Vitamin D and Calcium Supplementation in Women: Making Sense of Conflicting Data

Many clinicians are confused about the benefits and risks of vitamin D and calcium supplementation for midlife and older women. We offer guidance on the appropriate use of these supplements.

Vitamin D

Long recognized as important for skeletal health, vitamin D has garnered recent interest for its possible nonskeletal benefits. This vitamin is synthesized in the skin in response to sunlight and can also be ingested as vitamin D₃ (cholecalciferol) or vitamin D₂ (ergocalciferol). Natural dietary sources of vitamin D are few and include fatty fish and egg yolks. Vitamin D is also commonly added to milk and some other dairy products, cereals, and orange juice. Vitamin D is hydroxylated in the liver to 25-hydroxyvitamin D [25(OH)D], the major circulating metabolite, and is then further converted to 1,25-dihydroxyvitamin D (calcitriol).

A recent evidence-based Institute of Medicine (IOM) report1^,2 provides guidelines about the amount of vitamin D that most North American women should consume. The IOM's review confirmed that vitamin D clearly confers bone benefits, but found that current data are insufficient to conclude that it lowers risk for nonskeletal diseases (e.g., cardiovascular disease [CVD], diabetes, cancer); thus, the IOM based its recommendations only on the amount required for bone health:

• 600 international units (IU) daily for women aged ≤70 and 800 IU daily for those aged >70 will meet the vitamin D needs of at least 97.5% of U.S. and Canadian women.

• These recommended dietary allowances (RDAs) correspond to a 25(OH)D serum level of 20 ng/mL.

• 25(OH)D assessments are not necessary for most women who meet the RDA guidelines.

Because the IOM assumed little to no sun exposure, these guidelines apply even to individuals living in northern latitudes during the winter.

The IOM also reviewed safety data on high-dose vitamin D supplements and set the tolerable upper level of daily intake at 4000 IU (previously 2000 IU). Extremely high intakes can lead to hypercalcemia, thereby damaging the kidneys and heart, but data are lacking about the long-term safety of intakes above the RDA. Several ongoing randomized trials should clarify the benefit-risk balance of such doses. For example, in the large, 5-year VITamin D and OmegA-3 TriaL (VITAL), researchers are testing 2000-IU daily supplemental vitamin D₃ for primary prevention of cancer and CVD.3

The IOM's recommendations reflect a population-level, public-health orientation and are intended to complement but not replace individualized clinical decision making. Clinical guidelines that combine both perspectives are useful.4 Per the IOM, most healthy individuals should do their best to meet the aforementioned RDAs and do not need routine 25(OH)D testing. However, for individuals with risk factors for, or clinical conditions associated with, vitamin D insufficiency (e.g., malabsorption, osteoporosis), 25(OH)D measurement is prudent. If the level is <20 ng/mL, two approaches to vitamin D therapy are as follows:

• Administer 50,000 IU of vitamin D₂ once weekly for 8 weeks, followed by a daily maintenance dose of vitamin D (typically 800–1000 IU) to maintain the target 25(OH)D level.

• Start directly with daily vitamin D₃ supplementation (dose determined by extent of insufficiency).

Roughly speaking, 25(OH)D increases by 6 to 10 ng/mL for each additional 1000 IU daily of supplemental vitamin D₃.4 Reassessing 25(OH)D is necessary about 3 months after a dose change to check that the target level has been attained. Some organizations recommend maintenance levels >30 ng/mL for “at-risk” individuals. The IOM recommends avoiding 25(OH)D levels >50 ng/mL, as some research suggests excess risk for CVD,1 pancreatic cancer,5 all-cause mortality,6 and even fractures7 at these levels.

Calcium

The IOM also conducted a parallel assessment of calcium and concluded that this nutrient provides critical bone benefits.1^,2 The Women's Health Initiative (WHI), a randomized trial of the benefits and risks of daily calcium (1000 mg) and low-dose vitamin D (400 IU) supplements in 36,282 postmenopausal women (age range, 50–79), showed that treatment led to significantly less bone loss at the hip and a 12% reduction in hip fracture rate.8 Although the latter figure was lower than expected and not statistically significant, it was one of the findings that led to the influential U.S. Preventive Services Task Force's 2013 assertion that this treatment is ineffective for fracture prevention at midlife and beyond.9 However, among WHI participants aged ≥60 — the age group most likely to sustain osteoporotic fractures — the intervention was associated with a larger, statistically significant 21% reduction in hip fracture rate.8 Moreover, among participants who took their study pills regularly and were not already taking supplements, the intervention was associated with a still larger, statistically significant 30% reduction in hip fracture rate.8 Participants with intakes ≥1200 mg/daily at baseline did not clearly benefit from the intervention, suggesting that “more is not necessarily better.” The evidence as a whole points to the need for sufficient calcium to ensure bone health and prevent fractures.1^,2^,10

The IOM set the current RDA for calcium (from food plus supplements) at 1000 mg for women aged ≤50 and 1200 mg for those aged >50. Many women are consuming unnecessarily high doses of supplemental calcium. Instead, they should aim to meet the RDA by eating calcium-rich foods (e.g., milk, yogurt, cheese, and other dairy foods; fish such as sardines or salmon; tofu; calcium-fortified juice and cereals; broccoli, collard greens, and kale) and consider supplements only if their diet does not provide the recommended amount of calcium. Given that the median daily dietary calcium intake of midlife and older women is about 700 mg1 (equivalent to 2–3 servings of the above foods), many women need no more than about 500 mg daily in calcium supplements to meet the RDA.10

Calcium from food does not seem to raise CVD risk (indeed, observational data suggest that the opposite may be true11), but calcium supplements may raise blood calcium levels more rapidly than dietary calcium, thereby boosting risk for heart disease. This hypothesis, however, remains unproven.10 In the WHI, no overall elevation in myocardial infarction (MI) or stroke risk occurred,12 although a 22% increase in MI risk was noted among participants who first began taking calcium supplements as part of the trial (but not among those already taking them at baseline).13 However, the supplements did not increase coronary artery calcification at trial's end.14 Also, a review of randomized trials showed that, compared with placebo, calcium supplements (whether alone or with vitamin D) were not linked to CVD risk.11 Nevertheless, striving to obtain calcium from food rather than from supplements — while ensuring adequate concurrent vitamin D intake — is wise.

Regarding other clinical outcomes in the WHI, a significant 17% increase in risk for kidney stones was noted,8 but the background intake of calcium was high. Total mortality was reduced by 9% (a finding of borderline statistical significance),15 and risk for total, colorectal, or breast cancer was unaffected.16 Overall, the findings suggest that calcium supplementation to bring the total intake of this nutrient to the RDA level — but not to exceed it — can lower risk for hip fracture without raising risk for CVD or other major adverse events.10

Conclusion

To maintain bone health, current recommendations for daily vitamin D intake call for 600 IU for women aged ≤70 and 800 IU for those aged >70, and recommendations for daily calcium intake are 1000 mg for women aged ≤50 and 1200 mg for those aged >50. The benefit–risk balance of long-term supplementation with doses of vitamin D and/or calcium that exceed the RDA is the subject of ongoing research. Most women should endeavor to eat a diet rich in these nutrients and consider supplements only if necessary to meet the RDA.