Calcium Regulates FGF-23 Expression in Bone

David, Véronique; Dai, Bing; Martin, Aline; Huang, Jinsong; Han, Xiaobin; Quarles, L. Darryl

doi:10.1210/en.2013-1627

Cited by 118 publications

(116 citation statements)

References 72 publications

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“…Overall, these data suggest that the use of non-Ca-based binders seems to lower FGF-23 levels, whereas the use of Ca-containing binders either minimally affects or actually raises FGF-23 levels. This effect of Ca-containing binders is consistent with the known ability of Ca to stimulate FGF-23 (35).…”

Section: Discussionsupporting

confidence: 85%

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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Section: Discussionsupporting

confidence: 85%

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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“…PTH also stimulates FGF-23 as part of a negative endocrine feedback loop they share (35). High serum calcium is another recently appreciated stimulus of FGF-23 (36)(37)(38). This makes sense when considered in the broader context of global regulation of mineral metabolism and the parallel in PTH physiology.…”

Section: Physiologymentioning

confidence: 99%

Mineral (Mal)Adaptation to Kidney Disease—Young Investigator Award Address

Wolf

2015

Clinical Journal of the American Society of Nephrology

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In the short time since its initial discovery as the cause of rare hypophosphatemic disorders, fibroblast growth factor-23 (FGF-23) has emerged as a major regulator of mineral metabolism and critical component of the bone and mineral adaptation to CKD. However, because elevated FGF-23 levels are also a novel biomarker and possible molecular mediator of increased risks of cardiovascular disease and death in CKD, the initially adaptive response to increase FGF-23 levels to maintain neutral phosphate balance in CKD may ultimately become maladaptive. Incorporating FGF-23 into understanding the complex physiology that governs normal bone and mineral metabolism and its alterations in CKD has filled critical knowledge gaps and opened a new landscape of exciting hypotheses and novel therapeutic strategies to be tested in the continued quest to alleviate the burden of CKD.

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“…A recent study has revealed that Ca regulates bone FGF-23 expression and that HCD increases serum FGF-23 concentration in Cyp27b1 -/-and Gcm2 -/-mice (38). In parathyroidectomized rats, dietary Ca supplementation increased SCa and FGF-23 concentration (39).…”

Section: Discussionmentioning

confidence: 99%

High calcium diet alleviates 5/6 nephrectomy-induced bone deteriorations of lumbar vertebrae in mice

et al. 2018

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Abstract. Dietary calcium (Ca) supplementation has beneficial effects on bone health. However, it is not clear whether a high calcium diet (HCD) following 5/6 nephrectomy (5/6 Nx) is beneficial to bone health. The aim of the present study was to examine the effects of an HCD on bone metabolism using a chronic kidney disease (CKD) mouse model. Male C57BL/6J mice were divided into three groups: Sham group, 5/6 Nx group and 5/6 Nx + HCD group. Mice were sacrificed 12 weeks post-surgery. Calcium (Ca) and creatinine (Cr) were measured using standard colorimetric methods and picric acid methods, respectively. Bone metabolism-associated markers, FGF-23, PTH, ALP-b and TRAP-5b were measured using ELISA kits. Lumbar vertebrae histomorphological analysis was performed using hematoxylin and eosin staining. The expression of osteoprotegerin (OPG) and receptor activator of nuclear factor κB ligand (RANKL) mRNA was detected using reverse transcription-quantitative polymerase chain reaction. Impaired renal function and histopathological damage was indicated in 5/6 Nx mice. However, HCD had no significant effects on these changes in 5/6 Nx mice. Notably, mineral metabolism disorder and histopathological damage to lumbar vertebrae were markedly improved in HCD-treated 5/6 Nx mice. Compared with 5/6 Nx mice, HCD supplementation significantly elevated the ratio of OPG/RANKL and inhibited RANKL mRNA expression in lumbar vertebrae. To conclude, the present findings indicated that increased Ca intake is effective in increasing bone mineral content of the lumbar vertebrae in 5/6 Nx mice. These results may provide a basis for the clinical use of dietary Ca supplementation as a therapeutic approach to treat CKD-induced disturbance of mineral metabolism and bone loss.

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Calcium Regulates FGF-23 Expression in Bone

Cited by 118 publications

References 72 publications

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

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

Mineral (Mal)Adaptation to Kidney Disease—Young Investigator Award Address

High calcium diet alleviates 5/6 nephrectomy-induced bone deteriorations of lumbar vertebrae in mice

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