Aging is associated with the development of both osteo-porosis and vascular disease, and there is increasing evidence for a link between bone metabolism and the vasculature. 1 A number of cross-sectional and longitudinal studies have demonstrated inverse, independent associations between bone mineral density and vascular calcification, 2–5 which appear to be predictive of atherosclerosis and related cardiovascular risk. 6 In addition, low bone mineral density has been associated with increases in the risk of cardiovascular events in prospective studies. 3 Of interest, high bone turnover itself is associated with increased cardiovascular mortality in elderly subjects independently of age, sex, overall health, serum parathyroid hormone levels, and hip fracture status. 7 This raises the interesting and important question of possible underlying mechanisms that may be driving bone loss, vascular disease, and/or calcification. Inflammation and oxidative stress represent a common soil for osteoporosis and atherosclerosis and might explain the coincidence of these diseases. 8, 9 Researchers are also investigating the existence of a causal connection between bone and vascular diseases. These studies are focusing mainly on the osteoprotegerin/receptor activator of nuclear factor-κB (RANK)/RANK ligand triad, the plasma fetuin-A mineral complexes/calciprotein particles, fibroblast growth factor-23/Klotho axis, and circulating calcifying cells (Table 1). In mice, the lack of osteoprotegerin, an inhibitor of osteoclast maturation, is followed by the development of both osteoporosis and vascular calcification. 10 The original finding suggested a central role for dysregulation in the osteoprotegerin/RANK/RANK ligand triad in the pathobiology of the bone-vascular axis. However, despite a series of studies showing direct biological effects of osteoprotegerin on vascular cells, there is no definitive demonstration that prevention of arterial calcification by osteoprotegerin is independent of actions on bone resorption. Indeed, several studies report reduced vascular calcification in animals treated with antiresorptive drugs, 11 whereas the antiatherosclerotic statins may improve bone mineral density. 12

Fibroblast growth factor-23 is a bone hormone that promotes phosphate excretion and inhibits vitamin D biosynthesis in the kidney. Klotho, which acts as both a membraneassociated protein and a secreted mediator, is responsible for the kidney-specific action of fibroblast growth factor-23. 13 In mice, deletion of Klotho leads to accelerated aging, with osteopenia and extensive vascular calcification. 14 Although hyperphosphatemia is implicated in most of the vascular changes observed in Klotho and fibroblast growth factor-23–null mice, 15 additional studies are needed to dissect the contribution of fibroblast growth factor-23 and Klotho in the bone-vascular axis.