26 (95% CI, 1.00-1.59; P = .047) vs the placebo group (rates per 100 person-years, 4.9 vitamin D vs 3.9 placebo). A temporal pattern was observed in a post hoc analysis of falls. The incidence RR of falling in the vitamin D group vs the placebo group was 1.31 in the first 3 months after dosing and 1.13 during the following 9 months (test for homogeneity; P = .02). In the substudy, the median baseline serum 25-hydroxycholecalciferol was 49 nmol/L. Less than 3% of the substudy participants had 25-hydroxycholecalciferol levels lower than 25 nmol/L. In the vitamin D group, 25-hydroxycholecalciferol levels increased at 1 month after dosing to approximately 120 nmol/L, were approximately 90 nmol/L at 3 months, and remained higher than the placebo group 12 months after dosing.Among older community-dwelling women, annual oral administration of high-dose cholecalciferol resulted in an increased risk of falls and fractures.anzctr.org.au Identifier: ACTRN12605000658617; isrctn.org Identifier: ISRCTN83409867.

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Dietary Reference Intakes for Calcium and Vitamin D

2011-03-30

Institute of Medicine

Calcium and vitamin D are the two essential nutrients which are known for their vital role in the health of bones. But over the last few years, the general public … Calcium and vitamin D are the two essential nutrients which are known for their vital role in the health of bones. But over the last few years, the general public has heard conflicting reviews over the benefits of these nutrients- especially vitamin D-and also about how much calcium and vitamin D needs to be taken in order to stay healthy. To help and clarify this pertinent issue, major steps were drawn with the help of U.S and Canadian Governments and also by the European Commission to set a dietary reference value and also set the Tolerance upper intake level of both these nutrients. The purpose of this article is to cover exhaustively the potential health outcomes of these essential nutrients not just in bone health but also in overall health condition of an individual.

Vitamin D: Metabolism, Molecular Mechanism of Action, and Pleiotropic Effects

2015-12-23

Sylvia Christakos , Puneet Dhawan , Annemieke Verstuyf +2 more

1,25-Dihydroxvitamin D3 [1,25(OH)2D3] is the hormonally active form of vitamin D. The genomic mechanism of 1,25(OH)2D3 action involves the direct binding of the 1,25(OH)2D3 activated vitamin D receptor/retinoic X receptor … 1,25-Dihydroxvitamin D3 [1,25(OH)2D3] is the hormonally active form of vitamin D. The genomic mechanism of 1,25(OH)2D3 action involves the direct binding of the 1,25(OH)2D3 activated vitamin D receptor/retinoic X receptor (VDR/RXR) heterodimeric complex to specific DNA sequences. Numerous VDR co-regulatory proteins have been identified, and genome-wide studies have shown that the actions of 1,25(OH)2D3 involve regulation of gene activity at a range of locations many kilobases from the transcription start site. The structure of the liganded VDR/RXR complex was recently characterized using cryoelectron microscopy, X-ray scattering, and hydrogen deuterium exchange. These recent technological advances will result in a more complete understanding of VDR coactivator interactions, thus facilitating cell and gene specific clinical applications. Although the identification of mechanisms mediating VDR-regulated transcription has been one focus of recent research in the field, other topics of fundamental importance include the identification and functional significance of proteins involved in the metabolism of vitamin D. CYP2R1 has been identified as the most important 25-hydroxylase, and a critical role for CYP24A1 in humans was noted in studies showing that inactivating mutations in CYP24A1 are a probable cause of idiopathic infantile hypercalcemia. In addition, studies using knockout and transgenic mice have provided new insight on the physiological role of vitamin D in classical target tissues as well as evidence of extraskeletal effects of 1,25(OH)2D3 including inhibition of cancer progression, effects on the cardiovascular system, and immunomodulatory effects in certain autoimmune diseases. Some of the mechanistic findings in mouse models have also been observed in humans. The identification of similar pathways in humans could lead to the development of new therapies to prevent and treat disease.

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Hypovitaminosis D in Medical Inpatients

1998-03-19

Melissa K. Thomas , Donald M. Lloyd‐Jones , Ravi Thadhani +7 more

Vitamin D deficiency is a major risk factor for bone loss and fracture. Although hypovitaminosis D has been detected frequently in elderly and housebound people, the prevalence of vitamin D … Vitamin D deficiency is a major risk factor for bone loss and fracture. Although hypovitaminosis D has been detected frequently in elderly and housebound people, the prevalence of vitamin D deficiency among patients hospitalized on a general medical service is unknown.

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Vitamin D supplementation to prevent acute respiratory tract infections: systematic review and meta-analysis of individual participant data

2017-02-15

Adrian R. Martineau , David A. Jolliffe , Richard Hooper +7 more

Objectives To assess the overall effect of vitamin D supplementation on risk of acute respiratory tract infection, and to identify factors modifying this effect. Design Systematic review and meta-analysis of individual participant … Objectives To assess the overall effect of vitamin D supplementation on risk of acute respiratory tract infection, and to identify factors modifying this effect. Design Systematic review and meta-analysis of individual participant data (IPD) from randomised controlled trials. Data sources Medline, Embase, the Cochrane Central Register of Controlled Trials, Web of Science, ClinicalTrials.gov, and the International Standard Randomised Controlled Trials Number registry from inception to December 2015. Eligibility criteria for study selection Randomised, double blind, placebo controlled trials of supplementation with vitamin D3 or vitamin D2 of any duration were eligible for inclusion if they had been approved by a research ethics committee and if data on incidence of acute respiratory tract infection were collected prospectively and prespecified as an efficacy outcome. Results 25 eligible randomised controlled trials (total 11 321 participants, aged 0 to 95 years) were identified. IPD were obtained for 10 933 (96.6%) participants. Vitamin D supplementation reduced the risk of acute respiratory tract infection among all participants (adjusted odds ratio 0.88, 95% confidence interval 0.81 to 0.96; P for heterogeneity <0.001). In subgroup analysis, protective effects were seen in those receiving daily or weekly vitamin D without additional bolus doses (adjusted odds ratio 0.81, 0.72 to 0.91) but not in those receiving one or more bolus doses (adjusted odds ratio 0.97, 0.86 to 1.10; P for interaction=0.05). Among those receiving daily or weekly vitamin D, protective effects were stronger in those with baseline 25-hydroxyvitamin D levels <25 nmol/L (adjusted odds ratio 0.30, 0.17 to 0.53) than in those with baseline 25-hydroxyvitamin D levels ≥25 nmol/L (adjusted odds ratio 0.75, 0.60 to 0.95; P for interaction=0.006). Vitamin D did not influence the proportion of participants experiencing at least one serious adverse event (adjusted odds ratio 0.98, 0.80 to 1.20, P=0.83). The body of evidence contributing to these analyses was assessed as being of high quality. Conclusions Vitamin D supplementation was safe and it protected against acute respiratory tract infection overall. Patients who were very vitamin D deficient and those not receiving bolus doses experienced the most benefit. Systematic review registration PROSPERO CRD42014013953.

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Vitamin D Supplements and Prevention of Cancer and Cardiovascular Disease

2018-11-10

JoAnn E. Manson , Nancy R. Cook , I‐Min Lee +7 more

It is unclear whether supplementation with vitamin D reduces the risk of cancer or cardiovascular disease, and data from randomized trials are limited. It is unclear whether supplementation with vitamin D reduces the risk of cancer or cardiovascular disease, and data from randomized trials are limited.

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Evidence that Vitamin D Supplementation Could Reduce Risk of Influenza and COVID-19 Infections and Deaths

2020-04-02

William B. Grant , Henry Lahore , Sharon L. McDonnell +4 more

The world is in the grip of the COVID-19 pandemic. Public health measures that can reduce the risk of infection and death in addition to quarantines are desperately needed. This … The world is in the grip of the COVID-19 pandemic. Public health measures that can reduce the risk of infection and death in addition to quarantines are desperately needed. This article reviews the roles of vitamin D in reducing the risk of respiratory tract infections, knowledge about the epidemiology of influenza and COVID-19, and how vitamin D supplementation might be a useful measure to reduce risk. Through several mechanisms, vitamin D can reduce risk of infections. Those mechanisms include inducing cathelicidins and defensins that can lower viral replication rates and reducing concentrations of pro-inflammatory cytokines that produce the inflammation that injures the lining of the lungs, leading to pneumonia, as well as increasing concentrations of anti-inflammatory cytokines. Several observational studies and clinical trials reported that vitamin D supplementation reduced the risk of influenza, whereas others did not. Evidence supporting the role of vitamin D in reducing risk of COVID-19 includes that the outbreak occurred in winter, a time when 25-hydroxyvitamin D (25(OH)D) concentrations are lowest; that the number of cases in the Southern Hemisphere near the end of summer are low; that vitamin D deficiency has been found to contribute to acute respiratory distress syndrome; and that case-fatality rates increase with age and with chronic disease comorbidity, both of which are associated with lower 25(OH)D concentration. To reduce the risk of infection, it is recommended that people at risk of influenza and/or COVID-19 consider taking 10,000 IU/d of vitamin D3 for a few weeks to rapidly raise 25(OH)D concentrations, followed by 5000 IU/d. The goal should be to raise 25(OH)D concentrations above 40-60 ng/mL (100-150 nmol/L). For treatment of people who become infected with COVID-19, higher vitamin D3 doses might be useful. Randomized controlled trials and large population studies should be conducted to evaluate these recommendations.

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1,25-Dihydroxyvitamin D3 is a negative endocrine regulator of the renin-angiotensin system

2002-07-15

Yan Chun Li , Juan Kong , Minjie Wei +3 more

Inappropriate activation of the renin-angiotensin system, which plays a central role in the regulation of blood pressure, electrolyte, and volume homeostasis, may represent a major risk factor for hypertension, heart … Inappropriate activation of the renin-angiotensin system, which plays a central role in the regulation of blood pressure, electrolyte, and volume homeostasis, may represent a major risk factor for hypertension, heart attack, and stroke. Mounting evidence from clinical studies has demonstrated an inverse relationship between circulating vitamin D levels and the blood pressure and/or plasma renin activity, but the mechanism is not understood. We show here that renin expression and plasma angiotensin II production were increased severalfold in vitamin D receptor–null (VDR-null) mice, leading to hypertension, cardiac hypertrophy, and increased water intake. However, the salt- and volume-sensing mechanisms that control renin synthesis are still intact in the mutant mice. In wild-type mice, inhibition of 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] synthesis also led to an increase in renin expression, whereas 1,25(OH)2D3 injection led to renin suppression. We found that vitamin D regulation of renin expression was independent of calcium metabolism and that 1,25(OH)2D3 markedly suppressed renin transcription by a VDR-mediated mechanism in cell cultures. Hence, 1,25(OH)2D3 is a novel negative endocrine regulator of the renin-angiotensin system. Its apparent critical role in electrolytes, volume, and blood pressure homeostasis suggests that vitamin D analogues could help prevent or ameliorate hypertension.

