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Nelson B. Watts MD

Bone Health and Osteoporosis CenterMetabolic Bone Diseases and Mineral Disorders

VITAMIN D AND HEALTH


VITAMINS

• A vitamin is an organic compound required as a nutrient in tiny amounts by an organism. A compound is called a vitamin when it cannot be synthesized in sufficient quantities by an organism, and must be obtained from the diet.

• Derivation: vite + amine (the “e” was later dropped when it was found that ascorbic acid [vitamin C] was not an amine)

http://en.wikipedia.org/wiki/Vitamin accessed 11/11/2008


THE DISCOVERY OF VITAMINS AND THEIR SOURCES



VITAMINS


• Initially, lipid from fish oil was used to cure rickets in rats, and the fat-soluble nutrient was called "antirachitic A"

• Thus, the first "vitamin" bioactivity ever isolated, which cured rickets, was initially called "vitamin A", although this compound is now called vitamin D

• What we now call "vitamin A" was identified in fish oil as a separate factor that was inactivated by ultraviolet light

• 9 water-soluble (8 B vitamins and vitamin C)• 4 fat-soluble vitamins (A, D, E, K)


VITAMIN D

http://en.wikipedia.org/wiki/Vitamin_D accessed 11/11/2008

• Vitamin D is a group of fat-soluble prohormones…The term vitamin D also refers to metabolites and other analogues of these substances

• Vitamin D – Regulates calcium and phosphorus levels in the

blood by promoting• Absorption from the intestines• Re-absorption of calcium in the kidneys

– Enables normal mineralization of bone and prevents hypocalcemic tetany

– Also needed for bone growth and bone remodeling by osteoblasts and osteoclasts


• Vitamin D from animal sources is cholecalciferol (vitamin D3) (commercially produced by irradiation of 7-dehydrocholesterol from lanolin)

• Vitamin D from plant sources is ergocalciferol (vitamin D2) (commercially produced by irradiation of ergosterol from yeast)

• Vitamin D can be ingested from foods or supplements

SOURCES OF VITAMIN D


FOOD SOURCES OF VITAMIN D

http://lpi.oregonstate.edu/infocenter/vitamins/vitaminD/


VITAMIN D – THE SUNSHINE VITAMIN

• The primary source of vitamin D in humans is sunlight exposure

• 7-dehydrocholesterol in the skin is activated by UVB to form the parent compound cholecalciferol (vitamin D3)

• UVB is required at wavelengths between 270–300 nm, with peak synthesis occurring between 295-297 nm

• Adequate amounts of vitamin D3 can be made in the skin after only ten to fifteen minutes of sun exposure at least two times per week to the face, arms, hands, or back without sunscreen

• With longer exposure to UVB rays, an equilibrium is achieved in the skin and the vitamin simply degrades as fast as it is generated



42 N

35 N

N=198/362(54.7%)

N=259/532(48.7%)

N=342/642(53.3%)

Sites also in Alaska and Hawaii P=NS for test of trend

PREVALENCE OF VITAMIN D DEFICIENCY (25-OH D <30 ng/mL)

Holick M et al, J Clin Endocrinol Metab 2005;90:3215-3222

1536 postmenopausal women studied in winter, mean 25-OH D 30.4 ng/mL


PREVALENCE OF VITAMIN D DEFICIENCY (25-OH D <30 ng/mL)

Holick M et al, J Clin Endocrinol Metab 2005;90:3215-3222

1536 postmenopausal women studied in winter, mean 25-OH D 30.4 ng/mL


SUN EXPOSURE AND VITAMIN D

• Surfers in Hawaii, n=93• 29 hours sun exposure

per week• Blood 25-OH D

– Highest 62 ng/mL– Mean 31.6 ng/mL– 51% were less than

30 ng/mL

Binkley N et al, J Clin Endocrinol Metab 2007;92:2130-2135

←51%


• The generation of vitamin D in response to UV is regulated by– Amount of exposure

• Time • Exposed surface

– Skin pigment• The lighter the skin, the more vitamin D

is produced per “unit” of UV exposure



• The intensity of the UV exposure– Varies with time of day

• Greatest at midday– Varies with season

• Greatest during summer • Depending on latitude, little or none in

winter– Is less efficient in older subjects



AGE & SKIN VIT D SYNTHESIS

• whole body exposure of 0.032 J/cm2

• young: 20–30old: 62–80

TIME (days)

