Phosphate: The new cholesterol? The role of the phosphate axis in non-uremic vascular disease

Higher serum phosphate levels within the normal range are associated with substantially increased risk of cardiovascular disease events. Whether this reflects a causative relationship is unknown. Phosphate-responsive hormones (fibroblast growth factor-23, parathyroid hormone and calcitriol) are also predictors of cardiovascular mortality in populations without kidney disease or recognised disturbances of bone mineral metabolism. The high bioavailable phosphate content of Western diets may contribute to this apparent discrepancy between ‘normal’ and optimal phosphate axis parameters. Although uremic hyperphosphatemia is recognised to cause vascular medial calcification, this does not readily explain the association of higher-normal phosphate with common athero-occlusive phenomena. The phosphate axis may in fact play a role in atherogenesis; observational data link higher levels of phosphate and fibroblast growth factor-23 with coronary atheroma burden, whilst dietary phosphate supplementation accelerates atherosclerosis in a mouse model. In vitro studies show adverse effects of phosphate increases on both vascular smooth muscle cells and endothelium, though these observations have not yet been extended to phosphate increments within the normal range. Receptors for phosphate-responsive hormones are present throughout the cardiovascular system and may mediate atherogenic effects. Since interventions are already available to manipulate the phosphate axis, this is an important issue. If an atherogenic role for phosphate exposure is demonstrated then phosphate binders could become the new statins.