VITAMIN D REVEALED: A GUIDE TO CHOLECALCIFEROL

CONTENTS
1. Milestones in the history of Vitamin D
2. Introduction
3. More About of Vitamin D
Synthesis
Metabolism & Physiological funtions
Non Calcemic functions
Normal Levels of Vitamin D in Blood
Benefits of Optimal Levels of Vitamin D
Prevalence of Vitamin D Deficiency
4. Clinical Significance of Vitamin D
Cardiovascular Disease; Hypertension; Diabetes
Osteoarthritis; Multiple Sclerosis; Type 1 Diabetes
Depression; Epilepsy; Migraine
PCOS; Musculoskeletal Pain
Critical Illnesses
Cancer Prevention and Treatment
5. Vitamin D in Cardiovascular Diseases (CVD)
Clinical studies in CVD
6. Vitamin D in Hypertension
Clinical studies in Hypertension
7. Vitamin D in Diabetes
Clinical studies in Diabetes
8. Vitamin D in Auto-Immune Disease and Pains
Vitamin D deficiency in Spine Surgery
Vitamin D and Spinal Cord Disease
Vitamin D and BMD in premenopausal Women

CONTENTS
Vitamin D and Rheumatology
9. Vitamin D and Cancers
Colorectal Cancers
Breast Cancers
Prostate Cancers
Pancreatic Cancers
Rare Cancers
Skin Cancers
Modifying Cancer Risk
10. Vitamin D in Pregnancy
11. Vitamin D in Children
12.Gist of Clinical Studies
Cardiovascular Disease
Hypertension
Diabetes
Pains
Auto-Immune Diseases
Cancer
Falls in Elderly
Longevity
13.Dosing
14.References

MILESTONES IN THE HISTORY OF VITAMIN D
1645-Whistlerwrotethefirstscientificdescriptionofrickets.
1865 - In his textbook on clinical medicine, Trousseau recommended cod
liver oil as treatment for rickets. He also recognized the importance of
sunlightandidentifiedosteomalaciaastheadultformofrickets.
1919 - Mellanby proposed that rickets is due to the absence of a fat-
solubledietaryfactor.
1922 - McCollum and coworkers established the distinction between
vitaminAandtheantirachiticfactor.
1925 - McCollum and coworkers named the antirachitic factor vitamin D.
Hess and Weinstock show that a factor with antirachitic activity is
producedintheskinbyultravioletirradiation.
1936-WindausidentifiedthestructureofvitaminDincodliveroil.
1937 - Schenck obtained crystallized vitamin D3 by activation of 7-
dehydro-cholesterol.
1968 - Haussler and colleagues reported the presence of an active
metaboliteofvitaminDintheintestinalmucosaofchicks.
1969 - Haussler and Norman discovered calcitriol receptors in chick
intestine.
1970 - Fraser and Kodicek discovered that calcitriol is produced in the
kidney.
1971-Normanandcoworkersidentifiedthestructureofcalcitriol.
1973-Fraserandassociatesdiscoveredthepresenceofaninbornerrorof

vitamin D metabolism that produces rickets resistant to vitamin D
therapy.
1978 - De Luca's group discovered a second form of vitamin D-resistant
rickets(TypeII).
1981 - Abe and colleagues in Japan demonstrated that calcitriol is
involvedinthedifferentiationofbone-marrowcells.
1983 - Provvedini and colleagues demonstrated the presence of calcitriol
receptorsinhumanleukocytes.
1984 - The same group presented the evidence that calcitriol has a
regulatoryroleinimmunefunction.
1986 - Morimoto and associates suggested that calcitriol may be useful in
thetreatmentofpsoriasis.
1989 - Baker and associates showed that the vitamin D receptor belongs
tothesteroid-receptorgenefamily.
1994 - The U.S. Food and Drug Administration approved a vitamin D-
basedtopicaltreatmentforpsoriasis,calledcalcipotriol.
2003 - A prospective study from Feskanich and coworkers among 72,000
postmenopausal women in the U.S. over 18 years indicated that women
consuming at least 600 IU vitamin D/day from food plus supplements had
a37%lowerriskofhipfracture.
2006 - Researchers from Harvard School of Public Health examined
cancer incidence and vitamin D exposure in over 47,000 men in the
Health Professionals Follow-Up Study. They found that a high level of
vitamin D (~1500 IU daily) was associated with a 17% reduction in all
cancerincidencesanda29%reductionintotalcancermortalitywitheven
strongereffectsfordigestive-systemcancers.
Reference: Whistler, D. Morbo puerili Anglorum, quem patrio idiomate indigenae vocant The Rickets. Lugduni Batavorum 1-13 (1645).; Glisson, F. De Rachitide sive morbo puerili, qui vulgoThe Rickets diciteur, London 1-416
(1650).; Glisson, F. A treatise of the rickets being a disease common to children. London 1-373 (1668).; Mellanby, E. and Cantag, M.D. Experimental investigation on rickets. Lancet 196:407-412 (1919).; Mellanby, E.
Experimental rickets. Medical Research (G.B.), Special Report Series SRS-61:1-78 (1921).; Hess, A. Influence of light on the prevention of rickets. Lancet 2:1222 (1922).; Steenbock, H. The induction of growth promoting and
calcifying properties in a ration by exposure to light. Science 60:224-225 (1924).; Windaus, A., Linsert, O. Luttringhaus, A. and Weidlinch, G. Uber das krystallistierte Vitamin D2. Justis. Liebigs. Ann. Chem. 492:226-231
(1932).; Brockmann, H. Die Isolierung des antirachitischen Vitamins aus Thunfischleberol. H.-S.Zeit. Physiol. Chem. 241:104-115 (1936).; Crowfoot-Hodgkin, D., Webster, M.S. and Dunitz, J.D. Structure of calciferol. Chem.
Industry1148-1149(1957).;Solecki,R.S.Shanidar:TheHumanityofNeanderthalMan,NewYork:Knopf.pp.1-252(1971).

INTRODUCTION
VitaminDbelongstothegroupoffat-solublevitamins.Thetwoimportant
forms of Vitamin D are vitamin D2 or ergocalciferol - the plant source of
vitamin D - and vitamin D3 also referred as cholecalciferol. Vitamin D3 is
produced in the skin when the skin is exposed to the sun - when the light
energy is absorbed by it. If an individual is exposed adequately to sunlight
thereisnofurtherneedforVitaminDintheformofsupplements.Natural
food sources might not typically have the sufficient amount of Vitamin D
and so a conscious consumption of Vitamin D rich foods and deliberate
exposure of the skin to sunlight is required to prevent possible
deficiencies.
The World Health Organization has responsibility for defining the
"International Unit" of vitamin D3. Their most recent definition, provided
states that "the International Unit of vitamin D recommended for
adoption is the vitamin D activity of 0.025 micrograms of the
internationalstandardpreparationofcrystallinevitaminD3".Thus,1.0IU
ofvitaminD3is0.025micrograms,whichisequivalentto65.0pmoles.
In today’s world ultraviolet light from the sun may be blocked by air
pollution. The tendency to wear clothes, to live in cities where tall
buildings block adequate sunlight from reaching the ground, to live
indoors, to use synthetic sun-screens that block ultraviolet rays, and to
live in geographical regions of the world that do not receive adequate
sunlight, all contribute to the inability of the skin to biosynthesize
sufficient amounts of vitamin D3. Under these conditions vitamin D
becomes a true vitamin in that it must be supplied in the diet on a regular
basis.
Animal products constitute the bulk source of vitamin D. Salt water fish
such as herring, salmon, sardines, and fish liver oils are good sources of
vitamin D3. Small quantities of vitamin D3 are also derived from eggs,
veal, beef, butter, and vegetable oils while plants, fruits, and nuts are
extremelypoorsourcesofvitaminD.

The structures of vitamin D2 (ergocalciferol) and vitamin D3
(cholecalciferol) are presented below. Vitamin D is a generic term and
indicatesamoleculeofthegeneralstructureshownforringsA,B,C,andD
with differing side chain structures. The A, B, C, and D ring structure is
derived from the cyclopentanoperhydrophenanthrene ring structure for
steroids. Technically vitamin D is classified as a seco-steroid. Seco-
steroids are those in which one of the rings has been broken; in vitamin D,
the 9,10 carbon-carbon bond of ring B is broken, and it is indicated by the
inclusionof"9,10-seco"intheofficialnomenclature.
Reference: Utiger, R.D. The need for more vitamin D. N. Engl. J. Med. 228:828-829 (1998).; Holick, M.F. Vitamin D and bone health. J. Nutr. 126 Suppl. 159S-1164S (1996).; Collins, E.D. and Norman, A.W. Vitamin D. In:
Handbook of vitamins, edited by Machlin, L.J. New York: Marcel Dekker, pp. 59-98 (1990).; Subcommittee on the Tenth Edition of the RDAs, Food & Nutrition Board, Commission on Life Sciences and National Research
Council.Recommendeddietaryallowances,Washington,D.C.:NationalAcademyPress.Ed.10thpp.1-285(1989).

SYNTHESIS OF VITAMIN D
7-Dehydrocholesterol
Cholecalciferol
(Vitamin D3)
Dietary Intake
Liver
Kidney
25 Hydroxy
Vitamin D3
1, 25 Dihydroxy Vitamin D3
Vitamin D3 (fish & meat)
Vitamin D2 (Supplements)
SKIN
Reference:ClinicalLaboratoryNews,December2007:Volume33,Number12

METABOLISM OF VITAMIN D
Intestinal absorption
of calcium
PTH mediated
bone resorption
Renal Ca++ and
phosphate excretion
UV Light
7-dehydrocholesterol 7-dehydrocholesterol
Liver
Kidney
Cholecalciferol
Vitamin D3
Calcitriol
1,25 dihydroxy Vitamin D
24,25 dihydroxy Vitamin D
Ergocalciferol
Vitamin D2
Calcidiol
25-hydroxy Vitamin D
Reference:Literaturereview,ZalmanSAgus,MDEmeritusProfessorofMedicineandPhysiology;AssociateDean,CMEPerelmanSchoolofMedicineattheUniversityofPennsylvania

NON CALCEMIC FUNCTIONS OF 1,25-DIHYDROXY VITAMIN D
Vitamin D
Decreased
Renin
Adaptive
Immune
Modulation
VDR-RXR
VDR-RXR
Decreased
25 (OH)D 1-OHase
1-OHase
Increased
1-OHase
p21, p27 etc
25 (OH) D2
1,25 (OH) D2
Activated T & B
Lymphocytes
Pancreas
Increased
Insulin Secretion
Increased
25 (OH) D2
Innate
Immune Modulation
Cytokines
Macrophage
Increased
VDR mRNA,
1-OHase mRNA
M.Tuberculosis
Death
LPS
TLR
Solar UV
Radiation
Dietary
Sources
Liver
Maintenance of normal cell proliferation
in prostate, colon, breast etc
Increased
CD
Reference: Hewison M, et al. Molecular and Cellular Endocrinology 2004; 215: 31-38.; Helming L, et al. Blood 2005; 106: 4351-4358; Abu-Amer Y, Bar-Shavit Z. Cellular Immunology 1993; 151: 356-368. Cohen MS, et al.
JournalofImmunology1986;136:1049-1053.;WangTT,etal.JournalofImmunology2004;173:2909-2912.;OrvHetil.2011Aug14;152(33):1312-9.;Immunology.2011Oct;134(2):123-39

NORMAL LEVELS OF CIRCULATING 25 (OH)D
Severely deficient
Deficient
Insufficient
Sufficient
Optimal
<8ng/ml
8 - 19ng/ml
20 - 29ng/ml
30 - 49ng/ml
50 - 99ng/ml
25 Hydroxy Vitamin D (ng/ml)
PTH Levels
6-10 11-15 16-20 21-25 26-30 >30
Serum 25 (OH)D (nmol/L)
AbsorptionFraction
Calcium Absorption
0.0
20 40 60 80 100 120 140
0.1
0.2
0.3
0.4
0.5
Reference:EndocrineSociety’s ClinicalGuideline2011
ParaThyroidHormone(pg/ml)
20
0-5
30
40
50
60
70
80
90
100

BENEFITS WITH OPTIMAL LEVELS OF VITAMIN D
SKELETAL-MUSCULAR
STRONG MUSCLES AND BONES
INFECTIONS
PREVENT INFLUENZA, TREAT TUBERCULOSIS
CANCER
PREVENT BREAST, COLON, AND PROSTATE CANCER
AUTOIMMUNE DISEASES
PREVENT MULTIPLE SCLEROSIS AND TYPE 1 DIABETES
CARDIOVASCULAR DISEASE
SLOW PROGRESSION OF ATHEROSCLEROSIS
TREAT HYPERTENSION AND CONGESTIVE HEART FAILURE
NEUROPSYCHIATRIC DISORDERS
PREVENT SCHIZOPHRENIA AND RELIEVE DEPRESSION

