In a cohort of premenopausal women with newly diagnosed, early-stage breast cancer, we found a high prevalence of vitamin D deficiency (greater than 70%), particularly among black and Hispanic women. After 1 year of supplementation with vitamin D3 400 IU daily, which is twice the dietary reference intake for premenopausal women, only a small percentage (< 15%) of whites and Hispanics, and no blacks, achieved sufficient levels of 25-OHD.
Greater than 30% of healthy adults are vitamin D deficient.1–3
Similar prevalence rates have been reported among women with breast cancer.8,32,33
In a cohort of 1,026 predominantly white women with newly diagnosed breast cancer from Long Island, NY, our group found that 33% had vitamin D deficiency (ie, < 20 ng/mL), and an additional 27% had insufficient levels (ie, 20 to 29 ng/mL33a
). We report a much higher prevalence of vitamin D deficiency in this study population, perhaps because of the higher proportion of black and Hispanic women in our cohort. Melanin is extremely efficient at absorption of UVB radiation; as a result, increased skin pigmentation markedly reduces vitamin D photosynthesis.34
In addition, after a breast cancer diagnosis, dietary and behavioral changes, such as decreased dietary intake of vitamin D or sunlight exposure, may occur, which may alter circulating 25-OHD levels. A limitation of this study is the lack of information on sunlight exposure and dietary intake of vitamin D.
As expected, vitamin D levels did not correlate with BMD measurements, because the overwhelming majority of patients had normal bone densities at baseline, and because BMD is influenced by changes to the hormonal milieu that result from chemotherapy-induced ovarian dysfunction. A notable change in 25-OHD concentration after chemotherapy was not observed in two studies.35,36
The modest increase in serum 25-OHD that we observed with supplementation was consistent with what would be expected at this dose level,37
which suggests that chemotherapy did not significantly alter serum 25-OHD levels.
Vitamin D increases dietary calcium absorption by 30% to 40% and is directly related to BMD.9,37
Vitamin D deficiency is often associated with increases in serum parathyroid hormone, which can result in increased osteoclast-mediated bone resorption.38
Vitamin D supplementation is associated with decreased falls in the elderly because of increased muscle strength39
and with decreased risk of hip fracture in postmenopausal women, although these results are controversial.9,10
Premenopausal women diagnosed with breast cancer have higher-than-average rates of bone loss and fracture as they age, which results in a lifetime risk of vertebral fractures nearly five times that of the general population.40
Although bisphosphonates prevent bone loss during chemotherapy, the best time to initiate bisphosphonate therapy is uncertain. Moreover, although current guidelines recommend supplementation with calcium and vitamin D,12,29
neither the optimal dose to recommend nor the effect of supplementation with the commonly available dose of vitamin D 400 IU per day have been prospectively evaluated. Our results indicate clearly that vitamin D 400 IU per day has minimal efficacy in correcting this widespread problem.
In the United States, cancer mortality for several cancers, including breast, colon, and prostate, shows a latitudinal gradient, as mortality rates increase among individuals who reside at higher latitudes.8,41–46
In 1990, Garland et al47
reported an inverse association between total average annual sunlight energy that strikes the ground and age-adjusted breast cancer mortality in the United States. Studies from Norway demonstrated that prognosis was better for cancers diagnosed in the summer season (which corresponds to maximal 25-OHD levels) compared with winter months.48–50
Evidence suggests that high levels of vitamin D at the time of diagnosis and, thus, during cancer treatment may improve prognosis for breast, colon, and prostate cancer.49
Recent prospective cohort studies have associated higher circulating 25-OHD levels with improved survival for non–small-cell lung cancer,51
and breast cancer.8,53
On the basis of a single measurement of serum 25-OHD up to 12 years before cancer death, data from the third National Health and Nutrition Examination Survey demonstrated significant inverse correlations for breast and colorectal cancer but not for all-cancer mortality.53
The risk of breast cancer mortality was lower among individuals with serum 25-OHD between 50 and 80 nmol/L (ie, 20 to 32 ng/mL) compared with less than 50 nmol/L (ie, < 20 ng/mL; odds ratio, 0.28; 95% CI, 0.08 to 0.93). However, because of small numbers, the trend was not statistically significant.53
In a prospective cohort study of 512 women with early-stage breast cancer diagnosed in 1989 to 1995, 25-OHD was measured in archived blood specimens that were obtained at diagnosis.8
Mean plasma 25-OHD was 23 ng/mL, and 37.5% of patients were vitamin D deficient (ie, < 20 ng/mL). Compared with women who had sufficient levels of 25-OHD (ie, ≥ 30 ng/mL), distant-disease–free survival and overall survival were significantly worse in women with vitamin D deficiency (distant-disease–free survival: hazard ratio, 1.94; 95% CI, 1.16 to 3.34; and overall survival: hazard ratio, 1.73; 95% CI, 1.05 to 2.86).8
African Americans diagnosed with breast cancer generally have poorer survival rates compared with whites, even after adjustment for stage of disease, level of treatment received, and other prognostic factors. Possible explanations for the ethnic disparities in breast cancer clinical outcomes include differences in tumor biology and access to care. In general, African Americans have 25% to 50% lower circulating vitamin D levels compared with whites. Data from the third National Health and Nutrition Examination Survey showed that mean serum 25-OHD levels among white, Hispanic, and black women were 76.0 nmol/L (ie, 30 ng/mL), 56.7 nmol/L (ie, 23 ng/mL), and 45.3 nmol/L (ie, 18 ng/mL), respectively (P
Lower breast cancer survival rates among blacks may be partially explained by lower serum 25-OHD.54
This may represent a potentially modifiable risk factor that may alter breast cancer prognosis among black and Hispanic women.
