Clinical and preclinical evidence of the skeletal and vascular adverse health effects of high dietary phosphorus

High dietary phosphorus and hyperphosphatemia contribute to impair skeletal and vascular health. Hyperphosphatemia activates signaling pathways that impair bone remodeling and mineralization and increase the propensity to vascular calcification. In bone, hyperphosphatemia increases the expression of inhibitors of the Wnt pathway and favors osteoblast and osteocyte apoptosis and, in the vessels, induces the differentiation of vascular smooth muscle cells from a vascular to an osteoblastic, bone-forming phenotype. The elevations in serum parathyroid hormone (PTH) induced by hyperphosphatemia favor bone resorption and could worsen vascular calcification. These phosphorus/PTH interactions make it difficult to separate direct phosphorus actions on the bone/vasculature axis from those that are PTH driven. Phosphorus induction of fibroblast growth factor 23 (FGF23) could also reduce bone mass through FGF23-induced increases of Wnt inhibitors in bone. Severe vascular calcification may induce reduced bone mass and propensity to fractures. The mechanisms involving the reciprocal adverse interactions between vascular calcification and loss of bone mass are not fully understood; however, they could involve the inhibition of the Wnt pathway to protect vessels, but with a deleterious consequence to bone. This chapter presents the current understanding of the molecular and cellular mechanisms, as well as the yet unresolved basic and clinical controversies on the severe disturbances in the bone/vasculature axis induced by hyperphosphatemia. This knowledge is a mandatory first step to identify accurate biomarkers of subclinical disease and improve current therapeutic strategies.