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Vitamin D and physical activity as co-modifiers of muscle health and function - a narrative exploration

2025-06-25

Inshal Jawed , Hafiza Quratul Ain , Farah Abdul Razaq +7 more | Annals of Medicine and Surgery

Vitamin D and Cardiovascular Health: A Narrative Review of Risk Reduction Evidence

2025-06-25

William B. Grant , Barbara J. Boucher , Richard Z. Cheng +2 more | Nutrients

The role of vitamin D in reducing cardiovascular disease (CVD) risk remains debated despite growing evidence. Prospective observational studies consistently show that low serum 25-hydroxyvitamin D [25(OH)D] concentrations (below 40–50 … The role of vitamin D in reducing cardiovascular disease (CVD) risk remains debated despite growing evidence. Prospective observational studies consistently show that low serum 25-hydroxyvitamin D [25(OH)D] concentrations (below 40–50 nmol/L [16–20 ng/mL]) are associated with the highest risk of CVD incidence. In addition, a large prospective observational study found that serum 25(OH)D concentration was inversely correlated with CVD mortality rate to over 100 nmol/L. Randomized controlled trials have not generally demonstrated benefit due to faulty study designs, such as enrolling participants with baseline 25(OH)D levels > 50 nmol/L. However, a major trial found that 60,000 IU/month of vitamin D3 supplementation reduced the risk of major cardiovascular events for participants with predicted 25(OH)D concentrations ≥ 50 nmol/L or taking statins or CV drugs by ~13 to ~17%. In addition, vitamin D supplementation studies have found modest reductions in several CVD risk factors. Other observational studies of vitamin D supplementation have reported reduced CVD risks (e.g., ischemic heart disease, hypertension, and myocardial infarction). Temporal ecological studies further support this relationship, revealing that CVD incidence rates are lowest in summer and CVD mortality rates are significantly higher in late winter—when 25(OH)D concentrations are lowest—compared to late summer. A previously reported analysis using eight of Hill’s criteria for causality in a biological system further strengthens the biological plausibility of vitamin D’s role in CVD risk reduction. Its role in modulating inflammation and oxidative stress, improving endothelial function, and reducing several cardiometabolic risk factors supports its inclusion as part of a comprehensive, multi-modal approach to cardiovascular health. Therefore, vitamin D should be considered an integral component in the prevention and management of CVD. Preferably, it should be used in combination with other nutritional supplements, a heart-healthy diet, and prescription medications to reduce the risk of CVD incidence. People should consider vitamin D3 supplementation with at least 2000 IU/day (50 mcg/day) (more for those who are obese) when sun exposure is insufficient to maintain serum 25(OH)D concentrations above 75 nmol/L. To reduce CVD mortality rates, higher doses to achieve higher 25(OH)D concentrations might be warranted.

Vitamin D3, 25-Hydroxyvitamin D3, and 1,25-Dihydroxyvitamin D3 Uptake in Cultured Human Mature Adipocytes

2025-06-25

Nazlı Uçar , R. Taylor Pickering , PETER M. MUELLER +4 more | Nutrients

Background/Objectives: Vitamin D3 is predominantly sequestered in adipose tissue, where it is slowly mobilized under conditions of deficiency in vivo. However, the kinetics of its uptake, release, and interaction with … Background/Objectives: Vitamin D3 is predominantly sequestered in adipose tissue, where it is slowly mobilized under conditions of deficiency in vivo. However, the kinetics of its uptake, release, and interaction with its major metabolites, 25(OH)D3 and 1,25(OH)2D3, remain poorly understood. Given the close relationship between obesity, low-grade chronic inflammation, and disrupted vitamin D metabolism, a clearer understanding of these dynamics in adipocytes is essential. Thus, we sought to characterize time-dependent uptake and metabolites in differentiated human adipocytes. Methods: Human pre-adipocytes were differentiated in vitro and exposed to either vitamin D3 and 1,25(OH)2D3 or the combination of vitamin D3, 25(OH)D3 and 1,25(OH)2D3. Intracellular concentrations were quantified through HPLC at various time points. A separate efflux experiment assessed vitamin D3 release under basal and isoproterenol-stimulated conditions using 3H-vitamin D3 and scintillation counting. Results: Vitamin D3 uptake showed a gradual and sustained increase over 96 h, suggesting ongoing accumulation within lipid-rich compartments. In contrast, 25(OH)D3 and 1,25(OH)2D3 peaked rapidly within the first hour and declined sharply. Isoproterenol stimulation significantly enhanced vitamin D3 release into the extracellular medium from the adipocytes, indicating increased efflux during lipolytic activation. Conclusions: Adipocytes selectively retain vitamin D3 while rapidly clearing its hydroxylated forms. These findings highlight the distinct intracellular handling of vitamin D metabolites and suggest that tailored supplementation strategies—particularly in individuals with excess adiposity—may improve bioavailability and metabolic efficacy.

СОВРЕМЕННЫЕ ВЗГЛЯДЫ НА РОЛЬ ВИТАМИНА D В ОРГАНИЗМЕ ЧЕЛОВЕКА (ЛИТЕРАТУРНЫЙ ОБЗОР)

2025-06-25

Роза Султаналиева , Айниса Айтиева | Bulletin of Osh State University

Витамин D является важным биологически активным соединением, которое участвует в регуляции множества физиологических процессов. Он не является классическим витамином, а может быть назван D -гормоном, играющим ключевую роль в поддержании … Витамин D является важным биологически активным соединением, которое участвует в регуляции множества физиологических процессов. Он не является классическим витамином, а может быть назван D -гормоном, играющим ключевую роль в поддержании минерального обмена, модуляции иммунного ответа и функционировании сердечно-сосудистой системы. Настоящий обзор рассматривает современные представления о биологических функциях витамина D и его значении для здоровья человека.

Future Challenges of Vitamin D Deficiency: The Impact of Systemic Vitamin D Therapy on Serum Levels and Skin Diseases

2025-06-24

Tea Štrbac , Vana Stojić , Stjepan Frkanec +1 more | Journal of Applied Cosmetology

In recent years, research on the role of vitamin D in skin diseases has grown, revealing its dose-dependent effects on cell function and its immunomodulatory, antioxidative, and cytoprotective properties. These … In recent years, research on the role of vitamin D in skin diseases has grown, revealing its dose-dependent effects on cell function and its immunomodulatory, antioxidative, and cytoprotective properties. These findings have expanded their use in dermatology. However, the rising incidence of deficiency, linked to reduced sun exposure from indoor lifestyles and cultural practices, underscores the need for further investigation and therapeutic strategies. To review key insights on the systemic use of vitamin D in common immunomodulatory skin diseases, beyond its well-established topical applications. The electronic research of the literature included three databases: MEDLINE, Cochrane, and Google Scholar, as well as other available literature sources. Decreased serum vitamin D levels are observed in psoriasis, vitiligo, and alopecia areata. Systemic vitamin D therapy has shown clinical improvement in psoriasis, vitiligo, and atopic dermatitis, with limited but promising evidence in alopecia areata. It may play a role in managing acne vulgaris, though long-term data remain insufficient. The effects of systemic vitamin D analogs in the clinical treatment of many skin diseases are promising, but further clinical studies are needed.

The Vitamin D and IBD Nexus: Immune Links and Therapeutic Prospects

2025-06-24

Yogesh Garg , Nandini Sharma , Raj Kumar Narang +1 more | Journal of the American Nutrition Association

Prevalence and predictive factors for vitamin D deficiency in pregnant Lebanese women: a retrospective cohort study

2025-06-24

Muhieddine Seoud , Iman Jaafar , Dalal Kojok +4 more | Gynecological Endocrinology

This study aimed to determine the prevalence of vitamin D deficiency and its associated factors among women attending women's health clinics at a university medical center in Lebanon. We retrospectively … This study aimed to determine the prevalence of vitamin D deficiency and its associated factors among women attending women's health clinics at a university medical center in Lebanon. We retrospectively reviewed clinical and obstetric data, including 25-hydroxyvitamin D [25OHD] serum levels and vitamin D3 supplementation, from 873 healthy singleton pregnancies delivered between 2006 and 2017. Women with preexisting comorbidities or prior gestational complications were excluded. VDD was defined as a 25OHD serum level <20 ng/ml. At baseline, 63% of participants were vitamin D deficient. Poisson regression was used to identify independent predictors of deficiency. In early gestation, 25OHD levels varied significantly by age, pre-pregnancy BMI, parity, smoking status, and season of presentation (all p < 0.05). At late gestation, vitamin D levels were associated with pre-pregnancy BMI, hemoglobin status at delivery, and vitamin D status at early gestation. Women with 25OHD <20 ng/ml at late gestation were more likely to be anemic compared to those with levels ≥20 ng/ml (adjusted odds ratio 1.6; 95% CI: 1.1-2.5). Vitamin D deficiency is highly prevalent among pregnant Lebanese women. Identified risk factors including higher BMI, younger age, multiparity, and anemia should prompt consideration of more aggressive vitamin D supplementation strategies for women planning pregnancy. Vitamin D deficiency is quite prevalent among pregnant women in the Middle East. We aim to report the prevalence of Vitamin D deficiency and its associated predictors during pregnancy.

Papillon-Lefèvre Syndrome and Vitamin D Deficiency: An Intriguing Clinical Observation

2025-06-24

H. Mhiri , Manel Chalbi , Nadia Dridi +2 more | OBM Genetics

We report the case of a 3-year-old girl from a consanguineous marriage, initially diagnosed with vitamin D deficiency–associated periodontitis following early tooth mobility. Despite supplementation, her condition worsened with the … We report the case of a 3-year-old girl from a consanguineous marriage, initially diagnosed with vitamin D deficiency–associated periodontitis following early tooth mobility. Despite supplementation, her condition worsened with the onset of palmoplantar hyperkeratosis. Further investigations revealed the diagnosis of Papillon-Lefèvre Syndrome (PLS), a rare genetic disorder causing severe periodontitis and palmoplantar keratosis. The patient was managed with vitamin D supplementation, dental extractions, and a removable partial denture. A multidisciplinary approach led to the confirmation of PLS and appropriate management, highlighting the importance of considering genetic disorders in a severe form of periodontitis. This case underscores the potential role of vitamin D deficiency in exacerbating periodontal disease in genetically predisposed individuals, warranting further research into its impact on PLS progression.

