Role of vitamin D in vascular calcification: bad guy or good guy?

The role of vitamin D and its derivatives in vascular calcification is complex. It has long been known that in humans, hypervitaminosis D may be associated with extensive arterial calcium phosphate deposits, mostly in the form of apatite crystals. In experimental animals, the administration of pharmacological doses of vitamin D sterols can lead to widespread arterial calcification, especially in association with favourable conditions such as atherosclerosis, diabetes and chronic kidney disease (CKD) [1–5]. The mechanisms by which high doses of vitamin D or its derivatives induce vascular calcification include an increase in serum calcium and phosphate, the formation of fetuin-A mineral complexes in association with a decrease in free serum levels of fetuin-A [6] and the local induction of osteochondrogenic programmes with transformation of vascular smooth muscle cells (VSMCs) into osteoblast-like cells [7]. In adult patients with CKD, both before [8] and after the initiation of dialysis therapy [9], the severity and progression of vascular calcification have been found by two groups to correlate with circulating 25-hydroxyvitamin D [25(OH)D] levels. However, another group failed to identify an independent association of arterial calcification with serum 25(OH)D and 1,25-dihydroxyvitamin D [1,25(diOH)D] concentrations although both of them were negatively correlated with aortic pulse wave velocity and positively with brachial artery distensibility and flow-mediated dilatation [10]. Our group also did not find an association between serum 25(OH)D levels and aortic calcification or stiffness in patients with different stages of CKD [11]. The long-term administration of vitamin D sterols to children and young adults with CKD was found to induce vascular calcification [12, 13]. The prevalence of calcinosis was higher in the children treated with calcitriol than in those treated with vitamin D2 or vitamin D3 [13]. Differences between studies may be explained by different doses, types of vitamin D sterols used and treatment duration. Of note, different types of active vitamin D derivatives, when given in high amounts to animals with CKD, are not endowed with the same calcification-inducing capacity. Thus, paricalcitol has been shown to be less pro-calcifying in uraemic rats than calcitriol or doxercalciferol [3, 14]. Whether this also holds true for human patients with CKD remains a matter of debate. No prospective trials are available in such patients comparing the effects of calcitriol with those of the newer active vitamin D derivatives.