The WHI Studies on Calcium and Vitamin D

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 finds that calcium/vitamin D supplementation provides protection against hip fractures, and no reduction in colorectal cancer.

Source: Jackson RD, et al. Calcium plus vitamin D supplementation and the risk of fractures. N Engl J Med. 2006;354:669-683.

The Women’s Health Initiative (WHI) conducted a randomized trial of Calcium and Vitamin D supplementation.1 The 36,282 postmenopausal women were part of the WHI clinical trials involving postmenopausal hormone therapy or dietary modification. The average follow-up was 7 years; 37% of the women were age 50 to 59, 45.5% were 60 to 59, and 17.5% were 70 to 79. The treated group was supplemented with 1000 mg calcium and 400 IU vitamin D daily. Most of the women were overweight, with 37% having a BMI of 30 or higher. A subset of 1431 women were followed with bone density measurements. There were no bone density differences between treatment and placebo in the spine or whole body measurements, but in the hip, the treated group gained slightly more bone at year 3, and by year 6 the placebo group lost more bone at the hip. Fracture results were as follows:

Intention-to-treat analysis

Thus, the overall analysis indicated no significant reduction in fractures with calcium/vitamin D treatment. The women treated with calcium/vitamin D had a 17% greater risk of kidney stones (HR, 1.17; CI = 1.02-1.34).

This same study also assessed the impact of calcium/vitamin D on the risk of invasive colorectal cancer.2 No difference was observed between the treated group and the placebo group, even when only women adherent to treatment were analyzed. However, it is recognized that the latency period for colorectal cancer is 10 to 20 years. The length of follow-up in this study may have been insufficient to detect an effect. Furthermore, colorectal cancer was not a primary outcome in the study design, and the study design was very complicated by the fact that the women were simultaneously enrolled in 3 overlapping trials (calcium/vitamin D, low-fat diet, and hormone therapy).

Commentary

Do you remember when you first heard of the calcium/vitamin D study? I was watching NBC news prior to the Olympics telecast. The next day I heard it on NPR radio, and later I read it in Newsweek. All presentations said the same thing: New study produces disappointing news, no benefit for calcium/vitamin D supplementation. This was a typical demonstration of the guiding principle for the media: good news is no news. Contrary to the presentation in the media, the news in this WHI report was good. The women who most needed a benefit experienced a reduction in hip fractures with calcium/vitamin D if they continued to supplement their dietary intake. The results further support the conclusion that maximal protection against fractures is gained by combining calcium/vitamin D supplementation with hormone therapy.

Careful reading of the full report provides this good news:

  1. Correcting for compliance by analyzing just those women who continued their medication revealed a statistically significant 29% reduction in risk for hip fractures. Only 59% of the treated women at the end of the trial were taking the intended dose.
  2. Women who were 60 years and older had a 21% significant reduction in hip fracture (HR, 0.79; CI, 0.64-0.98).
  3. The reduction in hip fracture was greater in those women who were not taking calcium supplements other than what the study provided.
  4. The reduction in hip fractures was greatest (42%) in those women who combined calcium/vitamin D supplementation with postmenopausal hormone therapy (HR, 0.58; CI, 0.37-0.93).

In my view, the public presentation of these results in the WHI calcium/vitamin D study was not accurate. The population at greatest risk for fractures (the oldest women in the study) actually benefited, and the study confirmed something already known, that hormone therapy combined with calcium/vitamin D supplementation achieves the best results. Keep in mind that the women in this study were not at high risk for fractures. Indeed, whole body and spinal bone density increased in the placebo group. This is hard to explain; the average postmenopausal untreated woman loses spinal bone density. In this study, only hip bone density demonstrated a loss, and thus, it is not surprising that significant benefits were demonstrated only with hip fractures.

The fact that most of these women were overweight probably contributed to the protection against bone loss in the spine. In a population of women losing bone density in both hip and spine, and in women with other risk factors for fractures, I would expect calcium/vitamin D supplementation to yield even better results than those reported by the WHI, including a reduction in spinal and arm fractures.

The impact of calcium/vitamin D supplementation on the risk of colorectal cancer remains unsettled. A possible reduction in colorectal cancer is still possible in those women who have low levels of calcium and vitamin D prior to treatment, as documented in the Nurses Health Study and in the current WHI report (if you examine the report closely).2,3

What about the kidney stones? The women in this trial were allowed to continue their own programs of supplementation. Thus many took calcium and multivitamins (which contain 400 IU vitamin D). The average daily calcium intake of the study population was 1100 to 1200 mg, 2-fold higher than the average American woman. The WHI does not provide data to answer this most important question: Was the small increase in kidney stones observed in women who were taking excessive amounts of calcium and vitamin D?

These results support the following clinical recommendations. Because the average woman receives daily only about 500 mg 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 an additional 500 mg calcium because estrogen improves calcium absorption. Vitamin D is recommended for all women (and men) younger than age 70 in a daily dose of 400 IU, and 800 IU daily in women age 70 and older. To be sure, there are some women who derive sufficient amounts of calcium and vitamin D from their diets, and supplementation would be both unnecessary and perhaps risky for kidney stones.

References

  1. Jackson RD, et al. Calcium plus vitamin D supplementation and the risk of fractures. N Engl J Med. 2006;354:669-683.
  2. Wactawski-Wende J, et al. Calcium plus vitamin D supplementation and the risk of colorectal cancer. N Engl J Med. 2006;354:684-696.
  3. Feskanich D, et al. Plasma vitamin D metabolites and risk of colorectal cancer in women. Cancer Epidemiol Biomarkers Prev. 2004;13:1502-1508.