Osteocalcin, Vascular Calcification, and Atherosclerosis: A Systematic Review and Meta-analysis

Abstract

BackgroundOsteocalcin (OC) is an intriguing hormone, concomitantly being the most abundant non-collagenous peptide found in the mineralized matrix of bone, and expanding the endocrine function of the skeleton with far-reaching extra-osseous effects. A new line of enquiry between OC and vascular calcification has emerged in response to observations that the mechanism of vascular calcification resembles that of bone mineralisation. To date, studies have reported mixed results. This systematic review and meta-analysis aimed to identify any association between OC and vascular calcification and atherosclerosis.Methods and resultsDatabases were searched for original, peer reviewed human studies. A total of 1,453 articles were retrieved, of which 46 met the eligibility criteria. Overall 26 positive, 17 negative, and 29 neutral relationships were reported for assessments between OC (either concentration in blood, presence of OC-positive cells, or histological staining for OC) and extent of calcification or atherosclerosis. Studies that measured OC-positive cells or histological staining for OC reported positive relationships (11 studies). A higher percentage of Asian studies found a negative relationship (36%) in contrast to European studies (6%). Studies examining carboxylated and undercarboxylated forms of OC in the blood failed to report consistent results. The meta-analysis found no significant difference between OC concentration in the blood between patients with “atherosclerosis” and control (p = 0.13, n = 1,197).ConclusionNo definitive association was determined between OC and vascular calcification or atherosclerosis; however, the presence of OC-positive cells and histological staining had a consistent positive correlation with calcification or atherosclerosis. The review highlighted several themes, which may influence OC within differing populations leading to inconclusive results. Large, longitudinal studies are required to further current understanding of the clinical relevance of OC in vascular calcification and atherosclerosis.

Increased serum osteocalcin levels and vitamin K status by daily cheese intake

“…34,35 Both positive and negative associations have been found between circulating osteocalcin and aortic stiffness and calcification, but most studies have reported nonsignificant association. 3,36 One study including 1691 men and 1913 women found that the osteocalcin levels and stiffness in the arteries were related in an "inverse Jshaped curve". 37 That study did not report on the extent of osteocalcin carboxylation, an indicator of vitamin K status.…”

Vitamin K effects in human health: new insights beyond bone and cardiovascular health

“…In fact, 44% of the included studies did not adjust for confounding variables and the BGP forms were measured using different assays in the different studies [22]. Moreover, BGP displays a circadian rhythm with levels falling in the morning and reaching the peak in the evening [23].…”

Peer Review #1 of "Osteokines and the vasculature: a review of the in vitro effects of osteocalcin, fibroblast growth factor-23 and lipocalin-2 (v0.1)"

“…While these investigations have drawn evidence for the skeletal control of energy metabolism, mineral homeostasis and much more, the effects of these hormones on the vasculature itself has also gathered interest. Conflicting observational data exists between OCN, FGF23 and LCN-2 and markers of cardiovascular disease in humans (Dalal et al, 2011;Wang, 2012;Millar et al, 2017), which are discussed further within this review. In order to assess the relevance of these osteokines to cardiovascular health, we aimed to provide an analysis of the direct effects of OCN, FGF23 and LCN-2 on micro-and macro-vascular cells in vitro, and to highlight gaps in the literature which need addressing, for use by clinicians and researchers.…”