Review of Vitamin D Research on Cancers

 Copy from "2009 by American Society of Clinical Oncology

Vitamin D in Cancer Patients: Above All, Do No Harm

1. Pamela J. Goodwin

+ Author Affiliations

1. Samuel Lunenfeld Research Institute, Mount Sinai Hospital and Princess Margaret Hospital, University of Toronto, Toronto, Ontario, Canada

In this issue of Journal of Clinical Oncology, Crew et al¹ report results of an examination of vitamin D in 103 premenopausal breast cancer patients who participated in a 1-year trial of zoledronate compared with placebo, in which all women received daily vitamin D (400 IU) and calcium (1,000 mg). Seventy-four percent of women were vitamin D deficient at study entry shortly after diagnosis; deficiency was more common in black and Hispanic women than in white women. After 1 year, less than 15% of the white women (but no Hispanic or black women) who had been vitamin D deficient at baseline achieved sufficient levels in their blood. The authors conclude, “…our study suggests that a dose of 400 IU daily is inadequate in breast cancer patients even to maintain skeletal health, and is probably too low for meaningful anticancer effects.” They go on to comment that controversy exists as to the upper safe daily limit of vitamin D supplementation and suggest “…it may be prudent to follow serum levels of 25-OHD [25-hydroxyvitamin D]…” This carefully conducted study echoes results recently reported by Neuhouser et al² (that approximately three fourths of patients with breast cancer from Los Angeles had inadequate blood levels of vitamin D) and by our group³ (that the same proportion of patients with breast cancer in Toronto had inadequate levels).

A search on PubMed using the terms “vitamin D,” “vitamin D and cancer,” or “vitamin D and breast cancer” from 1990 to November 2008 yielded the results shown in Table 1. The total number of articles relating to vitamin D published annually during that period has more than doubled, the number relating to cancer and vitamin D has almost tripled, and the number relating to breast cancer and vitamin D has increased almost six-fold. It is likely this increase reflects both a desire to generate evidence on effects of vitamin D that are now recognized to extend beyond bone health and calcium metabolism (including effects on neuromuscular and cardiovascular health, autoimmunity, infection, and cancer)⁴ and a belief, not fully supported by evidence, that vitamin D deficiency is a cause of ill health in the general population that should be treated with increasingly high doses of vitamin D.⁵ A recent meta-analysis⁶ of nine studies of vitamin D supplementation showing that vitamin D supplementation in doses that ranged from 300 to 2,000 IU/d (mean, 528 IU/d) was associated with a modest but significant reduction in mortality (relative risk, 0.93; 95% CI, 0.87 to 0.99) provides some support for this belief; however, evidence for other health effects is weaker, and the authors recommended further study.

When one looks at the association of vitamin D with cancer, the evidence is intriguing.^5,7,8 For breast cancer,⁹ the strongest evidence is obtained from ecological studies that concluded that higher cancer rates in northern (v southern) latitudes were due to vitamin D deficiency. Observational studies examining the association between vitamin D intake or blood levels in relation to cancer risk in general, and breast cancer risk in particular, have yielded inconsistent results.^6–8 Evidence of an adverse effect of vitamin D deficiency in colorectal cancer has been most consistent.^10,11 Randomized trials, designed primarily for bone end points, have also yielded inconsistent results. Lappe et al¹² reported a reduction of overall cancer risk (a secondary end point) in postmenopausal women randomly assigned to receive calcium alone or calcium plus vitamin D (1,100 IU/d) versus placebo; there was no vitamin D–only arm and cancer risk did not differ between the two calcium-containing arms. In contrast, a recent report from the Women's Health Initiative¹³ failed to identify a beneficial effect of vitamin D supplementation (at a lower dose of 400 IU/d) on breast cancer risk compared with placebo. A note of caution is injected by reports that higher blood levels of vitamin D (well below the range considered toxic) may be associated with increased esophageal and prostate cancer risk or with more aggressive prostate cancer.^14,15 (check this reference out)  Taken together, the available information is inadequate to conclude whether vitamin D influences cancer risk or mortality; furthermore, in individual studies in which vitamin D has been associated with cancer, it is not clear whether it is vitamin D or the company that it keeps (eg, diet, outdoor activity, healthy weight, higher socioeconomic class) that is the potentially responsible agent. The issue of causality is of particular concern given previous failed attempts to confirm the potential cancer-lowering effects of micronutrients such as β-carotene in cancer in randomized trials, even though observational studies suggested important effects.¹⁶

