The Effect of Calcium Plus Vitamin D

on the Risk of Fractures and

Colorectal Cancer:

Principal and Follow-up Results of the

Women’s Health Initiative Calcium Plus

Vitamin D (CaD) Trial

Jane A, Cauley, DrPH

University of Pittsburgh

Participant Webinar May 19,2021

Vitamin D—Overhyped or Underused?by Ginny Graves

The benefits of D sound too good to be true. We investigate.

More.com/Sept 2010

Diseases Vitamin D Fights

08.24.2010

Health : Healthy Eating

What Does Oprah Say?

Your Vitamin D level should be >30

If you can’t get 15 min of sun per day, take a

supplement containing ≥1,000 IU of D3, or chug a

Tbsp of cod liver oil every morning

With her assistance, market growth of vitamin D

supplements reached triple digits

– In 2005-2006, 37% of people in the US

reported use of dietary supplement

containing vitamin D

– $366 million in 2009

(source: www.nutraingredients.com)

What did we Know about Calcium and

Vitamin D and Fractures when WHI was

initiated?• Little benefit of CaD in preventing bone loss at

menopause but beneficial in older women.

• Data regarding CaD and hip and other fractures not

conclusive.

− One study in a French Nursing home showed a

benefit of Vitamin D for hip fracture

− BUT NO

− Participants were all Vitamin D deficient.

Background: CAD and Colon and

Rectal Cancer• Studies suggested higher calcium and vitamin D

intakes may:

− Lower risk of colorectal cancer

− Lower risk of polyp recurrence

• Randomized trials found calcium supplements:

− Lowered risk of polyp recurrence

• No large randomized trials on CaD supplementation

and prevention of colorectal cancer

• NIH Consensus Development Conference (1994)

− 1,000-1,500 mg /day calcium

− 400 IU Vitamin D

What were the Calcium and Vitamin D

Guidelines when WHI started?

300 mg Ca in 1 Cup

HRT

27,348

WHI CaD: Relationship to CT

DM

48,837

Calcium + Vitamin D (CaD)

CaD

36,282

at 1st (or 2nd)

Annual Visit

Total CT = 68,135

CaD Trial Objectives

• To examine the effect of CaD on:

- Hip fractures (Primary)

- Total Fractures (Secondary)

- Colorectal Cancer (Secondary)

• Hypotheses: Women randomized to CaD will have a

lower risk of each outcome

• Examine the effect of adherence

• (Do you actually take your study medication)

CaD Intervention

• Randomly assigned to supplement or

placebo

• Each active tablet 500 mg calcium (as

CaCO3) and 200 IU vitamin D

• Two tablets per day

− Divided dose; with meals

• Chewable or swallowable choice

beginning Oct, 1997

Total Daily Calcium Intake

in WHI CaD Participants at the

beginning.Total Calcium

What were the scientific results?

Jackson RD. NEJM 2006;354:669-83.

HIP Fracture Results

Hip Fracture0.0

0.0

05

0.0

10

0.0

15

0.0

20

0.0

25

0 1 2 3 4 5 6 7 8

Time (years)

Cum

ula

tive

Ha

za

rd

CaDPlacebo

CaD:Events 9 16 14 26 34 30 20 22 4N at risk 18176 18063 17950 17801 17616 17243 14669 9144 4395

Placebo:Events 11 23 19 27 27 43 24 18 7N at risk 18106 17982 17839 17669 17464 17072 14507 9027 4343

HR = 0.88

(95% CI, 0.72-1.08)

P-value = 0.23

NO DIFFERENCEBetween Groups!

Jackson RD. NEJM 2006;354:669-83.

What about other Fractures?

Jackson RD. NEJM 2006;354:669-83.

