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Vitamin D: Secondary Analysis of the VITAL Randomized Clinical Trial (with a surprise!)

Maxone73 profile image
19 Replies

I don't know if this was previously posted (it's from 2020)...but it's fascinating. In their first analysis the researchers did not take into consideration...fat

pubmed.ncbi.nlm.nih.gov/332...

Ah the secondary analysis was done by the same researchers from the original study!

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Maxone73
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PCaWarrior profile image
PCaWarrior

The secondary analysis is one of the reasons I take vitamin D. I aim for blood levels of 30-52 ng/ml.

PCaWarrior profile image
PCaWarrior

1. VITAL clinical trial

i. Vitamin D and Omega-3 Trial (VITAL) - Study Results - ClinicalTrials.gov clinicaltrials.gov/ct2/show...

ii. In the active D group the average 25(OH)D went from 30.8 mg/dl to 42.7 ng/ml: Serum 25-hydroxyvitamin D in the VITamin D and OmegA-3 TriaL (VITAL): Clinical and demographic characteristics associated with baseline and change with randomized vitamin D treatment – PMC ncbi.nlm.nih.gov/pmc/articl...

iii. VITAL clinical trial cancer mortality significantly reduced: Principal results of the VITamin D and OmegA-3 TriaL (VITAL) and updated meta-analyses of relevant vitamin D trials – PubMed pubmed.ncbi.nlm.nih.gov/317...

iv. Effect of Vitamin D3 Supplements on Development of Advanced Cancer – PMC ncbi.nlm.nih.gov/pmc/articl...

v. Vitamin D for Preventing Fractures in Low-Risk Adults | Video grandroundsinurology.com/vi...

vi. Vitamin D and marine omega 3 fatty acid supplementation and incident autoimmune disease: VITAL randomized controlled trial | The BMJ bmj.com/content/376/bmj-202...

2. Disappointing results for vitamin D and/or aspirin. However, the trial was underpowered: A Study to Examine the Effectiveness of Aspirin and/or Vitamin D3 to Prevent Prostate Cancer Progression - Study Results - ClinicalTrials.gov

clinicaltrials.gov/ct2/show...

3. High dose vitamin D reduces bone density: Effect of High-Dose Vitamin D Supplementation on Volumetric Bone Density and Bone Strength: A Randomized Clinical Trial | Osteoporosis | JAMA | JAMA Network

jamanetwork.com/journals/ja...

4. Circulating vitamin D level and mortality in prostate cancer patients: a dose–response meta-analysis

ncbi.nlm.nih.gov/pmc/articl...

Maxone73 profile image
Maxone73 in reply toPCaWarrior

I had “barely normal” vitamin D levels when I had my psa checked, 31ng/ml and it was mid June in Italy….I decided I want to get to the middle, 50 will suffice 😀

timotur profile image
timotur

Interesting, thanks!

When stratified by BMI, there was a significant reduction for the vitamin D arm in incident metastatic or fatal cancer among those with normal BMI (BMI<25: HR, 0.62 [95% CI, 0.45-0.86]) but not among those with overweight or obesity (BMI 25-<30: HR, 0.89 [95% CI, 0.68-1.17]; BMI≥30: HR, 1.05 [95% CI, 0.74-1.49]) (P = .03 for interaction by BMI).

Conclusions and relevance: In this randomized clinical trial, supplementation with vitamin D reduced the incidence of advanced (metastatic or fatal) cancer in the overall cohort, with the strongest risk reduction seen in individuals with normal weight.

Schwah profile image
Schwah

I’d love to see TA’s thoughts. He’s usually very skeptical of any supplements but here they seem to have very good evidence of efficacy. TA???

Maxone73 profile image
Maxone73 in reply toSchwah

Actually I have watched a video from Zoe that hosted prof JoAnn Manson (Harvard school of public health) that was quite surprising. I am not interested in vit D intakes of 10k iu per day of course, I just feel more comfy having a mid range level. I live in the countryside in a sunny nation, at least 30 minutes of direct sun light daily as I must walk the dogs daily, and still I had barely normal levels in summer….and now it’s winter.