Notwithstanding lack of high-level evidence, an effect of vitamin D on cancer risk or outcome is biologically plausible.^17–20 Recent research has demonstrated that many tissues express 1,25-vitamin D hydroxylase, and are thus able to convert the predominant circulating form of vitamin D (inactive 25-OHD) to active 1,25-dihydroxyvitamin D. This 1,25-dihydroxyvitamin D can bind to vitamin D receptors, which are present on the nuclei of most cells. These vitamin D receptors are nuclear transcription factors that regulate the expression of more than 200 genes responsible for cell differentiation, proliferation, and apoptosis. The potential for major biologic effects underscores the critical importance of understanding the clinical impact of vitamin D on cancer risk and outcome, and should serve as stimulus for a targeted, adequately funded program of research in this area.

While awaiting results of this future research, as oncologists, we are being asked to advise our patients about whether they should take vitamin D supplements and, if so, what dose they should take. The unpredictable relationship between vitamin D intake and blood levels^13,21 (likely reflecting individual variability in diet, absorption, metabolism, and adiposity, and in sun exposure as an alternate source of vitamin D) makes it difficult to recommend a standard supplement dose and supports incorporating measurement of blood levels into recommendations. Although there is some minor disagreement about specific cut points,^4,21–24 most authorities suggest that a blood level of 25-OHD (the best marker of vitamin D status) of approximately 75 nmol/L (30 ng/mL) is required for vitamin D sufficiency, and levels above 375 nmol/L (150 ng/mL) are potentially toxic (associated with increased risk of hypercalcemia⁴; Table 2). One recent review²¹ suggests that there may be a “most advantageous” range of 25-OHD that starts at 75 nmol/L (30 ng/mL) and is ideally 90 to 100 nmol/L (36 to 40 ng/mL) that is associated with optimal musculoskeletal, neuromuscular, and cardiovascular health and immune function. Evidence regarding the safety of higher blood levels of vitamin D or supplementation with large doses of vitamin D focuses almost exclusively on short-term (up to 6 months) effects on calcium metabolism. Hypervitaminosis D (25-OHD > 375 nmol/L or > 150 ng/mL) is associated with hypercalcemia and resulting complications, including renal stones and bone demineralization.^22,24 Information regarding effects of high levels of vitamin D on cell proliferation, differentiation, and apoptosis (of great relevance to cancer) or on other non–calcium-related health outcomes is lacking and is urgently needed.

View this table:

• In this window
• In a new window

Table 2.

Interpretation of Blood 25-OHD Levels

With this background, what can we recommend to our patients? Current recommendations in the United States are 200, 400, and 600 IU per day of vitamin D₃ (available in over-the-counter preparations) in individuals age younger than 50, 50 to 70, and older than 70 years, respectively; an equal dose of vitamin D₂ (available by prescription) is approximately 30% as effective in maintaining vitamin D blood levels.²⁴ There is sufficient evidence that vitamin D supplementation at these doses is associated with reduced mortality⁶ and improved bone health that we should feel comfortable with these doses as a starting point. However, as Crew et al¹ point out, many of our cancer patients will be vitamin D deficient with this approach, and higher supplement doses will often be warranted, particularly in those whose therapy (eg, breast cancer patients receiving aromatase inhibitors) puts them at increased risk for adverse effects of vitamin D deficiency. In considering higher doses, oncologists should aim to achieve the benefits of adequate vitamin D levels but they should also be guided by the principle primum non nocere (above all, do no harm). Some oncologists may be comfortable endorsing a higher dose in all patients; a dose of 1,000 IU/d is often suggested.⁵ However, rather than endorsing an arbitrary higher dose, measurement of blood levels of 25-OHD is the most prudent approach to determine those who might benefit from vitamin D supplements, and to ensure that levels are in the advantageous range (90 to 100 nmol/L, or 36 to 40 ng/mL) in patients who are taking them. This approach should maximize known benefits and avoid both known (hypercalcemia and its associated complications) and potential unknown (cancer-related) adverse effects.

