Vitamin D Presentation By Dr. Robert P. Heaney, Md, Facp, Facn

WHAT WOULD IT LOOK LIKE IF EVERYONE HAD SUFFICIENT VITAMIN D? Robert P. Heaney, MD, FACP, FASN

Creighton University Osteoporosis Research Center

VIT D & CARDIOVASCULAR DISEASE

    

3.5 1739 Framingham 80 % increase Offspring members 3.0 in risk age: 59 yrs 2.5 follow-up: 5.4 yrs 2.0 120 individuals developed a CV event 1.5 HR calculated against 1.0 25(OH)D values > 15 ng/mL Wang et al. Circulation 0.5 2008

Hazard Ratio



0.0

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< 10 ng/mL

53 % increase in risk

< 15 ng/mL

> 15 ng/mL

ORC 2

BREAST CANCER RISK



Abbas et al., Carcinogenesis (2008) 29:93–99

1.2 1.0

Hazard Ratio

 Case-control study  1394 cases  1365 controls  Odds ratio for CA inversely associated with vit D status [25(OH)D]

69 % decrease in risk

0.8 0.6 0.4 0.2 0.0

<

30

5 0 5 –4 –6 –7 0 5 0 3 4 6

>

75

Serum 25(OH)D (nmol/L)

VITAMIN D & INFLUENZA*  208 African-American, postmenopausal women  3 yr DB-RCT  placebo or vit D3  800 IU/d – 2 yrs  2000 IU/d – 3rd yr  basal 25(OH)D: 18.8 ± 7.5

 P < 0.002

35 30 25 20 15 10 5 0

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Placebo

Vitamin D

ORC

*Aloia & U-Ng (2007) Epidemiol & Infect

4

VITAMIN D & THE COMMON COLD*

 P < 0.001  association stronger for those with asthma & COPD CU

25 20

% with URTI

 18,883 individuals in NHANES-III  tested association between serum 25(OH)D & recent URTI

15 10

29 % reduction

5 0

< 10

10–29.9

30+

Serum 25(OH)D (ng/mL)

ORC

Ginde et al., Arch Int Med 2009 169:

5

DIABETES & 25(OH)D

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ORC

White Hispanic

0.9

Relative Risk

 Scragg et al., 2004 Diabetes Care 27:2813–18  NHANES-III  6,228 adults  plasma glucose independently predicted by BMI & serum 25OHD (fasting and 2 hr post load)

1.0 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0

1st

2nd

3rd

4th

25(OH)D Quartiles 6

NEONATAL VIT D & DIABETES* 3-fold higher risk 10

Relative Risk

 10,366 northern Finnish children  2000 IU Vit D/d 1st year of life  prevalence of type I diabetes assessed at age 31  RR calculated vs. no supplementation

88% lower risk

*Hypponen et al., Lancet 2001;358:1500–03

1

0.1

0.01

R

u eg

l ar

Ir

u re g

l ar

?

k ri c

e ts

Vitamin D Administration

Similar clinical study results are being published weekly

Two questions: –

How can a single nutrient have such diverse effects in so many different tissues ? If these effects are correct, why haven’t they been apparent previously ?

Two questions: –

How can a single nutrient have such diverse effects in so many different tissues ? If these effects are correct, why haven’t they been apparent previously ?

THE VITAMIN D ICEBERG

Ca economy

cell cycle regulation gene control

THE VITAMIN D ICEBERG

endocrine

autocrine

VIT D – CANONICAL SCHEME skin

D3

liver

kidney

gut

25(OH)D3

1,25(OH)2D3

CaBP

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ORC 13

VIT D – EXPANDED SCHEME endocrine

skin D3

kidney

gut

1,25(OH)2D3

CaBP

liver 25(OH)D3

autocrine

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periphery 1,25(OH)2D3

various tissues cell signals

ORC 14

Autocrine functions

AUTOCRINE ACTION 25(OH)D 1,25D

VDR

1,25D

VDR

VDRE

RXR

Transcription

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ORC 16

AUTOCRINE ACTION 25(OH)D

    