PREVALENCE OF VITAMIN D DEFICIENCY
67% of healthy Indians from Lucknow has serum 25(OH)D levels < 15 ng/ml -Arya V,
Osteoporosis Int 2004
Vitamin D deficiency (25 (OH)D<20ng/dl) reported in 83% of healthy adults in
Kashmir - Zargar et al Postgraduate Medical Journal 2007
85% of healthy Indian adult men could not achieve normal serum 25(OH)D levels
despite adequate outdoor activities and sun exposure - Marwaha RK & Tandon N et al Journal of
Clinical Densitometry 2009
Prevalence of vitamin D deficiency in Indian lactating women and infants (<20
ng/ml) is 93.8% - Seth A and Marwaha RK et al;JPEM 2009
Studies on bone mineral health from different parts of India indicate wide
prevalence of vitamin D deficiency (VDD) in all age groups including neonates,
infants, school children, pregnant / lactating women and adult males and females
residing in rural and urban India- Marwaha RK et al
No. of
Patients
History of
Cancer
25-hydroxyvitamin D3
Level (ng/ml)
7 (9.6 %) 1 (colon) < 8 (severely deficient)
41 (56.2%) 6 8-19.9 (deficient)
9 (12.3%) 0 20-29.9 (insufficient)
13 (17.8%) 0 30-49.9 (sufficient)
3 (4.1%) 0 50-100 (optimal)
PREOP VITAMIN D3 LEVELS IN 73 VETERANS UNDERGOING HEART SURGERY AT THE
SEATTLE VA HOSPITAL

CLINICAL SIGNIFICANCE OF
VITAMIN D
REFERENCE: THE CLINICAL IMPORTANCE OF VITAMIN D (CHOLECALCIFEROL): A PARADIGM SHIFT WITH IMPLICATIONS FOR ALL HEALTHCARE PROVIDERS; Alex Vasquez, DC, ND, Gilbert Manso, MD, John Cannell, MD;
ALTERNATIVETHERAPIES,sept/oct2004,VOL.10,NO.5

CLINICAL SIGNIFICANCE OF VITAMIN D
CARDIOVASCULAR DISEASE
Deaths from cardiovascular disease are more common in the winter,
more common at higher latitudes and more common at lower altitudes,
observations that are consistent with vitamin D insufficiency. The risk of
heart attack is twice as high for those with 25(OH)D levels less than 34
ng/ml (85 nmol/L) than for those with vitamin D status above this level.
Patients with congestive heart failure were recently found to have
markedlylowerlevelsofvitaminDthancontrols,andvitaminDdeficiency
as a cause of heart failure has been documented in numerous case
reports.
HYPERTENSION
It has long been known that blood pressure is higher in the winter than
the summer, increases at greater distances from the equator and is
affected by skin pigmentation—all observations consistent with a role for
vitamin D in regulating blood pressure. When patients with hypertension
were treated with ultraviolet light three times a week for six weeks their
vitamin D levels increased by 162%, and their blood pressure fell
significantly. Even small amounts of oral cholecalciferol (800 IU) for eight
weeksloweredbothbloodpressureandheartrate.
Type2Diabetes
Hypovitaminosis D is associated with insulin resistance and beta-cell
dysfunction in diabetics and young adults who are apparently healthy.
Healthy adults with higher serum 25(OH)D levels had significantly lower
60 min, 90 min and 129 min postprandial glucose levels and significantly
better insulin sensitivity than those who were vitamin D deficient. The
authors noted that, compared with metformin, which improves insulin
sensitivity by 13%, higher vitamin D status correlated with a 60%
improvement in insulin sensitivity. In a recent clinical trial using 1,332
IU/day for only 30 days in 10 women with type 2 diabetes, vitamin D
supplementationwasshowntoimproveinsulinsensitivityby21%.

OSTEOARTHRITIS
We know that vitamin D prevents and treat osteoporosis, but few know
that the progression of osteoarthritis, the most common arthritis, is
lessened by adequate blood levels of vitamin D. Framingham data
showed osteoarthritis of the knee progressed more rapidly in those with
25(OH)D levels lower than 36 ng/ml (90 nmol/L). Another study found
that osteoarthritis of the hip progressed more rapidly in those with
25(OH)Dlevelslowerthan30ng/ml(75nmol/L).
MULTIPLE SCLEROSIS
Theautoimmune/inflammatorydiseasemultiplesclerosis(MS)isnotably
rare in sunny equatorial regions and becomes increasingly prevalent
among people who live farther from the equator and/or who lack
adequate sun exposure. In a clinical trial with 10 MS patients, Goldberg,
Fleming, and Picard prescribed daily supplementation with
approximately 1,000 mg calcium, 600 mg magnesium, and 5,000 IU
vitamin D (from 20 g cod liver oil) for up to two years and found a
reduction in the number of exacerbations and an absence of adverse
effects.Thisisoneofveryfewstudiesinhumansthatemployedsufficient
daily doses of vitamin D (5,000 IU) and had sufficient duration (2 years).
More recently, Mahon et al gave 800 mg calcium and 1,000 IU vitamin D
per day for six months to 39 patients with MS and noted a modest anti-
inflammatoryeffect.
PREVENTION OF TYPE 1DIABETES
Type 1 diabetes is generally caused by autoimmune/inflammatory
destruction of the pancreatic beta-cells. Vitamin D supplementation
shows significant preventive and ameliorative benefits in type 1
diabetics. In a study with more than 10,000 participants, showed that
supplementation in infants and children with 2,000 IU of vitamin D per
dayreducedtheincidenceoftype1diabetesbyapproximately80%.

Depression
Seasonal affective disorder (SAD) is a particular subtype of depression
characterized by the onset or exacerbation of melancholia during winter
months when bright light, sun exposure, and serum 25(OH)D levels are
reduced. Recently, a dose of 100,000 IU of vitamin D was found superior
to light therapy in the treatment of SAD after one month. Similarly, in a
study involving 44 subjects, supplementation with 400 or 800 IU per day
was found to significantly improve mood within five days of
supplementation.
EPILEPSY
Seizures can be the presenting manifestation of vitamin D deficiency.39
Hypovitaminosis D decreases the threshold for and increases the
incidence of seizures, and several “anticonvulsant” drugs interfere with
theformationofcalcitriolinthekidneyandfurtherreducecalcitriollevels
via induction of hepatic clearance. Therefore, antiepileptic drugs may
lead to iatrogenic seizures by causing iatrogenic hypovitaminosis D.
Conversely, supplementation with 4,000–16,000 IU per day of vitamin D2
was shown to significantly reduce seizure frequency in a placebo
controlledpilotstudybyChristiansenetal.
MIGRAINE HEADACHES
Calcium clearly plays a role in the maintenance of vascular tone and
coagulation, both of which are altered in patients with migraine. Thys-
Jacobs reported two cases showing a reduction in frequency, duration,
and severity of menstrual migraine attacks following daily
supplementationwith1,200mgofcalciumand 1,200–1,600IUofvitamin
DinwomenwithvitaminDdeficiency.

POLYCYSTIC OVARY SYNDROME
Polycystic ovary syndrome (PCOS) is a disease seen only in humans and is
classically characterized by polycystic ovaries, amenorrhea, hirsuitism,
insulin resistance, and obesity. Animal studies have shown that calcium is
essential for oocyte activation and maturation. Vitamin D deficiency was
highly prevalent among 13 women with PCOS, and supplementation with
1,500 mg of calcium per day and vitamin D normalized menstruation
and/or fertility in nine of nine women with PCOS-related menstrual
irregularitieswithinthreemonthsoftreatment.
MUSCULOSKELETAL PAIN
Patients with non-traumatic, persistent musculoskeletal pain show an
impressively high prevalence of overt vitamin D deficiency. Plotnikoff and
Quigley recently showed that 93% of their 150 patients with persistent,
nonspecific musculoskeletal pain were overtly deficient in vitamin D.
Masood et al found a high prevalence of vitamin D deficiency in children
with limb pain, and vitamin D supplementation ameliorated pain within
threemonths. AlFaraj and AlMutairifound vitaminD deficiencyin83%of
their 299 patients with low-back pain, and supplementation with
5,000–10,000 IU of vitamin D per day lead to pain reduction in nearly
100%ofpatientsafterthreemonths.

CRITICAL ILLNESS AND AUTOIMMUNE/INFLAMMATORY CONDITIONS
Deficiency of vitamin D is common among patients with inflammatory
and autoimmune disorders and those with prolonged critical illness. In
addition to the previously mentioned epidemic of vitamin D insufficiency
in patients with MS, we also see evidence of vitamin D insufficiency in a
largepercentageofpatientswithGrave’sdisease,ankylosingspondylitis,
systemic lupus erythematosus, and rheumatoid arthritis. Clinical trials
with proper dosing and duration need to be performed in these patient
groups. C-reactive protein was reduced by 23% and matrix
metalloproteinase-9 was reduced by 68% in healthy adults following
bolusinjectionsofvitaminDthatresultedinanaveragedoseof547IUper
day for 2.5 years. A recent trial of vitamin D supplementation in patients
withprolongedcriticalillnessshowedasignificantanddose-dependent
“anti-inflammatory effect” evidenced by reductions in IL-6 and CRP.
However, the insufficient dose of only 400 IU per day (administered
intravenously) for only ten days precluded more meaningful and
beneficialresults,andwepresentguidelinesforfuturestudieslaterinthis
paper.

CANCER PREVENTION AND TREATMENT
The inverse relationship between sunlight exposure and cancer mortality
was documented by Apperly in 1941. Vitamin D has anti-cancer effects
mediated by anti-proliferative and proapoptotic mechanisms which are
augmented by modulation of nuclear receptor function and enzyme
action, and limited research shows that synthetic vitamin D analogs may
have a role in the treatment of human cancers. Grant has shown that
inadequate exposure to sunlight, and hence hypovitaminosis D, is
associated with an increased risk of cancer mortality for several
malignancies, namely those of the breast, colon, ovary, prostate, bladder,
esophagus, kidney, lung, pancreas, rectum, stomach, uterus, and non-
Hodgkin lymphoma. He proposes that adequate exposure to ultraviolet
light and/or supplementation with vitamin D could save more than
23,000 American lives per year from a reduction in cancer mortality
alone.
The aforementioned clinical trials using vitamin D in a wide range of
health conditions have helped to expand our concept of vitamin D and to
appreciate its manifold benefits. However, in light of new research
showing that the physiologic requirement is 3,000–5,000 IU/day for
adults and that serum levels plateau only after 3-4 months of daily
supplementation, we must conclude that studies using lower doses
and/or shorter durations have underestimated the clinical efficacy of
vitaminD.

VITAMIN D IN CARDIO VASCULAR
DISEASES

VITAMIN D - BENEFITS IN CARDIOVASCULAR DISEASES
Inhibitionofvascularsmoothmuscleproliferation
The hormonal metabolite of vitamin D, 1,25-dihyroxyvitamin D inhibits
endothelin (ET)-dependent DNA synthesis and cell proliferation by
suppressing ET-induced activation of cyclin-dependent kinase 2 (Cdk2), a key
1
cellcyclekinase .
Suppressionofvascularcalcification
Medial calcification is associated with proliferation of vascular smooth
2
muscle cells . Vascular calcification can be affected by vitamin D receptors
(VDRs), which affect gene activation. When 25(OH)D levels are low, not
enough VDRs can be activated to inhibit calcification. The benefit of vitamin
D is likely due to its activation of the VDR in vasculature and cardiac
3
myocytes . One of the effects of calcitriol is to act upon osteoclast precursor
cells and suppresses their differentiation in addition to intestinal and renal
4
regulationofcalciumandphosphorus .
Vitamin D suppresses vascular calcification primarily by regulating
parathyroid hormone (PTH). High PTH causes mineral and skeletal
abnormalities predisposing to ectopic calcifications and increased
4
mortality . PTH levels decline fairly rapidly with increasing serum 25(OH)D
5,6
levels to about 75 nmol/L, with little change thereafter . There are various
lines of evidence that elevated PTH levels are linked to increased risk of
vascularproblemsanddementia.
Reductionofinflammation
An observational study in England found a statistically significant inverse
correlation between serum 25(OH)D and tissue plasminogen activator (tPA)
7
antigen, with tPA levels peaking in August . (tPA is a protein involved in the
breakdown of blood clots. As an enzyme, it catalyzes the conversion of
plasminogen to plasmin, the major enzyme responsible for clot breakdown.
Because it works on the clotting system, tPA is used in clinical medicine to
treat only embolic or thrombotic stroke.) tPA antigen was found to be
8
associatedwithincidenceofcoronaryheartdisease .

