Elsevier

Vascular Pharmacology

Volume 86, November 2016, Pages 77-86
Vascular Pharmacology

Review
Bone loss and vascular calcification: A bi-directional interplay?

https://doi.org/10.1016/j.vph.2016.07.003Get rights and content

Abstract

Vascular calcification (VC) represents a recognized adverse predictor for cardiovascular morbidity and mortality. Previously considered passive and degenerative, VC is now recognized as an active process that resembles bone formation, and shares a number of histopathological features, mineral composition, and initiation mechanisms with bone development and metabolism. Oxidative stress and inflammation are key factors in both VC and osteoporosis (OP). Biochemical factors known to be primarily involved in the healthy bone metabolism also regulate VC. These biomarkers include vitamin D, osteoprotegerin, osteopontin, matrix Gla protein, cathepsin K, fibroblast growth factor-23, and fetuin-A.

A better understanding of this highly controlled regulatory network, with multiple, nested feedback loops and cross talk between organs, may help to decrease the growing prevalence of calcific vasculopathy as well as OP in the aging population, and to advance in common preventive and therapeutic interventions targeted at both conditions.

Introduction

Osteoporosis (OP) and cardiovascular disease (CVD) represent the most important causes of mortality and morbidity. For a long time, these two diseases were traditionally considered independently related to aging and their association under-estimated [1]. Nonetheless, increasing data in the last years suggest a close relationship between OP and atherosclerosis. These two conditions shared many common risk factors, including dyslipidemia, hypertension, and Type 2 diabetes (T2D), smoking, alcohol consumption, physical activity and menopause, other than aging. Bone morphogenetic proteins (BMP), osteoprotegerin (OPG), parathyroid hormone (PTH), phosphate, oxidized lipids and vitamins D and K, oxidative stress (OxS) and inflammation, and nitric oxide are key factors in both conditions, suggesting common pathophysiologic mechanisms, and a common etiology [1].

Many data suggest that bone loss may promote CVD, and low bone mineral density (BMD) has been related to increased CV events, and subclinical measures of vascular atherosclerosis. In particular, many data evidenced that vascular calcification (VC) is the central event in the relationship between bone loss and CV risk, as molecular events of bone formation have been also observed at VC lesion levels [1]. Different traditional biochemical markers of bone remodeling retain significance for atherosclerosis, and influence energy balance, with important effects on development of CVD and its comorbidities. Conversely, some emerging findings also suggest that VC can have an impact on bone metabolism. Nonetheless, environmental factors can elicit differential effects and independent responses at bone and CV level, rendering this relationship more and more complicated. Interestingly, both diseases might be the target of common therapies as some findings suggested. This review focuses on pathophysiological similarities between OP and VC and presents an overview of main evidence supporting the relationship between these conditions.

Section snippets

Pathophysiological mechanisms which promote cellular differentiation and mineral deposition at vascular level

Vascular smooth muscle cells (VSMC) may locally differentiate into osteoblast-like cells, under upregulation of transcription factors such as Cfba1/Runx2 (core-binding factor subunit 1α/runt-related transcription factor 2) [2]. These cells can produce factors which can promote or inhibit mineralization and incorporate calcium and phosphorus with formation of hydroxyapatite crystals [2]. Less validated theories on the origin of osteoblast-like cells propose that they might originate from stem

Clinical evidence for the link between osteoporosis/bone loss and vascular calcification

There are several results linking OP and VC, and the strength of this relationship varies depending on the vascular bed, with the strongest associations for the aorta [30]. This finding may have a particular importance, because it is known that aortic calcification is associated with increased risk of stroke and myocardial infarction [31]. In particular, in the Prospective Epidemiological Risk Factors Study Group, aortic calcification was significantly associated with lower BMD and accelerated

Inflammation and oxidative stress

Inflammation and oxidative stress are two intermingled factors which represent potent inducers of both VC and OP, and drive the transition from VSMC to osteoblast-like cells in the vascular wall [1], [161], [162]. Pro-inflammatory cytokines such as IL-6 and TNF-α retain pro-atherogenic effects, as stimulation of bone resorption and inhibition of bone formation, facilitating activation of osteoclasts [1], [163]. Moreover, different OxS biomarkers, known predictors for CV risk and events, are

Vascular calcification inducing bone loss

Many findings suggest that impaired bone metabolism may have an important impact in the development of VC. However, some emerging evidence suggests that VC can also directly affect bone metabolism, thus suggesting the possible bi-directionality between these systems. In particular, an interesting experimental study demonstrated that an increase in aortic calcium content was associated with decreases in bone formation and matrix apposition in LDL receptor (LDLR)-null mice fed by

A lesson from the past

Medical examination on the corpse of the iceman found on the Alps, probably death at age 45, may offer interesting insights on the bone-vascular relationship [177]. In particular, its examination revealed very good bone mineral content and thick long bone cortices in the lower extremities [177]. Nonetheless, this man presented VC in numerous arterial sites, suggesting independence between bone and CV pathophysiology [177]. A reason for these findings may be that whereas at that time bone health

Conclusion

Available evidences point out the interaction between bone loss and VC, although in many cases the nature of this relationship is very complex and its clinical significance is still unclear. In particular, whether there are many data on the effect of bone on VC, some results are emerging on the reciprocal role of VC on bone, but in particular cases bone or VC alterations appear independent from each other. Different biomarker showed opposite effects in term of VC and bone pathophysiology,

Acknowledgments

The authors wish to thank Dr. Laura Sabatino for her editorial assistance and English revision.

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