This advice should be viewed as interim. There may be specific benefits and harms associated with vitamin D supplementation in cancer patients that are not present in the general population, despite the fact that these benefits and harms have not been conclusively demonstrated. As a result, oncologists making recommendations to individual patients should take a cautious approach. Although this advice may be controversial, these recommendations should have a high chance of benefit and they should not harm our patients. As results of ongoing and planned research become available, many unanswered questions will be resolved, and more definitive recommendations that can be embraced by oncologists will be forthcoming."  end article copy

ANALYSIS:  The Focus from this review is that there are still vital pieces of the vitamin D puzzle still waiting to be uncovered. BUT, the most opportune levels are mentioned as between 30-40 ng/mL, or 75-100 nmol/L. MDs should be careful not to recommend higher supplement levels for one specific condition without monitoring the effects increased D levels might have on other organs and tissues or disease conditions.

REMEMBER:  Certain Cancer cells develop the ability to generate an enzyme to suppress vitamin D activation and to speed it's elimination out of the body. Therefore, subjects with cancer would test lower vitamin D levels anyway. 

Here is a reference that shows how vitamin D might work in malignant melanoma, MM, cancer suppression. Strange that MM develops from Sun exposure and vitamin D from sun exposure helps prevent it.

Vitamin E and Selenium on Throat Cancer

The following abstract shows vitamins have more influence early rather than in later cancer stages:

'Chemopreventive effects of early-stage and late-stage supplementation of vitamin E and selenium on esophageal carcinogenesis in rats maintained on a low vitamin E/selenium diet

1. Hui Yang, Jin Fang, Xudong Jia, Chi Han, Xiaoxin Chen1, Chung S. Yang2 and Ning Li*

+ Author Affiliations

1. Department of Food Toxicology, Institute of Nutrition and Food Safety, Chinese Center for Disease Control and Prevention, 7 Panjiayuan Nanli, Beijing 100021, China
2. ¹Cancer Research Program, Julius L. Chambers Biomedical/Biotechnology Research Institute, North Carolina Central University, 700 George Street, Durham, NC 27707, USA
3. ²Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, 164 Frelinghuysen Road, Piscataway, NJ 08854, USA  

• Received August 25, 2010. Revision received December 9, 2010.
• Accepted December 17, 2010.

Abstract

Low vitamin E and selenium (Ve/Se) nutritional status is known to be associated with increased risk of esophageal squamous cell carcinoma (ESCC). A previous human intervention trial demonstrated that Ve/Se supplementation decreased the occurrence of esophageal cancer death among younger participants but not among older ones. In this study, we intended to mimic this human nutritional status to determine the chemopreventive effects of Ve/Se supplementation at the early or late stage of esophageal carcinogenesis in rats maintained on a low Ve/Se diet. ESCC was induced in F344 rats with N-nitrosomethylbenzylamine (NMBzA) (0.35 mg/kg body wt, subcutaneously, three times per week for 5 weeks). The rats were maintained on a modified AIN-93M diet with low levels of Ve/Se or supplementation to the normal level by using the AIN-93M diet. At Week 25, the numbers of visible tumors and ESCC were significantly lower in rats on AIN-93M diet during the entire experimental period (Group D) or during the early stage (Group B) but not during the late stage (Group C). Ve/Se supplementation (switching from the low Ve/Se diet to the AIN-93M diet) also decreased cell proliferation, angiogenesis, 8-hydroxy-2′-deoxyguanosine, biosynthesis of prostaglandin E2 and leukotriene B4, expression of cyclooxygenase 2 and 5-lipoxygenase in the esophagus. Our results demonstrated that Ve/Se supplementation inhibited NMBzA-induced esophageal carcinogenesis in rats on low Ve/Se diet, and supplementation during the early stage is more effective than during the late stage of carcinogenesis.'   (end copy article)

Selenium, Vitamin E on Prostate Cancer

The new vitamin criteria recommends a rather low amount for selenium, 50 mcg. or under. This article reveals WHY this is critical.