cell proliferation cell differentiation apoptosis immune response 24-hydroxylase

VDRE

Transcription

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ORC 17

AUTOCRINE ACTION 25(OH)D

~ 800 genes have VDREs VDRE

Transcription

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ORC 18

AUTOCRINE ACTION 25(OH)D 25OHD

25OHD

1,25D

1,25D

VDR VDRE

1,25D

VDR

RXR Transcription

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ORC 19

AUTOCRINE ACTION 25(OH)D 25OHD

25OHD

1,25D

1,25D

VDR VDRE

1,25D

VDR

RXR Transcription

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ORC 20

This scheme means that each tissue

 has the amount of 1,25(OH)2D it needs  when it needs it  and is not dependent upon a “one-sizefits all” systemic level of circulating 1,25(OH)2D

VITAMIN D & INNATE IMMUNITY* activated Toll-like receptor

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ORC

*Liu et al., Science 2006 22

VITAMIN D & INNATE IMMUNITY* 25(OH)D

bactericidal peptide

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Cathelicidin

ORC

*Liu et al., Science 2006 23

VITAMIN D & INNATE IMMUNITY* 25(OH)D

 human monocytes in fetal calf serum the Vit D 1-a hydroxylase

Cyp27B1 VDR

the Vit D receptor

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ORC

*Liu et al., Science 2006 24

VITAMIN D & INNATE IMMUNITY* 25(OH)D

 human monocytes in fetal calf serum  fetal calf serum is low in both 25(OH)D & 1,25(OH)2D

Cyp27B1 VDR …………

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ORC

*Liu et al., Science 2006 25

VITAMIN D & INNATE IMMUNITY* 25(OH)D

 human monocytes in fetal calf serum  add 1,25(OH)2D to the system

1,25D

Cyp27B1 VDR

Cathelicidin Cyp24

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ORC

*Liu et al., Science 2006 26

VITAMIN D & INNATE IMMUNITY* 25(OH)D

 human monocytes in fetal calf serum  add 25(OH) D to the system

25OHD

1,25D

Cyp27B1 VDR

Cathelicidin Cyp24

CU

ORC

*Liu et al., Science 2006 27

VITAMIN D & TUBERCULOSIS  human monocytes Cathelicidin mRNA activated with M. 4 Tuberculosis and incubated in human 3 serum 25(OH)D: serum 78 nmol/L  African-American 2 serum 25(OH)D:  White 22 nmol/L  African-American 1 with added 25(OH)D 0 A- A

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ORC

W

A- A + 25D

*Liu et al., Science 2006 28

VITAMIN D & TUBERCULOSIS these experiments show that:  vit D is an essential mediator in the innate immune response  serum 25(OH)D is the critical variable  at least some of the increased sensitivity to infection in vit D-deficiency is due to reduction in response to infectious agents because 25(OH)D is rate-limiting  the greater tuberculosis susceptibility of blacks is due in part to their low vit D status CU

ORC 29

If this new understanding is correct,

 do we see evidence of impaired function in patients with low vitamin D status?

VITAMIN D & TUBERCULOSIS*  67 pts with pulmonary TB  standard treatment for all  in addition, randomized to either vit D 10,000 IU/d or placebo  P = 0.002

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Sputum Conversion (%) 100 90 80 70 60 50

ORC

Placebo

Vit D

*Nursyam et al., Acta Med Indones 2006 31

CELL MODELS

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old:

DNA in somatic cells functions mainly to make faithful copies for tissue repair or replacement

new:

DNA functions constantly in synthesis of needed cellular apparatus

ORC ORC

HOW A CELL RESPONDS Signal/ . . . but I do have Demand the plans for what I need in my DNA I don’tlibrary. have . . . the equipment I need . . . . newly synthesized cellular equipment

Response CU

ORC 33

HOW A CELL RESPONDS 25(OH)D

Signal/ Demand 1,25(OH)2D is the key that unlocks the DNA library newly synthesized cellular equipment

Response CU

ORC 34

PERSPECTIVE  vitamin D is an integral component of the mechanism whereby cells control gene transcription in response to a variety of extracellular stimuli  adequate vitamin D status enables optimal response to a broad variety of signals  deficiency will manifest itself differently, depending upon the tissue being stressed, thus explaining the diversity of responses CU

ORC 35

Two questions: –

How can a single nutrient have such diverse effects in so many different tissues ? If these effects are real, why haven’t they been apparent previously ?

