Questions and Answers about the WHI Calcium and Vitamin D (CaD) Trial

These questions and answers supplement the February 16, 2006 NEJM publications on the effects of Calcium and Vitamin D supplements on the risk for hip fracture and colorectal cancer.
  1. What was the purpose of the Calcium and Vitamin D (CaD) Trial?
  2. Don’t health care providers already recommend that women take calcium and vitamin D for their bones?
  3. Who participated in the CaD Trial?
  4. What were the CaD Trial participants asked to do?
  5. What was in the active CaD supplement tablets?
  6. Why was vitamin D added to the calcium?
  7. Why were participants given a choice about taking chewable or “swallow-able” study tablets?
  8. Why were participants allowed to take their own personal calcium supplements?
  9. How long were the CaD Trial participants followed?
  10. What were the findings about fractures in the CaD Trial?
  11. What were the findings about bone density?
  12. How could bone density be significantly higher in the active CaD group than in the placebo group when there was no difference in the rate of hip fractures?
  13. The published findings suggest that there may be some additional benefit in decreasing hip fracture risk for women over age 60. How big is this benefit and is it “statistically significant”?
  14. Why were the rates of fracture lower than expected?
  15. What were the findings about colorectal cancer?
  16. Were the findings about hip fractures and colorectal cancers different based on a woman’s calcium and vitamin D intake or blood levels of vitamin D when she joined the study?
  17. If women with lower blood levels of vitamin D had a higher risk of colorectal cancer, shouldn’t those who take active CaD reduce their risk of colorectal cancer? Why do the published findings suggest that the risk didn’t change with vitamin D supplementation?
  18. Were the results of CaD different in women who were also on hormone therapy?
  19. Were there any side effects from taking the active CaD supplements?
  20. What were the overall conclusions? What do these findings mean?
  21. Do the risks of taking CaD supplements outweigh the benefits for hip fracture or colorectal cancer?
  22. What does this study tell us, should we still take CaD in an effort to decrease our risk of osteoporosis or at least prevent hip fractures?
  23. Are there other things women can do to increase their vitamin D levels besides taking supplements?
  24. What will be gained by continuing to follow the CaD Trial participants in the WHI Extension Study, given they are no longer taking study tablets?

GENERAL

1. What was the purpose of the Calcium and Vitamin D (CaD) Trial?
The CaD Trial was carried out to study the effects of calcium and vitamin D supplements on hip fractures (primary outcome) and colorectal cancer (secondary outcome). The effects of CaD on other fractures (secondary outcome) were also studied.
2. Don’t health care providers already recommend that women take calcium and vitamin D for their bones?
Scientists and health care providers have known for some time that calcium and vitamin D are important for bone health and may help to slow bone loss in older adults. However, when the CaD Trial started, it was not clear if taking calcium and vitamin D supplements would decrease a woman’s risk for hip fracture, which is a major cause of disability in older women.
3. Who participated in the CaD Trial?
Participants in the Hormone and Dietary Trials were invited to join the CaD Trial 1 to 2 years after joining the WHI. Between 1995 and 2000, a total of 36,282 participants joined the CaD Trial. These women were 50 to 79 years old when they first joined the WHI, represented diverse racial and ethnic groups, and were generally healthy and not at high risk for fracture.
4. What were the CaD Trial participants asked to do?
A computer randomly assigned half of the participants to be in the active CaD supplement group and half to be in the inactive placebo group. All CaD participants were asked to take one study tablet twice a day with meals (total of two tablets each day). The women could choose whether they wanted to take their assigned study tablets in a “chewable” or “swallow-able” form, and they could switch between these two forms of study tablets during the trial.
Participants answered questions every 6 months about their health and any problems they had taking the study tablets to make sure that the study tablets were safe and easy for them to take. Other than these tasks, CaD Trial participants were asked to continue their other WHI activities as before.

