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

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.

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.

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. 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 (or any other) 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 two 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 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 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.

Scragg et al. in a post-hoc analysis 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). While I'm aware of no studies of Vitamin D supplementation on BMD in men, there was a major meta-analysis mainly in post-menopausal women. 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.

 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).