VITAMIN D & INFLUENZA*  208 African-American, postmenopausal women  3 yr DB-RCT  placebo or vit D3  800 IU/d – 2 yrs  2000 IU/d – 3rd yr  basal 25(OH)D: 18.8 ± 7.5

 P < 0.002

35 30 25 20 15 10 5 0

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Placebo

Vitamin D

ORC

*Aloia & U-Ng (2007) Epidemiol & Infect

37

Such differences would not be apparent in ordinary medical practice because people who don’t get sick do not see the doctor – are not tracked and would not be recognized as having been protected. The protection is seen only when a cohort of well individuals is followed prospectively.

Endocrine mechanism

A VITAMIN D THRESHOLD ABSORPTION FRACTION

0.5

0.4

0.3

0.2

0.1

0.0 0

20

40

60

80

100

120

140

160

SERUM 25(OH)D (nmol/L)

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ORC 42

A VITAMIN D THRESHOLD 0.5

ABSORPTION FRACTION

physiological 0.4 regulation no longer limited by vit D 0.3 availability 0.2

0.1

0.0 0

20

40

60

80

100

120

140

160

SERUM 25(OH)D (nmol/L)

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A VITAMIN D THRESHOLD ABSORPTION FRACTION

0.5

0.4

0.3

0.2

0.1

0.0 0

20

40

60

80

100

120

140

160

SERUM 25(OH)D (nmol/L)

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ORC 44

VITAMIN D – Sources

?

Body D3 stores

25(OH)D

VITAMIN D – Sources

?

Body D3 stores

25(OH)D

VITAMIN D – Sources

150

Body D3 stores

25(OH)D

VITAMIN D – Sources

150

Body D3 stores

25(OH)D

typical input, all sources: ~2350 iu

VITAMIN D – Sources

150

Body D3 stores

25(OH)D

needed input, all sources: ~4000 iu

VIT D – EXPANDED SCHEME endocrine

skin D3

kidney

gut

1,25(OH)2D3

CaBP

liver 25(OH)D3

autocrine

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periphery 1,25(OH)2D3

various tissues cell signals

ORC 50

VIT D – EXPANDED SCHEME endocrine

skin D3

kidney

gut

1,25(OH)2D3

CaBP

liver 25(OH)D3

autocrine

periphery 1,25(OH)2D3

various tissues cell signals

Won’t calcitriol meet the body’s need for vitamin D?

NO!

VIT D – CANONICAL SCHEME skin

D3

liver

kidney

gut

25(OH)D3

1,25(OH)2D3

CaBP

Why not Answer: just give 1,25(OH) you can’t2give D? enough This is the value that It’s the active to achieve agent, isn’t needed it? levels. needs to be optimized

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Bone strength

Serum 25(OH)D and Hip BMD  NHANES-III  Adults Age 20 – 49 yrs  LOWESS plot of difference from lowest quantile

Non-Hispanic whites

Hispanics

African-Americans

Bischoff-Ferrari HA. Am J Med 2004; 116: 634-9.

VITAMIN D & FRACTURE RISK N = 2,686 ages 65–85 5 yr RCT Vit D  800 IU/d  Trivedi et al. BMJ 2003; 326:469    

(hip, forearm, spine)

FRACTURE RELATIVE RISK

1.0

–33%

0.8

0.6

0.4

0.2

0.0

0

25

50

75

100

125

150 (nmol/L)

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ORC 56

VITAMIN D & FRACTURES Relative Risk

 meta-analysis  9 RCTs  Vit D doses > 400 IU (but none > 800 IU)  n = ~ 32,000 

1.0 0.8 0.6

0.4

Bischoff-Ferrari et al. Arch Int Med (2009);169:551

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0.2 0.0

Non-vertebral

Hip

ORC 57

VITAMIN D & RISK OF FALLING*

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1.0

–49%

0.8

Fall Risk

 122 women  Age: 63–99  DB-RCT  Ca 1,200 mg/d  Ca + 800 IU Vit D  12 week duration  25(OH)D 12 ng/mL at baseline

0.6

0.4

0.2

0.0

Ca only

Ca + D

ORC

*Bischoff et al. JBMR. 2003;18:343–351.