Vitamin D deficiency and risk of postoperative complications in joint arthroplasty: a meta-analysis

2025-06-24

Rohit Tyagi , Ashish Dubey , Ashi Khurana +2 more | International Journal of Research in Orthopaedics

Vitamin D deficiency is prevalent among patients undergoing joint arthroplasty and may influence surgical outcomes. This meta-analysis aimed to evaluate the association between preoperative vitamin D deficiency and postoperative complications … Vitamin D deficiency is prevalent among patients undergoing joint arthroplasty and may influence surgical outcomes. This meta-analysis aimed to evaluate the association between preoperative vitamin D deficiency and postoperative complications following joint arthroplasty. A systematic search was conducted in PubMed/MEDLINE, Embase, Cochrane Library, Web of Science and Scopus from inception to January 2025. Random-effects models were used to calculate pooled odds ratios (ORs) and standardized mean differences (SMDs). Subgroup analyses were performed based on study design, joint type, vitamin D threshold and follow-up duration. Twenty-three studies (8,762 patients) were included. Vitamin D deficiency was significantly associated with increased risk of overall postoperative complications (OR 2.18, 95% CI 1.76-2.69), periprosthetic joint infection (OR 2.83, 95% CI 2.05-3.91), superficial surgical site infection (OR 1.89, 95% CI 1.45-2.47), aseptic loosening (OR 1.76, 95% CI 1.38-2.25), prosthetic dislocation (OR 1.82, 95% CI 1.31-2.53) and revision surgery (OR 2.25, 95% CI 1.72-2.94). Functional outcomes were significantly worse in vitamin D-deficient patients at 6 months and 12 months postoperatively. The association between vitamin D deficiency and complications was strongest with the <10 ng/mL threshold. Preoperative vitamin D deficiency is significantly associated with increased risk of multiple complications and poorer functional outcomes following joint arthroplasty. The risk appears to increase with the severity of deficiency suggesting that vitamin D status represent a modifiable risk factor. Future research should investigate whether preoperative vitamin D supplementation can reduce complication risk and improve outcomes.

Sexual Functioning and Depressive Symptoms in Levothyroxine-Treated Women with Postpartum Thyroiditis and Different Vitamin D Status

2025-06-24

Karolina Kowalcze , Joanna Kula-Gradzik , Anna Błaszczyk +1 more | Nutrients

Background/Objectives: Hypothyroidism and thyroid autoimmunity have a negative effect on women’s sexual health, which is only partially reversed by thyroid hormone substitution. Sexual functioning in thyroid disorders after delivery has … Background/Objectives: Hypothyroidism and thyroid autoimmunity have a negative effect on women’s sexual health, which is only partially reversed by thyroid hormone substitution. Sexual functioning in thyroid disorders after delivery has been poorly researched. The aim of our study was to compare the effect of levothyroxine on sexual response and depressive symptoms in women with postpartum thyroiditis (PPT) and different vitamin D status. Methods: The study population consisted of three matched groups of women with the hypothyroid phase of PPT: two groups with subclinical and one with overt thyroid hypofunction. Each group included similar numbers of women with normal and low vitamin D status. For the following six months, one group of women with subclinical hypothyroidism and all women with overt thyroid hypofunction received levothyroxine. At the beginning and at the end of the study, all participants completed questionnaires evaluating female sexual function (FSFI) and depressive symptoms (BMI-II). The remaining outcomes of interest included thyroid antibody titers, and the serum levels of 25-hydroxyvitamin D, TSH, free thyroid hormones, sex hormones, and prolactin. Results: Before levothyroxine substitution, women with overt and subclinical disease differed in the total FSFI score, all domain scores, and the overall BDI-II score. Within each study group, domain scores for desire were greater in women with vitamin D sufficiency than in those with vitamin D deficiency/insufficiency. Testosterone and estradiol levels were lower in women with overt than in women with subclinical hypothyroidism, while the opposite relationship was found for prolactin. Levothyroxine treatment improved all domains of female sexual function and reduced the total BDI-II score in both patients with overt and subclinical hypothyroidism and normal vitamin D status. In women with vitamin D deficiency/insufficiency, the impact of this agent was limited to arousal, lubrication, and sexual satisfaction. Levothyroxine replacement reduced thyroid antibody titers only in women with normal vitamin D status. The impact on testosterone was limited to women with normal vitamin D status, and was more pronounced in women with overt than subclinical disease. The effect on estradiol and prolactin, observed only in overt disease, was unrelated to vitamin D status. The increase in sexual functioning correlated with the following: 25-hydroxyvitamin D levels (in vitamin D-deficient/insufficient women); the impact on thyroid peroxidase antibodies, free triiodothyronine and testosterone (for desire and arousal); and the changes in the overall BDI-II score. Five years later, the quality of life was better in vitamin D-sufficient women receiving levothyroxine in the postpartum period. Conclusions: Low vitamin D status attenuates the impact of levothyroxine on female sexual function and depressive symptoms in women with the hypothyroid phase of PPT.

Are long-lasting nonspecific symptoms related to vitamin D deficiency among older adults living in nursing homes?

2025-06-24

Rebeka Arnljots , Egill Snaebjörnsson Arnljots , Jörgen Thorn +3 more | BMC Geriatrics

Confusion, restlessness, and fatigue are common among older adults living in nursing homes. These nonspecific symptoms are often treated with antibiotics since they are frequently misinterpreted as urinary tract infections. … Confusion, restlessness, and fatigue are common among older adults living in nursing homes. These nonspecific symptoms are often treated with antibiotics since they are frequently misinterpreted as urinary tract infections. Therefore, it is crucial to investigate other potential causes of these nonspecific symptoms. Impaired cognitive function in older adults may be associated with vitamin D deficiency and could lead to nonspecific symptoms. Currently, it is unknown whether there is a correlation between nonspecific symptoms, often misinterpreted as acute cystitis, and vitamin D deficiency. A cross-sectional study in which blood samples were collected from residents of 22 Swedish nursing homes for 25OHD (25-hydroxyvitamin D) analysis. Demographics and presence of nonspecific symptoms, such as: fatigue, restlessness, confusion, aggressiveness, reduced appetite, tendency to fall or a sense of not being oneself as well as symptom duration, were registered. incontinence, dementia too severe to cooperate when taking a blood test, terminally ill or refusing participation. Logistic regressions were performed to determine if nonspecific symptoms persisting ≥ 3 months were associated with vitamin D deficiency. Out of 901 residents in 22 nursing homes blood samples were taken from 545 participants, of whom 370 (68%) were women. The mean age was 86 years (SD 6.9), and 55% (299/545) had dementia. The prevalence of symptoms persisting ≥ 3 months was: fatigue 49% (268/545), restlessness 50% (270/545), confusion 53% (287/545), agitation/anger 47% (258/545), reduced appetite 45% (247/545), tendency to fall 48% (260/545), and a sense of not being oneself 35% (191/545). The 25OHD concentrations did not differ between various nonspecific symptoms. When adjusting for age, gender and dementia there was no association between any of the nonspecific symptoms and 25OHD. Nonspecific symptoms persisting ≥ 3 months and vitamin D deficiency were common among older adults living in nursing homes. However, there was no association between these long-lasting nonspecific symptoms and the concentration of vitamin D. In further research it is important to study other potential causes of nonspecific symptoms in older adults.

Key genes of vitamin D metabolism and their roles in the risk and prognosis of cancer

2025-06-24

Sijie Zheng , Lin Zhu , Yufei Wang +3 more | Frontiers in Genetics

Vitamin D is an essential vitamin for normal human metabolism and plays pivotal roles in various biological processes, such as maintaining calcium and phosphorus balance, regulating immune responses, and promoting … Vitamin D is an essential vitamin for normal human metabolism and plays pivotal roles in various biological processes, such as maintaining calcium and phosphorus balance, regulating immune responses, and promoting cell differentiation while inhibiting proliferation. Vitamin D is obtained through sunlight exposure and diet, and is metabolized into its active form via hydroxylation in liver and kidney. Vitamin D deficiency is linked to various diseases, including skeletal disorders, diabetes, and cardiovascular diseases. Recent epidemiology and oncology research have demonstrated that serum vitamin D level, as well as genetic polymorphisms and expression dysregulation of genes related with vitamin D metabolism, have significantly influences on the incidence and prognosis of various types of cancer, including breast cancer, prostate cancer, liver cancer, gastrointestinal malignancy, and hematologic malignancies. The mechanisms linking vitamin D metabolism dysregulation to malignancy are multifactorial, such as the alteration in cell metabolism, proliferation, differentiation, and tumor microenvironment. These findings suggest potential therapeutic benefits of targeting the vitamin D signaling pathway for the diagnosis and treatment of cancer. However, there is still a lack of clinical applications regarding the knowledge of vitamin D metabolic pathway, and future research is urgently needed to illustrate the underlying mechanisms for the rationale design of clinical trials. Therefore, this review summarizes the metabolic pathways of vitamin D and its association with cancer, highlighting the importance of genetic polymorphisms and expression dysregulation of genes involved in vitamin D metabolism in cancer susceptibility and prognosis.

Impact of vitamin D supplementation on cognitive impairment in elderly individuals with hypertension

2025-06-24

Lili Tan , Hongyan Li , Lina Zhao | Frontiers in Neurology

Background Older adults frequently experience vitamin D deficiency, which has been linked to both cognitive decline and hypertension. However, evidence on whether correcting vitamin D insufficiency can improve recognition memory … Background Older adults frequently experience vitamin D deficiency, which has been linked to both cognitive decline and hypertension. However, evidence on whether correcting vitamin D insufficiency can improve recognition memory and blood pressure (BP) control in this population remains inconclusive. Objective To evaluate the association between vitamin D supplementation and improvements in cognitive function and BP among older adults with hypertension and mild cognitive deficits. Methods We conducted a retrospective review of patient records from individuals aged ≥65 years who had documented hypertension, baseline 25-hydroxyvitamin D (25(OH)D) levels &lt; 30 ng/mL, and mild cognitive impairment (Montreal Cognitive Assessment [MoCA] &lt; 26) or subjective cognitive complaints. Patients were categorized into two groups based on recorded vitamin D supplementation (≥5,000 IU/day for ≥6 months vs. no or minimal supplementation). Recognition memory, global cognition (MoCA), systolic and diastolic BP, and serum 25(OH)D levels were compared between groups. Results Among 153 eligible records, those in the Supplemented group showed greater gains in recognition memory (+3.1 ± 2.4 vs. +1.2 ± 2.0 points; p = 0.01) and a larger decrease in systolic BP (−12.8 ± 7.2 vs. −7.1 ± 6.8 mmHg; p = 0.03). Sensitivity analyses confirmed these benefits. For instance, in adjusted multivariable regression, recognition memory improved by an additional +1.8 points (95% CI 0.9–2.7; p = 0.002) and systolic BP fell by −10.7 mmHg ( p = 0.01) in the Supplemented group. Multivariable regression and propensity-score-matched analyses yielded comparable cognitive and blood-pressure benefits. Stratified analyses indicated stronger responses in those with MoCA &lt; 22 (+2.9 points in recognition memory; p = 0.01) and in participants with baseline 25(OH)D &lt; 20 ng/mL (+2.8 points; p = 0.003). Both men and women derived similar cognitive and BP benefits. Mild hypercalcemia occurred in 3.8% of supplemented patients vs. 1.3% of comparisons. Conclusions In this retrospective cohort, vitamin D supplementation was associated with notable improvements in recognition memory, global cognition, and systolic BP among older adults with hypertension and mild cognitive deficits. These findings highlight the potential clinical benefits of correcting vitamin D insufficiency in this high-risk population, warranting further investigation in prospective trials.