In a study of the effects of calcitriol on synthesis of mitochondrial RNAs
encoding interleukin-6 (IL-6), interferon-gamma (IFN-gamma) in
trophoblasts challenged with TNF-alpha found calcitriol inhibited the
expression profile of inflammatory cytokine genes in a dose-response
9
manner (P<0.05) . Further findings regarding calcitriol and TNF-alpha are
6
giveninDussoetal .
Another way 25(OH)D reduces risk of CVD is through reduction in matrix
10
metalloproteinases (MMPs) such as MMP9 . MMPs are a class of enzymes
that can break down proteins, such as collagen and gelatin, and, thus,
damagetissuesinthevascularsystem. MMP-2,MMP-9,TIMP-1,andTIMP-2
plasma levels were higher in diabetic, ACS, and DACS patients, which may
reflect abnormal extracellular matrix metabolism in diabetes and in acute
11
coronary syndrome . Serum MMP-9 has a modest association with incident
CHD in the general population, which is not independent of cigarette
smoking exposure and circulating markers of generalized inflammation.
MMP-9 is unlikely to be a clinically useful biomarker of CHD risk, but may still
12
play a role in the pathogenesis of CHD . MMP-8 also plays a role in
13,14
atherosclerosis .
Reductionofbloodpressure
Hypertension is a risk factor for CVD. See the document on hypertension for
evidencethatvitaminDreducestheriskofhypertension.
Musclefunction
15
Muscle wasting is a characteristic of congestive heart failure . There is
16
growing evidence that vitamin D helps maintain muscle mass and strength
17
and avoid sarcopenia (lack of muscle mass) . The mechanism seems to be
18
avoidanceofhypophosphatemiarelatedtovitaminDdeficiency . VitaminD
also protects the myocardium, which protect against heart failure or
19
arrhythmias .
VITAMIN D - BENEFITS IN CARDIOVASCULAR DISEASES

CLINICAL STUDIES OF VITAMIN D
IN CARDIO VASCULAR DISEASES

Short-term vitamin D3 supplementation lowers plasma renin activity in
patientswithstablechronicheartfailure:anopen-label,blindedendpoint,
randomizedprospectivetrial(VitD-CHFtrial).
2013Aug;166(2):357-364.e2.
BACKGROUND:Manychronicheartfailure(CHF)patientshavelowvitaminD
(VitD) and high plasma renin activity (PRA), which are both associated with
poor prognosis. Vitamin D may inhibit renin transcription and lower PRA. We
investigated whether vitamin D3 (VitD3) supplementation lowers PRA in CHF
patients.
METHODS AND RESULTS: We conducted a single-center, open-label, blinded
end point trial in 101 stable CHF patients with reduced left ventricular
ejection fraction. Patients were randomized to 6 weeks of 2,000 IU oral VitD3
daily or control. At baseline, mean age was 64 ± 10 years, 93% male, left
ventricular ejection fraction 35% ± 8%, and 56% had VitD deficiency. The
geometric mean (95% CI) of 25-hydroxyvitamin D3 increased from 48 nmol/L
(43-54) at baseline to 80 nmol/L (75-87) after 6 weeks in the VitD3 treatment
group and decreased from 47 nmol/L (42-53) to 44 nmol/L (39-49) in the
control group (P < .001). The primary outcome PRA decreased from 6.5
ng/mL per hour (3.8-11.2) to 5.2 ng/mL per hour (2.9-9.5) in the VitD3
treatment group and increased from 4.9 ng/mL per hour (2.9-8.5) to 7.3
ng/mL per hour (4.5-11.8) in the control group (P = .002). This was paralleled
by a larger decrease in plasma renin concentration in the VitD3 treatment
group compared to control (P = .020). No significant changes were observed
in secondary outcome parameters, including N-terminal pro-B-type
natriureticpeptidenatriureticpeptideandfibrosismarkers.
CONCLUSIONS: Most CHF patients had VitD deficiency and high PRA levels.
Six weeks of supplementation with 2,000 IU VitD3 increased 25-
hydroxyvitamin D3 levels and decreased PRA and plasma renin
concentration.
AmHeartJ.

VITAMIN D DEFICIENCY AND SUPPLEMENTATION AND RELATION TO
CARDIOVASCULAR HEALTH.
AmericanJournalofCardiology2012Feb1;109(3):359-63.
Recent evidence supports an association between vitamin D deficiency and
hypertension, peripheral vascular disease, diabetes mellitus, metabolic
syndrome, coronary artery disease, and heart failure. The effect of vitamin D
supplementation, however, has not been well studied. We examined the
associations between vitamin D deficiency, vitamin D supplementation, and
patient outcomes in a large cohort. Serum vitamin D measurements for 5
years and 8 months from a large academic institution were matched to
patientdemographic,physiologic,anddiseasevariables.ThevitaminDlevels
were analyzed as a continuous variable and as normal (≥ 30 ng/ml) or
deficient (<30 ng/ml). Descriptive statistics, univariate analysis, multivariate
analysis, survival analysis, and Cox proportional hazard modeling were
performed. Of 10,899 patients, the mean age was 58 ± 15 years, 71% were
women(n=7,758),andtheaveragebodymassindexwas30±8kg/m(2).The
mean serum vitamin D level was 24.1 ± 13.6 ng/ml. Of the 10,899 patients,
3,294 (29.7%) were in the normal vitamin D range and 7,665 (70.3%) were
deficient.
In conclusion, vitamin D deficiency was associated with a
significant risk of cardiovascular disease and reduced survival. Vitamin D
supplementation was significantly associated with better survival,
specificallyinpatientswithdocumenteddeficiency.
Vitamin D deficiency was associated with several cardiovascular-
related diseases, including hypertension, coronary artery disease,
cardiomyopathy, and diabetes (all p <0.05). Vitamin D deficiency was a
strong independent predictor of all-cause death (odds ratios 2.64, 95%
confidence interval 1.901 to 3.662, p <0.0001) after adjusting for multiple
clinical variables. Vitamin D supplementation conferred substantial survival
benefit (odds ratio for death 0.39, 95% confidence interval 0.277 to 0.534, p
<0.0001).

PREVALENCE OF VITAMIN D DEFICIENCY IN PATIENTS WITH ACUTE MYOCARDIAL
INFARCTION.
AmericanJournalofCardiology2011Jun1;107(11):1636-8.
Deficiencyin25-hydroxyvitaminD(25[OH]D)isatreatableconditionthathas
been associated with coronary artery disease and many of its risk factors. A
practicaltimetoassessfor25(OH)Ddeficiency,andtoinitiatetreatment,isat
the time of an acute myocardial infarction. The prevalence of 25(OH)D
deficiency and the characteristics associated with it in patients with acute
myocardial infarction are unknown. In this study, 25(OH)D was assessed in
239 subjects enrolled in a 20-hospital prospective myocardial infarction
registry. Patients enrolled from June 1 to December 31, 2008, had serum
samples sent to a centralized laboratory for analysis using the DiaSorin
25(OH)D assay. Normal 25(OH)D levels are ≥ 30 ng/ml, and patients with
levels <30 and >20 ng/ml were classified as insufficient and those with levels
≤ 20 ng/ml as deficient. Vitamin D levels and other baseline characteristics
were analyzed with the linear or Mantel-Haenszel trend test. Of the 239
enrolled patients, 179 (75%) were 25(OH)D deficient and 50 (21%) were
insufficient, for a total of 96% of patients with abnormally low 25(OH)D
levels. No significant heterogeneity was observed among age or gender
subgroups, but 25(OH)D deficiency was more commonly seen in non-
Caucasian patients and those with lower social support, no insurance,
diabetes, and lower activity levels. Higher parathyroid hormone levels (45.3
vs 32.7 pg/ml, p = 0.029) and body mass indexes (31.2 vs 29.0 kg/m(2), p =
0.025) were also observed in 25(OH)D-deficient subjects. In conclusion,
vitamin D deficiency is present in almost all patients with acute myocardial
infarctioninamulticenterUnitedStatescohort.
VitaminDdeficiencyispresentinalmost(96%)ofpatientswithacuteMI

VITAMIN D, PARATHYROID HORMONE, AND SUDDEN CARDIAC DEATH: RESULTS FROM
THE CARDIOVASCULAR HEALTH STUDY.
Hypertension.2011Dec;58(6):1021-8.
Recent studies have demonstrated greater risks of cardiovascular events and
mortality among persons who have lower 25-hydroxyvitamin D (25-OHD)
and higher parathyroid hormone (PTH) levels. We sought to evaluate the
association between markers of mineral metabolism and sudden cardiac
death (SCD) among the 2312 participants from the Cardiovascular Health
Study who were free of clinical cardiovascular disease at baseline. We
estimated associations of baseline 25-OHD and PTH concentrations
individually and in combination with SCD using Cox proportional hazards
models after adjustment for demographics, cardiovascular risk factors, and
kidney function. During a median follow-up of 14 years, there were 73
adjudicated SCD events. The annual incidence of SCD was greater among
subjects who had lower 25-OHD concentrations, 2 events per 1000 for 25-
OHD ≥20 ng/mL and 4 events per 1000 for 25-OHD <20 ng/mL. Similarly, SCD
incidence was greater among subjects who had higher PTH concentrations, 2
eventsper1000forPTH<65pg/mLand4eventsper1000forPTH≥65pg/mL.
Multivariate adjustment attenuated associations of 25-OHD and PTH with
SCD. Finally, 267 participants (11.7% of the cohort) had high PTH and low 25-
OHD concentrations. This combination was associated with a >2-fold risk of
SCD after adjustment (hazard ratio: 2.19 [95% CI: 1.17-4.10]; P=0.017)
compared with participants with normal levels of PTH and 25-OHD. The
combination of lower 25-OHD and higher PTH concentrations appears to be
associated independently with SCD risk among older adults without
cardiovasculardisease.
Lower 25-OHD and higher PTH concentrations appears to increases sudden
cardiacarrestriskby>2fold.

VITAMIN D STATUS IS ASSOCIATED WITH ARTERIAL STIFFNESS AND VASCULAR
DYSFUNCTION IN HEALTHY HUMANS.
JournaloftheAmericanCollegeofCardiology2011Jul5;58(2):186-92.
OBJECTIVES: The primary objective of this study was to elucidate
mechanisms underlying the link between vitamin D status and
cardiovascular disease by exploring the relationship between 25-
hydroxyvitamin D (25-OH D), an established marker of vitamin D status, and
vascularfunctioninhealthyadults.
BACKGROUND: Mechanisms underlying vitamin D deficiency-mediated
increased risk of cardiovascular disease remain unknown. Vitamin D
influences endothelial and smooth muscle cell function, mediates
inflammation, and modulates the renin-angiotensin-aldosterone axis. We
investigated the relationship between vitamin D status and vascular function
inhumans,withthehypothesisthatvitaminDinsufficiencywillbeassociated
withincreasedarterialstiffnessandabnormalvascularfunction.
METHODS: We measured serum 25-OH D in 554 subjects. Endothelial
function was assessed as brachial artery flow-mediated dilation, and
microvascular function was assessed as digital reactive hyperemia index.
Carotid-femoral pulse wave velocity and radial tonometry-derived central
augmentation index and subendocardial viability ratio were measured to
assessarterialstiffness.
RESULTS: Mean 25-OH D was 31.8 ± 14 ng/ml. After adjustment for age, sex,
race, body mass index, total cholesterol, low-density lipoprotein,
triglycerides, C-reactive protein, and medication use, 25-OH D remained
independentlyassociatedwithflow-mediatedvasodilation(β=0.1,p=0.03),
reactive hyperemia index (β = 0.23, p < 0.001), pulse wave velocity (β = -0.09,
p = 0.04), augmentation index (β = -0.11, p = 0.03), and subendocardial
viability ratio (β = 0.18, p = 0.001). In 42 subjects with vitamin D insufficiency,
normalization of 25-OH D at 6 months was associated with increases in
reactivehyperemiaindex(0.38±0.14,p=0.009)andsubendocardialviability

VITAMIN D STATUS IS ASSOCIATED WITH ARTERIAL STIFFNESS AND VASCULAR
DYSFUNCTION IN HEALTHY HUMANS.
ratio (7.7 ± 3.1, p = 0.04), and a decrease in mean arterial pressure (4.6 ± 2.3
mmHg,p=0.02).
CONCLUSIONS: Vitamin D insufficiency is associated with increased arterial
stiffness and endothelial dysfunction in the conductance and resistance
blood vessels in humans, irrespective of traditional risk burden. Our findings
provide impetus for larger trials to assess the effects of vitamin D therapy in
cardiovasculardisease.
25-OH D remained independently associated with flow-mediated
vasodilation (p = 0.03), reactive hyperemia index (p < 0.001), pulse wave
velocity (p = 0.04), augmentation index (p = 0.03), and subendocardial
viabilityratio(p=0.001).

