The Women’s Health Initiative Trial of the Effect of Calcium Plus Vitamin D Supplementation on Risk of Fractures and Colorectal Cancer

February 2006

Findings Summary

Description and Overview
Between 1995 and 2000, participants already enrolled in the WHI Hormone or Dietary Studies were invited to join the WHI Calcium and Vitamin D (CaD) Study. A total of 36,282 WHI participants joined the CaD Study, making this the largest randomized clinical trial of calcium and vitamin D supplements ever done. The WHI CaD Study was designed to determine the effects of calcium and vitamin D supplements on the risks for hip fractures and colorectal cancer in postmenopausal women. The effects of CaD on other fractures and bone density were also studied.
When women joined this study, a computer program assigned half of the participants, by chance, to be in the group given study pills containing active calcium and vitamin D. The other half were given an inactive placebo. All CaD participants were asked to take one study pill twice a day (total of two pills each day). The women could choose whether they wanted to take a chewable or “swallow-able” form of study pill, and they could switch between these two forms during the study. For those in the active group, each pill contained 500 mg of calcium carbonate and 200 IU of vitamin D3, for a total of 1000 mg of calcium and 400 IU of vitamin D in their study pills each day. The placebo study pills contained no calcium or vitamin D. Participants in both the active and placebo groups were allowed to take limited amounts of calcium and/or vitamin D supplements on their own.
CaD Study participants were followed for an average of 7 years. They visited a WHI study clinic once a year. Every 6 months they answered questions about their health and about side effects related to study pills to monitor their safety. Participants were also asked to continue their other WHI activities (in the Hormone or Dietary Studies) as before. When the study ended in March 2005, most participants (75%) were still taking their study pills.
Fracture Findings
Over an average of 7 years, 374 CaD Study participants had hip fractures. The study found that for every 10,000 women taking active CaD supplements each year, on average 14 had a hip fracture, compared to 16 hip fractures for every 10,000 women taking placebo pills each year. Overall, women taking active CaD had 12% fewer hip fractures than those taking placebo. However, this difference was smaller than expected and could have happened by chance. Women taking active CaD supplements also had 4% fewer total fractures (overall, including all types of fracture combined). This difference was not statistically significant.
When scientists looked only at women who took their assigned study pills regularly, they found that women taking the active supplements had 29% fewer hip fractures than those taking placebo (on average, 10 compared to 14 cases per 10,000 women each year), which was a statistically significant difference.
Among women 60 years of age and older, those assigned to active CaD had a 21% decreased risk of hip fracture compared to women 60 and over who were taking placebo (17 compared to 23 cases per 10,000 women each year). This difference was statistically significant. Further research is needed to understand the findings about differences by age. The effect of the study pills did not differ by how much calcium women were taking or eating on their own at the time they joined the study. The findings also did not differ depending on women’s levels of vitamin D measured in the blood.
Women assigned to active CaD had 17% more kidney stones than women on placebo (an average of 34 compared to 29 cases per 10,000 women each year). Gastrointestinal side effects such as constipation, bloating, and gas did not differ between the two groups.
During the study, participants at three of the WHI clinical centers had regular bone mineral density scans. Analysis of these scans showed that women taking active CaD supplements had significantly higher hip bone density than those taking placebo, but the difference was small (1%).
There are several possible explanations why participants in the active CaD group had higher bone density, but no significant difference in hip fractures. It may be that the effect of CaD supplements on bone mineral density is not enough to show a large effect on actual hip fractures. Also, many CaD Study participants were already at a low risk for hip fractures when they joined the study and that might make finding differences less likely. Many participants had high personal calcium intake, they had higher than average weights, and many were taking postmenopausal hormone therapy. All of these factors decrease a woman’s risk for hip fractures. Finally, the dose of vitamin D (400 IU) may have been too low to affect hip fracture risk. More studies are needed to determine if higher amounts of vitamin D supplements will help to prevent hip fracture.
This study found that calcium plus vitamin D supplements improved hip bone density compared to placebo and lowered the risk of hip fractures in some groups. The current national recommendations say that women over 50 years should have daily total calcium intakes of 1000-1200 mg/day and vitamin D intakes in the range of 400-600 IU.
Colorectal Cancer Findings
Over an average of 7 years of following the 36,282 women in the WHI Calcium and Vitamin D Study, a total 322 women were diagnosed with invasive colorectal cancer. When scientists compared participants who took the active CaD supplements with those who took placebo pills, they found no differences in the rate of colorectal cancer diagnoses. The study found that for every 10,000 women assigned to take the active CaD, on average each year 13 were diagnosed with colorectal cancer compared to 12 colorectal cancers for every 10,000 women taking placebo pills.
There were also no differences between the two groups in the types of colorectal cancers themselves. For example, the cancer was not more or less advanced in one group compared to the other. In addition, there were no differences in the number of colon polyps reported by participants assigned to the active CaD group compared to the placebo group.
When scientists limited the analysis to only those taking most of their study pills, the findings about colorectal cancer did not change. Also, when scientists looked at participants’ personal calcium and vitamin D intakes, the colorectal cancer findings were similar—there were no differences between the active supplement and placebo groups.
Some scientists estimate that it may take 10 to 20 years for colorectal cancer to develop. The WHI CaD Study was limited to an average of 7 years and no women were followed for more than 10 years. It is possible that longer follow-up would be needed to find any impact of calcium and vitamin D on colorectal cancer. The WHI has an ongoing study to follow the participants 5 more years to see if findings change with longer follow-up.
The findings from the WHI Calcium and Vitamin D Study suggest that taking calcium and vitamin D supplements for an average of 7 years will not prevent colorectal cancer and, at this time, calcium and vitamin D should not be recommended for the prevention of colorectal cancer. However, it is possible that taking CaD for a longer period of time could be of benefit.
We now have some very valuable answers to questions about the effects of calcium and vitamin D on the health of postmenopausal women. We know that the use of these supplements for an average of 7 years slows loss of bone density and may help protect against hip fractures. We also know that these supplements, in the dosage used for this study and for 7 years of duration, do not prevent colorectal cancer in healthy postmenopausal women.
Because the effects of CaD supplements on hip fractures and colorectal cancer may take a long time to show up, continuing to follow participants in the WHI Extension Study can help us learn more about the longer-term effects of CaD supplementation.