CaD STUDY TABLETS

5. What was in the active CaD supplement tablets?
Each active CaD tablet contained 500 mg of calcium carbonate and 200 IU of vitamin D3. Because all CaD Trial participants were asked to take two study tablets each day, the women in the CaD supplement group got a total of 1000 mg of calcium and 400 IU of vitamin D in their study tablets each day.
6. Why was vitamin D added to the calcium?
Vitamin D increases the amount of calcium that is absorbed in the body. In addition, previous research suggested that vitamin D may have independent effects on fracture and colorectal cancer.
7. Why were participants given a choice about taking chewable or “swallow-able” study tablets?
Some participants did not like the taste or texture of the chewable tablets. Others thought that the swallow-able tablets were too big to swallow. They were offered a choice to make it easier for them to continue to take their study tablets. Both forms of active study tablets contained the same kind of calcium and vitamin D in the same dosage.
8. Why were participants allowed to take their own personal calcium supplements?
The National Academy of Sciences currently recommends 1200 mg of calcium for adults more than 50 years old in order to maintain good health, but even doses much higher than that are considered safe. Although most people rely on getting enough calcium in their diet, some also take calcium supplements to meet this requirement. The WHI scientists wanted to make sure that participants continued these health habits as before, regardless of their CaD Trial study tablet assignment. During the CaD Trial, data on calcium intake was collected, so that a participant’s personal use of calcium supplements could be taken into account.

FOLLOW-UP

9. How long were the CaD Trial participants followed?
They were followed for an average of 7 years. This length of follow-up is slightly shorter than the average follow-up for the Dietary Trial, because participants didn’t start the CaD Trial until they had already been in the WHI for 1 to 2 years.

CaD TRIAL FINDINGS

10. What were the findings about fractures in the CaD Trial?
Over an average of 7 years, 374 CaD Trial participants had hip fractures. Although women taking the active CaD supplements had 12% fewer hip fractures than those taking placebo tablets, this difference was smaller than expected and could have happened by chance. Another way of looking at this finding is that for every 10,000 women taking active CaD supplements each year, 14 on average had a hip fracture compared to 16 hip fractures for every 10,000 women taking placebo tablets each year. Women taking active CaD supplements had 4% fewer fractures overall when scientists analyzed data on all types of fractures combined, but this could also have happened by chance.
When scientists analyzed only the data obtained while participants adhered to the study tablet regimen (when they were taking most of their study tablets), women taking most of their active supplements had 29% fewer hip fractures than those taking placebo (10 compared to 14 cases per 10,000 per year, on average).
11. What were the findings about bone density?
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 did have significantly higher hip bone density than those taking placebo.
12. How could bone density be significantly higher in the active CaD group than in the placebo group when there was no difference in the rate of hip fractures?
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. It may also be that the bone quality, which is not measured by bone mineral density, was not better in the active group. 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.
13. The published findings suggest that there may be some additional benefit in decreasing hip fracture risk for women over age 60. How big is this benefit and is it “statistically significant”?
The most scientifically reliable findings from the CaD Trial are the overall “non-significant” effect of CaD supplements on risk of hip fracture. 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, on average). This difference was statistically significant. Further research is needed to understand the findings about differences by age.
14. Why were the rates of fracture lower than expected?
Hip fractures were about half as frequent as expected, and this may have been due to a number of factors: the average body mass index of the women was 29 (heavy women have stronger bones), there were relatively few women over age 70, and many were already using CaD supplements and hormone therapy. They also were healthy enough to have been participating in the WHI clinical trials.
15. What were the findings about colorectal cancer?
Over an average of 7 years, 322 women were diagnosed with invasive colorectal cancer. When scientists compared the colorectal cancers in participants who took the active CaD supplements with those who took placebo tablets, there were no differences. For every 10,000 women taking active CaD supplements each year, 13 on average were diagnosed with colorectal cancer compared to 12 colorectal cancers for every 10,000 women taking placebo tablets each year. There were also no differences between the two groups in the colorectal tumors themselves. For example, the tumors were not more advanced in one group over the other. In addition, there were no differences in the number of colon polyps reported by participants in the two groups.
When scientists analyzed only the data obtained while participants adhered to the study tablet regimen (when they were taking most of their study tablets), the findings about colorectal cancer did not change.
16. Were the findings about hip fractures and colorectal cancers different based on a woman’s calcium and vitamin D intake or blood levels of vitamin D when she joined the study?
Even when women’s calcium and vitamin D intake and blood levels of vitamin D at enrollment were taken into account, the findings about hip fractures and colorectal cancer were similar—there were no differences between the active supplement and placebo groups.
17. If women with lower blood levels of vitamin D had a higher risk of colorectal cancer, shouldn’t those who take active CaD reduce their risk of colorectal cancer? Why do the published findings suggest that the risk didn’t change with vitamin D supplementation?
The finding that women who started with lower levels of serum Vitamin D had higher risk of colorectal cancer is consistent with some other observational studies. However, those kinds of studies do not necessarily show that lower vitamin D levels were responsible for the increased risk of cancer or that higher levels would protect them. In observational studies there may be other factors, such as a healthy lifestyle, that influence the association. We do clinical trials because we need to be clear about the factors that influence study findings. In a clinical trial we can exclude the possible roles that other factors play in the association. In the CaD Trial, we did not show any benefit of CaD supplements, regardless of the baseline Vitamin D status.
18. Were the results of CaD different in women who were also on hormone therapy?
More than half of the women who joined the CaD Trial were taking hormone therapy, either on their own or because they were randomized to active hormones in the WHI Hormone Trials. CaD participants who were taking hormones (in the WHI Hormone Trial) already had lower rates of hip fracture, and appeared to benefit further if they also received active CaD. Though it could have occurred by chance, this finding is consistent with previous research showing that hormone therapy and CaD have additive effects on bone mineral density.
CaD supplements had no effect on colorectal cancer irrespective of whether participants were also taking hormone therapy or not.
19. Were there any side effects from taking the active CaD supplements?
Women in the active supplement group reported 17% more kidney stones during follow-up. For every 10,000 women taking active CaD each year, on average there were 35 kidney stones compared to 30 for every 10,000 women taking placebo tablets each year. There were no differences in symptoms like bloating and constipation—these frequencies were similar throughout the trial for both women taking active CaD supplements and those taking placebo tablets.

