Risk of Fractures in Individuals with Hemochromatosis HFE C282Y Homozygosity and in Individuals with Low or High Levels of Plasma Iron, Transferrin Saturation, or Ferritin: A Prospective Study of 142,146 General Population Individuals
Authors: Helby Jens , Warny Marie , Bojesen Stig Egil , Nordestgaard Boerge Groenne , Petersen Jesper , Ellervik Christina , Glenthoej Andreas 
Published: December 2024

Background:
Iron deficiency and/or iron overload may possibly increase risk of osteoporotic bone fractures. Therefore, we tested the hypothesis that for all individuals irrespective of HFE genotype, low and high levels of plasma iron, transferrin saturation, and ferritin are associated with increased risk of fractures. Furthermore, we tested whether individuals with hemochromatosis HFE C282Y homozygosity had increased risk of fractures even when having normal levels of plasma iron, transferrin saturation, or ferritin.
Methods:
We studied 142,146 individuals from three prospective cohorts of the Danish general population: The Copenhagen City Heart Study, the Copenhagen General Population Study, and the Danish General Suburban Population Study. All individuals attended a health examination and had blood samples drawn at study enrolment. HFE was genotyped for the C282Y and H63D variants in 132,525 individuals, while plasma iron, transferrin saturation, and ferritin were measured in 136,638, 136,582, and 37,990 individuals, respectively. After study enrolment, individuals were followed prospectively for a median of 11 years (range 0-41 years) for hospital admissions and emergency room visits due to fractures using the Danish National Patient Register, covering all hospitals in Denmark. Multivariable models were adjusted for potential risk factors for fractures including age, sex, study cohort, smoking status, cumulative smoking in pack-years, alcohol intake, body mass index, Charlson comorbidity index, C-reactive protein level, and menopausal status (women only).
Results:
During follow-up, 18,611 individuals were hospitalized with any fracture. When studying all individuals irrespective of genotype, risk of any fracture was increased in individuals with low plasma iron (multivariable adjusted hazard ratio [HR] 1.19;95%CI 1.09-1.30;P&lt;0.001 for iron at or below the 5th percentile compared to the 26-74th percentile), high plasma iron (HR 1.14;95%CI 1.03-1.25;P=0.008 for iron at or above the 95th percentile compared to the 26-74th percentile), low transferrin saturation (HR 1.22;95%CI 1.11-1.33;P&lt;0.001 for transferrin saturation at or below the 5th percentile), or high transferrin saturation (HR 1.24;95%CI 1.13-1.36;P&lt;0.001 for transferrin saturation at or above the 95th percentile). Similarly, risk of any fracture was increased in individuals with low ferritin (HR 1.23;95%CI 1.05-1.43;P=0.01 for ferritin at or below the 5th percentile), while risk was not increased in individuals with high ferritin (HR 1.08;95%CI 0.91-1.28;P=0.39 for ferritin at or above the 95th percentile).
When studying risk of fractures according to hemochromatosis HFE genotype, individuals with C282Y homozygosity had increased risk of any fracture (age and sex adjusted HR 1.38;95%CI 1.09-1.75;P=0.008 for C282Y homozygotes compared to non-carriers for C282Y and H63D) and fractures of the hip and femur (HR 1.78;95%CI 1.17-2.70;P=0.007). Even C282Y homozygotes with normal levels of ferritin had markedly increased risk of any fracture (HR 2.89;95%CI 1.50-5.56;P=0.001 for C282Y homozygotes with normal ferritin vs non-carriers with normal ferritin), while risk of any fracture was not increased in C282Y homozygotes with normal plasma iron or transferrin saturation. The increased risk of any fracture was also observed in C282Y homozygotes not diagnosed with diabetes or liver disease at any time before or after study enrolment. Likewise, risk of any fracture was increased in C282Y homozygotes not diagnosed with hemochromatosis at a hospital at any time before or after study enrolment.
Conclusions:
Risk of any fracture was increased in individuals with low or high iron, low or high transferrin saturation, or low ferritin when studying all individuals irrespective of HFE genotype. Hemochromatosis C282Y homozygotes had increased risk of any fracture and increased risk of fractures of the hip and femur. Importantly, even C282Y homozygotes with normal levels of ferritin had markedly increased risk of any fracture, meaning that fracture risk was increased in this subgroup of C282Y homozygotes who would usually not be recommended for HFE genotyping according to clinical guidelines. These results suggest that the current treatment strategy for hemochromatosis focusing on lowering ferritin levels through therapeutic phlebotomy may not sufficiently reduce risk of fractures in C282Y homozygotes.