Calcium and Vitamin D in the Women's Health Initiative

Abstract & Commentary

By Leon Speroff, MD, Editor, Professor of Obstetrics and Gynecology, Oregon Health and Science University, Portland, is Editor for OB/GYN Clinical Alert.

Synopsis: The Women's Health Initiative randomized trial of calcium/vitamin D supplementation found a small, nonsignificant reduction in overall mortality and mortality from stroke and cancers.

Source: LaCroix AZ, et al. Calcium plus vitamin D supplementation and mortality in postmenopausal women: The Women's Health Initiative calcium-vitamin D randomized controlled trial. J Gerontol A Biol Sci Med Sci 2009 Feb 16; doi:10.1093/gerona/glp006.

The Women's Health Initiative reported the effects on overall mortality in their randomized trial of calcium and vitamin D supplementation. This trial randomized 36,282 postmenopausal women to either placebo or 1000 mg calcium carbonate and 400 IU vitamin D daily. After an average follow-up of 7 years, there was no impact on total mortality (744 deaths in treated women and 807 deaths in the placebo group). There was a nonsignificant reduction (about 10%) in risks for stroke and cancer mortality. Comparing the women older than age 70 to those younger than age 70, there was a lower risk for mortality in the younger group, but this did not achieve statistical significance. When analysis was restricted to those participants who were adherent to therapy, the results for overall mortality and for the younger women were essentially unchanged. A nested case-control study assessed the results according to serum 25-hydroxyvitamin D levels at baseline; the results indicated that women with the lowest levels had a higher risk for death. The WHI investigators concluded that their results weakly support the hypothesis that calcium and vitamin D supplementation modestly reduces cancer and cardiovascular mortality. However, overall, the results indicated no major benefit of calcium and vitamin D supplementation on the risk of death due to cancer or cardiovascular disease.

Commentary

The WHI has published multiple findings from the calcium/vitamin D randomized trial. The conclusions are uniformly negative, summarized as follows:

  1. The incidence of invasive breast cancer was similar in the treated and placebo groups. The risk of breast cancer was not associated with baseline 25-hydroxyvitamin D levels.1
  2. Calcium and vitamin D supplementation did not protect against a decline in physical functioning or performance.2
  3. The incidence of newly diagnosed diabetes was the same in the treated and placebo groups.3
  4. Calcium and vitamin D supplementation did not protect against colorectal cancer.4
  5. Myocardial infarction and stroke events were similar in the treated and placebo groups.5

Smaller trials and observational studies have demonstrated small reductions in total mortality, reductions in blood pressure and cholesterol levels, and reduced risks of stroke and coronary heart disease — for this reason, the WHI results are disappointing. Vitamin D insufficiency, in particular, has been linked to a wide spectrum of problems, including more cancer and cardiovascular deaths. Low levels of serum 25-hydroxyvitamin D have been reported to be associated with higher all-cause mortality, a greater prevalence of peripheral arterial disease, and higher cardiovascular mortality.6-8

What could explain the lack of strong agreement between the WHI results and the rest of the literature? The answer can be found in the characteristics of the women in the WHI and the doses of calcium and vitamin D used for supplementation. The population of women in the WHI were not at high risk for fractures; in fact, the placebo group demonstrated a gain in whole body and spinal bone density during the study (the average postmenopausal women loses bone density, especially in the spine). The gain in bone density in the placebo group can be attributed to body weight; most of the women were overweight. Only one-third of the participants had a low calcium intake at entry to the study, and 29% were already taking calcium supplementation. The average daily calcium intake of the study population was 1100-1200 mg, twofold higher than the average American woman.9 Low serum levels of 25-hydroxyvitamin D were found in only 25% of the women in whom it was measured.

Currently, the recommended doses of vitamin D for supplementation far exceed the dose used in the WHI trial. Doses as high as 1500-2000 IU per day are being suggested as the levels required to achieve a beneficial impact. But even with the lower dose used in the WHI, there was a trend for a reduction in cardiovascular and cancer mortality, although the impact was nonsignificant in the WHI population.

