Interactions between calcium and phosphorus in the regulation of the production of fibroblast growth factor 23 in vivo

Quinn, Stephen; Thomsen, A.; Pang, Jian; Kantham, Lakshmi; Bräuner‐Osborne, Hans; Pollak, Martin R.; Goltzman, David; Brown, Edward M.

doi:10.1152/ajpendo.00460.2012

Cited by 98 publications

(91 citation statements)

References 48 publications

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“…These data, support recent experimental evidence pointing to interactions between calcium and phosphorus in the regulation of FGF-23 production (50,51). Because increases of FGF-23 in renal transplant patients have been correlated with both poor graft function and patient survival (52), it is reassuring that levels remained low.…”

Section: Evenepoel Et Alsupporting

confidence: 83%

A Randomized Study Evaluating Cinacalcet to Treat Hypercalcemia in Renal Transplant Recipients With Persistent Hyperparathyroidism

Evenepoel

Cooper

Holdaas

et al. 2014

American Journal of Transplantation

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Persistent hyperparathyroidism (HPT) after kidney transplantation (KTx) is associated with hypercalcemia, hypophosphatemia and abnormally high levels of parathyroid hormone (PTH). In this randomized trial, cinacalcet was compared to placebo for the treatment of hypercalcemia in adult patients with persistent HPT after KTx. Subjects were randomized 1:1 to cinacalcet or placebo with randomization stratified by baseline corrected total serum calcium levels ( 11.2 mg/dL [2.80 mmol/L] or >11.2 mg/dL [2.80 mmol/L]). The primary end point was achievement of a mean corrected total serum calcium value <10.2 mg/dL (2.55 mmol/L) during the efficacy period. The two key secondary end points were percent change in bone mineral density (BMD) at the femoral neck and absolute change in phosphorus; 78.9% cinacalcetversus 3.5% placebo-treated subjects achieved the primary end point with a difference of 75.4% (95% confidence interval [CI]: 63.8, 87.1), p < 0.001. There was no statistical difference in the percent change in BMD at the femoral neck between cinacalcet and placebo groups, p ¼ 0.266. The difference in the change in phosphorus between the two arms was 0.45 mg/dL (95% CI: 0.26, 0.64), p < 0.001 (nominal). No new safety signals were detected. In conclusion, hypercalcemia and hypophosphatemia were effectively corrected after treatment with cinacalcet in patients with persistent HPT after KTx.

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Section: Evenepoel Et Alsupporting

confidence: 83%

A Randomized Study Evaluating Cinacalcet to Treat Hypercalcemia in Renal Transplant Recipients With Persistent Hyperparathyroidism

Evenepoel

Cooper

Holdaas

et al. 2014

American Journal of Transplantation

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“…Ca and P have been shown to independently and synergistically stimulate FGF-23 (26). Thus, therapies for SHPT may indirectly affect FGF-23 production mediated by their effects on Ca and P metabolism.…”

Section: Discussionmentioning

confidence: 99%

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

Sprague

Wetmore

Gurevich³

et al. 2015

Clinical Journal of the American Society of Nephrology

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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 (Ca3P) were assessed. Correlations and logistic regression were used to explore relationships between changes in FGF-23 and changes in PTH, Ca, P, and Ca3P from baseline to week 52 by treatment arm.Results Median (quartiles 1, 3) decrease in FGF-23 concentrations was observed in the cinacalcet arm (240%; 263%, 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=20.04, 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 Ca3P 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 Ca3P 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.

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“…There are also data to suggest that calcium may participate in a synergistic fashion with phosphate to regulate FGF23 levels [42]. In a particularly informative study that involved the PTH knockout mouse, the calcium-sensing receptor knockout mouse and/or the double knockout mouse, Quinn et al showed that the greatest changes in serum FGF23 were accounted for by changes in the calcium x phosphate product, suggesting that both calcium and phosphorus may act in a synergistic fashion to regulate FGF23 levels.…”

Section: Pth and Fgf23mentioning

confidence: 99%

The PTH-Vitamin D-FGF23 axis

Blau

Collins

2015

Rev Endocr Metab Disord

135

105

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Fibroblast growth factor 23 (FGF23) has emerged as an important regulator of phosphate and vitamin D homeostasis. It is important to understand how FGF23 interacts with vitamin D and parathyroid hormone (PTH) in a FGF23-Vitamin D-PTH axis to regulate mineral homeostasis. In this review, we discuss the genomic structure, and transcriptional, translational, and posttranslational regulation of FGF23. We describe its interaction with PTH and vitamin D, disorders of altered FGF23 states, and emerging therapies for diseases of FGF23 based upon these findings. This discussion helps redefine the role of PTH and vitamin D in relation to a complex bone-kidney-parathyroid loop, and points to areas within this complicated field in need of further clarification and research.

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Interactions between calcium and phosphorus in the regulation of the production of fibroblast growth factor 23 in vivo

Cited by 98 publications

References 48 publications

A Randomized Study Evaluating Cinacalcet to Treat Hypercalcemia in Renal Transplant Recipients With Persistent Hyperparathyroidism

A Randomized Study Evaluating Cinacalcet to Treat Hypercalcemia in Renal Transplant Recipients With Persistent Hyperparathyroidism

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

The PTH-Vitamin D-FGF23 axis

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