Optimal Vitamin D Status

In the July issue of the Journal, Hansen et al. presented results of calcium absorption measurements in postmenopausal women studied at low (22 ng/ml) and high (64 ng/ml) vitamin D status. They report a statistically significant improvement in absorption efficiency (from 24% to 27%) but concluded that this improvement is too small to make much of a difference and that, therefore, the vitamin D status of individuals with 25(OH)D levels <30 ng/ml should not be designated ‘‘insufficient. ’’ Although quantitatively less than the result we had previously reported, the results of Hansen et al. are qualitatively confirmatory of our own findings, as are the results of Kendler et al. Now three studies—the only work of the sort in the world literature—point to the same conclusion: Raising serum 25(OH)D from basal values in the range of 20–25 ng/ml improves calcium absorption efficiency. What remains at issue is how much of a difference that improvement makes. The response found by Hansen et al., the smallest of the three reported effects, amounts to a 12.5% improvement in absorption efficiency. [Actually, it is slightly more than that (effectively equivalent to 13.9%) when one takes into consideration the countervailing secretion of calcium into the gut. ] Taking that figure and applying it to an intake of 1000 mg Ca/d (the recommended intake for premenopausal women) results in 34 mg additional absorbed Ca/d. This translates to 12.4 g Ca/yr, or a potential gain/loss of >30% of the skeleton in a 25-yr period. At the 1200-mg Ca intake level recommended for postmenopausal women, the difference would be +41 mg/d. I thus conclude that even the low estimate of Hansen et al. is clinically significant. Moreover, pooling the values from all three studies, truncating the rise in 25(OH)D at 32 ng/ml, and weighting for sample size yields a mean increase in absorption fraction of 0.0132/ng/ml, or a rise in absorption fraction of 0.13 for a change in 25(OH)D from 20 to 30 ng/ml. This is a biologically large and important effect. Perhaps what is most remarkable is the fact that the three studies showed any effect at all of improved 25(OH)D status. Although in pharmacologic doses, 25(OH)D has been shown to increase calcium absorption in its own right, under physiological circumstances, the body regulates calcium absorption efficiency by controlling the secretion of 1,25(OH)2D. It is a commonplace observation to those who measure calcium absorption that individuals with full vitamin D repletion (by any criterion) will often have low absorption efficiencies, reflecting the fact that the body has no perceived need for extra calcium. Thus, it is probably an oversimplification (which we and others have been guilty of in the past) to postulate that vitamin D causes calcium absorption. It seems better to conceptualize the action of vitamin D in this regard as enabling physiological regulation of calcium absorption rather than directly causing it. Thus, in studies such as the three that have been performed to date, the rise in absorption efficiency in women given vitamin D would seem to reflect the fact that they were not able to regulate absorption optimally at their prevailing levels of 25(OH)D. How25(OH)Dfunctionsinthisregardisunclear,butthereisa possible parallel in the role of serum 25(OH)D in enabling macrophage response to Mycobacterium tuberculosis. There the intracellular synthesis of 1,25(OH)2D in the macrophage is dependent on the ambient concentration of 25(OH)D. The 1-a-hydroxylation is not caused by the 25(OH)D but by the cellular genomic response to the tuberculosis antigen. However, this response needs an adequate quantity of 25(OH)D to be fully expressed. This is, I believe, a useful illustration of the distinction between an enabling and a causative effect of 25(OH)D. An instance of the fact that the body needs both molecules to stimulate and sustain calcium absorption is seen in the fact that patients with nutritional vitamin D deficiency and osteomalacia, who invariably have poor calcium absorption, commonly have normal to high levels of 1,25(OH)2D but low levels of 25(OH)D. Clearly, much more work needs to be done to understand the constructive interaction between the two molecules.