0 1 2 3 4 5 6 7

SERU

M D

3 (ng/m

L)

0

10

20

30

40Old Young

Holick et al. (1989) Lancet


METABOLISM OF VITAMIN D

• The parent compounds (vitamin D2 and vitamin D3) are biologically inert

• Vitamin D2 and vitamin D3 circulate ~90% bound to vitamin D binding protein (only ~10% is biologically active)

• There may be differences in clearance (and potency) between D2 and D3



• Vitamin D is hydroxylated at the 25 position by the liver to yield 25-hydroxyvitamin D (25-OH D)

• This is the major storage and circulating form of the vitamin

• 25-OH D binds to the nuclear vitamin D receptor but with low affinity



• 25-OH D is transported to the kidney where it is further hydroxylated at the 1α position yielding 1-25(OH)2D (calcitriol)

• This is the most biologically active form of the hormone

• The activity of 1-α hydroxylase is regulated by parathyroid hormone (PTH)


VITAMIN OR HORMONE?

• Hormones are chemicals released by cells that affect cells in other parts of the body. Only a small amount of hormone is required to alter cell metabolism. It is also a chemical messenger that transports a signal from one cell to another. All multicellular organisms produce hormones... Hormones in animals are often transported in the blood. Cells respond to a hormone when they express a specific receptor for that hormone. The hormone binds to the receptor protein, resulting in the activation of a signal transduction mechanism that ultimately leads to cell type-specific responses

http://en.wikipedia.org/wiki/Hormone accessed 11/11/2008


VITAMIN D IS REALLY A HORMONE

• Most “vitamin” D is produced in the skin (i.e., does not have to be ingested)

• Vitamin D and its metabolites are transported in the bloodstream

• Most tissues and cells in the body have receptors for vitamin D

• Several tissues can convert 25-hydroxyvitamin D to the more active 1,25-dihydroxyvitamin D

Holick MF, N Engl J Med 2007;357:266-281


PLASMA VITAMIN D

• 25-hydroxyvitamin D– Major storage form of the hormone – Best reflection of total body stores– Varies with season (highest in late summer

and early fall)– Reported in ng/mL or nmol/L

1 ng/mL = 2.5 nmol/L

30 ng/mL = 75 nmol/L


25-OH D AND SERUM PTH

SERUM 25(OH)D (nmol/L)

0 20 40 60 80 100

SERUM

PTH

(pg/m

L)

20

40

60

80

100

120

Thomas et al, N Engl J Med 1998;338:777-783

8 16 24 32 40

(ng/mL)


SERUM 25(OH)D (nmol/L)

0 25 50 75 100 125 150 175 200

SERU

M iPT

H (pg/m

L)

0

20

40

60

80

100

120

140

Chapuy et al Osteoporos Int 1997;7:439-443(ng/mL)

10 20 30 40 50 60 70 80

25-OH D AND SERUM PTH


D STATUS & THE Ca ECONOMY

• 31 women• age: 63.2 + 9.3

• Studied 2x, 1 yr apart in Spring

• Given 10 g 25-OH D/day (D+) or no treatment (D-)

25(OH)D

D+ D–

nm

ol/

L

0

20

40

60

80

100

+73%

Heaney R et al

40

32

24

16

8

ng

/mL

25(OH) D


CALCIUM ABSORPTION

• 500 mg Ca load

• 3 diff. Ca sources

• standard bkfst.

• low Ca lunch & dinner

• blood drawn for Ca & PTH for 10–12 hrs

TIME (hrs)

0 2 4 6 8 10 12

SE

RU

M C

ALC

IUM

(m

g/d

L)

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7D+D–

Heaney R et al


D STATUS & THE Ca ECONOMY

Serum Ca

D+ D–

mg/d

L

0.0

8.0

8.5

9.0

9.5

10.0

Fasting PTH

D+ D–

pg/d

L

0

10

20

30

40

50

Ca Absorption

D+ D–AUC (m

g·h

r/dL)

0

1

2

3

4

5

* *

*P < 0.001

+38%

Heaney R et al


VITAMIN D STATUS

• Best reflected by serum 25-OH D levels• Reference ranges in the 1990s given at 9-45 ng/mL• Current lab reference range is 20-100 ng/mL• Minimum desirable level is 30 ng/mL (75 nmol/L)• Reasonable range is 30 to 60 ng/mL (75 to 150

nmol/L)• Toxicity is unlikely with levels <100 ng/mL or even

150 ng/mL


MEASURE 25-OH D, NOT 1,25 (OH)2 D

Calcitriol (1,25 dihydroxyvitamin D)• Major active metabolite• No seasonal variation• May be normal or high in vitamin D deficiency• 1,25 D level useful in a few clinical situations

– Renal insufficiency– Some cases of hypercalcemia (sarcoidosis

and other granulomatous diseases)


MEASURE 25-OH D???????