Effect of Serum Vitamin D Level on Oral Health Status of Children

2025-06-24

Maknunnahar , Md Shakhawat Hossain , SM Rowshan Alam +4 more | Journal of Rangpur Medical College

Abstract not available J Rang Med Col. March 2025; Vol.10, No.1: 45-50 Abstract not available J Rang Med Col. March 2025; Vol.10, No.1: 45-50

Meta-analysis of the effects of vitamin D on growth, development and body weight of children of different ages

2025-06-23

Tiantian Song | Research Square (Research Square)

<title>Abstract</title> Objective Due to the rapid growth and development of children, they were easily affected by various bad living habits and other factors, resulting in insufficient intake of one or … <title>Abstract</title> Objective Due to the rapid growth and development of children, they were easily affected by various bad living habits and other factors, resulting in insufficient intake of one or more nutrients. Vitamin D drops could effectively promote children’s growth and development, but there was no comprehensive analysis of the effects of vitamin D drops on children’s growth and development. We want to systematically evaluate the effects of vitamin D drops on different ages of children’s growth and development by meta-analysis. Methods PubMed, EMBASE and Cochrane Library as search databases was collected from January 2000 to June 2023. The randomized controlled trials (RCTs) on the effects of vitamin D on children’s growth and development were searched, the literatures were screened, the data (height and weight) were extracted, and the risk of bias in the included studies was evaluated. The meta-analysis was conducted using Stata. 11 software. Results We included six studies, all randomized controlled trials of the effects of vitamin D supplementation on growth and development in children. The results showed that compared with the placebo group in the control group, vitamin D supplementation could significantly improve the level of serum 25(OH)D3 in children [n = 603, mean difference (MD) = 5.08 ng/ml, 95%CI (0.57,9.60), P = 0.03]. BMI, height, body weight and relative fat index had little effect, and there was no significant comparison between groups, which were [n = 1514, MD=-0,08 kg/m2, 95%CI (-0.47,0.30), P = 0.67], respectively. [n = 1426, MD = 0.18 cm, 95% CI (0.61, 0.97), P = 0.66). (n = 1426, MD = 0.10 kg, 95% CI (0.43, 0.22), P = 0.53) and (n = 1127, MD = 0.88%, 95% CI (26.24, 24.47), P = 0.95). Conclusion The study suggests that while vitamin D supplementation effectively boosts serum 25(OH)D3 levels in children, it has limited influence on other growth and development parameters such as BMI, height, body weight, and relative fat index.

Exploring the association between serum vitamin D levels and type 2 diabetes risk in US adults

2025-06-23

Jijun Zhang , Kaiqi Wu , Xiushan Dong | Annals of Medicine

Serum vitamin D levels have been linked to the risk of developing type 2 diabetes (T2D), but findings across studies remain inconsistent. This study included 9,522 participants with a mean … Serum vitamin D levels have been linked to the risk of developing type 2 diabetes (T2D), but findings across studies remain inconsistent. This study included 9,522 participants with a mean age of 43.55 ± 0.34 years, of whom 52.76% were male, from the 2007-2014 National Health and Nutrition Examination Survey (NHANES) with complete data on serum vitamin D, T2D diagnosis, and relevant covariates. Participants were categorized into three groups based on serum vitamin D levels: sufficient (>75 nmol/L), suboptimal (50-74 nmol/L), and deficient (<50 nmol/L). Restricted cubic spline and multivariable logistic regression models were used to analyze the relationship between serum vitamin D and T2D risk. After adjusting for confounders (sex, ethnicity, age, BMI, education, marital status, physical activity, alcohol consumption, smoking, PIR, and depressive symptoms), participants in the sufficient (OR = 0.68; 95% CI: 0.53-0.87) had significantly lower T2D risk compared to the deficient group (p for trend = 0.003). The relationship between vitamin D and T2D was non-linear, with the lowest T2D risk occurring at 74.99 nmol/L. Sufficient serum vitamin D levels are associated with a lower risk of T2D, with the optimal level identified as 74.99 nmol/L. Further randomized controlled trials are needed to confirm these findings.

Pregnancy vitamin D supplementation and bone mineral density of the mother: a post hoc analysis of the MAVIDOS randomised placebo-controlled trial

2025-06-23

Rebecca J. Moon , Stefania D’Angelo , Elizabeth Curtis +4 more | Osteoporosis International

Dysregulation and gene polymorphisms of Vitamin D receptor: its implications in lipid metabolic disorders

2025-06-23

Ashok Kumar Sekar , Anthony Josephine , Tamilselvan Jayavelu +3 more | Molecular Biology Reports

The Future of Vitamin D: Extraskeletal Effects

2025-06-23

Alexey N. Kuchmin , Olga V. Diskalenko , Anna B. Izotova +1 more | Bulletin of the Russian Military Medical Academy

This review highlights current Russian and international scientific data on the role of vitamin D in a wide range of physiological processes, with a special emphasis on its extraskeletal functions, … This review highlights current Russian and international scientific data on the role of vitamin D in a wide range of physiological processes, with a special emphasis on its extraskeletal functions, clinical implications, and manifestations. A search and analysis of the medical scientific data from 2004 to 2023 was undertaken using the databases eLibrary.RU, the Russian National Library, and the Fundamental Library of the S.M. Kirov Military Medical Academy, and the international search platforms PubMed and Medscape. Key scientific publications were reviewed, including outcomes from preclinical studies on laboratory animals utilizing vitamin D supplements and clinical studies involving patients with vitamin D deficiency. It examines vitamin D metabolism and its involvement in the immune function, as well as in the cardiovascular, respiratory, digestive, endocrine, nervous, reproductive, and other systems. Vitamin D deficiency is clearly reflected in the development, pathogenesis, and progression of diverse prevalent human diseases, including infectious, chronic inflammatory, allergic, systemic autoimmune, and various neoplastic conditions. The article highlights key historical milestones in the discovery of vitamin D and its metabolites, their health impacts, and the role of vitamin D deficiency in disease development. Preclinical and clinical studies have largely validated the effects of vitamin D at the cellular, tissue, and organ levels, including its role in regulating the function of various physiological systems as well as cellular proliferation and differentiation. Numerous long-term prospective studies are ongoing, linking low vitamin D levels to a wide spectrum of human diseases. This continues to generate considerable scientific interest and enthusiasm for exploring the effects of dietary vitamin D supplementation on human health, despite inconsistent results from clinical studies.

Effect of Psychological Stress on Salivary Cortisol and Trace Elements of Copper, Iron and Manganese in Patients with Periodontitis

2025-06-22

Shokhan H. Azeez , Nakhshaw Ahmed , Rebwar Hama +1 more | Kurdistan Journal of Applied Research

Periodontitis can be described as chronic multifactorial inflammatory disease which can be modified by genetic and environment risk factors such as stress. Trace minerals may impact periodontal tissue health by … Periodontitis can be described as chronic multifactorial inflammatory disease which can be modified by genetic and environment risk factors such as stress. Trace minerals may impact periodontal tissue health by influencing both locally, the hard and soft tissues, as well as systemically, the immune and inflammatory processes throughout the body. This study aimed to assess salivary levels of cortisol and trace elements between psychologically stressed and non-stressed individuals having healthy periodontium and periodontitis. In this study, eighty adult participants were included. Patients completed a stress self-assessment questionnaire by Perceived stress scale and unstimulated saliva was collected to test cortisol levels by ELISA and trace elements levels of copper (Cu), iron (Fe) and manganese (Mn) by inductively coupled plasma mass spectrometry. The study involved four groups: group 1: non stress with healthy periodontium (NSH), group 2: non stress with periodontitis (NSP), group 3: subjects with stress and healthy periodontium (SH), and group 4: subjects with stress and periodontitis (SP). The result showed that SP group had the highest salivary cortisol level (40.56±4.99), followed by SH (39.75±6.28), NSP (15.22±3.09) and NSH (13.66 ± 3.17) in nmol. Moreover, salivary concentrations of Fe (0.549±0.385mgL−1) and Cu (172±85.447μgL−1) were lowest in SP in comparison with other groups, and Mn (45.032±18.565μgL−1) was significantly reduced in SP group compared to NSP group. It was concluded that the impact of psychological stress on trace elements can result in a significant decrease in all elements in saliva and oral health is greatly influenced by dietary practices and an adequate intake of vital vitamins and minerals.

Severe Vitamin D Deficiency Elevates HSP70 Antibodies Indicating Ovarian Pathology

2025-06-21

Sarika Ahire , Kanchan Choudhary , Kaushiki M. Kadam | Fertility Science and Research

Objectives The vitamin D endocrine system has a systemic role in regulating the immune and reproductive systems. New research shows that both calcium and vitamin D are important for female … Objectives The vitamin D endocrine system has a systemic role in regulating the immune and reproductive systems. New research shows that both calcium and vitamin D are important for female fertility. Vitamin D deficiency (VDD) is associated with polycystic ovarian syndrome (PCOS) and premature ovarian insufficiency (POI). However, VDD is asymptotic, especially in adolescents and young adults. Further, vitamin D regulates Tregulatory lymphocytes, whose deficiency mediates T H 1 response, causing POI in women. Our lab has earlier reported that women with idiopathic POI and failed in vitro fertilization-embryo transfer harbour autoantibodies to heat shock proteins HSP70 and HSP90. Given the important role of Treg cells in immune tolerance and ovulation, we sought to assess whether severe VDD can compromise ovarian function and concomitantly elevate antibodies to HSP70. Material and Methods Immature Balb/c mice were weaned onto either a control or VDD diet and maintained for 150 days. Ovarian histology and serum anti-HSP70 levels were assessed at VDD60, 90 and 150 time points. Results Ovarian histology was unchanged at VDD60 and deteriorated by VDD90. Elevated anti-HSP70 titre was noted by VDD60, which was slightly increased by VDD90. Conclusion Our study shows that severe VDD can compromise ovarian function and concomitantly elevate antibodies to HSP70. This can be a potential early biomarker of severe VDD-induced underlying ovarian pathology.

