Calcium and Vitamin D Supplements

A healthy 56-year-old woman, who is seeing you for her annual checkup, asks if she still needs to continue the calcium supplements she has been taking. She has heard reports on the evening news that calcium and vitamin D were of negligible value in women her age--and could even cause kidney stones. How would you respond? What is the latest thinking about calcium and vitamin D supplements for postmenopausal women?

The widely publicized results of the Women's Health Initiative (WHI) study showed that supplementation with 1000 mg of calcium and 400 IU of vitamin D had no significant effect on fracture prevention in postmenopausal women.¹ Many of the headlines in the popular media were broadly dismissive (for example, the headline of one widely syndicated news service read: "Calcium, Vitamin D Won't Protect Older Women From Fracture"²). This coverage has led to considerable confusion--among patients and clinicians alike--about the proper role of calcium and vitamin D in bone health regimens. To advise patients with confidence and clarity, it is necessary to examine the study results closely--and to consider them in the broader context of all that is currently known about maintenance of bone health.

For years, physicians have advised postmenopausal women to take calcium and vitamin D supplements to reduce their risk of osteoporosis and the debilitating fractures associated with that disease (Figure). To test the premise for this widely recommended intervention, investigators from the WHI randomly assigned more than 35,000 postmenopausal women, aged 50 to 79 years, who were already enrolled in a WHI clinical trial, to receive either 1000 mg of elemental calcium (as calcium carbonate) with 400 IU of vitamin D₃ daily--or placebo. They monitored the women, measuring their bone density and tracking fractures, for an average of 7 years.¹

The results were not what the investigators had expected. Although the women who received calcium and vitamin D did show an increase in hip bone density, they experienced only a 12% decrease in hip fracture rate--which was not statistically significant--and no decrease at all in overall fracture rate. In fact, among women aged 50 to 59 years who received calcium and vitamin D, the fracture rate was actually higher than among those who received placebo. Moreover, a higher risk of kidney stones was noted in the women who received calcium and vitamin D than in those who received placebo. Thus, the study investigators were forced to conclude that the efficacy of calcium plus vitamin D to prevent fractures was only "equivocal."¹

WHY THE WHI RESULTS MAY NOT BE THE "LAST WORD"

Even though the WHI study did not show a statistically significant ability of calcium and vitamin D supplementation to reduce fracture risk in postmenopausal women, a closer look at the study reveals a number of reasons not to toss the calcium supplements just yet. Some of these reasons involve positive trends seen in certain subsets of the participants who received calcium and vitamin D supplements. Others involve subtle aspects of the study design that limit the strength of its conclusions with respect to certain outcomes.

Supplements were beneficial in those who took them regularly. By the end of the study, only 59% of participants were still taking the study medication at the intended dose. However, among women who took at least 80% of their study medication, there was a 29% decrease in the risk of hip fracture.¹

Supplements were effective in women older than 60 years. The hazard ratio in this age group was 0.79 (95% confidence interval, 0.64 to 0.98).¹

The study may not have been sufficiently powered to confirm a small benefit. Because the average body mass index (BMI) of participants was higher than anticipated and the number of women enrolled who were older than 70 years was lower than anticipated, the total number of fractures observed was lower than projected (16 per 10,000 persons per year compared with the projected rate of 34 per 10,000 persons per year). At this rate, the power of the study to detect an 18% reduction in hip fractures was only 48%, instead of the 85% power it was intended to have.

According to Rebecca Jackson, MD, lead author of the study, the low number of fractures may also help explain the increased hip fracture rate seen in women aged 50 to 59 years in the WHI study. The absolute number of fractures in this age group was very small--42--which greatly reduces the reliability of any conclusions based on the distribution. Dr Jackson also notes that hip fractures in younger women may be pathophysiologically different from those in older women: they may be more likely to involve trauma, secondary causes of bone fragility, and other factors.

