םירוקרז רואל שמשה רואמ – D ןימטיו םולש שיא היפוצ ' פורפ םילרנימהו םצעה םזילובטמל הדיחי

Outline

• History • Vitamin D deficiency – pandemic • Vitamin D production • Definition of vitamin D status • Vitamin D and bone health • Non calcemic actions of vitamin D • Vitamin D replenishment

Fish Oil

Rickets

תורפסב ומסרופש תוריקסו תכרעמה ירמאמ רפסמ 1981 תנשמ D ןימטיו לע תיאופרה

D ןימטיו

The Layers of Biomedical/Nutritional Evidence.

1.

Intervention studies (randomized with control subjects)

to show the nutrient in fact does what we think it will 2.

Mechanisms, based on “preclinical”,

basic-science studies 3.

Cross-sectional, epidemiological evidence

. In a court of law, this would be “circumstancial evidence”

Cod liver oil, Yeasts, Plants, Fortified Foods 290 – 315 nm SKIN 7 dehydrocholesterol Major circulating metabolite used to determine vitamin D status Regulation of immune function

No tan & No vitamin D at low sun angle

Low sun angles result in loss of UVB wavelengths Vitamin D is made when skin is exposed to UVB, light at wavelengths from 280-315 nm

Vitamin D Production

Sun exposure in a bathing suit 1 minimal erythema dose = ingestion of 2000 IU

20 000 IU

Use of sunscreen



100%



in vitamin D production

Exposure of arms and legs 25% minimal erythema dose (5 –15 min) 11 am – 2 pm x 3/w

Cod liver oil, Yeasts, Plants, Fortified Foods Prostate, Placenta Breast; Colon Osteoblasts Keratynocytes Immune cells 1,25(OH) 2 D 3 Regulation of cell growth (cancer prevention) Regulation Regulation function function 290 – 315 nm SKIN 7 dehydrocholesterol Major circulating metabolite used to determine vitamin D status

1,25(OH) 2 D - Control of Production

1 α OH ase CYP27B1, a mitochondrial P450 enzyme

Ca++ P Induction of CYP24

Bikle, JCEM 2008

Rationale for Nonclassic Action of Vitamin D • • Most tissues in the body have receptors for the active form of vitamin D,

1,25(OH) 2 D or calcitriol

-

VDR

• Many of these tissues also contain the enzyme,

CYP27B1

, responsible for converting the major circulating metabolite of vitamin D, 25(OH)D to 1,25(OH) 2 D.

Regulation of CYP27B1

in these non renal tissues generally differs from that in the kidney, and may be more

substrate dependent.

• This has led to the concept that maintenance of adequate 25OHD levels in the blood is required for vitamin D regulation of a large number of physiologic functions beyond that of the classic actions involved with bone mineral metabolism.

Definition of Vitamin D Status for Multiple Health Outcomes

Vitamin D Status Deficiency Insufficiency Normal 25(OH)D ng/ml x 2.5= nmol/l  10  25 10 – 15 25 – 37.5

>15 >37.5

 20  50 20 - 30 50 - 75 > 30 >75 M. Holick 2007 M Parfitt, 1970

J Nutr. 2005;135(2):304-9

Vitamin D Status in Primates and Early Humans

160 120 Winter 43 o N Latitude A

80

40 0

Old-World Primates Humans exposing full skin surface to Sunshine ’s UVB

16

“Normal” Sources, include Cosman, Osteoporosis Int 2000; Fuleihan NEJM 1999; Scharla Osteoporosis Int 1998; Vieth AJCN 1999, 2000

Blood Levels when taking 1000 IU/day

Northern People Taking 4000 IU/day

80

Physiological adult intake

Osteoporosis - definition

“a systemic skeletal disease characterized by microarchitectural deterioration with a consequent increase in bone susceptibility to fracture ” fragility and

S Ish-Shalom

םיאירב םירבג בר קב D ןימטיו תומר תוגלפתה לארשיב עדי תוריתע תורבחב םידבועה םיזוחא יפל

