Iron, inflammation, and fibroblast growth factor 23: Integrating molecular crosstalk, cardiovascular biology, and therapeutic perspectives

Table 5 Clinical trials informing iron treatment and fibroblast growth factor 23 modulation

Ref.	Design and population	Intervention	Findings and limits
FIRM[16]	Randomized double-blind trial; 1997 adults with iron-deficiency anemia; 185 in the physiological substudy; follow-up to week 5	Ferric carboxymaltose 750 mg vs ferumoxytol 510 mg, administered intravenously at baseline and week 1	Hypophosphatemia < 2.0 mg/dL: 50.8% vs 0.9% over 5 weeks. Intact FGF23 rose after ferric carboxymaltose. Biochemical and mechanistic outcomes; no cardiovascular efficacy inference
PHOSPHARE-IDA[17,99]	Two randomized open-label trials; 245 adults; reduced kidney function excluded; follow-up to day 35	Ferric derisomaltose 1000 mg once on day 0 vs ferric carboxymaltose 750 mg on days 0 and 7	Hypophosphatemia < 2.0 mg/dL through day 35: 7.9% vs 75.0% and 8.1% vs 73.7%. Severe or persistent hypophosphatemia occurred only with ferric carboxymaltose in the secondary analysis. Different total iron doses and short follow-up limit extrapolation
PHOSPHARE-IBD[100]	Randomized double-blind trial; 97 adults with inflammatory bowel disease and iron-deficiency anemia; follow-up to day 70; primary endpoint through day 35	Ferric derisomaltose vs ferric carboxymaltose: 1000 mg on day 0, followed by 500 or 1000 mg on day 35 according to calculated iron requirement	Hypophosphatemia < 2.0 mg/dL from baseline to day 35: 8.3% vs 51.0%; adjusted risk difference -42.8% (95%CI: -57.1% to -24.6%). Both corrected anemia. Longer-term clinical consequences remain uncertain
ExplorIRON-CKD[101]	Single-center randomized double-blind exploratory trial; 26 patients with CKD stages 3a-5; follow-up to 3 months	Ferric derisomaltose vs ferric carboxymaltose: 1000 mg at baseline, followed by 500-1000 mg at 1 month as required for iron repletion	Greater intact FGF23 rise and phosphate and calcitriol reduction with ferric carboxymaltose. Small mechanistic study, not powered for clinical events
AXLES-1[105]	Randomized double-blind placebo-controlled phase 3 trial; 134 adults with XLH; 24 weeks	Burosumab 1 mg/kg subcutaneously every 4 weeks vs placebo	Mean midpoint serum phosphate above the lower limit of normal: 94.1% vs 7.6%; fracture healing improved at week 24. Demonstrates efficacy in primary FGF23 excess, not CKD or cardiovascular disease
EVOLVE Biomarker analysis[107]	Secondary analysis of a randomized placebo-controlled trial in hemodialysis with secondary hyperparathyroidism; 2602 participants with paired baseline/week-20 samples	Cinacalcet 30-180 mg/day vs placebo, added to conventional treatment; dose titrated according to PTH and calcium	At least 30% FGF23 reduction by week 20: 68% vs 28%. Within the cinacalcet group, biomarker reduction was associated with fewer events; the secondary responder analysis does not establish causality

Trial acronyms identify the cited studies. Percentages are reported in the intervention order shown. Trials differ in eligibility, dosing, sampling, and endpoints and should not be compared as a pooled dataset. CI: Confidence interval; CKD: Chronic kidney disease; FGF23: Fibroblast growth factor 23; XLH: X-linked hypophosphatemia; PTH: Parathyroid hormone.