THE SELECT STUDY

A rather large study testing Vitamin E and Selenium for anti-prostate cancer effects, called the SELECT study, proved to be a major disappointment. ref  So much so that it was stopped after the mid-term analysis. Researchers found that not only did the nutrients fail to show protection against prostate cancer, there was a slight elevation of cancer cases in the vitamin E only group and the selenium group exhibited a slightly elevated diabetes risk.  Another study with same results. Remember before these results there were some reports showing selenium is effective against some cancers. It probably still has value as long as it is between proper levels and/or in balance with other related nutrients. 

THE ANALYSIS, Selenium First 

Many scientists assumed the obvious after the results were announced. And that is that Vitamin E and Selenium do not work. But, another group commented on possible explanations for these results. They reported that supplemental selenium appears to offer benefits if your levels are low, but not if you are already in the high range and add more. ref There are now two possible explanations. One is that diabetes changes and upsets protein carrier levels for Selenium, pushing selenium levels up into unhealthy levels for the next explanation. The other is the increased selenium could increase Glutathione Peroxidase production deactivating free radicals (ROS) which the body needs to turn on the switch for insulin and glucose uptake by cells. ref (selenium, Se, is an anti-oxidant) ref <caution on adjective selection to make it look like big differences but really quite small) ref <**(see summary below) ref  ref  (positive> + ref  ref

NOTE: From the "+ ref" above, copied here is an important message for selenium:  

"The difference between the beneficial effects and the harmful effects of selenium is very narrow," said Dr. Eliseo Guallar of Johns Hopkins University in Baltimore, who has studied the mineral's health effects but was not involved in the new study. "A little bit can be very good, but once you go above a certain level there can be side effects."

The Take Away for Selenium

Increasing levels from dietary food is protective against diabetes risk in a positive upward linear line influence. BUT, supplemental Selenium could push one into a detrimental action area if natural intake levels are already at top end of recommended amounts. ref See Antioxidant load balance.  This is why the new vitamin criteria puts Selenium at such a seemingly low amount, plus it might be wise to occasionally skip consumption days or even weeks if one does not test blood levels. Natural food dietary selenium amounts in the U.S.A. typically fall between 90 to 135 mcg. ref ref

Sidebar: Conclusion from one study listed above, ref, on Selenium and diabetes: CONCLUSIONS—In a probability sample of the U.S. population, high serum selenium levels were positively associated with the prevalence of diabetes. Until findings from prospective studies and randomized controlled trials are available, selenium intake, including selenium supplementation, should not be recommended for primary or secondary diabetes prevention in populations with adequate selenium status such as the U.S. population.

"Selenium as selenomethionine had nearly twice the bioavailability of selenium as selenite." Best not to consume the inorganic forms of sodium selenite and sodium selenate. Even in pet foods> ref

VITAMIN E in the SELECT study

The SELECT used the SYNTHETIC form of vitamin E. Here is what the results said about the vitamin E side of the SELECT prostate study. The Vitamin E group exhibited a slightly increased prostate cancer rate. In order to fully understand these results, one has to know these few facts about vitamin E: 

1. Vitamin E supplements contain only 1 of 4 tocopherols found in nature and none of the other related four E activity tocotrienol family members. (Alpha, Beta, Delta & Gamma tocotrienols)
2. This one tocohperol form can only be called vitamin E or given vitamin E units, the d'alpha tocopherol, or the synthetic form listed as dl'alpha tocopheryl acetate.
3. Many studies, including the SELECT study, use synthetic dl"alpha tocopheryl which has additional problems of interference in absorption by crowding absorption sites or maybe by crowding out docking sites for the other E family members,(natural E also has this action when isolated and given at higher amounts ).
4. Prostate cells can be attacked by two types of free radicals, oxygen and nitrogen radicals.
5. Alpha tocopherol works against the oxygen radical but not against the nitrogen.
6. It is Gamma tocopherol that works against the nitrogen radical.
7. Taking a high dose of supplemental vitamin E as Alpha tocopherol suppresses the blood levels of natural Gamma tocopherol arriving in food, plus also those of the other tocopherols and all four tocotrienols as well.
8. This reduction might compromise the prostate cell protection against nitrogen radicals.
9. Research shows Gamma tocopherol and some of the tocotrienols have greater ability to protect prostate tissue than alpha tocopherol by itself.   ref
10. The results of the SELECT study are not that unexpected when you know these facts. ref **
11. The SELECT study, initiated largely due to observed facts that higher vitamin E levels equated to less cancers, simply did not consider that many earlier study findings were mainly from food sources which provided lower selenium amounts than tested plus included quantities of all the vitamin E family members as nature puts in foods.  
12. Plus, Vitamin E increased prostate cancer risk only if selenium levels were low. ref

