Showing posts with label supplements. Show all posts
Showing posts with label supplements. Show all posts

Wednesday, December 16, 2020

Best Evidence So Far: Metformin Has No Benefit for Prostate Cancer

In studies of men with diabetes, men taking metformin seemed to have low incidence of prostate cancer and fewer deaths from prostate cancer. I stress the word "seemed" because all of the evidence for it came from observational studies rather than randomized clinical trials (RCTs). The problem with observational studies is "selection bias." Selection bias means that those taking the drug did so for a reason, and the reason may have affected prostate cancer incidence or progression because of some other reason, Observational studies can only show association. Only a randomized trial can prove causality. For example, we can easily observe that people who weigh less are more likely to get breast cancer (an association), but that does not mean that if one loses weight, one will get breast cancer (a causal factor). It is merely because almost all the people who get breast cancer are women and women, on the average, weigh less than men, that there is an association. In spite of this problem of "selection bias," some patients and doctors jumped to the conclusion that metformin can prevent progression. Let's examine the evidence for causation instead of association.

124 patients were randomly assigned to receive ADT+bicalutamide or metformin+ADT+bicalutamide. Newly diagnosed patients may have been diagnosed with either:
  • High-risk localized prostate cancer
  • Prostate cancer in distant sites (stage M1)
  • Prostate cancer in pelvic lymph nodes only (stage N1)

After short follow-up (18 months, median), 23% of the patients had died. The effects of metformin were:
  • Time to castration resistance was delayed in the high-risk group and in those with stage N1
  • Time to castration resistance was not slowed significantly in men staged M1, especially no effect in those with a high volume of metastases.
  • There was no effect on PSA
  • There was no effect on survival
So metformin may slow progression among men who may be cured by radical therapy (removing or irradiating the prostate with or without pelvic lymph nodes) anyway. It is possible that with larger sample size and longer follow-up there may be an effect on survival among metastatic men, but the lack of a PSA response suggests that won't happen.

28 patients with recurrent prostate cancer were given either metformin or observation for 8 weeks. All patients had a short PSA doubling time and a high body mass index. As metformin or placebo continued for 24 more weeks, bicalutamide (50 mg/day) was given to both groups.
  • After the initial 8 weeks, PSA dropped in the metformin group
  • By 32 weeks, however, there was no difference in PSA
  • The trial was ended early for futility

100 patients with metastatic castration-resistant prostate cancer (mCRPC) were randomly assigned to get docetaxel chemotherapy with or without metformin. By the end of chemotherapy (up to 10 infusions, every 3 weeks):
  • There was no difference in PSA response between the 2 groups
  • There was no difference in objective response
  • There was no difference in clinical progression-free response
  • There was no difference in overall survival
  • There was a higher incidence of diarrhea with metformin

36 patients were randomized to receive metformin+ADT or ADT-alone (+ placebo). Patients were either recurrent (n=15) or newly diagnosed with metastatic prostate cancer (n=21). All were beginning lifelong ADT for the first time. After 28 weeks:
  • There was no difference in PSA response between the 2 groups
  • There was no difference in metabolic syndrome ("PRIME RCT" terminated below) between the 2 groups
The researchers conclude that drugs that reduce metabolic syndrome in diabetics do not reduce metabolic syndrome among ADT users.

This RCT was conducted to detect any particular tissue effects metformin might cause. 20 patients were randomized to receive metformin or placebo for 4-12 weeks prior to surgery. Analysis of post-prostatectomy tissue revealed:
  • There were no differences in any of the biomarkers of hypothetical biochemical benefit for prostate cancer (see below)

This RCT was conducted to see if men on active surveillance could delay progression by taking metformin. 407 Canadian men at 12 centers starting on active surveillance were randomized to receive metformin or a placebo for 3 years. Metformin made no difference in whether their grade increased or if they received treatment. However, in obese patients, metformin caused a 2-fold increase in progression.

