Vitamin D

Deficiency, Insufficiency, and

Supplementation
Thomas Archie, MD
St. Lukes Wood River Family Medicine
Hailey, ID

Overview
Vitamin D receptors found in gut, bone, brain, breast,
prostate, lymphocytes, placenta, and other tissues
Routine screening is appropriate
Safe up to 4000iu/d without monitoring
Safe up to 10,000iu/d with monitoring
Supplementation helpful in:
DM, metabolic syndrome, CAD, depression, autoimmune
diseases, various cancers, HTN, osteoporosis, osteoarthritis,
pain, MS, epilepsy, elderly fall prevention, PCOS, pregnancy &
lactation, periodontal disease, URI and influenza, and
decreasing all-cause mortality

Physiology
Vitamin D3 (Cholecalciferol)
Produced in skin with direct sunlight, cod liver oil
Preferred form of supplementation

Vitamin D2 (Ergocalciferol)
Made by irradiating fungi
Less effective as precursor to 1,25(OH)2-Vit D

Physiology
Hepatic conversion of Vit D3 to 25-OH-Vit D
(calcidiol)
Conversion of 25-OH-Vit D to 1,25(OH)2-Vit D
(calcitriol)
Previously thought exclusively renal
Requires two factors
25OH-VitD3-1-alpha-OHase
Vitamin D Receptor (VDR)

Physiology
Autocrine Metabolism
Vitamin D functions as a steroid hormone
Cells containing 25OH-VitD3-1-alpha-OHase
Breast, prostate, lung, skin, lymph nodes, colon, pancreas,
adrenal medulla, brain, placenta
Holllick MF. Am J Clin Nutr. 2004. 79(3):362.
Zehnder et al. J Clin Endocrin Metab. 2001;86(2)

Cells containing Nuclear VDR

Pancreatic islet cells, monocytes, transformed B cells,
activated T cells, neurons, prostate, ovaries, pituitary, aortic
endothelium, placenta, skeletal muscle cells.
Zittermann A. Br J Nutr. 2003;89(5):552.
Bischoff HA, et al. Histochem J 2001;33:19.

Calcitriol
Most biologically active form of Vit D
Raises GI calcium and phosphorus
absorption
Induces osteoclast maturation for bone
remodelling
Promotes calcium deposition in bone and
reduction of PTH

Parathyroid Hormone
Secondary hyperPTH can be due to
hypovitaminosis D
25OH-Vit D levels 30-40ng/ml
Zittermann A. Br J Nutr. 2003;89(5):552.

Suppression of PTH important

Low PTH promotes good health
High PTH associated with increased risk of MI, HTN,
stroke
Kamycheva et al. Eur J Cardiovasc Prev Rehab.
2004;11(1).
Sato et al. Neurology. 2003;60(4):626.

Calcitriol and Cancer

Modulates the transcription of several
oncogenes involved with cell differentiation and
proliferation
C-myc, c-fos, c-sis
Inverse relationship b/t sun exposure and cancer
mortality
Grant. Cancer. 2002;94(6):1867.
Apperly. Cancer Res. 1941;1:191.

Calcitriol and CNS function

Vit D Modulates neurotransmitter and
neurological function
Anticonvulsant and antidepressant effect
Landsdowne et al. Psychopharmacology.
1998;135.
Christiansen et al. Br Med J.
1974;2(913):258.

Calcitriol
Reduces inflammation
Nuclear Vit D receptors in lymphocytes
Suppresses and may prevent autoimmune
diseases
Decreases risk of certain cancers
Seems to reduce severity and frequency of
childhood pneumonia

Wayse et al. Eur J Clin Nutr. 2004;58(4):563.

Calcium Absorption
Calcium absorption increases as 25(OH)D
blood levels increase.
Vit D levels of 34 ng/ml (about 3,000 IU/day) calcium absorption 65% higher than when
levels are 20 ng/ml
Implies that part of the reason humans need to
take so much extra calcium is because there is
widespread deficiency of vitamin D.
Heaney et al. J Am Coll Nutr. 2003 Apr;22(2):142.

