Why Measure Both Intact and C-Terminal FGF23?

FGF23 is an endocrine bone derived hormone that regulates phosphate homeostasis by modulating renal phosphate reabsorption, vitamin D metabolism, and parathyroid hormone (PTH) secretion. Elevated circulating levels of active vitamin D, calcium, and parathyroid hormone levels stimulate FGF23 production in bone. FGF23 then acts on the kidneys by binding to FGF receptors in conjunction with the co-receptor α-Klotho, promoting urinary phosphate excretion and lowering circulating 1,25(OH)₂D levels (1). These mineral-related stimuli promote the production and release of full-length, biologically active FGF23 by osteocytes. Once in circulation, intact FGF23 binds to FGF receptor 1–α-Klotho co-receptor complexes in the kidney to regulate mineral homeostasis (2).

FGF23 can also undergo cleavage, producing N-terminal and C-terminal fragments. C-terminal fragments can be measured in the bloodstream, whereas circulating N-terminal fragments cannot currently be assessed because a suitable measurement method is not available (3).

Epidemiological studies have linked elevated FGF23 concentrations to increased all-cause and cardiovascular mortality, as well as a greater risk of myocardial infarction, stroke, and heart failure (3, 4).

Why Measure Both Intact and C-Terminal FGF23?

Both circulating FGF23 concentrations and the ratio of intact FGF23 to its C-terminal fragments can be altered in genetic and acquired disorders. A primary excess of circulating intact FGF23 underlies conditions such as X-linked hypophosphatemia (XLH), autosomal dominant and autosomal recessive hypophosphatemic rickets (ADHR/ARHR), and tumor-induced osteomalacia. In these disorders, excessive FGF23 activity leads to renal phosphate wasting, reduced concentrations of active vitamin D, and impaired bone mineralization (4, 5).

In iron deficiency, by contrast, FGF23 synthesis and cleavage increase in parallel, resulting in normal intact FGF23 concentrations but elevated concentrations of C-terminal fragments (5). In a 2023 study published in Blood, Courbon et al. explored why bone cells produce more FGF23 during iron deficiency, only to quickly break it down (6). They found that the resulting C-terminal fragments help regulate iron levels. During inflammation-related iron deficiency, these fragments lower hepcidin, a hormone that limits iron absorption and availability. This feedback mechanism helps the body absorb and use more iron.

These differences highlight how measuring both intact and C-terminal FGF23 can help characterize condition-specific changes in FGF23 production and processing. Both intact FGF23 and its cleavage products can exert biological effects.

How can FGF23 be measured? 

Currently, two types of ELISA are used to assess circulating FGF23. The intact FGF23 (iFGF23) assay uses antibodies targeting the N- and C-terminal regions to selectively measure the intact molecule. In contrast, the C-terminal FGF23 (cFGF23) assay uses two antibodies targeting the C-terminal region and detects both intact FGF23 and its C-terminal cleavage products.

The cFGF23 assay therefore provides a combined measure of intact FGF23 and C-terminal fragments, rather than measuring cleaved fragments alone. If cleavage generates equal amounts of N- and C-terminal fragments, this measurement reflects both intact and cleaved FGF23.

iFGF23/cFGF23 ratio serves as an indirect indicator of the extent of FGF23 cleavage

Measuring both parameters is becoming increasingly important as emerging studies highlight the distinct biological roles of intact FGF23 and its cleavage products (3). To date, there is no commercially available solution to directly measure the N-terminal peptide alone. The ratio between the two measurements, iFGF23/cFGF23 or sometimes cFGF23/iFGF23, compares the intact and total forms, and is considered as an indicator of the cleavage rate (3).

A growing body of evidence shows that iFGF23 and cFGF23 are not always coupled and not always as efficient depending on the condition observed, supported by recent studies comparing the respective merits of measuring iFGF23 and cFGF23 in humans (3, 7, 8).  Instead, iFGF23 and cFGF23 could reflect different biological functions and different pathological features (3) and a combined use of both cFGF23 and iFGF23 will improve our understanding of mineral and non-mineral metabolism (3).