D ןימטיו ךר ע )ng/ml( deficiency <10 insufficiency 10-15 inadequacy 15-30 normal >30 N. Segal 2008

18% 31% 51% 0%

60% 50% 40% 30% 20% 10% 0%

םישנו םירבג לצא 25(OH)D תומר תוימינפ תוקלחמב םיזפשואמה

45 48% 40 26% 24% 2% 23% 41% 34% 2% 35 30 5 0 25 20 15 10 למ '\ גנ 32 לעמ למ '\ גנ 20-32 למ '\ גנ 10-20 למ '\ גנ 10 מ תוחפ םישנ םירבג .) p=0.018

( םירבג רשאמ D ןימטיו רסחמ רתוי ולבס םישנ  םישנ 63 לצא התלגתנ ל " מ / ג " נ 20 ל תחתמ .) 66.2% ( םירבג 43 D ןימטיו תמר תמועל ) 74.1% (  Nodelman M. 2008

Intestinal Calcium Absorption

1,25(OH) 2 D 3

Lumen ATP ADP Ca ++ calbindin In Vitamin D deficiency state we absorb Ca ++ < 10 – 15% of dietary calcium Ca ++ < 60% of dietary phosphorus saturation at 400 25(OH)D 3  1,25(OH) 2 D 3 30 mg per 100 mg of 70 – 80 % of dietary phosphorus

Vitamin D and Bone

Bone Effects of Vitamin D Deficiency • Ca X P insufficient  insufficient mineralization • Osteoblasts continue bone deposition • Endoosteal surface • Periosteal surface Rubbery matrix with insufficient support • Matrix hydrates and expands under periosteal covering  outward pressure on periosteal covering innervated with sensory nerves

Fish Oil

Rickets

Childhood Lack of Vitamin D Causes Rickets Normal shape of female pelvis Contracted pelvis, in a case of osteomalacia (adult rickets).

Normal childbirth would be impossible

.

Vieth 2001. Nutritional Aspects of Osteoporosis, Chapter 17, ed P Burckhardt, RP Heaney, B Dawson-Hughes; Academic Press

Positive Correlation Between 25-hydroxyvitamin D3 Values in Mothers and Newborn Infants • 87 newborn infants of healthy mothers • Risk group - dark skin and/or concealing clothing  63% vit D deficiency • Control group - light skin  15.8% vit D deficiency • Risk group ALKP > Control

Dijkstra, S H et al. Arch Dis Child 2007;92:750-753

Copyright ©2007 BMJ Publishing Group Ltd.

Scatter Plot of Knee-heel Length in Infants at Birth Vs Maternal 25OHD 28-32wk gestation

Morley, R. et al. J Clin Endocrinol Metab 2006;91:906-912

Summery of Observations

• Among infants of mothers who have good vitamin D stores fetal growth is normal, as is fetal mineral accretion.

• In addition, neonatal mineral homeostasis is better maintained and postnatal growth is normal , possibly irrespective of postnatal vitamin D supplementation.

• In cases of poor maternal vitamin D stores , fetal growth may be retarded , mineral accretion may be reduced, neonatal hypocalcaemia is more common, and postnatal linear growth and weight gain may be reduced.

Effect of Vitamin D Replacement on Musculoskeletal Parameters in School Children Age – 10-17 years Low dose -1,400 IU (equivalent to 200 IU/d) High dose - 14,000 IU (equivalent to 2,000 IU/d)

El-Hajj Fuleihan, G. et al. J Clin Endocrinol Metab 2006;91:405-412

Box plots showing the median and interquartile range of the percent change in lean mass (A), the percent change in hip trochanteric BMC (B), and the percent change in total hip BMC (C) by treatment group in premenarcheal girls lean mass hip trochanteric BMC total hip BMC El-Hajj Fuleihan, G. et al. J Clin Endocrinol Metab 2006;91:405-412

Osteoporosis - definition

“a systemic skeletal disease characterized by microarchitectural deterioration with a consequent increase in bone susceptibility to fracture ” fragility and

S Ish-Shalom

A High Prevalence of Vitamin D Inadequacy* Was Seen Across All Geographic Regions

In a cross-sectional, international study in postmenopausal women with osteoporosis

90

81.8% N=2589

80

Risk factors for vitamin D inadequacy :

70 • body mass index >30 kg/m 2

60.3%

(odds ratio, 2.4 [ 1.83, 3.14]) 50 30 • possessing fair to poor health (1.86 [1.49, 2.33]) • no recent travel to sunny areas (1.86 [1.54, 2.25]) 0 All Latin Europe Asia America East Australia *Vitamin D inadequacy was defined as serum 25(OH)D <30 ng/mL.

