Effects of iron deficiency anemia and its treatment on fibroblast growth factor 23 and phosphate homeostasis in women.
01 Aug 2013-Journal of Bone and Mineral Research (John Wiley & Sons, Ltd)-Vol. 28, Iss: 8, pp 1793-1803
TL;DR: It is proposed that intravenous iron lowers cF GF23 in humans by reducing fgf23 transcription as it does in mice, whereas carbohydrate moieties in certain iron preparations may simultaneously inhibit FGF23 degradation in osteocytes leading to transient increases in iFGF23 and reduced serum phosphate.
Abstract: Fibroblast growth factor 23 (FGF23) is an osteocyte-derived hormone that regulates phosphate and vitamin D homeostasis. Through unknown mechanisms, certain intravenous iron preparations induce acute, reversible increases in circulating FGF23 levels that lower serum phosphate in association with inappropriately low levels of calcitriol, similar to genetic diseases of primary FGF23 excess. In contrast, studies in wild-type mice suggest that iron deficiency stimulates fgf23 transcription but does not result in hypophosphatemia because FGF23 is cleaved within osteocytes by an unknown catabolic system. We tested the association of iron deficiency anemia with C-terminal FGF23 (cFGF23) and intact FGF23 (iFGF23) levels in 55 women with a history of heavy uterine bleeding, and assessed the longitudinal biochemical response over 35 days to equivalent doses of randomly-assigned, intravenous elemental iron in the form of ferric carboxymaltose (FCM) or iron dextran. Iron deficiency was associated with markedly elevated cFGF23 (807.8 ± 123.9 relative units [RU]/mL) but normal iFGF23 (28.5 ± 1.1 pg/mL) levels at baseline. Within 24 hours of iron administration, cFGF23 levels fell by approximately 80% in both groups. In contrast, iFGF23 transiently increased in the FCM group alone, and was followed by a transient, asymptomatic reduction in serum phosphate <2.0 mg/dL in 10 women in the FCM group compared to none in the iron dextran group. Reduced serum phosphate was accompanied by increased urinary fractional excretion of phosphate, decreased calcitriol levels, and increased parathyroid hormone levels. These findings suggest that iron deficiency increases cFGF23 levels, and that certain iron preparations temporarily increase iFGF23 levels. We propose that intravenous iron lowers cFGF23 in humans by reducing fgf23 transcription as it does in mice, whereas carbohydrate moieties in certain iron preparations may simultaneously inhibit FGF23 degradation in osteocytes leading to transient increases in iFGF23 and reduced serum phosphate.
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TL;DR: Simultaneous upregulation of F GF23 cleavage in osteocytes maintains near-normal levels of biologically active, intact circulating FGF23, whereas downregulated or impaired FGF24 cleavage may contribute to elevated intact serum FGF 23 in CKD.
367 citations
13 Jul 2017
TL;DR: The recent identification of a fusion of fibronectin and fibroblast growth factor receptor 1 (FGFR1) as a molecular driver in some tumours sheds light on the pathophysiology of TIO and opens the door to a better understanding of the transcription, translocation, post-translational modification and secretion of FGF23.
Abstract: Tumour-induced osteomalacia (TIO), also known as oncogenic osteomalacia, is a rare paraneoplastic disorder caused by tumours that secrete fibroblast growth factor 23 (FGF23). Owing to the role of FGF23 in renal phosphate handling and vitamin D synthesis, TIO is characterized by decreased renal tubular reabsorption of phosphate, by hypophosphataemia and by low levels of active vitamin D. Chronic hypophosphataemia ultimately results in osteomalacia (that is, inadequate bone mineralization). The diagnosis of TIO is usually suspected when serum phosphate levels are chronically low in the setting of bone pain, fragility fractures and muscle weakness. Locating the offending tumour can be very difficult, as the tumour is often very small and can be anywhere in the body. Surgical removal of the tumour is the only definitive treatment. When the tumour cannot be located or when complete resection is not possible, medical treatment with phosphate salts or active vitamin D is necessary. One of the most promising emerging treatments for unresectable tumours that cause TIO is the anti-FGF23 monoclonal antibody KRN23. The recent identification of a fusion of fibronectin and fibroblast growth factor receptor 1 (FGFR1) as a molecular driver in some tumours not only sheds light on the pathophysiology of TIO but also opens the door to a better understanding of the transcription, translocation, post-translational modification and secretion of FGF23, as well as suggesting approaches to targeted therapy. Further study will reveal if the FGFR1 pathway is also involved in tumours that do not harbour the translocation.
177 citations
TL;DR: A deeper understanding of the relationships between FGF23 regulation, iron homeostasis and erythropoiesis can be leveraged to devise novel therapeutic targets for treatment of anaemia and states of F GF23 excess, including chronic kidney disease.
