Vitamin D and Extraskeletal Health

24/9/2014
Vitamin D and extraskeletal health
Official reprint from UpToDate

www.uptodate.com 2014 UpToDate
Author
Roger Bouillon, MD, PhD,
FRCP
Section Editor
Clifford J Rosen, MD
Deputy Editor
Jean E Mulder, MD
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Aug 2014. | This topic last updated: Jul 25, 2014.
INTRODUCTION Vitamin D deficiency was originally discovered as the cause of rickets due to lack of
exposure to sunshine or vitamin D-rich food. This disease is still endemic in major parts of the world [1].
Subsequently, several meta-analyses showed that supplementation with vitamin D and calcium decreased
the risk of osteoporotic fractures in the elderly. The details of the protocols and overall results of the studies
are reviewed separately.
In addition to its role in calcium and bone homeostasis, vitamin D potentially regulates many other cellular
functions. The vitamin D receptor (VDR) is nearly universally expressed in nucleated cells. About 3 percent
of the human/mouse genome is under the control of 1,25-dihydroxyvitamin D, the active form of vitamin D.
Furthermore, at least 10 tissues outside the kidney express 1-alpha-hydroxylase (CYP27B1), the enzyme
responsible for converting vitamin D to its active form, and therefore the active hormone can be generated in
an auto or paracrine way. Thus, the spectrum of activity of the vitamin D endocrine system is much broader
than calcium/bone homeostasis, and in this regard, the vitamin D-VDR system resembles that of other
ligands of nuclear receptors, such as thyroid hormone [2-4].
This chapter will review the extraskeletal effects of vitamin D (deficiency), especially its effect on muscle
function, cancer, and on the immune, cardiovascular, and metabolic system. The skeletal manifestations,
causes, and treatment of vitamin D deficiency are discussed elsewhere. (See "Epidemiology and etiology of
osteomalacia" and "Causes of vitamin D deficiency and resistance" and "Vitamin D deficiency in adults:
Definition, clinical manifestations, and treatment".)
MUSCLE FUNCTION
Muscle weakness Observational studies suggest an association between poor vitamin D status and
muscle weakness. However, a causal relationship between vitamin D supplementation and improvement in
muscle weakness has not been clearly demonstrated in randomized trials, and the optimal 25hydroxyvitamin D (25[OH]D) concentration for muscle function is unknown. Any benefit of vitamin D
supplementation on muscle strength is likely to occur in patients with baseline 25(OH)D levels below 10 or
20 ng/mL (25 or 50 nmol/L).
There are several lines of evidence that suggest a relationship between vitamin D and muscle function [5].
Muscle from vitamin D receptor (VDR) null mice shows clear developmental abnormalities as immature
muscle genes and proteins survive in VDR null but not wild type adult muscle [4]. In addition, striated muscle
fibers are smaller in VDR null mice. Adult skeletal muscle, however, does not seems to express VDR protein
when measured by highly specific antibodies [6], but VDR is expressed in muscle cell precursors or stem
cells [4,5]. Children with hereditary vitamin D deficiency (ie, genetic CYP27B1 deficiency) who are deficient
in the production of 1,25-dihydroxyvitamin D have profound muscle weakness, which vitamin D or 1,25dihydroxyvitamin D therapy rapidly improves [4]. In addition, vitamin D supplementation improved muscle
weakness and recovery of energy stores (maximal mitochondrial oxidative phosphorylation rate, as
measured by in vivo magnetic resonance spectroscopy) after physical exercise in severely vitamin Ddeficient but otherwise healthy adults [7].
Observational studies also show a relationship between nutritionally-poor 25(OH)D status and muscle
weakness in children and elderly subjects [8-11]. In most studies, the lowest vitamin D concentrations (<20
http://www.uptodate.com.ezproxy.uniandes.edu.co:8080/contents/vitamin-d-and-extraskeletal-health?topicKey=ENDO%2F13915&elapsedTime
1/15
24/9/2014
ng/mL [<50 nmol/L] and especially <10 ng/mL [<25 nmol/L]) were associated with the poorest muscle
function, whereas higher levels of 25(OH)D (>20 ng/mL [>50 nmol/L]) were associated with better muscle
function [10,12].
In systematic reviews of randomized trials comparing vitamin D supplementation (with or without calcium) to
placebo or calcium alone, the results were mixed [13,14]. Six trials did not show any effect on muscle
strength (knee extension), and five did not show any effect on balance (postural sway, Timed Up and Go)
and/or gait (distance walked). In a meta-analysis of the three trials with doses of 800 to 1000 international
units daily, there was a small but significant improvement in balance and lower extremity muscle strength
with vitamin D supplementation [13]. There was no effect on gait. Among four trials with patients with
baseline serum 25(OH)D <10 ng/mL (25 nmol/L), three showed improvement in some aspects of muscle
strength with vitamin D supplementation [14]. Few studies used proximal muscle strength (the most affected
muscle function in clinical case reports) as a true endpoint, and no studies provided vitamin D
supplementation in doses higher than 2000 international units per day. In a subsequent trial from Norway,
251 healthy immigrant adults (from South Asia, Middle East, and Africa, mean age 36 to 39 years) with
vitamin D deficiency (mean serum 25[OH]D 10.4 ng/mL [26 nmol/L]) were randomly assigned to vitamin D3
supplementation (1000 or 400 international units daily) or to placebo [15]. After 16 weeks, mean serum
25(OH)D levels improved in the active treatment groups (20.8 and 17.2 ng/mL [52 and 43 nmol/L] in the
1000 and 400 international unit dose groups, respectively). However, there were no differences in
improvement in maximum jump height (a measure of proximal leg muscle strength), chair-rising (proximal
leg muscle strength), or handgrip strength.
Falls Although there are few data demonstrating improvement in muscle weakness after vitamin D
repletion in patients with nutritionally-poor vitamin D status, there are several meta-analyses showing a
reduction in risk of falls (relative risk [RR] reduction as high as 20 percent) following vitamin D
supplementation, particularly when the baseline vitamin D status is poor [16-20]. Supplementation with
doses ranging from 700 to 1000 units/day was effective. A subsequent meta-analysis showed that overall,
vitamin D supplementation in community-dwelling adults did not reduce falls but may have had some effect
in people with lower pretreatment 25(OH)D levels [21]. It is possible that the positive effect of vitamin D on
falls is more prevalent in frequent fallers, such that people who fall frequently have a reduced number of
falls, whereas the number of overall falls for the entire population may not be reduced [22]. In one metaanalysis, multicomponent group exercise and Tai Chi were even more effective in reducing risk of falls than
vitamin D supplementation (RRs 0.65 and 0.83 versus 0.96). These trials and suggestions for vitamin D
supplementation for fall prevention in older adults are reviewed in detail elsewhere. (See "Falls: Prevention
in community-dwelling older persons", section on 'Vitamin D supplementation'.)
A combined approach (vitamin D, calcium, exercise, and general interventions) may provide additional
advantage for the very elderly.
CANCER Although some data suggest an association between vitamin D deficiency and cancer, the
direction of the association may depend upon the serum 25-hydroxyvitamin D (25[OH]D) concentration. The
current evidence is insufficient to support large-dose vitamin D supplementation for cancer prevention or
treatment.
In the 1930s and 1940s it was observed that people living at higher latitudes were at higher risk of cancer
[23]. Subsequently, living at a higher latitude was linked to ultraviolet B (UVB) exposure and this observation
introduced the possible link with vitamin D status [24]. There is now a very extensive literature on vitamin D,
cell proliferation, and cancer. In vitro studies have shown that the active hormone or its analogues can
decrease cell proliferation, and a very large number of genes are coherently activated or inactivated to
generate this effect [4,25]. In animal studies, deficiency of the vitamin D receptor (VDR) predisposes to
precancerous lesions of the breast or intestine [26].
Observational studies in humans (cross sectional studies and especially long-term prospective studies)
revealed a link between poor vitamin D status (either evaluated by serum 25[OH]D or a surrogate
estimation) and the risk of nearly all cancers [27,28], but a re-analysis by a World Health Organization
(WHO) working group identified colon cancer as the greatest risk associated with poor vitamin D status [29].
This finding was supported by the results of a meta-analysis of nine case-control studies [30]. For each 4
2/15
24/9/2014
ng/mL (10 nmol/L) increase in pre-diagnosis serum 25(OH)D concentration, there was a 6 percent (95% CI
3-9 percent) reduction in colorectal cancer risk. In one of the largest studies in the meta-analysis, a nested
case-control study in European populations (2496 cases and controls), serum 25(OH)D levels between 10
and 20 ng/mL (25 to 50 nmol/L) compared with 20 to 30 ng/mL (50 to 75 nmol/L) were associated with a
higher incidence of colorectal cancer (incidence rate ratio 1.28, 95% CI 1.05-1.56) [31]. In contrast to these
results, a prospective case control study did not show a significant association between vitamin D status and
colon or colorectal cancer [32]. In addition, some observational studies have shown an elevated risk of some
cancers (eg, pancreatic) at higher 25(OH)D levels (relative risk [RR] 2.12, 95% CI 1.23-3.64 for levels 40
versus 20 to 30 ng/mL [100 versus 50 to 75 nmol/L]) [33-36].
Observational studies examining the relationship between vitamin D and breast cancer report inconsistent
results. A meta-analysis of prospective studies examining the relationship between serum 25(OH)D
concentrations and breast cancer risk showed a significant inverse association in postmenopausal but not
premenopausal women [37]. The risk of postmenopausal breast cancer decreased with 25(OH)D levels
between 27 and <35 ng/mL (67 to 87 nmol/L), with no further reduction for levels above 35 ng/mL. (See
"Factors that modify breast cancer risk in women", section on 'Calcium/Vitamin D'.)
A relationship between serum 25(OH)D levels and prostate cancer incidence has not been consistently
found [38,39]. In observational studies, higher (highest compared with lowest quartiles or quintiles) serum
25(OH)D levels have been associated with both an increased [40] and reduced [41] risk of more aggressive
disease (see "Risk factors for prostate cancer", section on 'Calcium and vitamin D'). Vitamin D and cancer
mortality are discussed below. (See 'Mortality' below.)
Results of vitamin D intervention trials on cancer risk are inconsistent [30]. In the Womens Health Initiative
(WHI), treatment with vitamin D3 (400 units/day) and calcium (1000 mg/day) did not have an effect on the
incidence of colorectal cancer [42]. However, in a much smaller trial of vitamin D3 (1100 units/day) and
calcium (1400 to 1500 mg/day) supplementation, there was a significant decrease in overall cancer risk, but
the number of events was small and calcium alone was nearly as efficient as calcium plus vitamin D [43]. In
other vitamin D supplementation studies, in which the primary endpoint was fracture risk, there were no
beneficial effects on cancer risk [44,45]. Additional studies are ongoing [39].
IMMUNE SYSTEM Vitamin D has major effects on nearly all cells of the immune system. Antigen
presenting cells, such as dendritic cells, macrophages, and T and B cells, express the vitamin D receptor
(VDR). Thus, the VDR-vitamin D endocrine system can modulate most aspects of the innate and acquired
immune system (and even mast cells) when challenged by extreme deficiency or exposure to high 1,25dihydroxyvitamin D (1,25-[OH]2D) (or its analogs). However, vitamin D supplementation does not appear to
reduce the incidence of upper respiratory infections in healthy adults with normal or near-normal serum 25hydroxyvitamin D (25[OH]D) levels. The causal link between poor vitamin D status and autoimmune
diseases or infections in humans remains unclear.
Acquired The active form of vitamin D, 1,25-dihydroxyvitamin D, is an inhibitor of dendritic cell maturation
and functions as an immune modulator, reducing activation of the acquired immune system. Therefore,
vitamin D deficiency could theoretically increase the risk of autoimmune diseases, which has been reported
in animal models [46].
Observational studies in humans suggest an association between vitamin D deficiency and type 1 diabetes
(T1D), multiple sclerosis (MS), and inflammatory bowel disease. Type 1 diabetes is reviewed below. (See
'Type 1 diabetes' below.)
In a large prospective case-control study involving over seven million United States military personnel,
Caucasian recruits with 25(OH)D levels below 20 ng/mL (50 nmol/L) had approximately a twofold increased
risk for later development of multiple sclerosis [47]. However, there are no randomized trials that have
confirmed the efficacy or safety of vitamin D supplementation in preventing autoimmune disease. Until such
data are available, vitamin D is not recommended for this purpose.
There are conflicting reports on the association between vitamin D status and allergic diseases. In some
reports, vitamin D deficiency (in pregnant women, children, or adolescents) has been associated with
increased as well as with decreased frequency of allergic diseases such as asthma or eczema [4,48,49].
3/15
24/9/2014
(See "Risk factors for asthma", section on 'Maternal diet during pregnancy'.)
Innate Although vitamin D reduces activation of the acquired immune system, it activates the innate
immune system, particularly monocytes and macrophages. Exposure of monocytes and/or macrophages to
bacterial infections upregulates VDR and 1-alpha-hydroxylase expression, and after 48 hours, increases the
production of several natural defensins (at least in human monocytes) capable of decreasing the intracellular
survival of such mycobacteria [2,50]. Therefore, it is not unexpected that vitamin D deficiency is historically
