Effect of Cinacalcet and Vitamin D Analogs on Fibroblast Growth Factor-23 during the Treatment of Secondary Hyperparathyroidism

Abstract

Background and objectives: Cinacalcet and vitamin D are often combined to treat secondary hyperparathyroidism (SHPT) in patients on dialysis. Independent effects on fibroblast growth factor-23 (FGF-23) concentrations in patients on hemodialysis administered cinacalcet or vitamin D analogs as monotherapies during treatment of SHPT are evaluated.

Design, setting, participants, & measurements: A multicenter, randomized, open-label study to compare the efficacy of cinacalcet versus traditional vitamin D therapy for management of secondary hyperparathyroidism among subjects undergoing hemodialysis (PARADIGM) was a prospective, phase 4, multicenter, randomized, open-label study conducted globally. Participants (n=312) were randomized 1:1 to cinacalcet (n=155) or vitamin D analog (n=157) for 52 weeks. Levels of FGF-23 were measured at baseline and weeks 20 and 52. The absolute and percentage changes from baseline in plasma FGF-23, parathyroid hormone (PTH), calcium (Ca), phosphorus (P), and calcium-phosphorus product (Ca×P) were assessed. Correlations and logistic regression were used to explore relationships between changes in FGF-23 and changes in PTH, Ca, P, and Ca×P from baseline to week 52 by treatment arm.

Results: Median (quartiles 1, 3) decrease in FGF-23 concentrations was observed in the cinacalcet arm (-40%; -63%, 16%) compared with median increase in the vitamin D analog arm (47%; 0%, 132%) at week 52 (P<0.001). Changes in FGF-23 in both arms were unrelated to changes in PTH (cinacalcet: r=0.17, P=0.11; vitamin D analog: r=-0.04, P=0.70). Changes in FGF-23 in the vitamin D analog but not the cinacalcet arm were correlated with changes in Ca (cinacalcet: r=0.11, P=0.30; vitamin D analog: r=0.32, P<0.01) and P (cinacalcet: r=0.19, P=0.07; vitamin D analog: r=0.49, P<0.001). Changes in FGF-23 were correlated with changes in Ca×P in both arms (cinacalcet: r=0.26, P=0.01; vitamin D analog: r=0.57, P<0.001). Independent of treatment arm, participants with reductions in P or Ca×P were significantly more likely to show reductions in FGF-23.

Conclusions: During treatment of SHPT, cinacalcet use was associated with a decrease in FGF-23 concentrations, whereas vitamin D analogs were associated with an increase. The divergent effects of these treatments on FGF-23 seem to be independent of modification of PTH. It is possible that effects of cinacalcet and vitamin D analogs on FGF-23 may be mediated indirectly by other effects on bone and mineral metabolism.

Trial registration: ClinicalTrials.gov NCT01181531.

Keywords: ESRD; clinical nephrology; dialysis; hyperparathyroidism.

Figure 1.

Change in concentrations of FGF-23, PTH, Ca, P, and Ca x P by treatment arm over time. (A) Mean (SEM) fibroblast growth factor-23 (FGF-23; nanograms per liter) concentrations by treatment arm over time. (B) Mean (SEM) parathyroid hormone (PTH; picograms per milliliter) concentrations by treatment arm over time. (Cinacalcet: n=155, 129, and 111 at weeks 0, 20, and 52, respectively; vitamin D analog: n=157, 127, and 111 at weeks 0, 20, and 52, respectively.) (C) Mean (SEM) serum calcium (Ca; milligrams per deciliter) by treatment arm over time. (Cinacalcet: n=155, 130, and 111 at weeks 0, 20, and 52, respectively; vitamin D analog: n=157, 124, and 112 at weeks 0, 20, and 52, respectively.) (D) Mean (SEM) serum phosphorus (milligrams per deciliter) by treatment arm over time. (Cinacalcet: n=155, 141, and 109 at weeks 0, 20, and 52, respectively; vitamin D analog: n=157, 135, and 110 at weeks 0, 20, and 52, respectively.) (E) Mean (SEM) serum calcium-phosphorus product (Ca×P; milligrams² per deciliter²) by treatment arm over time. (Cinacalcet: n=146, 129, and 108 at weeks 0, 20, and 52, respectively; vitamin D analog: n=150, 124, and 110 at weeks 0, 20, and 52, respectively.)

