Risk of fractures according to iron parameters and hemochromatosis <i>HFE</i> genotype in 142,146 general population individuals

Risk of fractures may be increased in individuals with iron deficiency, iron overload, and/or HFE hemochromatosis. To test this hypothesis, we followed 142,146 Danish general population individuals for a median of 11 years (range:0-41) after study enrolment for hospital and emergency room admissions with fractures. All individuals had blood samples drawn at study enrolment. We measured iron, transferrin saturation, and ferritin in 136,611, 136,555, and 37,990 individuals, respectively, while 132,499 individuals were genotyped for the HFE C282Y and H63D variants. We found a U-shaped relationship between fracture risk and concentrations of plasma iron and transferrin saturation when studying all individuals irrespective of genotype. When studied according to plasma ferritin, fracture risk was increased in individuals with low ferritin concentrations, while risk was not increased in individuals with high concentrations. When compared to non-carriers, HFE C282Y homozygotes had increased risk of any fracture (hazard ratio[HR]:1.38;95%CI:1.09-1.75;p=0.008), and risk was increased even in C282Y homozygotes with normal ferritin concentrations (HR:2.89;95%CI:1.50-5.56), which is important as these individuals would not usually be recommended for HFE genotyping according to clinical guidelines. When compared to non-carriers, risk of fracture of the hip and femur was increased in C282Y homozygotes (HR:1.78;95%CI:1.17-2.70;p=0.007) but surprisingly also in H63D homozygotes (HR:1.21;95%CI:1.00-1.47;p=0.04), C282Y heterozygotes (HR:1.10;95%CI:1.00-1.21;p=0.04), and C282Y/H63D compound heterozygotes (HR:1.23;95%CI:1.00-1.51;p=0.05). The markedly increased fracture risk in C282Y homozygotes with normal ferritin may challenge the presumption that systemic iron accumulation is the primary mechanism causing their increased fracture risk. Further studies are needed to examine whether phlebotomy reduces fracture risk.