CONCLUSIONS

20. What were the overall conclusions? What do these findings mean?
We now have some very valuable answers to questions about the effects of calcium and vitamin D on postmenopausal women’s health. We know that the use of these supplements for 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 over 7 years, do not prevent colorectal cancer in postmenopausal women. These findings, therefore, do not support the general use of CaD supplements to prevent colorectal cancer.
21. Do the risks of taking CaD supplements outweigh the benefits for hip fracture or colorectal cancer?
The only significant risk found in the CaD Trial was that of kidney stones (renal calculi). There was a suggestion of a reduction in hip fractures, and no effect on colorectal cancer. From the results it can be calculated that on average, for every 10,000 women taking the supplement for one year, there might be 6 more kidney stones and 2 fewer hip fractures. For women 60 and older, there might be 6 fewer hip fractures. It is not possible to calculate an overall benefit compared to risk, because hip fractures are much more serious than kidney stones. Also, the kidney stones were self -reported by the women, while the fractures and colorectal cancer cases were evaluated by trained physicians who reviewed actual medical records, and were therefore more reliable. There was no increase in total mortality in the active supplement group compared to the placebo group. The most important finding for the CaD Trial is the benefit to bone density and possible decreased risk of hip fracture, particularly in women who were 60 and older and in women who took their supplements regularly.
22. What does this study tell us, should we still take CaD in an effort to decrease our risk of osteoporosis or at least prevent hip fractures?
Women should continue to have adequate intakes of calcium and vitamin D to maintain bone density and prevent osteoporosis. Current guidelines state that most of the calcium intake should come from the diet, and most of the vitamin D from food and sunlight, but some women need supplements to meet recommended amounts of calcium and vitamin D. This study, like others, showed that these supplements improve bone mineral density. Additionally, in at least some subgroups of women (those age 60 years and over and those who adhered to the study tablet regimen), the findings suggest a reduced risk of hip fracture. Further studies are needed to see if higher doses of vitamin D would be of more benefit. 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.
23. Are there other things women can do to increase their vitamin D levels besides taking supplements?
Yes, exposure to sunlight is very effective at raising serum Vitamin D levels. The exposure does not need to be very long (15 minutes on most days of the week is sufficient). Because of the risk of skin cancer, the exposure should be limited and not long enough to get sunburn.
24. What will be gained by continuing to follow the CaD Trial participants in the WHI Extension Study, given they are no longer taking study tablets?
Because the effects of CaD supplements on hip fractures and colorectal cancer may take a long time to show up, continuing to follow these women in the Extension Study can help us learn more about the longer-term effects of CaD supplementation.

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