METAb-Pro - prospective trial (not randomized)

25 patients with metastatic castration-resistant prostate cancer (mCRPC) who were already taking abiraterone received metformin. After 12 weeks:
  • Only 12% were free of progression (35% progression-free survival was the benchmark for an effect)
  • Most had PSA progression; almost half had radiographic progression
  • There was higher-than-expected gastrointestinal toxicity (nausea, diarrhea, loss of appetite)

(Update 5/24/2022) The MA.32 RCT among 3,649 women with breast cancer proved that metformin has no effect on breast cancer survival. There were, however, statistically significant increases in serious (Grade 3) toxicities among those taking metformin vs placebo: 21.5% vs 17.5%, respectively. While we cannot extend this result to prostate cancer, it does increase skepticism.

Purported Anti-Carcinogenic Biochemical Mechanisms

Metformin has been used for many years in diabetic people to reduce blood sugar (it blocks glucose production by the liver), counteract the effects of metabolic syndrome, maintain insulin sensitivity, and diminish appetite. Its effects are mediated through its ability to activate an enzyme called AMPK. 

There are several hypotheses about how metformin might exert an anti-carcinogenic effect in prostate cancer. All of the hypotheses are based on lab tests rather than clinical data. Some of its purported effects might arise because metformin activates an enzyme called AMPK.
  • AMPK in turn activates an enzyme called Acetyl Coenzyme A Carboxylase (ACC) which regulates fatty acid oxidation - the chief source of energy for the prostate cancer cell. 
  • AMPK also activates a protein (p53) that is an important tumor suppressor. 
  • AMPK inhibits an enzyme called mTOR. mTOR inhibitors prevent cancer protein synthesis and reduce Cyclin D1 activity. This leads to cell-cycle arrest.
Other proposed anticarcinogenic mechanisms are that metformin: 
  • increases Cleaved Caspase 3 (CC3), which is needed for apoptosis of mutated cells
  • decreases Insulinlike Growth Factor (IGF-1) that allows energy utilization by the cancer. However, because more specific IGF-1 inhibitors have been found to have no effect on prostate cancer: lisitinib, figitumumab, and cixitumumab, this is an unlikely mechanism.
  • decreases testosterone formation (it is known to slightly decrease testosterone in women with polycystic ovary syndrome)
  • decreases free testosterone formation by increasing sex hormone binding globulin - SHBG.
Nguyen et al. showed that men taking metformin had no differences in serum or tissue levels of  CC3, Cyclin D1, IGF-1, testosterone, SHBG, or mTOR inhibition.  This leaves metformin without a plausible mechanism by which it could slow prostate cancer progression.

Lower detection among diabetic men using metformin is a confounder

So why have so many observational studies of metformin in diabetic men found an association with reduced prostate cancer progression? And why has the association failed to be observed in non-diabetic men? A Stockholm study provides a plausible explanation: Beckmann et al. reported that diabetic men using metformin were less likely to get a biopsy for elevated PSA compared to a matched sample of men who did not use metformin. This suggests that the lower incidence of prostate cancer among men taking metformin is simply that their prostate cancer was less likely to be detected.

Contradictory Evidence from Observational Studies

Because so many patients have relied on observational studies to make a metformin treatment decision, it's worth seeing just what those studies say. All observational studies have been conducted among diabetic men.

This meta-analysis is large. It encompasses 30 cohort studies, covering 1.7 million diabetic men. While there was no association with incidence of prostate cancer (no protective effect),  there were positive associations with overall survival, prostate cancer-specific survival, and recurrence-free survival. No correction for risk factors or patient matching was possible.

This UK database analysis of over 55,000 diabetic men, using inverse probability weighting to account for selection bias, found there was no association between metformin use and the detection of any kind of cancer.

This secondary analysis of the REDUCE RCT compared 194  metformin users to 205 non-users of diabetic medications and 141 who used some other diabetic medication. All were diabetic and had at least one biopsy. After correction for all risk factors, there was no association for incidence of prostate cancer, neither high grade nor low grade.

