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Recent studies and guidelines are suggesting iron supplements every other day is better for absorption:

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.

https://www.thelancet.com/journals/lanhae/article/PIIS2352-3026(17)30182-5/fulltext?_ga=2.4503923.1914623440.1560364900-1544426462.1560364899

I think this study has looked a the incorrect variable though. It seems like time, rather than doses, should be studied if the goal is to increase iron.

In my view, the study should have compared the difference between taking iron every day for 28 days vs every other day for 28 days (not 14 days with 1 dose vs. 28 days with dose every other day).

Is my line of thinking off? Unless access to the number of pills is an issue, I am failing to see why taking every other day is being advised above taking daily.

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  • If they studied time rather than doses then one group would be getting twice the amount of iron as the other group. How could you then compare those groups? – Carey Gregory Jun 12 '19 at 20:33
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    This is actually a fascinating paradigm shift in iron supplementation. I have started this with some people and have seen excellent results so far. This is speculative without reviewing the entire study, but it seems in this study they wanted to give the same QUANTITY of iron to compare how well it is absorbed and incorporated between groups of different FREQUENCY regimens. This would control for total iron received as a confounding factor in the results. However, one based just on TIME would be valuable, to compare whether the every other day regimen can increase serum stores as quickly. – DoctorWhom Jun 13 '19 at 2:49
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    @DoctorWhom I think some of that comment could make an answer, especially if you can provide some speculation or background as to why this might be chosen (i.e., for the "twice daily" regimen they gave half doses; why not give a double dose every other day to keep the quantity+time constant?). – Bryan Krause Jun 13 '19 at 6:05
  • I'm just failing to see why the standard was revised to every other day. Patients don't care about how many doses they have to take, they care about the speed of recovery. Showing every other day vs everyday over the same time period seems so much more relevant to me. Unless you are on a desert island with one bottle of pills, efficient absorption should not matter, only the speed of the recovery (unless of course there are side effects to taking daily, which to my knowledge was not really shown). – user250123 Jun 13 '19 at 12:11
  • @user250123 I don't think patient preference was their prime consideration. Doing a well designed study that holds up to critical analysis and provides valid data was probably the driving consideration. Once you have that, you can move on to time vs. doses studies, but you have to have that first. – Carey Gregory Jun 13 '19 at 23:35
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The summary of 2 small studies (by the same leading author) is that fractional iron absorption (the percent of iron from a given dose absorbed) is greater by 30-50% with supplementation every other day than every day, BUT the total iron absorption in a given period is about the same, so it does not result in a quicker normalization of the iron status. The alternative day regime may be associated with fever side effects, though.

First study

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 (The Lancet Haematology, 2017)

Different groups of women aged 18-40 who were "iron-depleted," but not necessary anemic, (serum ferritin ≤25 μg/L), took oral radioactively labelled isotopes of iron supplements (ferrous sulfate). They divided the study into 2 studies:

Study 1 (iron absorption):

  1. 60 mg/day once a day for 14 days (cumulative total absorbed dose: 131·0 mg [71·4 - 240·5 mg])
  2. 60 mg/day every other day for 28 days, so the same total dose as in 1. (cumulative total absorbed dose: 175·3 mg [110·3 - 278·5 mg])

NOTE, that in the regime 1, the cumulative total absorbed dose (131 mg) was in 14 days, while in the regime 2 the dose (175.3 mg) was in 28 days, which means that in the alternative day regime more iron was absorbed from the same total dose as in every day regime, but in a period twice as long.

Study 2 (hepcidin levels):

  1. 120 mg/day once a day for 3 days
  2. 60 mg twice a day for 3 days, so the same daily and total dose as in 3. (At the end, this group had higher serum hepcidin levels.)

Hepcidin is a protein synthesized in the liver and detected in the blood.

High hepcidin levels block intestinal iron absorption (Frontiers in Physiology, 2019).

Interpretation of the study by the authors:

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.

Second study

This was a study in anemic women (mean serum ferritin ~10 μg/L).

Iron absorption from supplements is greater with alternate day than with consecutive day dosing in iron-deficient anemic women (Haematologica, 2019):

Alternate day dosing of oral iron supplements in anemic women may be preferable because it sharply increases fractional iron absorption. In order to provide the same total amount of iron with alternate day dosing, twice the daily target dose should be given on alternate days as total iron absorption from a single dose of 200 mg given on alternate days was approximately twice that from 100 mg given on consecutive days (p<0.001).

BUT

Consequently, TIA from a single dose of 200 mg given on alternate days was approximately twice that from 100 mg given on consecutive days (p<0.001). This suggests that TIA would be similar from alternate day dosing of 200 mg compared to daily dosing of 100 mg. (TIA = total iron absorption)

but:

In conclusion, as in our previous studies using a daily dose of 60 mg in iron-depleted nonanemic women, our data show that with higher doses of 100-200 mg iron in women with IDA, alternate day dosing results in higher FIA and a trend for lower incidence of gastrointestinal side effects compared to consecutive day dosing. (IDA = iron deficiency anemia, FIA = fractional iron absorption)

but:

These potential benefits need to be confirmed in long-term intervention studies in anemic women with clinical endpoints, such as change in Hb, iron status and side effects, as primary outcomes.

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