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Vitamin D and Calcium Therapy: how much is enough

Daniel D Bikle, MD, PhD Professor of Medicine

VA Medical Center and University of California San Francisco

DISCLOSURE

Nothing to disclose

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RECOMMENDATIONS FROM THE INSTITUTE OF MEDICINE

25OHD level of 20ng/ml is enough (UL 50ng/ml)

600 IU/qd is enough (800 IU qd for >71yo) (UL 4000IU qd)

Calcium intake during puberty: 1300 mg qd (UL 3000 mg qd)

Calcium intake ages 19-50: 1000mg qd (UL 2500 mg qd)

Calcium intake ages 51-70 males: 1000mg qd (UL 2000 mg qd)

Calcium intake ages 51-70 females: 1200mg qd (UL 2000 mg qd)

Calcium intake ages >70: 1200mg qd (UL 2000 mg qd)

But Controversy Reigns

Are these recommendations appropriate for our patients? The Endocrine Society Guidelines

25OHD level of 30ng/ml

1500-2000IU Vitamin D qd Calcium recommendations

comparable to IOM

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• Associations do not prove causality

• We do not know the optimal dose of vitamin D and calcium or the optimal level of 25OHD for most diseases for which it is used

• Too much of a good thing may be a bad thing

• We need RCTs of sufficient power and duration to answer these questions

Much of our data comes from epidemiologic studies

The Calcium Controversy

Is Calcium Supplementation associated with cardiovascular

events and myocardial infarction?

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Metaanalysis suggesting calcium is hazardous to

your health.

Mark J Bolland et al. BMJ 2010;341:bmj.c3691

Random effects models of effect of calcium supplementation on

cardiovascular events and death.

Mark J Bolland et al. BMJ 2010;341:bmj.c3691

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But Maybe Not The Effects of Calcium Supplementation on Verified Coronary Heart Disease Hospitalization and Death in Postmenopausal

Women: A Collaborative Meta‐Analysis of Randomized Controlled Trials

Lewis et al. Journal of Bone and Mineral Research 30:165-175, 2014

The Effects of Calcium Supplementation on All Cause Mortality

Lewis et al. Journal of Bone and Mineral Research 30:165-175, 2014

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How much calcium do we need? Relation between calcium output (fecal calcium + urinary

calcium excretion) and calcium intake

Curtiss D Hunt, and LuAnn K Johnson Am J Clin Nutr 2007;86:1054-1063

What About Vitamin D?

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THE BIKLE APPROACH TO THE LITERATURE ON VITAMIN D THERAPY

• Rule 1: Someone somewhere has found an association between low vitamin D levels and every disease: clinical potential may be limitless

• Rule 2: If someone finds a disease with no association to low vitamin D levels, see rule 1

VITAMIN D DEFICIENCY WITH AGING

• Decreased vitamin D production in the skin

• Decreased vitamin D intake in the diet

• Decreased vitamin D absorption by intestine

• Decreased 1,25D production by the kidney

• Decreased intestinal response to 1,25D

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Vitamin D Production in the Skin of Elderly vs Young Adults Following Total Body UVR

Holick MF et al., Lancet 2:1104-1105 1989

Declining Ability to Respond to PTH re 1,25D Production with Age

Riggs et al J Cell Biochem 88: 209-215, 2002

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Decline in Intestinal Calcium Absorption in Response to 1,25D with Age

Riggs et al J Cell Biochem 88: 209-215, 2002

How do we judge vitamin D sufficiency?

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How much vitamin D does it take to suppress PTH?

Depends on basal levels of 25OHD and calcium intake

25(OH)D & SERUM iPTH*

SERUM 25(OH)D (nmol/L)

0 20 40 60 80 100

SER

UM

PT

H (

pg/m

L)

20

40

60

80

100

120

*after Thomas et al., 1998 NEJM;338:777–783

290 consecutive

pts. on a

general medical

ward – MGH

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Various levels of serum 25OHD (nanograms per milliliter) at which serum

PTH (picograms per milliliter) plateaus and/or is maximally suppressed.

