REF-1416 · von Siebenthal et al., 2023 · eClinicalMedicine · Paper · PubMed · Free full text

Daily or every other day?

In 150 iron-depleted women the same 100-mg doses gave the same ferritin (43.8 vs 44.8 µg/L) with fewer gut side effects on alternate days, but over 6 months instead of 3. Not athletes.

Main caveat: Not athletes; women only; few mildly anaemic and no moderately or severely anaemic participants.
strong evidenceMeasured on non-athletes and recreational people

Building on their stable-isotope studies (REF-1415; REF-970), the ETH Zurich group tested whether alternate-day oral iron beats daily iron on outcomes that matter.

They randomised 150 healthy women aged 18-45 with ferritin ≤30 µg/L, CRP below 5 mg/L and haemoglobin above 11 g/dL to 100 mg of iron as ferrous sulphate every day for 90 days followed by 90 days of placebo (consecutive-day group), or iron and placebo on alternate days for 180 days (alternate-day group), so both groups received the same total dose.

Adherence and gastrointestinal symptoms were logged daily in a purpose-built app; adherence was over 97% in both groups. At equal total doses, median ferritin was 43.8 µg/L (IQR 31.7-58.2) vs 44.8 µg/L (33.8-53.6), P = 0.98, while GI side effects on days of iron intake were 1.56 times as frequent with daily dosing (95% CI 1.38 to 1.77) and hepcidin was higher (3.0 vs 1.9 nM).

Absorption estimated from the ferritin rise was 36.0% higher on alternate days (5.5% vs 4.1%), but that did not make up for receiving iron half as often: ferritin was higher in the daily group at 46 and 93 days.

After stopping, the daily group's ferritin fell, and at 6 months iron deficiency was 11.4% in the daily group (on placebo for 3 months) vs 3.0% in the alternate-day group at the end of its treatment (P = 0.049).

The authors conclude that alternate-day dosing does not raise ferritin more but is better tolerated, which may help adherence, and that it may not suit women in whom rapid repletion is needed.

Our reading: alternate days are a tolerability tool, not a faster fix — the outcome trial behind the base's alternate-day line in SYNTH-06, which currently says alternate days were "absorbed better".

Protocol

Participants: n = 150 healthy women (75 per group), 18-45 years, serum ferritin ≤30 µg/L, CRP <5 mg/L, haemoglobin >11 g/dL, no major chronic disease, not pregnant or lactating; median age 26 and 24; 32.0% and 44.0% vegetarian; baseline iron deficiency (ferritin <15 µg/L and/or sTfR >8.3 μg/mL) in 48.0% and 46.7%, anaemia in 4.0% and 5.3%.
Randomisation and masking: computer-generated list from the Cantonal Pharmacy of Zurich, blocks of six, sealed envelopes held by an independent monitor; identical iron and placebo capsules; participants and investigators masked until the analysis was complete.
Intervention: 100 mg elemental iron as anhydrous ferrous sulphate in capsules; consecutive-day group iron daily for 90 days then placebo daily for 90 days; alternate-day group iron and placebo alternating for 180 days. Capsules taken in the morning at least 1 h before breakfast, with a dietary source of ascorbic acid such as citrus juice (as advised by the investigators, in both groups).
Measurements: fasting morning visits on days 0, 46, 90, 139 and 183, plus days 93 and 186 after a 3-day pause in capsules so that ferritin was not acutely raised by the last dose; ferritin adjusted for inflammation; stool calprotectin and serum I-FABP for gut effects.
Side effects: daily forced-choice app questions (nausea, constipation, diarrhoea, stomach pain; mild or severe).
Outcomes: co-primary — ferritin and longitudinal prevalence of GI side effects at equal total dose (consecutive day 90 vs alternate day 180); secondary — iron deficiency, hepcidin, iron and inflammation markers.
Funding and interests: Swiss National Science Foundation; the funder had no role in design, analysis or writing; "The authors declare no competing interests." Capsules were manufactured by Soho Flordis International Switzerland SA from pharmaceutical-grade ferrous sulphate (Dr. Paul Lohmann GmbH).

Key Results

OutcomeConsecutive-dayAlternate-dayP
Median ferritin at equal total dose (day 90 vs day 180), µg/L43.8 (31.7-58.2)44.8 (33.8-53.6)0.98
Median hepcidin at end of treatment, nM3.0 (2.0-5.0)1.9 (1.4-2.9)<0.0001
Iron deficiency at end of treatment5.5%3.0%0.46
Iron deficiency at 3 months5.5%4.3%0.74
Iron deficiency at 6 months11.4% (3 months after stopping)3.0%0.049
Ferritin months after treatment ended, µg/L27.0 (18.4-42.0) at 3 months39.4 (23.6-58.7) at 4 months0.030
Estimated fractional absorption (from the ferritin rise)4.1% (2.9-5.4)5.5% (4.7-6.5)<0.0001
GI side effects on days of iron intake, LPR1.56 (1.38-1.77)reference<0.0001
All GI side effects to end of treatment (0-3 vs 0-6 months), LPR1.91 (1.71-2.13)reference<0.0001
Stomach pain, LPR2.54 (2.05-3.14)reference<0.0001
Severe GI side effects over 6 months, LPR1.17 (0.87-1.57)reference0.30
Same time, different dose: ferritin was higher in the consecutive-day group at 46 and 93 days (P < 0.01 for both) and higher in the alternate-day group at 183 days (P < 0.0001).
Side effects over the study: LPR 1.33 (1.19 to 1.50) in months 0-3 and no difference in months 4-6 (P = 0.070), when the consecutive-day group was on placebo; side effects fell over time in the alternate-day group.
Adherence and dropouts: median capsule adherence 98.3% and 98.9%; 5 and 8 discontinued, two in each group because of side effects; inflammation <8% throughout.
Gut markers: no group-time effect on calprotectin or I-FABP.

