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Vitamin D for Health: A Global Perspective

  • Arash Hossein-nezhad
    Affiliations
    Department of Medicine, Section of Endocrinology, Nutrition, and Diabetes, Vitamin D, Skin, and Bone Research Laboratory, Boston University Medical Center, Boston, MA
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  • Michael F. Holick
    Correspondence
    Correspondence: Address to Michael F. Holick, PhD, MD, Boston University School of Medicine, 85 E Newton St, M-1013, Boston, MA 02118.
    Affiliations
    Department of Medicine, Section of Endocrinology, Nutrition, and Diabetes, Vitamin D, Skin, and Bone Research Laboratory, Boston University Medical Center, Boston, MA
    Search for articles by this author

      Abstract

      It is now generally accepted that vitamin D deficiency is a worldwide health problem that affects not only musculoskeletal health but also a wide range of acute and chronic diseases. However, there remains cynicism about the lack of randomized controlled trials to support the association studies regarding the nonskeletal health benefits of vitamin D. This review was obtained by searching English-language studies published up to April 1, 2013, in PubMed, MEDLINE, and the Cochrane Central Register of Controlled Trials (search terms: vitamin D and supplementation) and focuses on recent challenges regarding the definition of vitamin D deficiency and how to achieve optimal serum 25-hydroxyvitamin D concentrations from dietary sources, supplements, and sun exposure. The effect of vitamin D on fetal programming epigenetics and gene regulation could potentially explain why vitamin D has been reported to have such wide-ranging health benefits throughout life. There is potentially a great upside to increasing the vitamin D status of children and adults worldwide for improving musculoskeletal health and reducing the risk of chronic illnesses, including some cancers, autoimmune diseases, infectious diseases, type 2 diabetes mellitus, neurocognitive disorders, and mortality.

      Abbreviations and Acronyms:

      CD (Crohn disease), DBP (vitamin D binding protein), DC (dendritic cell), ESCEO (European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis), GWAS (genome-wide association study), HR (hazard ratio), ILT (immunoglobulin-like transcript), IOM (Institute of Medicine), IVF (in vitro fertilization), LC-MS/MS (liquid chromatography–tandem mass spectrometry), LPS (lipopolysaccharide), miRNA (microRNA), MS (multiple sclerosis), NHANES (National Health and Nutrition Examination Survey), OR (odds ratio), PTH (parathyroid hormone), PTHrP (parathyroid hormone–related protein), RA (rheumatoid arthritis), RDA (recommended dietary allowance), RCT (randomized controlled trial), RR (risk rate), SE (standard error), SNP (single nucleotide polymorphism), TH (T helper cell), VDR (vitamin D receptor), WHI (Women's Health Initiative), 1,25(OH)2D (1α,25-dihydroxyvitamin D), 7-DHC (7-dehydrocholesterol), 25(OH)D (25-hydroxyvitamin D)
      Article Highlights
      • Vitamin D deficiency is a common underdiagnosed condition.
      • Recent evidence from hundreds of studies suggests that vitamin D is important for reducing the risk of type 1 diabetes mellitus, cardiovascular disease, certain cancers, cognitive decline, depression, pregnancy complications, autoimmunity, allergy, and even frailty.
      • The blood level of 25(OH)D is the best method to determine vitamin D status.
      • Vitamin D deficiency during pregnancy may influence fetal “imprinting” that may affect chronic disease susceptibility soon after birth as well as later in life.
      • An effective strategy to prevent vitamin D deficiency and insufficiency is to obtain some sensible sun exposure, ingest foods that contain vitamin D, and take a vitamin D supplement.
      Vitamin D deficiency has been recognized as a pandemic with a myriad of health consequences.
      • Holick M.F.
      Vitamin D: extraskeletal health.
      • Hossein-nezhad A.
      • Holick M.F.
      Optimize dietary intake of vitamin D: an epigenetic perspective.
      Low vitamin D status has been associated with an increased risk of type 1 diabetes mellitus, cardiovascular disease, certain cancers, cognitive decline, depression, pregnancy complications, autoimmunity, allergy, and even frailty.
      • Holick M.F.
      Vitamin D: extraskeletal health.
      • Hossein-nezhad A.
      • Holick M.F.
      Optimize dietary intake of vitamin D: an epigenetic perspective.
      • Smit E.
      • Crespo C.J.
      • Michael Y.
      • et al.
      The effect of vitamin D and frailty on mortality among non-institutionalized US older adults.
      • Holick M.F.
      Nutrition: D-iabetes and D-eath D-efying vitamin D.
      Low prenatal and neonatal vitamin D status may also increase susceptibility to schizophrenia, type 1 diabetes, and multiple sclerosis (MS) in later life via specific target organ effects, including the immune system, or through epigenetic modification.
      • Lucas R.M.
      • Ponsonby A.L.
      • Pasco J.A.
      • Morley R.
      Future health implications of prenatal and early-life vitamin D status.
      Despite the many important health benefits of vitamin D, there is controversy regarding the definition of vitamin D deficiency and what the vitamin D requirement should be.
      • Hossein-nezhad A.
      • Holick M.F.
      Optimize dietary intake of vitamin D: an epigenetic perspective.
      • Brannon P.M.
      • Picciano M.F.
      Vitamin D in pregnancy and lactation in humans.
      • Holick M.F.
      Vitamin D deficiency.
      In addition, critical windows of exposure to adequate vitamin D levels during fetal maturation remain to be defined
      • Lucas R.M.
      • Ponsonby A.L.
      • Pasco J.A.
      • Morley R.
      Future health implications of prenatal and early-life vitamin D status.
      • Brannon P.M.
      • Picciano M.F.
      Vitamin D in pregnancy and lactation in humans.
      owing, in part, to the lack of well-designed controlled clinical trials with long-term follow-up.
      • Lucas R.M.
      • Ponsonby A.L.
      • Pasco J.A.
      • Morley R.
      Future health implications of prenatal and early-life vitamin D status.
      • Brannon P.M.
      • Picciano M.F.
      Vitamin D in pregnancy and lactation in humans.
      • Holick M.F.
      Vitamin D deficiency.
      This review, obtained, in part, from searching English-language studies published up to April 1, 2013, in PubMed, MEDLINE, and the Cochrane Central Register of Controlled Trials (search terms: vitamin D and supplementation), focuses on recent challenges about how to achieve an optimal serum level of 25-hydroxyvitamin D [25(OH)D] from dietary sources, supplements, and sun exposure and evidence-based benefits for skeletal and nonskeletal health. Also, we explore fetal programming and epigenomic mechanisms that could potentially explain why vitamin D has been reported to have such wide-ranging health benefits throughout life.