Study Design: Cross-sectional, international study of 2589 community-dwelling women with osteoporosis from 18 countries to evaluate serum 25(OH)D distribution Adapted from Lips P et al. J Intern Med. 2006 Sep;260(3):245-54.

25(OH)D3 Serum Level in Hip Fracture Patients

94 (98 %) patients had inadequate 25(OH)D3 serum level Adequate lower limit of normal 30 ng/ml ( 75 nmol/l) 40 15 10 5 0 35 30 25 20

36.8

25.3

35.5

2.3

<10ng/m l 10-15ng/m l 15-25ng/m l >25ng/m l

E Segal, S. Ish-Shalom, JAGS 2004

Vitamin D Supplementation Decreased Fracture Risk

• 5-year randomized, double blind, controlled trial • N=2686 • Age 65 to 85 years • Vitamin D = 100,000 IU once every 4 months (equivalent to 800 IU/day) • The incidence of fracture of the hip, wrist, forearm, or vertebra was 4.5% in vitamin D group and 6.5% in those given placebo (

P

=0.02) 1.2

1.0

0.8

0.6

0.4

0.2

0.0

Untreated (n=1341)

P

=0.02

–33% Treated (n=1345)

Adapted from Trivedi D et al.

BMJ.

2003;326:469.

Relative risks (RRs; {square}) of hip fracture (A) and nonvertebral fracture (B) between subjects who took vitamin D and control subjects

Optimal prevention of fracture occurred only in trials providing 700 to 800 IU/d of D3 in patients whose baseline mean concentration of 25(OH)D < 17 ng/ml concentration of 25(OH)D  to approximately 40 ng/ml whose mean

Bischoff-Ferrari, H. A et al. Am J Clin Nutr 2006

Vitamin D and Muscle

Vitamin D and Muscle Function

Bischoff Ferrari, H. A et al. Am J Clin Nutr 2006

Vitamin D and Muscle Function

• Vitamin D deficiency causes muscle weakness • Skeletal muscles have a vitamin D receptor and may require vitamin D for maximum function • Performance speed and proximal muscle strength were markedly improved when 25(OH)D  from 4 to 16 ng/ml (10 to 40 nmol/l) and continued to improve as the levels increased to > 40 ng per milliliter (100 nmol/l). Bischoff-Ferrari, H. A et al. Am J Clin Nutr 2006

Vitamin D and Falls

• A metaanalysis of five randomized clinical trials (with a total of 1237 subjects) revealed that increased vitamin D intake  the risk of falls by 22% (pooled corrected odds ratio, 0.78; 95% CI, 0.64 to 0.92) as compared with only calcium or placebo • 400 IU/day of vitamin D3 was not effective in preventing falls Bischoff-Ferrari, H. A et al. Am J Clin Nutr 2006

Vitamin D and Falls

• 800 IU of vitamin D3 per day plus calcium reduced the risk of falls (corrected pooled odds ratio, 0.65; 95% CI, 0.4 to 1.0).

• In a randomized controlled trial conducted over a 5-month period, nursing home residents receiving 800 IU/day of vitamin D2 plus calcium had a 72%  in the risk of falls as compared with the placebo group (adjusted rate ratio, 0.28%; 95% CI, 0.11 to 0.75) Bischoff-Ferrari, H. A et al. Am J Clin Nutr 2006

Vitamin D and Immunity

Metabolism of 25(OH)D 3 to 1,25(OH) 2 D 3 Nonskeletal Functions for

) 1887 – 1837 ( Kramskoi, Ivan Nikolaevich Mulher com Guarda-Sol - 1883 Woman with Parasol - 1883

What went wrong with sanatoriums?