Clinical Relevance
Coronary artery disease
Hypertension
Diabetes Type I and
Type 2
Osteoarthritis
Depression
Epilepsy

Polycystic Ovaries
Musculoskeletal Pain
Autoimmune Disease
Multiple Sclerosis
Cancers
Falls in the Elderly
Pregnancy and Lactation

Laboratory Assessment
25-OH-Vitamin D level is the appropriate test
Typical labeled normal range is 8-40ng/ml
Population based

Optimal range for best health is 40-65ng/ml

Based on epidemiologic assessment of normal
levels in tropical humans
Based on physiologic changes, increases in PTH,
and clinical disease states associated with levels
under 40ng/ml

Heart Disease
MI risk doubles in pts with 25OHVitD
levels < 34ng/ml
Scragg et al. Int J Epidemiol. 1990;19(3):559.

CHF pts have much lower 25OHVitD

levels than controls
Zitterman et al. J Am Coll Cardiol. 2003;41:105.

Deaths from CAD more common in

winter
Scragg. Int J Epidemiol. 1981;10(4):337.

Heart Disease
1,739 individuals without cardiovascular disease
Baseline 25-OH-Vitamin D levels were assessed and
participants were followed for a mean of 5.4 years.
Compared to having a level >15ng/ml
25-(OH)D < 10 ng/mL - 80% greater risk of having a
cardiovascular incident
25 (OH)D of 10-15 ng/mL - 53% increased risk

The authors concluded vitamin D deficiency is

positively correlated with incident cardiovascular
disease.
Wang TJ, Pencina MJ, Booth Sl, et al. Vitamin D deficiency and
risk of cardiovascular disease. Circulation 2008;117:503-511.

Hypertension

BP higher in winter
BP higher with increasing latitude
BP higher with darker skin pigmentation
HTN pts given UV light treatments 3 times per
week for 6 weeks had Vit D level increases of
162% and saw mild decreases in BP
Krause et al. Lancet. 1998;352(9129):709.

Small doses of Vit D (800iu) for 8 weeks

decreased BP and pulse rate
Pfeifer et al. J Clin Endocrinol Metab. 2001;86(4):258.

Hypertension
Studies
BP is reduced significantly by ultraviolet radiation
comparable to about oral intake of 3,000 IU of
vitamin D a day
Krause R, Bohring M, Hopfenmhller W, Holick MF, Sharma
AM: Ultraviolet B and blood pressure. Lancet. 1998;3
52:709-710

BP not routinely reduced by small amounts of

vitamin D
Scragg R, Khaw KT, Murphy S: Effect of winter oral vitami
n D3 supplementation on cardiovascular risk factors in el
derly adults. European Journal of Clinical Nutrition. 199
5;49:640-646

Diabetes Type 1
Study with > 10,000 people
Supplementation of infants and children with
Vit D 2000iu/day decreased incidence of DM
type 1 by 80%
Hypponen et al. Lancet. 2001;358(9292):1500.

Cod liver studies also show significant

reduction of incidence of Type I DM

Diabetes Type 2
Low Vit D levels assoc with insulin
resistance and Beta-cell dysfunction
Postprandial glucose and insulin
sensitivity
Better in healthy adults with highest Vit D
levels
Chiu. Am J Clin Nutr. 2004;79:820.

Diabetes Type 2
Metformin improves insulin sensitivity by
13%
Highest Vit D levels associated with 60%
improvement in insulin sensitivity
Chiu. Am J Clin Nutr. 2004;79:820.

Small trial of 10 women with DM Type 2

Vit D 1332iu per day x 30 days
21% increase in insulin sensitivity
Borrisova et al. Int J Clin Pract. 2003;57(4):258.

Upper Respiratory
Infection and Influenza
Three-year RCT of 208 African-American postmenopausal women
(who are at great risk of vitamin D deficiency)
Vitamin D 800iu/day for Years 1-2 and 2000iu/day Year 3
In the three years of the study 34 patients reported cold and flu
symptoms,
8 in the supplemented group
26 in the placebo group (p<0.002).

Participants who got a placebo had a 300% greater risk of having

a cold or flu, and that vitamin D supplementation provided a highly
significant protective effect.
Aloia JF. Epidemic influenza and vitamin D. Epidemiol Infect
2007;135:1095-1096.

Osteoarthritis
Framingham data
Knee OA advanced most quickly in patients
with 25OHVitD < 36ng/ml
McAlindon et al. Ann Intern Med. 1996;125(5):353.

Hip OA advanced most quickly in patients

with 25OHVitD < 30 ng/ml
Lane et al. Arthritis Rheum. 1999;42(5):854.