      Vitamin D Metabolism and Biological Functions

      Vitamin D (D represents D2, D3, or both) is a secosterol produced endogenously in the skin from sun exposure or obtained from foods that naturally contain vitamin D, including cod liver oil and fatty fish (eg, salmon, mackerel, and tuna); UV-irradiated mushrooms; foods fortified with vitamin D; and supplements.
      • Hossein-nezhad A.
      • Holick M.F.
      Optimize dietary intake of vitamin D: an epigenetic perspective.
      • Holick M.F.
      Vitamin D deficiency.
      During exposure to sunlight, 7-dehydrocholesterol (7-DHC) in the skin is converted to previtamin D3. The 7-DHC is present in all the layers of human skin.
      • Holick M.F.
      Vitamin D deficiency.
      • Holick M.F.
      Sunlight and vitamin D for bone health and prevention of autoimmune diseases, cancers, and cardiovascular disease.
      • Holick M.F.
      • MacLaughlin J.A.
      • Clark M.B.
      • et al.
      Photosynthesis of previtamin D3 in human skin and the physiologic consequences.
      Approximately 65% of 7-DHC is found in the epidermis, and greater than 95% of the previtamin D3 that is produced is in the viable epidermis and, therefore, cannot be removed from the skin when it is washed.
      • Holick M.F.
      • MacLaughlin J.A.
      • Clark M.B.
      • et al.
      Photosynthesis of previtamin D3 in human skin and the physiologic consequences.
      Once previtamin D3 is synthesized in the skin, it can undergo either a photoconversion to lumisterol, tachysterol, and 7-DHC or a heat-induced membrane-enhanced isomerization to vitamin D3 (Figure 1).
      • Holick M.F.
      Vitamin D deficiency.
      • Holick M.F.
      Sunlight and vitamin D for bone health and prevention of autoimmune diseases, cancers, and cardiovascular disease.
      The cutaneous production of previtamin D3 is regulated. Solar photoproducts (tachysterol and lumisterol) inactive on calcium metabolism are produced at times of prolonged exposure to solar UV-B radiation, thus preventing sun-induced vitamin D intoxication.
      • Holick M.F.
      Vitamin D deficiency.
      • Holick M.F.
      Sunlight and vitamin D for bone health and prevention of autoimmune diseases, cancers, and cardiovascular disease.
      Vitamin D3 is also sensitive to solar irradiation and is, thereby, inactivated to suprasterol 1 and 2 and to 5,6-trans-vitamin D3.
      • Holick M.F.
      Vitamin D deficiency.
      Cutaneous vitamin D3 production is influenced by skin pigmentation, sunscreen use, time of day, season, latitude, altitude, and air pollution.
      • Holick M.F.
      Vitamin D: extraskeletal health.
      • Hossein-nezhad A.
      • Holick M.F.
      Optimize dietary intake of vitamin D: an epigenetic perspective.
      • Holick M.F.
      Vitamin D deficiency.
      • Holick M.F.
      Sunlight and vitamin D for bone health and prevention of autoimmune diseases, cancers, and cardiovascular disease.
      An increase in the zenith angle of the sun during winter and early morning and late afternoon results in a longer path for the solar UV-B photons to travel through the ozone layer, which efficiently absorbs them. This is the explanation for why above and below approximately 33° latitude little if any vitamin D3 is made in the skin during winter.
      • Webb A.R.
      • Kline L.
      • Holick M.F.
      Influence of season and latitude on the cutaneous synthesis of vitamin D3: exposure to winter sunlight in Boston and Edmonton will not promote vitamin D3 synthesis in human skin.
      • Holick M.F.
      • Chen T.C.
      • Lu Z.
      • Sauter E.
      Vitamin D and skin physiology: a D-lightful story.
      This is also the explanation for why—whether being at the equator and in the far northern and southern regions of the world in summer, where the sun shines almost 24 hours a day—vitamin D3 synthesis occurs only between approximately 10 am and 3 pm.
      • Holick M.F.
      Vitamin D: extraskeletal health.
      • Holick M.F.
      • Chen T.C.
      • Lu Z.
      • Sauter E.
      Vitamin D and skin physiology: a D-lightful story.
      Similarly, in urban areas, such as Los Angeles, California, and Mexico City, Mexico, where nitrogen dioxide and ozone levels are high, few vitamin D3–producing UV-B photons reach the people living in these cities.
      • Holick M.F.
      Vitamin D deficiency.
      • Holick M.F.
      • Chen T.C.
      • Lu Z.
      • Sauter E.
      Vitamin D and skin physiology: a D-lightful story.
      Similarly, because glass absorbs all UV-B radiation, no vitamin D3 is produced in the skin when the skin is exposed to sunlight that passes through glass.
      Figure thumbnail gr1
      Figure 1Schematic representation of the synthesis and metabolism of vitamin D for skeletal and nonskeletal function. 1-OHase = 25-hydroxyvitamin D-1α-hydroxylase; 24-OHase = 25-hydroxyvitamin D-24-hydroxylase; 25(OH)D = 25-hydroxyvitamin D; 1,25(OH)2D = 1,25-dihydroxyvitamin D; CaBP = calcium-binding protein; CYP27B1, Cytochrome P450-27B1; DBP = vitamin D–binding protein; ECaC = epithelial calcium channel; FGF-23 = fibroblast growth factor-23; PTH = parathyroid hormone; RANK = receptor activator of the NF-kB; RANKL = receptor activator of the NF-kB ligand; RXR = retinoic acid receptor; TLR2/1 = Toll-like receptor 2/1; VDR = vitamin D receptor; vitamin D = vitamin D2 or vitamin D3.
      Copyright Holick 2013, reproduced with permission.
      Once formed, vitamin D3 is ejected out of the keratinocyte plasma membrane and is drawn into the dermal capillary bed by the vitamin D binding protein (DBP).
      • Holick M.F.
      Vitamin D deficiency.
      • Holick M.F.
      Sunlight and vitamin D for bone health and prevention of autoimmune diseases, cancers, and cardiovascular disease.
      Vitamin D that is ingested is incorporated into chylomicrons, which are released into the lymphatic system, and enters the venous blood,
      • Hossein-nezhad A.
      • Holick M.F.
      Optimize dietary intake of vitamin D: an epigenetic perspective.
      • Holick M.F.
      Vitamin D deficiency.
      where it binds to DBP and lipoproteins transported to the liver.
      • Holick M.F.
      Vitamin D: extraskeletal health.
      • Hossein-nezhad A.
      • Holick M.F.
      Optimize dietary intake of vitamin D: an epigenetic perspective.
      • Holick M.F.
      Vitamin D deficiency.
      Vitamin D2 and vitamin D3 are 25-hydroxylated by the liver vitamin D-25-hydroxylase (CYP2R1) to produce the major circulating vitamin D metabolite, 25(OH)D, which is used to determine a patient's vitamin D status.
      • Holick M.F.
      Vitamin D: extraskeletal health.
      • Hossein-nezhad A.
      • Holick M.F.
      Optimize dietary intake of vitamin D: an epigenetic perspective.
      • Holick M.F.
      Vitamin D deficiency.
      This metabolite undergoes further hydroxylation by the 25(OH)D-1α-hydroxylase (CYP27B1) in the kidneys to form the secosteroid hormone 1α,25-dihydroxyvitamin D [1,25(OH)2D] (Figure1).
      • Hossein-nezhad A.
      • Holick M.F.
      Optimize dietary intake of vitamin D: an epigenetic perspective.
      • Holick M.F.
      Vitamin D deficiency.
      • Negri A.L.
      Proximal tubule endocytic apparatus as the specific renal uptake mechanism for vitamin D-binding protein/25-(OH)D3 complex.
      The 25(OH)D bound to DBP is filtered in the kidneys and is reabsorbed in the proximal renal tubules by megalin cubilin receptors.
      • Brannon P.M.
      • Picciano M.F.
      Vitamin D in pregnancy and lactation in humans.
      • Negri A.L.
      Proximal tubule endocytic apparatus as the specific renal uptake mechanism for vitamin D-binding protein/25-(OH)D3 complex.
      The renal 1α-hydroxylation is closely regulated, being enhanced by parathyroid hormone (PTH), hypocalcemia, and hypophosphatemia and inhibited by hyperphosphatemia, fibroblast growth factor-23, and 1,25(OH)2D itself.
      • Holick M.F.
      Vitamin D deficiency.
      • Shimada T.
      • Kakitani M.
      • Yamazaki Y.
      • et al.
      Targeted ablation of Fgf23 demonstrates an essential physiological role of FGF23 in phosphate and vitamin D metabolism.
      • Nair R.
      • Maseeh A.
      Vitamin D: the “sunshine” vitamin.
      The 1,25(OH)2D performs many of its biologic functions by regulating gene transcription through a nuclear high-affinity vitamin D receptor (VDR).
      • Holick M.F.
      The D-lightful vitamin D for child health.
      • Nagpal S.
      • Na S.
      • Rathnachalam R.
      Noncalcemic actions of vitamin D receptor ligands.
      This active metabolite of vitamin D binds to the nuclear VDR, which binds retinoic acid X receptor to form a heterodimeric complex that binds to specific nucleotide sequences in the DNA known as vitamin D response elements. Once bound, a variety of transcription factors attach to this complex, resulting in either up-regulation or down-regulation of the gene's activity.
      • Hossein-nezhad A.
      • Holick M.F.
      Optimize dietary intake of vitamin D: an epigenetic perspective.
      • Holick M.F.
      Vitamin D deficiency.
      • Hossein-nezhad A.
      • Spira A.
      • Holick M.F.
      Influence of vitamin D status and vitamin D3 supplementation on genome wide expression of white blood cells: a randomized double-blind clinical trial.
      There are estimated to be 200 to 2000 genes that have vitamin D response elements or that are influenced indirectly, possibly by epigenetics, to control a multitude of genes across the genome.
      • Hossein-nezhad A.
      • Holick M.F.
      Optimize dietary intake of vitamin D: an epigenetic perspective.
      • Nagpal S.
      • Na S.
      • Rathnachalam R.
      Noncalcemic actions of vitamin D receptor ligands.
      A recent microarray study on the influence of vitamin D status and vitamin D3 supplementation on genome-wide expression in white blood cells before and after vitamin D3 supplementation found that an improved serum 25(OH)D concentration was associated with at least a 1.5-fold alteration in the expression of 291 genes.
      • Hossein-nezhad A.
      • Spira A.
      • Holick M.F.
      Influence of vitamin D status and vitamin D3 supplementation on genome wide expression of white blood cells: a randomized double-blind clinical trial.
      This study suggested that any improvement in vitamin D status will significantly affect the expression of genes that have a variety of biologic functions of more than 80 pathways linked to cancer, autoimmune disorders, and cardiovascular disease, which have been associated with vitamin D deficiency.
      • Hossein-nezhad A.
      • Spira A.
      • Holick M.F.
      Influence of vitamin D status and vitamin D3 supplementation on genome wide expression of white blood cells: a randomized double-blind clinical trial.
      One of the major physiologic functions of vitamin D is to maintain serum calcium and phosphorus levels in a healthy physiologic range to maintain a variety of metabolic functions, transcription regulation, and bone metabolism (Figure 1).
      • Hossein-nezhad A.
      • Holick M.F.
      Optimize dietary intake of vitamin D: an epigenetic perspective.
      • Holick M.F.
      Vitamin D deficiency.
      The 1,25(OH)2D interacts with its VDR in the small intestine to increase the efficiency of intestinal calcium absorption from approximately 10% to 15% up to 30% to 40% and intestinal phosphorus absorption from approximately 60% to 80%.
      • Holick M.F.
      Vitamin D deficiency.
      It also interacts with VDR in osteoblasts to stimulate a receptor activator of nuclear factor κB ligand, which, in turn, interacts with receptor activator of nuclear factor κB on immature preosteoclasts, stimulating them to become mature bone-resorbing osteoclasts (Figure 1).
      • Holick M.F.
      Vitamin D deficiency.
      • Kitazawa S.
      • Kajimoto K.
      • Kondo T.
      • Kitazawa R.
      Vitamin D3 supports osteoclastogenesis via functional vitamin D response element of human RANKL gene promoter.
      The mature osteoclast removes calcium and phosphorus from the bone to maintain blood calcium and phosphorus levels. In the kidneys, 1,25(OH)2D stimulates calcium reabsorption from the glomerular filtrate.
      • Hossein-nezhad A.
      • Holick M.F.
      Optimize dietary intake of vitamin D: an epigenetic perspective.
      • Holick M.F.
      Vitamin D deficiency.
      The VDR is present in most tissues and cells in the body.
      • Holick M.F.
      Vitamin D: extraskeletal health.
      • Hossein-nezhad A.
      • Holick M.F.
      Optimize dietary intake of vitamin D: an epigenetic perspective.
      • Holick M.F.
      Vitamin D deficiency.
      • Cui X.
      • Pelekanos M.
      • Liu P.Y.
      • Burne T.H.
      • McGrath J.J.
      • Eyles D.W.
      The vitamin D receptor in dopamine neurons; its presence in human substantia nigra and its ontogenesis in rat midbrain.
      • Gonzalez-Parra E.
      • Rojas-Rivera J.
      • Tunon J.
      • Praga M.
      • Ortiz A.
      • Egido J.
      Vitamin D receptor activation and cardiovascular disease.
      • Nowak R.
      • Szota J.
      • Mazurek U.
      Vitamin D receptor gene (VDR) transcripts in bone, cartilage, muscles and blood and microarray analysis of vitamin D responsive genes expression in paravertebral muscles of juvenile and adolescent idiopathic scoliosis patients.
      • Doig C.L.
      • Singh P.K.
      • Dhiman V.K.
      • et al.
      Recruitment of NCOR1 to VDR target genes is enhanced in prostate cancer cells and associates with altered DNA methylation patterns.
      • Alimirah F.
      • Peng X.
      • Yuan L.
      • et al.
      Crosstalk between the peroxisome proliferator-activated receptor γ (PPARγ) and the vitamin D receptor (VDR) in human breast cancer cells: PPARγ binds to VDR and inhibits 1α,25-dihydroxyvitamin D3 mediated transactivation.
      • Nagy L.
      • Szanto A.
      • Szatmari I.
      • Szeles L.
      Nuclear hormone receptors enable macrophages and dendritic cells to sense their lipid environment and shape their immune response.
      • Kaludjerovic J.
      • Vieth R.
      Relationship between vitamin D during perinatal development and health.
      Many of these organs and cells, including the brain, vascular smooth muscle, prostate, breast, and macrophages, not only have a VDR but also have the capacity to produce 1,25(OH)2D.
      • Holick M.F.
      Vitamin D: extraskeletal health.
      • Hossein-nezhad A.
      • Holick M.F.
      Optimize dietary intake of vitamin D: an epigenetic perspective.
      • Holick M.F.
      Vitamin D deficiency.
      • Cui X.
      • Pelekanos M.
      • Liu P.Y.
      • Burne T.H.
      • McGrath J.J.
      • Eyles D.W.
      The vitamin D receptor in dopamine neurons; its presence in human substantia nigra and its ontogenesis in rat midbrain.
      • Gonzalez-Parra E.
      • Rojas-Rivera J.
      • Tunon J.
      • Praga M.
      • Ortiz A.
      • Egido J.
      Vitamin D receptor activation and cardiovascular disease.
      • Nowak R.
      • Szota J.
      • Mazurek U.
      Vitamin D receptor gene (VDR) transcripts in bone, cartilage, muscles and blood and microarray analysis of vitamin D responsive genes expression in paravertebral muscles of juvenile and adolescent idiopathic scoliosis patients.
      • Doig C.L.
      • Singh P.K.
      • Dhiman V.K.
      • et al.
      Recruitment of NCOR1 to VDR target genes is enhanced in prostate cancer cells and associates with altered DNA methylation patterns.
      • Alimirah F.
      • Peng X.
      • Yuan L.
      • et al.
      Crosstalk between the peroxisome proliferator-activated receptor γ (PPARγ) and the vitamin D receptor (VDR) in human breast cancer cells: PPARγ binds to VDR and inhibits 1α,25-dihydroxyvitamin D3 mediated transactivation.
      • Nagy L.
      • Szanto A.
      • Szatmari I.
      • Szeles L.
      Nuclear hormone receptors enable macrophages and dendritic cells to sense their lipid environment and shape their immune response.
      • Kaludjerovic J.
      • Vieth R.
      Relationship between vitamin D during perinatal development and health.
      This production probably depends on the availability of circulating 25(OH)D, indicating the biological importance of sufficient blood levels of this vitamin D metabolite.
      • Hossein-nezhad A.
      • Holick M.F.
      Optimize dietary intake of vitamin D: an epigenetic perspective.
      • Holick M.F.
      The D-lightful vitamin D for child health.
      • Adams J.S.
      • Hewison M.
      Update in vitamin D.
      The estimated 2000 genes that are directly or indirectly regulated by 1,25(OH)2D
      • Hossein-nezhad A.
      • Holick M.F.
      Optimize dietary intake of vitamin D: an epigenetic perspective.
      • Holick M.F.
      Vitamin D deficiency.
      • Hossein-nezhad A.
      • Spira A.
      • Holick M.F.
      Influence of vitamin D status and vitamin D3 supplementation on genome wide expression of white blood cells: a randomized double-blind clinical trial.
      • Kitazawa S.
      • Kajimoto K.
      • Kondo T.
      • Kitazawa R.
      Vitamin D3 supports osteoclastogenesis via functional vitamin D response element of human RANKL gene promoter.
      • Cui X.
      • Pelekanos M.
      • Liu P.Y.
      • Burne T.H.
      • McGrath J.J.
      • Eyles D.W.
      The vitamin D receptor in dopamine neurons; its presence in human substantia nigra and its ontogenesis in rat midbrain.
      • Gonzalez-Parra E.
      • Rojas-Rivera J.
      • Tunon J.
      • Praga M.
      • Ortiz A.
      • Egido J.
      Vitamin D receptor activation and cardiovascular disease.
      • Nowak R.
      • Szota J.
      • Mazurek U.
      Vitamin D receptor gene (VDR) transcripts in bone, cartilage, muscles and blood and microarray analysis of vitamin D responsive genes expression in paravertebral muscles of juvenile and adolescent idiopathic scoliosis patients.
      • Doig C.L.
      • Singh P.K.
      • Dhiman V.K.
      • et al.
      Recruitment of NCOR1 to VDR target genes is enhanced in prostate cancer cells and associates with altered DNA methylation patterns.
      • Alimirah F.
      • Peng X.
      • Yuan L.
      • et al.
      Crosstalk between the peroxisome proliferator-activated receptor γ (PPARγ) and the vitamin D receptor (VDR) in human breast cancer cells: PPARγ binds to VDR and inhibits 1α,25-dihydroxyvitamin D3 mediated transactivation.
      • Nagy L.
      • Szanto A.
      • Szatmari I.
      • Szeles L.
      Nuclear hormone receptors enable macrophages and dendritic cells to sense their lipid environment and shape their immune response.
      • Adams J.S.
      • Hewison M.
      Update in vitamin D.
      have a wide range of proven biological actions, including inhibiting cellular proliferation and inducing terminal differentiation, inhibiting angiogenesis, stimulating insulin production, inducing apoptosis, inhibiting renin production, and stimulating macrophage cathelicidin production.
      • Holick M.F.
      Vitamin D: extraskeletal health.
      • Hossein-nezhad A.
      • Holick M.F.
      Optimize dietary intake of vitamin D: an epigenetic perspective.
      • Holick M.F.
      Vitamin D deficiency.
      • Nagpal S.
      • Na S.
      • Rathnachalam R.
      Noncalcemic actions of vitamin D receptor ligands.
      • Hossein-nezhad A.
      • Spira A.
      • Holick M.F.
      Influence of vitamin D status and vitamin D3 supplementation on genome wide expression of white blood cells: a randomized double-blind clinical trial.
      • Adams J.S.
      • Hewison M.
      Update in vitamin D.
      In addition, 1,25(OH)2D stimulates its own destruction in the kidneys and in cells that have a VDR and responds to 1,25(OH)2D by enhancing expression of the 25(OH)D–24-hydroxylase (CYP24A1) to metabolize 25(OH)D and 1,25(OH)2D into water-soluble inactive forms that are excreted in the bile (Figure 1).
      • Holick M.F.
      Vitamin D: extraskeletal health.
      • Holick M.F.
      Vitamin D deficiency.
      • Cui X.
      • Pelekanos M.
      • Liu P.Y.
      • Burne T.H.
      • McGrath J.J.
      • Eyles D.W.
      The vitamin D receptor in dopamine neurons; its presence in human substantia nigra and its ontogenesis in rat midbrain.
      • Shin J.S.
      • Choi M.Y.
      • Longtine M.S.
      • Nelson D.M.
      Vitamin D effects on pregnancy and the placenta.