associated with infections. As an example, there is an association between vitamin D deficiency and
tuberculosis (TB) and a putative beneficial (historic) effect of ultraviolet B (UVB) exposure of such patients
before antibiotic therapy became available [51]. A small-scale intervention study in India showed that vitamin
D supplementation accelerated sputum clearance in patients with TB [52]. In contrast, supplementation with
vitamin D compared with placebo did not improve clinical outcomes (including mortality) among 281 West
African patients [53] or among 146 patients from London [54] who had active TB and were receiving
antituberculosis treatment. In the latter trial, patients with a mean baseline 25-hydroxyvitamin D level of 8.4
ng/mL (21 nmol/L) were randomly assigned to vitamin D (100,000 units [2.5 mg] every two weeks for two
months) or placebo [54]. Although median time to sputum culture conversion was better in the vitamin D
group (36 versus 43.5 days with placebo), the results were not statistically significant (hazard ratio [HR]
1.39, 95% CI 0.90-2.16). Thus, there are currently insufficient data to define a role for vitamin D in the
prevention or treatment of tuberculosis [55].
Vitamin D supplementation also did not reduce the rate of exacerbations in the majority of patients with
chronic obstructive pulmonary disease (COPD) [56]. Compared with placebo, high-dose vitamin D
supplementation (100,000 int. units of vitamin D3 every four weeks for 12 months) in severe COPD patients
showed no benefit on time to first exacerbation (usually a new infection) or exacerbation rates, except in
patients with a baseline 25(OH)D level below 10 ng/mL (25 nmol/L) [56] (see "Management of exacerbations
of chronic obstructive pulmonary disease", section on 'Prevention'). In addition, supplementation with vitamin
D in children with poor vitamin D status did not improve the risk of pneumonia in infants living in Kabul [57].
There is a hypothesis that common virologic infections have a marked seasonal variation because of the
seasonal variation of the vitamin D status [58,59]. However, a causal relationship between vitamin D and
viral infections has not been established. As an example, in a randomized trial of vitamin D (2000 units D3
daily) or matching placebo in 162 adults for 12 weeks during the winter season, there was no difference in
the incidence of upper respiratory infections between the groups [60]. Similar negative findings were noted
among 164 Finnish military recruits who were randomly assigned to vitamin D (400 units D3 daily) versus
placebo for six months during the winter season [61], among 322 healthy adults (mean baseline 25hydroxyvitamin D level 29 ng/mL [72 nmol/L]) who were randomly assigned to high-dose vitamin D (200,000
units monthly for two months followed by 100,000 units monthly) or placebo for 18 months [62], and among
2259 healthy adults ages 45 to 75 years (serum 25-hydroxyvitamin D level 12 ng/mL [30 nmol/L]) who were
randomly assigned to vitamin D (1000 units D3 daily), calcium, both, or placebo [63]. There were no
differences in the number of upper respiratory tract infection events, in days absent from duty due to acute
respiratory tract infection, in self reported symptoms of acute respiratory infection (cough, runny nose, sore
throat, fever), or in hospitalization due to acute respiratory infection. In contrast, compared with ingestion of
unfortified milk, daily ingestion of milk fortified with 300 int. units of vitamin D3 did decrease the risk of acute
respiratory infections in Mongolian children with baseline median serum 25(OH)D level of 7 ng/mL (17.5
nmol/L) [64].
There are several ongoing randomized trials to clarify the possible beneficial effects of vitamin D
supplementation on infectious diseases (see National Institutes of Health [NIH] and European clinical trial
registers) [65,66].
CARDIOVASCULAR SYSTEM Although observational studies show an association between low vitamin
D status and risk of hypertension and cardiovascular events [67], the results of randomized trials are
inconclusive. Thus, the causal nature of the association between vitamin D and cardiovascular disease and
whether the association differs across patient populations (eg, different genders and racial/ethnic groups,
chronic kidney disease, diabetes) remain uncertain [68,69].
Hypertension There is geographic and racial variation in blood pressure, with risk of hypertension
4/15
24/9/2014
increasing from south to north in the Northern hemisphere. One proposed explanation for the association
with latitude is that exposure to sunlight may be protective, either because of an effect of ultraviolet radiation
or of vitamin D [70]. In animal studies, 1,25-dihydroxyvitamin D has been shown to regulate the reninangiotensin system. Vitamin D receptor (VDR) null mice or mice with inborn deficiency of the 1-alphahydroxylase gene develop high renin hypertension and cardiac hypertrophy [4,71]. Moreover, vascular
endothelial and smooth muscle cells respond to exposure to 1,25-dihydroxyvitamin D with a favorable
cardioprotective gene response. This corresponds well with reduced thrombogenesis and increased
fibrinolysis as observed in vivo [2,4].
Observational studies are consistent with these preclinical data. In normotensive and hypertensive
individuals, there is an inverse association between 25-hydroxyvitamin D (25[OH]D) concentration and blood
pressure [72-75]. The link between vitamin D status and hypertension is complicated by a strong negative
association between body mass index (BMI), a well known risk factor for hypertension, and 25(OH)D.
Prospective randomized intervention trials are therefore needed to prove causality and, if present, to define
the optimal dose for each target population. A meta-analysis of eight randomized trials examining the effects
of vitamin D supplementation on blood pressure in hypertensive (140/90 mmHg) men and women showed
a small but significant reduction in diastolic blood pressure (-3.1 mmHg, 95% CI -5.5 to -0.6) and a
nonsignificant reduction in systolic blood pressure (-3.6 mmHg, 95% CI -8.0 to 0.7) in the vitamin D group
compared with placebo [76]. In another meta-analysis of 10 trials (including four trials included in the
previous meta-analysis), there was a nonsignificant reduction in systolic blood pressure (weighted mean
difference -1.9 mmHg) with vitamin D supplementation but no effect on diastolic blood pressure [77]. A
subsequent trial in 283 black adults (approximately 50 percent with hypertension) showed that vitamin D
supplementation significantly decreased systolic blood pressure (-1.4 mmHg for each additional 1000
units/day of cholecalciferol) but did not affect the diastolic pressure [78]. In another trial in elderly patients
with isolated systolic hypertension (mean 25[OH]D 18 ng/mL [45 nmol/L]), vitamin D supplementation
(100,000 units every three months for one year) did not improve blood pressure more than placebo [79].
Additional trials are required to confirm or refute a beneficial clinical effect on blood pressure and to
determine if specific populations are more likely to benefit from vitamin D supplementation.
Cardiovascular events The link between vitamin D and cardiovascular disease involves a much broader
spectrum of cardiovascular risks beyond its association with hypertension [67,80]. In a meta-analysis of 19
prospective studies (65,994 patients), there was an inverse relationship between serum 25(OH)D levels
(ranging from 8 to 24 ng/mL [20 to 60 nmol/L]) and risk of cardiovascular disease (relative risk [RR] of 1.03,
95% CI 1.00-1.60, per 10 ng/mL [25 nmol/L] decrement in serum 25[OH]D) [81]. Examples of individual
studies include the following:
In the Framingham Offspring Study, participants who had a 25(OH)D <15 ng/mL (37.5 nmol/L) were
more likely to have their first cardiovascular event during 5.4 years (mean) of observation than those
with values 15 ng/mL (hazard ratio [HR] 1.62, 95% CI 1.11-2.36) [82].
In the National Health and Nutrition Examination Study (NHANES) 2001 to 2004, the prevalence of
coronary heart disease (angina, myocardial infarction) was more common in adults with 25(OH)D
levels <20 ng/mL compared with 30 ng/mL (odds ratio [OR] adjusted for age, race, and gender 1.49,
95% CI 1.17-1.91) [83,84]. Adjusting for other risk factors (body mass index, chronic kidney disease,
hypertension, diabetes mellitus, smoking, use of vitamin D supplements) attenuated the association
(OR 1.24, 95% CI 0.95-1.62). The prevalence of heart failure and peripheral arterial diseases was also
higher among those with 25(OH)D values <20 ng/mL (ORs 2.10 and 1.82, respectively) with similar
attenuation after adjustment for other risk factors.
In a review of four interventional randomized trials and a meta-analysis of six trials, however, there was no
effect of supplementation on cardiovascular outcomes, including myocardial infarction and stroke [77,85].
The meta-analysis also did not show a significant effect of vitamin D supplementation on cardiovascular risk
factors (lipids, glucose, blood pressure) [85]. In one of the larger trials included in the meta-analysis, there
was no beneficial effect on cardiovascular or metabolic risks after increasing baseline 25(OH)D levels from
23 to well above 40 ng/mL (58 to 100 nmol/L) [86].
In a subsequent randomized trial of an active vitamin D preparation (oral paricalcitol) versus placebo in 227
2
5/15
24/9/2014
patients with chronic kidney disease (estimated glomerular filtration rate 15 to 60 mL/min/1.73 m2), there
was no difference in left ventricular mass index or improvement in measures of diastolic dysfunction
between the two groups [87].
DIABETES There are a number of reasons to link type 1 and type 2 diabetes with vitamin D status [88].
For type 1 diabetes, the link is largely mediated by the effects of vitamin D on the immune system (see
'Acquired' above). For type 2 diabetes, the potential mechanisms include improving both beta-cell activity as
well as insulin sensitivity [89].
Type 1 diabetes Some [90,91], but not all [92], observational studies in humans suggest an association
between vitamin D deficiency and type 1 diabetes. Several observational studies, mainly case-control
studies, showed that vitamin D supplementation in early infancy reduced the subsequent risk of type 1
diabetes by about 30 percent [89,93,94]. However, there are no randomized trials evaluating the effect of
vitamin D supplementation on the incidence of type 1 diabetes in childhood. (See "Prevention of type 1
diabetes mellitus", section on 'Vitamin D supplements'.)
Variation in serum 25-hydroxyvitamin D (25[OH]D) concentrations has been attributed to genetic factors (see
'Genes and vitamin D status' below). In a case control study of 720 children with type 1 diabetes compared
with 2610 age-matched children without diabetes, there was an association between type 1 diabetes and
key genetic polymorphisms linked to vitamin D deficiency, lending support to the possibility of an association
between vitamin D deficiency and type 1 diabetes [95].
Type 2 diabetes and metabolic syndrome Vitamin D status is lower in individuals with obesity and with
type 2 diabetes, but the causality of this relationship is unknown. In nearly all human studies, obesity is
associated with low 25(OH)D concentrations [96]. A large genetic study of more than 40,000 individuals
showed that higher body mass index (and the genes that predispose for obesity) decreases serum 25(OH)D
levels, whereas lower 25(OH)D levels (or the genes that are associated with reduced serum concentration of
25[OH]D) have, at most, very small effects on obesity [97].
In several cross-sectional and prospective cohort studies, type 2 diabetes and conditions known to be part of
the metabolic syndrome were associated with a poor vitamin D status [77,98-105]. As an example, a metaanalysis of 21 prospective studies showed an inverse relationship between circulating 25-hydroxyvitamin D
levels and the risk of type 2 diabetes (relative risk [RR] 0.62, 95% CI 0.54-0.70, for patients with the highest
versus lowest category of 25-hydroxyvitamin D levels) [106].
However, the existing intervention studies are either negative or showed only limited beneficial effects
[86,107-109]. In a meta-analysis of eight trials evaluating the effect of vitamin D supplementation on
glycemia, there was no effect of supplementation on glycemia or incident diabetes [77]. However, a
subsequent trial in severely vitamin D-deficient Asians living in New Zealand revealed a modest
improvement of their insulin sensitivity after six months of vitamin D supplementation [110].
NEUROPSYCHIATRIC FUNCTION The vitamin D receptor (VDR) and the 1-alpha-hydroxylase enzyme
that converts vitamin D to its active form are expressed in the human brain [111]. Through its effects on
neuronal proliferation, differentiation, migration, and apoptosis, vitamin D may play an important role in brain
development [112,113]. In addition, it has been proposed that prenatal vitamin D deficiency may increase
the risk of neuropsychiatric disorders, such as schizophrenia [114]. There are inconsistent small effects of
vitamin D deficiency on postnatal brain function [115]. Low levels of 25-hydroxyvitamin D (25[OH]D) are
frequently found in patients with depression or Alzheimers disease [116-118], and a meta-analysis of
observational studies showed lower Mini-Mental State Examination scores in patients with lower serum
vitamin D concentrations (25[OH]D <20 versus 20 ng/mL [<50 versus 50 nmol/L]) [117]. (See "Risk factors
for cognitive decline and dementia", section on 'Vitamin D deficiency'.)
There are few trials evaluating the effects of vitamin D supplementation on neuropsychiatric symptoms. In a
meta-analysis of six trials evaluating vitamin D supplementation compared with placebo in adults with a
diagnosis of depression or at risk for depression, there was no significant effect of vitamin D
supplementation on depression symptoms [119]. The meta-analysis was limited by heterogeneity of study
results and the overall low quality of the included trials. Thus, the causal nature of the association between
vitamin D and neuropsychiatric function remains uncertain. Vitamin D deficiency in this population may be a
6/15
24/9/2014
consequence of their limited mobility and sun exposure.