Mediating role of inflammatory markers (NLR, PLR, SII, SIRI) in the association between 25(OH)D deficiency and obesity in children and adolescents

2025-06-21

Y. Li , Xiaoshan M. Shao | Journal of Health Population and Nutrition

The association between vitamin D deficiency and obesity in children and adolescents has garnered significant attention; however, the underlying mechanisms remain unclear. It is hypothesized that the inflammatory response may … The association between vitamin D deficiency and obesity in children and adolescents has garnered significant attention; however, the underlying mechanisms remain unclear. It is hypothesized that the inflammatory response may mediate the relationship between vitamin D deficiency and obesity. This study aims to investigate the mediating roles of inflammatory markers-namely, the neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR), systemic immune inflammation index (SII), and systemic inflammatory response index (SIRI)-in the association between 25(OH)D deficiency and obesity. This study utilized data from the 2009-2018 National Health and Nutrition Examination Survey (NHANES) and included a sample of children and adolescents aged 2 to 17 years. The analysis employed complex sampling design weights, with continuous variables expressed as weighted means and categorical variables as weighted percentages. Baseline characteristics were compared using chi-square tests and t-tests. Inflammatory markers were categorized into quartiles, while the 25(OH)D levels were classified into three groups: deficiency, insufficiency, and adequacy. Multivariate logistic regression was conducted to examine the association between 25(OH)D deficiency, inflammatory markers, and obesity. Additionally, the mediating effect of inflammatory markers on the relationship between 25(OH)D deficiency and obesity was investigated through mediation analysis. A total of 10,613 children and adolescents were included in the study, with 1,650 classified in the obesity group. The findings indicated a significant association between 25(OH)D deficiency and obesity risk (OR = 0.634, 95% CI: 0.440-0.915, p = 0.018). Inflammatory markers, specifically NLR, PLR, SII, and SIRI, partially mediated the relationship between 25(OH)D deficiency and obesity, with NLR and SII exhibiting the most substantial mediating effects (mediation ratios of 3.85% and 4.29%, respectively, p < 0.001). Mediation analysis revealed that the total effect (TE), direct effect (DE), and indirect effect (IE) were all negative, suggesting that an increase in 25(OH)D levels is associated with a reduced risk of obesity, with inflammatory markers serving as intermediaries in this process. This study demonstrates a significant association between 25(OH)D deficiency and obesity in children and adolescents, with inflammatory markers-particularly NLR and SII-playing a partial mediating role in this relationship. These findings indicate that 25(OH)D may influence the development of obesity by modulating the inflammatory response.

Vitamin D and omega-3 fatty acids attenuate MSG-induced neurodegeneration by modulating tau pathology, neuroinflammation, and VDR expression in rats

2025-06-20

Rasha Z Alshahawy , Sally M. Safwat , Sanad S. El-Kholy +3 more | Scientific Reports

Abstract Monosodium glutamate (MSG)-induced excitotoxicity is a major factor contributing to cognitive decline and neurodegeneration. Given the well-established roles of vitamin D (Vit D) and omega-3 polyunsaturated fatty acids (N-3 … Abstract Monosodium glutamate (MSG)-induced excitotoxicity is a major factor contributing to cognitive decline and neurodegeneration. Given the well-established roles of vitamin D (Vit D) and omega-3 polyunsaturated fatty acids (N-3 PUFAs), especially eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), in neuroprotection, the present study aimed at analyzing their possible neuroprotective efficacy against MSG-induced neurotoxicity in rats, concerning the behavioral performance, hippocampal histological integrity, and pathological protein accumulation, along with determination of the inflammatory marker levels and mRNA expression of vitamin D receptors (VDR) and other neurodegeneration-related genes. Fifty male Sprague Dawley rats were randomly allocated to a control, an MSG, and three treatment groups that received MSG and either Vit D or N-3 PUFA supplements in combinations or alone for 4 weeks. At the end of the study, five behavioral tests were conducted to assess cognitive functions, motor activity, and anxiety-related behaviors, and hippocampal tissues were analyzed for tau pathology, neuroinflammation, expression of VDR, and neurodegeneration-related markers. The results demonstrated that supplementation with Vit D (1 mcg/kg) and N-3 PUFAs (300 mg/kg EPA + DHA) profoundly attenuated MSG-induced neurodegeneration. The combined therapy decreased neuronal damage caused by MSG by 87% and tau pathology by 83%. The combined treatment further suppressed pro-inflammatory cytokines (TNF-α: 52%; IL-6: 65%) and elevated anti-inflammatory IL-10 by 2.8-fold, demonstrating a dual anti-inflammatory action. A major upregulation of hippocampal VDR by 4.6-fold was noted, with stabilization of calcium homeostasis and normalization of caspase-3 and α-synuclein expression. Our findings confirm that Vit D and N-3 PUFAs exhibit substantial synergistic neuroprotective abilities that might be mediated through synergistic VDR upregulation, providing a promising dietary intervention against MSG-induced excitotoxicity and highlighting their broader implications for supporting cognitive health and mitigating the adverse effects of other neurotoxins.

Vitamin D deficiency in prostate cancer: Prevalence in a sun-rich climate and influence of androgen deprivation therapy

2025-06-20

Md Nazmul Hasan , Desiree Rafizadeh , Spencer B. Gibson +5 more | World Journal of Clinical Oncology

Vitamin D deficiency has been associated with prostate cancer, particularly in ethnic minorities. Patients with prostate cancer may still be deficient even in areas of high sun exposure. Although androgen … Vitamin D deficiency has been associated with prostate cancer, particularly in ethnic minorities. Patients with prostate cancer may still be deficient even in areas of high sun exposure. Although androgen deprivation therapy (ADT) is well documented to affect bone health, its impact on vitamin D levels is still uncertain. This study investigates the subgroups of prostate cancer patients most associated with vitamin D deficiency and ADT's relation to this. To examine how prevalent vitamin D deficiency is among prostate cancer patients in a sun-rich environment, with focus on differences by race and disease stage. It also assessed whether ADT is associated with changes in vitamin D levels. Prostate cancer patients treated at Chao Family Comprehensive Cancer Center between 2014-2024 were retrospectively studied with regards to vitamin D levels across racial groups, disease stages, and ADT exposure. Changes in vitamin D levels pre- and post-ADT over 24 months were assessed by statistical methods including paired t-tests. Among 120 patients (mean age: 74 years, mean body mass index: 27.6 kg/m²), African American (33.3%) and Hispanic (31.8%) patients had the greatest prevalence of vitamin D deficiency (< 20 ng/mL). With a 28.6% deficit rate, metastatic castration-resistant prostate cancer had the highest prevalence rates of deficiency. There was no significant difference between pre- and post-ADT vitamin D levels (P = 0.45). Vitamin D deficiency is common in prostate cancer patients, especially racial minorities and those with advanced disease, despite residing in an area with high sun exposure. ADT does not significantly impact vitamin D levels in the short term. Routine screening and supplementation should be considered in these high-risk groups.

An isotope dilution-liquid chromatography-tandem mass spectrometry based candidate reference measurement procedure for the simultaneous quantification of 25-hydroxyvitamin D3 and 25-hydroxyvitamin D2 in human serum and plasma

2025-06-20

Konrad Kandler , N. S. Singh , Friederike Bauland +4 more | Clinical Chemistry and Laboratory Medicine (CCLM)

Abstract Objectives An isotope dilution-liquid chromatography-tandem mass spectrometry (ID-LC-MS/MS)-based candidate reference measurement procedure (RMP) for the quantification of 25-hydroxyvitamin D2 (25OHD2) and 25-hydroxyvitamin D3 (25OHD3) in human serum and plasma … Abstract Objectives An isotope dilution-liquid chromatography-tandem mass spectrometry (ID-LC-MS/MS)-based candidate reference measurement procedure (RMP) for the quantification of 25-hydroxyvitamin D2 (25OHD2) and 25-hydroxyvitamin D3 (25OHD3) in human serum and plasma is presented. Methods Quantitative Nuclear Magnetic Resonance (qNMR) spectroscopic methodology has been utilized to assign absolute content (g/g) and International System of Units (SI)-traceability to the reference materials used as primary calibrators. This RMP was developed for the simultaneous quantification of 25OHD2 and 25OHD3 in human samples, utilizing supported liquid extraction (SLE) clean-up and a two-dimensional heart-cut ID-LC-MS/MS method to minimize matrix effects and prevent the co-elution of 3-Epi-25OHD3 and 3-Epi-25OHD2. The method underwent validation in accordance with current guidelines. Selectivity was assessed using spiked samples. To evaluate potential matrix effects, a post-column infusion experiment and a comparison of standard line slopes were performed. A 5-day validation study was conducted to determine precision, accuracy and trueness of the method. Measurement uncertainty for reference value assignment was evaluated in line with the Guide to the Expression of Uncertainty in Measurement (GUM). Equivalence to Joint Committee on Traceability in Laboratory Medicine (JCTLM) listed RMPs was demonstrated through the participation in the CDC Vitamin D Standardization-Certification Program (VDSCP) as well as the RELA scheme. Results The RMP enabled the quantification of 25OHD2 and 25OHD3 within the range of 1.50 ng/mL–180 ng/mL (3.64–436 nmol/L for 25OHD2 and 3.74–449 nmol/L for 25OHD3), without interference from their respective epimer and no evidence of matrix effects. Intermediate precision was determined to be ≤4.0 % for 25OHD2 and ≤3.6 % for 25OHD3, while repeatability was ≤3.3 % for 25OHD2 and ≤2.9 % for 25OHD3 across all concentration levels. The relative mean bias for the secondary reference materials varied from −1.0 to 1.1 %, regardless of the analyte. For the spiked samples, the relative mean bias ranged from −4.2 to 1.0 % for 25OHD2 and from −3.9 to 0.9 % for 25OHD3, irrespective of all levels and matrices. Expanded measurement uncertainties (k=2) for target value assignment (n=6) were ≤3.9 % for 25OHD2 and ≤3.2 % for 25OHD3. Participation in the VDSCP and the RELA scheme showed a good agreement with results from the JCTLM listed RMPs and laboratories. Conclusions The RMP enables the accurate, precise and consistent determination of 25OHD3 and 25OHD2. The robust performance of this method supports standardization of routine assays and guarantees traceability in the measurement of individual patient samples.

