Serum biomarkers for arterial calcification in humans: A systematic review

Abstract

Aim: To clarify the role of mediators of ectopic mineralization as biomarkers for arterial calcifications.

Methods: MEDLINE and Embase were searched for relevant literature, until January 4th 2022. The investigated biomarkers were: calcium, phosphate, parathyroid hormone, vitamin D, pyrophosphate, osteoprotegerin, receptor activator of nuclear factor-kappa B ligand (RANKL), fibroblast growth factor-23 (FGF-23), Klotho, osteopontin, osteocalcin, Matrix Gla protein (MGP) and its inactive forms and vitamin K. Studies solely performed in patients with kidney insufficiency or diabetes mellitus were excluded.

Results: After screening of 8985 articles, a total of 129 articles were included in this systematic review. For all biomarkers included in this review, the results were variable and more than half of the studies for each specific biomarker had a non-significant result. Also, the overall quality of the included studies was low, partly as a result of the mostly cross-sectional study designs. The largest body of evidence is available for phosphate, osteopontin and FGF-23, as a little over half of the studies showed a significant, positive association. Firm statements for these biomarkers cannot be drawn, as the number of studies was limited and hampered by residual confounding or had non-significant results. The associations of the other mediators of ectopic mineralization with arterial calcifications were not clear.

Conclusion: Associations between biomarkers of ectopic mineralization and arterial calcification are variable in the published literature. Future longitudinal studies differentiating medial and intimal calcification could add to the knowledge of biomarkers and mechanisms of arterial calcifications.

Keywords: 1,25(OH)2D, 1,25-dihydroxyvitamin D; 25(OH)D, 25-hydroxyvitamin D; Arterial calcification; Biomarkers; CAC, coronary artery calcification; CAD, coronary artery disease; CVD, cardiovascular disease; FGF-23, fibroblast growth factor-23; GACI, generalized arterial calcification of infancy; MGP, matrix Gla protein; MK, menaquinone; OPG, osteoprotegerin; PIVKA-2, protein induced by vitamin K absence or antagonist-2; PK, phylloquinone; PTH, parathyroid hormone; PXE, pseudoxanthoma elasticum; RANKL, receptor activator of nuclear factor-kappa B ligand; Review; dp-cMGP, carboxylated but dephosphorylated MGP; dp-ucMGP, uncarboxylated an dephosphorylated MGP; uc-MGP, uncarboxylated MGP.