Merrick et al. reported on 65 diabetic men at Wheeling Hospital treated with metformin (median, 6 years), compared to 88 diabetic men treated with another antidiabetic medication, and 881 non-diabetic men who were biopsied. There were no significant differences in prostate cancer diagnosis, Gleason score, number of positive cores, or risk group based on metformin usage. Nor did diabetes make a difference.

A study at Mayo looked at recurrences among men following prostatectomy. There were 323 diabetic metformin users and 562 diabetic non-users. After 5 years of follow-up, and after correction for known confounders, there were no differences in biochemical recurrence, progression, or all-cause mortality. Neither were there any differences in postprostatectomy pathological findings: Gleason score, stage, positive surgical margin rate, or tumor volume.

Taira et al, reported on 126 diabetic men at Wheeling Hospital treated with metformin (median, 6 years), compared to 144 diabetic men treated with another antidiabetic medication, and to 2,028 non-diabetic men. All received brachytherapy. There were no 15-year differences in biochemical failures, or prostate cancer-specific mortality. 

A 1:5 case-control study of diabetic men diagnosed with prostate cancer was conducted in Ontario. There were 1,104 men who had high-grade and 1,117 men who had low-grade PCa after prostatectomy. In addition, there 3,524 men diagnosed with a biopsy only. Metformin use made no difference in prostate cancer incidence, detection of high-grade PCa, low-grade PCa, or biopsy-detected PCa.

A SEARCH database study looked at diabetic men who underwent prostatectomies, 156 used metformin, 215 didn't. There was no association found between metformin use, dose or duration of use and time to biochemical recurrence, High metformin dose was associated with earlier castration resistance, metastases, and PC-specific mortality.

A 1:10 case-control UK Database study looked at 536 diabetic men who had used metformin and 203 diabetic men who hadn't. Metformin use was not associated with prostate cancer incidence. In fact, prostate cancer risk increased in proportion to the number of metformin prescriptions.

Tan et al. used the SEER database to see if there was an association between metformin, statins, or the combination of the two on prostate cancer mortality in high-risk men. They found that metformin alone had no association. However, statins alone and the combination did have an association. The association disappeared in men with advanced (Stage IV) prostate cancer.

Possible Metformin Danger

In a secondary analysis of two randomized clinical trial databases, there were 486 patients treated with radiation and ADT. Follow-up was over 10 years. 10-year biochemical recurrence-free survival was:
  • 73% if they used metformin
  • 85% if they did not use metformin
Metformin was associated with inferior biochemical outcomes.

Should I take metformin?

All of the higher-level evidence so far is consistently showing that there is no benefit in taking metformin for prostate cancer. Also, a plausible mechanism for a beneficial effect is so far lacking. However, all the RCTs so far have been small and short-term, so it is possible that a very large trial with long follow-up, like STAMPEDE, might yet prove there is a small effect, or metformin might prove useful if used early enough, as in men on active surveillance, or in combination with other substances (e.g., statins). There are several ongoing randomized clinical trials (see below).

While metformin does not have serious side effects in most men, it does commonly have gastrointestinal side effects (diarrhea, cramps, nausea, vomiting, and flatulence). It should be avoided in men with known contraindications: lactic acidosis, metabolic acidosis, poor liver or kidney function, and hypoglycemia. There are many drug/supplement interactions that should be carefully checked.

Metformin has been recalled repeatedly by the FDA because of carcinogenic (NDMA) impurities.

Ongoing/Terminated RCTs:

STAMPEDE - ARM K: Metformin+SOC vs SOC for locally advanced and newly-diagnosed metastatic patients. Results expected: 2024
IMPROVE:  Enzalutamide vs Metformin+Enzalutamide for mCRPC. This trial was terminated.
LIGAND: Metformin+atorvastatin vs placebo for recurrent men: Trial terminated for no expected benefit in recurrent men.
PRIME: Metformin vs placebo to prevent metabolic syndrome in men starting ADT: This trial was terminated.
SAKK 08/15 - PROMET Metformin vs placebo with salvage radiation. Terminated early.