• Samples from 10 healthy volunteers

• Split and sent to 6 labs

Binkley NF et al, J Clin Endocrinol Metab 2004;89:3152-3157

Best results seen with HPLC or DiaSorin assay, which provide results for25-OH D225-OH D325-OH D total


VITAMIN D DEFICIENCY


• Vitamin D deficiency can result from – Inadequate intake coupled with inadequate

sunlight exposure– Disorders that limit absorption– Conditions that impair conversion into

active metabolites (e.g., liver or kidney disorders) or increase metabolic clearance

– A number of hereditary disorders (rare)



Farhat G et al, Neurology 2002;58:1348-1353

AFFECTS OF ANTI-EPILEPSY DRUGS ON VITAMIN D AND CALCIUM

Altered vitamin D metabolismInduction of cytochrome P450 enzymesIncreased degradation of vitamin D

Vitamin D-independent mechanismsImpaired calcium absorptionResistance to PTHSex steroid deficiency



Haney EM et al, Calcif Tiss Int 2005;76:11-16




• Vitamin D deficiency results in impaired bone mineralization and leads to– Rickets in children – Osteomalacia in adults and – Contributes to osteoporosis


RICKETS

• A disorder of infants and children• Bones are soft and deformed• Epiphyses enlarged and tender


RICKETS

• VITAMIN D DEFICIENT RICKETS– Results from malabsorption or malnutrition of vitamin D– Most common form of rickets

• VITAMIN D DEPENDENT RICKETS (1α hydroxylase deficiency)– Results from absence of renal hydroxylase enzyme– Inborn error of metabolism

• VITAMIN D RESISTANT RICKETS– Results from renal phosphate wasting– Often an X-linked genetic defect, also autosomal

dominant


OSTEOMALACIA

• Adult form of rickets, etiology is similar

• Bones are “soft,” not brittle (unlike osteoporosis)

• 400 IU (10 mcg) per day of ergocalciferol (D2) or cholecalciferol (D3) will prevent rickets and osteomalacia

• In societies where foods are fortified with vitamin D, rickets and osteomalacia are uncommon


2000 NIH Consensus Development Conference

DEFINITION OF OSTEOPOROSIS

Normal Bone

Osteoporotic Bone

• A skeletal disorder characterized by– compromised bone strength

predisposing to– an increased risk of fracture.

• Bone strength reflects the integration of two main features: – bone density and – bone quality.


FRACTURES IN 2005 (US)

Burge R et al, J Bone Miner Res 2007;22:465-475

Other 33% Humerus Clavicle Hands/fingers Patella Tibia/fibula

Hip 14%Vertebra 27%

Wrist 19%

Pelvis 7%2 million fractures in 2005

73% were at nonvertebral sites

29% occurred in men14% occurred in nonwhites

Prepared by Nelson Watts MD 2007


VITAMIN D REDUCES FRACTURES

Trivedi DP et al, BMJ 2003;326-469-475

Fractures (hip, wrist, forearm, vertebra)

Vitamin D 100,000 IU Q 4 months or placeboN=2037 men and 649 women ages 65-85

OR 0.78 (0.61,0.99)

22%↓


META-ANALYSIS OF EFFECT OF VITAMIN D ON FRACTURES

Bischoff-Ferrari HA et al, JAMA 2005;293:2257-2264

RR 0.74 (CI 0.61-0.88) RR 0.77 (CI 0.68-0.87)

26%↓ 23%↓


VITAMIN D REDUCES FRACTURESAND MAY REDUCE MORTALITY

Trivedi DP et al, BMJ 2003;326-469-475

Fractures (hip, wrist, forearm, vertebra)

Survival

Vitamin D 100,000 IU Q 4 months or placeboN=2037 men and 649 women ages 65-85

OR 0.78 (0.61,0.99) OR 0.88 (0.74,1.06)