VITAMIN D STATUS AND OUTCOMES IN HEART FAILURE PATIENTS.
EuropeanJournalofHeartFailure2011Jun;13(6):619-25.
AIMS: Vitamin D status has been implicated in the pathophysiology of heart
failure (HF). The aims of this study were to determine whether a low vitamin
D status is associated with prognosis in HF and whether activation of the
renin-angiotensin system (RAS) and inflammatory markers could explain this
potentialassociation.
METHODS AND RESULTS: We measured 25-hydroxy-vitamin D (25(OH)D),
plasma renin activity(PRA), interleukin-6(IL-6), C-reactive protein (CRP), and
the incidence of death or HF rehospitalization in 548 patients with HF.
Median age was 74 (64-80) years, left ventricular ejection fraction was 30%
(23-42), and mean follow-up was 18 months. Low 25(OH)D levels were
associated with female gender (P< 0.001), higher age (P= 0.002), and higher
N-terminal pro-brain natriuretic peptide (NT-proBNP) levels (P< 0.001).
Multivariable linear regression analysis showed that PRA (P= 0.048), and CRP
levels (P= 0.006) were independent predictors of 25(OH)D levels. During
follow-up, 155 patients died and 142 patients were rehospitalized. Kaplan-
Meier analysis showed that
After adjustment in a multivariable Cox
regression analysis, low 25(OH)D concentration remained independently
associated with an increased risk for the combined endpoint [hazard ratio
(HR) 1.09 per 10 nmol/L decrease; 95% confidence interval (CI) 1.00-1.16; P=
0.040] and all-cause mortality (HR 1.10 per 10 nmol/L decrease; 95% CI 1.00-
1.22;P=0.049).
CONCLUSION: A low 25(OH)D concentration is associated with a poor
prognosis in HF patients. Activation of the RAS and inflammation may confer
theadverseeffectsoflowvitaminDlevels.
lower 25(OH)D concentration was associated
with an increased risk for the combined endpoint (all-cause mortality and HF
rehospitalization; log rank test P= 0.045) and increased risk for all-cause
mortality (log rank test P= 0.014).

VITAMIN D - BENEFITS IN HYPERTENSION
Vitamin D lowers blood pressure by affecting the renin angiotensin
1 2 3
aldosterone system by suppressing renin . Renin is a proteolytic enzyme
secreted by the kidneys, which catalyzes the production of angiotensin,
which, in turn, mediates extracellularfluid volume (blood plasma, lymph and
4
interstitialfluid)andarterialvasoconstriction .
5
Parathyroid hormone (PTH) is associated with increased blood pressure ,
6
with a larger effect on diastolic pressure . PTH decreases with increasing
serum 25(OH)D until about 30 ng/ml, after which there is little additional
7
change .
8
Vitamin D also increases insulin sensitivity . Insulin resistance is a risk factor
910
forhypertension .
Arterial calcification increases blood pressure by stiffening the arterial
11
walls . Serum 25(OH)D levels are inversely correlated with arterial
12
calcifications for those on hemodialysis . Related to arterial stiffening is
endothelial dysfunction. (The epithelium is the thin layer of cells that lines
13
the interior surface of blood vessels.) Too little 25(OH)D and much calcium
in the blood leads to endothelial dysfunction, which also contributes to
14
increased blood pressure . The paper by Rostand has a figure outlining his
modelforelevatedbloodpressureamongAfrican-Americans.

IN HYPERTENSION

BLOOD 25-HYDROXYVITAMIN D CONCENTRATION AND HYPERTENSION:
A META-ANALYSIS.
JournalofHypertension2011Apr;29(4):636-45.
OBJECTIVES: Increasing evidence indicates that vitamin D may influence the
risk of hypertension, which is a major risk factor for cardiovascular disease.
We conducted a meta-analysis to quantitatively review and summarize the
results on the association between blood 25-hydroxyvitamin D
concentrationsandhypertension.
METHODS: Relevant studies were identified by a search of PubMed and
EMBASE databases until November 2010. We also reviewed the references
of retrieved articles. We included prospective and cross-sectional studies
with blood 25-hydroxyvitamin D concentrations as the exposure and
hypertension as the outcome. Studies had to report results as a relative risk
oranoddsratio.Weusedrandom-effectsmodel.
RESULTS: Of the 18 studies included in the meta-analysis, 4 were prospective
studies and 14 were cross-sectional studies. The pooled odds ratio of
hypertension was 0.73 [95% confidence interval (CI) 0.63-0.84] for the
highest versus the lowest category of blood 25-hydroxyvitamin D
concentration. In a dose-response meta-analysis, the odds ratio for a 40
nmol/l (16 ng/ml) (approximately 2 SDs) increment in blood 25-
hydroxyvitaminDconcentrationwas0.84(95%CI0.78-0.90).
CONCLUSION: Findings from this meta-analysis indicate that blood 25-
hydroxyvitaminDconcentrationisinverselyassociatedwithhypertension.

RENIN-ANGIOTENSIN SYSTEM ACTIVITY IN VITAMIN D DEFICIENT, OBESE INDIVIDUALS
WITH HYPERTENSION: AN URBAN INDIAN STUDY.
Indian Journal of Endocrinology and Metabolism 2011 Oct;15 Suppl 4:S395-
401.
BACKGROUND: Elevated renin-angiotensin-aldosterone system (RAAS)
activity is an important mechanism in the development of hypertension.
Both obesity and 25-hydroxy vitamin D [25(OH)D] deficiency have been
associated with hypertension and augmented renin-angiotensin system
(RAS) activity. We tried to test the hypothesis that vitamin D deficiency and
obesity are associated with increased RAS activity in Indian patients with
hypertension.
MATERIALSANDMETHODS:Fiftynewlydetectedhypertensivepatientswere
screened. Patients with secondary hypertension, chronic kidney disease, or
coronaryarterydiseasewereexcluded.Patientsunderwentmeasurementof
vitamin D and plasma renin and plasma aldosterone concentrations. They
were divided into three groups according to their baseline body mass index
(BMI; normal <25 kg/m(2), overweight 25-29.9 kg/m(2) and obese ≥ 30
kg/m(2)) and 25(OH)D levels (deficient <20 ng/ml, insufficient 20-29 ng/ml
andoptimal≥30ng/ml).
RESULTS: A total of 50 (male:female - 32:18) patients were included, with a
mean age of 49.5 ± 7.8 years, mean BMI of 28.3 ± 3.4 kg/m(2) and a mean
25(OH)D concentration of 18.5 ± 6.4 ng/ml. Mean systolic blood pressure
(SBP) was 162.4 ± 20.2 mm Hg and mean diastolic blood pressure (DBP) was
100.2 ± 11.2 mm Hg.
Though all the three blood pressure
parameters (SBP, DBP and MAP) were higher among individuals with higher
BMIs, they were not achieving statistical significance. Increasing trends in
PRAandPACwerenoticedwithlower25(OH)DandhigherBMIlevels.
All the three blood pressure parameters [SBP, DBP and
mean arterial pressure (MAP)] were significantly higher among individuals
with lower 25(OH)D levels. The P values for trends in SBP, DBP and MAP were
0.009, 0.01 and 0.007, respectively.

RENIN-ANGIOTENSIN SYSTEM ACTIVITY IN VITAMIN D DEFICIENT, OBESE INDIVIDUALS
WITH HYPERTENSION: AN URBAN INDIAN STUDY.
Indian Journal of Endocrinology and Metabolism 2011 Oct;15 Suppl 4:S395-
401.
CONCLUSION: Vitamin D deficiency and obesity are associated with
stimulation of RAAS activity. Vitamin D supplementation along with weight
loss may be studied as a therapeutic strategy to reduce tissue RAS activity in
individualswithVitaminDdeficiencyandobesity.

SERUM 25-HYDROXYVITAMIN D LEVELS AND ALL-CAUSE AND CARDIOVASCULAR
DISEASE MORTALITY AMONG US ADULTS WITH HYPERTENSION: THE NHANES
LINKED MORTALITY STUDY.
JournalofHypertension2012Feb;30(2):284-9.
OBJECTIVES: Research suggests that serum concentrations of 25-
hydroxyvitamin D [25(OH)D] are inversely associated with hypertension
incidence. This study examined whether concentrations of 25(OH)D are
inverselyassociatedwithmortalityriskamongUSadultswithhypertension.
METHODS: We analyzed data from the 2001-2004 National Health and
Nutrition Examination Survey with mortality data obtained through 2006.
Hazard ratios with 95% confidence intervals (CIs) for all-cause and
cardiovascular disease (CVD) mortality were estimated using Cox
proportionalhazardmodels.
RESULTS:Of2609participantswithhypertension,191died(including68CVD
deaths) during an average of 3.7-year follow-up. Compared with participants
with 25(OH)D concentrations in the highest quartile (≥29ng/ml), the hazard
ratios for all-cause mortality were 1.93 (95% CI 1.06-3.49), 1.32 (95% CI 0.85-
2.04), and 1.36 (95% CI 0.84-2.22), respectively (P for trend <0.05), and the
hazard ratios for CVD mortality were 3.21 (95% CI 1.14-8.99), 2.42 (95% CI
0.85-6.90), and 2.33 (95% CI 0.88-6.12), respectively (P for trend <0.05), in
the first (<17ng/ml), second (17-<23ng/ml) and third (23-<29ng/ml)
quartiles of 25(OH)D after adjustment for potential confounding variables.
Additionally, concentrations of 25(OH)D as a continuous variable were
linearly and inversely associated with the risk of mortality from all causes
(P=0.012) and from CVD (P=0.010). These relationships were not affected
muchbyadjustmentforbaselinebloodpressureanduseofantihypertension
medications.
CONCLUSION: Concentrations of 25(OH)D were inversely associated with all-
cause and CVD mortality among adults with hypertension in the US.
Enhancing vitamin D intake may contribute to a lower risk for premature
death.

PREDIABETES AND PREHYPERTENSION IN HEALTHY ADULTS ARE ASSOCIATED WITH
LOW VITAMIN D LEVELS.
DiabetesCare.2011Mar;34(3):658-60.
OBJECTIVE: To determine whether modest elevations of fasting serum
glucose(FSG)andrestingbloodpressure(BP)inhealthyadultsareassociated
withdifferentialserumvitaminDconcentrations.
RESEARCH DESIGN AND METHODS: Disease-free adults in the National
Health and Nutrition Examination Survey 2001-2006 were assessed.
Prediabetes (PreDM) and prehypertension (PreHTN) were diagnosed using
American Diabetes Association and Seventh Report of the Joint National
Committee on Prevention, Detection, and Treatment of High Blood Pressure
criteria: FSG 100-125 mg/dL and systolic BP 120-139 mmHg and/or diastolic
BP 80-89 mmHg. Logistic regression was used to assess the effects of low
vitamin D levels on the odds for PreDM and PreHTN in asymptomatic adults
(n=1,711).
RESULTS: The odds ratio for comorbid PreDM and PreHTN in Caucasian men
(n = 898) and women (n = 813) was 2.41 (P < 0.0001) with vitamin D levels ≤
76.3versus>76.3nmol/Lafteradjustingforage,sex,andBMI.
CONCLUSIONS: This study strengthens the plausibility that low serum
vitamin D levels elevate the risk for early-stage diabetes (PreDM) and
hypertension(PreHTN).

LOW 25(OH)D3 LEVELS ARE ASSOCIATED WITH TOTAL ADIPOSITY, METABOLIC
SYNDROME, AND HYPERTENSION IN CAUCASIAN CHILDREN AND ADOLESCENTS.
EuropeanJournalofEndocrinology2011Oct;165(4):603-11.
OBJECTIVES: Evidence of the association between vitamin D and
cardiovascular risk factors in the young is limited. We therefore assessed the
relationships between circulating 25-hydroxyvitamin D(3) (25(OH)D(3)) and
metabolic syndrome (MetS), its components, and early atherosclerotic
changes in 452 (304 overweight/obese and 148 healthy, normal weight)
Caucasianchildren.
METHODS: We determined serum 25(OH)D(3) concentrations in relation to
MetS, its components (central obesity, hypertension, low high-density
lipoprotein (HDL)-cholesterol, hypertriglyceridemia, glucose impairment,
and/or insulin resistance (IR)), and impairment of flow-mediated
vasodilatation (FMD) and increased carotid intima-media thickness (cIMT) -
twomarkersofsubclinicalatherosclerosis.
RESULTS: Higher 25(OH)D(3) was significantly associated with a reduced
presence of MetS. Obesity, central obesity, hypertension,
hypertriglyceridemia, low HDL-cholesterol, IR, and MetS were all associated
with increased odds of having low 25(OH)D(3) levels, after adjustment for
age, sex, and Tanner stage. After additional adjustment for SDS-body mass
index, elevated blood pressure (BP) and MetS remained significantly
associated with low vitamin D status. The adjusted odds ratio (95%
confidence interval) for those in the lowest (<17 ng/ml) compared with the
highest tertile (>27 ng/ml) of 25(OH)D(3) for hypertension was 1.72 (1.02-
2.92), and for MetS, it was 2.30 (1.20-4.40). A similar pattern of association
between 25(OH)D(3), high BP, and MetS was observed when models were
adjusted for waist circumference. No correlation was found between
25(OH)D(3)concentrationsandeitherFMDorcIMT.
CONCLUSIONS: Low 25(OH)D(3) levels in Caucasian children are inversely
relatedtototaladiposity,MetS,andhypertension.