58

VIT D & NEUROMUSCULAR FUNCTION* Performance Score

 1359 men & women; mean age 75.5  Amsterdam longitud. aging study  neuromuscular performance measured on a scale of 0 to 12 (higher is better)  each step statistically significant *Wicherts et al. JBMR. 2005.

9 8 7 6 5 4 3 2 1 0

<25

25–50 50–75 SERUM 25(OH)D

>75

In brief, raising serum 25(OH)D from 50 to ~80 nmol/L improves Ca absorption, raises BMD, and reduces falls and osteoporotic fracture risk

OTHER CHRONIC DISEASES? Disease            

Status of Evidence

osteoporosis osteoarthritis falls/neuromusc. fcn multiple sclerosis fibromyalgia-like syndrome type I diabetes insulin sensitivity cardiovascular disease periodontal disease various cancers tuberculosis hypertension CU

++++ + ++++ ++ ++ ++ ++ +++ ++++ ++++ ++++ ++++

ORC 61

Cardiovascular effects

VIT D & BLOOD PRESSURE*

–5.7

–13.1

125

0

*Pfeifer et al., JCEM 2001; 86:1633–37

P < 0.01 P < 0.01

Systolic BP (mm Hg)

 148 women, aged 74 ± 1  DB–RCT  baseline 25(OH)D < 50 nmol/L  treated for 8 wks with: Ca 1200 mg/d or Ca + 800 IU vit D/d

P < 0.02

150

Ca only

Ca+D

INTERVENTION

VIT D & BLOOD PRESSURE* 10

Relative Risk

 1811 men & women with measured 25(OH)D levels**  4 yrs’ observation  97 cases of incident hypertension  RR computed for 25(OH)D <15ng/mL vs. >30 ng/mL

3.18 1

0.1

*Forman at al., 2007;Hypertension 49:1063 ** Health Profs Follow-up Study & Nurses Health Study

>30

<15

Anti-promotion for cancer

VITAMIN D & PROSTATE CA* 2.5

2.0

RELATIVE RISK

 13 yr longitudinal study  19,000 men  149 cases prostate CA

1.5

1.0

0.5

0.0

*Ahonen et al., CancerCauses&Control 11:847-852 (2000)

1

2

3

25(OH)D QUARTILES

4

VITAMIN D & PROSTATE CA* 2.0

RELATIVE RISK

 those below the median 25(OH)D level were 70% more likely to develop prostate CA than those above

2.5

1.5

1.0

0.5

0.0

*Ahonen et al., CancerCauses&Control 11:847-852 (2000)

1

2

3

25(OH)D QUARTILES

4

COLORECTAL CANCER

0.6

0.4

0.2

0

5t

h– 4

1 h– 3

7

4t

d– 2

3r

2n

d– 2

2

0.0

t– 16

Feskanich et al., Cancer Epidemiol Biomarkers Prev 2004 13:1502–08

0.8

1s



1.0

Odds Ratio

 Nurses’ Health Study  ages 46–78  nested case-control study  193 incident cases  25(OH)D measured twice, prior to diagnosis

25(OH)D Quintiles (with medians*)

*ng/mL

COLORECTAL CANCER 1.0

P < 0.001

0.8

Odds Ratio

 5 prospective studies  > 200,000 individuals  430 cases  ORs computed for 25(OH)D quantiles  Garland et al, 2005

0.6

0.4

0.2

0.0 0

20

40

60

80

100

120

Serum 25(OH)D (nmol/L) CU

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MAMMOGRAPHIC DENSITIES



[Berube et al., 2004; Cancer Epidemiol Biomarkers Prev 13:1466–72]