22%↓ 12%↑


EFFECTS OF A SHORT-TERM VITAMIN D AND CALCIUM SUPPLEMENTATION

ON BODY SWAY AND SECONDARY HYPERPARATHYROIDISM

IN ELDERLY WOMEN

Pfeiffer M, Begerow B, Minne HW,

Abrams C, Nachtigall D, Hansen C

J Bone Miner Res2000;15:1113-1118


VITAMIN D REDUCES BODY SWAY AND RISK OF FALLING

Pfeiffer M et al, J Bone Mineral Res 2000;15:1113-1118

• 148 women, age mid-70s, with low serum 25-hydroxyvitamin D levels (<20 ng/mL)

• Calcium 1200 mg alone or with 800 IU vitamin D for 8 weeks

• PTH, bone turnover markers, body sway measured after 8 weeks

• Falls and fractures assessed after 1 year




0

20

40

60

80

100

120

140

160

180

25-OH D

-30

-25

-20

-15

-10

-5

0

PTH

-45

-40

-35

-30

-25

-20

-15

-10

-5

0

NTx

Per

cen

t C

han

ge

fro

m B

asel

ine

*

*

*P<0.05

Calcium alone Calcium + vitamin D



1200 mg calcium 1200 mg calcium

Change in alone 800 IU vitamin D

Front sway -13% -24%

Side sway +2% -6%

Sway area -16% -31%

148 women, age mid 70s, serum 25-OH vitamin D <20 ng/mL8 weeks treatment

P<0.05 for all comparisons




Calcium alone Calcium + D (n=67) (n=70)

Subjects who fell 19 (28%) 11 (16%)*

Number of falls 30 (45%) 17 (24%)*

Number of fractures 6 (9%) 3 (4%)

Radius or ulna 3 2

Pelvis 1 0

Hip 1 0

Ankle or foot 1 1

*P<0.05 Pfeiffer M et al, J Bone Mineral Res 2000;15:1113-1118


VITAMIN D REDUCES RISK OF FALLING

Bischoff-Ferrari HA et al. JAMA 2004;291:1999-2006

Meta-Analysis


VITAMIN D AND CANCER

• At higher latitudes there is an increased risk for Hodgkin’s lymphoma, cancer of the colon, pancreas, prostate, ovary, breast and others

• 25-OH D <20 ng/mL is associated with 30%-50% increase risk of colon, prostate and breast cancers, along with higher mortality from these cancers

• In WHI, women with baseline 25-OH D <12 ng/mL had a 253% increase in the risk of colorectal cancer over a follow-up period of 8 years

• Among men with prostate cancer, the disease developed 3 to 5 years later in men who worked outdoors vs those who worked indoors




• The kidneys tightly regulate production of 1,25-dihydroxyvitamin D; serum levels do not rise in response to increased exposure to sunlight or increased intake of vitamin D

• 1,25-D levels are often normal or even elevated in a vitamin D-insufficient state

• Colon, prostate, breast and other tissues express 1α-hydroxylase and produce 1,25-dihydroxyvitamin D locally to control genes that help to prevent cancer by keeping cellular proliferation and differentiation in check




• If a cell becomes malignant, 1,25-D may induce apoptosis and prevent angiogenesis, thereby reducing the potential for the malignant cell to survive

• Once 1,25-D completes these tasks, it initiates its own destruction by stimulating the CYP24 gene to produce the inactive calcitroic acid. This guarantees that 1,25-D does not enter the circulation to influence calcium metabolism



Liu PT et al, Science 2006;311:1770-1771

• Activation of Toll-like receptors (TLRs) triggers direct antimicrobial activity against intracellular bacteria

• TLR activation of human macrophages – Up-regulates expression of the vitamin D receptor and the vitamin

D-1-hydroxylase genes, leading to induction of the antimicrobial peptide cathelicidin and killing of intracellular Mycobacterium tuberculosis

– Sera from African-American individuals, known to have increased susceptibility to tuberculosis, had low 25-hydroxyvitamin D and were inefficient in supporting cathelicidin messenger RNA induction

• These data support a link between TLRs and vitamin D-mediated innate immunity and suggest that differences in ability of human populations to produce vitamin D may contribute to susceptibility to microbial infection