Abstract: Fibroblast growth factor 23 (FGF23) was initially characterized as an important regulator of phosphate and calcium homeostasis. New research advances demonstrate that FGF23 is also linked to iron economy, inflammation and erythropoiesis. These advances have been fuelled, in part, by the serendipitous development of two distinct FGF23 assays that can substitute for invasive bone biopsies to infer the activity of the three main steps of FGF23 regulation in bone: transcription, post-translational modification and peptide cleavage. This 'liquid bone biopsy for FGF23 dynamics' enables large-scale longitudinal studies of FGF23 regulation that would otherwise be impossible in humans. The balance between FGF23 production, post-translational modification and cleavage is maintained or perturbed in different hereditary monogenic conditions and in acquired conditions that mimic these genetic disorders, including iron deficiency, inflammation, treatment with ferric carboxymaltose and chronic kidney disease. Looking ahead, a deeper understanding of the relationships between FGF23 regulation, iron homeostasis and erythropoiesis can be leveraged to devise novel therapeutic targets for treatment of anaemia and states of FGF23 excess, including chronic kidney disease.
146 citations
TL;DR: In 2 randomized trials of patients with iron-deficiency anemia who were intolerant of or unresponsive to oral iron, iron isomaltoside (now called ferric derisomaltose), compared with ferric carboxymaltose, resulted in lower incidence of hypophosphatemia over 35 days, but further research is needed to determine the clinical importance of this difference.
Abstract: Importance Intravenous iron enables rapid correction of iron-deficiency anemia, but certain formulations induce fibroblast growth factor 23–mediated hypophosphatemia. Objective To compare risks of hypophosphatemia and effects on biomarkers of mineral and bone homeostasis of intravenous iron isomaltoside (now known as ferric derisomaltose) vs ferric carboxymaltose. Design, Setting, and Participants Between October 2017 and June 2018, 245 patients aged 18 years and older with iron-deficiency anemia (hemoglobin level ≤11 g/dL; serum ferritin level ≤100 ng/mL) and intolerance or unresponsiveness to 1 month or more of oral iron were recruited from 30 outpatient clinic sites in the United States into 2 identically designed, open-label, randomized clinical trials. Patients with reduced kidney function were excluded. Serum phosphate and 12 additional biomarkers of mineral and bone homeostasis were measured on days 0, 1, 7, 8, 14, 21, and 35. The date of final follow-up was June 19, 2018, for trial A and May 29, 2018, for trial B. Interventions Intravenous administration of iron isomaltoside, 1000 mg, on day 0 or ferric carboxymaltose, 750 mg, infused on days 0 and 7. Main Outcomes and Measures The primary end point was the incidence of hypophosphatemia (serum phosphate level Results In trial A, 123 patients were randomized (mean [SD] age, 45.1 [11.0] years; 95.9% women), including 62 to iron isomaltoside and 61 to ferric carboxymaltose; 95.1% completed the trial. In trial B, 122 patients were randomized (mean [SD] age, 42.6 [12.2] years; 94.1% women), including 61 to iron isomaltoside and 61 to ferric carboxymaltose; 93.4% completed the trial. The incidence of hypophosphatemia was significantly lower following iron isomaltoside vs ferric carboxymaltose (trial A: 7.9% vs 75.0% [adjusted rate difference, –67.0% {95% CI, –77.4% to –51.5%}],P Conclusions and Relevance In 2 randomized trials of patients with iron-deficiency anemia who were intolerant of or unresponsive to oral iron, iron isomaltoside (now called ferric derisomaltose), compared with ferric carboxymaltose, resulted in lower incidence of hypophosphatemia over 35 days. However, further research is needed to determine the clinical importance of this difference. Trial Registration ClinicalTrials.gov Identifiers:NCT03238911andNCT03237065
142 citations
TL;DR: These findings uncover a second level of FGF23 regulation within osteocytes, failure of which culminates in elevated levels of biologically active FGF 23 in ADHR and perhaps CKD.
Abstract: Purpose of reviewHigh levels of fibroblast growth factor 23 (FGF23) cause the rare disorders of hypophosphatemic rickets and are a risk factor for cardiovascular disease and death in patients with chronic kidney disease (CKD). Despite major advances in understanding FGF23 biology, fundamental aspect
132 citations
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TL;DR: Increased FGF-23 levels appear to be independently associated with mortality among patients who are beginning hemodialysis treatment, and a potential biomarker that can be used to guide strategies for the management of phosphorus balance in patients with chronic kidney disease is investigated.