      Vitamin D Metabolism During Pregnancy

      Vitamin D metabolism is enhanced during pregnancy and lactation. The placenta is formed at 4 weeks of gestation.
      • Hossein-nezhad A.
      • Holick M.F.
      Optimize dietary intake of vitamin D: an epigenetic perspective.
      • Kaludjerovic J.
      • Vieth R.
      Relationship between vitamin D during perinatal development and health.
      From this time to term, 25(OH)D is transferred across the placenta, and the fetal cord blood concentration of 25(OH)D is correlated with the mother's concentration.
      • Shin J.S.
      • Choi M.Y.
      • Longtine M.S.
      • Nelson D.M.
      Vitamin D effects on pregnancy and the placenta.
      However, the active metabolite 1,25(OH)2D does not readily cross the placenta.
      • Kaludjerovic J.
      • Vieth R.
      Relationship between vitamin D during perinatal development and health.
      • Shin J.S.
      • Choi M.Y.
      • Longtine M.S.
      • Nelson D.M.
      Vitamin D effects on pregnancy and the placenta.
      The fetal kidneys and the placenta provide the fetal circulation with 1,25(OH)2D by expressing CYP27B1 (Figure 2).
      • Adams J.S.
      • Hewison M.
      Extrarenal expression of the 25-hydroxyvitamin D-1-hydroxylase.
      Figure thumbnail gr2
      Figure 2Vitamin D metabolism during pregnancy and lactation. Maternal 25(OH)D is thought to freely cross the human placenta. The placenta expresses vitamin D receptors (VDR) and also produces 1-OHase to convert 25(OH)D to 1,25(OH)2D. 1,25-dihydroxyvitamin D does not readily cross the placenta, and fetal 1,25(OH)2D levels are normally lower than maternal serum levels. The low fetal concentrations of 1,25(OH)2D reflect the low fetal PTH and high phosphorus concentrations, which suppress renal 1-OHase. Although PTHrP is elevated in the fetal circulation, it appears to be less able to stimulate the renal 1-OHase than PTH. Total (free and bound) 1,25(OH)2D concentrations double or triple in the maternal circulation starting in the first trimester, but studies have only shown increased free concentrations during the third trimester. This increase is due to maternal synthesis by the renal 1-OHase. Vitamin D passes readily into breast milk, 25(OH)D passes very poorly, and 1,25(OH)2D does not appear to pass at all.
      • Hossein-nezhad A.
      • Holick M.F.
      Optimize dietary intake of vitamin D: an epigenetic perspective.
      1,25(OH)2D levels fall rapidly after pregnancy and are normal during lactation.
      • Holick M.F.
      Vitamin D deficiency.
      Near-exclusive breastfeeding for 6 months leads, on average, to maternal calcium loss 4 times higher than that in pregnancy. Phosphorus can rise above the normal range, probably because of accelerated resorption from the skeleton. Parathyroid hormone-related protein levels are higher than PTH concentrations in nonpregnant women and show some pulsatility in response to suckling. Parathyroid hormone-related protein (produced by the lactating breast) in combination with low estradiol concentrations appears to drive the main physiologic adaptation to meet the calcium demands of lactation. Suckling and prolactin both inhibit ovarian function and stimulate PTHrP. Together, PTHrP and low estradiol concentrations stimulate skeletal resorption. Renal calcium reabsorption rates increase, presumably due to PTHrP, which mimics the actions of PTH on the renal tubules. For definitions of abbreviations, see .
      Copyright Holick 2013, reproduced with permission.
      The maternal (decidual) and fetal placental (trophoblastic) components of the placenta have CYP27B1 activity; cultured human syncytiotrophoblasts and decidual cells synthesize 1,25(OH)2D3.
      • Shin J.S.
      • Choi M.Y.
      • Longtine M.S.
      • Nelson D.M.
      Vitamin D effects on pregnancy and the placenta.
      The spatiotemporal organization of placental CYP27B1 and the VDR across gestation has also been characterized, confirming that the enzyme and receptor are localized to the maternal and fetal parts of the placenta.
      • Grayson R.
      • Hewison M.
      Vitamin D and human pregnancy.
      Serum levels of DBP increase 46% to 103% during pregnancy, suggesting that DBP may play a role in directing vitamin D metabolism and function during pregnancy.
      • Hossein-nezhad A.
      • Holick M.F.
      Optimize dietary intake of vitamin D: an epigenetic perspective.
      • Shin J.S.
      • Choi M.Y.
      • Longtine M.S.
      • Nelson D.M.
      Vitamin D effects on pregnancy and the placenta.
      • Powe C.E.
      • Seely E.W.
      • Rana S.
      • et al.
      First trimester vitamin D, vitamin D binding protein, and subsequent preeclampsia.
      The DBP has a much higher binding affinity for 25(OH)D than for 1,25(OH)2D, and in kidney epithelial cells, DBP plays a pivotal role in conserving 25(OH)D by facilitating the recovery of 25(OH)D from the glomerular filtrate.
      • Zella L.A.
      • Shevde N.K.
      • Hollis B.W.
      • Cooke N.E.
      • Pike J.W.
      Vitamin D-binding protein influences total circulating levels of 1,25-dihydroxyvitamin D3 but does not directly modulate the bioactive levels of the hormone in vivo.
      • Liu N.Q.
      • Hewison M.
      Vitamin D, the placenta and pregnancy.
      Transplacental transfer of calcium to the fetus is also facilitated by expression of all the key mediators of vitamin D metabolism in the placenta. Hormones involved in fetal growth and that influence CYP27B1 activity include insulin-like growth factor 1 and human placental lactogen, PTH-related protein (PTHrP), estradiol, and prolactin.
      • Hossein-nezhad A.
      • Holick M.F.
      Optimize dietary intake of vitamin D: an epigenetic perspective.
      • Zella L.A.
      • Shevde N.K.
      • Hollis B.W.
      • Cooke N.E.
      • Pike J.W.
      Vitamin D-binding protein influences total circulating levels of 1,25-dihydroxyvitamin D3 but does not directly modulate the bioactive levels of the hormone in vivo.
      • Ardawi M.S.
      • Nasrat H.A.
      • BA'Aqueel H.S.
      Calcium-regulating hormones and parathyroid hormone-related peptide in normal human pregnancy and postpartum: a longitudinal study.
      • Weisser J.
      • Riemer S.
      • Schmidl M.
      • et al.
      Four distinct chondrocyte populations in the fetal bovine growth plate: highest expression levels of PTH/PTHrP receptor, Indian hedgehog, and MMP-13 in hypertrophic chondrocytes and their suppression by PTH (1-34) and PTHrP (1-40).
      The PTHrP acts as a calciotropic hormone during fetal life and in lactation.
      • Kovacs C.S.
      • Kronenberg H.M.
      Maternal-fetal calcium and bone metabolism during pregnancy, puerperium, and lactation.
      • Mahadevan S.
      • Kumaravel V.
      • Bharath R.
      Calcium and bone disorders in pregnancy.
      • Kovacs C.S.
      Vitamin D in pregnancy and lactation: maternal, fetal, and neonatal outcomes from human and animal studies.
      The exact role of circulating PTHrP in pregnancy is unknown, but its rise may stimulate renal CYP27B1 and contribute to the increase in 1,25(OH)2D concentration and, indirectly, the suppression of PTH levels.
      • Shin J.S.
      • Choi M.Y.
      • Longtine M.S.
      • Nelson D.M.
      Vitamin D effects on pregnancy and the placenta.
      • Kovacs C.S.
      • Kronenberg H.M.
      Maternal-fetal calcium and bone metabolism during pregnancy, puerperium, and lactation.
      • Kovacs C.S.
      Vitamin D in pregnancy and lactation: maternal, fetal, and neonatal outcomes from human and animal studies.
      The PTHrP arises from several sources, including the breast, myometrium, decidua, amnion, and fetal parathyroids.
      • Mahadevan S.
      • Kumaravel V.
      • Bharath R.
      Calcium and bone disorders in pregnancy.
      Several roles of PTHrP are postulated from animal studies, including fetal chondrocyte maturation, fetal calcium transfer, and stimulation of CYP27B1 activity.
      • Ardawi M.S.
      • Nasrat H.A.
      • BA'Aqueel H.S.
      Calcium-regulating hormones and parathyroid hormone-related peptide in normal human pregnancy and postpartum: a longitudinal study.
      • Weisser J.
      • Riemer S.
      • Schmidl M.
      • et al.
      Four distinct chondrocyte populations in the fetal bovine growth plate: highest expression levels of PTH/PTHrP receptor, Indian hedgehog, and MMP-13 in hypertrophic chondrocytes and their suppression by PTH (1-34) and PTHrP (1-40).
      • Mahadevan S.
      • Kumaravel V.
      • Bharath R.
      Calcium and bone disorders in pregnancy.
      Furthermore, the carboxy terminal of PTHrP (osteostatin) may suppress osteoclastic activity and may have a possible bone protection role in the mother during pregnancy.
      • Liu N.Q.
      • Hewison M.
      Vitamin D, the placenta and pregnancy.
      • Kovacs C.S.
      • Kronenberg H.M.
      Maternal-fetal calcium and bone metabolism during pregnancy, puerperium, and lactation.
      • Mahadevan S.
      • Kumaravel V.
      • Bharath R.
      Calcium and bone disorders in pregnancy.
      • Kovacs C.S.
      Vitamin D in pregnancy and lactation: maternal, fetal, and neonatal outcomes from human and animal studies.
      Calcitonin, an important component of calcium homeostasis during pregnancy,
      • Kovacs C.S.
      Calcium and bone metabolism disorders during pregnancy and lactation.
      • Moller U.K.
      • Streym S.
      • Mosekilde L.
      • et al.
      Changes in calcitropic hormones, bone markers and insulin-like growth factor I (IGF-I) during pregnancy and postpartum: a controlled cohort study.
      is known to promote transcription of CYP27B1
      • Zhong Y.
      • Armbrecht H.J.
      • Christakos S.
      Calcitonin, a regulator of the 25-hydroxyvitamin D3 1α-hydroxylase gene.
      and may, therefore, be a key determinant of placental vitamin D metabolism.
      • Kovacs C.S.
      Bone development in the fetus and neonate: role of the calciotropic hormones.
      Thus, PTHrP and calcitonin, as well as other factors, cause 1,25(OH)2D levels to increase, being 2-fold higher in serum of women in the third trimester of pregnancy than in nonpregnant or postpartum women.
      • Hossein-nezhad A.
      • Holick M.F.
      Optimize dietary intake of vitamin D: an epigenetic perspective.
      • Shin J.S.
      • Choi M.Y.
      • Longtine M.S.
      • Nelson D.M.
      Vitamin D effects on pregnancy and the placenta.
      Normally, 1,25(OH)2D regulates its own metabolism via a feedback loop such that elevated concentrations induce the expression of CYP24A1, with concomitant down-regulation of CYP27B1.
      • Holick M.F.
      Vitamin D deficiency.
      • Kaludjerovic J.
      • Vieth R.
      Relationship between vitamin D during perinatal development and health.
      • Jones G.
      • Kano K.
      • Yamada S.
      • Furusawa T.
      • Takayama H.
      • Suda T.
      Identification of 24,25,26,27-tetranor-23-hydroxyvitamin D3 as a product of the renal metabolism of 24,25-dihydroxyvitamin D3.
      This process results in a reduction of 25(OH)D and 1,25(OH)2D levels.
      • Holick M.F.
      • MacLaughlin J.A.
      • Clark M.B.
      • et al.
      Photosynthesis of previtamin D3 in human skin and the physiologic consequences.
      • Grayson R.
      • Hewison M.
      Vitamin D and human pregnancy.
      • Powe C.E.
      • Seely E.W.
      • Rana S.
      • et al.
      First trimester vitamin D, vitamin D binding protein, and subsequent preeclampsia.
      However, during pregnancy, this process becomes uncoupled, resulting in elevated maternal concentrations of circulating 1,25(OH)2D.
      • Shin J.S.
      • Choi M.Y.
      • Longtine M.S.
      • Nelson D.M.
      Vitamin D effects on pregnancy and the placenta.
      • Papapetrou P.D.
      The interrelationship of serum 1,25-dihydroxyvitamin D, 25-hydroxyvitamin D and 24,25-dihydroxyvitamin D in pregnancy at term: a meta-analysis.
      The placental methylation of the CYP24A1 promoter reduces the capacity for CYP24A1 induction and down-regulates basal promoter activity and abolishes vitamin D–mediated feedback activation. This epigenetic decoupling of vitamin D feedback catabolism also plays an important role in enhancing 1,25(OH)2D bioavailability at the fetomaternal interface.
      • Novakovic B.
      • Sibson M.
      • Ng H.K.
      • et al.
      Placenta-specific methylation of the vitamin D 24-hydroxylase gene: implications for feedback autoregulation of active vitamin D levels at the fetomaternal interface.

