Although current clinical studies are insufficient to support those findings and the hypothesis that FGF23 is independently associated with bone mineralization decline in the elderly and CKD-MBD, several clinical studies show that FGF23 has been a potential predictor for fragility fractures. High circulating FGF23 levels were discovered to be an independent risk factor for overall fragility fracture in elderly men [29]. Furthermore, the three aforementioned studies discovered an independent association between elevated FGF23 and the incidence of fragility fractures in both moderate CKD and ESRD patients [28,34,35]. Even though FGF23 levels had an independent negative relationship with BMD in postmenopausal women [1,4], it was not an effective discriminator between osteopenia/osteoporosis and normal bone mass [4]. In addition, utilizing the FGF23 level for osteoporosis prediction in hemodialysis patients resulted in poor discrimination [44]. Considering that various fragility fracture prediction models (e.g., the FRAX score, Q Fracture) are based on well-established clinical predictors (e.g., gender, BMI, CKD, alcohol, smoking, and corticosteroid use), there are currently no models that incorporate clinical predictors describing both systemic and local bone mineral homeostasis. The growing evidence indicates that FGF23 can represent the status of systemic bone mineral balance, renal function, and probably bone remodelling, thus the value-added of FGF23 on fragility fracture prediction awaits upcoming studies to explore its clinical potential to improve the prognostication of osteoporosis and CKD-MBD patients.

Since none of the commercially available FGF23 assays have been validated for clinical use, FGF23 is not presently applicable for routine clinical practices. For the measurement of FGF23, four immunoassays are commercially available: Immutopics (1st and 2nd generation, San Clemente, CA, USA), Kainos (Tokyo, Japan), Millipore (Billerica, MA, USA), and DiaSorin (Saluggia, Italy). The majority of assays detect the intact 251 amino acid protein (iFGF23) by simultaneously recognizing epitopes on the N- and C-terminal domains located near the proteolytic cleavage site. Additionally, Immutopics provides an assay that quantifies both iFGF23 and the C-terminal fragment (cFGF23) using two antibodies against two C-terminal epitopes. iFGF23 is measured in picograms per milliliter (pg./mL), with a normal reference range of 11.7–48.6 pg./mL in a healthy individual, whereas cFGF23 is reported in relative units (RU) per milliliter, with a normal reference range of 21.6–91.0 RU/mL [47]. Due to the possibility that iFGF23 may be degraded by protease enzyme or changed after venipuncture, two iFGF23 stability studies discovered decreasing FGF23 levels following an 8-h delay in centrifugation, but no evidence of deterioration after storing processed samples at −80 °C [48]. Biological variability studies in healthy individuals revealed that iFGF23 levels have a diurnal variation that peaks in the early morning and gradually declines during the day [47]. In comparison, the concentrations of cFGF23 could be slightly increased throughout the day [49] and see no significant change after dietary or phosphate intake [50]. Despite the stability and biological variability advantages of cFGF23, cFGF23 assays may be more applicable than iFGF23 assays, particularly for diagnostic and prognostic studies. In contrast, iFGF23 may outperform in representing the biological effects of FGF23 in etiognostic and therapeutic research because the c-terminal fragments might have counter-regulatory effects on the physiologically active FGF23 [51]. The schematic summary of FGF23 production and its measurement are illustrated in Figure 4.

5. Conclusions

A pivotal role of FGF23 was found in local and systemic bone remodelling with supraphysiological levels causing abnormal bone formation, although any direct effect on osteoblasts remains unclear as well as a controversial links between FGF23 with osteoclastogenesis and bone resorption. Current evidence from clinical studies indicates that FGF23 could be a risk factor of bone fragility in CKD-MBD, but not a major contributor to age-related osteoporosis. An increased FGF23 level may represent an abnormal state of bone mineral homeostasis, but is not a direct indicator of decreased BMD. Since clinical studies, both in healthy elderly and in patients with impaired renal function, showed that elevated FGF23 levels were an independent risk factor of fragility fracture, a future predictive model for fragility fracture may incorporate FGF23 as a factor to represent bone mineral homeostasis status. FGF23 is putative factor in the fragility of CKD-MBD, less so in age-related bone loss; future elucidation of pathogenesis requires remodelling biomarkers, while gender differences need elucidation with respect to abnormal bone mineral homeostasis and reduced BMD as part of a future model of fragility risk factors.