[ Editorials | Departments and Series | Index ]

Menopause Health

The Dietary Clinical Trials of the Women’s Health Initiative: Part 1

J. Kell Williams, MD; H. James Brownlee, MD

With all of the controversy surrounding the Women’s Health Initiative (WHI), virtually all of the attention has been given to the 26,000 women in the placebo-controlled hormone trial. It is easy to forget that more than 68,000 women were enrolled in other overlapping clinical trials, and almost 160,000 women are being followed as part of an ongoing observational study.1 Here we will address the 2 completed nonhormone clinical trials.

Low-Fat Diet Modification Versus No Modification

The first of the WHI nonhormonal prospective clinical trials was the low-fat diet modification arm. The total population studied numbered 48,835. These women were randomized to a “treatment” group that was instructed to reduce dietary fat intake to 20% of total energy intake, increase fruits and vegetables to 5 or more servings per day, and increase grain products to at least 6 servings per day. The control group continued their “normal” diets. A concern in all the following reports was there was no mechanism to evaluate compliance.

Tinker et al reported on the effect of the low-fat diet on diabetes mellitus.2 In this population of more than 48,000 women, 3,342 self-reported new-onset diabetes treated with oral agents or insulin. Comparing the study group with the control group, the hazard ratio (HR) was 0.96, with a 95% confidence interval (CI) of 0.90 to 1.03. The conclusion was that a low-fat diet among generally healthy postmenopausal women showed no evidence of reducing diabetes risk after 8.1 years. Of separate note was the fact that the study group did lose weight (P<.001).

Using the same population, Howard et al examined the relationship of the low-fat diet on cardiovascular disease (CHD).3 They found that the diet group decreased their fat intake by 8.2% and showed significant decrease in LDL cholesterol, coagulation factor VII(c), and diastolic blood pressure, but no change in HDL cholesterol, trigylcerides, glucose, or insulin. However, with 2,549 incidents of CHD, the HR was 0.97 (CI, 0.90-1.06), and with 1,058 incidents of stroke, the HR was 1.02 (CI, 0.90-1.15), concluding that this diet modification does not reduce the risk for CHD or stroke in postmenopausal women.

The possible relationship between a low-fat diet and benign proliferative breast disease was also examined.4 In the population (N = 48,835), women without breast cancer had biennial mammograms and regular clinical exams. There were 1,363 noncancer biopsies performed. The authors concluded that modest dietary changes do not alter risk for benign proliferative breast disease. Of even greater importance is the possible link between diet and breast cancer. During the 8.1 years of follow-up, there were 1,727 incident cases of breast cancer.5 When comparing groups, the HR was 0.91 (CI, 0.83-1.01), showing a trend that did not reach statistical significance. However, secondary analysis suggests a lower HR among women who strictly adhered to the diet, a lower HR among women on a high-fat diet at baseline, and that dietary effect varies by hormone receptor characteristics.

Other authors looking at the same data analyzed that if diet had a major impact on breast cancer risk, it would mainly be mediated through growth rates during childhood and weight gain in later life.6 They suggested that minimizing weight gain during midlife or weight loss after menopause might reduce the risk of postmenopausal breast cancer. They also admitted that massive randomized trials of behavior change to prevent cancer will usually not be a good “investment,” as clear answers are unlikely.

However, on the positive side, there may be a small reduction of the risk for ovarian cancer in the diet group.7 Although the overall ovarian cancer HR was not significantly less than 1.0, it decreased with increasing duration. For the first 4 years, the risk for ovarian cancer was similar in the intervention and control groups (HR, 1.16; CI, 0.73-1.84). Over the next 4 years, the risk was significantly lower in the intervention group (HR, 0.60; CI, 0.38-0.96).

back to top

Calcium Plus Vitamin D Supplementation Versus Placebo

The second WHI nonhormonal prospective clinical trial was the calcium plus vitamin D arm. This was a prospective, randomized, placebo-controlled trial of 36,282 women at 3 of the WHI centers. They were randomized to a daily dose of 1,000 mg elemental calcium plus 400 IU of vitamin D3 or matching placebo pills. Average follow-up was 7 years after a baseline evaluation of bone mineral density (BMD).

