Hypophosphatemia induced by intravenous administration of saccharated ferric oxide

Shimizu, Yuichiro; Tada, Yuko; Yamauchi, Mika; Okamoto, Takahiro; Suzuki, Hisanori; Ito, Nobuaki; Fukumoto, Seiji; Sugimoto, Toshitsugu; Fujita, Toshiro

doi:10.1016/j.bone.2009.06.017

Cited by 132 publications

(129 citation statements)

References 21 publications

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“…2E), a result that appears converse to the aforementioned case reports involving iron infusion. The physiological reasons for this divergence are currently unknown; however, it is noteworthy that in the clinical reports both saccharated ferric oxide and ironpolymaltose infusion caused an elevation of FGF23, but dextriniron infusions did not (39)(40)(41). Thus, the difference in the kinetics of iron release from these pharmacological preparations or a rapid increase of iron may affect FGF23 expression differently than the long-term, physiologic regulation of iron in humans during normal variations in puberty or pregnancy or than the changes in dietary iron intake over weeks in mice during alterations in dietary iron exposure.…”

Section: Discussionmentioning

confidence: 99%

Iron deficiency drives an autosomal dominant hypophosphatemic rickets (ADHR) phenotype in fibroblast growth factor-23 (Fgf23) knock-in mice

Farrow

Summers

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

334

324

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Autosomal dominant hypophosphatemic rickets (ADHR) is unique among the disorders involving Fibroblast growth factor 23 (FGF23) because individuals with R176Q/W and R179Q/W mutations in the FGF23 176 RXXR 179 /S 180 proteolytic cleavage motif can cycle from unaffected status to delayed onset of disease. This onset may occur in physiological states associated with iron deficiency, including puberty and pregnancy. To test the role of iron status in development of the ADHR phenotype, WT and R176Q-Fgf23 knock-in (ADHR) mice were placed on control or low-iron diets. Both the WT and ADHR mice receiving low-iron diet had significantly elevated bone Fgf23 mRNA. WT mice on a low-iron diet maintained normal serum intact Fgf23 and phosphate metabolism, with elevated serum C-terminal Fgf23 fragments. In contrast, the ADHR mice on the low-iron diet had elevated intact and C-terminal Fgf23 with hypophosphatemic osteomalacia. We used in vitro iron chelation to isolate the effects of iron deficiency on Fgf23 expression. We found that iron chelation in vitro resulted in a significant increase in Fgf23 mRNA that was dependent upon Mapk. Thus, unlike other syndromes of elevated FGF23, our findings support the concept that late-onset ADHR is the product of gene-environment interactions whereby the combined presence of an Fgf23-stabilizing mutation and iron deficiency can lead to ADHR.Online Mendelian Inheritance in Man no. 193100) is characterized by low serum phosphate concentrations due to isolated renal phosphate wasting, inappropriately normal or low serum 1,25(OH) 2 vitamin D (1,25D) concentrations, and rickets/osteomalacia and fracture (1). Heterozygous missense mutations in the fibroblast growth factor-23 (FGF23) gene cause ADHR (2). These mutations replace the arginine (R) residues at positions 176 or 179 with glutamine (Q) or tryptophan (W) within a 176 RXXR 179 / S 180 subtilisin-like proprotein convertase (SPC) site that separates the conserved FGF-like N-terminal domain from the variable Cterminal tail (2-4). Acting through the coreceptor α-Klotho (5) and a fibroblast growth factor receptor (FGFR) (5, 6), FGF23 reduces renal phosphate reabsorption through down-regulation of the sodium phosphate cotransporters NPT2a and NPT2c and suppresses kidney 1,25(OH) 2 vitamin D production by inhibiting and increasing vitamin D 1α-hydroxylase (Cyp27b1) and 24-hydroxylase expression (Cyp24), respectively (7). Compared with WT Fgf23 protein, ADHR-mutant FGF23 shows increased but not complete resistance to SPC proteolytic cleavage (3, 4). When expressed in mammalian cells, the R176Q-, R179Q-, and R179W-FGF23 proteins are secreted primarily as the full-length (32-kDa) polypeptide, in contrast to the full-length and cleavage products (20 and 12 kDa) typically observed for WT FGF23 (3). This proteolytic event inactivates the mature FGF23 polypeptide, as full-length FGF23, but not N-terminal fragments (residues 25-179) or C-terminal fragments (residues 180-251), reduces serum phosphate concentrations when injected into rodents (4).The ADHR...