Depression
Seasonal Affective Disorder
Single dose 100,000 iu Vit D superior to light
therapy for one month
Gloth et al. J Nutr Health Aging. 1999;3(1):5.

Vit D 400-800iu per day associated with

improved mood within 5 days
Landsdowne et al. Psychopharmacology.
1998;135.

Mental Illness
Comorbidities
Mental Illness and Vitamin D deficiency
share similar comorbidities
Cardiac mortality, DM type I and II,
osteoporosis, MS, rheumatoid arthritis, HTN

Epilepsy
Seizures can be first sign of Vit D def
Johnson, Willis. Med J Aust. 2003;178(9):467.

Hypovitaminosis D decreases Seizure

threshold
Several anticonvulsants

Interfere with renal calcitriol formation

Induce hepatic clearance of calcitriol
May cause iatrogenic seizures via iatrogenic
hypovitaminosis D
Ali et al. Ann Pharmacother. 2004;38(6):1002.

Epilepsy
Placebo controlled pilot study

4000-16000iu/day of Vit D2
Decrease in seizure frequency
Christiansen et al. Br Med J. 1974;2(913):258.

Polycystic Ovary Syndrome

Small study of 13 PCOS pts

9 of 13 w/ Vit D deficiency
Ca 1500mg/day + Vit D2 50,000iu/week
9 of 9 pts with normalization of menses
and/or fertility within 3 months
Thys-Jacobs S. Steroids. 1999;64(6):430.

Pain
Study with 150 pts with persistent, nonspecific
musculoskeletal pain at Mayo clinic
93% had Vit D deficiency
Plotnikoff, Quigley. Mayo Clin Proc. 2003;78(12):1463.

Children w/ limb pain improved in 3 months

Low Back Pain
83% of 299 LBP pts had Vit D def
5000-10,000iu/day
Decrease in pain medication in nearly 100% after 3 months
Al Faraj, Al Mutairi. Spine 2003;28(2):177.

Autoimmune Disease
Vitamin D insufficiency in:
50% of pts w/ fibromyalgia + SLE
Huisman et al. J Rheumatol. 2001;28(11):2535.

58% Japanese Fs with Graves Disease

Yamashita et al. Endocr J. 2001;48(1):63.

73% Austrian pts w/ Ankylosing Spondilitis

Falkenbach et al. Wien Klin Wochenschr.
2001;113(9):328

Rhematoid Arthtritis
Cantorna.Proc Soc Exp Biol Med. 2000;223(3):230

Multiple Sclerosis
48% of MS pts are Vit D deficient
Mahon. J Neuroimmunol. 2003;134(1-2):128.

MS rare near equator

Zittermann A. Br J of Nutr. 2003;89:552-572

5,000iu/d plus Ca 1000mg and Mag

600mg decreased the relapse rate in MS
patients no side effects
Goldberg P. Medical Hypothesis. 1986;21:193-200

Inflammation
Vit D injections averaging 547iu/day x 2-5 years
23% decrease in CRP
Timms et al. QJM. 2002;95:787.

25(OH)Vit D level should be checked in any

patient with any inflammatory condition
Michael Hollick, PhD, MD Professor of Medicine,
Dermatology, Physiology and BioPhysics, Director of the
General Clinical Research Center and Director of the Bone
Health Care Clinic at Boston University Medical Center

Vit D supp in pts w/ prolonged clinical illness

saw decreases in IL-6 and CRP
Van den Berghe et al. J Clin Endocrinol Metab.
2003;88(10):4623.

Cancer
Vitamin D levels inversely correlated to colon
cancer mortality (but not to all cancer mortality)
Freedman et al. J Natl Cancer Inst. 2007. 99(21):1563.

47,800 men over 14 years

10 ng/ml rise in Vitamin D level of associated w/
17% reduction in cancer incidence
29% reduction in all cancer mortality
45% reduction in GI cancer mortality
Giovanucchi et al. J Natl Cancer Inst. 2006. 98(7):428.

Cancer
Long-term study of 50,000 men at Harvard
School of Public Health suggests vitamin D may
reduce the risk of all cancers by at least 30
percent.
Giovannucci. J Natl Cancer Inst. 2006 Apr 5:98(7):428.