Researchshortcut profile image
Researchshortcut in reply toMaxone73

Thank you for taking the time to respond in a linear, logical, fact based manner. Your opinion continues to carry significant weight. Please continue.

Jeff

Maxone73 profile image
Maxone73 in reply toResearchshortcut

Well I think TA is the most factual here, I am more on the hopeful (but hopefully not clueless) side! :-)

Tall_Allen profile image
Tall_Allen in reply toSchwah

I had seen this, of course. It is bad statistics. As you go deeper and deeper you get more surprising results. If one is intent on finding a surprising result, one will. But it is not statistically valid.

In fact, look at Table 2. You immediately see that VD made no difference across all invasive cancers. And looking at those with prostate cancer, 1.5% of those taking VD had PCa, and 1.7% of those not taking VD had PCa, which was not a statistically significant difference. There was also no statistically significant difference among those who had metastases, or those who died of cancer. It was only when they fudged the numbers by adding those together that the difference was below the 95% significance threshhold. And when they excluded those who died within 2 years of being diagnosed (which would include ALL men diagnosed with PCa after the start of the trial, there was again no significance. This should prove to men with prostate cancer that VD confers no benefit.

Their analysis of BMI also suffers from finagling, technically known as "p hacking." That is, they looked to find tiny sample-size subgroups (only 58 and 98 out of 25,254) that were significant at the 95% confidence level. Because of such violations of statistical practice, most journals now will not accept such analyses.

The following illustrates why unprespecified subgroups should never be taken seriously. The STAMPEDE authors "proved" that abiraterone had no statistically significant effect on patients born on Thursday through Sunday and had maximal effect on patients born on a Monday. However, if they were diagnosed on a Monday, abiraterone did not have a statistically significant effect.

annalsofoncology.org/articl...

In fact, several Level 1 clinical trials have now proven that VD has no effect on PCa, heart disease, or bone mineral density.

prostatecancer.news/2018/07...

The D-Health trial, however, found that, excluding those who died during the first 2 years of follow-up (which would exclude men with PCa), cancer mortality was 24% higher among those taking Vitamin D. There will be a more detailed analysis of this finding from D-Health at some point.

Meanwhile, patients should only supplement VD if serum levels are low (below 20 ng/ml).

I know that most patients don't want to hear this because popping a pill seems like at least some way of taking control.

Maxone73 profile image
Maxone73 in reply toTall_Allen

I want to underline the fact that the people who did the second analysis are the same who did the first.

Tall_Allen profile image
Tall_Allen in reply toMaxone73

I know. It is very tempting to pull data out. But as you see, it leads to erroneous conclusions and misleads patients like you.

Maxone73 profile image
Maxone73

youtube.com/watch?v=N83s8pz... JoAnn Manson (from the original team of VITAL study) about Vitamin D and Omega 3 related to VITAL research

benefits > costs according to her anyway, as long as you do not exaggerate and you keep your level checked, it's worth to supplement it if you re borderline insufficient as I am (in summer)

I must add that in my specific case, I am also getting zoledronic acid infusions every 28 days

Tall_Allen profile image
Tall_Allen in reply toMaxone73

You are desperate and I can certainly understand the temptation to pop a few pills. But it is bad science, as I said. I notice, that the fact that cancer mortality was 24% higher among those taking Vitamin D in the D-Health trial doesn't seem to affect you. This is called "confirmation bias" and it affects all humans.

Maxone73 profile image
Maxone73 in reply toTall_Allen

I have checked it and noted it Allen. As I said I am worried about my next stage. On the other hand D-Health was designed for cardiovascular events and still, VITAL study JoAnn Manson thinks that such results are random...it's a fight

Tall_Allen profile image
Tall_Allen in reply toMaxone73

VITAL clearly showed that supplementing Vitamin D had no effect on prostate cancer. I doubt that D-Health showed any effect on prostate cancer either - perhaps it harmed people with other kinds of cancer. There is no fight by an stretch of the imagination for men with prostate cancer.