      Vitamin D, Placenta Development, Fetal Programming, and Epigenetic Modification

      Epidemiologic evidence has suggested a link between fetal life events and susceptibility to disease in adult life.
      • Dror D.K.
      Vitamin D status during pregnancy: maternal, fetal, and postnatal outcomes.
      • Morris G.S.
      • Zhou Q.
      • Hegsted M.
      • Keenan M.J.
      Maternal consumption of a low vitamin D diet retards metabolic and contractile development in the neonatal rat heart.
      • Kim B.G.
      • Chang S.K.
      • Kim S.M.
      • Hwang J.S.
      • Jung J.W.
      Dilated cardiomyopathy in a 2 month-old infant: a severe form of hypocalcemia with vitamin D deficient rickets.
      This paradigm, referred to as fetal programming or developmental origins of health and disease, may have a profound effect on public health strategies for the prevention of major illnesses.
      • Hossein-nezhad A.
      • Holick M.F.
      Optimize dietary intake of vitamin D: an epigenetic perspective.
      • Jansson T.
      • Powell T.L.
      Role of the placenta in fetal programming: underlying mechanisms and potential interventional approaches.
      The role of vitamin D in implantation tolerance and placental development has been studied. The 1,25(OH)2D3 regulates key target genes associated with implantation, such as Homeobox A10 (HOXA10), whereas the potent immunosuppressive effects of 1,25(OH)2D3 suggest a role in placental development.
      • Evans K.N.
      • Bulmer J.N.
      • Kilby M.D.
      • Hewison M.
      Vitamin D and placental-decidual function.
      Increasing expression of CYP27B1 and VDR in first-trimester human trophoblasts and deciduas
      • Ma R.
      • Gu Y.
      • Zhao S.
      • Sun J.
      • Groome L.J.
      • Wang Y.
      Expressions of vitamin D metabolic components VDBP, CYP2R1, CYP27B1, CYP24A1, and VDR in placentas from normal and preeclamptic pregnancies.
      may be related to the immunosuppressive effects of 1,25(OH)2D3 and may help improve implantation tolerance. Placental development plays a critical role in pregnancy health, and its link to maternal vitamin D deficiency may explain related adverse outcomes.
      • Lucas R.M.
      • Ponsonby A.L.
      • Pasco J.A.
      • Morley R.
      Future health implications of prenatal and early-life vitamin D status.
      • Dror D.K.
      Vitamin D status during pregnancy: maternal, fetal, and postnatal outcomes.
      In neonatal rats exposed prenatally to low maternal serum 25(OH)D levels, there was a general slowing of cardiac development, with significantly lower heart weights, decreased citrate synthase and 3-hydroxyacyl CoA dehydrogenase activity, and a 15% lower myofibrillar protein content.
      • Morris G.S.
      • Zhou Q.
      • Hegsted M.
      • Keenan M.J.
      Maternal consumption of a low vitamin D diet retards metabolic and contractile development in the neonatal rat heart.
      A 2-month-old human infant with dilated cardiomyopathy and severe vitamin D deficiency had dramatic improvement of her ejection fraction (17%-66%) after vitamin D supplementation.
      • Kim B.G.
      • Chang S.K.
      • Kim S.M.
      • Hwang J.S.
      • Jung J.W.
      Dilated cardiomyopathy in a 2 month-old infant: a severe form of hypocalcemia with vitamin D deficient rickets.
      In addition, maternal vitamin D deficiency in rats stimulated nephrogenesis in offspring, with a 20% increase in nephron number but a decrease in renal corpuscle size observed between replete and deficient rats, despite there being no difference in body weight or kidney weight and volume.
      • Lucas R.M.
      • Ponsonby A.L.
      • Pasco J.A.
      • Morley R.
      Future health implications of prenatal and early-life vitamin D status.
      • Maka N.
      • Makrakis J.
      • Parkington H.C.
      • Tare M.
      • Morley R.
      • Black M.J.
      Vitamin D deficiency during pregnancy and lactation stimulates nephrogenesis in rat offspring.
      These findings support the role of vitamin D influencing fetal programming and placental development.
      Epigenetic modification refers to heritable changes in gene expression that are not mediated by alterations in DNA sequence.
      • Stefanska B.
      • Karlic H.
      • Varga F.
      • Fabianowska-Majewska K.
      • Haslberger A.
      Epigenetic mechanisms in anti-cancer actions of bioactive food components: the implications in cancer prevention.
      This hypothesis, first articulated by Barker et al,
      • Barker D.J.
      • Eriksson J.G.
      • Forsen T.
      • Osmond C.
      Fetal origins of adult disease: strength of effects and biological basis.
      postulated that in utero epigenetic fetal programming (as a result of environmental events during pregnancy) induced specific genes and genomic pathways that controlled fetal development and subsequent disease risk. The role of vitamin D in epigenetic modification and fetal programming could potentially explain why vitamin D has been reported to have such wide-ranging health benefits. Recent studies have suggested that epigenetic decoupling of vitamin D feedback catabolism plays an important role in maximizing 1,25(OH)2D bioavailability at the fetomaternal interface.
      • Kaludjerovic J.
      • Vieth R.
      Relationship between vitamin D during perinatal development and health.
      • Novakovic B.
      • Sibson M.
      • Ng H.K.
      • et al.
      Placenta-specific methylation of the vitamin D 24-hydroxylase gene: implications for feedback autoregulation of active vitamin D levels at the fetomaternal interface.
      Modified expression of the genes encoding placental calcium transporters, by epigenetic regulation by 1,25(OH)2D, might represent the means whereby maternal vitamin D status could influence bone mineral accrual in the neonate.
      • Karlic H.
      • Varga F.
      Impact of vitamin D metabolism on clinical epigenetics.
      • Martin R.
      • Harvey N.C.
      • Crozier S.R.
      • et al.
      Placental calcium transporter (PMCA3) gene expression predicts intrauterine bone mineral accrual.
      Vitamin D deficiency during pregnancy may, therefore, not only impair maternal skeletal preservation and fetal skeletal formation but also influence fetal “imprinting” that may affect chronic disease susceptibility soon after birth as well as later in life (Figure 3).
      • Holick M.F.
      The D-lightful vitamin D for child health.
      • Lapillonne A.
      Vitamin D deficiency during pregnancy may impair maternal and fetal outcomes.
      Transgenerational hormonal imprinting caused by vitamin D treatment of newborn rats has been previously reported.
      • Tekes K.
      • Gyenge M.
      • Hantos M.
      • Csaba G.
      Transgenerational hormonal imprinting caused by vitamin A and vitamin D treatment of newborn rats: alterations in the biogenic amine contents of the adult brain.
      A recent study reported that VDR binds to the ɛ germline gene promoter and exhibits transrepressive activity.
      • Milovanovic M.
      • Heine G.
      • Hallatschek W.
      • Opitz B.
      • Radbruch A.
      • Worm M.
      Vitamin D receptor binds to the epsilon germline gene promoter and exhibits transrepressive activity.
      Inhibition of IgE production by 1,25(OH)2D was mediated by its transrepressive activity through the VDR-corepressor complex, affecting chromatin compacting around the Iɛ region.
      • Milovanovic M.
      • Heine G.
      • Hallatschek W.
      • Opitz B.
      • Radbruch A.
      • Worm M.
      Vitamin D receptor binds to the epsilon germline gene promoter and exhibits transrepressive activity.
      Also, the associations of early-life sun exposure and germline variation in VDR and CYP24A1 with non-Hodgkin lymphoma risk was reported in a clinic-based case-control study.
      • Kelly J.L.
      • Drake M.T.
      • Fredericksen Z.S.
      • et al.
      Early life sun exposure, vitamin D-related gene variants, and risk of non-Hodgkin lymphoma.
      Figure thumbnail gr3
      Figure 3Vitamin D, placenta development, fetal programming, and epigenetic modification. A= adenosine; CH3 = methyl group; HIV = human immunodeficiency virus; IVF = in vitro fertilization; miRNA, micro RNA; SAH = S-adenosylhomocysteine; SAM= single carbon from adenosylmethionine.
      Copyright Holick 2013, reproduced with permission.

      Definition of Vitamin D Deficiency

      The blood level of 25(OH)D is the best method to determine vitamin D status. Although 1,25(OH)2D is the biologically active form, it provides no information about vitamin D status because it is often normal or even elevated in children and adults who are vitamin D deficient.
      • Holick M.F.
      Vitamin D deficiency.
      • Holick M.F.
      The D-lightful vitamin D for child health.
      • Holick M.F.
      • Binkley N.C.
      • Bischoff-Ferrari H.A.
      • et al.
      Evaluation, treatment, and prevention of vitamin D deficiency: an Endocrine Society clinical practice guideline.
      • Bischoff-Ferrari H.A.
      • Giovannucci E.
      • Willett W.C.
      • Dietrich T.
      • Dawson-Hughes B.
      Estimation of optimal serum concentrations of 25-hydroxyvitamin D for multiple health outcomes.
      • Ross A.C.
      • Manson J.E.
      • Abrams S.A.
      • et al.
      The 2011 report on dietary reference intakes for calcium and vitamin D from the Institute of Medicine: what clinicians need to know.
      • Hewison M.
      • Adams J.S.
      Vitamin D insufficiency and skeletal development in utero.
      Recently, the Institute of Medicine (IOM) and the Endocrine Society released separate guidelines for vitamin D requirements.
      • Holick M.F.
      • Binkley N.C.
      • Bischoff-Ferrari H.A.
      • et al.
      Evaluation, treatment, and prevention of vitamin D deficiency: an Endocrine Society clinical practice guideline.
      • Ross A.C.
      • Manson J.E.
      • Abrams S.A.
      • et al.
      The 2011 report on dietary reference intakes for calcium and vitamin D from the Institute of Medicine: what clinicians need to know.
      The recommended dietary allowances (RDAs) of the IOM and the Endocrine Society guidelines for vitamin D intake are summarized in Figure 4.
      Figure thumbnail gr4
      Figure 4Vitamin D intakes recommended by the Institute of Medicine and the Endocrine Practice Guidelines Committee. 25(OH)D = 25-hydroxyvitamin D; AI= adequate intake; RDA = recommended dietary allowance; SE = standard error; UL= tolerable upper intake level.
      Copyright Holick 2013, reproduced with permission.
      The revised guidelines by the IOM stress that the daily requirements for vitamin D are generally met by most of the population and are appropriate to reach the “sufficient” level of 20 ng/mL (to convert to nmol/L, multiply by 2.496).
      • Ross A.C.
      • Manson J.E.
      • Abrams S.A.
      • et al.
      The 2011 report on dietary reference intakes for calcium and vitamin D from the Institute of Medicine: what clinicians need to know.
      The IOM guidelines used a population model to prevent vitamin D deficiency in 97.5% of the general population. Also, note that the IOM report focuses only on bone health (calcium absorption, bone mineral density, and osteomalacia/rickets) and found no evidence that a serum 25(OH)D concentration greater than 20 ng/mL had beneficial effects at a population level. However, considering the available evidence on skeletal and extraskeletal effects of vitamin D, the few negative studies, and the lack of toxicity potential of vitamin D supplementation at recommended doses, the US Endocrine Society, which used a medical model, recommended that serum 25(OH)D levels of 30 ng/mL should be attained to avoid other risks connected with an inadequate vitamin D status.
      • Holick M.F.
      Vitamin D deficiency.
      • Holick M.F.
      • Binkley N.C.
      • Bischoff-Ferrari H.A.
      • et al.
      Evaluation, treatment, and prevention of vitamin D deficiency: an Endocrine Society clinical practice guideline.
      Therefore, the Endocrine Society recommended that vitamin D deficiency be defined as a 25(OH)D level of 20 ng/mL or less, vitamin D insufficiency as 21 to 29 ng/mL, and vitamin D sufficiency as 30 ng/mL or greater for children and adults.
      • Holick M.F.
      • Binkley N.C.
      • Bischoff-Ferrari H.A.
      • et al.
      Evaluation, treatment, and prevention of vitamin D deficiency: an Endocrine Society clinical practice guideline.
      It suggested that maintenance of a 25(OH)D level of 40 to 60 ng/mL is ideal (this takes into account assay variability) and that up to 100 ng/mL is safe.
      • Holick M.F.
      • Binkley N.C.
      • Bischoff-Ferrari H.A.
      • et al.
      Evaluation, treatment, and prevention of vitamin D deficiency: an Endocrine Society clinical practice guideline.

