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Department of Medicine, Section of Endocrinology, Nutrition, and Diabetes, Vitamin D, Skin, and Bone Research Laboratory, Boston University Medical Center, Boston, MA
Department of Medicine, Section of Endocrinology, Nutrition, and Diabetes, Vitamin D, Skin, and Bone Research Laboratory, Boston University Medical Center, Boston, MA
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.
Vitamin D deficiency is a common underdiagnosed condition.
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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.
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The blood level of 25(OH)D is the best method to determine vitamin D status.
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Vitamin D deficiency during pregnancy may influence fetal “imprinting” that may affect chronic disease susceptibility soon after birth as well as later in life.
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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.
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.
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.
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.
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.
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.
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.
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).
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.
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.
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.
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.
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.
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 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).
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.
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).
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.
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.
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.
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.
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.
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).
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%.
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).
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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).
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.
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.
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, seeFigure 1.
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.
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.
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.
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.
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.
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.
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.
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 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.
Several roles of PTHrP are postulated from animal studies, including fetal chondrocyte maturation, fetal calcium transfer, and stimulation of CYP27B1 activity.
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).
Furthermore, the carboxy terminal of PTHrP (osteostatin) may suppress osteoclastic activity and may have a possible bone protection role in the mother during pregnancy.
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.
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.
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.
Placenta-specific methylation of the vitamin D 24-hydroxylase gene: implications for feedback autoregulation of active vitamin D levels at the fetomaternal interface.
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.
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.
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.
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.
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.
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.
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.
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.
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).
Transgenerational hormonal imprinting caused by vitamin A and vitamin D treatment of newborn rats: alterations in the biogenic amine contents of the adult brain.
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.
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.
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.
The recommended dietary allowances (RDAs) of the IOM and the Endocrine Society guidelines for vitamin D intake are summarized in Figure 4.
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).
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.
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.
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.
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.
The skeletal consequences of 25(OH)D insufficiency include secondary hyperparathyroidism, increased bone turnover and bone loss, and increased risk of low-trauma fractures.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Bone mineralization defects and vitamin D deficiency: histomorphometric analysis of iliac crest bone biopsies and circulating 25-hydroxyvitamin D in 675 patients.
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.
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.
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.
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.
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
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.
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)
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.
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.
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).
Bone mineralization defects and vitamin D deficiency: histomorphometric analysis of iliac crest bone biopsies and circulating 25-hydroxyvitamin D in 675 patients.
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.
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
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.
Need for additional calcium to reduce the risk of hip fracture with vitamin D supplementation: evidence from a comparative metaanalysis of randomized controlled trials.
5 RCTs for hip fracture 7 RCTs for nonvertebral fracture risk
19,114
Older people
Oral vitamin D supplementation (cholecalciferol, ergocalciferol) with or without calcium supplementation vs calcium supplementation
Preventing hip and nonvertebral fractures
Positive 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
Healthy children and adolescents (aged 1 mo to <20 y)
Vitamin D supplementation vs placebo for ≥3 mo
Improving 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
Positive effect of dietary calcium/dairy products, with and without vitamin D, on total body and lumbar spine BMC in children (with low baseline intakes)
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.
Adults; 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 intervention
Beneficial and harmful effects of vitamin D for prevention of mortality
Positive effect of vitamin D3 on mortality Negative effect of vitamin D3 combined with calcium on nephrolithiasis Negative effect on hypercalcemia
Positive 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
Glycemia, insulin resistance, progression to diabetes, and complications of diabetes
No 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
Vitamin D supplements varied from 300 to 2000 IU/d
Any health condition
Not 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).
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
The findings from prospective case-control cohort studies in which blood collection occurred many years before diagnosis add another dimension to the evidence.
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.
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.
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.
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.