Because 60% of individuals who live in northern latitudes have low serum levels of 25-hydroxyvitamin D, the WHI results do not rule out the possibility of beneficial effects of adequate supplementation in a large segment of our population.10 It makes sense to titer the dose of vitamin D supplementation by measuring the circulating level of 25-hydroxyvitamin D, and I have been urging that this be incorporated into a patient's annual health assessment. A value < 30 ng/mL is below normal; < 20 ng/mL is a definitive indication of vitamin D deficiency. A normal level in sunny countries is 55-90 ng/mL. The WHI nested case-control study documented that the risk of hip fracture steadily increases in women as their serum levels of 25-hydroxyvitamin D decrease.11

Because the average American woman receives only about 500 mg daily of calcium in her diet, most women not on hormone therapy require a daily supplement of 1000 mg calcium (best as single doses of 500 mg with meals). Most women on hormone therapy require only 500 mg calcium daily because estrogen improves calcium absorption. But, calcium absorption requires vitamin D. Adequate vitamin D supplementation requires a dose of at least 1000 IU daily, a dose that cannot be obtained through the use of multivitamins (multivitamins contain only 400 IU vitamin D3, the dose used in the WHI).

The negative publicity associated with the WHI publications has obscured the importance of fracture risk in women. In the observational arm of the WHI, the risk of fracture was compared to the risks of cardiovascular events and breast cancer in a prospective cohort of 83,724 women, aged 70-79.12 The recorded events indicated that the number of women who experience a fracture in one year's time exceeded the combined number of women experiencing invasive breast cancer or cardiovascular disease (except in blacks in whom cardiovascular events dominated). And don't forget that in the WHI the women adherent to their calcium/vitamin D supplementation had a 29% reduction in risk for hip fractures, and the reduction in hip fractures (42%) was greatest in those women who combined calcium/vitamin D supplementation with hormone therapy.9

References

  1. Chlebowski RT, et al. Calcium plus vitamin D supplementation and the risk of breast cancer. J Natl Cancer Inst 2008;100:1581-1591.
  2. Brunner RL, et al. Calcium, vitamin D supplementation, and physical function in the Women's Health Initiative. J Am Diet Assoc 2008;108:1472-1479.
  3. de Boer IH, et al. Calcium plus vitamin D supplementation and the risk of incident diabetes in the Women's Health Initiative. Diabetes Care 2008;31:701-707.
  4. Wactawski-Wende J, et al. Calcium plus vitamin D supplementation and the risk of colorectal cancer. N Engl J Med 2006;354:684-696.
  5. Hsia J, et al. Calcium/vitamin D supplementation and cardiovascular events. Circulation 2007;115:846-854.
  6. Melamed ML, et al. 25-hydroxyvitamin D levels and the risk of mortality in the general population. Arch Intern Med 2008;168:1629-1637.
  7. Melamed ML, et al. Serum 25-hydroxyvitamin D levels and the prevalence of peripheral arterial disease: Results from NHANES 2001 to 2004. Arterioscler Thromb Vasc Biol 2008;28:1179-1185.
  8. Pilz S, et al. Vitamin D and mortality in older men and women. Clin Endocrinol 2009 Feb 18; Epub ahead of print.
  9. Jackson RD, et al. Calcium plus vitamin D supplementation and the risk of fractures. N Engl J Med 2006;354:669-683.
  10. Holick MF. High prevalence of vitamin D inadequacy and implications for health. Mayo Clin Proc 2006;81:353-373.
  11. Cauley JA, et al. Serum 25-hydroxyvitamin D concentrations and risk for hip fractures. Ann Intern Med 2008;149:242-250.
  12. Cauley JA, et al. Incidence of fractures compared to cardiovascular disease and breast cancer: The Women's Health Initiative Observational Study. Osteoporosis Int 2008;19:1717-1723.