If you know the serum level you can ignore dosage. I think the reason why so many conflicting results occur with vitamin D studies is that people focus on the dosage and not the timing of dosage.
Hence we have spectacularly illogical studies with monthly bolus doses of cholecalciferol.
chatGPT(5.5 paid) has given me a list:
Yes. Monthly bolus dosing of cholecalciferol (vitamin D₃) has been studied quite extensively, including two very large long-term trials. The most informative studies are these:
| Study | Participants | Monthly cholecalciferol | Duration | Main finding |
|---|---|---|---|---|
| ViDA, New Zealand | 5,108, age 50–84 | 100,000 IU/month after a 200,000-IU loading dose | median 3.3 y | No reduction in CVD, cancer, falls, fractures or respiratory infections overall |
| D-Health, Australia | 21,315, age ≥60 | 60,000 IU/month | up to 5 y | No reduction in all-cause mortality or cancer; possible small reduction in major cardiovascular events |
| Bischoff-Ferrari 2016 | 200, age ≥70 with prior fall | 24,000 vs 60,000 IU/month, plus another arm with 24,000 IU + calcifediol | 1 y | Higher doses raised 25(OH)D more but increased falls without improving leg function |
| Ginde et al. 2017 | 107 nursing-home residents | approx. 100,000 IU/month equivalent | 12 mo | Fewer acute respiratory infections but more falls |
| Mazahery et al. 2015 | Premenopausal women | 50,000 or 100,000 IU/month | 6 mo | Both raised 25(OH)D; useful pharmacokinetic/dose-response study |
| AlAteeq et al. 2021 | 65 adults | 50,000 IU/month vs 50,000 every 2 weeks | 3 mo | Monthly 50,000 IU was often inadequate to maintain >75 nmol/L; fortnightly worked better |
1. ViDA — 100,000 IU every month
This is probably the most important experiment if you are interested specifically in large monthly cholecalciferol boluses.
Scragg et al. randomized 5,108 New Zealand adults aged 50–84 to vitamin D₃ or placebo. They received 200,000 IU initially, followed by 100,000 IU every month, equivalent on average to about 3,300 IU/day.
Mean baseline 25(OH)D was about 66 nmol/L (26.5 ng/mL). The intervention raised average 25(OH)D by more than 20 ng/mL in the measured subgroup. (PubMed Central (PMC))
Despite this substantial biochemical effect:
- cardiovascular events: 11.8% vitamin D vs 11.5% placebo, HR 1.02
- no convincing reduction in cancer
- no reduction in falls
- no reduction in non-vertebral fractures
- no overall reduction in acute respiratory infection.
Importantly, 100,000 IU/month for around 3.3 years did not produce a detectable increase in reported adverse events overall. (ScienceDirect)
So ViDA gives quite strong evidence that 100,000 IU/month is capable of maintaining substantially elevated 25(OH)D for years, but that this does not translate into broad prevention of chronic disease in a mostly vitamin-D-replete population.
2. D-Health — 60,000 IU every month
This is much larger: 21,315 Australians aged ≥60, randomized to
60,000 IU vitamin D₃ once monthly
or placebo for as long as 5 years. That’s an average equivalent dose of about 2,000 IU/day. (PubMed)
The principal mortality result was essentially null:
- vitamin D deaths: about 5.3%
- placebo: about 5.1%
- HR 1.04 (95% CI 0.93–1.18).
It also did not clearly reduce cancer incidence or cancer mortality. (ScienceDirect)
Interestingly, a later cardiovascular analysis produced a somewhat different signal. Major cardiovascular events were modestly less common in the vitamin-D group. Myocardial infarction had an HR of 0.81 (0.67–0.98), although the overall absolute difference in major cardiovascular events was small and the confidence limits were compatible with only a modest effect. (BMJ)
Fractures overall were not significantly reduced by 60,000 IU/month. (ScienceDirect)
3. Bischoff-Ferrari et al. — the particularly interesting dose comparison
This small but mechanistically interesting RCT involved 200 people aged ≥70 who had already fallen during the preceding year.
They were randomized monthly to:
- 24,000 IU D₃/month ≈ 800 IU/day
- 60,000 IU D₃/month ≈ 2,000 IU/day
- 24,000 IU D₃ + calcifediol each month
for one year. (Osteoporosis Canada |)
The higher-dose regimens were much more successful at getting participants above a target 25(OH)D concentration, but they did not improve lower-extremity function.
More strikingly, people receiving the higher-dose regimens had more falls.
This was one of the studies that raised the concern that there might be a difference between:
maintaining the same average vitamin-D exposure with frequent small doses versus producing large transient peaks with bolus dosing.
That finding has subsequently influenced interpretation of intermittent vitamin-D studies. (Nature)
4. Respiratory-infection studies
There have also been monthly/high intermittent dose trials specifically looking at infection.
For example, Ginde et al. studied older long-term-care residents. High-dose vitamin D roughly equivalent to 100,000 IU/month reduced acute respiratory infections, but the vitamin-D group had more falls. (PubMed)
In contrast, the much larger ViDA study found no significant overall prevention of acute respiratory infections with 100,000 IU/month. (PubMed)
This distinction is important because benefit from vitamin D against respiratory infections seems more apparent in people with very low baseline vitamin-D status and with daily rather than large intermittent doses.
What the monthly trials tell us about dose
A useful way to compare them is:
| Monthly dose | Daily-dose equivalent |
|---|---|
| 24,000 IU | ~800 IU/day |
| 50,000 IU | ~1,650 IU/day |
| 60,000 IU | ~2,000 IU/day |
| 100,000 IU | ~3,300 IU/day |
But biologically these are not necessarily equivalent to the same total dose taken daily.
After a large D₃ bolus, circulating cholecalciferol itself rises sharply and then falls, whereas 25(OH)D rises more slowly and remains elevated much longer. Thus tissues experience a very different D₃/25(OH)D exposure profile from that produced by daily supplementation.
That may explain why meta-analyses increasingly distinguish daily dosing from bolus/intermittent dosing, particularly for falls and possibly cancer mortality. One recent analysis found a mortality signal with daily vitamin D that was not apparent with intermittent bolus regimens. (PubMed Central (PMC))
The especially interesting conclusion
If your interest is in the biological effects of high 25(OH)D, rather than simply vitamin-D supplementation, the monthly trials have a major limitation:
They randomize the dose, not the achieved 25(OH)D concentration.
There is considerable variation in the 25(OH)D response to the same 60,000- or 100,000-IU dose. Consequently, an intervention-vs-placebo analysis can conceal a concentration-response relationship.
For the question you were asking earlier about whether 25(OH)D itself produces a concentration-dependent increase in autophagic flux, the more interesting thing would therefore be to examine the ViDA and D-Health biobanks for analyses stratified by achieved 25(OH)D, rather than merely by treatment allocation. (PubMed Central (PMC))
I can dig specifically into the monthly-bolus studies and extract the peak and trough 25(OH)D concentrations after 24k, 50k, 60k and 100k IU, which would give us a useful dose → 25(OH)D time-course and show how much fluctuation monthly dosing actually creates.