PREGNANCY OUTCOMES There are several observational studies suggesting an association between
poor maternal vitamin D status and pregnancy outcome [67,120,121]. As an example, in a meta-analysis of
31 studies, insufficient serum 25-hydroxyvitamin D (25[OH]D) concentrations were associated with a higher
risk of gestational diabetes, pre-eclampsia, and small for gestational age infants [120]. However, the
absence of a dose response relationship between serum 25(OH)D and reported complications and the
inclusion of studies that measured the 25(OH)D levels with variable precision raise significant doubt about
the effects of vitamin D deficiency on the reported outcomes.
In a large long-term prospective study (Avon Longitudinal Study of Parents and Children), which involved
3960 mother-and-offspring pairs mainly of white European origin, maternal 25(OH)D concentration was
measured during pregnancy and offspring underwent dual-energy x-ray absorptiometry at age 9 to 10 years
[122]. There was no significant association between maternal vitamin D status in pregnancy and offspring
bone mineral content in late childhood. In contrast, a smaller cohort study (341 mother-and-offspring pairs)
found that vitamin D deficiency during pregnancy was associated with lower bone mass in their children at
20 years of age [123].
Few randomized intervention studies evaluating vitamin D supplementation in pregnancy have been
performed. A 2012 meta-analysis of vitamin D supplementation during pregnancy concluded that the number
of trials was too low to draw conclusions about the safety and efficacy of vitamin D supplementation for
protecting against adverse gestational outcomes (eg, pre-eclampsia, preterm birth, low birthweight) [124]. In
a subsequent trial of vitamin D supplementation (400, 2000, or 4000 international units D3 daily) in 192
pregnant Arab women (12 to 16 weeks gestation) with severe vitamin D deficiency (mean serum 25[OH]D
8.2 ng/mL [20.5 nmol/L]), all doses were safe, and the highest dose was most effective in increasing vitamin
D levels to 32 ng/mL [125]. There were no significant differences in the mean birth weight, length, head
circumference, and gestational age among the groups. More research is needed before vitamin D can be
recommended for the prevention of low birthweight, preterm birth, or pre-eclampsia. The timing of vitamin D
supplementation will also need to be evaluated in future studies, since the earliest interventions made in
published trials were in the late first trimester; initiation of therapy with vitamin D prior to conception has not
been evaluated. In addition, more trials are needed to confirm the safety and efficacy of high-dose vitamin D
supplementation in pregnant women with vitamin D deficiency. (See "Vitamin D deficiency in adults:
Definition, clinical manifestations, and treatment", section on 'Pregnancy'.)
Severe and prolonged vitamin D deficiency can result in osteomalacia and in pregnant women,
cephalopelvic disproportion, necessitating cesarean delivery. This topic is reviewed separately. (See
"Clinical manifestations, diagnosis, and treatment of osteomalacia", section on 'Pregnancy'.)
MORTALITY Some [126-134], but not all [135-137], epidemiologic studies suggest that low 25hydroxyvitamin D (25[OH]D) levels (especially <10 to 20 ng/mL [25 to 50 nmol/L]) are associated with higher
mortality. In some of these studies, the relationship between serum 25(OH)D and mortality was defined by a
U- or reverse J-shaped curve, indicating higher mortality at very low (<20 ng/mL) and high (>30 to 50 ng/mL,
75 to 125 nmol/L) serum 25(OH)D concentrations [36,127,130].
There are few data regarding cause-specific mortality [30,138]. In a prospective study using National Health
and Nutrition Examination Survey (NHANES) data, there was an inverse association between 25(OH)D
levels and all-cause and cardiovascular mortality with serum 25(OH)D levels <21 ng/mL (52 nmol/L) [139]. In
another study using NHANES data, there was no association between serum 25(OH)D levels and overall
cancer mortality [140]. In men, cancer mortality was significantly higher at the highest quintiles of 25(OH)D
(relative risks [RRs] 1.66 and 1.85 for those with 25[OH]D levels of 32 to 40 and 40 ng/mL [80 to 100 and
100 nmol/L], respectively). When the risk for particular cancer sites was evaluated, there was a significant
positive association between 25(OH)D levels and risk of mortality from lung cancer and an inverse
association between 25(OH)D levels and colorectal cancer, which did not reach statistical significance.
There was no relationship between 25(OH)D levels and cancer mortality in women. An association between
higher baseline serum 25(OH)D concentrations and higher total cancer mortality among men, but not
women, has also been reported in other prospective cohort studies [30,135,141], whereas a meta-analysis
of 25 studies suggested that higher serum 25(OH)D levels at the time of diagnosis were associated with
7/15
24/9/2014
reduced cancer mortality [142].

