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A normal mineral metabolism is integral for skeletal development and preservation of bone integrity. Fibroblast growth factor 23 (FGF-23) is a bone-derived circulating factor that decreases serum concentrations of inorganic phosphorous (P(i)) and 1,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)]. Increased FGF-23 expression is a direct or indirect culprit in several skeletal disorders; however, the relation between FGF-23 and fracture risk remains undetermined. We evaluated the prospective relation between serum intact FGF-23 (measured by a two-site monoclonal antibody ELISA) and fracture risk employing the Swedish part of the population-based Osteoporotic Fractures in Men Study (MrOS; n = 2868; mean age 75.4 ± 3.2 years; median follow-up period 3.35 years). The incidence of at least one validated fracture after baseline was 20.4 per 1000 person-years. FGF-23 was directly related to the overall fracture risk [age-adjusted hazard ratio (HR) per SD increase = 1.20, 95% confidence interval (CI) 1.03-1.40] and vertebral fracture risk (HR = 1.33, 95% CI 1.02-1.75). Spline models revealed a nonlinear relation between FGF-23 and fracture risk, with the strongest relation at FGF-23 levels above 55.7 pg/mL. FGF-23 levels above 55.7 pg/mL also were associated with an increased risk for hip and nonvertebral fractures (HR = 2.30, 95% CI 1.16-4.58, and HR = 1.63, 95% CI 1.01-2.63, respectively). These relations remained essentially unaltered after adjustment for bodymass index (BMI), bone mineral density (BMD), glomerular filtration rate, 25(OH)(2)D(3), parathyroid hormone (PTH), and other fracture risk factors. In conclusion, FGF-23 is a novel predictor of fracture risk in elderly men.
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