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ORC

1.0 Vit D Ca

0.8

Odds Ratio

 543 women aged 40–60  1989–90  dietary intakes assessed with FFQ  odds ratios developed for <30% vs. >70% of film with densities

0.6 0.4 0.2 0.0

1st

2nd

3rd

4th

Quartiles 70

VITAMIN D & CANCER* 1179 healthy women aged 66.7 ± 7.3 four year trial 1032 finished (87.5%) baseline 25(OH)D: 71.8 nmol/L ± 20.3 three treatment groups:  control  Ca (1400–1500 mg/d)  Ca plus D3 (1100 IU/d)  achieved 25(OH)D: 96 nmol/L ± 21.4      

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ORC

*Lappe et al. AJCN 2007 71

VITAMIN D & CANCER* Fraction Cancer-Free

1.00

0.98

Ca+D 0.96

Ca-only 0.94

0.92

RR P< = 0.01 0.402

Placebo

0.90 0

1

2

Time (yrs)

3

4

*Lappe et al. AJCN 2007

VITAMIN D & CANCER* Fraction Cancer-Free

1.00

Ca+D

0.98

0.96

Ca-only

RR = 0.232

0.94

Placebo 0.92

0.90 0

1

2

3

Time (yrs)

4

5

*Lappe et al. AJCN 2007

VITAMIN D & CANCER* Fraction Cancer-Free

1.00

96 nmol/L Ca+D

0.98

0.96

Ca-only

71.8 nmol/L

0.94

Placebo 0.92

0.90 0

1

2

3

Time (yrs)

4

5

*Lappe et al. AJCN 2007

CANCERS BY TREATMENT (YRS 2–4) Site

Placebo (n=266)

Ca+D (n = 403)

Breast

7 (2.6%)

4 (1.0%)

Colon

2 (0.7%)

0 (0.0%)

Lung

3 (1.1%)

1 (0.2%)

Marrow/Lymphoma

4 (1.5%)

2(0.5%)

Other

2 (0.7%)

1 (0.2%)

Total

18 (6.8%)

8 (2.0%)*

* P < 0.05

Safety

Serum 25(OH)D (nmol/L)

VITAMIN D INTAKE & TOXICITY* 1,800

1,600 below no toxicity 30,000 IU/d 1,400

15 studies of adults receiving vitamin D supplementation (means)

1,200 1,000

8 studies reporting toxicity (individual values)

800 600 400

no toxicity below 500 nmol/L (200 ng/mL)

200 0 1,000

10,000

100,000

1,000,000

10,000,000

Vitamin D Intake (IU/day) * Hathcock JN et al. Am J Clin Nutr. 2007;85:6–18.

TUIL: 10,000 IU/d*

*Hathcock et al.,(2007) AJCN 85:6–18

TWO KEY QUESTIONS assuming a target value of 80 nmol/L: how much of an increase in daily inputs would be required to ensure that no more than 2.5% of the population fell below the target value?  what , if anything, is the risk of raising their 25(OH)D in those who already are at or above the target value? 

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ORC 79

25(OH)D IN OLDER WOMEN* 100

80

Frequency

 1168 women aged 55 & older  latitude 41º N  25(OH)D values adjusted for season  median vit D supplement dose = 200 IU

*Lappe et al., JACN 2006

60

40

20

0 0

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ORC

40

80

120

160

25(OH)D (nmol/L) 80

SHIFTING THE DISTRIBUTION  improving vitamin D status at a population level means raising everybody’s value, i.e., moving the distribution to the right

RELATIVE FREQUENCY

0.025

0.020

0.015

0.010

0.005

0.000 0

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ORC

20

40

60

80 100 120 140 160 180

25(OH)D (nmol/L) 81

SHIFTING THE DISTRIBUTION 0.025

RELATIVE FREQUENCY

 using an effect size of 1 nmol/L/mg/d  it would require ~2000 IU of additional D each day to shift the distribution sufficiently to ensure that no more than 2.5 % fell below 80 nmol/L