Abstract: BACKGROUND Fibroblast growth factor 23 (FGF-23) is a hormone that increases the rate of urinary excretion of phosphate and inhibits renal production of 1,25-dihydroxyvitamin D, thus helping to mitigate hyperphosphatemia in patients with kidney disease. Hyperphosphatemia and low 1,25-dihydroxyvitamin D levels are associated with mortality among patients with chronic kidney disease, but the effect of the level of FGF-23 on mortality is unknown. METHODS We examined mortality according to serum phosphate levels in a prospective cohort of 10,044 patients who were beginning hemodialysis treatment and then analyzed FGF-23 levels and mortality in a nested case-control sample of 200 subjects who died and 200 who survived during the first year of hemodialysis treatment. We hypothesized that increased FGF-23 levels at the initiation of hemodialysis would be associated with increased mortality. RESULTS Serum phosphate levels in the highest quartile (>5.5 mg per deciliter [1.8 mmol per liter]) were associated with a 20% increase in the multivariable adjusted risk of death, as compared with normal levels (3.5 to 4.5 mg per deciliter [1.1 to 1.4 mmol per liter]) (hazard ratio, 1.2; 95% confidence interval [CI], 1.1 to 1.4). Median C-terminal FGF-23 (cFGF-23) levels were significantly higher in case subjects than in controls (2260 vs. 1406 reference units per milliliter, P<0.001). Multivariable adjusted analyses showed that increasing FGF-23 levels were associated with a monotonically increasing risk of death when examined either on a continuous scale (odds ratio per unit increase in log-transformed cFGF-23 values, 1.8; 95% CI, 1.4 to 2.4) or in quartiles, with quartile 1 as the reference category (odds ratio for quartile 2, 1.6 [95% CI, 0.8 to 3.3]; for quartile 3, 4.5 [95% CI, 2.2 to 9.4]; and for quartile 4, 5.7 [95% CI, 2.6 to 12.6]). CONCLUSIONS Increased FGF-23 levels appear to be independently associated with mortality among patients who are beginning hemodialysis treatment. Future studies might investigate whether FGF-23 is a potential biomarker that can be used to guide strategies for the management of phosphorus balance in patients with chronic kidney disease.
1,524 citations
TL;DR: It is concluded that overproduction of F GF23 causes TIO, whereas mutations in the FGF23 gene result in autosomal dominant hypophosphatemic rickets possibly by preventing proteolytic cleavage and enhancing biological activity of FGF 23.
Abstract: Tumor-induced osteomalacia (TIO) is one of the paraneoplastic diseases characterized by hypophosphatemia caused by renal phosphate wasting. Because removal of responsible tumors normalizes phosphate metabolism, an unidentified humoral phosphaturic factor is believed to be responsible for this syndrome. To identify the causative factor of TIO, we obtained cDNA clones that were abundantly expressed only in a tumor causing TIO and constructed tumor-specific cDNA contigs. Based on the sequence of one major contig, we cloned 2,270-bp cDNA, which turned out to encode fibroblast growth factor 23 (FGF23). Administration of recombinant FGF23 decreased serum phosphate in mice within 12 h. When Chinese hamster ovary cells stably expressing FGF23 were s.c. implanted into nude mice, hypophosphatemia with increased renal phosphate clearance was observed. In addition, a high level of serum alkaline phosphatase, low 1,25-dihydroxyvitamin D, deformity of bone, and impairment of body weight gain became evident. Histological examination showed marked increase of osteoid and widening of growth plate. Thus, continuous production of FGF23 reproduced clinical, biochemical, and histological features of TIO in vivo. Analyses for recombinant FGF23 products produced by Chinese hamster ovary cells indicated proteolytic cleavage of FGF23 at the RXXR motif. Recent genetic study indicates that missense mutations in this RXXR motif of FGF23 are responsible for autosomal dominant hypophosphatemic rickets, another hypophosphatemic disease with similar features to TIO. We conclude that overproduction of FGF23 causes TIO, whereas mutations in the FGF23 gene result in autosomal dominant hypophosphatemic rickets possibly by preventing proteolytic cleavage and enhancing biological activity of FGF23.
1,290 citations
"Effects of iron deficiency anemia a..." refers background in this paper
...Third, certain iron preparations could induce ectopic production of FGF23 by other organs that are involved in iron metabolism and have the capacity to express FGF23, including the liver and lymphatic system.((25)) Additional mechanistic studies are needed to investigate these hypotheses....
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01 Jan 2001
1,187 citations
TL;DR: Circulating FGF-23 was significantly elevated in patients with CKD and its concentration correlated with renal creatinine clearance, and in healthy volunteers, F GF-23 levels did not change after phosphate deprivation or phosphate loading.
657 citations
531 citations
"Effects of iron deficiency anemia a..." refers background in this paper
...The first novel finding is that iron deficiency anemia is associated with normal iFGF23 but markedly elevated cFGF23 levels to an extent rarely seen except in renal failure or hereditary rachitic diseases.((23)) Second, rapid correction of iron deficiency with different intravenous iron preparations reduced cFGF23 levels by approximately 80% within 24 hours....
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