Sunday, April 28, 2019

If you are using PSA to monitor your cancer, you may want to avoid curcumin (and some other supplements)

Curcumin (a turmeric extract) is one of the most popular natural substances subjected to pre-clinical research. Based on mouse and lab studies, it has been touted as the cure to cancer and just about everything else, with reports of activity including anti-inflammatory, anti-HIV, antibacterial, antifungal, nematocidal, antiparasitic, antimutagenic, antidiabetic, antifibrinogenic, radioprotective, wound healing, lipid lowering, antispasmodic, antioxidant, immunomodulating, anticarcinogenic, and Alzheimer’s disease, among others. This "panacea" and the low level evidence behind it are satirized in this amusing video.

It is one of the most widely researched supplements - in mouse and lab studies. In spite of its spectacular success with mice, randomized clinical trials in humans have been lacking. Choi et al. reported on a double-blinded randomized clinical trial of curcumin on 82 evaluable men who completed one treatment cycle of intermittent hormone therapy. They were then given 1440 mg/day of curcumin or a placebo for 6 months. The goal of the study was to see whether curcumin could extend their time off of hormone treatment.
  • Those taking curcumin were able to avoid hormone therapy for 16.3 months
  • Those taking the placebo were able to avoid hormone therapy for 18.5 months
  • The difference was not statistically significant
  • 10% of patients taking curcumin had PSA progression during the curcumin treatment period vs 30% of those taking the placebo.
The fact that those taking the placebo had an insignificantly longer break from hormone therapy in spite of the fact that their PSA progression was greater than those who were taking curcumin in the first 6 months, indicates that curcumin may have interfered with the PSA tests while they were taking it. Clearly, curcumin did not delay clinical progression.

Ide et al. found in a small (n=85) double-blind randomized clinical trial that a mixture of soy isoflavones and curcumin suppressed the serum PSA readings of men with high PSA (>10 ng/ml) who were confirmed by biopsy to not have prostate cancer. The curcumin mixture suppresses the PSA reading independent of prostate cancer.

A multi-center, blinded randomized clinical trial in France of curcumin+docetaxel compared to docetaxel alone in men who were metastatic and castration-resistant was ended early because of futility. Although not statistically significant, combining docetaxel and curcumin consistently gave worse outcomes (progression, survival) than docetaxel plus placebo.

Fabiani et al. reported on 50 consecutive patients with PSA over 4.0 ng/ml or PSA velocity > .75 ng/ml/year. They were given curcumin for 30 days.
  • Baseline % free PSA was 17%
  • After 30 days of curcumin, % free PSA was 20%
  • The changes in PSA and % free PSA were statistically significant
It seems that curcumin suppressed PSA. Although it is possible that 30 days of curcumin reversed the prostate cancer, that is unlikely. It is more plausible that curcumin affected the PSA assay.

This effect has been noted in the literature. The authors of this analysis and this one label curcumin as a Pan-Assay Interference Compound (PAINS), which means that it is known to interfere with assay readouts. Curcumin particularly confounds tests of molecules, like prostate specific antigen (PSA) and prostate-specific membrane antigen (PSMA), that penetrate the cell wall. According to this analysis, other common supplements that may interfere with the integrity of the cell wall without actually binding to a site on the proteins (which would be a real drug effect) include genistein (a soy isoflavone), EGCG (green tea), resveratrol (grapes),  and capsaicin (chili peppers).  Some of these compounds, including curcumin, are capable of forming stable metal ion complexes and should be scrupulously avoided by patients taking Ga-68-PSMA-11, Lu-177-PSMA-617, technetium bone scan, or gadolinium MRI contrast agent. Glutamate (MSG used in Chinese food) is also a powerful chelator. It has been found to markedly decrease the effectiveness of PSMA theranostics (see this link).