TocontrolType2diabetes:
Regulatesinsulinsynthesisandsecretionbyregulatingcalciumlevelsin
theblood
Directlyaffectfunctionofthepancreas(theorganthanmakesinsulin)
Affectgenesassociatedwithglucosetolerance
Reducesinsulinresistance
Type1Diabetes:
VitaminDreducestheriskofautoimmunediseasebystrengthening
theimmunesystem.
VitaminDsupplementsimprovespoorbloodsugarcontrol.Based
ontheavailableinformation,theriskofType1diabetesmaybe
reducedif:
MaternalvitaminDlevelsareabove30–40ng/mL(75–100
nmol/L)duringpregnancy.
Infantsobtain1000-2000IU(25–50mcg)/dayofvitaminD3from
supplementsormother’smilk.
InfantsmaintainvitaminDbloodlevelsabove30ng/mL(75
nmol/L).
VITAMIN D - BENEFITS IN DIABETES

IN DIABETES

Effects of vitamin D supplementation on glucose metabolism, lipid
concentrations, inflammation, and oxidative stress in gestational diabetes:
adouble-blindrandomizedcontrolledclinicaltrial.
OBJECTIVE: This study was designed to assess the effects of vitamin D
supplementation on metabolic profiles, high-sensitivity C-reactive protein,
andbiomarkersofoxidativestressinpregnantwomenwithGDM.
DESIGN: This randomized, double-blind, placebo-controlled clinical trial was
conducted in 54 women with GDM. Subjects were randomly assigned to
receiveeithervitamin D supplements or placebo.Individuals in the vitamin D
group (n = 27) received capsules containing 50,000 IU vitamin D3 2 times
during the study (at baseline and at day 21 of the intervention) and those in
the placebo group (n = 27) received 2 placebos at the same times. Fasting
blood samples were collected at baseline and after 6 wk of the intervention
toquantifyrelevantvariables.
RESULTS: Cholecalciferol supplementation resulted in increased serum 25-
hydroxyvitamin D concentrations compared with placebo (+18.5 ± 20.4
comparedwith+0.5±6.1ng/mL;P<0.001).Furthermore,intakeofvitaminD
supplements led to a significant decrease in concentrations of fasting plasma
glucose (-17.1 ± 14.8 compared with -0.9 ± 16.6 mg/dL; P < 0.001) and serum
insulin (-3.08 ± 6.62 compared with +1.34 ± 6.51 μIU/mL; P = 0.01) and
homeostasis model of assessment-insulin resistance (-1.28 ± 1.41 compared
with +0.34 ± 1.79; P < 0.001) and a significant increase in the Quantitative
Insulin Sensitivity Check Index (+0.03 ± 0.03 compared with -0.001 ± 0.02; P =
0.003) compared with placebo. A significant reduction in concentrations of
total (-11.0 ± 23.5 compared with +9.5 ± 36.5 mg/dL; P = 0.01) and low-
densitylipoprotein(LDL)(-10.8±22.4comparedwith+10.4±28.0mg/dL;P=
0.003)cholesterolwasalsoseenaftervitaminDsupplementation.
CONCLUSIONS: Vitamin D supplementation in pregnant women with GDM
had beneficial effects on glycemia and total and LDL-cholesterol
concentrationsbutdidnotaffectinflammationandoxidativestress.
AmJClinNutr.2013Dec;98(6):1425-32.

Improvement in Pancreatic β Cell Function with Vitamin D and Calcium
SupplementationinVitaminDDeficientNon-DiabeticSubjects.
2013Sep6:1-33.
OBJECTIVE: There are varied reports on the effect of vitamin D
supplementation on beta cell function and plasma glucose levels. To study
the effect of vitamin D and calcium supplementation on β cell function and
plasmaglucoselevelsinsubjectswithvitaminDdeficiency.
METHODS: Non-diabetic subjects(n=48) were screened for their serum
vitamin D(25 OHD) status along with serum albumin, creatinine, calcium,
phosphorus, alkaline phosphatase, and intact parathyroid hormone
status(PTH). Subjects with vitamin D deficiency underwent two hour oral
glucose tolerance test. Cholecalciferol (9570 IU/day)(upper tolerable level
intake 10,000 IU/day-Endocrine Society guidelines for vitamin D
supplementation)andcalciumof1gram/daywassupplemented.
RESULTS: Thirty seven patients with vitamin D deficiency participated in the
study. The baseline, post vitamin D and calcium supplementation, and(the
difference) in serum calcium(corrected)(mg/dl) was 9±0.33and 8.33±1.09(-
0.66±1.11); 25 OHD(ng/ml) 8.75 ±4.75 and 36.83±18.68(28.00±18.33);
PTH(pg/ml) 57.90±29.30 and 36.33±22.48(-20.25±22.45); Fasting plasma
glucose(mg/dl) 78.23±7.60 and 73.47± 9.82(-4.88±10.65) and; HOMA 2-%B-
C Peptide 183.17±88.74 and 194.67±54.71(11.38±94.27). There was
significant difference in baseline and post vitamin D and calcium
supplementation serum levels of corrected calcium(Z - 3.751;P<0.0001); 25
OHD levels(Z -4.9;P<0.0001);intact PTH(Z-4.04;P<0.0001);fasting plasma
glucose(Z-2.7;P<0.007) and HOMA 2-%B- C Peptide(Z-1.923;P<0.05) by
Wilcoxon Signed Rank Test. Insulin resistance measured by HOMA is
unchanged.
CONCLUSIONS: Optimizing serum 25OHD concentrations and
supplementationofcalciumimprovesthefastingplasmaglucoselevelsandβ
cellsecretoryreserve.Largerrandomizedcontrolstudiesareneededtoseeif
correction of vitamin D deficiency will improve insulin secretion and prevent
abnormalitiesofglucosehomeostasis.
EndocrPract.

SERUM 25-HYDROXYVITAMIN D CONCENTRATION AND ARTERIAL STIFFNESS AMONG
TYPE 2 DIABETES.
DiabetesResClinPract.2012Jan;95(1):42-7
AIM: To evaluate the association between serum 25-hydroxyvitamin D
[25(OH)D]andarterialstiffnessinpatientswithtype2diabetes.
METHODS: Serum 25(OH)D was measured in a cross-sectional sample of 131
men and 174 women aged 30 years and over in Korea. Arterial stiffness was
assessed by pulse wave velocity (PWV) obtained with a VP-2000 pulse wave
unit. Fasting plasma glucose, insulin, lipid profile, HbA1c, calcium,
phosphorous,andHS-CRPweremeasured.
RESULTS: The prevalence of vitamin D deficiency was high (85.9%). Those
withlowervitaminDlevelshadincreasedPWV.Usingmultivariateregression
analysis, low 25(OH)D concentrations independently predicted PWV
(p<0.001) in people with type 2 diabetes after adjustment for other risk
factors such as age, smoking, hypertension, HS-CRP, diabetes duration,
hypertensionduration,HbA1c,andBMI.
CONCLUSIONS:
Vitamin D may influence the development of cardiovascular
disease. Clinical intervention studies are needed to clarify whether
treatment with vitamin D decreases the risk of cardiovascular disease in
patientswithtype2diabetes.
Vitamin D deficiency is common in type 2 diabetes, and a low
25(OH)D level is significantly associated with increased arterial stiffness in
these patients.

SERUM 25-HYDROXYVITAMIN D LEVELS AND PREDIABETES AMONG SUBJECTS FREE
OF DIABETES.
DiabetesCare.2011May;34(5):1114-9.
OBJECTIVE: Animal studies suggest that low serum 25-hydroxyvitamin D
(25[OH]D) may impair insulin synthesis and secretion and be involved in the
pathogenesis of diabetes. Results in studies in humans have not been
consistent, however. Prediabetes is a stage earlier in the
hyperglycemia/diabetes continuum where individuals are at increased risk
of developing diabetes and where prevention efforts have been shown to be
effective in delaying or preventing the onset of diabetes. However, previous
studies have not examined the association between low serum 25(OH)D
levelsandprediabetes.
RESEARCH DESIGN AND METHODS: We examined the 12,719 participants
(52.5% women) in the third National Health and Nutrition Examination
Survey aged >20 years who were free of diabetes. Serum 25(OH)D levels
were categorized into quartiles (≤ 17.7, 17.8-24.5, 24.6-32.4, >32.4 ng/mL).
Prediabeteswasdefinedasa2-hglucoseconcentrationof140-199mg/dL,or
a fasting glucose concentration of 110-125 mg/dL, or an A1C value of 5.7-
6.4%.
RESULTS: Lower serum 25(OH)D levels were associated with prediabetes
after adjusting for age, sex, race/ethnicity, season, geographic region,
smoking, alcohol intake, BMI, outdoor physical activity, milk consumption,
dietary vitamin D, blood pressure, serum cholesterol, C-reactive protein, and
glomerular filtration rate. Compared with quartile 4 of 25(OH)D (referent),
the odds ratio of prediabetes associated with quartile 1 was 1.47 (95% CI
1.16-1.85; P = 0.001 for trend). Subgroup analyses examining the relation
between 25(OH)D and prediabetes by sex, BMI, and hypertension categories
alsoshowedaconsistentpositiveassociation.
CONCLUSIONS: Lower serum 25(OH)D levels are associated with prediabetes
inarepresentativesampleofU.S.adults.

SERUM 25-HYDROXYVITAMIN D, CALCIUM INTAKE, AND RISK OF TYPE 2 DIABETES
AFTER 5 YEARS: RESULTS FROM A NATIONAL, POPULATION-BASED PROSPECTIVE STUDY
(THE AUSTRALIAN DIABETES, OBESITY AND LIFESTYLE STUDY).
DiabetesCare.2011May;34(5):1133-8.
OBJECTIVE: To examine whether serum 25-hydroxyvitamin D (25OHD) and
dietarycalciumpredictincidenttype2diabetesandinsulinsensitivity.
RESEARCH DESIGN AND METHODS: A total of 6,537 of the 11,247 adults
evaluated in 1999-2000 in the Australian Diabetes, Obesity and Lifestyle
(AusDiab) study, returned for oral glucose tolerance test (OGTT) in 2004-
2005. We studied those without diabetes who had complete data at baseline
(n = 5,200; mean age 51 years; 55% were women; 92% were Europids).
Serum 25OHD and energy-adjusted calcium intake (food frequency
questionnaire) were assessed at baseline. Logistic regression was used to
evaluate associations between serum 25OHD and dietary calcium on 5-year
incidence of diabetes (diagnosed by OGTT) and insulin sensitivity
(homeostasis model assessment of insulin sensitivity [HOMA-S]), adjusted
formultiplepotentialconfounders,includingfastingplasmaglucose(FPG).
RESULTS: During the 5-year follow-up, 199 incident cases of diabetes were
diagnosed. Those who developed diabetes had lower serum 25OHD (mean
58vs.65nmol/L;P<0.001)andcalciumintake(mean881vs.923mg/day;P=
0.03) compared with those who remained free of diabetes. Each 25 nmol/L
increment in serum 25OHD was associated with a 24% reduced risk of
diabetes (odds ratio 0.76 [95% CI 0.63-0.92]) after adjusting for age, waist
circumference, ethnicity, season, latitude, smoking, physical activity, family
history of diabetes, dietary magnesium, hypertension, serum triglycerides,
and FPG. Dietary calcium intake was not associated with reduced diabetes
risk. Only serum 25OHD was positively and independently associated with
HOMA-Sat5years.
CONCLUSIONS: Higher serum 25OHD levels, but not higher dietary calcium,
were associated with a significantly reduced risk of diabetes in Australian
adultmenandwomen.

PLASMA 25-HYDROXYVITAMIN D LEVELS ARE FAVORABLY ASSOCIATED WITH
B-CELL FUNCTION.
Pancreas.2012Jan17.
OBJECTIVE: The association of hypovitaminosis D with type 2 diabetes is well
recognized.AlthoughhypovitaminosisDisassociatedwithinsulinresistance,
thereismuchlessinformationaboutitsimpactonβ-cellfunctioninhumans.
METHODS: We enrolled 150 healthy, glucose-tolerant subjects for the
assessment of β-cell function (acute insulin response) and insulin sensitivity
index (ISI) using a hyperglycemic clamp. Adjusted β-cell function (ABCF) was
defined as the product of acute insulin response and ISI. The relations of
plasma 25-hydroxyvitamin D [25(OH)D] level with insulin sensitivity and
ABCFwereexamined.
RESULTS: Plasma 25(OH)D levels were positively associated with ABCF (P =
0.00004) and ISI (P < 0.00001). The associations remained significant after
adjustment for age, sex, body mass index, physical activity, ethnicity, and
seasonofstudy.
CONCLUSIONS:Plasma25(OH)Dlevelsarepositivelyassociationwithbothβ-
cell function and insulin sensitivity. Our observations suggest the roles of
vitaminDdeficiencyinthedualdefectoftype2diabetes.