Randomized trials of vitamin D supplementation with mortality as a primary endpoint are lacking. The results
of intervention studies with mortality included as a secondary endpoint are conflicting, as illustrated by the
following [85,133,143,144]:
A meta-analysis of individual patient data from eight fracture-prevention trials showed that vitamin D
with calcium supplementation reduced mortality (hazard ratio [HR] 0.91, 95% CI 0.84-0.98), but vitamin
D alone did not [143].
In a meta-analysis (51 trials), the reduction in mortality with vitamin D supplementation did not reach
statistical significance (RR 0.96, 95% CI 0.93-1.00) [85].
In a meta-analysis of 56 randomized trials that compared any type of vitamin D supplementation with
placebo or no intervention, there was a small but significant reduction in all-cause mortality (12.5
versus 12.7 percent, RR 0.97, 95% CI 0.97-0.99) [144]. When different forms of vitamin D were
assessed, only vitamin D3 significantly reduced all-cause (11 versus 11.4 percent, RR 0.94, 95% CI
0.91-0.98) and cancer (RR 0.88, 95% CI 0.78-0.98) mortality.
Since mortality is not reported in all trials, there is the possibility of reporting bias where trials showing a
mortality effect would be more likely to include results on mortality.
GENES AND VITAMIN D STATUS A large proportion of the variation in serum 25-hydroxyvitamin D
(25[OH]D) concentrations has been attributed to genetic factors. Twin studies suggest a high degree of
heritability of serum 25(OH)D levels [145]. A very large international consortium identified four gene
polymorphisms that were strongly associated with serum 25(OH)D levels [146]. In addition, a meta-analysis
of cohort studies identified common polymorphisms in the vitamin D receptor (VDR) gene that significantly
modified the association of serum 25(OH)D and major health outcomes [147]. Thus, part of the large interindividual variation in 25(OH)D levels in normal individuals living in very comparable situations and the risk
of adverse health outcomes associated with low serum 25(OH)D levels may be purely genetic.
OPTIMAL VITAMIN D FOR EXTRASKELETAL HEALTH There are a large number of epidemiologic
data indicating that the risks of cancer and infectious, autoimmune, and cardiovascular diseases are higher
when 25-hydroxyvitamin D (25[OH]D) levels are <20 ng/mL (50 nmol/L) and that risks decrease with higher
25(OH)D concentrations. However, there are no convincing randomized trial data that vitamin D
supplements can decrease cancer risk or prognosis, decrease the risk or severity of infections or
autoimmune diseases, or decrease cardiovascular risks or metabolic diseases [29,39,108,148]. In addition,
there are no prospective studies to define optimal 25(OH)D levels for extra-skeletal health. Thus, we do not
suggest vitamin D supplementation above and beyond what is required for osteoporosis or fall prevention
(see 'Falls' above and "Calcium and vitamin D supplementation in osteoporosis"). This recommendation is
consistent with the recommendations of The Standing Committee of European Doctors [149].
SUMMARY AND RECOMMENDATIONS
In addition to its role in calcium and bone homeostasis, vitamin D could potentially regulate many other
cellular functions. (See 'Introduction' above and "Calcium and vitamin D supplementation in
osteoporosis".)
Vitamin D supplementation (700 to 1000 units/day) reduces the risk of falls in elderly populations.
However, a causal association between poor vitamin D status and nearly all major diseases (cancer,
infections, autoimmune diseases, cardiovascular and metabolic diseases) has not been established.
(See 'Falls' above and 'Optimal vitamin D for extraskeletal health' above.)
We suggest not administering vitamin D supplements above and beyond what is required for
osteoporosis or fall prevention (Grade 2C). (See 'Falls' above and "Falls: Prevention in communitydwelling older persons", section on 'Vitamin D supplementation' and "Calcium and vitamin D
supplementation in osteoporosis".)
The treatment of vitamin D deficiency is reviewed separately. (See "Vitamin D deficiency in adults:
8/15
24/9/2014
Definition, clinical manifestations, and treatment".)