Maxone73 profile image
Maxone73 in reply toTall_Allen

"In VITAL, vitamin D did not significantly reduce the primary endpoint of total invasive cancer incidence (hazard ratio [HR]=0.96 [95% confidence interval 0.88-1.06]) but showed a promising signal for reduction in total cancer mortality (HR=0.83 [0.67-1.02]), especially in analyses that accounted for latency by excluding the first year (HR=0.79 [0.63-0.99]) or first 2 years (HR=0.75 [0.59-0.96]) of follow-up (Table 2) [2]. The cumulative incidence curves for cancer mortality began to diverge clearly at 4 years (Figure 2). The HRs for incidence of prespecified site-specific cancers were 1.02 (0.79-1.31) for breast cancer, 0.88 (0.72-1.07) for prostate cancer, and 1.09 (0.73-1.62) for colorectal cancer."

This still from the same VITAL researcher...it's late here but I will copy/paste what chat GPT said about this (ok I am sorry, today it's my chat gpt day, I am testing it on basically everything, including recipes creation!)

Primary Endpoint - Total Invasive Cancer Incidence:

Hazard Ratio (HR) = 0.96 [95% Confidence Interval: 0.88-1.06]: This suggests that vitamin D did not significantly reduce the overall incidence of invasive cancer. The HR close to 1 indicates no strong effect, and the confidence interval crossing 1 reinforces this lack of significant effect.

Total Cancer Mortality:

Initial HR = 0.83 [0.67-1.02]: Indicates a trend towards reduced cancer mortality with vitamin D, but not statistically significant as the confidence interval includes 1.

Excluding First Year of Follow-up: HR = 0.79 [0.63-0.99]: When the first year is excluded, there's a significant reduction in cancer mortality (HR less than 1 and confidence interval does not include 1).

Excluding First 2 Years: HR = 0.75 [0.59-0.96]: Excluding the first 2 years shows a stronger effect in reducing cancer mortality.

Cumulative Incidence Curves: These curves began to diverge clearly at 4 years, suggesting that the effect of vitamin D on reducing cancer mortality becomes more evident over time.

Site-Specific Cancers:

Breast Cancer: HR = 1.02 [0.79-1.31]: No significant effect on breast cancer incidence.

Prostate Cancer: HR = 0.88 [0.72-1.07]: Suggests a possible reduction in prostate cancer incidence, but not statistically significant.

Colorectal Cancer: HR = 1.09 [0.73-1.62]: No significant effect on colorectal cancer incidence.

Overall, the study indicates that while vitamin D supplementation does not significantly reduce the incidence of invasive cancer in general, there is a potential for it to reduce total cancer mortality, especially when considering a latency period by excluding the initial years of follow-up. The effects on specific types of cancer like breast, prostate, and colorectal cancer are not significant.

Tall_Allen profile image
Tall_Allen in reply toMaxone73

"Promising signal" is research code for "it showed nothing, but I want to make it seem like it did." So there was clearly no positive signal for prostate cancer. When the HR crosses 1.0, it means that the true value may have been that it caused prostate cancer.

I really don't care what ChatGPT said - I can read it for myself. I have 20 years of research experience. I also understand how desperate patients want to believe things that aren't true.

It does not show that "there is a potential for it to reduce total cancer mortality." It shows that there was no effect on cancer mortality. It is just wishful thinking on your part. IMO, patients are better off with the truth than with nursing fantasies.

j-o-h-n profile image
j-o-h-n

FYI T_A is a statistician by trade.

Note: I wish to offer my apologies if I offended anyone regarding my so-called humor about "race" or "misogyny". To me, humor is boundless and since we entered this word crying, I thought it would be a good idea to exit laughing.

Good Luck, Good Health and Good Humor.

j-o-h-n Wednesday 12/20/2023 3:39 PM EST

Maxone73 profile image
Maxone73 in reply toj-o-h-n

I know John

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