VITAMIN D LEVELS AND ASYMPTOMATIC CORONARY ARTERY DISEASE IN TYPE 2 DIABETIC
PATIENTS WITH ELEVATED URINARY ALBUMIN EXCRETION RATE.
DiabetesCare.2012Jan;35(1):168-72..
OBJECTIVE: Coronary artery disease (CAD) is the major cause of morbidity
and mortality in type 2 diabetic patients. Severe vitamin D deficiency has
beenshowntopredictcardiovascularmortalityintype2diabeticpatients.
RESEARCH DESIGN AND METHODS: We investigated the association among
severevitaminDdeficiency,coronarycalciumscore(CCS),andasymptomatic
CAD in type 2 diabetic patients with elevated urinary albumin excretion rate
(UAER) >30 mg/24 h. This was a cross-sectional study including 200 type 2
diabetic patients without a history of CAD. Severe vitamin D deficiency was
definedasplasma25-hydroxyvitaminD(p-25[OH]D3)<12.5nmol/L.Patients
with plasma N-terminal pro-brain natriuretic peptide >45.2 ng/L or CCS ≥400
were stratified as being high risk for CAD (n= 133). High-risk patients were
examined by myocardial perfusion imaging (MPI; n = 109), computed
tomography angiography (n = 20), or coronary angiography (CAG; n = 86).
Patients' p-25(OH)D3 levels were determined by high-performance liquid
chromatography/tandemmassspectrometry.
RESULTS: The median (range) vitamin D level was 36.9 (3.8-118.6) nmol/L.
The prevalence of severe vitamin D deficiency was 9.5% (19/200). MPI or
CAG demonstrated significant CAD in 70 patients (35%). The prevalence of
CCS ≥400 was 34% (68/200). Severe vitamin D deficiencywas associated with
CCS ≥400 (odds ratio [OR] 4.3, 95% CI [1.5-12.1], P = 0.005). This association
persisted after adjusting for risk factors (4.6, 1.5-13.9, P = 0.007).
Furthermore,severevitaminDdeficiencywasassociatedwithasymptomatic
CAD(adjustedOR2.9,1.02-7.66,P=0.047).
CONCLUSIONS: In high-risk type 2 diabetic patients with elevated UAER, low
levelsofvitaminDareassociatedwithasymptomaticCAD.

VITAMIN D IN AUTO-IMMUNE
DISEASES AND PAINS
REFERENCE:ByStewartB.Leavitt,MA,PhD;PracticalPAINMANAGEMENT,July/August2008

According to extensive clinical research examining adult patients of all ages,
inadequate concentrations of vitamin D have been linked to nonspecific
muscle, bone, or joint pain, muscle weakness or fatigue, fibromyalgia
syndrome, rheumatic disorders, osteoarthritis, hyperesthesia, migraine
headaches,andotherchronicsomaticcomplaints.
Deficiency of Vitamin D leads to Hypocalcemia, which leads to a cascade of
bio-chemical reactions that negatively affects bone metabolism and health.
Even mild hypocalcemia results in an elevation of parathyroid hormone
(PTH) that can diminish bone density (osteopenia) and/or more severely
affect bone architecture (osteoporosis). The effect relating more closely to
musculoskeletal aches and pains is the increased PTH levels. This also impair
properbonemineralizationcausingaspongymatrixtoformunderperiosteal
membranes covering the skeleton. This gelatin-like matrix can absorb fluid,
expand, and cause outward pressure on periosteal tissues, which generates
pain since these tissues are highly innervated with sensory pain fibers. This
dysfunction of bone metabolism (osteomalacia) is proposed in the literature
as an explanation of why many patients with vitamin D inadequacies may
complain of dull, persistent, generalized musculoskeletal aches, pains, and
weakness. Therefore, experts recommend that vitamin D deficiency and its
potential for associated osteomalacia should be considered in the
differential diagnosis of all patients with chronic musculoskeletal pain,
muscleweaknessorfatigue,fibromyalgia,orchronicfatiguesyndrome.
Clinical researchers have also found that the role of vitamin D extends
beyond bone and muscle involvement in chronic pain syndromes. For
example, vitamin D receptors have been identified in various brain
structures, the spinal cord, and sensory ganglia. Accordingly, results of some
studies suggest non-musculoskeletal benefits of vitamin D supplementation,
asfollows:
VITAMIN D - AUTO-IMMUNE DISEASE OR PAINS

Neuropathy - A recently reported prospective study of 51 patients with type
2 diabetes and associated with neuropathy found that conservative vitamin
D supplementation (about 2000 IU/day) for 3 months resulted in nearly a
50%decreaseinpainscores
Inflammation - Clinical research indicates that vitamin D supplementation
modulates or decreases pro-inflammatory cytokines (eg, C-reactive protein,
interleukin 6 and 12, and tumor necrosis factor-alpha) while increasing anti-
inflammatory cytokines (eg, interleukin-10). Investigators have further
suggestedthatvitaminDmayhelptomoderatepainfulchronicinflammatory
autoimmune conditions that are influenced by excessive cytokine activity,
suchasinflammatoryboweldisease.
Migraine Headaches -There have been case reports of vitamin D combined
with calcium supplementation to alleviate migraine headaches in
postmenopausal and premenopausal women. Reductions in both frequency
andintensityofmigraineswereachievedwithin2months.
Affective (Mood) Disturbances - In patients with fibromyalgia syndrome,
pain, depression, and anxiety were found to be strongly associated with
insufficient vitamin D. Furthermore, large studies examining older persons
(aged >65 years) found significant associations between 25(OH)D
deficiencies and depressive disorders. In one of the studies, inadequate
25(OH)Danddepressionalsowerehighlycorrelatedwithchroniclower-back
painspecificallyinfemalepatients.

Fibromyalgia syndrome patients are highly Vitamin D deficient, (4.76 ±
1.46 ng/mL), and lower vitamin D levels were significantly correlated
withgreaterwidespreadpain.
More than half of 313 patients undergoing spinal fusion surgery had
inadequate levels of vitamin D; a quarter of them were severely
deficient
93% of 150 patients with persistent, nonspecific musculoskeletal pain
wereovertlydeficientinvitaminD.
There is high prevalence of vitamin D deficiency in children with limb
pain, and vitamin D supplementation ameliorated pain within three
months.
Vitamin D deficiency is found in 83% of 299 patients with low-back pain,
and supplementation with 5,000–10,000 IU of vitamin D per day lead to
painreductioninnearly100%ofpatientsafterthreemonths.
Current best evidence demonstrates that supplemental vitamin D can
help many patients who have been unresponsive to other therapies for
pain.

Speaking at the 26th Annual Meeting of the North American Spine Society,
orthopaedic surgeons from Washington University School of Medicine in St.
Louis reported that more than half of 313 patients undergoing spinal fusion
surgery had inadequate levels of vitamin D; a quarter of them were severely
deficient[Stokeretal.2011].
One of the study authors, Jacob M. Buchowski, MD, said he became aware of
thevitaminDproblemwhenapatientinher40sexperiencedaslowrecovery
after spinal fusion surgery. While he was trying to determine why the
vertebrae did not fuse properly the woman mentioned that she had recently
been diagnosed with vitamin D deficiency. “It was like a 'light bulb' went off,”
he stated. Consequently, Buchowski and colleagues started routinely
screeningpatientspriortospinalfusionsurgeryforvitaminDdeficiency.
Low vitamin D levels are known to be common in elderly patients;
surprisingly, however, patients in this study most likely to have inadequate
levels were younger; on average, 55 years old. One quarter of the patients,
predominantly those who were older, had taken vitamin D supplements in
thepast.
The researchers found that the main risk factors for inadequate vitamin D
were smoking, obesity, disability prior to surgery, and never having taken
vitaminDormultivitaminsupplements.Althoughanearlierstudyhadshown
inadequate vitamin D levels in 43% of patients undergoing orthopedic
procedures,thisisthefirsttolooksolelyatpatientshavingspinesurgery.
Vitamin D is important for calcium absorption and patients with a deficiency
are at risk for osteomalacia that hinders new bone formation. As a follow-up
to this study, Buchowski and colleagues are planning an investigation of
whether there is a link between low vitamin D and poor outcomes following
spinal fusion. In the meantime, he recommends that patients should be
gettingsufficientvitaminDpriortoorthopedicsurgery.
VITAMIN D DEFICIENCIES HAMPER RECOVERY FROM SPINE SURGERY

This one from researchers at Johns Hopkins University, Baltimore — suggests
that vitamin D levels are significantly lower in patients with recurrent
inflammatory spinal cord disease, including transverse myelitis and
neuromyelitis optica [Mealy et al. 2011]. In transverse myelitis (TM) there is
involvement of the myelin sheath that protects nerve fibers; symptoms
include back pain and weakness in the legs. Neuromyelitis optica (NMO) is a
disease of the central nervous system that affects the optic nerves and spinal
cord.
Writing in an early online edition of the Archives of Neurology, Maureen A.
Mealy, RN, BSN, and colleagues report a retrospective analysis of vitamin D
levels among 77 patients, comparing monophasic versus recurrent
inflammatory diseases of the spinal cord (TM/NMO), and adjusting for
season,age,sex,andrace.TheyfoundthatvitaminDlevelsweresignificantly
deficient — 25(OH)D < 20 ng/mL — in patients who developed recurrent
spinal cord disease compared with those having nonrecurring monophasic
disease.
This is consistent with other recurrent autoimmune conditions and points to
a common link between low vitamin D levels and immunologic
dysregulation,” the researchers write. They suggest that further studies are
needed to assess the relationship between vitamin D and painful, recurrent
spinalcorddisease.
LOW VITAMIN D MAY INFLUENCE INFLAMMATORY SPINAL
CORD DISEASE

Pseudoarthrosis and fracture: interaction between severe vitamin D
deficiencyandprimaryhyperparathyroidism.
A young woman with severe vitamin D deficiency presented with proximal
muscle weakness, fragility fracture and pseudoarthrosis. On evaluation, she
was found to have hypercalcaemia, a single parathyroid adenoma and an
undetectable 25-hydroxyvitamin D level. She received parenteral
cholecalciferol and subsequently underwent curative parathyroidectomy.
Postoperatively, she had hungry bone syndrome, which she gradually
recoveredfromwithcalciumandcalcitriolreplacement.Notably,hercalcium
levels were in the lower limit of normal range and associated with elevated
alkaline phosphatase levels at postoperative Day 14. Follow-up for the next
four years showed that the patient had remarkable symptomatic and
radiological improvements. In this report, we discuss the pathophysiological
interactions between vitamin D deficiency and associated primary
hyperparathyroidism.
SingaporeMedJ.2013Nov;54(11):e224-7.

SERUM VITAMIN D LEVEL AND BONE MINERAL DENSITY IN PREMENOPAUSAL
EGYPTIAN WOMEN WITH FIBROMYALGIA.
RheumatolInt.2012Feb4.
Patients with fibromyalgia syndrome (FMS) have impaired mobility and
therefore get less sunlight exposure, we postulated that they may be at
increased risk of developing osteoporosis (OP). The aim of this study was to
assess and compare serum vitamin D level and bone mineral density (BMD)
value in patients with primary FMS (PFMS) and healthy controls. A total of 50
patients with PFMS participated in this case-control study, and 50 healthy
females who were age-matched to the patients were used as the control
group. Venous blood samples collected from all subjects were used to
evaluate serum 25-hydroxyvitamin D3 (25-OHD). BMD was measured at the
lumbar spine (L2-L4) anteroposterior, femoral neck and forearm by dual-
energy X-ray absorptiometry. Patients with PFMS had significantly lower
serum 25-OHD than controls (15.1 ± 6.1 and 18.8 ± 5.4 ng/ml, respectively, p
= 0.0018). Apart from the BMD in the lumbar spine, which was significantly
lower in the PFMS patients compared with controls (p = 0.0012), no
significant difference was found in other measures of BMD. Compared to
PFMS patients who had serum level of the 25-OHD >20 ng/ml, the patients
with 25-OHD ≤20 ng/ml are more likely to have impaired short memory (46.4
vs. 13.6%, respectively, p = 0.0136), confusion (50 vs. 18.2%, respectively, p =
0.0199), mood disturbance (60.7 vs. 27.3%, respectively, p = 0.0185), sleep
disturbance (53.6 vs. 22.7%, respectively, p = 0.0271), restless leg syndrome
(57.1 vs. 27.3%, respectively, p = 0.0346) and palpitation (67.9 vs. 36.4%,
respectively, p = 0.0265). Serum level of the 25-OHD is inversely correlated
withvisualanaloguescale(VAS)ofpain(p=0.016),Beckscorefordepression
(p = 0.020) and BMD at lumbar spine (p = 0.012). The lumbar BMD inversely
correlated with VAS of pain (p = 0.013) and Beck score for depression (p =
0.016). This study confirmed high prevalence of hypovitaminosis D among in
patients with PFMS. This study confirmed the concept that FMS is a risk
factor for OP. Based on this, an early nutrition program rich in calcium and
vitamin D, appropriate exercise protocols, and medical treatment should be
consideredinthesepatientsintermsofpreventingOPdevelopment.