There are other supplements that may mask PSA readings without affecting progression. These include saw palmetto, pygeum, and beta-sitosterol. 5-alpha-reductase inhibitors (Proscar and Avodart) affect PSA in men with BPH and prevent the occurrence of prostate cancer. Because they affect PSA in a known way in men with BPH, we are able to correct for the PSA aberration (by doubling the PSA reading). The FDA has warned that biotin, in many multivitamin preparations, may interfere with many laboratory blood tests. Men taking statins should also be aware that it may produce artificially low PSA readings (see this link and this one). Statins, which seem to be beneficial in some observational studies but not in others, may only have an apparent benefit because of masking of PSA, as in this study and this study.

In designing future clinical trials on curcumin, like this one or this one that tests its benefit as an adjuvant therapy to active surveillance, it is important that the measured endpoint not be dependent on PSA. PSA doubling time, biochemical recurrence-free survival, and time before ADT is initiated (which is usually given as a result of increasing PSA) are artificially increased by curcumin. Only endpoints like radiographic progression-free survival and metastasis-free survival are useful. Incidentally, this is also why those endpoints must be chosen when evaluating the effectiveness of metastasis-directed therapy, which will lower PSA arising out of macroscopic metastases but may or may not slow the cancer's progression.

I spent a very short career as a chemist developing radioimmunoassays for biological substances, like PSA, that were only detected in serum in nanomolar and picomolar amounts. I can attest that even small amounts of impurities that adsorb, quench fluorescence, or react with the protein or its antibody can completely invalidate a test. Curcumin seems to do this.

The biggest problem with curcumin as a medication is its oral bioavailability, which is less than 1% and its elimination half-life, which is about a half hour in rats. It is doubtful that enough is bioavailable to have any therapeutic effect. This is true in spite of substances like piperine that aid passage through the gut wall. It is metabolized very quickly by the liver. Moreover, what is actually in a pill labeled as curcumin is highly variable, and curcumin is chemically unstable.

Many men rely on PSA to monitor prostate cancer progression. It may be misleading to use a supplement that may invalidate this important test. If there were any valid clinical studies indicating a true benefit, the corruption of a biomarker might be forgivable. But curcumin has only shown a benefit to mice so far. There are also some safety concerns (see this link). Patients must be wary of any supplement whose benefit is only supported by mouse/lab studies, and which only seems to affect PSA measurements. It is entirely possible to treat PSA without actually treating the cancer.

Sunday, July 22, 2018

Vitamin D has no effect on prostate cancer, heart disease, or bone mineral density*


Observational studies have reported conflicting effects of Vitamin D on prostate cancer - some reported no association (as in this study), some reported a positive association (as in this study), and some reported an inverse association (as in this study). We now have three large randomized clinical trials (Level 1a evidence) that show that large doses of Vitamin D have no effect on cancer incidence or deaths. This trumps all previous observational and epidemiological studies.

Manson et al.  reported the results of the VITAL randomized clinical trial (RCT) on 25,871 (including 5,000 African-Americans) men over 50 and women over 55 who were given either:
  1. Vitamin D3 at 2,000 IU per day and marine omega-3 fatty acids (1000 mg/day containing 840 mg EPA and DHA)
  2. Vitamin D3 placebo and fish oil placebo
  3. Fish oil and Vitamin D3 placebo
  4. Vitamin D3 and fish oil placebo
Blood samples were taken and questionnaires were administered to assure compliance. The group assignment was double-blind. Participants agreed to keep vitamin D from all other sources (like sunlight, milk, multi-vitamins, etc.) to under 800 IU per day.

After a year, serum 25-hydroxyVitamin D increased from 30 ng/ml to 42 ng/ml among those supplementing Vitamin D and didn't change in the placebo groups.