BIOMEDICA FGF23 intact ELISA Assay Kit (cat. no. BI-20700)

 

Image of the antibody pairs used in the BIOMEDICA FGF23 intact ELISA assay (cat. no. BI-20700)

 

BIOMEDICA FGF23 (C-terminal) ELISA Assay Kit (cat. no. BI-20702)

OF NOTE: all FGF23 c-terminal assays that are commercially available detect both c-terminal FGF23 fragments as well as the intact FGF23 molecule (9).

FGF23 intact ELISA (cat. no.BI-20700) and FGF23 (C-terminal) (cat. no. BI-20702)

• RELIABLE – Validated following international quality guidelines
• TRUSTED – Cited in over100 publications
• EASY – 8 standards and 2 controls included
• FLEXIBLE – For SERUM & PLASMA samples

 

The FGF 23 ELISA Assays are Developed & Manufactured by BIOMEDICA

 Literature: 

1. Regulation of FGF23 production and phosphate metabolism by bone-kidney interactions. Agoro R, White KE. Nat Rev Nephrol. 2023 Mar;19(3):185-193. doi: 10.1038/s41581-022-00665-x. Epub 2023 Jan 9. PMID: 36624273.
2. FGF23 factories in iron deficiency and anemia of CKD. Wolf M. Blood. 2026 Aug 27;148(9):1079-1080. doi: 10.1182/blood.2026034346. PMID: 42658520.
3. FGF23: A player not only in bone diseases. Cifuentes A, Laskar-Marchesseau Z, Courbon G. Joint Bone Spine. 2026 Mar;93(2):105988. doi: 10.1016/j.jbspin.2025.105988. Epub 2025 Oct 6. PMID: 41062019.
4. Regulation of FGF23: Beyond Bone. Simic P, Babitt JL. Curr Osteoporos Rep. 2021 Dec;19(6):563-573. doi: 10.1007/s11914-021-00703-w. Epub 2021 Nov 10. PMID: 34757587; PMCID: PMC8958553.
5. Coupling fibroblast growth factor 23 production and cleavage: iron deficiency, rickets, and kidney disease. Wolf M, White KE. Curr Opin Nephrol Hypertens. 2014 Jul;23(4):411-9. doi: 10.1097/01.mnh.0000447020.74593.6f. PMID: 24867675; PMCID: PMC4322859.
6. Bone-derived C-terminal FGF23 cleaved peptides increase iron availability in acute inflammation. Courbon G, Thomas JJ, Martinez-Calle M, Wang X, Spindler J, Von Drasek J, Hunt-Tobey B, Mehta R, Isakova T, Chang W, Creemers JWM, Ji P, Martin A, David V.Blood. 2023 Jul 6;142(1):106-118. doi: 10.1182/blood.2022018475. PMID: 37053547; PMCID: PMC10356820.
7. C-terminal and intact FGF23 in kidney transplant recipients and their associations with overall graft survival. Chu C, Elitok S, Zeng S, Xiong Y, Hocher CF, Hasan AA, Krämer BK, Hocher B. BMC Nephrol. 2021 Apr 8;22(1):125. doi: 10.1186/s12882-021-02329-7. PMID: 33832449; PMCID: PMC8033679.
8. Determination of FGF23 Levels for the Diagnosis of FGF23-Mediated Hypophosphatemia. Hartley IR, Gafni RI, Roszko KL, Brown SM, de Castro LF, Saikali A, Ferreira CR, Gahl WA, Pacak K, Blau JE, Boyce AM, Salusky IB, Collins MT, Florenzano P.J Bone Miner Res. 2022 Nov;37(11):2174-2185. doi: 10.1002/jbmr.4702. Epub 2022 Oct 17. PMID: 36093861; PMCID: PMC9712269.
9. The Measurement and Interpretation of Fibroblast Growth Factor 23 (FGF23) Concentrations. Calcif Tissue Int. Heijboer AC, Cavalier E. 2023 Feb;112(2):258-270. PMID: 35665817; PMCID: PMC9859838.