Annualized

fracture rates per

10,000 person-

years

CaD Adherence Over Time

0

10

20

30

40

50

60

70

80

90

100

Year 1 Year 2 Year 3 Year 4 Year 5 Year 6 Year 7 Year 8

Perc

en

t o

f P

art

icip

an

ts

CaD = 50% Placebo = 50%

CaD = 80% Placebo = 80%

Wactawski-Wende J et al. NEJM 2006;354:684-96

Hip Fracture Results while Adherent

Hip Fracture - Censor at <80% adherence

0.0

0.0

05

0.0

10

0.0

15

0.0

20

0.0

25

0 1 2 3 4 5 6 7 8

Time (years)

Cum

ula

tive

Ha

za

rd

CaDPlacebo

CaD:Events 9 7 7 12 8 9 7 6 3N at risk 18176 14212 9939 8796 8042 7415 5881 3182 1342

Placebo:Events 11 16 11 13 12 19 7 6 4N at risk 18106 14351 10365 9213 8465 7785 6175 3350 1408

HR = 0.71

(95% CI, 0.52-0.97)

P-value = 0.03

HR = 0.71(95% CI, 0.52-0.97)P-value = 0.03)

Time (years)Jackson RD. NEJM 2006;354:669-83

29% Reduction!

Bone Mineral Density Results

Greater preservation in total

hip BMD

Average differences between

CaD and placebo groups:

− 0.56% at AV3

− 0.83% at AV6

− 1.01% at AV9

Total Hip

-3

-2

-1

0

1

2

3

4

5

Yr 1 Yr 3 Yr 6 Yr 9

Clinical Trial Annual Visit

Mean

Ch

an

ge

in B

MD

fro

m Y

ea

r1,

%

CaD

Placebo

P=<0.001

P=<0.001

P=0.01

Jackson RD. NEJM 2006;354:669-83.

Colorectal Cancer Results

HR = 1.08(95% CI, 0.86 – 1.34)P-value = 0.51

Wactawski-Wende J et al. NEJM 2006;354:684-96

No Difference !

Similar Polyp reports

Cumulative Mortality (Number of Deaths)

LaCroix AZ et al. JGMS 2009;64a(5):559.

Slightly Lower

Mortality: Pursue

during Extension

Follow-up

Long-term Follow-up: Thank you for

continuing your participation!

• Duration of supplement use

• Among women taking on CaD supplements

• 12 year follow-up results

Hip Fracture: Longer Years of CaD

supplement use lower hip fractures

All Subjects

Years

<2 0.81 (0.5,1.3)

2-5 1.03 (0.8,1.4)

>5 0.78 (0.6, 1.0)

NO personal use of

supplements

Years

<2 1.15 (0.6, 2.3)

2-5 1.04 (0.7, 1.6)

>5 0.65 (0.4, 0.98)

35% Reduction for

5+ Years of use

Cauley JA et al. Journal of Women’s Health

2013;22(11):915.

12 Year CaD Extension results

13 % Lower risk Of Spine

fracture, the most common

fracture associated with

osteoporosis

Conclusions

• Daily CaD supplementation for an average of 7 years

did not prevent hip fractures or colorectal cancer

• Sensitivity Analyses

• Adherent women: 21 % lower Hip Fracture

• Older women: beneficial effect for hip fracture

• Longer duration of CaD use may be beneficial

• Continued follow-up over an additional 5 years: 13 %

Lower Spine fracture

• Analyses continuing

Interpretation of Study Results

• Was the Dose of Vitamin D: Too low

400 IU/d

Vitamin D Dose

700-800 IU/d

Rela

tive R

isk (

95%

CI)

Achieved 25-Hydroxyvitamin D Level, nmol/L

50 64 72 98 106 1200

0.5

1.0

1.5

2.0

Hip Fracture Efficacies by Achieved

25-Hydroxyvitamin D Levels in 400 IU/d and 700-

800 IU/d Vitamin D-Treated Groups

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

WHI CaD

What is research… but a Blind

Date with Knowledge.

Thank you for taking the leap with us. We

could not have done it without you.

Thank you to All WHI Participants!