After 5.3 years of follow-up, there was:
  • No difference in incidence any kind of cancer (including prostate, breast and colorectal cancers) between Vitamin D3 and Placebo.
  • No difference in deaths from any kind of cancer
  • Low BMI  (<25) may potentiate the effect of Vitamin D on cancer.
  • No difference in any kind of cardiovascular disease, including myocardial infarction, stroke or death from myocardial causes or of interventions like PCI or coronary bypass.
  • There was no synergism with omega-3 fatty acids.
  • There were no statistically significant differences in any subgroup.

Manson et al. also did a separate analysis of omega-3 fatty acids. After 5.3 years of follow-up, there was:
  • No difference in incidence any kind of cancer (including prostate, breast and colorectal cancers) between omega-3 and Placebo.
  • No difference in deaths from any kind of cancer.
  • There was no synergism with Vitamin D.
  • Those with low fish consumption (<1.5 servings per week) may gain some cardiovascular benefit from omega-3 supplementation.
  • No difference in cardiovascular disease overall, stroke or death or of interventions like PCI or coronary bypass.
  • There was significant improvement in the rate of myocardial infarctions and total coronary heart disease among those taking omega-3s.
  • African-Americans, especially those with multiple CV risk factors, taking omega-3s had lower incidence of myocardial infarctions.
  • Myocardial infarctions (MI) were also better for those taking omega-3s among younger people (<67), men, smokers, diabetics, people with hypertension, people taking cholesterol medications, no parental history of MI, 3 or more risk factors, baseline aspirin use, and baseline statin use.
(update 11/18/20) Chandler et al. reported on an updated analysis of the VITAL RCT. They looked at whether Vitamin D supplementation affected the risk of developing metastatic or fatal cancer among people who were cancer-free at baseline. With a median intervention period of 5.3 years, there was almost no chance of finding metastatic or fatal prostate cancer in men who were prostate cancer-free at baseline (In the ProtecT trial, 10-year prostate cancer survival among men initially diagnosed with localized prostate cancer was 99%, and metastasis-free survival was 96%.) Because the metastasis-free and cause-specific survival with prostate cancer are so long when starting from a "no cancer" diagnosis, the authors looked for the effect on other cancers, excluding prostate cancer. They found:
  • there were no significant differences due to Vitamin D on the incidence of any cancer
  • there were no significant differences due to Vitamin D on the metastatic spread across all cancers
  • there were no significant differences due to Vitamin D on all-cancer mortality
  • Adding together metastases and fatalities due to all cancers, the difference (2.1% vs 1.7%) was statistically significant, especially after the first two years
  • The reduction was only statistically significant among those with a normal body-mass index (<25)
  • For prostate cancer patients, there were only 6 such cases among those who got Vitamin D and 14 such cases among those who got the placebo - not significantly different. Presumably, they were missed at diagnosis or had a rare virulent type of PCa.
(Update 3/16/2021) in an ancillary analysis of the VITAL trial data, Albert et al. reported that neither Vitamin D nor Omega-3 supplementation had any effect on the incidence of atrial fibrillation.

(update 2/19/2022) Neale et al. reported the results of the D-Health RCT. This was a randomized double-blind prospective trial among 21,315 Australians aged 60 or over.
  • 10,662 were given Vitamin D; 10,653 were given a placebo
  • Vitamin D3 was given as 60,000 IU/month for 5 years
  • A random sample of both groups was checked for compliance via a blood test for serum 25-hydroxyVitamin D; it was 115 nmol/L in the treatment group vs 77 nmol/L in the placebo group.

