Vitamin D for health: a global perspective

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.

FIGURE 1

Schematic representation of the synthesis and metabolism of vitamin D for skeletal and nonskeletal function. 1-OHase = 25-hydroxyvitamin D-1a–hydroxylase; 24-OHase = 25-hydroxyvitamin D-24-hydroxylase; 25(OH)D = 25-hydroxyvitamin D; 1,25(OH)2D = 1,25-dihydroxyvitamin D; CaBP = calciumbinding protein; DBP = vitamin D-binding protein; ECaC = epithelial calcium channel; FGF-23 = fibroblast growth factors; 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.

FIGURE 2

Vitamin 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(OH)2D 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. 1,25(OH)2D levels fall rapidly after pregnancy and are normal during lactation. Near-exclusive breastfeeding for 6 months leads, on average, to maternal calcium loss 4 times higher than in pregnancy. Phosphorus can rise above the normal range, probably because of accelerated resorption from the skeleton. PTHrP levels are higher than PTH concentrations in nonpregnant women and show some pulsatility in response to suckling. PTHrP (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. Copyright Holick 2013, reproduced with permission.

FIGURE 3

Vitamin D, placenta development, fetal programming, and epigenetic modification. Copyright Holick 2013, reproduced with permission.

FIGURE 4

Vitamin D intakes recommended by the IOM and the Endocrine Practice Guidelines Committee. IOM, Institute of Medicine. Copyright Holick 2013, reproduced with permission.

FIGURE 5

Reported incidence of vitamin D deficiency defined as a 25-hydroxyvitamin D level below 20 ng/ml around the globe in pregnant women and general population. To convert 25(OH)D values to nmol/L, multiply by 2.496. Copyright Holick 2013, reproduced with permission.

FIGURE 6

Risk factors of low vitamin D status. Copyright Holick 2013, reproduced with permission.