Calcimimetics as an adjuvant treatment for familial hypophosphatemic rickets

Abstract

Background and objectives: 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.

Design, setting, participants, and measurements: 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.

Figure 1.

Effect of P loading alone (day 1) compared with P + cinacalcet (day 2) on serum (A) ionized calcium, (B) PTH, and (C) phosphate, in 8 subjects with XLH. Blood samples were obtained every 30 minutes. Data are shown using Random Intercept Mixed Linear Model. The change in ionized calcium was −0.011 during the first day and −0.033 mmol/L per hour during the second day (P = 0.0001, 95% CI −0.032 to −0.014). The change in PTH was 4.1 during the first day and −1.9 pg/ml per hour on the second day (P = 0.001, 95% CI −9.6 to −2.5). The change in phosphorus was 0.25 during the first day and 0.34 mg/dl per hour during the second day (P = 0.088, 95% CI −0.013 to 0.195).