Sai A J et al. JCEM 2011;96:E436-E446

The relationship between PTH suppression and vitamin D depends on calcium intake

S Adami et al Bone 42:267-270, 2008

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Malabanan A et al. Lancet 351:805-806, 1998

Response of PTH to Vitamin D Depends on Basal 25OHD Levels

How Much Vitamin D is Required to Stimulate Intestinal Calcium

Absorption

Depends on basal levels of 25OHD

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Modest increase in 12-month calcium absorption (percent

absorbed) on vitamin D3 doses of 400–4800 IU daily in

healthy adults.

Gallagher J C et al. JCEM 2012;97:3550-3556

How Much Vitamin D is Required for Skeletal Health?

Depends on basal vitamin D levels and calcium intake

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Serum 25(OH)D and Hip BMD

• NHANES-III

• Adults Age 20 – 49 yrs

• LOWESS plot of slope of BMD on 25(OH)D

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

Non-Hispanic whites

African-Americans

Hispanics

Baseline values Delta values (value at end of study minus baseline)

DD group DP group PP group DD group DP group PP group

N 110 97 105

Males (%) 40.0 40.2 39.0

Age (years) 47.3 ± 11.1 47.7 ± 11.6 50.8 ± 10.7

BMI (kg/m2) 34.4 ± 3.9 33.7 ± 3.5* 35.2 ± 3.9 0.01 ± 1.33 0.13 ± 1.10 0.09 ± 1.35

Smokers (%) 20.9 20.6 17.1

BMD L2-L4

(g/cm2) 1.270 ± 0.155 1.235 ± 0.161 1.251 ± 0.170 0.008 ± 0.036 0.008 ± 0.039 0.007 ± 0.042

BMD total hip

(g/cm2) 1.107 ± 0.133 1.067 ± 0.128 1.092 ± 0.130 0.008 ± 0.014 0.011 ± 0.014 0.009 ± 0.017

OPG (pg/ml) 1875 ± 509 1961 ± 600 2092 ± 650 56 ± 3061 - 34 ± 4722

RANKL (pg/ml) 0.09 ± 0.15 0.10 ± 0.27 0.05 ± 0.10 - 0.01 ± 0.101 0.00 ± 0.062

Serum 25(OH)D

(nmol/L) 61.3 ± 20.7 58.3 ± 21.2 60.1 ± 22.3 79.9 ± 31.3† 41.7 ± 22.8† - 2.2 ± 16.8

Serum PTH (pmol/L) 5.1 ± 1.6 5.4 ± 1.8 5.7 ± 1.7 - 0.9 ± 1.5† - 0.7 ± 1.4* - 0.2 ± 1.6

Serum calcium (mmol/L) 2.30 ± 0.11 2.32 ± 0.11 2.31 ± 0.10 - 0.01 ± 0.12 - 0.02 ± 0.12 - 0.01 ± 0.11

Jorde et al. Nutrition J 9:1, 2010

Lack of increase in BMD with vitamin D supplementation in D replete subjects

DD 40,000IU D per wk, DP 20,000IU D per wk, PP placebo; all on 500mg Ca/day

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Priemel M et al JBMR 25: 305, 2010

Increased osteoid at 25OHD < 50nM

FRACTURE RISK ACCORDING TO VITAMIN D DOSE AND 25OHD LEVEL METAANALYSIS OF 12 STUDIES (n=42279)

Bischoff-Ferrari HA et al Arch Int Med:169:551-561, 2009

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Fragility and Falls Contribute to Fracture Risk

Vitamin D Helps But Doses Required are Moderate

Mobility decreases with decreasing 25OHD levels

0 20 40 60 80 100 120 140 160 180 200 220 240

3.5

4

4.5

0 20 40 60 80 100 120 140 160 180 200 220 240

14

15

16

8-foot walk Repeated sit-to-stand

25-OHD nmol/l 25-OHD nmol/l

Bischoff-Ferrari HA et al Am J Clin Nutr 2004;80:752–758.