After 5 years of follow-up:
  • There was no statistically significant difference in the number of deaths (5% in each group)
  • There was no statistically significant difference in cardiovascular disease mortality
  • There was no statistically significant difference in cancer mortality
  • There was no statistically significant difference in all other causes of mortality
  • Excluding those who died during the first 2 years of follow-up, cancer mortality was 24% higher among those taking Vitamin D

Scragg et al. in a post-hoc analysis of the ViDA trial reported on 5,110 50-84 year-old people seen in community practice in NZ between 2011 and 2012. The study was originally set up to investigate cardiovascular benefit to Vitamin D supplementation (it found none), but they also asked about incidence of cancer and tracked deaths from cancer.
  • 2558 were given Vitamin D; 2552 were given a placebo
  • Vitamin D3 was initially given as one 200,000 IU pill, followed by 100,000 IU monthly pills
  • Serum 25-hydroxyVitamin D was 26.5 ng/ml (seasonally adjusted) at baseline
  • Serum 25-hydroxyVitamin D consistently increased by 20 ng/ml among a sample of treated patients
  • Compliance was excellent
  • There was no difference in the percent who took calcium or Vitamin D supplements or in sun exposure
After a median of 3.3 years of follow-up, there were:
  • 375 new cancer cases; 60 died of new cancers. 
  • 24% had a pre-existing cancer diagnosis; 29 died
  • no significant difference between the Vitamin D cohort and the placebo cohort in the number of new cancers or cancer deaths.
  • 6% had a pre-existing prostate cancer diagnosis; 7 died
  • 64 new cases of prostate cancer (1 died)
  • no significant difference between the Vitamin D cohort and the placebo cohort in the number of new prostate cancers or in prostate cancer deaths.
One can argue that a consistent daily Vitamin D3 intake might have had an effect, or that it takes more than 3 years for an effect (whether beneficial or increased risk) to be observed. There is, at present, only observational studies for either assertion. Sample size prevents consideration of the hypothesis that Vitamin D may prevent early growth of prostate cancer but may accelerate metastases (as in this mouse study).

Jiang et al. report the results of a Mendelian randomization study of the causal connection between serum Vitamin D levels and prostate cancer. They identified 6 genetic mutations associated with low serum levels and looked for them in 79,148 men who were diagnosed with prostate cancer. They found no greater incidence of those genetic mutations in men with prostate cancer or advanced prostate cancer. Nor was there any association in women with breast cancer. The genetic mutations were also not statistically different in 73,699 people who did not have breast or prostate cancer. This proves there is no causal connection between low Vitamin D and prostate cancer.

No Effect or Negative Effect on Bone Mineral Density*

Some men on hormone therapy take Vitamin D and calcium for the purpose of maintaining bone mineral density (BMD). 

(update 7/27/22) An update of the VITAL randomized clinical trial reported no difference in fractures among people supplementing Vitamin D vs. people not supplementing it. There were no differences by age, sex, race, BMI, baseline use of calcium or Vitamin D supplements, or serum Vitamin D levels.

Reid et al. reported that Vitamin D supplementation had no effect on bone mineral density. They further noted that lower doses had more effect than higher doses, probably because Vitamin D has been found to pull calcium out of bones at high doses. However, Datta and Schwartz reported that at 200-500 IU/day Vitamin D and 400 mg-1,000 mg calcium supplementation had no effect on men's bone mineral density. Calcium supplementation has been associated with increased risk of prostate cancer (see this link or this link). Trajanoska et al. found that mutations in the genes responsible for regulating serum Vitamin D levels had no effect on fracture risk, nor did the genes regulating the tolerance for dairy (which is correlated with calcium intake). They also question the routine use of Vitamin D and calcium supplements in men who are taking Xgeva or a bisphosphonate like Zometa to preserve bone mineral density. (Estrogen patches may also prevent loss of bone mineral density.) They wrote:

Studies seeking to show whether these supplements do increase the efficacy of osteoporotic treatment or decrease adverse events (that is, hypocalcaemia) are lacking. In either case, screening for vitamin D deficiency and seeking its correction should be warranted before the initiation of anti-resorptive treatment [e.g., Zometa or Xgeva].  Moreover, in a recent mendelian randomisation study investigating the role of vitamin D in maintaining bone mineral density, increased levels of vitamin D had no effect on bone mineral density measured by [DEXA scan]. However, increased 25-hydroxy-vitamin D was associated with a slight reduction in heel bone mineral density estimated by ultrasonography. These results are consistent with our mendelian randomisation findings of no causal effect of vitamin D levels on fracture.
(Update 9/2/2019) Burt et al. published the results of a randomized clinical trial (RCT) of three different doses of Vitamin D on the bone mineral density of 311 men with 3 years of follow up. The experiment was set up as follows:

  • 1/3 received 400 IU/day; 1/3 received 4000 IU/day; 1/3 received 10,000 IU/day
  • none had osteoporosis at baseline
  • all had baseline serum Vitamin D between 30-125 nmol/L (12-50 ng/ml)
  • those whose total intake of calcium (dietary+supplements) was < 1200 mg/day received calcium supplements
  • baseline serum calcium was 8.4-10.2 mg/dl
  • 53% were men
  • average age was 62 (range:55-70)

After 3 years on their vitamin D regimen:
  • Serum Vitamin D was 77 nmol/L, 132 nmol/L, and 144 nmol/L in those taking 400 IU/day, 4000 IU/day, and 10,000 IU/day, respectively
  • BMD in the radius bone of the arm decreased in all groups in a dose-dependent manner:
    • -1.2% in the 400 IU/day group
    • -2.4% in the 4,000 IU/day group
    • -3.5% in the 10,000 IU/day group
  • Hypercalcemia (too much calcium in the blood) and hypercalciuria (too much calcium in the urine) increased with increased Vitamin D dose
  • Kidney/liver dysfunction, falls, fractures and cancer did not vary with dose.

In a Medpage interview, the authors point out that this is plausible because of two effects of Vitamin D:
  • It increased bone resorption (more than bone formation), as measured by an increase in CTx.
  • It increased parathyroid hormone, either directly or by increasing calcium absorption from the gut

The study did not include people taking bisphosphonates, Zometa or Xgeva.

Also, the dose-dependent effect (higher doses were more damaging than lower doses) increases the plausibility of this being a real effect.

(update 3/23/24) *Peppone et al. found in a small randomized trial that ultra-high doses of Vitamin D (50,000 IU/wk!) could lessen the deleterious effect on BMD of  ADT in men who recently (last 6 months) started ADT and had low-end baseline serum Vitamin D (<27 ng/ml). Even so, they still lost BMD after 24 weeks of ADT but at about ⅓ the rate of those who only took much smaller amounts of Vitamin D. There were no differences in toxicity at 24 weeks. Of course, these men started with a deficiency, only took ADT for a short time, and they weren't followed long enough for the megadoses of Vitamin D to rob their bones of BMD.

 It’s worth noting that Vitamin D, unlike other vitamins, is a steroid. Steroids tend to interact and to have wide-ranging effects in humans. Overwhelming our steroid-control systems with massive doses of any one steroid is bound to have unintended consequences.

Possible increase in testosterone 

It should be remembered that Vitamin D is a steroidal hormone (like testosterone, estrogen, progesterone, and cortisol) and there are receptors for it on virtually all cells, healthy and cancerous. It has far-ranging effects. It also is part of the human biochemical factory that inter-converts many different kinds of steroids. In fact, Anic et al. showed there was a positive association between serum Vitamin D level and the amount of serum testosterone - not an effect that a man who is taking androgen deprivation wants.

Given that Vitamin D has no effect on incidence of cancer or cancer mortality, that it has no cardiovascular benefit, and no effect on bone mineral density, there is no reason to take supplemental Vitamin D unless serum levels are too low (below 20 ng/ml). 

Supplementing Vitamin D and Calcium increases risk of Myocardial Infarction

Li et al.Xiao et al., and Boland et al. reported that supplementing calcium, but not dietary calcium intake, was associated with a higher risk of myocardial infarction, and increased rates of plaque deposition (see this link). Kassis et al. found the association was true whether or not Vitamin D was supplemented with it. It is possible that increasing calcium absorption using Vitamin D may increase the risk of myocardial infarction. It also increases the risk of kidney stones.