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Measuring Vitamin D in Serum: Have we been doing it all wrong?

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Adequate vitamin D levels are essential for bone health (1) and may influence any number of other organ systems. Vitamin D in the strictest definition is not a vitamin, since it can be made in the skin under the influence of ultraviolet radiation and hence, is not an essential nutrient. Rather, it is best thought of as a hormone since its most active metabolite (1, 25 (OH)2 vitamin D) is produced, for the most part, in the kidneys by a highly regulated mechanism and then acts throughout the body. Pigmentation can filter the ultraviolet radiation that converts provitamin-D (7 dehydrocholesterol) to vitamin D in skin. This is one reason that individuals with highly pigmented skin are typically found to have lower total serum 25 OH vitamin D levels (the most abundant circulating form) than those with less pigmented skin.


Given the critical role that vitamin D plays in regulating calcium homeostasis and bone health, one would expect that individuals with lower total circulating vitamin D levels would be more prone to osteoporosis and fragility fracture. However, this is not always the case. While this hypothesis holds for individuals of a particular ancestry, it falls apart when comparing individuals of different racial groups. In the United States comparison of the bone mass and the incidence of osteoporosis in white and black Americans demonstrates that on average bone mass is lower and the incidence of osteoporosis higher in white Americans compared to black Americans. Counterintuitively, white Americans have significantly higher mean total serum 25 OH vitamin D levels than do black Americans.


Until now the reason for this paradox was unknown. However, a recent publication by Powe et al (2) has added clarity to our understanding of the differences in vitamin D biology between individuals of different ancestries. The key is to understand the relationship between circulating vitamin D levels and vitamin D binding protein (VDBP). The vast majority (85 to 90%) of vitamin D in serum is bound to VDBP, which appears to act primarily as a storage form of vitamin D. The rest is either bound to albumin (10 to 15%) or circulates unbound (less than 1%). There are a number of common polymorphisms of VDBP, which alter the affinity of VDBP for vitamin D. Bioavailable vitamin D, as defined by Powe et al, consists of that fraction of vitamin D, which is not bound to VDBP and is, therefore, most available to interact with cellular vitamin D receptors. Powe et al found that there were significant differences in the level of VDBP between black and white Americans, with black Americans having, on average, about half the level of whites. In addition, the type of VDBP most commonly found in black Americans had a higher affinity for vitamin D than did the type of VDBP most commonly found in white Americans (3). When the authors examined the bioavailable levels of vitamin D in both ethnic groups, they were essentially identical for all levels of serum parathyroid hormone, a measure of vitamin D sufficiency. The authors conclude; “…on the basis of the current guidelines (suggesting a threshold for sufficiency of 20 or 30 ng per milliliter), 77 to 96% of our black participants would be classified as vitamin D–deficient. Labeling the majority of the black participants as vitamin D–deficient would be inconsistent with the observation that they had higher BMD, higher calcium levels, and only slightly higher parathyroid hormone levels than their white counterparts.” They then go on to say that; “…low levels of total 25-hydroxyvitamin D probably do not indicate true vitamin D deficiency when levels of vitamin D–binding protein are also low, as in many black Americans. Bioavailable 25-hydroxyvitamin D may be a more appropriate cross-racial marker of vitamin D sufficiency; however, investigations in populations with overt vitamin D deficiency are required before routine clinical use is warranted.”


In retrospect, one has to wonder why it took so long to appreciate the role that VDBP has in the paradox of high bone mass in certain groups with low total serum 25 OH vitamin D levels. In comparison, we have known for years that the effects of estrogen and testosterone, which are also cholesterol metabolites and hormones that circulate on a binding protein, are greatly affected by changes in binding protein levels (4). Hence, it is not unexpected that a similar relationship would exist between vitamin D, its metabolites and VDBP. In any event, now that this relationship has been highlighted, it is time to further investigate how we measure and interpret vitamin D levels so that we can make better clinical decisions about vitamin D replacement.


Joe Lorenzo

Farmington, CT U.S.A.

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