      Musculoskeletal Consequences of Vitamin D Deficiency

      According to current evidence from biochemical testing, observational studies, and randomized controlled trials (RCTs), serum 25(OH)D levels of at least 20 ng/mL are required for normalization of PTH levels, to minimize the risk of osteomalacia, and for optimal bone and muscle function, with many experts regarding 30 ng/mL as the threshold for optimal bone health.
      • Holick M.F.
      Vitamin D deficiency.
      • Nagpal S.
      • Na S.
      • Rathnachalam R.
      Noncalcemic actions of vitamin D receptor ligands.
      • Bischoff-Ferrari H.A.
      • Giovannucci E.
      • Willett W.C.
      • Dietrich T.
      • Dawson-Hughes B.
      Estimation of optimal serum concentrations of 25-hydroxyvitamin D for multiple health outcomes.
      • Sanders K.M.
      • Nicholson G.C.
      • Ebeling P.R.
      Is high dose vitamin D harmful?.
      • Mahon P.
      • Harvey N.
      • Crozier S.
      • et al.
      Low maternal vitamin D status and fetal bone development: cohort study.
      • Holick M.F.
      • Lim R.
      • Dighe A.S.
      Case records of the Massachusetts General Hospital: case 3-2009: a 9-month-old boy with seizures.
      The skeletal consequences of 25(OH)D insufficiency include secondary hyperparathyroidism, increased bone turnover and bone loss, and increased risk of low-trauma fractures.
      • Holick M.F.
      Vitamin D deficiency.
      • Holick M.F.
      The D-lightful vitamin D for child health.
      • Bischoff-Ferrari H.A.
      • Giovannucci E.
      • Willett W.C.
      • Dietrich T.
      • Dawson-Hughes B.
      Estimation of optimal serum concentrations of 25-hydroxyvitamin D for multiple health outcomes.
      • Sanders K.M.
      • Nicholson G.C.
      • Ebeling P.R.
      Is high dose vitamin D harmful?.
      The most common etiology of rickets, historically and presently, is vitamin D deficiency. Low maternal 25(OH)D levels were found to correlate with increased fetal distal femoral splaying, determined by ultrasonography measurements of femoral length and metaphyseal width.
      • Hewison M.
      • Adams J.S.
      Vitamin D insufficiency and skeletal development in utero.
      • Mahon P.
      • Harvey N.
      • Crozier S.
      • et al.
      Low maternal vitamin D status and fetal bone development: cohort study.
      Children begin to manifest classic clinical signs of rickets between 6 months and 1.5 years that include rachitic rosary, widened epiphyseal plates at the end of long bones, and bowing deformities of the legs.
      • Holick M.F.
      • Lim R.
      • Dighe A.S.
      Case records of the Massachusetts General Hospital: case 3-2009: a 9-month-old boy with seizures.
      A common early symptom in newborns is excessive sweating due to neuromuscular irritability,
      • Holick M.F.
      • Lim R.
      • Dighe A.S.
      Case records of the Massachusetts General Hospital: case 3-2009: a 9-month-old boy with seizures.
      and a 25(OH)D level less than 20 ng/mL is common in children presenting with vague limb or back pain.
      From a skeletal perspective for adults, evidence from RCTs suggests that vitamin D may be considered a threshold nutrient, with little bone benefit observed at levels of 25(OH)D above which PTH is normalized.
      • Ross A.C.
      • Manson J.E.
      • Abrams S.A.
      • et al.
      The 2011 report on dietary reference intakes for calcium and vitamin D from the Institute of Medicine: what clinicians need to know.
      • Nowson C.A.
      • McGrath J.J.
      • Ebeling P.R.
      • et al.
      Vitamin D and health in adults in Australia and New Zealand: a position statement.
      A literature review of 70 studies generally found a threshold for a decline in serum PTH levels with increasing serum 25(OH)D levels, but there was no consistency in the threshold level of serum 25(OH)D, which varied from 20 to 50 ng/mL.
      • Sai A.J.
      • Walters R.W.
      • Fang X.
      • Gallagher J.C.
      Relationship between vitamin D, parathyroid hormone, and bone health.
      A study of 4100 older adults (>60 years old) from the Third National Health and Nutrition Examination Survey (NHANES III) found that higher 25(OH)D levels were associated with better lower extremity function.
      • Bischoff-Ferrari H.A.
      • Giovannucci E.
      • Willett W.C.
      • Dietrich T.
      • Dawson-Hughes B.
      Estimation of optimal serum concentrations of 25-hydroxyvitamin D for multiple health outcomes.
      Much of the improvement occurred at 25(OH)D levels ranging from 9 to 16 ng/mL but continued to be seen at levels up to 40 ng/mL.
      • Bischoff-Ferrari H.A.
      • Dietrich T.
      • Orav E.J.
      • et al.
      Higher 25-hydroxyvitamin D concentrations are associated with better lower-extremity function in both active and inactive persons aged ≥60 y.
      A systematic review revealed that supplemental vitamin D at daily doses of 800 to 1000 IU consistently had beneficial effects on muscle strength and balance.
      • Muir S.W.
      • Montero-Odasso M.
      Effect of vitamin D supplementation on muscle strength, gait and balance in older adults: a systematic review and meta-analysis.
      Several RCTs have reported positive effects of vitamin D supplementation on muscle function and fall prevention.
      • Pramyothin P.
      • Holick M.F.
      Vitamin D supplementation: guidelines and evidence for subclinical deficiency.
      • Pfeifer M.
      • Begerow B.
      • Minne H.W.
      • Suppan K.
      • Fahrleitner-Pammer A.
      • Dobnig H.
      Effects of a long-term vitamin D and calcium supplementation on falls and parameters of muscle function in community-dwelling older individuals.
      • Bischoff-Ferrari H.A.
      • Shao A.
      • Dawson-Hughes B.
      • Hathcock J.
      • Giovannucci E.
      • Willett W.C.
      Benefit-risk assessment of vitamin D supplementation.
      Adequate calcium intake is imperative to gain optimal benefit from improving the vitamin D status in those with insufficient 25(OH)D levels.
      • Nowson C.A.
      • McGrath J.J.
      • Ebeling P.R.
      • et al.
      Vitamin D and health in adults in Australia and New Zealand: a position statement.
      In contrast, a study of 173 young Asian Indian females revealed that after supplementation with vitamin D3 (60,000 IU/wk for 8 weeks followed by 60,000 IU every 2 weeks) and calcium (500 mg twice per day for 6 months), and despite significant improvement in serum 25(OH)D levels, there was no significant change in their skeletal muscle strength.
      • Goswami R.
      • Vatsa M.
      • Sreenivas V.
      • et al.
      Skeletal muscle strength in young Asian Indian females after vitamin D and calcium supplementation: a double-blind randomized controlled clinical trial.
      Thus, age, baseline and final 25(OH)D concentrations, and whether and how much calcium supplementation was included in the clinical trial could affect outcome measures related to muscle performance and vitamin D status.
      Proximal muscle weakness is a prominent clinical feature of vitamin D deficiency.
      • Holick M.F.
      Vitamin D deficiency.
      • Holick M.F.
      • Binkley N.C.
      • Bischoff-Ferrari H.A.
      • et al.
      Evaluation, treatment, and prevention of vitamin D deficiency: an Endocrine Society clinical practice guideline.
      The relative contributions of vitamin D and calcium for reducing fracture risk remain unclear
      • Abrahamsen B.
      • Masud T.
      • Avenell A.
      • et al.
      Patient level pooled analysis of 68 500 patients from seven major vitamin D fracture trials in US and Europe.
      because improving calcium intake is also associated with suppression of PTH levels independent of vitamin D status.
      • Nowson C.A.
      • McGrath J.J.
      • Ebeling P.R.
      • et al.
      Vitamin D and health in adults in Australia and New Zealand: a position statement.
      • Elders P.J.
      • Lips P.
      • Netelenbos J.C.
      • et al.
      Long-term effect of calcium supplementation on bone loss in perimenopausal women.
      • Reid I.R.
      • Mason B.
      • Horne A.
      • et al.
      Randomized controlled trial of calcium in healthy older women.
      A meta-analysis of data from RCTs found a dose-response relationship between a higher vitamin D dose and higher achieved serum 25(OH)D levels, with prevention of falls and fractures.
      • Bischoff-Ferrari H.A.
      • Shao A.
      • Dawson-Hughes B.
      • Hathcock J.
      • Giovannucci E.
      • Willett W.C.
      Benefit-risk assessment of vitamin D supplementation.
      The greatest benefit was observed at 700 to 1000 IU/d or a mean serum 25(OH)D concentration of 30 to 44 ng/mL.
      • Pramyothin P.
      • Holick M.F.
      Vitamin D supplementation: guidelines and evidence for subclinical deficiency.
      • Bischoff-Ferrari H.A.
      • Shao A.
      • Dawson-Hughes B.
      • Hathcock J.
      • Giovannucci E.
      • Willett W.C.
      Benefit-risk assessment of vitamin D supplementation.
      Similar results were reported in a more recent meta-analysis of pooled participant-level data from 11 double-blind RCTs of oral vitamin D supplementation, with or without calcium, compared with placebo or calcium alone in persons 65 years or older.
      • Bischoff-Ferrari H.A.
      • Willett W.C.
      • Orav E.J.
      • et al.
      A pooled analysis of vitamin D dose requirements for fracture prevention.
      Reduction in the risk of fracture occurred only at the highest vitamin D intake level (median, 800 IU/d; range, 792-2000 IU/d), with a 30% reduction in the risk of hip fracture and a 14% reduction in the risk of any nonvertebral fracture.
      • Bischoff-Ferrari H.A.
      • Willett W.C.
      • Orav E.J.
      • et al.
      A pooled analysis of vitamin D dose requirements for fracture prevention.
      This reduction was independent of the assigned treatment dose of vitamin D, age group, sex, type of dwelling, and study.
      • Bischoff-Ferrari H.A.
      • Willett W.C.
      • Orav E.J.
      • et al.
      A pooled analysis of vitamin D dose requirements for fracture prevention.
      Several previous meta-analyses have suggested that the dose of vitamin D is irrelevant when vitamin D is combined with calcium.
      • Priemel M.
      • von Domarus C.
      • Klatte T.O.
      • et al.
      Bone mineralization defects and vitamin D deficiency: histomorphometric analysis of iliac crest bone biopsies and circulating 25-hydroxyvitamin D in 675 patients.
      • Bergman G.J.
      • Fan T.
      • McFetridge J.T.
      • Sen S.S.
      Efficacy of vitamin D3 supplementation in preventing fractures in elderly women: a meta-analysis.
      • Bischoff-Ferrari H.A.
      • Willett W.C.
      • Wong J.B.
      • et al.
      Prevention of nonvertebral fractures with oral vitamin D and dose dependency: a meta-analysis of randomized controlled trials.
      • Avenell A.
      • Gillespie W.J.
      • Gillespie L.D.
      • O'Connell D.
      Vitamin D and vitamin D analogues for preventing fractures associated with involutional and post-menopausal osteoporosis.
      In contrast, a pooled subgroup analysis of the 8 double-blind RCTs that used vitamin D combined with calcium indicated that with combined supplementation, the risk of fracture was reduced only at the highest actual intake level of vitamin D. These findings support that a 25(OH)D level of more than 24 ng/mL may be most beneficial for reducing the risk of fractures.
      • Bischoff-Ferrari H.A.
      • Willett W.C.
      • Orav E.J.
      • et al.
      A pooled analysis of vitamin D dose requirements for fracture prevention.
      With a similar tone and theme, a report from the US Preventive Services Task Force concluded that current evidence is insufficient to assess the balance of benefits and harms of combined vitamin D and calcium supplementation for the primary prevention of fractures in premenopausal women or in men.
      • Moyer V.A.
      • U.S. Preventive Services Task Force
      Vitamin D and calcium supplementation to prevent fractures in adults: U.S. Preventive Services Task Force recommendation statement.
      Furthermore, they concluded that there was insufficient evidence to assess the balance of benefits and harms of daily supplementation with greater than 400 IU of vitamin D3 and greater than 1000 mg of calcium for primary prevention of fractures in noninstitutionalized postmenopausal women. They recommended against daily supplementation with 400 IU or less of vitamin D3 and 1000 mg or less of calcium for the primary prevention of fractures in noninstitutionalized postmenopausal women. They also stated that it was unclear whether higher doses of vitamin D and calcium are effective in preventing fractures in postmenopausal women, younger women, or men.
      • Moyer V.A.
      • U.S. Preventive Services Task Force
      Vitamin D and calcium supplementation to prevent fractures in adults: U.S. Preventive Services Task Force recommendation statement.
      The Task Force, however, concluded that vitamin D supplementation is effective in preventing falls in community-dwelling adults 65 years or older, which, in turn, reduces the risk of fracture. This could help explain the observation by the Women's Health Initiative (WHI) that, in the subgroup of long-adherent women who took their calcium and vitamin D, there was a reduced risk of hip but not total fractures.
      • Bolland M.J.
      • Grey A.
      • Gamble G.D.
      • Reid I.R.
      Calcium and vitamin D supplements and health outcomes: a reanalysis of the Women's Health Initiative (WHI) limited access data set.
      Therefore, what is still unknown is whether adequate intake of calcium, especially from dietary sources, and maintenance of serum 25(OH)D levels of at least 20 ng/mL as recommended by the IOM
      • Ross A.C.
      • Manson J.E.
      • Abrams S.A.
      • et al.
      The 2011 report on dietary reference intakes for calcium and vitamin D from the Institute of Medicine: what clinicians need to know.
      or at least 30 ng/mL as recommended by the Endocrine Society
      • Holick M.F.
      • Binkley N.C.
      • Bischoff-Ferrari H.A.
      • et al.
      Evaluation, treatment, and prevention of vitamin D deficiency: an Endocrine Society clinical practice guideline.
      throughout life will reduce the risk of fracture. Most evidence suggests that adequate calcium and vitamin D intake along with exercise during childhood will maximize bone mineral content that can be sustained in young and middle-aged adults as long as they also have a healthy lifestyle, adequate calcium intake, and a healthy vitamin D status.
      • Holick M.F.
      • Binkley N.C.
      • Bischoff-Ferrari H.A.
      • et al.
      Evaluation, treatment, and prevention of vitamin D deficiency: an Endocrine Society clinical practice guideline.
      • Bischoff-Ferrari H.A.
      • Giovannucci E.
      • Willett W.C.
      • Dietrich T.
      • Dawson-Hughes B.
      Estimation of optimal serum concentrations of 25-hydroxyvitamin D for multiple health outcomes.
      • Ross A.C.
      • Manson J.E.
      • Abrams S.A.
      • et al.
      The 2011 report on dietary reference intakes for calcium and vitamin D from the Institute of Medicine: what clinicians need to know.
      • Bolland M.J.
      • Grey A.
      • Gamble G.D.
      • Reid I.R.
      Calcium and vitamin D supplements and health outcomes: a reanalysis of the Women's Health Initiative (WHI) limited access data set.
      • Winzenberg T.
      • Powell S.
      • Shaw K.A.
      • Jones G.
      Effects of vitamin D supplementation on bone density in healthy children: systematic review and meta-analysis.
      • Huncharek M.
      • Muscat J.
      • Kupelnick B.
      Impact of dairy products and dietary calcium on bone-mineral content in children: results of a meta-analysis.
      Accruing maximum bone mineral content during childhood, and maintaining peak bone mineral density in young and middle-aged adults, will likely reduce the risk of fracture later in life, when there is a disruption in bone remodeling due to menopause and aging.
      Recent recommendations of the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO)
      • Rizzoli R.
      • Boonen S.
      • Brandi M.L.
      • et al.
      Vitamin D supplementation in elderly or postmenopausal women: a 2013 update of the 2008 recommendations from the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO).
      for the optimal management of elderly and postmenopausal women regarding vitamin D supplementation have also indicated that patients with serum 25(OH)D levels less than 20 ng/mL have increased bone turnover, bone loss, and, possibly, mineralization defects compared with patients with serum 25(OH)D levels of 20 ng/mL or greater. Similar relationships have been reported for frailty, nonvertebral and hip fracture, and all-cause mortality, with poorer outcomes at less than 20 ng/mL.
      • Rizzoli R.
      • Boonen S.
      • Brandi M.L.
      • et al.
      Vitamin D supplementation in elderly or postmenopausal women: a 2013 update of the 2008 recommendations from the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO).
      Thus, ESCEO recommended that 20 ng/mL be the minimal serum 25(OH)D concentration at the population level and in patients with osteoporosis to ensure optimal bone health. Also, in fragile elderly individuals who are at elevated risk for falls and fractures, ESCEO recommended a minimal serum 25(OH)D level of 30 ng/mL for the greatest effect on fracture.
      • Rizzoli R.
      • Boonen S.
      • Brandi M.L.
      • et al.
      Vitamin D supplementation in elderly or postmenopausal women: a 2013 update of the 2008 recommendations from the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO).
      This coincides with the recommendation from the Endocrine Society
      • Holick M.F.
      • Binkley N.C.
      • Bischoff-Ferrari H.A.
      • et al.
      Evaluation, treatment, and prevention of vitamin D deficiency: an Endocrine Society clinical practice guideline.
      and with the observation of Priemel et al,
      • Priemel M.
      • von Domarus C.
      • Klatte T.O.
      • et al.
      Bone mineralization defects and vitamin D deficiency: histomorphometric analysis of iliac crest bone biopsies and circulating 25-hydroxyvitamin D in 675 patients.
      who reported that of 675 presumed healthy adults (aged 20-90+ years) who died in an accident, 36% had evidence of osteomalacia. However, Priemel et al
      • Priemel M.
      • von Domarus C.
      • Klatte T.O.
      • et al.
      Bone mineralization defects and vitamin D deficiency: histomorphometric analysis of iliac crest bone biopsies and circulating 25-hydroxyvitamin D in 675 patients.
      observed no osteomalacia in those who had a 25(OH)D level greater than 30 ng/mL.

