Clinical bottom line
Anti-Fibroblast Growth Factor 23 (FGF23) therapies represent a promising, yet still investigational, approach to managing Chronic Kidney Disease-Mineral and Bone Disorder (CKD-MBD), a complex systemic condition characterized by disrupted mineral metabolism, bone abnormalities, and vascular calcification. Elevated FGF23 levels are implicated in CKD progression and cardiovascular morbidity, suggesting that targeted modulation of FGF23 signaling could improve clinical outcomes. Current evidence remains preliminary and hypothesis-generating, warranting cautious interpretation and further validation before routine clinical adoption.
What the evidence shows
CKD-MBD encompasses a spectrum of mineral metabolism disturbances, including abnormalities in calcium, phosphate, parathyroid hormone (PTH), vitamin D, and FGF23 homeostasis, contributing to renal osteodystrophy and cardiovascular complications (Igor et al., 2012; Moe et al., 2010). FGF23, a bone-derived hormone, rises early in CKD and acts to reduce phosphate reabsorption and suppress vitamin D activation, but chronically elevated levels are associated with left ventricular hypertrophy, vascular calcification, and increased mortality (Fish et al., 2014; Fish et al., 2022).
Recent preclinical and early-phase clinical studies have explored anti-FGF23 antibodies and receptor antagonists as potential therapies to mitigate CKD-MBD manifestations. These agents aim to normalize phosphate metabolism and reduce FGF23-mediated toxicity. For example, experimental models demonstrate that FGF23 blockade can improve bone mineralization and reduce cardiac hypertrophy, although effects on serum phosphate levels require careful monitoring to avoid hyperphosphatemia (Alatawi et al., 2026).
Clinical data remain limited. Small cohort studies and early trials suggest that selective inhibition of FGF23 signaling may ameliorate bone disease and cardiovascular parameters in CKD patients, but the risk of disrupting phosphate balance and inducing vascular calcification is a significant concern (Shroff et al., 2021; Bakkaloglu et al., 2010). Moreover, the heterogeneity of CKD-MBD pathophysiology across CKD stages and patient populations complicates therapeutic targeting.
Caveats and uncertainty
The therapeutic targeting of FGF23 in CKD-MBD is still in an early investigational phase with several unresolved issues:
- Safety concerns: FGF23 blockade may precipitate hyperphosphatemia, accelerating vascular calcification and worsening cardiovascular risk, necessitating stringent biochemical monitoring (Fish et al., 2014).
- Patient selection: The optimal CKD stage and patient phenotype for intervention remain undefined, as FGF23 levels and mineral metabolism disturbances vary widely (Igor et al., 2012).
- Long-term outcomes: There is a lack of robust randomized controlled trials assessing the impact of anti-FGF23 therapies on hard clinical endpoints such as fracture risk, cardiovascular events, or mortality.
- Interaction with existing therapies: How anti-FGF23 agents integrate with current CKD-MBD management, including phosphate binders, vitamin D analogs, and calcimimetics, is unclear.
- Pediatric considerations: CKD-MBD in children presents unique challenges, and data on anti-FGF23 therapies in this population are sparse (Bakkaloglu et al., 2010; Shroff et al., 2021).
How this may change practice
If ongoing and future studies confirm safety and efficacy, anti-FGF23 therapies could become a novel adjunct in CKD-MBD management, particularly for patients with refractory mineral metabolism abnormalities and high cardiovascular risk. Clinicians may need to incorporate FGF23 level monitoring into routine practice and tailor treatment regimens to balance phosphate control with mitigation of FGF23-related toxicity.
However, given current evidence limitations, these therapies should remain within clinical trial settings or specialized centers until more definitive data emerge. Awareness of the complex interplay between FGF23, phosphate, and bone health is essential to avoid unintended harm. Multidisciplinary collaboration involving nephrologists, endocrinologists, and cardiologists will be critical for integrating these agents into comprehensive CKD care.