Of obvious interest was the relationship between calcium plus vitamin D supplementation and fractures.8 The results revealed that, indeed, healthy postmenopausal women in the treatment group had 1.6% higher hip BMD (P<.01), but this did not translate into a significantly lower fracture rate over 7.1 years. The HR for hip fracture was 0.88 (CI, 0.72-1.08), for clinical spine fracture 0.90 (CI, 0.74-1.10), and for total fractures 0.96 (CI, 0.91-1.34).

Other authors looked at calcium plus vitamin D supplementation and physical function.9 Physical functioning was subjectively assessed by questionnaire at enrollment for 1 year prior to treatment randomization and then 7.1 years into the study. Objective physical performance and exercise at 1 year prior to treatment randomization and at 2 and 4 years into the study were also assessed. Neither intention-to-treat nor high adherence analyses produced substantial effects compared with placebo.

Weight gain was another factor studied.10 After an average 7 years of follow-up, the treatment group had minimal but consistent favorable difference in weight change. After 3 years, they were 11% less likely to gain more than moderate amounts of weight (>3 kg). But bottom line, these supplements had, at best, a small effect on prevention of weight gain.

Margolis and colleagues evaluated the effect on hypertension.11 They found no difference in change of systolic or diastolic blood pressure in hypertensive women nor an increased risk for hypertension in nonhypertensive women (HR, 1.01; CI, 0.96-1.06). De Boer et al looked at calcium plus vitamin D supplementation and diabetes.12 Excluded in the analyses were women who were already known to be diabetic, bringing the subject count down to 33,951. All were monitored with fasting glucose, insulin levels, and insulin resistance. There were 2,291 new cases of diabetes diagnosed, but no relationship to the supplementation was associated at these doses (HR, 1.01; CI, 0.94-1.10).

Although not a primary outcome for study, cardiovascular events were evaluated.13 In the entire population of 36,282 women, there were 974 reported myocardial infarctions (MIs) over a 7-year period. There were 739 incident strokes. With an HR of 1.04 (CI, 0.92-1.18) for MIs and 0.95 (CI, 0.82-1.10) for strokes, there was no difference in the risk for a cardiovascular event.

As was done in the low-fat diet arm, the risk for benign proliferate breast disease was also studied.14 Regular mammograms and clinical breast exams were performed in both groups. Breast biopsies confirmed benign proliferative disease in 915 women, but calcium plus vitamin D neither increased nor decreased the risk.

The same was true for colorectal cancer.15 There were 322 confirmed diagnoses, with no difference in baseline characteristics and no difference in risk for colorectal cancer (HR, 1.08; CI, 0.86-1.34). Interestingly, a subgroup of women in the study who were also taking estrogen had different findings. Bottom line, when controlled for estrogen use, calcium plus vitamin D did not lower risk; estrogen lowered risk; and calcium plus vitamin D plus estrogen lowered risk even more.16

A potentially adverse consequence of the addition of calcium to the diet is the risk for kidney stones, which was borne out in this trial.17 In fact, the incidence of clinically significant stone formation in the treatment arm (300/100,000/year), with a HR of 1.17 (CI, 1.02-1.34), was greater than shown in previous similar investigations, such as the Nurses’ Health Study (190/100,000/year) or the Olmstead County Study (70/100,000/year).

Calcium plus vitamin D supplementation, while showing a trend, had no statistically significant effect on overall mortality rates (HR, 0.91; CI, 0.83-1.01).18

Even though certain outcomes were not objectives of this trial, its sheer size can lead to some worthwhile observations. Brunner and colleagues examined the data and were able to determine predictors of adherence.19 Adherence was defined as taking 80% or more of the supplied tablets. Factors related to adherence were past pill-use experiences, personal supplement use, and relevant symptoms. They found factors that increased adherence the greatest were phone contact early in the study and direct social contact later in the study.

With the WHI being the largest, most expensive trial undertaken by the National Institutes of Health (NIH), the question “Was it all worth it?” is still to be answered. According to Robert N. Hoover, MD, ScD, Director of the Epidemiology and Biostatistics Program at the NIH, the “discussion and debate, often acrimonious,” has resulted in “an impressive improvement in methods to contrast and combine studies of differing designs” and “dramatic illustrations of some central epidemiologic principles.”20 Not all has been lost.

The authors report no actual or potential conflicts of interest in relation to this article.