      Evidence-Based Skeletal and Nonskeletal Health Benefits of Vitamin D

      Observational studies have found a decreased risk of many disorders, including certain types of cancer, mental disorders, infectious disease, cardiovascular disease, type 2 diabetes mellitus, and autoimmune disorders, associated with serum 25(OH)D levels greater than 28 to 32 ng/mL.
      • Holick M.F.
      Vitamin D deficiency.
      • Holick M.F.
      • Binkley N.C.
      • Bischoff-Ferrari H.A.
      • et al.
      Evaluation, treatment, and prevention of vitamin D deficiency: an Endocrine Society clinical practice guideline.
      • Nowson C.A.
      • McGrath J.J.
      • Ebeling P.R.
      • et al.
      Vitamin D and health in adults in Australia and New Zealand: a position statement.
      It has, therefore, been argued that 25(OH)D levels should be in the range of 28 to 40 ng/mL to maximize these nonskeletal benefits.
      • Holick M.F.
      Vitamin D: extraskeletal health.
      • Hossein-nezhad A.
      • Holick M.F.
      Optimize dietary intake of vitamin D: an epigenetic perspective.
      • Holick M.F.
      Vitamin D deficiency.
      • Cui X.
      • Pelekanos M.
      • Liu P.Y.
      • Burne T.H.
      • McGrath J.J.
      • Eyles D.W.
      The vitamin D receptor in dopamine neurons; its presence in human substantia nigra and its ontogenesis in rat midbrain.
      • Holick M.F.
      • Binkley N.C.
      • Bischoff-Ferrari H.A.
      • et al.
      Evaluation, treatment, and prevention of vitamin D deficiency: an Endocrine Society clinical practice guideline.
      • Bischoff-Ferrari H.A.
      • Giovannucci E.
      • Willett W.C.
      • Dietrich T.
      • Dawson-Hughes B.
      Estimation of optimal serum concentrations of 25-hydroxyvitamin D for multiple health outcomes.
      The results of some clinical trials provide evidence confirming the results of observational and association studies, whereas others do not. The Table summarizes the meta-analyses on vitamin D supplementation, comparing the beneficial and nonbeneficial effects of vitamin D supplementation in randomized trials for musculoskeletal and nonskeletal outcomes. The Table provides the foundation for clinical decision making for recommending vitamin D supplementation and identifies gaps in our knowledge that require additional RCTs to provide insights as to whether vitamin D supplementation has nonskeletal health benefits.
      TableSummary of Meta-analyses of Vitamin D Supplementation
      Reference, yearIncluded studiesSample size (No.)ParticipantsDose/durationOutcomesEffects
      Thorne-Lyman and Fawzi,
      • Thorne-Lyman A.
      • Fawzi W.W.
      Vitamin D during pregnancy and maternal, neonatal and infant health outcomes: a systematic review and meta-analysis.
      2012
      5 randomized trials

      2 observational studies
      28,943Pregnant womenVitamin D2 and vitamin D3

      Various doses and patterns of intake during pregnancy
      Perinatal and infant healthPositive effect on low birth weight

      No effect on small-for-gestational-age (2 trials)

      No effect on preterm delivery
      De-Regil et al,
      • De-Regil L.M.
      • Palacios C.
      • Ansary A.
      • Kulier R.
      • Pena-Rosas J.P.
      Vitamin D supplementation for women during pregnancy.
      2012
      6 trials1023Women during pregnancyVitamin D (1200 IU/d) alone or combined with 375 mg of elemental calciumSafely improve maternal and neonatal outcomesNo effect on preeclampsia

      Positive effect on concentrations of 25(OH)D in serum

      Positive effect on birth weight

      No effect on adverse effects
      Bischoff-Ferrari et al,
      • Bischoff-Ferrari H.A.
      • Willett W.C.
      • Orav E.J.
      • et al.
      A pooled analysis of vitamin D dose requirements for fracture prevention.
      2012
      11 double-blind RCTs31,022Persons aged ≥65 yOral vitamin D supplementation with or without calciumFracture reductionNo effect on risk of hip fracture until 800 IU/d

      Positive effect on hip and any nonvertebral fracture by highest intake level according to quartiles
      Lai et al,
      • Lai J.K.
      • Lucas R.M.
      • Clements M.S.
      • Roddam A.W.
      • Banks E.
      Hip fracture risk in relation to vitamin D supplementation and serum 25-hydroxyvitamin D levels: a systematic review and meta-analysis of randomised controlled trials and observational studies.
      2010
      7 eligible RCTs and 17 identified case-control studies801Persons aged 74.8-85 yVitamin D2 and vitamin D3 (400-1100 IU)Hip fracture riskNo effect on hip fracture risk
      Bergman et al,
      • Bergman G.J.
      • Fan T.
      • McFetridge J.T.
      • Sen S.S.
      Efficacy of vitamin D3 supplementation in preventing fractures in elderly women: a meta-analysis.
      2010
      8 controlled trials12,658Postmenopausal womenVitamin D3 supplementation (800 IU/d) with or without calciumIncreasing BMD

      Preventing fractures
      Positive effect on nonvertebral and hip fractures
      Bischoff-Ferrari et al,
      • Bischoff-Ferrari H.A.
      • Willett W.C.
      • Wong J.B.
      • et al.
      Prevention of nonvertebral fractures with oral vitamin D and dose dependency: a meta-analysis of randomized controlled trials.
      2009
      12 double-blind RCTs83,165Older individuals (≥65 y)>400 IU/dPreventing nonvertebral and hip fracturesPositive effect on nonvertebral fracture prevention with vitamin D is dose dependent (only high dose)
      Avenell et al,
      • Avenell A.
      • Gillespie W.J.
      • Gillespie L.D.
      • O'Connell D.
      Vitamin D and vitamin D analogues for preventing fractures associated with involutional and post-menopausal osteoporosis.
      2009
      45 trials83,741Older peopleVitamin D or related compoundsPreventing fracturesPositive effect by vitamin D with calcium on hip fracture