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Section: Discussionmentioning

confidence: 99%

Iron deficiency drives an autosomal dominant hypophosphatemic rickets (ADHR) phenotype in fibroblast growth factor-23 (Fgf23) knock-in mice

Farrow

Summers

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

334

324

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“…(7) However, excess actions of FGF-23 cause hypophosphatemic rickets/ osteomalacia, including X-linked hypophosphatemic rickets/ osteomalacia (XLH), (8,9) autosomal dominant and recessive hypophosphatemic rickets/osteomalacia (ADHR and ARHR), (10)(11)(12) tumor-induced rickets/osteomalacia (TIO), (8,9) hypophosphatemic rickets/osteomalacia associated with McCune-Albright syndrome/fibrous dysplasia, (13,14) and hypophosphatemic diseases caused by intravenous administration of iron polymaltose. (15,16) Hypophosphatemic rickets/osteomalacia usually has been treated by oral phosphate and active vitamin D 3 . (1) However, these medications sometimes cause adverse events, including diarrhea and secondary or tertiary hyperparathyroidism.…”

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confidence: 99%

Anti-FGF-23 neutralizing antibodies ameliorate muscle weakness and decreased spontaneous movement of Hyp mice

Aono

Higuchi

Yamazaki

et al. 2010

Journal of Bone and Mineral Research

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102

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Fibroblast growth factor 23 (FGF-23) plays causative roles in the development of several hypophosphatemic rickets/osteomalacia such as X-linked hypophosphatemic rickets/osteomalacia (XLH) and tumor-induced rickets/osteomalacia. Patients with hypophosphatemic rickets/osteomalacia often complain of muscle weakness and bone pain that severely affect daily activities of these patients. The purpose of this study was to examine whether anti-FGF-23 antibodies, which have been shown to improve hypophosphatemia and rachitic changes of juvenile Hyp mice in a murine model of XLH, also ameliorate hypophosphatemic osteomalacia and affect muscle force and spontaneous motor activity in adult Hyp mice. Repeated injections of anti-FGF-23 antibodies increased serum phosphate and 1,25-dihydroxyvitmain D levels and enhanced mineralization of osteoid in adult Hyp mice, whereas bone length did not change. We found that grip strength was weaker and that spontaneous movement was less in adult Hyp mice than in wild-type mice. In addition, FGF-23 antibodies increased grip strength and spontaneous movement. These results suggest that the inhibition of excess FGF-23 action not only ameliorates hypophosphatemia and impaired mineralization of bone but also improves muscle weakness and daily activities of patients with FGF-23-related hypophosphatemic rickets/osteomalacia. ß

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“…Recently, it has additionally been reported that FGF23 plays a central role in the development of hypophosphatemia and inappropriately low 1,25(OH) 2 D induced by iron therapy for iron-deficiency anemia [21,22]. Although the exact mechanism remains unclear, it is suggested that treatment with saccharated ferric oxide stimulates FGF23 secretion, thereby increasing the urinary phosphorus excretion and reducing the production of 1,25(OH) 2 D. Hemodialysis patients often develop iron-deficiency anemia and receive intravenous administration of saccharated ferric oxide [23,24].…”

Section: Introductionmentioning

confidence: 99%

Effect of Intravenous Saccharated Ferric Oxide on Serum FGF23 and Mineral Metabolism in Hemodialysis Patients

et al. 2011

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Background/Aims: Fibroblast growth factor-23 (FGF23) plays a central role in the development of hypophosphatemia and inappropriately low 1,25-dihydroxyvitamin D induced by iron therapy for iron-deficiency anemia. The aim of this study was to examine the effect of intravenous saccharated ferric oxide on serum FGF23 levels and mineral metabolism in hemodialysis patients. Methods: This prospective study enrolled 27 hemodialysis patients who had iron-deficiency anemia defined by a hemoglobin concentration <10.5 g/dl and serum ferritin <100 ng/ml. Intravenous saccharated ferric oxide at a dose of 40 mg was administered three times weekly over 3 weeks. The dose of active vitamin D and phosphate binders was kept unchanged. Serum FGF23, intact parathyroid hormone (PTH) and other parameters were prospectively monitored for 5 weeks. Results: Serum FGF23 levels were markedly elevated [3,453 (338–6,383) pg/ml] at baseline. After 3 weeks of intravenous saccharated ferric oxide treatment, serum FGF23 further increased to 4,701 (1,251–14,396) pg/ml, and returned to the baseline values after 2 weeks of observation. There was also a significant decrease in intact PTH but no changes in serum calcium and phosphorus. Conclusions: Intravenous saccharated ferric oxide induces further increase in elevated FGF23 levels in hemodialysis patients. This increase does not induce hypophosphatemia and inappropriately low 1,25-dihydroxyvitamin D in the absence of functioning kidney, but may result in transient PTH suppression – possibly by directly acting on the parathyroid.

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Hypophosphatemia induced by intravenous administration of saccharated ferric oxide

Cited by 132 publications

References 21 publications

Iron deficiency drives an autosomal dominant hypophosphatemic rickets (ADHR) phenotype in fibroblast growth factor-23 (Fgf23) knock-in mice

Iron deficiency drives an autosomal dominant hypophosphatemic rickets (ADHR) phenotype in fibroblast growth factor-23 (Fgf23) knock-in mice

Anti-FGF-23 neutralizing antibodies ameliorate muscle weakness and decreased spontaneous movement of Hyp mice

Effect of Intravenous Saccharated Ferric Oxide on Serum FGF23 and Mineral Metabolism in Hemodialysis Patients

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