The level of serum phosphate (Pi) is tightly regulated to remain in the optimal range. However, long-term disruption of this regulation leads to chronic hypophosphatemia and insufficient formation of hydroxyapatite as well as a compensatory increase in osteoid. This results in rickets, with short stature, bone deformity in the skull, rib cage, and legs, and endodontitis among pediatric patients due to inadequate endochondral ossification and hypoplasia of the enamel and dentinal matrix. Chronic hypophosphatemia causes osteomalacia presenting with pseudofracture, fracture, endodontitis; in severe cases, bone deformity in the rib cage among adult patients can occur. In contrast, patients with chronic hyperphosphatemia develop massive periarticular calcification, especially in relatively large joints and calcification of the arterial media [1]. It has also been observed that serum Pi levels are elevated in children and adolescents, and these levels might be beneficial and required for appropriate endochondral ossification [2]. Among patients with X-linked hypophosphatemic rickets (XLH, OMIM ID #307800), pseudofracture and fracture are rarely observed before adulthood. Perhaps this is because the lower serum Pi level in pediatric XLH patients is still within the normal range of that for adults, which is insufficient for endochondral ossification. Regardless, it is sufficient for adequate turnover in bone and preventing pseudofracture and fracture.

As the serum Pi level is strictly regulated to avoid development of the abovementioned disorders, there must be an elaborative system to regulate the inflow and outflow of Pi in the small intestine, bone, and renal tubules. Nevertheless, such a system remained elusive and was not consistently explained by the effect of parathyroid hormone (PTH) and 1,25-dihydroxyvitamin D (1,25OH2D) until early in this century fibroblast growth factor (FGF) 23 was identified as the master regulator of the chronic state of serum Pi in patients with autosomal dominant hypophosphatemic rickets (ADHR, OMIM ID #193100) and tumor-induced osteomalacia (TIO) *[3], *[4].

In this review article, the mechanisms for the physiological regulation of serum Pi, mainly through the FGF receptor (FGFR) 1-FGF23-Klotho/FGFR1 axis, PTH-PTH 1 receptor (PTH1R) axis, and 25OHD-1,25OH2D-vitamin D receptor (VDR) axis are presented. The etiologies underlying acute/chronic and inherited/acquired hypophosphatemia are concisely described with a table of chronic hypophosphatemic disorders and a flowchart for differential diagnosis of chronic hypophosphatemia suggested by the authors.