Decreased sunlight assoc with increased cancer

mortality
Breast, colon, cancer, prostate, bladder, esophagus,
kidney, lung, pancreas, rectum, stomach, uterus,
non-Hodgkins Lymphoma
Grant. Cancer. 2002;94(6):1867.

Falls in the Elderly

Vit D receptors in skeletal muscle

Bischoff HA, et al. Histochem J 2001;33:19.

Vit D deficiency reported to affect predominantly the

weight-bearing antigravity muscles of the lower limb,
which are necessary for postural balance and walking
Glerup H et al. Calcif Tissue Int 2000;66:419.

Significant correlation between serum 25(OH)D3

concentration and the occurrence of falls in elderly
reported in literature.

Mow M et al. J Am Geriatr Soc 1999;47:220

Stein MS et al. J Am Geriatr Soc 1999;47:1195

Falls in the Elderly

STOP/IT (Sites Testing Osteoporosis Prevention and Intervention
Treatments) trial
489 women randomly assigned to receive estrogen, calcitriol, both
estrogen and calcitriol, or a placebo for 3 years.
The increase in bone density was twice as large with estrogen as
with calcitriol.
The subjects w/ calcitriol had fewer fractures from falls than did
the group who took estrogen (odds ratio: 0.78 and 0.94,
respectively).
Improvement in lower extremity muscle strength and balance with
vitamin D supplementation thought to explain the reduced number
of fall-related fractures.
Dawson-Hughes et al. N Engl J Med 1997;337:670

Pregnancy
Vit D2 100,000 iu/day throughout pregnancy
associated with no fetal abnormalities
Current recommendation of 200-400iu per day
inadequate
Hollis & Wagner recommend up to 4000iu

Pre-eclamsia and SGA babies associated with

Vit D deficiency
Halhali et al. J Clin Endocrin & Met 2000. 85(5), 18281833 .

Lactation
Breast-feeding mothers need 4,000 units
of vitamin D a day in order to maintain
adequate infant Vit D status.
2,000 iu/day was not effective.
Wagner CL, et al. Pediatr Res 2003.
Hollis et al. Am J Clin Nutr 2004;80(suppl):1752S
8S.
Basile et al. Breastfeeding Medicine. March 1,
2006, 1(1): 27-35

Lactation
25-OH-D content of maternal milk responsible
for vitamin D concentrations of serum of
exclusively breast-fed infants
Cancela et al. J Endocrinol. 1986 Jul;110(1):43-50.

Hypovitaminosis D common in summer in

exclusively breast-feeding infants and their
mothers
Dawodu et al. J Pediatr. 2003 Feb;142(2):169

Breastfed infants should be given Vit D 1000iu

Increase this to 2000iu in family hx of DM type 1

Periodontal Disease
Periodontal attachment loss inversely
associated with 25-OH-Vitamin D levels
in adults > 50yrs old
Dietrich Am J Clin Nutr. 2004 Jul;80(1):108-13.

Medical Inpatients
290 medical inpatients in Boston
screened
57% with Vitamin D < 15ng/ml
Thomas et al. N Engl J Med 1998;338(12):777-83

Separate Finish study

40-70% medical patients deficient

Lake Almanor Clinic

T Archie - unpublished case series of over 90
patients with range of diagnoses (40 deg
latitude)
25OHVitD levels checked Sept 04-Jan 07
HTN, chronic kidney disease, osteoarthritis,
depression, SAD, musculoskeletal pain, autoimmune
disease, CHF, DM, overweight, CVA, elevated CRP,
healthy pregnancy, screening
All but 5 patients had levels below 40ng/ml
95% incidence among this group

Common to see level 12-25ng/ml

Longevity
Meta-analysis of 18 RCTs 57,311 patients
Range of 300-2000iu/day
Highest intake 7% reduction in all-cause
mortality
Based on the total body of evidence of health
conditions associated with vitamin D deficiency,
abetted with the results from this metaanalysis, a more proactive attitude to identify,
prevent and treat vitamin D deficiency should
be part of standard medical care.

Giovannuchi. Arch Intern Med. 2007;167:1709-1710.

Toxicity
No credible evidence of toxicity at Vit D
levels <150ng/ml
No evidence for toxicity at doses of
10,000iu/d indefinitely
Vieth R. Am J Clin Nutr. 1999;69

Indicator of direct Vit D toxicity

Elevated serum calcium - AND 25OHVitD > 90ng/ml
Berkow. Merck Manual. 1987:928.

