scholarly journals Effects of etelcalcetide on fibroblast growth factor 23 in patients with secondary hyperparathyroidism receiving hemodialysis

2019 ◽  
Vol 13 (1) ◽  
pp. 75-84 ◽  
Author(s):  
Myles Wolf ◽  
Geoffrey A Block ◽  
Glenn M Chertow ◽  
Kerry Cooper ◽  
Bruno Fouqueray ◽  
...  
Keyword(s):  
Growth Factor ◽  
Bone Turnover ◽  
Secondary Hyperparathyroidism ◽  
Fibroblast Growth Factor ◽  
Bone Turnover Markers ◽  
Calcium Supplementation ◽  
Fibroblast Growth Factor 23 ◽  
Fibroblast Growth ◽  
Secondary Analyses ◽  
Turnover Markers

Abstract Background Etelcalcetide is an intravenous calcimimetic approved for treatment of secondary hyperparathyroidism (sHPT) in patients receiving hemodialysis. Besides lowering parathyroid hormone (PTH), etelcalcetide also significantly reduces fibroblast growth factor 23 (FGF23), but the mechanisms are unknown. Methods To investigate potential mediators of etelcalcetide-induced FGF23 reduction, we performed secondary analyses of the 26-week randomized trials that compared the effects on PTH of etelcalcetide (n = 509) versus placebo (n = 514) and etelcalcetide (n = 340) versus cinacalcet (n = 343) in adults with sHPT receiving hemodialysis. We analyzed changes in FGF23 in relation to changes in PTH, calcium, phosphate and bone turnover markers. We also investigated how concomitant treatments aimed at mitigating hypocalcemia altered the FGF23-lowering effects of etelcalcetide. Results Etelcalcetide reduced FGF23 [median % change (quartile 1–quartile 3)] from baseline to the end of the trial significantly more than placebo [–56% (–85 to –7) versus +2% (–40 to +65); P < 0.001] and cinacalcet [–68% (–87 to –26) versus –41% (–76 to +25); P < 0.001]. Reductions in FGF23 correlated strongly with reductions in calcium and phosphate, but not with PTH; correlations with bone turnover markers were inconsistent and of borderline significance. Increases in concomitant vitamin D administration partially attenuated the FGF23-lowering effect of etelcalcetide, but increased dialysate calcium concentration versus no increase and increased dose of calcium supplementation versus no increase did not attenuate the FGF23-lowering effects of etelcalcetide. Conclusion These data suggest that etelcalcetide potently lowers FGF23 in patients with sHPT receiving hemodialysis and that the effect remains detectable among patients who receive concomitant treatments aimed at mitigating treatment-associated decreases in serum calcium.

scholarly journals Bone Formation Regulates Circulating Concentrations of Fibroblast Growth Factor 23

Endocrinology ◽  
2009 ◽  
Vol 150 (11) ◽  
pp. 4835-4845 ◽  
Author(s):  
Rana Samadfam ◽  
Christian Richard ◽  
Loan Nguyen-Yamamoto ◽  
Isabel Bolivar ◽  
David Goltzman
Keyword(s):  
Gene Expression ◽  
Growth Factor ◽  
Bone Formation ◽  
Bone Turnover ◽  
Fibroblast Growth Factor ◽  
Fibroblast Growth Factor 23 ◽  
Negative Regulator ◽  
Fibroblast Growth ◽  
Osteoblastic Cell Line ◽  
High Calcium

We examined the role of bone remodeling in the regulation of circulating concentrations of FGF23 using mouse models manifesting differing degrees of coupled and uncoupled bone turnover. Administration of the antiresorptive agent osteoprotegerin produced a profound reduction in bone resorption and formation in male and oophorectomized female mice, accompanied by an increase in serum levels of fibroblast growth factor 23 (FGF23) and a reduction in circulating 1,25-dihydroxyvitamin D [1,25(OH)2D]. In contrast, exogenous PTH(1-34) administration increased bone turnover and reduced circulating FGF23. In 1,25(OH)2D-deficient, 25-hydroxyvitamin D 1α-hydroxylase null mice on a high-calcium diet, endogenous PTH was elevated, bone formation but not resorption was increased, and serum FGF23 was virtually undetectable; on a rescue diet, serum calcium was normalized, PTH levels were reduced, bone formation was reduced, and serum FGF23 levels increased. After PTH treatment of wild-type mice, gene expression of dentin matrix protein 1 (DMP1) in bone was increased, whereas gene expression of FGF23 was reduced. In vitro studies in the osteoblastic cell line UMR-106 showed that externally added DMP1 could inhibit FGF23 gene expression and production stimulated by 1,25(OH)2D3. The results show that osteoblastic bone formation is a potent modulator of FGF23 production and release into the circulation, suggest that the biological consequences on mineral homeostasis of circulating FGF23 may also be dependent on the prevailing rate of bone turnover, and provide evidence that DMP1 may be a direct negative regulator of FGF23 production in osteoblastic cells.

Sign in / Sign up

Export Citation Format

Share Document