Use of UpToDate is subject to the Subscription and License Agreement.
REFERENCES
1. Prentice A. Vitamin D deficiency: a global perspective. Nutr Rev 2008; 66:S153.
2. Bouillon R. Vitamin D: from photosynthesis, metabolism and action to clinical applications. In:
Endocrinology, Jameson JL, De Groot LJ (Eds), Saunders Elsevier, Philadelphia 2010. Vol 1, p.1089.
3. Holick MF. Vitamin D deficiency. N Engl J Med 2007; 357:266.
4. Bouillon R, Carmeliet G, Verlinden L, et al. Vitamin D and human health: lessons from vitamin D
receptor null mice. Endocr Rev 2008; 29:726.
5. Girgis CM, Clifton-Bligh RJ, Hamrick MW, et al. The roles of vitamin D in skeletal muscle: form,
function, and metabolism. Endocr Rev 2013; 34:33.
6. Wang Y, DeLuca HF. Is the vitamin d receptor found in muscle? Endocrinology 2011; 152:354.
7. Sinha A, Hollingsworth KG, Ball S, Cheetham T. Improving the vitamin D status of vitamin D deficient
adults is associated with improved mitochondrial oxidative function in skeletal muscle. J Clin
Endocrinol Metab 2013; 98:E509.
8. Plotnikoff GA, Quigley JM. Prevalence of severe hypovitaminosis D in patients with persistent,
nonspecific musculoskeletal pain. Mayo Clin Proc 2003; 78:1463.
9. Glerup H, Mikkelsen K, Poulsen L, et al. Hypovitaminosis D myopathy without biochemical signs of
osteomalacic bone involvement. Calcif Tissue Int 2000; 66:419.
10. Bischoff-Ferrari HA, Dietrich T, Orav EJ, et al. Higher 25-hydroxyvitamin D concentrations are
associated with better lower-extremity function in both active and inactive persons aged > or =60 y. Am
J Clin Nutr 2004; 80:752.
11. Visser M, Deeg DJ, Lips P, Longitudinal Aging Study Amsterdam. Low vitamin D and high parathyroid
hormone levels as determinants of loss of muscle strength and muscle mass (sarcopenia): the
Longitudinal Aging Study Amsterdam. J Clin Endocrinol Metab 2003; 88:5766.
12. Wicherts IS, van Schoor NM, Boeke AJ, et al. Vitamin D status predicts physical performance and its
decline in older persons. J Clin Endocrinol Metab 2007; 92:2058.
13. Muir SW, Montero-Odasso M. Effect of vitamin D supplementation on muscle strength, gait and
balance in older adults: a systematic review and meta-analysis. J Am Geriatr Soc 2011; 59:2291.
14. Stockton KA, Mengersen K, Paratz JD, et al. Effect of vitamin D supplementation on muscle strength:
a systematic review and meta-analysis. Osteoporos Int 2011; 22:859.
15. Knutsen KV, Madar AA, Lagerlv P, et al. Does vitamin D improve muscle strength in adults? A
randomized, double-blind, placebo-controlled trial among ethnic minorities in Norway. J Clin Endocrinol
Metab 2014; 99:194.
16. Bischoff-Ferrari HA, Dawson-Hughes B, Willett WC, et al. Effect of Vitamin D on falls: a meta-analysis.
JAMA 2004; 291:1999.
17. Jackson C, Gaugris S, Sen SS, Hosking D. The effect of cholecalciferol (vitamin D3) on the risk of fall
and fracture: a meta-analysis. QJM 2007; 100:185.
18. Bischoff-Ferrari HA, Dawson-Hughes B, Staehelin HB, et al. Fall prevention with supplemental and
active forms of vitamin D: a meta-analysis of randomised controlled trials. BMJ 2009; 339:b3692.
19. Cameron ID, Murray GR, Gillespie LD, et al. Interventions for preventing falls in older people in nursing
care facilities and hospitals. Cochrane Database Syst Rev 2010; :CD005465.
20. Murad MH, Elamin KB, Abu Elnour NO, et al. Clinical review: The effect of vitamin D on falls: a
systematic review and meta-analysis. J Clin Endocrinol Metab 2011; 96:2997.
21. Gillespie LD, Robertson MC, Gillespie WJ, et al. Interventions for preventing falls in older people living
in the community. Cochrane Database Syst Rev 2012; 9:CD007146.
22. Krkkinen MK, Tuppurainen M, Salovaara K, et al. Does daily vitamin D 800 IU and calcium 1000 mg
supplementation decrease the risk of falling in ambulatory women aged 65-71 years? A 3-year
randomized population-based trial (OSTPRE-FPS). Maturitas 2010; 65:359.
23. Apperly FL. The relation of solar radiation to cancer mortality in North America. Cancer Res 1941;
1:1991.
9/15
24/9/2014
24. Garland CF, Comstock GW, Garland FC, et al. Serum 25-hydroxyvitamin D and colon cancer: eightyear prospective study. Lancet 1989; 2:1176.
25. Bouillon R, Eelen G, Verlinden L, et al. Vitamin D and cancer. J Steroid Biochem Mol Biol 2006;
102:156.
26. Welsh J. Vitamin D and breast cancer: insights from animal models. Am J Clin Nutr 2004; 80:1721S.
27. Giovannucci E. The epidemiology of vitamin D and cancer incidence and mortality: a review (United
States). Cancer Causes Control 2005; 16:83.
28. Feskanich D, Ma J, Fuchs CS, et al. Plasma vitamin D metabolites and risk of colorectal cancer in
women. Cancer Epidemiol Biomarkers Prev 2004; 13:1502.
29. IARC. Vitamin D and Cancer. IARC Working Group Reports Vol.5, International Agency for research
on Cancer, Lyon. November 2008. http://www.iarc.fr/en/publications/pdfsonline/wrk/wrk5/Report_VitD.pdf .
30. Chung M, Lee J, Terasawa T, et al. 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. Ann
Intern Med 2011; 155:827.
31. Jenab M, Bueno-de-Mesquita HB, Ferrari P, et al. Association between pre-diagnostic circulating
vitamin D concentration and risk of colorectal cancer in European populations:a nested case-control
study. BMJ 2010; 340:b5500.
32. Weinstein SJ, Yu K, Horst RL, et al. Serum 25-hydroxyvitamin D and risks of colon and rectal cancer in
Finnish men. Am J Epidemiol 2011; 173:499.
33. Stolzenberg-Solomon RZ, Vieth R, Azad A, et al. A prospective nested case-control study of vitamin D
status and pancreatic cancer risk in male smokers. Cancer Res 2006; 66:10213.
34. Helzlsouer KJ, VDPP Steering Committee. Overview of the Cohort Consortium Vitamin D Pooling
Project of Rarer Cancers. Am J Epidemiol 2010; 172:4.
35. Stolzenberg-Solomon RZ, Jacobs EJ, Arslan AA, et al. Circulating 25-hydroxyvitamin D and risk of
pancreatic cancer: Cohort Consortium Vitamin D Pooling Project of Rarer Cancers. Am J Epidemiol
2010; 172:81.
36. http://books.nap.edu/openbook.php?record_id=13050&page=366 (Accessed on January 31, 2011).
37. Bauer SR, Hankinson SE, Bertone-Johnson ER, Ding EL. Plasma vitamin D levels, menopause, and
risk of breast cancer: dose-response meta-analysis of prospective studies. Medicine (Baltimore) 2013;
92:123.
38. Gilbert R, Martin RM, Beynon R, et al. Associations of circulating and dietary vitamin D with prostate
cancer risk: a systematic review and dose-response meta-analysis. Cancer Causes Control 2011;
22:319.
39. Bouillon R, Van Schoor NM, Gielen E, et al. Optimal vitamin D status: a critical analysis on the basis of
evidence-based medicine. J Clin Endocrinol Metab 2013; 98:E1283.
40. Ahn J, Peters U, Albanes D, et al. Serum vitamin D concentration and prostate cancer risk: a nested
case-control study. J Natl Cancer Inst 2008; 100:796.
41. Shui IM, Mucci LA, Kraft P, et al. Vitamin D-related genetic variation, plasma vitamin D, and risk of
lethal prostate cancer: a prospective nested case-control study. J Natl Cancer Inst 2012; 104:690.
42. Wactawski-Wende J, Kotchen JM, Anderson GL, et al. Calcium plus vitamin D supplementation and
the risk of colorectal cancer. N Engl J Med 2006; 354:684.
43. Lappe JM, Travers-Gustafson D, Davies KM, et al. Vitamin D and calcium supplementation reduces
cancer risk: results of a randomized trial. Am J Clin Nutr 2007; 85:1586.
44. Trivedi DP, Doll R, Khaw KT. Effect of four monthly oral vitamin D3 (cholecalciferol) supplementation
on fractures and mortality in men and women living in the community: randomised double blind
controlled trial. BMJ 2003; 326:469.
45. Chlebowski RT, Johnson KC, Kooperberg C, et al. Calcium plus vitamin D supplementation and the
risk of breast cancer. J Natl Cancer Inst 2008; 100:1581.
46. Ponsonby AL, McMichael A, van der Mei I. Ultraviolet radiation and autoimmune disease: insights from
epidemiological research. Toxicology 2002; 181-182:71.
47. Munger KL, Levin LI, Hollis BW, et al. Serum 25-hydroxyvitamin D levels and risk of multiple sclerosis.
JAMA 2006; 296:2832.
48. Lange NE, Litonjua A, Hawrylowicz CM, Weiss S. Vitamin D, the immune system and asthma. Expert
Rev Clin Immunol 2009; 5:693.
10/15
24/9/2014
49. Gale CR, Robinson SM, Harvey NC, et al. Maternal vitamin D status during pregnancy and child
outcomes. Eur J Clin Nutr 2008; 62:68.
50. Liu PT, Stenger S, Li H, et al. Toll-like receptor triggering of a vitamin D-mediated human antimicrobial
response. Science 2006; 311:1770.
51. Nnoaham KE, Clarke A. Low serum vitamin D levels and tuberculosis: a systematic review and metaanalysis. Int J Epidemiol 2008; 37:113.
52. Nursyam EW, Amin Z, Rumende CM. The effect of vitamin D as supplementary treatment in patients
with moderately advanced pulmonary tuberculous lesion. Acta Med Indones 2006; 38:3.
53. Wejse C, Gomes VF, Rabna P, et al. Vitamin D as supplementary treatment for tuberculosis: a doubleblind, randomized, placebo-controlled trial. Am J Respir Crit Care Med 2009; 179:843.
54. Martineau AR, Timms PM, Bothamley GH, et al. High-dose vitamin D(3) during intensive-phase
antimicrobial treatment of pulmonary tuberculosis: a double-blind randomised controlled trial. Lancet
2011; 377:242.
55. Sinclair D, Abba K, Grobler L, Sudarsanam TD. Nutritional supplements for people being treated for
active tuberculosis. Cochrane Database Syst Rev 2011; :CD006086.
56. Lehouck A, Mathieu C, Carremans C, et al. High doses of vitamin D to reduce exacerbations in chronic
obstructive pulmonary disease: a randomized trial. Ann Intern Med 2012; 156:105.
57. Manaseki-Holland S, Maroof Z, Bruce J, et al. Effect on the incidence of pneumonia of vitamin D
supplementation by quarterly bolus dose to infants in Kabul: a randomised controlled superiority trial.
Lancet 2012; 379:1419.
58. Cannell JJ, Vieth R, Umhau JC, et al. Epidemic influenza and vitamin D. Epidemiol Infect 2006;
134:1129.
59. Ginde AA, Mansbach JM, Camargo CA Jr. Association between serum 25-hydroxyvitamin D level and
upper respiratory tract infection in the Third National Health and Nutrition Examination Survey. Arch
Intern Med 2009; 169:384.
60. Li-Ng M, Aloia JF, Pollack S, et al. A randomized controlled trial of vitamin D3 supplementation for the
prevention of symptomatic upper respiratory tract infections. Epidemiol Infect 2009; 137:1396.
61. Laaksi I, Ruohola JP, Mattila V, et al. Vitamin D supplementation for the prevention of acute respiratory
tract infection: a randomized, double-blinded trial among young Finnish men. J Infect Dis 2010;
202:809.
62. Murdoch DR, Slow S, Chambers ST, et al. Effect of Vitamin D3 Supplementation on Upper Respiratory
Tract Infections in Healthy Adults: The VIDARIS Randomized Controlled Trial. JAMA 2012; 308:1333.