Toxicity
Toxicity rare and requires long-term
administration of at least 40,000iu/day in
infants (or 100,000iu/d in adults) for several
months
Berkow. Merck Manual. 1987:928.

Toxicity sxs appear with level >125ng/ml

Anorexia, nausea, vomiting, weakness,
nervousness, pruritis, polyuria, polydipsia, renal
impairment, soft tissue calcifications
Holick. Am J Clin Nutr. 2001;73(2):288.

Toxicity
Caution in Sarcoidosis
Macrophages in sarcoid patients have
considerably increased rates of conversion
of 25OHVitamin D to 1,25(OH)2Vitamin D.

Supplementing
Physiologic requirement 3000-5000iu/day
Vitamin D deficiency
<20ng/ml (some authors believe this should be
<30ng/ml and some labs have cut off at 32ng/ml)

Vitamin D insufficiency
<40ng/ml
PTH levels increase at 30-40ng/ml
Elderly men and women shown to have increasing
PTH levels at Vit D levels <45ng/ml

Supplementing
Optimal goal is 40-65ng/ml
Humans living near the equator have mean serum
25(OH)D levels of more than 40 ng/ml
Solar input equivalent to about 4,000 IU of vitamin D
a day
Linhares et al. Am J Clin Nutr. 1984:39(4):625-630

American lifeguards, working in swimsuits, have

even higher 25(OH)D levels (64 ng/ml), in spite of
temperate latitudes.
Holmes R, Kummerow F. J Amer Coll Nutr. 1983;2:173.

Supplementing
All patients at higher latitudes (above 35
degrees) should be screened
High latitude and high prevalence of Vit D deficiency
in local small case series (95% incidence)
42% health adolescents Vit D def
Gordon et al. Arch Pediatr Adolesc Med. 2004;158(6):531.

62% morbidly obese pts Vit D def

Buffington et al. Obes Surg. 1993;3:421.

High risk of avoiding supplementation

Low risk of supplementing

Supplementing
28 Adults given 4000iu/d x 5 months
Levels averaged 40ng/ml
Vieth. Am J Clin Nutr 2001.73(2):288.

67 men given higher doses x 20 weeks

5000iu/d avg 25OHVitD level 60ng/ml

10,000iu/d average level 90ng/ml
No toxicity seen
Heany et al. Am J Clin Nutr. 2004;79(3):362.

Supplementing in
Obesity
Double the Vitamin D dosage in the
patient with obesity
Excessive adipose tissue absorbs
Vitamin D and decreases bioavailability
by 57%
Wortsman et al. Am J Clin Nutrition, 2000: 72 (3),
690-693

Supplementing
Replacement
4000-10,000iu per day for 5-9 months

Baseline supplementation

Infants 1000iu/day
Children 2000iu/day
Adults 2000iu - 4000iu/day
Pregnancy and Lactation 4000iu/day

Supplementation
Serum levels plateau after 3-4 months of
daily supplementation
Heaney. Am J Clin Nutr. 2003;77(1):204.

Therefore, be prepared to increase

supplementation if necessary.

Supplementation
Cod Liver Oil (concern is Vit A toxicity
depending on dose)
Vitamin D3 (cholecalciferol)
Highest single dose available 5000iu per softgel
(Pure Encapsulations). 1000iu Life Extension
Source
Preferred source
Capsule can be opened into milk for infants

Vitamin D2 (ergocalciferol)
Available as 50,000iu given every 1-2 weeks
Less effective for conversion to calcitriol

Monitoring
25-OH-Vit D levels and serum calcium
Re-check every 2-4 months when
starting with levels below 35ng/ml.
Re-check every 1-2 months when levels
over 35ng/ml until levels plateau.
Consider continuing age-appropriate
supplementing with infrequent monitoring

Repeating the Overview

Vitamin D receptors found in gut, bone, brain,
breast, prostate, lymphocytes, placenta, and
other tissues
Routine screening is appropriate at Lat >35deg
Safe up to 4000iu/d without monitoring
Safe up to 10,000iu/d with monitoring
Supplementation helpful in:
DM, metabolic syndrome, CAD, depression, autoimmune
diseases, various cancers, HTN, osteoporosis,
osteoarthritis, pain, MS, epilepsy, elderly fall prevention,
PCOS, pregnancy & lactation, periodontal dz, URI/flu
prevention, all-cause mortality