A "threshold effect" may explain the lack of significant benefit with the study medication. Participants in the WHI study were allowed to take whatever personal supplements and medications they usually took (up to certain limits). Many were already taking calcium supplements; the average total calcium intake at baseline was 1150 mg/d. A number of studies have suggested that beyond a certain threshold level, additional calcium intake confers no additional benefits.³ In fact, the recommended daily allowances of calcium for various age groups are based on analyses of threshold levels. "The data in this trial are consistent with a threshold effect with calcium intake," notes Dr Jackson. "There was a trend toward benefit in those participants who had lower baseline calcium intakes and in those who did not start a personal calcium supplement during the trial (0.70 hazard ratio [95% confidence interval, 0.51 to 0.98])."

The threshold effect may also help explain the lower-than-projected overall fracture rate in the study--ie, there may have been fewer fractures than expected because many participants already had some protection against fractures as a result of the personal calcium supplements they were taking.

The vitamin D dosage used in the WHI study may have been insufficient. The majority of studies that support a benefit from calcium and vitamin D supplementation used vitamin D dosages of 600 IU/d or higher.¹ However, participants in the WHI study received only 400 IU/d. The 400 IU/d dosage "reflected the current thinking about the amount of vitamin D required to enhance calcium absorption," says Dr Jackson. But she adds, "We can't exclude the possibility that the amount of vitamin D participants received was insufficient."

The appropriate target for vitamin D is the subject of much current research. Some experts hold that a higher target dosage should be adopted, while others advocate use of a target blood level (eg, 32 ng/mL) instead. In fact, Dr Jackson feels that additional research is urgently needed on the role of vitamin D in fracture prevention--what constitutes an appropriate target, what the effects of the different forms of the vitamin are, and its benefits and risks for overall health as well as bone health.

WHAT TO TELL PATIENTS

Prudent advice to patients would include a continuing recommendation of calcium and vitamin D supplementation but would also stress the need for other interventions that can help maintain bone health and prevent fractures. Such interventions can include:

• Smoking cessation.
• Avoidance of excessive alcohol consumption (no more than 7 drinks per week).
• Regular exercise that involves resistance.
• Osteoporosis risk factor analysis.
• Bone density testing.
• Medication review.
• Bone-active agents.
• Hormone therapy (HT).

Dr Jackson forcefully underscores the importance of not smoking. She is also a strong proponent of resistance exercise. Although it is not possible to compare the relative efficacies of exercise and calcium and vitamin D supplementation (because of the lack of comparative studies that look at fracture as their primary outcome), "resistance exercise is unequivocally a major contributor to attainment of peak bone density," she asserts. "Resistance is a key word here. Bone responds to magnitude of load, not to repetition."

Although HT is in most cases inadvisable because of its adverse cardiovascular and cancer-promoting effects, it remains an effective means of reducing fracture risk and may be appropriate in certain circumstances--for example, in women with severe vasomotor symptoms and risk factors for fracture (and low cardiovascular risk). Data from the WHI study suggest that supplementation with calcium and vitamin D may work synergistically with HT to further augment the fracture protection provided by the latter. Close to half of the women in the WHI calcium and vitamin D study were also enrolled in the WHI Hormone Therapy trial. The annualized percentage for fractures in those crossover participants who received neither HT nor calcium and vitamin D supplements was 22%. Among those who received HT but not calcium and vitamin D supplements, this value was 17%--and among those who received both HT and calcium and vitamin D supplements, it fell to 10%. Although the same synergistic benefit was not seen when participants who used personal HT were included in the calculations, Dr Jackson suggests that selection bias may explain this result (women who took personal HT were more likely to be taking it because they had risk factors for osteoporosis than were those taking it as part of the WHI trial, which was well randomized).

The interventions that are most appropriate for a given patient depend on her age and risk factors. Dr Jackson's recommendations for various groups appear in the Table.

WHAT ABOUT THE RISK OF KIDNEY STONES?

In the WHI study, 17% more women who received calcium and vitamin D supplements reported kidney stones than did women who received placebo. This increase in kidney stone risk received disproportionate emphasis in some popular reporting of the trial results. The WHI study is not the first in which such an effect has been observed; there have been several other studies in which a small increase in the risk of kidney stones was reported with calcium carbonate supplementation (but not with dietary calcium or other calcium salts). Dr Jackson notes that simple measures, such as maintaining adequate hydration (8 or more glasses of water or nondiuretic liquids a day) and trying to meet one's daily calcium requirement primarily through dietary intake, can help prevent the formation of stones. *