VITAMIN D AND INFECTION


VITAMIN D AND CARDIOVASCULAR DISEASE

• Living at higher latitudes increases the risk of hypertension and cardiovascular disease

• In a study of patients with hypertension exposed to UVB radiation three times a week for 3 months, 25-OH D levels increased ~180% and blood pressure became normal (both systolic and diastolic blood pressure reduced by 6 mm Hg)

• Vitamin D deficiency is associated with congestive heart failure and blood levels of inflammatory factors, including C-reactive protein and IL-10



VITAMIN D AND CARDIOVASCULAR DISEASE

Wang TJ et al, Circulation 2008;117:503-511

With hypertension Without hypertension


VITAMIN D AND AUTOIMMUNE DISEASE

• Living at higher latitudes increases the risk of type 1 diabetes, multiple sclerosis and Crohn’s disease

• Living below 35 degrees latitude for the first 10 years of life reduces the risk of multiple sclerosis by approximately 50%

• Among white men and women, the risk of multiple sclerosis decreased by 41% for every increase of 20 ng/mL in 25-OH D above approximately 24 ng/mL

• Women who ingested more than 400 IU of vitamin D per day had a 42% reduced risk of developing multiple sclerosis

• Similar observations have been made for rheumatoid arthritis and osteoarthritis

• Several studies suggest that vitamin D supplementation in children reduces the risk of type 1 diabetes. Increasing vitamin D intake during pregnancy reduces the development of islet autoantibodies in offspring



VITAMIN D AND MULTIPLE SCLEROSIS

Munger KL et al JAMA 2006;296;2832-2838


VITAMIN D AND MENTAL HEALTH

• Vitamin D deficiency has been linked to an increased incidence of schizophrenia and depression

• Maintaining vitamin D sufficiency in utero and during early life, to satisfy the vitamin D receptor transcriptional activity in the brain, may be important for brain development as well as for maintenance of mental function later in life



VITAMIN D AND LUNG FUNCTION

• Men and women with 25-OH D level above 35 ng/mL had a 176 mL increase in FEV-1

• Children of women living in an inner city who had vitamin D deficiency during pregnancy are at increased risk for wheezing illnesses


www.uc-osteoporosis.comCopyright restrictions may apply.

Autier, P. et al. Arch Intern Med 2007;167:1730-1737.

VITAMIN D AND MORTALITY:META-ANALYSIS OF 9 TRIALS

8% increase In survival


HOW TO TREAT VITAMIN D DEFICIENCY?

• D2 or D3, or does it matter?• How much?

– OTC, readily available, usually D3• 400 IU (10 mcg) • 800 IU (20 mcg) • 1,000 IU (25 mcg) • 2,000 IU (50 mcg)

– Prescription, only D2• 50,000 IU (1.25 mg)


Armas LAG et al, J Clin Endocrinol Metab 2004;89:5387-5391


Holick MF et al, J Clin Endocrinol Metab 2008;93;676-681


HOW TO TREAT VITAMIN D DEFICIENCY?

• There may be differences in potency, D3>D2• 1000 IU D3 per day will raise blood levels by ~10 ng/mL• 50,000 IU D2 per week will raise blood levels by 20-30

ng/mL• A steady state should be reached in 8-12 weeks, sooner in

lean individuals, later in obese patients• Give enough to achieve and maintain blood 25-OH D

between 30 and 60 ng/mL• If you can’t measure the level and titrate replacement,

recommend 1000-2000 IU per day or 50,000 IU twice a month


VITAMIN D TOXICITY?

• No direct organ toxicity; too much vitamin D causes hypercalciuria and hypercalcemia

• Safe level for virtually anyone is 2000 IU/d

• Most people are safe up to 5000 IU/d or 50,000 IU every two weeks

• Toxicity is unlikely with blood levels <100 ng/mL and rarely seen up to 150-200 ng/mL


SUMMARY AND CONCLUSIONS

• Vitamin D has important skeletal and extra-skeletal effects• Vitamin D deficiency is common• Adequate 25-hydroxyvitamin D level is ≥30 ng/dL• Most patients require 1,000-2,000 IU vitamin D per day to

achieve an adequate level• “Safe upper limit” is 2,000 IU per day• Supplements of 1,000 IU and 2000 IU tablets are now

widely available• Rx 50,000 IU ergocalciferol may be required (weekly, every

other week)


VITAMIN D

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