The roles of the skeleton and phosphorus in the CKD mineral bone disorder

Abstract

The CKD mineral bone disorder is a new term coined to describe the multiorgan system failure that is a major component of the excess cardiovascular mortality and morbidity complicating decreased kidney function. This syndrome embodies new discoveries of organ-to-organ communication including the skeletal hormone fibroblast growth factor-23 (FGF-23), which signals the status of skeletal mineral deposition to the kidney. The CKD mineral bone disorder begins with mild decreases in kidney function (stage 2 CKD) affecting the skeleton, as marked by increased FGF-23 secretion. At this stage, the stimulation of cardiovascular risk has begun and the increases in FGF-23 levels are strongly predictive of cardiovascular events. Later in CKD, hyperphosphatemia ensues when FGF-23 and hyperparathyroidism are no longer sufficient to maintain phosphate excretion. Hyperphosphatemia has been shown to be a direct stimulus to several cell types including vascular smooth muscle cells migrating to the neointima of atherosclerotic plaques. Phosphorus stimulates FGF-23 secretion by osteocytes and expression of the osteoblastic transcriptome, thereby increasing extracellular matrix mineralization in atherosclerotic plaques, hypertrophic cartilage, and skeletal osteoblast surfaces. In CKD, the skeleton positively contributes to hyperphosphatemia through excess bone resorption and inhibition of matrix mineralization. Thus, through the action of phosphorus, FGF-23, and other newly discovered skeletal hormones, such as osteocalcin, the skeleton plays an important role in the occurrence of cardiovascular morbidity in CKD.

Figure 1

Failure of a multiorgan system in CKD. The discoveries that disorders of mineral metabolism are causally linked to mortality, that hyperphosphatemia causes vascular calcification, and that kidney failure directly impairs skeletal anabolism establishes a multiorgan system which fails in CKD. The system consists of the kidney, the skeleton, the intestine, the vasculature, and the heart. The system is established by direct connections between each organ, which have not been completely defined in the case of kidney–bone and kidney–heart. However, the contribution of the skeleton and the kidney to hyperphosphatemia, the role of hyperphosphatemia in causing vascular calcification, and the effects of vascular calcification on the heart have been established. The kidney–intestine connection is represented by calcitriol and the intestine–bone connection by serotonin and an intestinal phosphatonin under study.

Figure 2

Skeletal remodeling contributes to phosphate balance and serum phosphorus levels. (A) The phosphate balance diagram is amplified to show that the serum phosphorus is a small component of a rapidly exchangeable phosphorus pool comprising cellular phosphorus and the bone mineralization front. (B) When bone formation is decreased (adynamic bone disorders), the exchangeable pool size is diminished and intestinal absorption from food intake will produce larger fluctuations in the serum phosphorus. These fluctuations are sufficient to activate the signaling actions of the serum inorganic phosphorus, even though the fasting serum inorganic phosphorus is normal. Stimulation of bone anabolism increases the exchangeable phosphorus pool size and decreases serum phosphorus fluctuations. In end-stage kidney disease, treatment of secondary hyperparathyroidism with a calcimimetic, which does not affect phosphate absorption, decreases the serum phosphate level, demonstrating the role of the skeleton in hyperphosphatemia.