THE PREVALENCE OF VITAMIN D DEFICIENCY IN CONSECUTIVE NEW PATIENTS SEEN
OVER A 6-MONTH PERIOD IN GENERAL RHEUMATOLOGY CLINICS.
ClinRheumatol.2011Jun;30(6):789-94.
The objectives of this study are to assess: (a) the prevalence of vitamin D
deficiency among new patients attending rheumatology outpatient
departments, (b) the age profile of these low vitamin D patients and (c)
whether any diagnostic category had a particularly high number of vitamin
D-deficient patients. All new patients seen consecutively in general
rheumatologyclinicsbetweenJanuarytoJune2007inclusivewereeligibleto
partake in this study, and 231 out of 264 consented to do so. Parathyroid
hormone, 25-hydroxyvitamin D, creatinine, calcium, phosphate, albumin
and alkaline phosphatase levels were measured. We defined vitamin D
deficiency as ≤53 nmol/l and severe deficiency as ≤25 nmol/l. Overall, 70% of
231 patients had vitamin D deficiency, and 26% had severe deficiency. Sixty-
five percent of patients aged ≥65 and 78% of patients aged ≤30 years had low
vitamin D levels. Vitamin D deficiency in each diagnostic category was as
follows: (a) inflammatory joint diseases/connective tissue diseases
(IJD/CTD), 69%; (b) soft tissue rheumatism, 77%; (c) osteoarthritis, 62%; (d)
non-specific musculoskeletal back pain, 75% and (e) osteoporosis, 71%.
SeasonalvariationofvitaminDlevelswasnotedinalldiagnosticgroupsapart
fromIJD/CTDgroup,wherethedegreeofvitaminDdeficiencypersistedfrom
latewintertopeaksummer.VeryhighprevalenceofvitaminDdeficiencywas
noted in all diagnostic categories (p = 0.006), and it was independent of age
(p = 0.297). The results suggest vitamin D deficiency as a possible modifiable
risk factor in different rheumatologic conditions, and its role in IJD/CTD
warrantsfurtherattention.

VITAMIN D IN CANCERS
REFERENCE:VITAMIN DAND CANCER PREVENTION:STRENGTHS AND LIMITS OF THE EVIDENCE;NATIONAL CANCER INSTITUTE AT NIH

ROLE OF VITAMIN D IN REDUCING CANCERS.
A large number of scientific studies have investigated the possible role for
vitaminDincancerprevention.
The first results came from epidemiologic studies known as geographic
correlation studies. In these studies, an inverse relationship was found
between sunlight exposure levels in a given geographic area and the rates of
incidence and death for certain cancers in that area. Individuals living in
southern latitudes were found to have lower rates of incidence and death for
these cancers than those living at northern latitudes. Because sunlight/UV
exposure is necessary for the production of vitamin D3, researchers
hypothesized that variation in vitamin D levels accounted for the observed
relationships.
Evidence of a possible cancer-protective role for vitamin D has also
been found in laboratory studies of the effect of vitamin D treatment on
cancer cells in culture. In these studies, vitamin D promoted the
differentiation and death (apoptosis) of cancer cells, and it slowed their
proliferation.
Randomized clinical trials designed to investigate the effects of vitamin
D intake on bone health have suggested that higher vitamin D intakes may
reduce the risk of cancer. One study involved nearly 1,200 healthy
postmenopausal women who took daily supplements of calcium (1,400 mg
or 1,500 mg) and vitamin D (25 μg vitamin D, or 1,100 IU―a relatively large
dose) or a placebo for 4 years. The women who took the supplements had a
60 percent lower overall incidence of cancer; however, the study did not
include a vitamin D-only group. Moreover, the primary outcome of the study
was fracture incidence; it was not designed to measure cancer incidence.
This limits the ability to draw conclusions about the effect of vitamin D intake
oncancerrisk.

ROLE OF VITAMIN D IN REDUCING CANCERS.
A number of observational studies have investigated whether people
with higher vitamin D levels or intake have lower risks of specific cancers,
particularly colorectal cancer and breast cancer. Associations of vitamin D
with risks of prostate, pancreatic, and other, rarer cancers have also been
examined. These studies have yielded inconsistent results, most likely
because of the challenges of conducting observational studies of diet.
Information about dietary intakes is obtained from the participants through
the use of food frequency questionnaires, diet records, or interviews in
which the participants are asked to recall information about their dietary
intakes. Information collected in this manner can be inaccurate. In addition,
only recently has a comprehensive food composition database with vitamin
D values for the U.S. food supply become available. Other dietary
componentsorenergybalancemayalsomodifyvitaminDmetabolism.
Measuring blood levels of 25-hydroxyvitamin D to determine vitamin D
status avoids some of the limitations of assessing dietary intake. However,
vitamin D levels in the blood vary by race, with the season, and possibly with
the activity of genes whose products are involved in vitamin D transport and
metabolism. These variations complicate the interpretation of studies that
measuretheconcentrationofvitaminDinserumatasinglepointintime.
Finally, it is difficult to separate the effects of vitamin D and calcium
because of the complicated biological interactions between these
substances. To fully understand the effect of vitamin D on cancer and other
health outcomes, new randomized trials will need to be carried out.
However, the appropriate dose of vitamin D to use in such trials is still not
clear.

VITAMIN D AND COLORECTAL CANCERS
Epidemiologic studies of the association between vitamin D and the
risk of colorectal cancer have provided some indications that higher levels of
intakeareassociatedwithareducedrisk.However,thedataareinconsistent.
In the American Cancer Society's Cancer Prevention Study (CPS) II Nutrition
Cohort, the diet, medical history, and lifestyle of more than 120,000 men and
women were analyzed. Men who had the highest intakes of vitamin D
through both their diet and supplement use (greater than 13 μg, or 525 IU,
per day) had a slightly lower risk of colorectal cancer than men who had the
lowest vitamin D intakes. However, this association was not observed among
women.
In a pooled analysis of data from 10 cohort studies (including the CPS II
cohort), individuals with the highest dietary vitamin D intakes had a slightly
lower risk of colorectal cancer than those with the lowest intakes, but the
reductioninriskwasnotstatisticallysignificant.
In the Women's Health Initiative randomized trial, healthy
postmenopausal women took daily supplements that contained both
calcium (1,000 mg) and vitamin D (10 μg, or 400 IU) or a placebo for an
average of 7 years. Supplementation did not reduce the incidence of
colorectal cancer. However, some scientists have raised the possibility that
the relatively low level of vitamin D supplementation and the short duration
ofparticipantfollow-upmightaccountforthenegativeresults.
At least one epidemiologic study has reported an association between
vitamin D and reduced mortality from colorectal cancer. Among the 16,818
participants in the Third National Health and Nutrition Examination Survey,
those with higher vitamin D blood levels (≥80 nmol/L) had a 72 percent lower
risk of colorectal cancer death than those with lower vitamin D blood levels
(<50nmol/L).

Most colorectal cancers develop from pre-existing colorectal
adenomas, and interventions that reduce the risk of adenoma development
or recurrence are likely to reduce the risk of colorectal cancer. Several large
studies have investigated the association of vitamin D intake or serum status
withadenomarisk.
A cohort from the National Cancer Institute (NCI)-sponsored Polyp
Prevention Trial (PPT) was evaluated for the association of vitamin D intake
with recurrence of colorectal adenomas in individuals who previously had
one or more adenomas removed during a qualifying colonoscopy. PPT was a
multicenter randomized clinical trial to determine the effects of a diet high in
fiber, fruits, and vegetables and low in fat on adenoma recurrence. The
detailed dietary information obtained during the trial allowed the
researchers to investigate the association between additional dietary factors
andadenomarecurrence.TotalvitaminDintake(thatis,fromdietarysources
and supplements combined) was not associated with a reduced risk of
adenoma recurrence. However, individuals who used any amount of vitamin
Dsupplementshadalowerriskofadenomarecurrence.
In another study, the vitamin D intakes of 3,000 people from several
Veterans Affairsmedicalcenterswereexaminedto determinewhetherthere
was an association between intake and advanced colorectal neoplasia (an
outcome that included high-risk adenomas as well as colon cancer).
Individuals with the highest vitamin D intakes (more than 16 μg, or 645 IU,
per day) had a lower risk of developing advanced neoplasia than those with
lowerintakes.
A pooled analysis of data from these and a number of other
observational studies found that higher circulating levels of vitamin D and
higher vitamin D intakes were associated with lower risks of colorectal
adenoma.Inverseassociationswereseenwithbothdietaryandtotalvitamin
DintakebutnotwithsupplementalvitaminDintake.Howevertheassociati-

onswithdietaryintakewerenotstatisticallysignificant.
Another large, NCI-sponsored randomized, placebo-controlled trial
explored the effects of calcium supplementation and blood levels of vitamin
D on adenoma recurrence. Calcium supplementation reduced the risk of
adenoma recurrence only in individuals with vitamin D blood levels above 73
nmol/L. Among individuals with vitamin D levels at or below this level,
calciumsupplementationwasnotassociatedwithareducedrisk.

VITAMIN D AND BREAST CANCERS
Epidemiologic studies of the association between vitamin D and breast
cancer risk had conflicting results. Although several studies have suggested
aninverseassociationbetweenvitaminDintakeandtheriskofbreastcancer,
others have shown no association or even a positive association (that is,
individuals with higher intakes had higher risks). A meta-analysis of six
studies that investigated the relationship between vitamin D intake and
breast cancer risk found no association. However, most women in these
studies had relatively low vitamin D intakes, and, when the analysis was
restrictedtowomenwiththehighestvitaminDintakes(>10μg,or400IU,per
day), their breast cancer risks were lower than those of women with the
lowestintakes(typically<1.25μg,or50IU,perday).
IntheWomen'sHealthInitiative,calciumplusvitaminDsupplementationfor
an average of 7 years did not reduce the incidence of invasive breast cancer
comparedwithplacebo.
.
The association between blood levels of vitamin D and breast cancer risk was
examined in a cohort of postmenopausal women who were enrolled in NCI's
Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial and
from whom blood was drawn at study entry. During the subsequent follow-
up period, 1,005 of these women developed breast cancer. When
researchers compared the blood vitamin D levels of these women with those
of 1,005 similar control women who did not develop breast cancer, they
foundnoassociationbetweenvitaminDstatusandriskofbreastcancer.

VITAMIN D AND PROSTATE CANCERS
Somegeographiccorrelationstudieshavesuggestedthatmenexposed
to higherlevelsof sunlight may havea lowerriskof prostatecancer.Although
some epidemiologic studies have suggested that men with higher vitamin D
levels have an increased risk of prostate cancer, most studies have not shown
suchanassociation.
In one relatively large study of men diagnosed 1 to 8 years after their blood
was drawn, higher vitamin D blood levels were not associated with a lower
risk of prostate cancer overall. Indeed, there was some evidence that men
withhighervitaminDlevelshadanincreasedriskforaggressivedisease.
In another study, the European Prospective Investigation into Cancer and
Nutrition (EPIC), blood samples obtained at study entry were examined for
652 men who developed prostate cancer during follow-up and 752 matched
control subjects. No association was observed between serum vitamin D
levelsandriskofprostatecancer,eitheroverallorbycancerstage.

VITAMIN D AND PANCREATIC CANCERS
There is conflicting evidence about vitamin D's relationship to risk of
pancreatic cancer. A study of more than 120,000 men and women from the
Health Professionals Follow-Up Study and the Nurses' Health Study showed
that participants with higher dietary intake of vitamin D had progressively
lower risk of pancreatic cancer, compared with those who had the lowest
intake. The estimates of vitamin D intake were based on detailed dietary
informationprovidedthroughquestionnaires.Participantswerefollowedfor
16 years for the incidence of pancreatic cancer, and 365 cases were
identified.
In a study of men and women enrolled in the PLCO Screening Trial, no
association between vitamin D level and pancreatic cancer risk was
observed. The PLCO study examined vitamin D levels in blood from 184
individuals who were diagnosed with pancreatic cancer during nearly 12
yearsoffollow-upand368matchedcancer-freecontrolsubjects.Incontrast,
among Finnish male smokers participating in the Alpha-Tocopherol, Beta-
Carotene (ATBC) Cancer Prevention Study, higher blood levels of vitamin D
wereassociatedwithanincreasedriskofpancreaticcancer.Morerecently,in
the NCI Cohort Consortium Vitamin D Pooling Project of Rarer Cancers, men
and women with the highest blood vitamin D levels (greater than 100
nmol/L, or 40 ng/mL) had twice the pancreatic cancer risk of men and
women whose blood vitamin D levels were in the normal range of 50-75
nmol/L(20-30ng/mL).