SIDEBAR: The preceding points 4, 5 & 6 relate to anti-oxdiant activity. There is a delicate balance needed by the body between anti- and pro- oxidation actions for various metabolic and protective functions. Some studies on Vitamin E do not show a positive result. It could be that the amount of vitamin E used unbalanced the anti-oxidant load. The body has developed ways to harness the reactive nature of free radicals for positive functions which too much vitamin E could disrupt..

For complete nutritional protection, DO NOT SUPPLEMENT WITH high dose FRACTIONATED VITAMIN E as natural d'alpha tocopherol or synthetic dl'alpha tocopheryl etc. You should take some of the other family members too. The proper amounts still need to be determined. It could be 1:1 for gamma and alpha tocopherols, or 2:1. This needs research but is not getting any yet. Three studies using 50, 200, and 400 of alpha tocopherol found the most benefit at just 50 with a slight negative at 400, possibly from interference with the other family E members absorption or enhanced elimination. This could be related to the anti-oxidant activity generated by each amount.

STUDY CONCLUSIONS

** Here is the conclusion from this study: "Statistically significant protective associations for high levels of selenium and alpha-tocopherol were observed only when gamma-tocopherol concentrations were high."  Did you catch that the SELECT study began AFTER this study results were posted that showed gamma tocopherol was needed. DOES THIS MEAN THE SELECT STUDY SET OUT TO FAIL?

SIDEBAR: News about Statin use increasing Diabetes risk. Could this same above mentioned mechanism of too much anti-oxidant activity be at play with Statin use too.  ref  Obviously, statin patients may have heart conditions and be at a higher risk of diabetes even without considering selenium levels.

Summary from ref above: First, they indicate that an optimal degree of ROS production is requisite for normal activation of glucose transport during exercise. Second, they indicate that excessive administration of antioxidants can have deleterious effects on glucose utilization during exercise and possibly glycogen resynthesis during recovery from exercise. This could have negative consequences for skeletal muscle performance.

SELENIUM IN SOIL AND DIABETES

One last research needs to be mentioned to add clarity to these selenium results. The diabetes risk varied for different regions of China. After analyzing for an association, selenium levels showed a connection. In regions where there was a naturally high level of selenium in soil and thus a higher amount in foods grown there, the diabetes rates were higher. ref

SELENIUM ON CANCER

From the SELECT study, the group that took both Selenium and vitamin E and the selenium only group both exhibited greater advanced prostate cancers. ref Although only the vitamin E group was significant for overall prostate cancer, both the selenium only and selenium and vitamin E groups had increases that were very small and not significant. At 200 mcg, selenium could upset the antioxidant balance when added with dietary amounts. Plus, it is also possible that selenium works synergistic to enhance the vitamin E results mentioned below.

But, these last two references should seal the deal. Selenium levels and cancer got off the a fast protective start looking only at levels ingested from food. But research studies using supplements told a different story. Most used 200 mcg. of selenium. Selenium and skin cancer. ref   Remember, selenium is a trace mineral only needed in a rather small range of amounts. There are adverse effects at both too low and too high. Supplements over 50 mcg should NOT be used, period. Especially since few people have blood levels of selenium tested. PLus, it might be precautionary to skip days at even the 50 mcg too.