Vitamin D Levels, Periodontal Parameters, and VDR Gene Polymorphism in Dental Implant Osseointegration Outcomes: A Case-Control Study in Egyptians

2025-06-20

Ayman A. Diab , Mohamad Andri Ibrahim , Amal Ahmed Mohamed +7 more | The Open Biomarkers Journal

Introduction Failure of dental implants due to inadequate osseointegration continues to pose a major clinical issue, with increasing evidence suggesting that systemic and genetic factors play a role in the … Introduction Failure of dental implants due to inadequate osseointegration continues to pose a major clinical issue, with increasing evidence suggesting that systemic and genetic factors play a role in the outcomes. It is proposed that vitamin D deficiency and genetic variations, such as those in the vitamin D receptor (VDR) gene, may affect bone metabolism and the success of implants. This case-control study aimed to evaluate the association of serum vitamin D levels and VDR gene polymorphism (SNP rs228570) with dental implant osseointegration success or failure. Methods A case-control study with 42 cases of implant failure and 42 controls with successful osseointegration was conducted in patients aged 31–60 years. Sociodemographic, clinical, and periodontal parameters were analyzed, and VDR SNP rs228570 was genotyped using real-time PCR, and serum vitamin D, TNF, and IL-6 levels were measured. Statistical analysis was performed using SPSS v28.0, with univariate and multivariable logistic regression with significance (p < 0.05). Results No significant association was found between VDR gene polymorphism (SNP rs228570) and implant failure (p > 0.05). However, there is a significant association between higher vitamin D levels and successful osseointegration. Vitamin D levels were significantly higher in the successful group (36.85 ng/ml ± 11.55) compared to the failed group (17.03 ng/ml ± 9.16) (p < 0.001). Clinical parameters revealed significant differences, with the successful group showing lower bleeding on probing (BOP) at 25.15% (SD ± 5.31) compared to 42.46% (SD ± 7.59) in the failed group (p < 0.001) and a shallower probing depth of 2.21 mm (SD ± 0.85) compared to 5.62 mm (SD ± 1.32) in the failed group (p < 0.001). Biochemical markers such as TNF and IL-6 did not show significant differences between the groups, P-value = 0.181 and 0.186, respectively. Conclusion The study highlights the importance of vitamin D levels and clinical parameters such as BOP and PD in predicting osseointegration outcomes. Although VDR gene polymorphism showed no significant association with implant failure, higher vitamin D levels were positively correlated with successful osseointegration. These findings suggest that optimizing vitamin D levels and managing peri-implant health may improve dental implant success rates, emphasizing clinical over genetic predictors.

The relationship between vitamin D levels and Alzheimer’s disease risk: insights from a centenarian study of Chinese women

2025-06-20

Yupeng Li , Xujie Wang , Yi Mei +7 more | Frontiers in Nutrition

Background While vitamin D₃ (VD₃) has been implicated in Alzheimer’s disease (AD) prevention, limited evidence exists among centenarians—particularly women—who exhibit unique cognitive aging trajectories. This study aimed to examine the … Background While vitamin D₃ (VD₃) has been implicated in Alzheimer’s disease (AD) prevention, limited evidence exists among centenarians—particularly women—who exhibit unique cognitive aging trajectories. This study aimed to examine the association between serum 25-hydroxyvitamin D [25(OH)D] levels and AD risk in Chinese female centenarians. Methods We included 514 female participants aged ≥100 years from the China Healthy Longevity Multicenter Study (CHLMS). AD was diagnosed using education-adjusted MMSE thresholds and clinical exclusion of non-AD dementias. Serum 25(OH)D and biochemical markers were measured using standardized laboratory protocols. Logistic regression models (unadjusted and progressively adjusted) assessed associations between 25(OH)D and AD. Restricted cubic spline (RCS) and piecewise regressions evaluated non-linear and threshold effects, while subgroup analyses explored effect modification. Results Higher serum 25(OH)D levels were independently associated with lower odds of AD (adjusted OR per 1 ng/mL: 0.95; 95% CI: 0.90–1.00; p = 0.037). Compared to the lowest quartile, participants in the highest quartile had an 87% reduced risk (OR = 0.13; 95% CI: 0.03–0.50; p = 0.007). RCS analysis revealed a significant inverse dose–response relationship, with a potential threshold effect observed at 29.3 ng/mL. Piecewise regression confirmed that the protective association was strongest below this threshold. Subgroup analyses across smoking, hypertension, and early-life indicators showed consistent effects with no significant interactions. Conclusion Among Chinese female centenarians, serum vitamin D₃ levels are inversely associated with AD risk in a dose-dependent manner, particularly below 29.3 ng/mL. These findings highlight the relevance of vitamin D₃ as a potentially modifiable factor in cognitive aging and support further interventional studies in the oldest-old population.

Vitamin D and risk of thyroid cancer: a two-sample Mendelian randomization study

2025-06-20

Yunbin Shi , Lihui Qian , Tao Ma +1 more | Discover Oncology

To investigate the causal effect of serum 25-hydroxyvitamin D (25(OH)D) on the risk of thyroid cancer (TC) by a two-sample Mendelian randomization (MR) analysis. We analyzed data from two genome-wide … To investigate the causal effect of serum 25-hydroxyvitamin D (25(OH)D) on the risk of thyroid cancer (TC) by a two-sample Mendelian randomization (MR) analysis. We analyzed data from two genome-wide association studies (GWAS), including 25(OH)D concentration levels in 417,580 individuals and 1415 individuals for TC. Genetic variants associated with serum 25(OH)D were selected as instrumental variables (IVs). The inverse-variance weighted (IVW) method served as the primary approach of MR analysis was used to evaluate the sensitivity of 25(OH)D to TC risk, while the weighted-median method, MR-Egger method, weighted mode and simple mode were employed as supplementary analyses. Cochran's Q test was used to test IV heterogeneity, MR-Egger regression test and MR-PRESSO global test were used to determine IV pleiotropy, and Leave-one-out analysis was used to check the stability of the results. 112 SNPs associated with serum 25(OH)D were identified as IVs. The IVW method showed a causal relationship between 25(OH)D and TC risk (OR = 0.761, 95% CI 0.584-0.991, P = 0.043). The results of the weighted-median method (OR = 0.858, 95%CI 0.606-1.216, P = 0.389), MR-Egger method (OR = 0.782, 95% CI 0.552-1.108, P = 0.169), weighted mode (OR = 0.779, 95%CI 0.568-1.068, P = 0.123) and simple mode (OR = 0.616, 95% CI 0.218-1.739, P = 0.362) enhance the credibility of the IVW results. Cochran's Q test, MR-Egger regression test and MR-PRESSO global test suggest that there is no significant heterogeneity and pleiotropy in IV. The leave-one-out analysis indicates that the results are stable. There is a causal relationship between circulating vitamin D concentration and TC risk in the population. The lower the vitamin D levels, the higher the TC risk.

Vitamin D status in Faroese adults and its association with inflammatory bowel diseases - a cross-sectional study from the FarGen 2 project

2025-06-20

Randi Næss Lisberg , Kári Rubek Nielsen , Leivur N. Lydersen +6 more | International Journal of Circumpolar Health

Vitamin D is vital for physiological functions and is obtained primarily through sunlight and a few dietary sources. With limited sunlight exposure, the Faroe Islands face challenges in maintaining sufficient … Vitamin D is vital for physiological functions and is obtained primarily through sunlight and a few dietary sources. With limited sunlight exposure, the Faroe Islands face challenges in maintaining sufficient levels of vitamin D, while the Faroese population has documented the highest incidence and prevalence of inflammatory bowel disease worldwide. This study investigates vitamin D status among Faroese adults and its association with inflammatory bowel disease as well as other self-reported diseases in a subset of the Faroe Genome Project 2. Cross-sectional study including 1,748 participants aged 18-86 years. Among participants, 74.3% maintained sufficient vitamin D levels, while 25.7% were insufficient (<50 nmol/l). Individuals with conditions like hypertension, type 2 diabetes, and inflammatory bowel disease showed significantly higher rates of vitamin D sufficiency compared to those without these conditions. Notably, 83% of participants with inflammatory bowel disease had sufficient vitamin D. Our data reveal higher vitamin D levels compared to previous studies in the Faroe Islands. Furthermore, contrary to our hypothesis, our data shows higher vitamin D levels for participants reporting diseases including inflammatory bowel disease, indicating patients with inflammatory bowel disease can attain high vitamin D levels, which is of considerable clinical importance.

CCL20 expression is elevated in inflammatory bowel disease and attenuated by vitamin D metabolites

2025-06-20

Johannes Stallhofer , Franz‐Xaver Reichl , Michael Lauseker +7 more | Scientific Reports

Abstract Intestinal epithelial overexpression of the Th17 cell chemoattractant CCL20 is implicated in inflammatory bowel disease and influenced by NOD2 mutations in Crohn’s disease. Vitamin D metabolites have been shown … Abstract Intestinal epithelial overexpression of the Th17 cell chemoattractant CCL20 is implicated in inflammatory bowel disease and influenced by NOD2 mutations in Crohn’s disease. Vitamin D metabolites have been shown to ameliorate inflammatory bowel disease. Considering NOD2 mutations in Crohn’s disease, we investigated whether Vitamin D deficiency (serum 25-hydroxyvitamin D concentration < 20 ng/mL) increases circulating CCL20 levels in inflammatory bowel disease patients and healthy controls and whether active 1,25-dihydroxyvitamin D (calcitriol) downregulates systemic and intestinal CCL20 expression. In a cross-sectional study, serum concentrations of CCL20, 25-hydroxyvitamin D, and calcitriol were measured in 170 NOD2 -genotyped Crohn’s disease patients, 80 ulcerative colitis patients, and 60 healthy controls. Additionally, the effect of calcitriol on experimentally induced CCL20 expression was examined using human intestinal epithelial HT-29 cells. Multivariable linear regression analyses revealed that both the diagnosis of inflammatory bowel disease and vitamin D deficiency were independently associated with elevated CCL20 levels. Compared to healthy controls, Crohn’s disease patients and ulcerative colitis patients exhibited significantly higher circulating CCL20 levels. Unlike in Crohn’s disease patients, vitamin D deficiency was associated with higher CCL20 levels in healthy controls and ulcerative colitis patients, whereas the calcitriol/25-hydroxyvitamin D activation ratios were negatively correlated with serum CCL20 levels in healthy controls and ulcerative colitis patients with sufficient serum 25-hydroxyvitamin D status. Furthermore, calcitriol markedly inhibited intestinal epithelial induction of CCL20. In Crohn’s disease patients, cholecalciferol supplementation was associated with lower serum CCL20 levels, which were unaffected by NOD2 mutations. These findings suggest that although vitamin D metabolites may downregulate CCL20 expression in healthy controls and ulcerative colitis patients, this regulatory effect appears to be impaired in Crohn’s disease patients.

Impact of ultraviolet radiation on bone density and muscle strength in postmenopausal women: a randomized controlled study

2025-06-19

Wafaa M. Kamal , Ahmed M. Maged , Noha Salah +3 more | Obstetrics & Gynecology Science

This study aimed to evaluate the effects of narrowband ultraviolet-B (UV-B) irradiation on bone and muscle health in postmenopausal women. A randomized controlled trial was conducted involving 70 postmenopausal women … This study aimed to evaluate the effects of narrowband ultraviolet-B (UV-B) irradiation on bone and muscle health in postmenopausal women. A randomized controlled trial was conducted involving 70 postmenopausal women with vitamin D deficiency (<20 ng/mL) and osteopenia. Participants were randomly assigned to two groups. For 6 months, 35 postmenopausal women in study group (A) received three weekly sessions of narrowband UV-B therapy and vitamin D supplements in the form of 100,000 IU cholecalciferol weekly as loading therapy for 8 weeks. This was followed by the daily administration of cholecalciferol 3,000 IU as maintenance therapy for 16 weeks. The control group (B) consisted of thirty-five postmenopausal women who were administered vitamin D supplements alone for 6 months. ELISA kits were used to test the serum levels of 25-hydroxyvitamin D (25(OH)D), DEXA (COMPANY, CITY, STATE, COUNTRY) was used to test the bone mineral density of the lumbar spine and right femur, and a Biodex System 3 (COMPANY, CITY, STATE, COUNTRY) isokinetic dynamometer was used to assess the peak torque of the extensors and flexors of the dominant knee. Serum 25(OH)D levels (P=0.000*), Lumbar T-score (P=0.008*), femoral T-score (P=0.002*), and knee extensor peak torque (P=0.030*) significantly increased in both groups after 6 months of treatment, favoring study group (A) over the control group (B). Narrowband UV-B combined with vitamin D3 supplementation is more effective than vitamin D supplementation alone.