      No effect by vitamin D alone on hip fracture
      Abrahamsen et al,
      • Abrahamsen B.
      • Masud T.
      • Avenell A.
      • et al.
      Patient level pooled analysis of 68 500 patients from seven major vitamin D fracture trials in US and Europe.
      2010
      7 major randomized trials68,517Persons aged 47-107 yVitamin D2 and vitamin D3 (10 μg/d to 300,000 IU/12 mo)Antifracture efficacyPositive effect of vitamin D with calcium on fracture

      No effect of vitamin D alone
      Izaks,
      • Izaks G.J.
      Fracture prevention with vitamin D supplementation: considering the inconsistent results.
      2007
      11 trialsNAGeneral populationVitamin D2 and vitamin D3 follow-up >1 yFracture riskHigh-dose vitamin D may be effective in institutionalized persons but probably is not effective in the general population
      Jackson et al,
      • Jackson C.
      • Gaugris S.
      • Sen S.S.
      • Hosking D.
      The effect of cholecalciferol (vitamin D3) on the risk of fall and fracture: a meta-analysis.
      2007
      9 studies2410Postmenopausal womenVitamin D3 (excluding the potential effect of calcium supplementation)Risk of fall and fracturePositive effect on risk of fall in patients treated with vitamin D3
      Boonen et al,
      • Boonen S.
      • Lips P.
      • Bouillon R.
      • Bischoff-Ferrari H.A.
      • Vanderschueren D.
      • Haentjens P.
      Need for additional calcium to reduce the risk of hip fracture with vitamin D supplementation: evidence from a comparative metaanalysis of randomized controlled trials.
      2007
      10 RCTs54,592Postmenopausal women and/or older men (≥50 y)Oral vitamin D with or without calcium vs placebo/no treatmentPrevention of hip fracturesPositive effect of oral vitamin D on reducing the risk of hip fractures only with calcium supplementation
      Avenell et al,
      • Avenell A.
      • Gillespie W.J.
      • Gillespie L.D.
      • O'Connell D.L.
      Vitamin D and vitamin D analogues for preventing fractures associated with involutional and post-menopausal osteoporosis.
      2005
      57 trials82,986Older peopleVitamin D or an analogue, alone or with calcium, vs placeboFracturePositive effect of vitamin D with calcium supplements on hip and other nonvertebral fractures
      Bischoff-Ferrari et al,
      • Bolland M.J.
      • Grey A.
      • Gamble G.D.
      • Reid I.R.
      Calcium and vitamin D supplements and health outcomes: a reanalysis of the Women's Health Initiative (WHI) limited access data set.
      2005
      5 RCTs for hip fracture

      7 RCTs for nonvertebral fracture risk
      19,114Older peopleOral vitamin D supplementation (cholecalciferol, ergocalciferol) with or without calcium supplementation vs calcium supplementationPreventing hip and nonvertebral fracturesPositive effect (700-800 IU/d) on hip and any nonvertebral fractures in ambulatory or institutionalized elderly persons

      No effect (400 IU/d) on fracture prevention
      Winzenberg et al,
      • Winzenberg T.
      • Powell S.
      • Shaw K.A.
      • Jones G.
      Effects of vitamin D supplementation on bone density in healthy children: systematic review and meta-analysis.
      2011
      6 studies884Healthy children and adolescents (aged 1 mo to <20 y)Vitamin D supplementation vs placebo for ≥3 moImproving BMD (effects vary with factors such as vitamin D dose and vitamin D status)No effect on total body BMC or on hip or forearm BMD

      Positive small effect on lumbar spine BMD

      Positive effect with low serum vitamin D on total body BMC and lumbar spine bone
      Huncharek et al,
      • Huncharek M.
      • Muscat J.
      • Kupelnick B.
      Impact of dairy products and dietary calcium on bone-mineral content in children: results of a meta-analysis.
      2008
      21 RCTsNAChildrenDietary calcium/dairy supplementationBMCPositive effect of dietary calcium/dairy products, with and without vitamin D, on total body and lumbar spine BMC in children (with low baseline intakes)
      Bischoff-Ferrari et al,
      • Bischoff-Ferrari H.A.
      • Dawson-Hughes B.
      • Staehelin H.B.
      • et al.
      Fall prevention with supplemental and active forms of vitamin D: a meta-analysis of randomised controlled trials.
      2009
      8 RCTs2426Older individualsVitamin D2 and vitamin D3 (200-1000 IU) with or without calciumPreventing fallsPositive effect of supplemental vitamin D (700-1000 IU/d) on the risk of falling

      No effect at a dose <700 IU
      Kalyani et al,
      • Kalyani R.R.
      • Stein B.
      • Valiyil R.
      • Manno R.
      • Maynard J.W.
      • Crews D.C.
      Vitamin D treatment for the prevention of falls in older adults: systematic review and meta-analysis.
      2010
      10 articles2932Older adults (aged ≥60 y)200-1000 IU/d of vitamin D for 1-36 moFall preventionPositive effect on fall prevention
      Chung et al,
      • Chung M.
      • Lee J.
      • Terasawa T.
      • Lau J.
      • Trikalinos T.A.
      Vitamin D with or without calcium supplementation for prevention of cancer and fractures: an updated meta-analysis for the U.S. Preventive Services Task Force.
      2011
      19 RCTs (3 for cancer and 16 for fracture outcomes)

      28 observational studies (for cancer outcomes)
      NAAdultsVitamin D with or without calcium (limited data from RCTs assessed high-dose vitamin D [1000 IU/d])Benefits and harms of vitamin D with or without calcium supplementation on clinical outcomes of cancer and fracturesPositive effect of high-dose vitamin D on reduced risk of total cancer

      Positive effect on fracture

      Negative effect on renal and urinary tract stones
      Buttigliero et al,
      • Buttigliero C.
      • Monagheddu C.
      • Petroni P.
      • et al.
      Prognostic role of vitamin D status and efficacy of vitamin D supplementation in cancer patients: a systematic review.
      2011
      25 studies (3 randomized trials involving patients with advanced prostate cancer explored the prognostic role of vitamin D supplementation)1273Cancer patients1 trial: doxercalciferol

      2 trials: calcitriol

      Duration: 11.7-18.32 mo
      Influence of hypovitaminosis D on prognosis of cancer

      Improvement outcome of vitamin D supplementation
      No effect on survival
      Bjelakovic et al,
      • Bjelakovic G.
      • Gluud L.L.
      • Nikolova D.
      • et al.
      Vitamin D supplementation for prevention of mortality in adults.
      2011
      50 randomized trials94,148Adults; Most trials included elderly women (>70 y)Supplemental vitamin D (vitamin D3 [cholecalciferol] or vitamin D2 [ergocalciferol]) or an active form of vitamin D (1α-hydroxyvitamin D [alfacalcidol] or 1,25-dihydroxyvitamin D [calcitriol]) at any dose, duration, and route of administration vs placebo or no interventionBeneficial and harmful effects of vitamin D for prevention of mortalityPositive effect of vitamin D3 on mortality

      Negative effect of vitamin D3 combined with calcium on nephrolithiasis

      Negative effect on hypercalcemia
      Irlam et al,
      • Irlam J.H.
      • Visser M.M.
      • Rollins N.N.
      • Siegfried N.
      Micronutrient supplementation in children and adults with HIV infection.
      2010
      16 additional trials (only 1 trial was single supplements of vitamin D)22,120 participants in the trialsAdults and children with HIV infectionNAReducing mortality and morbidityNo effect
      Autier et al,
      • Autier P.
      • Gandini S.
      • Mullie P.
      A systematic review: influence of vitamin D supplementation on serum 25-hydroxyvitamin D concentration.
      2012
      76 trials6207White persons aged >50 yDoses of 5-250 μg/d (median, 20 μg/d)Circulating 25(OH)D levelPositive effect of vitamin D3 intake without calcium on serum 25(OH)D concentrations

      No effect of concomitant use of calcium supplementation and high 25(OH)D concentration at baseline
      Bjorkman et al,
      • Bjorkman M.
      • Sorva A.
      • Tilvis R.
      Responses of parathyroid hormone to vitamin D supplementation: a systematic review of clinical trials.
      2009
      52 clinical trials6290Chronically immobile patientsVitamin D supplementationResponses of parathyroid hormonePositive effect in chronically immobile patients on 25(OH)D levels but a slight effect on PTH decrease
      Tripkovic et al,
      • Tripkovic L.
      • Lambert H.
      • Hart K.
      • et al.
      Comparison of vitamin D2 and vitamin D3 supplementation in raising serum 25-hydroxyvitamin D status: a systematic review and meta-analysis.
      2012
      17 studies1016Persons aged 18-97 yVarying dosages and treatment periodsCompared the effects of vitamin D2 and vitamin D3 on serum 25(OH)D concentrationsPositive effect of vitamin D3 compared with vitamin D2 in the raising of serum 25(OH)D concentrations
      Kandula et al,
      • Kandula P.
      • Dobre M.
      • Schold J.D.
      • Schreiber Jr., M.J.
      • Mehrotra R.
      • Navaneethan S.D.
      Vitamin D supplementation in chronic kidney disease: a systematic review and meta-analysis of observational studies and randomized controlled trials.
      2011
      22 studies264Patients with non–dialysis-dependent CKD, dialysis-dependent CKD, and renal transplantErgocalciferol or cholecalciferolBenefits and harms of vitamin D supplementationPositive effect on 25(OH)D and PTH levels
      Song et al,
      • Song Y.
      • Wang L.
      • Pittas A.G.
      • et al.
      Blood 25-hydroxy vitamin D levels and incident type 2 diabetes: a meta-analysis of prospective studies.
      2013
      21 prospective studies81,216Healthy individuals and patients with type 2 diabetesCirculating 25(OH)DAssociation between blood levels of 25(OH)D and risk of incident type 2 diabetesInverse and significant association between circulating 25(OH)D levels and risk of type 2 diabetes
      George et al,
      • George P.S.
      • Pearson E.R.
      • Witham M.D.
      Effect of vitamin D supplementation on glycaemic control and insulin resistance: a systematic review and meta-analysis.
      2012
      15 trialsNANondiabetes to diabetesVitamin D or analoguesGlycemia, insulin resistance, progression to diabetes, and complications of diabetesNo effect on fasting glucose, hemoglobin A1c, or insulin resistance

      Small positive effect on fasting glucose and insulin resistance in patients with diabetes or impaired glucose tolerance

      No effect on glycated hemoglobin in diabetic patients
      Bath-Hextall et al,
      • Bath-Hextall F.J.
      • Jenkinson C.
      • Humphreys R.
      • Williams H.C.
      Dietary supplements for established atopic eczema.
      2012
      11 studies596Atopic eczema/dermatitisVitamin D vs vitamin ETreating established atopic eczema/dermatitisNegative effect at high doses
      Muir et al,
      • Muir S.W.
      • Montero-Odasso M.
      Effect of vitamin D supplementation on muscle strength, gait and balance in older adults: a systematic review and meta-analysis.
      2011
      13 trialsNAOlder adults (≥60 y)Vitamin D (800-1000 IU/d)Muscle strength, gait, and balancePositive effect on balance and muscle strength
      Annweiler et al,
      • Annweiler C.
      • Schott A.M.
      • Berrut G.
      • Fantino B.
      • Beauchet O.
      Vitamin D-related changes in physical performance: a systematic review.
      2009
      16 trials24-33,067Persons aged ≥80 yNAMuscle, balance, and gait performanceNo significant effect on balance and gait

      Positive/no effect on muscle strength

      No effect on sit-to-stand test
      Wang et al,
      • Wang L.
      • Manson J.E.
      • Song Y.
      • Sesso H.D.
      Systematic review: vitamin D and calcium supplementation in prevention of cardiovascular events.
      2010
      18 trialsNAAdultsNAReduce the risk of cardiovascular eventsNo effect on cardiovascular disease risk
      Pittas et al,
      • Pittas A.G.
      • Chung M.
      • Trikalinos T.
      • et al.
      Systematic review: vitamin D and cardiometabolic outcomes.
      2010
      18 trials37,162Generally healthy adultsVitamin D (400-8571 IU/d) with or without calciumCardiometabolic outcomesNo effect on glycemia or incident diabetes, blood pressure, and cardiovascular outcomes
      Ferguson and Chang,
      • Ferguson J.H.
      • Chang A.B.
      Vitamin D supplementation for cystic fibrosis.
      2009
      3 double-blind randomized crossover trials41Adults and children with cystic fibrosis800 and 1600 IU of vitamin D alone with or without 1 g of calciumRespiratory outcomesNo adequate evidence of benefit or harm
      Abba et al,
      • Abba K.
      • Sudarsanam T.D.
      • Grobler L.
      • Volmink J.
      Nutritional supplements for people being treated for active tuberculosis.
      2008
      12 trials3393Patients with tuberculosisSeveral vitamins and minerals and dietsPromote the recovery of tuberculosisNo effect on number of deaths or number of participants with positive sputum test results
      Autier and Gandini,
      • Autier P.
      • Gandini S.
      Vitamin D supplementation and total mortality: a meta-analysis of randomized controlled trials.
      2007
      18 independent RCTs57,311At risk for dying of any causeVitamin D supplements varied from 300 to 2000 IU/dAny health conditionNot enough evidence for effective decision
      BMC = bone mineral content; BMD = bone mineral density; CKD = chronic kidney disease; HIV = human immunodeficiency virus; NA = not available; PTH = parathyroid hormone; RCT = randomized controlled trial; 25(OH)D =25-hydroxyvitamin D.