OF INTEREST FOR FUTURE Analysis: Why prostate cancer often spreads to bone? Looking at PGE2 and Bone factors RANKL and OPG on stimulation of bone building or osteoblastogenesis versus bone tearing down for osteoclastogenesis actions on prostate cancer spreading to bones. ref

Breast Cancer and Bone Density

This association is of critical significance. For the most part, Breast Cancer Risk is elevated with higher Bone Density in older women. This paradox needs an evaluation to clarify this observation. There are many possible variables; Estrogen levels, Dietary calcium intake and other bone building nutrients, Type of Dietary foods associated with higher bone densities like Dairy, Supplements such as vitamin D, E, & K, Type of Fats Consumed, Exercise influences, etc.  ref  ref   ref

One possibility is that greater bone density, associated with greater calcium uptake and thus greater dairy, is the result of higher IGF-1 levels from dairy foods. This does make sense. Check out these.  ref 

This next review is important, it shows how much calcium and vitamin D to take and blood levels for vitamin D to maintain for the lowest breast cancer risk from studies to date. Look at how close they are to recommendations of this new vitamin Criteria...interesting!  Would take some additional sun exposure to get vitamin D body levels to 30 ng/ml.

Breast Cancer Res Treat. 2012 Jul 25.

NEW TOPIC FOR DISCUSSION: OPG to RANKL balance

This is a very new direction for bone health that explains quite a few past mysteries and gives immense understanding to what should be the proper protocol for osteoporosis treatment. ref  Here are some of the issues:

• The normal bone building, maintenance, and repair process means more bone is built when young until about age 40 when a slight 1%/year reduction begins to occur until menopause when the accelerated reduction of estrogen production equates to between a 3-5% bone loss for a few years. Then a return to again about a 1% lost per year. But this pattern can be modified by diet and exercise. And it is probably influenced by gene polymorphism.

• Osteoporosis occurs when more bone is being torn down than is being re-built back up, and/or as bone structure suffers breakdown. Bone intregrity is a combination of density and structure. 

• How this occurs has been the subject of many theories in the past. 
• Calcium levels and vitamin D played a major role in some of these theories. 
• Long term research has now shot holes in most of these theories, they simply do not work at protecting against fractures or even to explain the observed events.

• Fosamax is one of the older bone drugs which tries to regulate the bone repair process by using an agent to kill some of the overactive tear down cells in an attempt to re-balance with the lower level action bone re-building cells.

• Today, new research is looking at a system called TNF for Tumour Necrosis Factor.
• This system includes 3 key proteins, RANK (the gene), RANKL (a ligand), and Osteoprotegerin, or OPG for the decoy that balances RANKL activity on cell receptors. ref
• These 3 proteins are influenced by many hormones, like estrogen, and body messengers; cytokines, PTH (directed by calcium blood levels), Vitamin D, and PGE2 (an inflammatory agent connected to fatty acids thru the omega 6 to omega 3 ratio)
• Up until menopause, estrogen controls RANKL activity thru OPG and maintains a normal and balanced bone re-building to renew and strengthen bones one section at a time.
• Recently it was found that in breast cancer and bone disease, the balance between RANKL and OPG needed for normal bone rebuilding was disturbed. Too much RANKL, the activator, and not enough of OPG, the regulator to control RANKL activity. ref
• RANKL is responsible for activating the development of bone cells (osteoclasts) that tear down small sections of bone as part of the repair process to allow bone rebuilding by osteoblasts in that empty space.
• Science is now looking for ways to get the body back into balance between RANKL and OPG. ref
• Resveratrol at non-toxic concentrations dose-dependently inhibited RANKL-induced osteoclast differentiation and induced apoptosis, and, suppressed RANKL-induced ROS generation  ref
• Magnesium also has RankL inhibitor actions, but at current consumption levels of only 68% of RDA level, it fails to protect bones. ref
• Higher magnesium levels associated with improved survival from breast cancer. ref
• The most recent drugs introduced to quiet RANKL activity, i.e. Prolia, have proved to be a disaster for side effects and were approved for and only used in very high risk osteoporosis patients. ref
• These drugs have simply pointed out that RANKL needs to be in balance and not almost completely shut down since it is necessary for functions in other vital body processes, like the immune system protection against infections and cancer. ref
• This OPG and RANKL balance is also the area of influence for Strontium initially on bone building. CAUTION: Strontium at 680 mg should only be used under medical supervision. There are some side effects, and after a number of years, Heart disease risk is increasing with more heart attacks.

