1 Osteoporosis : Public Health Impact WHI Calcium/Vitamin D (Ca/D) - - PDF document

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North American Menopause Society Annual Meeting Orlando, FL October 8, 2016

Vitamin D and Calcium in Midlife Women

JoAnn E. Manson, MD, DrPH, NCMP Chief, Division of Preventive Medicine Brigham and Women's Hospital Professor of Medicine and the Michael and Lee Bell Professor of Women's Health Harvard Medical School

I have no financial conflicts of interest related to this presentation. Faculty/Presenter Disclosure

Objectives

• To review current guidelines for intake of calcium and

vitamin D in midlife women.

• To summarize the evidence on calcium/vitamin D and the

risk of fractures, falls, cardiovascular disease, cancer, and all-cause mortality.

• To present an update on the status of ongoing randomized

trials of vitamin D nationally and internationally.

Calcium and Vitamin D Dietary Reference Intakes for Adults, by Life Stage

Calcium Vitamin D Life Stage (gender) RDA (mg/d) Tolerable upper intake level (mg/d)* RDA (IU/d) Tolerable upper intake level (IU/d)* 19-50 yr (men and women) 1,000 2,500 600 4,000 51-70 yr (men) 1,000 2,000 600 4,000 51-70 yr (women) 1,200 2,000 600 4,000 71+ yr (men and women) 1,200 2,000 800 4,000

Source: Ross AC, Manson JE, Abrams SA, et al. J Clin Endocrinol Metab 2011; 96(1):53.

RDA = Recommended Dietary Allowance *The tolerable upper intake level is the threshold above which is a risk of adverse events.

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• At age 50, lifetime risk of fracture is
• 1:2 women
• 1:5 men
• Affects 10 million Americans
• 8 million women
• 2 million men
• 2 million fractures yearly

(more common in women than MI, stroke, and breast cancer combined)

NOF Fast Facts, www.nof.org Burge R, et al. J Bone Miner Res 2007; 22:465-475.

Osteoporosis : Public Health Impact

WHI Calcium/Vitamin D (Ca/D) Trial Design: Double Blind

Randomization

Intervention (CaD supplement)

• 1000 mg elemental calcium as

calcium carbonate and 400 IU vitamin D3 Control (Placebo)

(50%) (50%) N=36,282 women

Bone Mineral Density Results

Greater preservation in total hip BMD Average differences between CaD and placebo groups:

• 0.59% at year 3
• 0.86% at year 6
• 1.01% at year 9

Source: Jackson RD, et al. NEJM 2006; 354:669-83.

Calcium/Vitamin D Supplementation and Risk of Hip Fracture: WHI

Source: Jackson RD, et al. NEJM 2006; 354:669-83.

5 10 15 20 Ca/D Group

Placebo Group

Ca/D Group Placebo Group N = 175 N = 199

HR = 0.88

(95% CI, 0.72-1.08) P = 0.23 (n=374 cases) Rate of Hip Fracture (Cases/10,000/Yr)

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Additional Fracture Findings

• 29% fewer hip fractures in CaD

than placebo (HR 0.71; 95% CI

0.52-0.97) in adherent women (>80% of study pills)

• 21% fewer hip fractures among

women ≥60 years

(HR 0.79; 95% CI 0.64-0.98; p for interaction by age = 0.05) Hip Fracture – Adherent Women

0.0 0.005 0.010 0.015 0.020 0.025 1 2 3 4 5 6 7 8

Time (years) Cumulative Hazard CaD Placebo

HR = 0.71 (95% CI, 0.52-0.97) P-value = 0.03 Source: Jackson RD, et al. NEJM 2006; 354:669-83.

Calcium/Vitamin D and Risk of Hip Fracture, Stratified by Baseline Intake of Supplemental and Dietary Calcium

Source: Jackson RD, et al. NEJM 2006; 354:669-83.

0.0 0.3 0.5 0.8 1.0 1.3 1.5 1.8 2.0 0.70 0.87 1.22 Hazard Ratio * p <0.05

*

Nonusers <500 mg/d 500+ mg/d Baseline Use of Calcium Supplements

The DIPART Group. BMJ 2010; 340:b5463.

Calcium/Vitamin D and Fractures: Randomized Trials DIPART Meta-analysis (n=68,500 pts; 7 trials)

• Any Fracture

All Trials 0.95 (0.90, 1.00) Ca+ D Trials 0.92 (0.86, 0.99) D alone Trials 1.01 (0.92, 1.12)

• Hip Fracture

All Trials 0.97 (0.86, 1.10) Ca+ D Trials 0.84 (0.70, 1.01) D alone Trials 1.09 (0.92, 1.29) *No vitamin D dose effect comparing 400 IU and 800 IU.*

All Fractures Hip Fractures

Source: Weaver CM, et al. Osteoporos Int 2016; 27:367-376.

National Osteoporosis Foundation: Meta-Analysis of Calcium/D Studies

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Australian cohort age 40-69 Recruited 1990-1994 12 years follow-up Dietary Calcium Q1 473 mg/d Q2 686 mg/d Q3 903 mg/d Q4 1348 mg/d

Dietary Calcium Intake and Health Outcomes

Source: Khan B, et al. J Bone Miner Res 2015; 30:1758-1766.