VITAMIN D AND RARE CANCERS
A recent large collaborative effort analyzed data from 10 prospective cohort
studies to examine whether vitamin D levels in blood were associated with
seven rare cancers. The NCI Cohort Consortium Vitamin D Pooling Project of
Rarer Cancers included information on blood vitamin D levels and incidence
of rare cancers in a subset of more than 12,000 men and women. The
researchers matched participants on date and season of blood draw and
used other statistical techniques to adjust for seasonal variation in blood
vitamin D levels. When the data from the different studies were pooled,
there was no overall association between vitamin D level and risk of non-
Hodgkin lymphoma or cancers of the endometrium, esophagus, stomach,
kidney,orovary.Anincreasedriskofpancreaticcancerwasobservedinthose
with the highest blood levels of vitamin D (greater than 100 nmol/L or 40
ng/mL).
VITAMIN D AND SKIN CANCER
AlthoughpeopleobtainsomevitaminDfromdietarysources,mostvitaminD
is made in the body after the skin is exposed to sunlight. Despite the known
and potential health benefits of vitamin D, increasing sun exposure increases
the risk of skin cancer. In general, most experts believe that people should
continue to use sun protection when UV levels are moderate or higher. Some
researchers have suggested that brief daily exposure to UV will ensure
adequate vitamin D production, but many variables (such as skin color,
latitude, and season) can affect the production of vitamin D, and such
recommendations have proven controversial. Other experts recommend
vitamin D supplementation to avoid the problem of increasing skin cancer
risk.

VITAMIN D IN MODIFYING THE CANCER RISK
Mechanisms by which vitamin D may modify cancer risk are not fully
understood.LaboratorystudieshaveshownthatvitaminDpromotescellular
differentiation,decreasescancercellgrowth,andstimulatesapoptosis.
Vitamin D acts on cells by binding to the vitamin D receptor (VDR). The VDR is
a regulator of gene transcription that is found in the nucleus of cells. Vitamin
D-bound VDR binds to the retinoid-X receptor (RXR), and the resulting
complex activates the expression of specific genes. Among the many genes
regulated by vitamin D are those that produce the proteins calbindin and
TPRV6, both of which are involved in the absorption of calcium by intestinal
cells. Another vitamin D-regulated gene is CYP3A4, whose protein product
detoxifies the bile acid lithocholic acid (LCA). LCA is believed to damage the
DNA of intestinal cells and may promote colon carcinogenesis. Stimulating
the production of a detoxifying enzyme by vitamin D could explain a
protectiveroleforvitaminDagainstcoloncancer.
Further insight into the mechanisms by which vitamin D might modify cancer
risk could come from study of the vitamin D receptor itself. A large number of
variant forms of the VDR gene have been identified, some of which are
known to alter the structure or function of the VDR protein. Some of these
variants have been linked to risk for certain cancers, including prostate,
colorectal, breast, bladder, and melanoma. The association of VDR variants
with cancer risk differs by cancer site and appears to be modified by
environmentalexposures,suchasdietandsunexposure.

VITAMIN D IN PREGNANCY
VitaminDstatusandhypertensivedisordersduringpregnancy
Maternal vitamin D deficiency in pregnancy has been associated with an
increased risk of pre-eclampsia (new-onset gestational hypertension and
proteinuria after 20 weeks of gestation), a condition associated with an
increaseinmaternalandperinatalmorbidityandmortality.
Womenwithpre-eclampsiahavelowerconcentrationsof25-hydroxyvitamin
D compared with women with normal blood pressure. The low levels of
urinary calcium (hypocalciuria) in women with pre-eclampsia may be due to
a reduction in the intestinal absorption of calcium impaired by low levels of
vitamin D. Additionally, pre-eclampsia and vitamin D deficiency are directly
and indirectly associated through biologic mechanisms including immune
dysfunction, placental implantation, abnormal angiogenesis, excessive
inflammation,andhypertension.
VitaminDstatusandothermaternalconditions
Maternal vitamin D deficiency in early pregnancy has been associated with
elevated risk for gestational diabetes mellitus, Poor control of maternal
diabetes in early pregnancy is inversely correlated with low bone mineral
contentininfants,asislowmaternalvitaminDstatus.
VDD may lead to a high bone turnover, bone loss, osteomalacia (softening of
the bones) and myopathy (muscle weakness) in the mother in addition to
neonatal and infant VDD. An adequate vitamin D status may also protect
against other ad verse pregnancy outcomes. For example, maternal vitamin
D deficiency has been linked to caesarean section in a single recent study.
Low prenatal and perinatal maternal vitamin D concentrations can affect the
function of other tissues, leading to a greater risk of multiple sclerosis,
cancer,insulin-dependentdiabetesmellitus,andschizophrenialaterinlife

VitaminDstatusandpretermbirthandlowbirth-weight
A potential inverse association between maternal vitamin D status and
preterm birth(lessthan37 weeks’ gestation) has been reported. Conversely,
not all the studies show significant associations between maternal calcidiol
levelsand any measureof the child’s sizeat birth or during the first months of
life. There is not much information on maternal vitamin D status and low
birth weight or preterm birth in children born from HIV-infected pregnant
women.
VitaminDstatusandpostnatalgrowth
Some observational studies suggest that vitamin D levels during pregnancy
influence fetal bone development and children’s growth. While head
circumference in children nine years of age has been significantly associated
withmaternalcalcidiollevels,thereisstillinconsistentinformationaboutthe
association of maternal vitamin D status and infants’ bone mass. It is not
clearifmaternalvitaminDdeficiencyleadstoneonatalrickets,sincericketsis
usually identified later in childhood. Early studies indicate a possible risk for
neonatal rickets in the offspring of women with osteomalacia, abnormal
softeningofthebonebydeficiencyofphosphorus,calciumorvitaminD.
More recent studies have found that vitamin D deficiency (serum levels
lower than 25 nmol/L) was identified in 92% of rachitic (having rickets) Arab
children and 97% of their mothers compared with 22% of nonrachitic
childrenand 52%of theirmothers.Apositivecorrelationwasfound between
maternalandchildvitaminDlevels.

VitaminDstatusandimmuneresponse
Vitamin D has direct effects on both adaptive and innate immune systems. In
children, vitamin D insufficiency is linked to autoimmune diseases such as
type 1 diabetes mellitus, multiple sclerosis, allergies and atopic diseases.
Various studies have also shown that vitamin D deficiency is strongly
associated with tuberculosis, pneumonia, and cystic fibrosis and both
prenatal and perinatal vitamin D deprivation might influence early-life
respiratory morbidity as this vitamin is important for lung growth and
development.VitaminDmayhavepositiveeffectsontheimmunesystemby
up-regulating the production of the antimicrobial peptides by macrophages
and endothelial cells which may inactivate viruses and suppress
inflammation, andsubsequentlyreducetheseverityofinfections.
CochraneDatabaseofSystematicReviews2012,Issue2

Vitamin D supplementation affects serum high-sensitivity C-reactive
protein, insulin resistance, and biomarkers of oxidative stress in pregnant
women.
2013Sep;143(9):1432-8.
Unfavorable metabolic profiles and oxidative stress in pregnancy are
associated with several complications. This study was conducted to
determine the effects of vitamin D supplementation on serum
concentrations of high-sensitivity C-reactive protein (hs-CRP), metabolic
profiles, and biomarkers of oxidative stress in healthy pregnant women. This
randomized, double-blind, placebo-controlled clinical trial was conducted in
48pregnantwomenaged18-40yoldat25wkofgestation.Participantswere
randomly assigned to receive either 400 IU/d cholecalciferol supplements (n
= 24) or placebo (n = 24) for 9 wk. Fasting blood samples were taken at study
baseline and after 9 wk of intervention to quantify serum concentrations of
hs-CRP,lipidconcentrations,insulin,andbiomarkersofoxidativestress.After
9 wk of intervention, the increases in serum 25-hydroxyvitamin D and
calcium concentrations were greater in the vitamin D group (+3.7 μg/L and
+0.20 mg/dL, respectively) than in the placebo group (-1.2 μg/L and -0.12
mg/dL,respectively;P<0.001forboth).VitaminDsupplementationresulted
in a significant decrease in serum hs-CRP (vitamin D vs. placebo groups: -1.41
vs. +1.50 μg/mL; P-interaction = 0.01) and insulin concentrations (vitamin D
vs. placebo groups: -1.0 vs. +2.6 μIU/mL; P-interaction = 0.04) and a
significant increase in the Quantitative Insulin Sensitivity Check Index score
(vitamin D vs. placebo groups: +0.02 vs. -0.02; P-interaction = 0.006), plasma
total antioxidant capacity (vitamin D vs. placebo groups: +152 vs. -20
mmol/L; P-interaction = 0.002), and total glutathione concentrations
(vitamin D vs. placebo groups: +205 vs. -32 μmol/L; P-interaction = 0.02)
compared with placebo. Intake of vitamin D supplements led to a significant
decrease in fasting plasma glucose (vitamin D vs. placebo groups: -0.65 vs. -
0.12 mmol/L; P-interaction = 0.01), systolic blood pressure (vitamin D vs.
placebo groups: -0.2 vs. +5.5 mm Hg; P-interaction = 0.01), and diastolic
blood pressure (vitamin D vs. placebo groups: -0.4 vs. +3.1 mm Hg; P-
interaction = 0.01) compared with placebo. In conclusion, vitamin D
supplementation for 9 wk among pregnant women has beneficial effects on
metabolicstatus
JNutr.

Maternal Vitamin D Supplementation to Improve the Vitamin D Status of
Breast-fedInfants:ARandomizedControlledTrial.
OBJECTIVE: To determine whether a single monthly supplement is as
effective as a daily maternal supplement in increasing breast milk vitamin D
toachievevitaminDsufficiencyintheirinfants.
PATIENTS AND METHODS: Forty mothers with exclusively breast-fed infants
wererandomizedtoreceiveoralcholecalciferol(vitaminD3)5000IU/dfor28
days or 150,000 IU once. Maternal serum, breast milk, and urine were
collected on days 0, 1, 3, 7, 14, and 28; infant serum was obtained on days 0
and28.EnrollmentoccurredbetweenJanuary7,2011,andJuly29,2011.
RESULTS:Inmothersgivendailycholecalciferol,concentrationsofserumand
breast milk cholecalciferol attained steady levels of 18 and 8 ng/mL,
respectively, from day 3 through 28. In mothers given the single dose, serum
and breast milk cholecalciferol peaked at 160 and 40 ng/mL, respectively, at
day 1 before rapidly declining. Maternal milk and serum cholecalciferol
concentrations were related (r=0.87). Infant mean serum 25-hydroxyvitamin
D concentration increased from 17±13 to 39±6 ng/mL in the single-dose
group and from 16±12 to 39±12 ng/mL in the daily-dose group (P=.88). All
infantsachievedserum25-hydroxyvitaminDconcentrationsofmorethan20
ng/mL.
CONCLUSION: Either single-dose or daily-dose cholecalciferol
supplementation of mothers provided breast milk concentrations that result
invitaminDsufficiencyinbreast-fedinfants.
MayoClinProc.2013Dec;88(12):1378-87

Prevalence of maternal vitamin D deficiency in neonates with delayed
hypocalcaemia.
ActaMedIran.2012Nov;50(11):740-5.
Maternal vitamin D deficiency is one of the major risk factors for neonatal
vitamin D deficiency followed by neonatal hypocalcaemia. The aim of this
study is to determine the relationship between delayed neonatal
hypocalcaemia and maternal vitamin D deficiency. This is a descriptive cross-
sectionalstudy.Targetpopulationofthisstudyincludedalltermandpreterm
neonates with delayed hypocalcaemia (after the first 72 hours of birth)
admitted to Ali-Asghar Hospital. The sample size was 100 neonates included
in the study. Demographic, clinical and paraclinical data including Ca, P, PTH
and level of maternal and neonatal vitamin D were recorded according to
patients records. 67 neonates (67%) were term and 33(33%) were preterm
neonates. The mean of serum calcium in neonates was 6.49± 0.68mg/dL (in
the range of 4.3-7.8 mg/dL). 85% of neonates and 74% of mothers had
vitamin D deficiency. 100% of neonates born to mothers with vitamin D
deficiencywerehypocalcaemia.Astatisticallysignificantdifferencewasseen
between the mean values of serum Ca (6.67 in term vs. 6.12 in preterm
neonates) and vitamin D in term and preterm neonates was 16.34 vs. 20.18
(P= 0.0001 and P=0.01 respectively). Also, a significant correlation was seen
between maternal and neonatal level of vitamin D (P=0.0001, r=0.789). With
regard to the socio-cultural status in Iran besides women's clothing style and
nutritional deficiencies before and during pregnancy, health authorities and
policy makers are responsible to focus their serious attention on
hypocalcaemiaandhypovitaminosisDinneonates.
85% of neonates and 74% of mothers had vitamin D deficiency. 100% of
neonatesborntomotherswithvitaminDdeficiencywerehypocalcaemia.

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