Sec Sec

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Physical performance in 1234 older persons in relation to 25-OHD.

Wicherts I S et al. JCEM 2007;92:2058-2065

Fall prevention with high dose (700-1000 IU a day) and low

dose (200-600 IU a day) of supplemental vitamin D

Bischoff-Ferrari H A et al. BMJ 2009;339:bmj.b3692

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WHAT ABOUT NON CLASSIC ACTIONS OF VITAMIN D

• Prodifferentiation, Antiproliferation

• Regulation of Hormone Secretion

• Modulation of Immune Function

COLORECTAL CANCER

• Nurses’ Health Study

• ages 46–78

• nested case-control study

• 193 incident cases

• 25(OH)D measured twice, prior to diagnosis

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

0.0

0.2

0.4

0.6

0.8

1.0

Od

ds R

atio

1st–16

2nd–22

3rd–27

4th–31

5th–40

25(OH)D Quintiles (with medians*)

*ng/mL

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Table 1: Meta-analyses of human epidemiologic studies

Cancer Author n Studies/Analysis Pooled Relative Risks (RR)

A. Colorectal

Ma et al. ⁴ 9 0.88 (0.8-0.96) Vit D Intake

0.67 (0.54-0.80) 250HD levels

Yin et al. ⁵ 10 0.82 (0.69-0.97) 250HD levels

B. Breast

Chen et al 12 11 0.91 (0.85-0.97) Vit D intake

8 0.55 (0.38-0.80) 250HD levels

Gandini et al 19 0.83 (0.79-0.87)a case control (5)

10 250HD levels

0.97 (0.92-1.03)b prospective (5)

C. Prostate

Gandini et al 19 11 0.99 (0.95-1.03) 250HD levels

Gilbert et al 21 13 1.14 (0.99-1.31) Vit D Intake

14 1.04 (0.99-1.10) 250HD levels

Bikle, Endocrine 46: 29-38, 2014

Epidemiologic Studies are Mixed

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Effect of calcium and vitamin D on progression to DM

Pittas et al Diabetes Care 30:980-86, 2007

500mg Ca + 700u D3 placebo

Pittas et al. Ann Int Med 152:307-14, 2010

No clear benefit of vitamin D + calcium on BP

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Potential benefit for preventing MI

Giovannucci et al Arch Int Med 168:1174-1180, 2008

Role of Calcium and Vitamin D in Overall Mortality over Time

Rejnmark L et al. JCEM 2012;97:2670-2681

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Adaptive Immunity

CD4

Th17 Th2 Th1

Treg

CYP27B1

Macrophage or Keratinocyte

Dendritic Cell

1,25(OH)2D

25OHD +

+

-

-

-

Innate Immunity

Cathelicidin

Macrophage or Keratinocyte

+ +

1,25(OH)2D

25OHD

VDR

+

+

CYP27B1

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Martineau AR et al. Lancet 377:242-250, 2011

Vitamin D Did Not Enhance TB Rx

Vit D 100,000IU days 0, 14, 28, 42

SUMMARY

• Vitamin D and calcium deficiency is detrimental to health

• The optimal levels of vitamin D intake and 25OHD levels in blood are not established with certainty and may vary with calcium intake and disease process.

• Megadoses of vitamin D are NOT indicated and may be detrimental

• Calcium has an important synergistic role with vitamin D in maintaining health—calcium does not increase the risk of CVD or death

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RECOMMENDATIONS

• 800-2000 IU vitamin D per day is safe and generally sufficient to achieve a serum level of 25OHD around 30ng/ml. Higher levels have not been proven to be better

• Rule of thumb: For repletion, supplement with 100IU vitamin D for each 1ng/ml increment of 25OHD desired

• 800-1200mg calcium per day in adults should suffice to maintain balance in most individuals without malabsorption—urine calcium provides a good guide with a goal around 150mg/24hr