0.020

0.015

0.010

0.005

0.000 0

50

100

150

200

25(OH)D (nmol/L) CU

ORC 82

SHIFTING THE DISTRIBUTION 0.025

RELATIVE FREQUENCY

 taking an effect size of 1 nmol/L/mg/d  it would require ~2000 IU of additional D each day to shift the distribution sufficiently to ensure that no more than 2.5 % fell below 80 nmol/L

0.020

0.015

0.010

0.005

0.000 0

50

100

150

200

25(OH)D (nmol/L) CU

ORC 83

SHIFTING THE DISTRIBUTION 0.025

RELATIVE FREQUENCY

 what about those already 2 SD above the mean?  the rise with an extra ~2000 IU/d would be predicted to bring them to no more than 170–180 nmol/L – well below the toxic range

0.020

0.015

0.010

0.005

0.000 0

50

100

150

200

25(OH)D (nmol/L) CU

ORC 84

CONCLUSIONS  vitamin D acts in multiple systems  serum 25(OH)D levels below 80 nmol/L are not adequate for any body system  levels of as high as 120 nmol/L may be closer to optimal  inputs from all sources combined (needed to sustain 80 nmol/L) are in the range of ~4,000 IU/d and higher CU

ORC 86

WHAT IS THE OPERATIVE MODEL?    

for for for for

the media? regulators? nutritional policy makers? nutritional physiologists?

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ORC 87

WHAT IS THE OPERATIVE MODEL?  for the media and for regulators  nutrition is about killing yourself

with a fork  it’s about avoiding risks  it’s about warnings & cautions

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ORC 88

For a package of macaroni & cheese

http://vm.cfsan.fda.gov/~dms/foodlab.html

Limit these nutrients

Get enough of these nutrients

MEDIA REPORTING  the overwhelming majority of media reports about nutrition emphasizes harm and risk  while the explanation is partly that harm is more newsworthy than benefit (and the media battens on controversy)  still the impression unwittingly conveyed to the general public is one of concern and danger CU

ORC 91

WHAT IS THE OPERATIVE MODEL?  for nutritional policy makers  nutrition is about determining

the least one can get by on without suffering overt disease  (once called MDRs)

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ORC 92

WHAT IS THE OPERATIVE MODEL?  for nutritional physiologists  adult nutrition is about preventive maintenance of tissues and organs  it’s about keeping them from wearing out or breaking down prematurely  its referent is the intake that prevailed when human physiology evolved

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ORC 93

THE PREVENTIVE MAINTENANCE MODEL  foundational premises:  all tissues need all nutrients  shortages impair the functioning of all body systems  premature organ/system “wearing out”, as a consequence of nutrient deficiency, will vary from person to person, depending on variable genetic composition; and  therefore, expression of nutrient deficiency will usually be pluriform – both between and within individuals CU

ORC 94

THE PREVENTIVE MAINTENANCE MODEL  also recognizes that:  the organism will work perfectly well without maintenance – for a while . . .  it thus reconciles the seeming paradox that an organism can be “deficient” without being clinically “sick” – for a while . . .  it’s also about squaring the morbidity/ mortality curve CU

ORC 95

THEORETICAL MORTALITY CURVE

0

20

40

60

80

100

AGE (yrs) CU

ORC 96

THEORETICAL MORTALITY CURVE 100

SURVIVAL (%)

80

60

40

20

0 0

10

20

30

40

50

60

70

80

90

100

AGE (yrs) CU

ORC 97

SQUARING THE MORTALITY CURVE

Percent alive/well

100

80

Optimal nutrition has the 60 to contribute to potential this improvement 40

Certainly, NCEP and DGA take this for granted

20

0 0

10

20

30

40

50

60

70

80

90

100

Age (yrs) CU

ORC 98

WHAT WOULD IT BE LIKE?       

fewer cancers less diabetes fewer osteoporotic fractures less hypertension & CV disease less periodontal disease less multiple sclerosis less severe infectious disease CU

ORC 99

We don’t really know the true burden of chronic disease. And we won’t, until everyone has enough vitamin D.

Thank you . . .