Vitamin D Deficiency May Be Overestimated in Blacks

Laurie Barclay, MD

November 20, 2013

Community-dwelling blacks have lower levels of total 25-hydroxyvitamin D and vitamin D binding protein compared with whites, but similar estimated concentrations of bioavailable 25-hydroxyvitamin D, according to a US cohort study. To avoid overestimating vitamin D deficiency in blacks, methods other than total 25-hydroxyvitamin D levels may therefore be needed, the researchers write in the November 21 issue of the New England Journal of Medicine.

"Our goal was to understand why blacks are routinely diagnosed with vitamin D deficiency, yet have a higher bone density and lower rate of fractures than their white counterparts," senior author Ravi I. Thadhani, MD, MPH, professor of medicine at Harvard Medical School and chief of nephrology at Massachusetts General Hospital in Boston, told Medscape Medical News. "We first examined levels of total vitamin 25-hydroxyvitamin D, as has traditionally been done, but also then examined levels of the major carrier protein for vitamin D; namely, vitamin D binding protein."

Using the Healthy Aging in Neighborhoods of Diversity across the Life Span cohort of 2085 blacks and whites, Camille E. Powe, MD, from the Department of Medicine, Brigham and Women’s Hospital, and colleagues measured bone mineral density (BMD) and levels of total 25-hydroxyvitamin D, vitamin D binding protein, and parathyroid hormone. They also genotyped study participants for rs7041 and rs4588, which are 2 common polymorphisms in the vitamin D binding protein gene, and estimated levels of bioavailable 25-hydroxyvitamin D in homozygous participants.

Blacks Had Lower 25-Hydroxyvitamin D and Vitamin D Binding Protein Levels

Compared with whites, blacks had lower mean levels of total 25-hydroxyvitamin D and vitamin D binding protein. Mean total 25-hydroxyvitamin D was 15.6 ± 0.2 ng per milliliter vs 25.8 ± 0.4 ng per milliliter (P < .001), and mean vitamin D binding protein was 168 ± 3 μg per milliliter vs 337 ± 5 μg per milliliter (P < .001). Genetic polymorphisms independently appeared to explain 79.4% of the variation in of vitamin D binding protein levels and 9.9% of the variation in total 25-hydroxyvitamin D levels.

In blacks, mean BMD was 1.05 ± 0.01 g per square centimeter compared with 0.94 ± 0.01 g per square centimeter in whites (P < .001). With decreasing levels of total or bioavailable 25-hydroxyvitamin D, levels of parathyroid hormone increased (P < .001 for both relationships). However, blacks had significantly lower levels of total 25-hydroxyvitamin D than whites within each quintile of parathyroid hormone concentration.

Homozygous blacks and whites had similar levels of bioavailable 25-hydroxyvitamin D overall (2.9 ± 0.1 ng per milliliter and 3.1 ± 0.1 ng per milliliter, respectively; P = .71), as well as within quintiles of parathyroid hormone concentration.

"We found that blacks have lower levels of the carrier protein, and the reason for this is because of a genetic variant commonly found in blacks and not in whites," Dr. Thadhani said. "Genetics therefore determine the levels of the carrier protein. Importantly, we also know that the vitamin D bound to the carrier protein is not what cells in the body take up routinely, and that the form of vitamin D not bound to the carrier protein, called bioavailable D, may be most important. When we compared the 'bioavailable' levels, they were the same if not higher in blacks."

New Definition of Vitamin D Status May Be Needed for Blacks

'It is difficult to believe that most blacks in the US are classified as vitamin D–deficient based on our current methods of testing," Dr. Thadhani said. "If we look at bioavailable levels, then blacks are not deficient. Moving forward we should ask whether signs or symptoms of vitamin D deficiency are present, and not just base our treatments only on the currently available test."

In the community-dwelling population studied, overt vitamin D deficiency was rare, and few participants had parathyroid hormone levels outside the normal range. However, based on the current guidelines, which suggest a threshold for sufficiency of 20 or 30 ng per milliliter, 77% to 96% of the black participants would be classified as vitamin D–deficient. This diagnosis would conflict with the observation that these participants had higher BMD, higher calcium levels, and slightly higher parathyroid hormone levels than white participants.

"We identified a common genetic reason [why] total vitamin D levels in blacks would be different than whites, and therefore our cut-points to define deficiency should be based on genetic-specific or race-specific standards and not simply overall population-based reference ranges," Dr. Thadhani concluded. "Vitamin D deficiency does exist, [but] it may not be as we thought. We hope in the future we can use bioavailable D levels to diagnose deficiency."

Limitations of this study include cross-sectional and observational design precluding determination of the effects of vitamin D binding protein levels on the risk for fracture. Data were lacking on bone-turnover markers, levels of 1,25-dihydroxyvitamin D, urinary calcium excretion, and use of vitamin D supplements. In addition, the study relied predominantly on calculation of bioavailable 25-hydroxyvitamin D, rather than direct measurement.

"Further investigation is needed to determine the effects of supplementation on total and bioavailable 25-hydroxyvitamin D levels in persons with different vitamin D–binding protein genotypes," the authors write.

"Our data should provide an impetus for the development of assays that directly measure bioavailable 25-hydroxyvitamin D."

Vitamin D Bioavailability May Be Key

In an accompanying editorial, Michael F. Holick, MD, PhD, from the Department of Medicine, Section of Endocrinology, Nutrition, and Diabetes, and the Vitamin D, Skin, and Bone Research Laboratory, Boston University Medical Center, notes that the definition of vitamin D deficiency has long been controversial. Part of this conundrum results from varying interpretations of different markers for vitamin D status.

To maximize bone health, the Institute of Medicine recommends a 25-hydroxyvitamin D target exceeding 20 ng per milliliter. Others determine vitamin D status from parathyroid hormone levels, which reach a nadir and plateau when 25-hydroxyvitamin D levels are 30 to 40 ng per milliliter.

Dr. Holick describes various proteins involved in vitamin D metabolism, including megalin, a transmembrane protein that transports bioavailable 25-hydroxyvitamin D bound to the vitamin D binding protein and albumin.

"However, the liver prefers unbound vitamin D3," Dr. Holick writes. "Immune and other cells lack megalin and thus may be able to use only unbound 25-hydroxyvitamin D. Therefore, more research is needed to fully appreciate what bioavailable versus total vitamin D status means — for 25-hydroxyvitamin D as well as 1,25-dihydroxyvitamin D. Full elucidation will be important not only for bone health but also for physiological aspects of vitamin D in health and disease."

This study was supported by the National Institute on Aging Intramural Research Program and the National Institutes of Health. One coauthor is a Howard Hughes Medical Institute investigator. Dr. Thadhani and 3 coauthors report being coinventors on a patent pending on the use of bioavailable vitamin D to assess vitamin D status. The authors have disclosed no other relevant financial relationships. Full conflict-of-interest information is available on the journal's Web site.

N Engl J Med. 2013;369:1991-2000, 2047-2048.


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