WHI Calcium/D Trial (2006)

Primary Endpoints HR (95% CI) Hip fracture 0.88 (0.72,1.08) Adherent 0.71 (0.52,0.97) Secondary Endpoints HR (95% CI) Colorectal cancer 1.08 (0.86,1.34) Breast cancer 0.96 (0.85,1.09) All cancers 0.98 (0.90,1.05) Stroke 0.95 (0.82,1.10) MI or CHD death 1.04 (0.92,1.18) Total mortality 0.91 (0.83,1.01)

Source: Jackson RD, et al. NEJM 2006; 354:669-83.

Effect of Calcium/D on CVD Events: Based on Data from Two RCT of Ca/D and the WHI Ca/D Study Participants Not Taking Personal Calcium Supplements at Baseline

Source: Bolland MJ, et al. BMJ 2011:342:d2040.

What Are Skeletal Health Indicators for Vitamin D?

Conceptualization of integrated bone health outcomes and vitamin D exposure

Source: IOM: DRIs for calcium and vitamin D. National Academies Press, 2011.

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• Older age
• Living in the North
• Avoidance of sun
• Dark skin pigmentation
• Obesity
• Low intake
• Genetic factors
• Various medical conditions

Risk Factors for Low Vitamin D Levels

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

Meta-Analysis 31% decrease in fall risk

Vitamin D and Risk of Falling Institute of Medicine (IOM) Committee’s Conclusion

• n Vitamin D and CVD, Cancer, and Other

Nonskeletal Outcomes Evidence for an association with nonskeletal outcomes is:

• Inconsistent.
• Inconclusive as to causality.
• Not yet sufficient to inform dietary guidelines.

Source: IOM: DRIs for Calcium and Vitamin D, National Academies Press, 2011. Source: Elamin MB, et al. JCEM 2011; 96:1931-42.

Meta-Analysis of Vitamin D Supplementation and CVD: Secondary Analyses from Randomized Clinical Trials

51 eligible trials: Endpoint HR (95% CI) P-Value Myocardial Infarction 1.02 (0.93-1.13) 0.64 Stroke 1.05 (0.88-1.25) 0.59 All-Cause Mortality 0.96 (0.93-1.00) 0.08

No significant changes in lipids, glucose, BP (systolic or diastolic).

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Potential Sources of Confounding in the Relationship between Serum 25(OH) Vitamin D and Health Outcomes Poor Nutrition: Low Dietary Intake of Vitamin D Low Sun Exposure Obesity Low 25(OH)D Low Physical Activity

 CVD, type 2 diabetes, and cancer

?

Source: Powe CE, et al. N Engl J Med 2013; 369:1991-2000.

Vitamin D Potential Indicators for Excess Intake

• Hypercalcemia; hypercalciuria
• Emerging evidence for all-cause mortality, cancer,

CVD, falls and fractures at high exposures

Ongoing Large-Scale Randomized Trials (N ≥10,000) of Vitamin D Supplementation Worldwide*

*Several moderate-size randomized trials (2,000 - <10,000 participants) also are in progress in the US and worldwide. #In pilot phase. CVD denoted cardiovascular disease.

Trial

Sample Age Treatment Vitamin D Primary Location Size+ Range Duration Intervention Endpoints

VITamin D and 25,874 ≥50 M 5 yrs 2000 IU/d Cancer; OmegA-3 TriaL ≥55 F (oral) CVD (VITAL) USA D-Health 20,000 ≥60 5 yrs 60,000 IU/ Total Australia month; mortality; (oral) cancer Vitamin D and 20,000 ≥65 5 yrs 100,000 IU/ Total Longevity month (oral) mortality; (VIDAL) UK# cancer

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The VITamin D and OmegA-3 TriaL (VITAL): Design

Mean Treatment Period = 5.0 years 5107 African Americans Blood collection in ~16,953, follow-up bloods in ~6000 Primary Outcomes: Cancer (total) and CVD (MI, stroke, CVD death)

Vitamin D3 (2000 IU/d); N=12,937 Placebo N=12,937 25,874 Initially Healthy Men and Women (Men >50 yrs; Women >55 yrs)

Placebo N=6468 EPA+DHA (1 gm/d); N=6468 Placebo N=6469 EPA+DHA (1 gm/d); N=6469

Adapted from: Manson JE, Bassuk SS, Lee I-M, et al. Cont Clinical Trials, 2011.

Acknowledgements

Jane Cauley, DrPH Nelson Watts, MD Rebecca Jackson, MD Philomena Quinn Researchers, staff, participants in these studies Many others

• Adequate calcium and vitamin D (along with weight-bearing

exercise) are necessary for optimal bone health.

• Total calcium intake of 1200 mg/d is recommended in midlife women;

supplementation >1000 mg/d is rarely needed.

• Vitamin D 1000-2000 IU/d is reasonable supplement for most midlife

women.

• For higher-risk patients, measure 25-OH D, with a target blood level

≥30 ng/dl (75 nmol/L).

• More is not necessarily better!

Calcium and Vitamin D Summary

Thank you!