Mechanisms

Measured: hepcidin was higher on daily dosing (days 46 and 90); estimated absorption was 36.0% higher on alternate days, similar to the 34% the same group measured with isotopes (REF-970).
Authors' interpretation: the higher fractional absorption on alternate days "does not entirely offset" receiving the dose half as often; over 6 months obligatory losses (about 1.34 mg a day in menstruating women) and an absorption plateau near ferritin 50 µg/L may also flatten the gain; the fall in ferritin after stopping shows these women were in negative iron balance on diet alone.
Authors' interpretation: GI symptoms on placebo show how common such symptoms are anyway; alternate days produced few.
Inference: for a clinician choosing a schedule, the trade-off is speed (daily) against tolerability (alternate days); the trial does not test doubling the alternate-day dose to equalise dose per unit time, which the authors suggest for future work.

Practical Application

Daily or every other day? In 150 iron-depleted women the same 100-mg doses gave the same ferritin (43.8 vs 44.8 µg/L) with fewer gut side effects on alternate days, but over 6 months instead of 3. Not athletes.
What alternate days buy (a conflict to settle in [SYNTH-06]): until 2026-10-29 the base's line said alternate-day dosing was "absorbed better" and "favours a single morning dose on alternate days" (now corrected in SYNTH-06).The outcome evidence: equal ferritin at equal total dose, fewer GI effects, twice the time; at equal time, daily raised ferritin more by 3 months (A, non-athlete women). So alternate days are a tolerability option, not a faster route; the schedule is the prescriber's.
When speed matters: the authors themselves say alternate days "may not be optimal" when "rapid repletion of body iron is needed" (their example: symptomatic iron-deficiency anaemia). Whether a block or camp counts is a clinician's judgement.
After stopping: ferritin fell back on diet alone, and deficiency reappeared in some within 3 months; re-testing after a course matters (REF-1410).
Vitamin C: the protocol had everyone take capsules with citrus juice — a design choice in both arms, not a test of vitamin C; the BSG does not recommend vitamin C with a tablet (REF-1411).
In runners: REF-1417 (B-, abstract) found equal ferritin gains over 8 weeks and fewer severe GI complaints on alternate days.

Limitations

Not athletes; women only; few mildly anaemic and no moderately or severely anaemic participants.
Design: the same total dose over 3 vs 6 months, not the same dose per unit time; the comparison at 6 months sets an untreated (placebo-phase) daily group against an alternate-day group just finishing treatment.
App reminders may have raised adherence above real life (authors' limitation).
Self-reported side effects (daily and blinded, but subjective); objective gut markers showed no difference.
Funding and interests: Swiss National Science Foundation; no competing interests declared; the capsules were made by a company (Soho Flordis International), which is not named as a funder.
How this entry was checked and changed
Why this level

a registered double-blind RCT with more than 100 participants (rubric A), with daily app-recorded adherence and side effects; read from the full text (Europe PMC, CC BY-NC-ND 4.0). Non-athletes, so its use for athletes is a transfer

Full text (checked 2026-10-28)
75 women were assigned to each group; daily 100 mg iron for 90 d, followed by daily placebo for another 90 d, or the same daily dose of iron and placebo on alternate days for 180 d (full text)
At equal total iron doses, median serum ferritin was 43.8 μg/L (31.7–58.2) versus 44.8 μg/L (33.8–53.6) (P = 0.98) (full text)
The LPR for gastrointestinal side effects on days of iron intake was 1.56 (95% CI: 1.38, 1.77; P < 0.0001) (full text)
Median serum hepcidin was 3.0 nM (IQR 2.0–5.0) versus 1.9 nM (1.4–2.9) (P < 0.0001) (full text)
Iron deficiency prevalence after 3 months was 5.5% versus 4.3% (P = 0.74) and after 6 months was 11.4% and 3.0% (P = 0.049) (full text)
Serum ferritin was higher in the consecutive-day group than in the alternate-day group at 46 and 93 days (P < 0.01 for both) (full text)
The estimated median FIA was 4.1% (IQR 2.9–5.4) and 5.5% (4.7–6.5), equating to 36.0% higher absorption in the alternate-day group (full text)
The LPRs for mild and severe side effects were 1.20 (95% CI: 1.07, 1.35; P = 0.002) and 1.17 (95% CI: 0.87, 1.57; P = 0.30) (full text)
Capsules were to be consumed in the morning at least 1 h before breakfast with a dietary source of ascorbic acid, such as citrus fruit juice (full text)
Funded by the Swiss National Science Foundation; the authors declare no competing interests (full text)