63. Rees JR, Hendricks K, Barry EL, et al. Vitamin D3 supplementation and upper respiratory tract
infections in a randomized, controlled trial. Clin Infect Dis 2013; 57:1384.
64. Camargo CA Jr, Ganmaa D, Frazier AL, et al. Randomized trial of vitamin D supplementation and risk
of acute respiratory infection in Mongolia. Pediatrics 2012; 130:e561.
65. http://clinicaltrials.gov/ct2/results?term=Vitamin+D+and+infection (Accessed on August 05, 2010).
66. https://eudract.emea.europa.eu/ (Accessed on August 05, 2010).
67. Theodoratou E, Tzoulaki I, Zgaga L, Ioannidis JP. Vitamin D and multiple health outcomes: umbrella
review of systematic reviews and meta-analyses of observational studies and randomised trials. BMJ
2014; 348:g2035.
68. Robinson-Cohen C, Hoofnagle AN, Ix JH, et al. Racial differences in the association of serum 25hydroxyvitamin D concentration with coronary heart disease events. JAMA 2013; 310:179.
69. Norris KC, Williams SF. Race/ethnicity, serum 25-hydroxyvitamin D, and heart disease. JAMA 2013;
310:153.
70. Rostand SG. Ultraviolet light may contribute to geographic and racial blood pressure differences.
Hypertension 1997; 30:150.
71. Li YC, Kong J, Wei M, et al. 1,25-Dihydroxyvitamin D(3) is a negative endocrine regulator of the reninangiotensin system. J Clin Invest 2002; 110:229.
72. Bouillon R. Vitamin D as potential baseline therapy for blood pressure control. Am J Hypertens 2009;
22:816.
73. Forman JP, Giovannucci E, Holmes MD, et al. Plasma 25-hydroxyvitamin D levels and risk of incident
hypertension. Hypertension 2007; 49:1063.
74. Scragg R, Sowers M, Bell C. Serum 25-hydroxyvitamin D, ethnicity, and blood pressure in the Third
National Health and Nutrition Examination Survey. Am J Hypertens 2007; 20:713.
11/15
24/9/2014
75. Schmitz KJ, Skinner HG, Bautista LE, et al. Association of 25-hydroxyvitamin D with blood pressure in
predominantly 25-hydroxyvitamin D deficient Hispanic and African Americans. Am J Hypertens 2009;
22:867.
76. Witham MD, Nadir MA, Struthers AD. Effect of vitamin D on blood pressure: a systematic review and
meta-analysis. J Hypertens 2009; 27:1948.
77. Pittas AG, Chung M, Trikalinos T, et al. Systematic review: Vitamin D and cardiometabolic outcomes.
Ann Intern Med 2010; 152:307.
78. Forman JP, Scott JB, Ng K, et al. Effect of vitamin D supplementation on blood pressure in blacks.
Hypertension 2013; 61:779.
79. Witham MD, Price RJ, Struthers AD, et al. Cholecalciferol treatment to reduce blood pressure in older
patients with isolated systolic hypertension: the VitDISH randomized controlled trial. JAMA Intern Med
2013; 173:1672.
80. McGreevy C, Williams D. New insights about vitamin D and cardiovascular disease: a narrative review.
Ann Intern Med 2011; 155:820.
81. Wang L, Song Y, Manson JE, et al. Circulating 25-hydroxy-vitamin D and risk of cardiovascular
disease: a meta-analysis of prospective studies. Circ Cardiovasc Qual Outcomes 2012; 5:819.
82. Wang TJ, Pencina MJ, Booth SL, et al. Vitamin D deficiency and risk of cardiovascular disease.
Circulation 2008; 117:503.
83. Kim DH, Sabour S, Sagar UN, et al. Prevalence of hypovitaminosis D in cardiovascular diseases (from
the National Health and Nutrition Examination Survey 2001 to 2004). Am J Cardiol 2008; 102:1540.
84. Kendrick J, Targher G, Smits G, Chonchol M. 25-Hydroxyvitamin D deficiency is independently
associated with cardiovascular disease in the Third National Health and Nutrition Examination Survey.
Atherosclerosis 2009; 205:255.
85. Elamin MB, Abu Elnour NO, Elamin KB, et al. Vitamin D and cardiovascular outcomes: a systematic
review and meta-analysis. J Clin Endocrinol Metab 2011; 96:1931.
86. Jorde R, Sneve M, Torjesen P, Figenschau Y. No improvement in cardiovascular risk factors in
overweight and obese subjects after supplementation with vitamin D3 for 1 year. J Intern Med 2010;
267:462.
87. Thadhani R, Appelbaum E, Pritchett Y, et al. Vitamin D therapy and cardiac structure and function in
patients with chronic kidney disease: the PRIMO randomized controlled trial. JAMA 2012; 307:674.
88. Takiishi T, Gysemans C, Bouillon R, Mathieu C. Vitamin D and diabetes. Endocrinol Metab Clin North
Am 2010; 39:419.
89. Mathieu C, Gysemans C, Giulietti A, Bouillon R. Vitamin D and diabetes. Diabetologia 2005; 48:1247.
90. Pozzilli P, Manfrini S, Crin A, et al. Low levels of 25-hydroxyvitamin D3 and 1,25-dihydroxyvitamin D3
in patients with newly diagnosed type 1 diabetes. Horm Metab Res 2005; 37:680.
91. Borkar VV, Verma S, Bhalla AK. Low levels of vitamin D in North Indian children with newly diagnosed
type 1 diabetes. Pediatr Diabetes 2010; 11:345.
92. Thorsen SU, Mortensen HB, Carstensen B, et al. No difference in vitamin D levels between children
newly diagnosed with type 1 diabetes and their healthy siblings: a 13-year nationwide Danish study.
Diabetes Care 2013; 36:e157.
93. Dong JY, Zhang WG, Chen JJ, et al. Vitamin D intake and risk of type 1 diabetes: a meta-analysis of
observational studies. Nutrients 2013; 5:3551.
94. Zipitis CS, Akobeng AK. Vitamin D supplementation in early childhood and risk of type 1 diabetes: a
systematic review and meta-analysis. Arch Dis Child 2008; 93:512.
95. Cooper JD, Smyth DJ, Walker NM, et al. Inherited variation in vitamin D genes is associated with
predisposition to autoimmune disease type 1 diabetes. Diabetes 2011; 60:1624.
96. Ozfirat Z, Chowdhury TA. Vitamin D deficiency and type 2 diabetes. Postgrad Med J 2010; 86:18.
97. Vimaleswaran KS, Berry DJ, Lu C, et al. Causal relationship between obesity and vitamin D status: bidirectional Mendelian randomization analysis of multiple cohorts. PLoS Med 2013; 10:e1001383.
98. Zhao G, Ford ES, Li C. Associations of serum concentrations of 25-hydroxyvitamin D and parathyroid
hormone with surrogate markers of insulin resistance among U.S. adults without physician-diagnosed
diabetes: NHANES, 2003-2006. Diabetes Care 2010; 33:344.
99. Kayaniyil S, Vieth R, Retnakaran R, et al. Association of vitamin D with insulin resistance and beta-cell
dysfunction in subjects at risk for type 2 diabetes. Diabetes Care 2010; 33:1379.
100. Kositsawat J, Freeman VL, Gerber BS, Geraci S. Association of A1C levels with vitamin D status in
12/15
24/9/2014
U.S. adults: data from the National Health and Nutrition Examination Survey. Diabetes Care 2010;
33:1236.
101. Cheng S, Massaro JM, Fox CS, et al. Adiposity, cardiometabolic risk, and vitamin D status: the
Framingham Heart Study. Diabetes 2010; 59:242.
102. Reis JP, von Mhlen D, Miller ER 3rd, et al. Vitamin D status and cardiometabolic risk factors in the
United States adolescent population. Pediatrics 2009; 124:e371.
103. Knekt P, Laaksonen M, Mattila C, et al. Serum vitamin D and subsequent occurrence of type 2
diabetes. Epidemiology 2008; 19:666.
104. Liu S, Song Y, Ford ES, et al. Dietary calcium, vitamin D, and the prevalence of metabolic syndrome in
middle-aged and older U.S. women. Diabetes Care 2005; 28:2926.
105. Liu E, Meigs JB, Pittas AG, et al. Predicted 25-hydroxyvitamin D score and incident type 2 diabetes in
the Framingham Offspring Study. Am J Clin Nutr 2010; 91:1627.
106. Song Y, Wang L, Pittas AG, et al. Blood 25-hydroxy vitamin D levels and incident type 2 diabetes: a
meta-analysis of prospective studies. Diabetes Care 2013; 36:1422.
107. Wang H, Xia N, Yang Y, Peng DQ. Influence of vitamin D supplementation on plasma lipid profiles: a
meta-analysis of randomized controlled trials. Lipids Health Dis 2012; 11:42.
108. Rosen CJ, Adams JS, Bikle DD, et al. The nonskeletal effects of vitamin D: an Endocrine Society
scientific statement. Endocr Rev 2012; 33:456.
109. Sollid ST, Hutchinson MY, Fuskevg OM, et al. No effect of high-dose vitamin d supplementation on
glycemic status or cardiovascular risk factors in subjects with prediabetes. Diabetes Care 2014;
37:2123.
110. von Hurst PR, Stonehouse W, Coad J. Vitamin D supplementation reduces insulin resistance in South
Asian women living in New Zealand who are insulin resistant and vitamin D deficient - a randomised,
placebo-controlled trial. Br J Nutr 2010; 103:549.
111. Eyles DW, Smith S, Kinobe R, et al. Distribution of the vitamin D receptor and 1 alpha-hydroxylase in
human brain. J Chem Neuroanat 2005; 29:21.
112. Eyles DW, Feron F, Cui X, et al. Developmental vitamin D deficiency causes abnormal brain
development. Psychoneuroendocrinology 2009; 34 Suppl 1:S247.
113. Holmy T, Moen SM. Assessing vitamin D in the central nervous system. Acta Neurol Scand Suppl
2010; :88.
114. McGrath J. Does 'imprinting' with low prenatal vitamin D contribute to the risk of various adult
disorders? Med Hypotheses 2001; 56:367.
115. Tuohimaa P, Keisala T, Minasyan A, et al. Vitamin D, nervous system and aging.
Psychoneuroendocrinology 2009; 34 Suppl 1:S278.
116. Lee DM, Tajar A, O'Neill TW, et al. Lower vitamin D levels are associated with depression among
community-dwelling European men. J Psychopharmacol 2011; 25:1320.
117. Balion C, Griffith LE, Strifler L, et al. Vitamin D, cognition, and dementia: a systematic review and
meta-analysis. Neurology 2012; 79:1397.
118. Anglin RE, Samaan Z, Walter SD, McDonald SD. Vitamin D deficiency and depression in adults:
systematic review and meta-analysis. Br J Psychiatry 2013; 202:100.
119. Li G, Mbuagbaw L, Samaan Z, et al. Efficacy of vitamin D supplementation in depression in adults: a
systematic review. J Clin Endocrinol Metab 2014; 99:757.
120. Aghajafari F, Nagulesapillai T, Ronksley PE, et al. Association between maternal serum 25hydroxyvitamin D level and pregnancy and neonatal outcomes: systematic review and meta-analysis
of observational studies. BMJ 2013; 346:f1169.
121. Tabesh M, Salehi-Abargouei A, Tabesh M, Esmaillzadeh A. Maternal vitamin D status and risk of preeclampsia: a systematic review and meta-analysis. J Clin Endocrinol Metab 2013; 98:3165.
122. Lawlor DA, Wills AK, Fraser A, et al. Association of maternal vitamin D status during pregnancy with
bone-mineral content in offspring: a prospective cohort study. Lancet 2013; 381:2176.
123. Zhu K, Whitehouse AJ, Hart PH, et al. Maternal vitamin D status during pregnancy and bone mass in
offspring at 20 years of age: a prospective cohort study. J Bone Miner Res 2014; 29:1088.
124. De-Regil LM, Palacios C, Ansary A, et al. Vitamin D supplementation for women during pregnancy.
Cochrane Database Syst Rev 2012; 2:CD008873.
125. Dawodu A, Saadi HF, Bekdache G, et al. Randomized controlled trial (RCT) of vitamin D
supplementation in pregnancy in a population with endemic vitamin D deficiency. J Clin Endocrinol
13/15
24/9/2014
Metab 2013; 98:2337.

