Iron absorption from oral iron supplements given on consecutive versus alternate days and as single morning doses versus twice-daily split dosing in iron-depleted women: two open-label, randomised controlled trials

Background Current guidelines to treat iron deficiency recommend daily provision of ferrous iron divided through the day to increase absorption. However, daily dosing and split dosing might increase serum hepcidin and decrease iron absorption from subsequent doses. Our study aim was to compare iron absorption from oral iron supplements given on consecutive versus alternate days and given as single morning doses versus twice-daily split dosing. Methods We did two prospective, open-label, randomised controlled trials assessing iron absorption using (Fe-54)-labelled, (Fe-57)-labelled, or (Fe-58)-labelled ferrous sulfate in iron-depleted (serum ferritin <= 25 mu g/L) women aged 18-40 years recruited from ETH Zurich and the University of Zurich, Switzerland. In study 1, women were randomly assigned (1:1) to two groups. One group was given 60 mg iron at 0800 h (+/- 1 h) on consecutive days for 14 days, and the other group was given the same doses on alternate days for 28 days. In study 2, women were assigned to two groups, stratified by serum ferritin so that two groups with similar iron statuses could be formed. One group was given 120 mg iron at 0800 h (+/- 1 h) and the other was given the dose split into two divided doses of 60 mg at 0800 h (+/- 1 h) and 1700 h (+/- 1 h) for three consecutive days. 14 days after the final dose, the groups were each crossed over to the other regimen. Within-individual comparisons were done. The co-primary outcomes in both studies were iron bioavailability (total and fractional iron absorption), assessed by measuring the isotopic label abundance in erythrocytes 14 days after administration, and serum hepcidin. Group allocations in both studies were not masked and primary and safety analyses were done on an intention-to-treat basis. The studies were registered at ClinicalTrials. gov, numbers NCT02175888 (study 1) and NCT02177851 (study 2) and are complete. Findings For study 1, 40 women were enrolled on Oct 15-29, 2015. 21 women were assigned to the consecutive-day group and 19 to the alternate-day group. At the end of treatment (14 days for the consecutive-day group and 28 days for the alternate-day group), geometric mean (-SD, +SD) cumulative fractional iron absorptions were 16.3%(9.3, 28.8) in the consecutive-day group versus 21.8% (13.7, 34.6) in the alternate-day group (p=0.0013), and cumulative total iron absorption was 131.0 mg (71.4, 240.5) versus 175.3 mg (110.3, 278.5; p=0.0010). During the first 14 days of supplementation in both groups, serum hepcidin was higher in the consecutive-day group than the alternate-day group (p=0.0031). In study 2, 20 women were enrolled between Aug 13 and 18, 2015. Ten women were assigned to receive once-daily dosing and ten were assigned to receive twice-daily divided dosing. No significant differences were seen in fractional (day 1-3 geometric mean: 11.8% [7.1, 19.4] once daily vs 13.1% [8.2, 20.7] twice daily; p=0.33) or total iron absorption (day 1-3: 44.3 mg [29.4, 66.7] once daily vs 49.4 [35.2, 69.4] twice daily; p=0.33) between the two dosing regimens. Twice-daily divided doses resulted in a higher serum hepcidin concentration than once-daily dosing (p=0.013). No grade 3 or 4 adverse events were reported in either study. Interpretation In iron-depleted women, providing iron supplements daily as divided doses increases serum hepcidin and reduces iron absorption. Providing iron supplements on alternate days and in single doses optimises iron absorption and might be a preferable dosing regimen. These findings should be confirmed in iron-deficient anaemic patients.