Editor’s note: Part 2 of this article will appear in the April 2010 issue.

back to top

J. Kell Williams, MD, is Professor and Director, Division of Gynecology, Department of Obstetrics and Gynecology, and H. James Brownlee, MD, is Professor and Chairman, Department of Family Medicine, both at the University of South Florida College of Medicine, Tampa.

References

1. Women’s Health Initiative Study Group. Design of the Women’s Health Initiative clinical trial and observational study. Control Clin Trials. 1998;19(1):61-109.
2. Tinker LF, Bonds DE, Margolis KL, et al. Low-fat dietary pattern and risk of treated diabetes mellitus in postmenopausal women: the Women’s Health Initiative randomized controlled dietary modification trial. Arch Intern Med. 2008;168(14):1500-1511.
3. Howard BV, Manson JE, Stefanick ML, et al. Low-fat dietary pattern and weight change over 7 years: the Women’s Health Initiative Dietary Modification Trial. JAMA. 2006;295(1):39-49.
4. Rohan TE, Negassa A, Caan B, et al. Low-fat dietary pattern and risk of benign proliferative breast disease: a randomized, controlled dietary modification trial. Cancer Prev Rev (Phila Pa). 2008;1(4):275-284.
5. Prentice RL, Caan B, Chlebowski RT, et al. Low-fat dietary pattern and risk of invasive breast cancer: the Women’s Health Initiative Randomized Controlled Dietary Modification Trial. JAMA. 2006;295(6):629-642.
6. Michels KB, Willett WC. The Women’s Health Initiative Randomized Controlled Dietary Modification Trial: a post-mortem. Breast Cancer Res Treat. 2009;114(1):1-6.
7. Prentice RL, Thomson CA, Caan B, et al. Low-fat dietary pattern and cancer incidence in the Women’s Health Initiative Dietary Modification Randomized Controlled Trial. J Natl Cancer Inst. 2007;99(20):1534-1543.
8. Jackson RD, LaCroix AZ, Gass M, et al. Calcium plus vitamin D supplementation and the risk of fractures. N Engl J Med. 2006;354(7):669-683.
9. Brunner RL, Cochrane B, Jackson RD, et al. Calcium, vitamin D supplementation, and physical function in the Women’s Health Initiative. J Am Diet Assoc. 2008;108(9): 1472-1479.
10. Caan B, Neuhouser M, Aragaki A, et al. Calcium plus vitamin D supplementation and the risk of postmenopausal weight gain. Arch Intern Med. 2007;167(9):893-902.
11. Margolis KL, Ray RM, Van Horn L, et al. Effect of calcium and vitamin D supplementation on blood pressure: the Women’s Health Initiative Randomized Trial. Hypertension. 2008;52(2):847-855.
12. de Boer IH, Tinker LF, Connelly S, et al. Calcium plus vitamin D supplementation and the risk of incident diabetes in the Women’s Health Initiative. Diabetes Care. 2008; 31(4):701-707.
13. Hsia J, Margolis KL, Eaton CB, et al. Prehypertension and cardiovascular disease risk in the Women’s Health Initiative. Circulation. 2007;115(7):855-860.
14. Rohan TE, Negassa A, Chlebowski RT, et al. A randomized controlled trial of calcium plus vitamin D supplementation and risk of benign proliferative breast disease. Breast Cancer Res Treat. 2009;116(2):339-350.
15. Wactawski-Wende J, Kotchen JM, Anderson GL, et al. Calcium plus vitamin D supplementation and the risk of colorectal cancer. N Engl J Med. 2006;354(7):684-696.
16. Ding EL, Mehta S, Fawzi WW, Giovannucci EL. Interaction of estrogen therapy with calcium and vitamin D supplementation on colorectal cancer risk: reanalysis of Women’s Health Initiative randomized trial. Int J Cancer. 2008;122(8):1690-1694.
17. Heaney RP. Calcium supplementation and incident kidney stone risk: a systematic review. J Am Coll Nutr. 2008; 27(5):519-527.
18. LaCroix AZ, Kotchen J, Anderson G, 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;64(5):559-567.
19. Brunner R, Dunbar-Jacob J, Leboff MS, et al. Predictors of adherence in the Women’s Health Initiative Calcium and Vitamin D Trial. Behav Med. 2009;34(4):145-155.
20. Hoover RN. The sound and the fury: was it all worth it? Epidemiology. 2008;19(6):780-782.

back to top