126. Hagenau T, Vest R, Gissel TN, et al. Global vitamin D levels in relation to age, gender, skin
pigmentation and latitude: an ecologic meta-regression analysis. Osteoporos Int 2009; 20:133.
127. Melamed ML, Michos ED, Post W, Astor B. 25-hydroxyvitamin D levels and the risk of mortality in the
general population. Arch Intern Med 2008; 168:1629.
128. Ginde AA, Scragg R, Schwartz RS, Camargo CA Jr. Prospective study of serum 25-hydroxyvitamin D
level, cardiovascular disease mortality, and all-cause mortality in older U.S. adults. J Am Geriatr Soc
2009; 57:1595.
129. Virtanen JK, Nurmi T, Voutilainen S, et al. Association of serum 25-hydroxyvitamin D with the risk of
death in a general older population in Finland. Eur J Nutr 2011; 50:305.
130. Jia X, Aucott LS, McNeill G. Nutritional status and subsequent all-cause mortality in men and women
aged 75 years or over living in the community. Br J Nutr 2007; 98:593.
131. Zhao G, Ford ES, Li C, Croft JB. Serum 25-hydroxyvitamin D levels and all-cause and cardiovascular
disease mortality among US adults with hypertension: the NHANES linked mortality study. J Hypertens
2012; 30:284.
132. Zittermann A, Iodice S, Pilz S, et al. Vitamin D deficiency and mortality risk in the general population: a
meta-analysis of prospective cohort studies. Am J Clin Nutr 2012; 95:91.
133. Chowdhury R, Kunutsor S, Vitezova A, et al. Vitamin D and risk of cause specific death: systematic
review and meta-analysis of observational cohort and randomised intervention studies. BMJ 2014;
348:g1903.
134. Schttker B, Jorde R, Peasey A, et al. Vitamin D and mortality: meta-analysis of individual participant
data from a large consortium of cohort studies from Europe and the United States. BMJ 2014;
348:g3656.
135. Cawthon PM, Parimi N, Barrett-Connor E, et al. Serum 25-hydroxyvitamin D, parathyroid hormone,
and mortality in older men. J Clin Endocrinol Metab 2010; 95:4625.
136. Lin SW, Chen W, Fan JH, et al. Prospective study of serum 25-hydroxyvitamin D concentration and
mortality in a Chinese population. Am J Epidemiol 2012; 176:1043.
137. Noordam R, de Craen AJ, Pedram P, et al. Levels of 25-hydroxyvitamin D in familial longevity: the
Leiden Longevity Study. CMAJ 2012; 184:E963.
138. Chung M, Balk EM, Brendel M, et al. The relationship of vitamin D and calcium intakes to nutrient
status indicators and health outcomes. Evidence Report No. XXX (prepared by the Tufts Evidencebased Practice Center under Contract No. HHSA-290-2007-10055-1). AHRQ publication No. 0XE0XX. Rockville, MD: Agency for Healthcare Research and Quality. June 2009.
139. Amer M, Qayyum R. Relationship between 25-hydroxyvitamin D and all-cause and cardiovascular
disease mortality. Am J Med 2013; 126:509.
140. Freedman DM, Looker AC, Abnet CC, et al. Serum 25-hydroxyvitamin D and cancer mortality in the
NHANES III study (1988-2006). Cancer Res 2010; 70:8587.
141. Michalsson K, Baron JA, Snellman G, et al. Plasma vitamin D and mortality in older men: a
community-based prospective cohort study. Am J Clin Nutr 2010; 92:841.
142. Li M, Chen P, Li J, et al. Review: the impacts of circulating 25-hydroxyvitamin D levels on cancer
patient outcomes: a systematic review and meta-analysis. J Clin Endocrinol Metab 2014; 99:2327.
143. Rejnmark L, Avenell A, Masud T, et al. Vitamin D with calcium reduces mortality: patient level pooled
analysis of 70,528 patients from eight major vitamin D trials. J Clin Endocrinol Metab 2012; 97:2670.
144. Bjelakovic G, Gluud LL, Nikolova D, et al. Vitamin D supplementation for prevention of mortality in
adults. Cochrane Database Syst Rev 2014; 1:CD007470.
145. Hunter D, De Lange M, Snieder H, et al. Genetic contribution to bone metabolism, calcium excretion,
and vitamin D and parathyroid hormone regulation. J Bone Miner Res 2001; 16:371.
146. Wang TJ, Zhang F, Richards JB, et al. Common genetic determinants of vitamin D insufficiency: a
genome-wide association study. Lancet 2010; 376:180.
147. Levin GP, Robinson-Cohen C, de Boer IH, et al. Genetic variants and associations of 25hydroxyvitamin D concentrations with major clinical outcomes. JAMA 2012; 308:1898.
148. Kupferschmidt K. Uncertain verdict as vitamin D goes on trial. Science 2012; 337:1476.
149. The Standing Committee of European Doctors. Vitamin D nutritional policy in Europe, 2009.
http://cpme.dyndns.org:591/adopted/2009/CPME_AD_Brd_241009_179_final_EN.pdf (Accessed on
September 21, 2011).
14/15
24/9/2014
Topic 13915 Version 27.0
Disclosures
Disclosures: Roger Bouillon, MD, PhD, FRCP Patent Holder of university patent licensed to a
company: Hybrigenics France [Vitamin D analogs (Inecalcitol)]. Clifford J Rosen, MD Nothing to
disclose. Jean E Mulder, MD Employee of UpToDate, Inc.
Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these
are addressed by vetting through a multi-level review process, and through requirements for
references to be provided to support the content. Appropriately referenced content is required of all
authors and must conform to UpToDate standards of evidence.
Conflict of interest policy
15/15

