Calcimimetics as an adjuvant treatment for familial hypophosphatemic rickets.
OBJECTIVE
The treatment for X-linked hypophosphatemia (XLH) with phosphate and calcitriol can be complicated by secondary hyperparathyroidism and nephrocalcinosis. Furthermore, vitamin D and phosphate stimulate FGF23 production, the pathogenic factor causing XLH. We investigated in XLH patients: 1) whether treatment with the calcimimetic agent, cinacalcet, will block the rise in parathyroid hormone (PTH) caused by phosphate administration; and 2) whether treatment with oral phosphate and calcitriol increases FGF23 levels.


METHODS
Eight subjects with XLH were given a single oral dose of phosphate, followed the next day by combined treatment with phosphate and cinacalcet. Serum measurements of ionized calcium (Ca), phosphate, creatinine, intact PTH, 1,25(OH)(2)D, FGF23, and tubular threshold for phosphate/glomerular filtration rate (TP/GFR) were assessed in response to short-term treatment with phosphate and cinacalcet and compared with long-term administration of phosphate and calcitriol.


RESULTS
Oral phosphate load increased serum phosphate, decreased ionized calcium, and increased PTH. Twenty-four hours later, FGF23 significantly increased and 1,25(OH)(2)D decreased. The concomitant administration of phosphate and cinacalcet resulted in further decrease in serum Ca(2+) but suppression of PTH and greater increase in serum phosphate and TP/GFR. Chronic treatment with phosphate and calcitriol resulted in a smaller increment in serum phosphate and high serum FGF23.


CONCLUSIONS
Traditional therapy of XLH with phosphate and calcitriol elevates FGF23 and has the potential to stimulate PTH. Short-term treatment with cinacalcet suppresses PTH, leading to increase in TP/GFR and serum phosphate. Thus, long-term clinical studies are needed to investigate whether cinacalcet may be a useful adjuvant in the treatment of XLH, allowing the use of lower doses of phosphate and calcitriol.
Alon
Uri S
US
Pediatric Nephrology, Bone and Mineral Disorders Clinic, Children's Mercy Hospital, University of Missouri, Kansas City, MO 64108, USA. ualon@cmh.edu
Levy-Olomucki
Rachel
R
Moore
Wayne V
WV
Stubbs
Jason
J
Liu
Shiguang
S
Quarles
L Darryl
LD
D000284:Administration, Oral; D000293:Adolescent; D002117:Calcitriol / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000627:therapeutic use*; D002118:Calcium / Q000097:blood; D002648:Child; D000069449:Cinacalcet; D003404:Creatinine / Q000097:blood; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D053098:Familial Hypophosphatemic Rickets / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D005260:Female; D000089703:Fibroblast Growth Factor-23; D005346:Fibroblast Growth Factors / Q000097:blood; D040181:Genetic Diseases, X-Linked; D005919:Glomerular Filtration Rate; D006801:Humans; D006962:Hyperparathyroidism, Secondary / Q000139:chemically induced / Q000517:prevention & control; D008297:Male; D009281:Naphthalenes / Q000008:administration & dosage / Q000627:therapeutic use*; D009397:Nephrocalcinosis / Q000139:chemically induced / Q000517:prevention & control; D010281:Parathyroid Hormone / Q000097:blood; D010710:Phosphates / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000627:therapeutic use*; D017680:Potassium Compounds / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000627:therapeutic use*; D016896:Treatment Outcome; D014815:Vitamins / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*
C000717427:FGF23 protein, human; D009281:Naphthalenes; D010281:Parathyroid Hormone; D010710:Phosphates; D017680:Potassium Compounds; D014815:Vitamins; D005346:Fibroblast Growth Factors; D000089703:Fibroblast Growth Factor-23; D003404:Creatinine; C013216:potassium phosphate; D002117:Calcitriol; D002118:Calcium; D000069449:Cinacalcet