This is one of the first studies to examine the effects of standard-dose vitamin D supplementation on serum 25-OHD levels in breast cancer patients. We observed that cholecalciferol 400 IU daily for 1 year raised serum 25-OHD levels only modestly, by less than 3 ng/mL. At this dose of vitamin D, the proportion of breast cancer patients with vitamin D deficiency did not change appreciably, particularly among blacks and Hispanics. In the United States, the recommended dietary allowance of vitamin D is 200, 400, and 600 IU daily for adults less than 50 years old, aged 50 to 70 years, and aged greater than 70 years of age, respectively.55
The 2005 Dietary Guidelines for Americans recommend that groups at high risk for vitamin D deficiency, including older adults, people with dark skin, and those exposed to insufficient UV radiation, should consume vitamin D 1,000 IU daily.56
However, these recommendations had not been widely adopted during the time of enrollment for this study.
Oral daily intake of vitamin D 1,000 IU can increase serum 25-OHD levels by about 10 ng/mL; however, variability in response may be due to other factors, such as sunlight exposure, BMI, and dietary intake.37
Our analysis did not account for dietary intake or UV radiation. However, all patients resided in the northeast United States for the duration of the study. Given the high prevalence of vitamin D deficiency in the general population and among breast cancer patients, women may have to consume vitamin D up to 3,000 IU daily to increase serum 25-OHD to sufficient levels (ie, ≥ 30 ng/mL), which exceeds the National Academy of Sciences upper limit of 2,000 IU/d.56
Although circulating 25-OHD levels of 32 ng/mL are associated with normal mineral metabolism, data from observational studies suggest that optimal levels for breast cancer prevention exceed 40 to 50 ng/mL.5
Potential toxic effects of vitamin D, such as hypercalcemia, hypercalciuria, bone demineralization, or nephrocalcinosis, are rare and generally only occur when serum 25-OHD levels exceed 150 ng/mL.57
Our study has several strengths, including the relatively large, ethnically diverse patient population and the serial measurements of vitamin D status by an assay that takes into account both exogenous sources and endogenous production. In addition, the vitamin D assay used had high precision. Patients undergoing chemotherapy may have been less adherent to the recommendations to take supplements, as nausea may have interfered. Although we encouraged patients at each visit to take the supplements, we did not perform pill counts or administer pill diaries. In addition, lack of adherence may have influenced the minimal effect of supplementation. Despite the large proportion of minorities in our study population, the number of women in each ethnic group was small, which limited our ability to control for other factors that influence circulating vitamin D levels, such as age, BMI, and season of blood draw.
In summary, although the RDA of vitamin D in premenopausal women is only 200 IU daily, our study suggests that a dose of 400 IU daily is inadequate in breast cancer patients, even to maintain skeletal health,58
and is probably too low for meaningful anticancer effects. In the time since the upper safety limit of 2,000 IU daily of vitamin D was set in 1997, accumulating evidence in trials of healthy adults suggests that doses well above those currently recommended are safe.59
However, controversy in this field remains. Although the efficacy of vitamin D supplementation for reducing breast cancer mortality is still uncertain, it may be prudent to follow serum levels of 25-OHD and replete to sufficient levels in premenopausal women with breast cancer to improve bone health for this large and growing population of breast cancer survivors.