With advancing age, regulatory pathways involved in bone remodeling are activated inappropriately in smooth muscle cells of blood vessel walls and cardiac tissue. The result is calcification of tissue, making it inflexible, and disrupting the normal elasticity. That leads to hypertension and other, worse cardiovascular issues. Inflammatory signaling and the presence of senescent cells appear to be involved in causing this process, but firmly proven chains of cause and effect are yet to be established, as is the case for all too much of the panoply of dysfunctions that arise in the progression of degenerative aging.
Separately, the mechanisms of bone remodeling are disrupted in bone tissue itself, giving rise to an imbalance between deposition on the part of osteoblast cells and resorption on the part of osteoclast cells. The density and resilience of bone decreases over time, leading to osteoporosis. In today's review materials, researchers discuss the regulatory mechanisms involved in both osteoporosis and vascular calcification, noting that while incidence of these conditions are correlated with one another to some degree, it remains unclear as to whether one condition is driving the other, or whether they develop independently from shared root causes, such as the age-related increase in chronic inflammation.
A recent review paper elucidates the numerous pathophysiological mechanisms shared by vascular calcification and bone loss, identifying the following key associations. Firstly, vascular calcification is an active process of calcium and phosphate precipitation that involves the transition of the vascular smooth muscle cells (VSMCs) into osteoblast-like cells. Secondly, among the molecules involved in this process, parathyroid hormone (PTH) plays a key role, acting through several mechanisms which include the regulation of the RANK/RANKL/OPG system and the Wnt/ß-catenin pathway, the main pathways for bone resorption and bone formation, respectively. Thirdly, some microRNAs have been implicated as common regulators of bone metabolism, vascular calcification, left ventricle hypertrophy and myocardial fibrosis.
The increase or decrease in tissue and/or serum levels of PTH, the RANK/RANKL/OPG system and the Wnt/bcatenin pathways, calcium, phosphate, FGF23, among the most studied factors, may play a pathogenic role but can also be used as markers of bone and cardiovascular diseases. However, levels of some serum markers should be interpreted with caution, as the correlation between hormone levels and tissue levels needs to be better investigated.
This review shows that vascular calcification and bone loss that often coexist in ageing individuals, share numerous pathophysiological mechanisms. In this context, PTH, the RANK/RANKL/OPG system and the Wnt/ß-catenin pathway are the most studied factors. High PTH thus increases bone resorption and bone loss, but also triggers mechanisms that favour vascular calcification involving the RANK/RANKL/OPG and Wnt/ß-catenin pathways. Furthermore, other closely related factors such as calcium, phosphate, FGF23, Klotho, vitamin D and other regulatory factors that regulate PTH render these interactions extremely complex. The presence of low or high PTH levels, and consequently of low or high bone turnover, facilitate the process of deposition of hydroxyapatite in the wall of the vessels, leading to progression of vascular calcification when present for prolonged periods. The process eventually becomes severe, potentially increasing vascular molecular signals in order to reduce "bone deposition in the vessels", which in turn could favour the reduction of normal bone formation. Thus, in the presence of severe vascular calcification, a vicious circle may be established, further reducing bone mass.
The increase or decrease in tissue and/or serum levels of any these factors may play a pathogenic role in both bone loss and vascular calcification, and may be potentially promisingly used as a marker of bone and cardiovascular disease. However, caution should be exerted in the interpretation of these markers. For instance, whereas higher serum levels of sclerostin have been associated with vascular calcification and poor outcomes, this may not necessarily be due to a cause and effect relationship, but to a potential overproduction of sclerostin as a protective factor against vascular calcification. Similarly, serum sclerostin levels have been positively, and not negatively, associated with higher bone mass.
Although the pathogenesis and progression of vascular calcification and bone loss shares several common factors and pathways, it remains a "chicken-and-egg" situation, where it difficult to stablish cause and effect as to whether bone loss is driving vascular calcification or vice-versa, or whether there is a higher level of dysregulation generated by the ageing process that impacts on both tissues simultaneously, using common mechanisms.