Figure 2.

Correlation between FGF-23 and PTH, Ca, P, or Ca x P by treatment arm. (A) Change from baseline in FGF-23 (nanograms per liter) versus change from baseline in PTH (picograms per milliliter) at week 52. (B) Change from baseline in FGF-23 (nanograms per liter) versus change from baseline in Ca (milligrams per deciliter) at week 52. (C) Change from baseline in FGF-23 (nanograms per liter) versus change from baseline in phosphorus (P;milligrams per deciliter) at week 52. (D) Change from baseline in FGF-23 (nanograms per liter) versus change from baseline in Ca×P (milligrams² per deciliter²) at week 52.

Figure 2.

Correlation between FGF-23 and PTH, Ca, P, or Ca x P by treatment arm. (A) Change from baseline in FGF-23 (nanograms per liter) versus change from baseline in PTH (picograms per milliliter) at week 52. (B) Change from baseline in FGF-23 (nanograms per liter) versus change from baseline in Ca (milligrams per deciliter) at week 52. (C) Change from baseline in FGF-23 (nanograms per liter) versus change from baseline in phosphorus (P;milligrams per deciliter) at week 52. (D) Change from baseline in FGF-23 (nanograms per liter) versus change from baseline in Ca×P (milligrams² per deciliter²) at week 52.

Figure 3.

Quadrant analysis showing the differences in the patterns of the most commonly observed concurrent laboratory changes by treatment arm. (A) Quadrant analysis—FGF-23 (nanograms per liter) versus PTH (picograms per milliliter) decrease/increase from baseline to week 52. FGF+, PTH−: cinacalcet, 18.5%; vitamin D analogs, 47.0%; FGF+, PTH+: cinacalcet, 10.9%; vitamin D analogs, 18.1%; FGF−, PTH−: cinacalcet, 48.9%; vitamin D analogs, 20.9%; FGF−, PTH+: cinacalcet, 21.7%; vitamin D analogs, 14.5%. (B) Quadrant analysis—FGF-23 (nanograms per liter) versus Ca (milligrams per deciliter) decrease/increase from baseline to week 52. FGF+, Ca−: cinacalcet, 27.2%; vitamin D analogs, 26.5%; FGF+, Ca+: cinacalcet, 2.2%; vitamin D analogs, 38.6%; FGF−, Ca−: cinacalcet, 63.0%; vitamin D analogs, 18.1%; FGF−, Ca+: cinacalcet, 7.6%; vitamin D analogs, 16.9%. (C) Quadrant analysis—FGF-23 (nanograms per liter) versus P (milligrams per deciliter) decrease/increase from baseline to week 52. FGF+, P−: cinacalcet, 11.0%; vitamin D analogs, 20.7%; FGF+, P+: cinacalcet, 17.6%; vitamin D analogs, 45.1%; FGF−, P−: cinacalcet, 56.0%; vitamin D analogs, 25.6%; FGF−, P+: cinacalcet, 15.4%; vitamin D analogs, 8.5%. (D) Quadrant analysis—FGF-23 (nanograms per liter) versus Ca×P (milligrams² per deciliter²) decrease/increase from baseline to week 52. FGF+, Ca×P−: cinacalcet, 16.5%; vitamin D analogs, 19.5%; FGF+, Ca×P+: cinacalcet, 12.1%; vitamin D analogs, 46.3%; FGF−, Ca×P−: cinacalcet, 60.4%; vitamin D analogs, 25.6%; FGF−, Ca×P+: cinacalcet, 11.0%; vitamin D analogs, 8.5%.