Prevention of allergies by vitamin D

2025-06-19

Taiji Nakano | Nihon Shoni Arerugi Gakkaishi The Japanese Journal of Pediatric Allergy and Clinical Immunology

Age-specific serum calcium levels in healthy individuals from the Xing’an League: a descriptive study

2025-06-19

Haiyan Hu , W Y Wang , ZeNan Chang +5 more | Journal of Health Population and Nutrition

The mushrooms on the menu (MOM) study: vitamin D mushrooms (UV-exposed) are a feasible and acceptable way to increase vitamin D intake in a residential aged care facility

2025-06-18

Celeste Ferraris , Michelle Blumfield , Emily Duve +5 more | Frontiers in Public Health

Background Vitamin D deficiency is highly prevalent in aged care due to reduced endogenous synthesis of vitamin D and less time outdoors, and is associated with poorer health outcomes. Supplementation … Background Vitamin D deficiency is highly prevalent in aged care due to reduced endogenous synthesis of vitamin D and less time outdoors, and is associated with poorer health outcomes. Supplementation implementation is variable and dosages are often suboptimal. Due to limited food sources, diet is frequently overlooked, yet mushrooms can raise vitamin D levels in deficient individuals similar to a supplement. Objectives Mushrooms on the Menu (MOM) was a 10-week prospective pre-post mixed method study that evaluated the feasibility of adding vitamin D mushrooms to the menu of a residential aged care facility. Methods During the 4-week baseline phase, residential care (RC) participants ordered meals from the standard food service menu, while independent living (IL) followed their usual diet. During the 4-week MOM phase, participants were instructed to consume at least one mushroom meal containing 75 g of UV-exposed mushrooms daily. In RC, 26 recipes were modified and two recipes newly created to include mushrooms. RC participants chose a minimum of one mushroom meal from the lunch or dinner menu, and IL residents were instructed to prepare at least one mushroom meal daily. Dietary intakes were estimated by plate wastage (RC) or 24-h recalls (IL), while qualitative data were collected during and post the MOM. Results In RC ( n = 60), vitamin D provision via mushrooms from the MOM menu increased by 180% compared to the standard menu (7.0 vs. 2.5 μg, p &lt; 0.0001), with no significant differences in total energy and other nutrients. During MOM, vitamin D intake increased by 212% for RC (6.0 vs. 18.7 μg; p &lt; 0.0001) and 740% for IL participants ( n = 12; 8.7 vs. 73.1 μg; p &lt; 0.0001) compared to baseline, representing 125 and 1,387% of the adequate intake (AI) for over 70-year-old’s, respectively. Over 75% of participants rated the taste of vitamin D mushroom meals as good or excellent, while qualitative data reported participants enjoyed mushrooms as both hero and complimentary ingredients. Over 75% of staff understood the health benefits of vitamin D mushrooms and found the meals easy to prepare, but preferred low-burden ordering and preparation processes. Both participants and staff supported the continued inclusion of MOM. Conclusion MOM is a well-accepted food-first approach that provides substantial vitamin D to aged care residents.

An Observational Study on Serum 25(OH) Vitamin D Levels in Patients with Coronary Artery Disease in a Tertiary Care Hospital in Eastern India

2025-06-18

Sanchita Saha , Niladri Sarkar , Arundhati Das | Bengal Physician Journal

The Influence of Solar-Simulated UV Radiation on Circulating 25(OH)D3, 24,25(OH)2D3 and Their Ratio in Younger and Older Adults

2025-06-18

Oktawia Borecka , Jonathan Tang , William D. Fraser +2 more | Nutrients

Background: In addition to the well-known vitamin D metabolites 25(OH)D and 1,25(OH)2D, the catabolite 24,25(OH)2D may also reflect vitamin D status and influence biological and skeletal processes. However, the effects … Background: In addition to the well-known vitamin D metabolites 25(OH)D and 1,25(OH)2D, the catabolite 24,25(OH)2D may also reflect vitamin D status and influence biological and skeletal processes. However, the effects of UVR-induced synthesis on 24,25(OH)2D levels and the 25-VMR (24,25(OH)2D3:25(OH)D3 ratio) remain unclear. Objectives: We aimed to assess how a single standardised UVR dose influences the production of 25(OH)D3, 24,25(OH)2D3, 1,25(OH)2D3 and 25-VMR, with a comparison between younger and older adults being conducted to explore potential age-related differences in vitamin D metabolism. Methods: A total of 11 young (18-40 years; 7M, 4F) and 10 older (65-89 years; 6M, 4F) skin type I-III volunteers received a single sub-erythemal dose of solar simulated UVR (SSR) (95% UVA: 320-400 nm, 5% UVB: 290-320 nm, 1.3 standard erythemal dose) during winter time in the UK (vitamin D trough season), exposing approximately 35% of the body surface area. The Blood was assayed for 25(OH)D3, 24,25(OH)2D3 and 1,25(OH)2D3 using LC-MS/MS at baseline, 24 h and 7 days following UVR exposure. Results: There was a significant increase in 25(OH)D3 from baseline (44 ± 22 nmoL/L) to 24 h post-UVR (48 ± 22 nmoL/L) in the combined age group (p = 0.044), but no significant differences were found in 24,25(OH)2D3 in the combined group, or between young and older volunteers for both metabolites. 1,25(OH)2D3 concentrations were higher in young groups (163 ± 60 pmoL/L) than in older (105 ± 38 pmoL/L) groups at 7 days post-UVR (p = 0.044). The 25-VMR decreased from baseline (9 ± 3) to 24 h post-UVR (7.5 ± 2.1) in the combined group (p = 0.003). Conclusions: Our data suggest that a single sub-erythemal UVR challenge does not influence 24,25(OH)2D3 concentration in younger and older adults at 24 h and 7 days post-UVR and that the significant difference seen in the 25-VMR between baseline and 24 h post-UVR is due to the increase in 25(OH)D3 concentration post-UVR. This is in line with vitamin D oral supplementation studies, and indicates that low doses of UVR trigger the metabolic pathway, without affecting the catabolic pathway.

Association between vitamin D deficiency and clinical outcome in patients with COVID-19 in the post-Omicron phase

2025-06-18

I‐Wen Chen , Ting‐Sian Yu , Yi-Chen Lai +3 more | Frontiers in Nutrition

Background Vitamin D deficiency (VDD) has been associated with adverse outcomes in COVID-19 patients during the early pandemic phases, but whether this association persists in the post-Omicron era remains uncertain. … Background Vitamin D deficiency (VDD) has been associated with adverse outcomes in COVID-19 patients during the early pandemic phases, but whether this association persists in the post-Omicron era remains uncertain. This study aimed to investigate the evolving relationship between VDD and COVID-19 outcomes across pandemic phases using a large healthcare database. Methods We conducted a retrospective cohort study using the TriNetX Analytics Network, analyzing propensity-matched cohorts comprising 24,236 pairs from the post-Omicron phase (June 2022–December 2023) and 22,638 pairs from the pre-Omicron phase (January 2020–December 2021). VDD was defined as a serum 25-hydroxyvitamin D level &lt; 20 ng/ml, with vitamin D-sufficient patients (≥30 ng/ml) serving as controls. The primary outcome was 30-day all-cause mortality, with secondary outcomes including acute kidney injury, respiratory failure, pneumonia, sepsis, and ICU admission. Results The 30-day mortality in VDD vs. vitamin D-sufficient patients decreased from 1.43% vs. 0.39% [odds ratio (OR), 3.67; 95% CI, 2.90–4.64; p &lt; 0.001] in the pre-Omicron phase to 0.89% vs. 0.49% (OR, 1.82; 95% CI, 1.46–2.28; p &lt; 0.001) in the post-Omicron phase. Similar risk attenuation was observed across all secondary outcomes, including acute kidney injury (OR, 2.11; 95% CI, 1.92–2.31 vs. OR, 1.41; 95% CI, 1.29–1.54; both p &lt; 0.001), respiratory failure (OR, 1.66; 95% CI, 1.44–1.92 vs. OR, 1.34; 95% CI, 1.16–1.54; both p &lt; 0.001), and pneumonia (OR, 1.34; 95% CI, 1.16–1.55 vs. OR, 1.23; 95% CI, 1.07–1.42; p &lt; 0.001 and p = 0.004, respectively). Risk factor analysis identified several significant mortality predictors among patients with VDD in the post-Omicron phase, including malnutrition (OR, 4.34; 95% CI, 3.18–5.92; p &lt; 0.001), liver disease (OR, 3.08; 95% CI, 2.23–4.25; p &lt; 0.001), and neoplasms (OR, 2.63; 95% CI, 2.01–3.45; p &lt; 0.001). Conclusion VDD continues to be associated with adverse COVID-19 outcomes in the post-Omicron phase, albeit with a reduced magnitude. These findings support the importance of vitamin D screening in high-risk COVID-19 patients, while emphasizing the need for adaptive risk assessment strategies that incorporate both established and emerging risk factors in the current pandemic landscape.

Vitamin D Receptor Polymorphisms and their role in Invasive Breast Cancer progression

2025-06-18

Zineb Sakhi , Mouad Najih , Khaoula Elghazali +3 more | The Journal of Steroid Biochemistry and Molecular Biology

Efectos de la suplementación con vitamina D en la salud ósea de mujeres postmenopáusicas

2025-06-17

José Luis Guzmán Mallqui , Clara Cristina Núñez Barrón , Guadalupe Citlalli Alfaro Rodas +2 more | Nutrición clínica y dietética hospitalaria/Nutrición clínica, dietética hospitalaria

Introducción: La osteoporosis afecta aproximadamente al 33% de mujeres mayores de 50 años, y 4 de cada 10 presentan fracturas asociadas. La vitamina D es fundamental para la homeostasis ósea, … Introducción: La osteoporosis afecta aproximadamente al 33% de mujeres mayores de 50 años, y 4 de cada 10 presentan fracturas asociadas. La vitamina D es fundamental para la homeostasis ósea, pero su eficacia en mujeres posmenopáusicas muestra resultados contradictorios en la literatura científica actual. Objetivo: Sintetizar la evidencia sobre la suplementación con vitamina D en la mejora de la salud ósea en mujeres posmenopáusicas mayores de 50 años. Material y métodos: Revisión narrativa de estudios publicados hasta octubre de 2024 en Medline, Web of Science y SciELO. Se incluyen artículos de texto completo con acceso abierto en inglés, español o portugués (2014-2024) que evalúan la suplementación con vitamina D en mujeres posmenopáusicas mayores de 50 años. De 511 artículos identificados, se seleccionaron 13 para análisis. Resultados: La suplementación con 400 UI diarias de vitamina D mejoró biomarcadores óseos cuando se combinó con colágeno y calcio. Dosis mayores (2.000 UI) elevaron niveles séricos de 25(OH)D sin efectos en masa muscular. La suplementación prolongada redujo fracturas vertebrales (20% en osteoporosis, 12% en osteopenia). Las matrices lácteas fortificadas beneficiaron marcadores de remodelado óseo. Los efectos adversos principales fueron hipercalciuria (30,6%) y litiasis renal, principalmente atribuidos al calcio concomitante. Discusión: La eficacia de la vitamina D en mujeres posmenopáusicas depende del estado nutricional basal, duración del tratamiento y dosis administrada. La suplementación aislada mostró efectos limitados, mientras que combinaciones con calcio y péptidos de colágeno mejoraron biomarcadores óseos. Conclusión: La efectividad de la vitamina D en la salud ósea de mujeres posmenopáusicas depende de factores individuales como niveles séricos, composición corporal y comorbilidades, por lo que se requiere un enfoque personalizado.

