Searchable abstracts of presentations at key conferences in endocrinology
Endocrine Abstracts (2014) 34 S4.3 | DOI: 10.1530/endoabs.34.S4.3

SFEBES2014 Symposia Putting flesh on the bones (3 abstracts)

Management of hypophosphatemic rickets

Thomas Carpenter


Yale University, New Haven, Connecticut, USA.


Hypophosphatemia due to excess urinary phosphate losses and rachitic bone disease occur in several related disorders. The most common form of the heritable hypophosphatemic disorders, X-linked hypophosphatemia (XLH, estimated incidence: 1/10 000–1/20 000), is due to loss-of-function mutations of the osteocyte/osteoblast protein, PHEX. Associated elevations in circulating FGF23 lead to reduced abundance of phosphate transporters on the luminal surface of renal tubular cells, and to inappropriately normal (or frankly low) circulating levels of 1,25 dihydroxyvitamin D (1,25D). Thus currently available therapies for XLH employ supplementation with phosphate and 1,25D. The primary clinical manifestations of XLH in childhood are bowing and other leg deformities. Dental disease occurs and is progressively problematic throughout adult life. Other complications in later years include arthritis, calcified entheses, and osteophyte formation, often leading to progressive pain and limited range of motion. FGF23 mediates other forms of hypophosphatemic rickets, including rare autosomal dominant and recessive forms and an acquired variant (tumor induced osteomalacia) which results from paraneoplastic secretion of FGF23 by small, frequently benign tumors. In contrast, hereditary hypophosphatemic rickets with hypercalciuria (HHRH) is due to loss-of-function mutations in the NaPi2c renal phosphate transporter, occurring independently of FGF23 activity. These differing features compel an accurate diagnosis, as treatment strategies differ.

Current replacement with phosphate and 1,25D is a cumbersome approach, is fraught with complications, and does not address all features of the disease. Novel approaches include targeted inhibition of FGF23 action with neutralizing antibodies to FGF23, and with the inactive, receptor binding C-terminus of FGF23; decreasing FGF23 secretion via calcitonin; and stimulation of FGF23 catabolism (via enhancement of subtilisin protein convertase activity). Other strategies aim to reduce secretion of parathyroid hormone, a factor which may enhance FGF23 activity. Treatment for HHRH employs a different strategy altogether, aiming to reduce 1,25D levels and to avoid renal stone risks.

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