Vitamin D and Extraskeletal Health

Diunggah oleh

Informasi Dokumen

Hak Cipta

Format Tersedia

Bagikan dokumen Ini

Bagikan atau Tanam Dokumen

Opsi Berbagi

Apakah menurut Anda dokumen ini bermanfaat?

Apakah konten ini tidak pantas?

Hak Cipta:

Format Tersedia

Vitamin D and Extraskeletal Health

Diunggah oleh

Hak Cipta:

Format Tersedia

24/9/2014

Vitamin D and extraskeletal health

Official reprint from UpToDate

Vitamin D and extraskeletal health

Vitamin D and extraskeletal health

Vitamin D and extraskeletal health

Vitamin D and extraskeletal health

Vitamin D and extraskeletal health

Vitamin D and extraskeletal health

consequence of their limited mobility and sun exposure.

Vitamin D and extraskeletal health

reduced cancer mortality [142].

Vitamin D and extraskeletal health

Definition, clinical manifestations, and treatment".)

Vitamin D and extraskeletal health

Vitamin D and extraskeletal health

Vitamin D and extraskeletal health

Vitamin D and extraskeletal health

Vitamin D and extraskeletal health

Metab 2013; 98:2337.

Vitamin D and extraskeletal health

Topic 13915 Version 27.0

Anda mungkin juga menyukai