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

Clin J Am Soc Nephrol. 2015 Jun 5;10(6):1021-30. doi: 10.2215/CJN.03270314. Epub 2015 Apr 14.

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.

Publication types

  • Clinical Trial, Phase IV
  • Comparative Study
  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Australia
  • Biomarkers / blood
  • Calcimimetic Agents / adverse effects
  • Calcimimetic Agents / therapeutic use*
  • Calcium / blood
  • Canada
  • Chi-Square Distribution
  • Cinacalcet / adverse effects
  • Cinacalcet / therapeutic use*
  • Female
  • Fibroblast Growth Factors / blood*
  • Humans
  • Hyperparathyroidism, Secondary / blood
  • Hyperparathyroidism, Secondary / diagnosis
  • Hyperparathyroidism, Secondary / drug therapy*
  • Kidney Failure, Chronic / blood
  • Kidney Failure, Chronic / complications
  • Kidney Failure, Chronic / diagnosis
  • Kidney Failure, Chronic / therapy*
  • Logistic Models
  • Male
  • Middle Aged
  • Parathyroid Hormone / blood
  • Phosphorus / blood
  • Prospective Studies
  • Renal Dialysis* / adverse effects
  • Risk Factors
  • Russia
  • Time Factors
  • Treatment Outcome
  • United States
  • Vitamin D / adverse effects
  • Vitamin D / analogs & derivatives
  • Vitamin D / therapeutic use*

Substances

  • Biomarkers
  • Calcimimetic Agents
  • PTH protein, human
  • Parathyroid Hormone
  • Vitamin D
  • Phosphorus
  • Fibroblast Growth Factors
  • fibroblast growth factor 23
  • Calcium
  • Cinacalcet

Associated data

  • ClinicalTrials.gov/NCT01181531