Vitamin D — still much to learn

Vitamin D that we absorb from the sun or get in our diet appears to be biologically inert. It is not until it is hydroxylated in the liver to form calcediol (25-hydroxyvitamin D; 25D) that binding to the vitamin receptor is possible. The next step is further hydroxylation in the kidney to calcitriol (1-25 dihydroxyvitamin D; 1-25D), a process tightly regulated by parathyroid hormone. Circulating levels of 25D are about 1,000-fold those of 1-25D, while binding to the receptor favors 1-25D by about 100:1.

For decades it was thought that the effects of vitamin D and its metabolites were all centered on the skeleton and serum calcium. We now know that this was very shortsighted and that there are many potential extra-skeletal effects. I use the word “potential” deliberately because the newer information is derived from basic science experiments and increasingly from epidemiologic studies. That does not negate the importance of the observations but simply reminds me that we still have much to learn.

For example it has been demonstrated that 1-25D will inhibit the growth of the MCF7 breast cancer cell line and that in mouse models of adjuvant arthritis 1-25D has very effective anti-inflammatory properties. Finding a dose or derivative that can be beneficial without being toxic with respect to serum calcium has proven more difficult but progress is being made.

The epidemiologic data linking circulating levels of 25D and 1-25D to the risk of myocardial infarction¹, all cause mortality including cardiovascular mortality², and stroke³ have been reported in the last six months. We have still a lot to learn about these important observations and how vitamin D supplementation may prove beneficial. In the breast cancer literature there are data suggesting that low intake of vitamin D may increase breast cancer risk⁴ and may explain ethnic differences in breast cancer risk and outcomes⁵. Before we rush to increase intakes of vitamin D in everyone there is now a suggestion that high levels of vitamin D metabolites may increase prostate cancer risk⁶.

Perhaps the most surprising new information! African American adolescent girls absorb more calcium than non-Hispanic white girls despite substantially lower circulating levels of 25D⁷.

I have included the references to each of these observations (go to www.nlm.nih.gov and paste the PMID number into the search line) and draw to your attention that these have all been published in the last six months. An important exploding area of epidemiologic research.

For more information:

1: Pilz S et al Low vitamin d levels predict stroke in patients referred to coronary angiography. Stroke. 2008;39:2611-2613. PMID: 18635847.

2: Dobnig H et al. Independent association of low serum 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D levels with all-cause and cardiovascular mortality. Arch Intern Med. 2008;168:1340-1349. PMID: 18574092.

3: Giovannucci E et al. 25-hydroxyvitamin D and risk of myocardial infarction in men: a prospective study. Arch Intern Med. 2008;168:1174-1180. PMID: 18541825.

4: Gissel T et al. Intake of vitamin D and risk of breast cancer — a meta-analysis. J Steroid Biochem Mol Biol. 2008;111:195-199. PMID: 18590821.

5: Grant WB. Differences in vitamin-D status may explain black-white differences in breast cancer survival rates. J Natl Med Assoc. 2008;100:1040. PMID: 18807432 (no abstract available).

6: Ahn J et al. Serum vitamin D concentration and prostate cancer risk: a nested case-control study. J Natl Cancer Inst. 2008;100:796-804. PMID: 18505967.

7: Weaver CM et al. Vitamin D status and calcium metabolism in adolescent black and white girls on a range of controlled calcium intakes. J Clin Endocrinol Metab. 2008;93:3907-3914. PMID: 18682505.