      Vitamin D and Nonskeletal Health Associations and Mechanisms

      Cancers

      Association studies have related higher serum levels of 25(OH)D to reduced incidence of many types of cancers. It has been hypothesized that the local conversion of 25(OH)D to 1,25(OH)2D in healthy cells in the colon, breast, and prostate can help prevent malignancy by inducing cellular maturation, inducing apoptosis, and inhibiting angiogenesis while enhancing the expression of genes including P21 and P27 to control cellular proliferation (Figure 1).
      • Holick M.F.
      Vitamin D: extraskeletal health.
      • Hossein-nezhad A.
      • Holick M.F.
      Optimize dietary intake of vitamin D: an epigenetic perspective.
      • Holick M.F.
      Vitamin D deficiency.
      • Nagpal S.
      • Na S.
      • Rathnachalam R.
      Noncalcemic actions of vitamin D receptor ligands.
      • Adams J.S.
      • Hewison M.
      Update in vitamin D.
      Another vitamin D–regulated gene is CYP3A4, whose protein product detoxifies the bile acid lithocholic acid.
      • Harris D.M.
      • Go V.L.
      Vitamin D and colon carcinogenesis.
      Lithocholic acid is believed to damage the DNA of intestinal cells, and it may promote colon carcinogenesis. Stimulating the production of a detoxifying enzyme by 1,25(OH)2D could explain a protective role for improving vitamin D status against colon cancer.
      • Harris D.M.
      • Go V.L.
      Vitamin D and colon carcinogenesis.
      Because vitamin D regulates a gamut of physiologic processes, including immune modulation, resistance to oxidative stress, and modulation of other hormones, it is not surprising that low vitamin D status has been associated with increased risk of several cancers and cancer mortality.
      • Holick M.F.
      Vitamin D deficiency.
      • Bischoff-Ferrari H.A.
      • Giovannucci E.
      • Willett W.C.
      • Dietrich T.
      • Dawson-Hughes B.
      Estimation of optimal serum concentrations of 25-hydroxyvitamin D for multiple health outcomes.
      • Shui I.M.
      • Mucci L.A.
      • Kraft P.
      • et al.
      Vitamin D-related genetic variation, plasma vitamin D, and risk of lethal prostate cancer: a prospective nested case-control study.
      • Giangreco A.A.
      • Nonn L.
      The sum of many small changes: microRNAs are specifically and potentially globally altered by vitamin D(3) metabolites.
      • Holick M.F.
      Vitamin D and sunlight: strategies for cancer prevention and other health benefits.
      • Freedman D.M.
      • Looker A.C.
      • Abnet C.C.
      • Linet M.S.
      • Graubard B.I.
      Serum 25-hydroxyvitamin D and cancer mortality in the NHANES III study (1988-2006).
      • Garland C.F.
      • Gorham E.D.
      • Mohr S.B.
      • et al.
      Vitamin D and prevention of breast cancer: pooled analysis.
      • Grant W.B.
      An estimate of premature cancer mortality in the U.S. due to inadequate doses of solar ultraviolet-B radiation.
      • Lee J.E.
      • Li H.
      • Chan A.T.
      • et al.
      Circulating levels of vitamin D and colon and rectal cancer: the Physicians' Health Study and a meta-analysis of prospective studies.
      • Holick M.F.
      Calcium plus vitamin D and the risk of colorectal cancer.
      • Bischoff-Ferrari H.A.
      • Willett W.C.
      • Wong J.B.
      • Giovannucci E.
      • Dietrich T.
      • Dawson-Hughes B.
      Fracture prevention with vitamin D supplementation: a meta-analysis of randomized controlled trials.
      • Holick M.F.
      Evidence-based D-bate on health benefits of vitamin D revisited.
      • Grant W.B.
      Geographic variation of prostate cancer mortality rates in the United States: implications for prostate cancer risk related to vitamin D.
      • Durup D.
      • Jorgensen H.L.
      • Christensen J.
      • Schwarz P.
      • Heegaard A.M.
      • Lind B.
      A reverse J-shaped association of all-cause mortality with serum 25-hydroxyvitamin D in general practice: the CopD study.
      As the importance of noncoding RNAs has emerged, the ability of 1,25(OH)2D to regulate microRNAs (miRNAs) has been found in several cancer cell lines, patient tissues, and sera. In vitamin D3 intervention trials, significant differences in miRNAs were observed between treatment groups or between baseline and follow-up.
      • Giangreco A.A.
      • Nonn L.
      The sum of many small changes: microRNAs are specifically and potentially globally altered by vitamin D(3) metabolites.
      In patient sera from population studies, specific miRNA differences were associated with serum levels of 25(OH)D. The findings thus far indicate that increasing vitamin D3 intake in patients and 1,25(OH)2D3 in vitro not only regulates specific miRNA(s) but also up-regulates global miRNA levels.
      • Giangreco A.A.
      • Nonn L.
      The sum of many small changes: microRNAs are specifically and potentially globally altered by vitamin D(3) metabolites.
      Epidemiologic studies have suggested that adequate levels of 25(OH)D are critical for the prevention of various solid tumors, including prostate, breast, ovarian, and colon cancers.
      • Chung M.
      • Lee J.
      • Terasawa T.
      • Lau J.
      • Trikalinos T.A.
      Vitamin D with or without calcium supplementation for prevention of cancer and fractures: an updated meta-analysis for the U.S. Preventive Services Task Force.
      • Harris D.M.
      • Go V.L.
      Vitamin D and colon carcinogenesis.
      • Shui I.M.
      • Mucci L.A.
      • Kraft P.
      • et al.
      Vitamin D-related genetic variation, plasma vitamin D, and risk of lethal prostate cancer: a prospective nested case-control study.
      • Holick M.F.
      Vitamin D and sunlight: strategies for cancer prevention and other health benefits.
      • Freedman D.M.
      • Looker A.C.
      • Abnet C.C.
      • Linet M.S.
      • Graubard B.I.
      Serum 25-hydroxyvitamin D and cancer mortality in the NHANES III study (1988-2006).
      • Garland C.F.
      • Gorham E.D.
      • Mohr S.B.
      • et al.
      Vitamin D and prevention of breast cancer: pooled analysis.
      • Grant W.B.
      An estimate of premature cancer mortality in the U.S. due to inadequate doses of solar ultraviolet-B radiation.
      A meta-analysis for the US Preventive Services Task Force regarding vitamin D supplementation concluded that each 4-ng/mL increase in blood 25(OH)D levels was associated with a 6% reduced risk of colorectal cancer but not with statistically significant dose-response relationships for prostate and breast cancer.
      • Chung M.
      • Lee J.
      • Terasawa T.
      • Lau J.
      • Trikalinos T.A.
      Vitamin D with or without calcium supplementation for prevention of cancer and fractures: an updated meta-analysis for the U.S. Preventive Services Task Force.
      In a large prospective study of lethal prostate cancer (1260 cases vs 1331 controls), men with the highest quartile of plasma 25(OH)D levels had less than half the risk of lethal prostate cancer compared with men with the lowest quartile of plasma 25(OH)D levels.
      • Shui I.M.
      • Mucci L.A.
      • Kraft P.
      • et al.
      Vitamin D-related genetic variation, plasma vitamin D, and risk of lethal prostate cancer: a prospective nested case-control study.
      A meta-analysis including 1822 colon and 868 rectal cancers reported an inverse association between circulating 25(OH)D levels and colorectal cancer, with a stronger association for rectal cancer.
      • Chung M.
      • Lee J.
      • Terasawa T.
      • Lau J.
      • Trikalinos T.A.
      Vitamin D with or without calcium supplementation for prevention of cancer and fractures: an updated meta-analysis for the U.S. Preventive Services Task Force.
      • Lee J.E.
      • Li H.
      • Chan A.T.
      • et al.
      Circulating levels of vitamin D and colon and rectal cancer: the Physicians' Health Study and a meta-analysis of prospective studies.
      Participants in the WHI who had a baseline 25(OH)D level less than 12 ng/mL and who took 400 IU of vitamin D3 and 1000 mg of calcium daily had a 253% increased risk of colorectal cancer compared with women who took the same amount of vitamin D3 and calcium for 7 years and had baseline serum 25(OH)D levels greater than 24 ng/mL.
      • Bolland M.J.
      • Grey A.
      • Gamble G.D.
      • Reid I.R.
      Calcium and vitamin D supplements and health outcomes: a reanalysis of the Women's Health Initiative (WHI) limited access data set.
      • Holick M.F.
      Calcium plus vitamin D and the risk of colorectal cancer.
      Although cross-sectional data have many limitations, the findings are hypothesis generating and can be used to develop protocols for RCTs.
      • Bolland M.J.
      • Grey A.
      • Gamble G.D.
      • Reid I.R.
      Calcium and vitamin D supplements and health outcomes: a reanalysis of the Women's Health Initiative (WHI) limited access data set.
      • Bischoff-Ferrari H.A.
      • Willett W.C.
      • Wong J.B.
      • Giovannucci E.
      • Dietrich T.
      • Dawson-Hughes B.
      Fracture prevention with vitamin D supplementation: a meta-analysis of randomized controlled trials.
      • Holick M.F.
      Evidence-based D-bate on health benefits of vitamin D revisited.
      The findings from prospective case-control cohort studies in which blood collection occurred many years before diagnosis add another dimension to the evidence.
      • Freedman D.M.
      • Looker A.C.
      • Abnet C.C.
      • Linet M.S.
      • Graubard B.I.
      Serum 25-hydroxyvitamin D and cancer mortality in the NHANES III study (1988-2006).
      The results of these studies generally support vitamin D supplementation in those with “low” vitamin D status. However, some have argued for caution before increasing 25(OH)D levels and associated dosing regimens beyond quantities clearly supported by RCTs and meta-analyses.
      • Holick M.F.
      Vitamin D deficiency.
      • Chung M.
      • Lee J.
      • Terasawa T.
      • Lau J.
      • Trikalinos T.A.
      Vitamin D with or without calcium supplementation for prevention of cancer and fractures: an updated meta-analysis for the U.S. Preventive Services Task Force.
      • Tripkovic L.
      • Lambert H.
      • Hart K.
      • et al.
      Comparison of vitamin D2 and vitamin D3 supplementation in raising serum 25-hydroxyvitamin D status: a systematic review and meta-analysis.
      There are now several observational studies reporting a U- or J-shaped association between some cancers and serum 25(OH)D and latitude or UV-B radiation levels, in which those in the highest percentiles have an inverse risk compared with those in the lowest.
      • Freedman D.M.
      • Looker A.C.
      • Abnet C.C.
      • Linet M.S.
      • Graubard B.I.
      Serum 25-hydroxyvitamin D and cancer mortality in the NHANES III study (1988-2006).
      • Grant W.B.
      Geographic variation of prostate cancer mortality rates in the United States: implications for prostate cancer risk related to vitamin D.
      • Durup D.
      • Jorgensen H.L.
      • Christensen J.
      • Schwarz P.
      • Heegaard A.M.
      • Lind B.
      A reverse J-shaped association of all-cause mortality with serum 25-hydroxyvitamin D in general practice: the CopD study.
      • Vieth R.
      Enzyme kinetics hypothesis to explain the U-shaped risk curve for prostate cancer vs. 25-hydroxyvitamin D in Nordic countries.
      Many RCTs that were evaluated for nonskeletal benefits of vitamin D had problems with a high incidence of nonadherence, misinterpretation of the original data, and use of doses of vitamin D below the 2010 IOM recommendations.
      • Ross A.C.
      • Manson J.E.
      • Abrams S.A.
      • et al.
      The 2011 report on dietary reference intakes for calcium and vitamin D from the Institute of Medicine: what clinicians need to know.
      • Bischoff-Ferrari H.A.
      • Willett W.C.
      • Wong J.B.
      • Giovannucci E.
      • Dietrich T.
      • Dawson-Hughes B.
      Fracture prevention with vitamin D supplementation: a meta-analysis of randomized controlled trials.