Assessment of the Relationship between Serum Vitamin D Levels and its Cardiovascular Outcomes: A Systematic Review and Meta-analysis Study

2025-06-17

Reza Madadi , Sina Bakhshaei , Arian Tavasol +3 more | Journal of the Saudi Heart Association

Toksisitet ved høyt inntak av vitamin D

2025-06-17

Jacob J. Christensen | Norsk tidsskrift for ernæring

Assessment of Determinants of Dietary Vitamin D Intake in a Polish National Sample of Male Adolescents

2025-06-17

Małgorzata Stachoń , Katarzyna Lachowicz | Nutrients

Calcitriol, the active form of vitamin D, has a broad physiological effect, and its deficiency has been identified as a risk factor for many diseases. This study aimed to analyze … Calcitriol, the active form of vitamin D, has a broad physiological effect, and its deficiency has been identified as a risk factor for many diseases. This study aimed to analyze the dietary intake of vitamin D and the factors determining its intake among Polish post-primary school students. The data obtained were then related to the dietary recommendations for the Polish population. The study was conducted on a nationwide sample of 3257 male adolescents (aged 14-20 years) recruited from all macroregions of Poland. Dietary vitamin D intake (dVDi) was assessed using the Vitamin D Estimation Only-Food Frequency Questionnaire (VIDEO-FFQ). The median dietary intake of vitamin D was 4.36 µg daily. This value was below the recommended intake of 15 µg of vitamin D, according to Polish standards, in almost 80% of the study group. The observed dietary vitamin D intake bellow the recommended level ranged from 35.5% of students attending schools in the North-Western macroregion to 93.7% in the Central macroregion, from 45.4% of students attending schools located in the countryside to 92.7% in big cities, from 85.3% among underweight students to 76.7% of obese students, over 77% in both age groups (14-17 and 18-20 years old), and over 78% in both groups: supplementing and not supplementing vitamin D. Fish and fish products provided the highest vitamin D (38.7%), while cereal products and fats provided the lowest (4.49% and 4.35%, respectively). The highest amounts of vitamin D were provided by salmon, rainbow trout, herring, and eel (fish species containing 7-15 µg of vitamin D in 100 g of product), and halibut, mackerel, brook trout, sole, and tuna (fish species containing 1.05-4 µg of vitamin D in 100 g of product), and these fish were consumed in the largest quantities by male adolescents. Dietary vitamin D intake was notably higher in adolescents from the North-Western macroregion of Poland (median: 50.57 vs. 3.72-5.18 µg daily for other macroregions), those attending schools in the countryside (median: 49.49 vs. 3.97-4.39 µg daily for other locations of the school), those with a normal body weight (median: 4.59 vs. 3.38 µg daily for adolescents with underweight), and those who took vitamin D supplements (median: 4.71 vs. 4.06 µg daily for adolescents not supplemented with vitamin D). However, the results showed that dVDi was not dependent on age. The study results indicate that low dVDi among Polish male adolescents can be attributed to the limited supply of vitamin D from dietary sources, especially fish and fish products. The necessity for interventions has been identified, including nutritional education on the role of vitamin D and its sources in the diet.

The impacts of vitamin D supplementation on serum levels of thyroid autoantibodies in patients with autoimmune thyroid disease: a meta-analysis

2025-06-16

Dongdong Luo , B.-J. Li , Zhongyan Shan +3 more | PeerJ

Background Although vitamin D (VitD) deficiency had been found with close relationship with autoimmune thyroid disorders (AITD), the findings about the impacts of VitD supplementation on the production of anti-thyroid … Background Although vitamin D (VitD) deficiency had been found with close relationship with autoimmune thyroid disorders (AITD), the findings about the impacts of VitD supplementation on the production of anti-thyroid peroxidase (TPOAb) and anti-thyroglobulin antibodies (TgAb) remained inconsistent. Thus, a systemic meta-analysis was conducted to figure out the exact effects of VitD intervention on the production of TPOAb and TgAb in AITD patients. Methods We searched PubMed, Web of Science, Embase and The Cochrane Library databases for all clinical studies up to May 2023, which evaluated the changes in serum TPOAb and TgAb titers of AITD patients after VitD intervention. In addition, three subgroup analyses were carried out based on the duration of vitamin D supplementation, the initial nutritional status of participants, and the frequency of vitamin D administration. Results A total of 10 cohorts from 10 clinical trials with 577 patients with AITD were included. The serum titers of TPOAb and TgAb were significantly decreased after VitD supplementation as compared with their pre-treatment levels, respectively. However, a significant post-treatment reduction of serum TPOAb level was found only in the AITD patients with initial VitD insufficiency/deficiency, while an obvious decrease of serum TgAb was shown if only those studies without consideration of the pre-treatment VitD status were included. Serum TPOAb and TgAb titers were significantly decreased in the patients receiving VitD supplementation for at least 3 months, but not in the ones for less than 3 months. Serum titers of TPOAb and TgAb were both pronouncedly reduced in the patients receiving daily administration of VitD rather than weekly regimen. This study provides new evidence for the potential role of vitamin D supplementation in the treatment of AITD. Conclusions AITD patients may benefit with the reduction of TPOAb and TgAb production after a VitD supplementation (2800–60000 IU/week) for at least 3 months, especially with a decrease of serum TPOAb level when initially VitD insufficient/deficient, which mechanisms await further investigation. Systematic Review Registration PROSPERO, identifier CRD42023424029.

Vitamin D and cognition: Demographic disparities in memory recall and word intrusion in a multiethnic cohort

2025-06-16

Juan Carlos López-Alvarenga , Isabel Omaña‐Guzmán , Óscar Rosas‐Carrasco +3 more | Journal of Alzheimer s Disease

Background Vitamin D3 is essential for calcium metabolism and exerts pleiotropic effects, including neuroprotective activities in cognition. Its insufficiency has been linked to dementia, Alzheimer's disease, and cognitive impairments. The … Background Vitamin D3 is essential for calcium metabolism and exerts pleiotropic effects, including neuroprotective activities in cognition. Its insufficiency has been linked to dementia, Alzheimer's disease, and cognitive impairments. The association between vitamin D3 and particular cognitive functions, including memory recall and word intrusion, remains imprecise, particularly among diverse ethnic and socioeconomic groups. Objective To examine the relationship between vitamin D3 levels with memory recall and word intrusion in individuals aged 60 and above, emphasizing demographic differences. Methods Data was collected from 2759 individuals in the NHANES 2011–2014 surveys. Cognitive performance was evaluated with the CERAD Word Learning, Animal Fluency, and Digit Symbol Substitution assessments. Factor analysis was employed to identify two cognitive domains: F1 ‘Memory Recall’ and F2 ‘Word Intrusion’. Linear and quantile regression models, controlled for demographic variables, were performed to assess the association between vitamin D3 levels and cognitive domains. Bootstrap techniques were used for standard error estimation, and nonparametric regression was applied to identify non-linear correlations. Results Vitamin D3 levels positively correlated in linear models and quantile regression with F1 ‘Memory Recall’ at diminished cognitive function levels. F2 was not associated with vitamin D3. Socioeconomic factors influenced these correlations, revealing inequalities among ethnic and income groups. Conclusions Elevated vitamin D3 levels correlate with improved memory recall, especially in individuals with lower cognitive percentiles. These findings suggest the potential of vitamin D3 to alleviate cognitive decline, including Alzheimer's disease, highlighting the need for focused interventions, particularly in underrepresented demographic groups.

Serum 25‐hydroxyvitamin D, vitamin D‐related variants, and risk of chronic liver disease

2025-06-14

Qian Shen , Shanshan Shi , Haoxue Wang +7 more | International Journal of Cancer

Abstract The associations of serum 25‐hydroxyvitamin D (25(OH)D) with cirrhosis and liver cancer have not been well examined. It remained unclear whether functional vitamin D‐related variants modify these associations. During … Abstract The associations of serum 25‐hydroxyvitamin D (25(OH)D) with cirrhosis and liver cancer have not been well examined. It remained unclear whether functional vitamin D‐related variants modify these associations. During follow‐up of 401,551 UK Biobank participants with valid 25(OH)D data, we documented 4404 incident non‐alcoholic fatty liver disease (NAFLD), 1989 incident cirrhosis, and 480 incident liver cancer. The binding affinity values of 25(OH)D to vitamin D binding protein (VDBP) were estimated based on combinations of VDBP variants rs4588 and rs7041. Vitamin D receptor (VDR) activity was calculated by summing the number of related alleles for rs11568820, rs2228570, and rs1544410. Hazard ratio (95% confidence intervals) for serum 25(OH)D of ≥50 nmol/L (vs. <25 nmol/L) were 0.70 (0.63–0.77) for NAFLD ( p trend = 1.37 × 10 −14 ), 0.43 (0.38–0.49) for cirrhosis ( p trend = 8.66 × 10 −29 ) and 0.65 (0.48–0.87) for liver cancer ( p trend = .010). We observed differential associations of 25(OH)D with hepatic fibrosis and cirrhosis ( p interaction = .024), and portal hypertension ( p interaction = .019) by VDR activity, with a stronger inverse association among participants with low VDR activity ( p trend = 1.28 × 10 −9 for hepatic fibrosis and cirrhosis and p trend = 1.52 × 10 −14 for portal hypertension). The association of 25(OH)D with liver cancer differed by GC isoforms ( p interaction = .033), with a stronger inverse association among participants with low affinity isoforms ( p trend = .001). Serum 25(OH)D appears to prevent NAFLD, cirrhosis, and liver cancer, especially for participants with low VDR activity/low affinity GC isoforms.