Vitamin D and Cancer

• People living at higher latitudes are at  risk for Hodgkin's lymphoma, colon, pancreatic, prostate, and are more likely to die from these cancers, as compared with people living at lower. • Prospective and retrospective epidemiologic studies - levels of 25(OH)D< 20 ng/ml   30 to 50% risk of incident colon and prostate, along with  mortality from these cancers

Prostate cancer death rates double that of Whites.

US Annual Average per 100 000 Men Whites, 22/yr Blacks, 47/yr

South North Gradient

25-Hydroxyvitamin D3, the Prohormone of 1,25 Dihydroxyvitamin D3, Inhibits the Proliferation of Primary Prostatic Epithelial Cells

Andrea M. Barreto, Gary G. Schwartz, Ralph Woodruff, and Scott D. Cramer1 100 nnmol/L is the middle of the physiological range for 25(OH)D Bareto et al. Cancer Epidemiology, Biomarkers & Prevention 2000 9:267 10 nnmol/L is 100 times the physiological concentration of 1,25(OH)2D

Effect of vitamin D

(2000 IU/day) on

rate of rise in PSA in Prostate Cancer Patients

“biochemical failures” to surgery or radiation

Vitamin D Supplementation and Rate of PSA Increase

Median shown by 16.0% 14.0% 12.0% 10.0% 8.0% 6.0% 4.0% 2.0%

0.0

-2.0% -4.0%

In press, Nutrition and Cancer.

-6.0%

Vieth, Nutrition and Cancer, 2004.

Early Pre Late Pre

0.0

slope post Vit D

But it prevents prostate cancer Sunshine … … causes skin cancer

Positive effects of Vitamin D on Factors Affecting Cardiovascular System • Fibrinolysis • Blood lipids • Thrombogenicity • Endothelial regeneration • Smooth muscle cell growth

Kaplan-Meier Plots of All-Cause and Cardiovascular Mortality in the 25(OH)D Quartiles 28.4

13.3

7.6

Dobnig et al. Arch Intern Med. 2008;168(12):1340-1349

Effects on mortality rates when 25(OH)D and 1,25(OH) 2 D levels were considered concomitantly.

Dobnig et al. Arch Intern Med. 2008;168(12): 1340-1349

Adherence Rate to Vitamin D Supplement in Men and Women After Hip Fracture

P=0.04

40 30 20 10 0 29% w om en 5% m en

E Segal, S. Ish-Shalom, JAGS 2004

Serum 25(OH)D by dosing protocol of vitamin D supplementation

70 60 Dosing Protocol

Daily Monthly Weekly

50 40 30 20 10 0 0 1 7 28 35 56 Days from Start of Vitamin D Administration

S. Ish-Shalom et al JCEM 2008

Effect of Initial 25(OH)D Concentration on 25(OH)D Level Attained after 56 Days of Vitamin D Supplementation. baseline final 25(OH)D 3 likelihood of a 25(OH)D >29 ng/m L <10 – 50% 10-15 – 52% >20 – 82% S. Ish-Shalom et al JCEM 2008

םותב 25(OH)D לש הניקת המרל עיגהל יוכיס תרוקיבה תצובקבו תוברעתהה תצובקב רקחמה המר תיתלחתה 25(OH) D לש ל מ תוחפ " מ '/ גנ 10 10-20 ל " מ '/ גנ 20-32 ל " מ '/ גנ 32 לעמ ל " מ '/ גנ תצובק תוברעתה 100000 IU 40% 30.4% 79% 100% תצובק תוריקב 0% 0% 18.2% 100% Nodelman M. 2008

Conclusions

• To eradicate widespread genuine vitamin D deficiency is a formidable task.

• Recommending increased exposure to sunlight or ultraviolet B tanning equipment might result in increased skin photoaging and carcinogenesis. • Prospective, human, long term studies should clarify whether higher vitamin D intake can further improve bone and general health and can do so safely.

הבשקהה לע ה

D

ות