Are there other NATURAL ways to CONTROL RANKL?

• Hinted above is that Fish oil Omega 3 (EPA exactly) is necessary to balance with Omega 6, largely from vegetable oils, to limit and control PGE2 production, a possible factor in creating inflammatory actions that increase RANKL. ref
• PTH, a parathyroid hormone activated when blood calcium levels get too low, can decrease OPG levels plus later increase RANKL.  ref
• Controlling PTH secretion is why certain amounts of calcium and vitamin D are needed in the diet. To balance out the calcium that is lost each day, an intake of about 600 mg. of calcium may be needed. This amount from research in the USA has varied from 300 to 720 mg in different diets and activity conditions.  Vitamin D appears not to be directly related to OPG or RANKL levels except through PTH levels. ref 
• Remember, other body and dietary conditions influence how much calcium gets absorbed. Since the average calcium absorption is about 33%, this means the calcium requirement in the USA is set at 1200+ milligrams a day. This is still to this day somewhat controversial since even at 1200+ mg, bones still fracture.  In the rest of the World, the calcium requirement is about 750 mg or less, and bones exhibit fewer fractures. WHY and HOW?
• Certain foods, herbs, and spices contain actives that possibly influence RANKL expression. Check out this article on Curcumin, an element in Tumeric.
• Plus, an element in Olive leaf extract has shown RANKL control on another level, thru Notch 1 cell to cell communication for TNF ref ref (listed by description only at bottom) 
• Or how about dried plums, yes only animal studies, but.. ref ref
• Tocotrienols, other vital Vitamin E family members, are mentioned here, especially number 4 & 5.   

What all this means to bone health is still to be worked out. But, in breast cancer...?

The take away is to avoid the drugs that block RANKL almost completely and possibly cause the jaw bone to deteriorate. Age would certainly play a major role in decisions. And bone fracture and cancer risks both need to be part of the calculations.

To be continued...

NOTE: While research continues to refine knowledge about RANK, RANKL, and OPG,  it appears that when there is a disruption between them, disease is often the result. Estrogen positive Breast cancers exhibit different expression levels versus estrogen negative cancers. How does this next study fit in with the above RANKL and OPG story for drug action. It says lower expression of RANK and RANKL is associated with greater bone metastasis and increased mortality from breast cancer while lower OPG is associated with better outcomes. Compare to this study. They seem to be at odds with each other. The important aspect appears to be that an upset ratio of RANKL to OPG is not healthy, regardless of expression level of RANKL compared to healthy tissues. Both RANKL and OPG may vary over the bone cell development process so absolute levels may not be as important as the overall balanced long term ratios, especially as demonstrated in cancers that matastize to bone. Prostate Cancer link to RANKL and OPG.

WRAP UP: Another Breast Cancer article for your consideration found under Health Theory Development. One last thought: Remember that this RANK system is involved in developing both the tear down and build up cells for healthy bone remodelling, a process that is necessary and lifelong to maintain healthy bones. The happenings after the bone cell development process are another story? Bone building nutrients and exercise forces still play a significant role in health of the finished bone. Bones need both the proper density of minerals as well as a strong and pliable STRUCTURE. article 

Along Comes Vitamin B1

Did you notice the title phase for this section: Cancer on Vitamins. Cancer cells love certain vitamins because the way vitamins function supports cancer rapid cell growth. ref (NOTE: This same study will appear in many references on this page from different sources. Some offer new information.) Here is a positive use of B1 on some cancers. But there is another story. So far this new connection for vitamin B1 is only from a few abstracts, but when you add in the fact that certain cancer drugs function by reducing available vitamin B1 activity in cells, more support for this concept is generated and this needs immediate attention to clarify! ref ref  Copy from preceding reference: "When there is too much vitamin B₁ there may be a risk that cancer cells grow faster." ref General info on Vitamin B1

                  ...not heard of this before?

You very likely have not heard this one before! Vitamin B1 functions to increase energy from food and also for cell proliferation through the ribose energy connection. Since tumor cells divide very rapidly, they quickly use up vitamin B1 and a deficiency can often be found in cancer patients. But, this does not mean you should take vitamin B1 since that would also feed the cancer cells to grow faster as well. In fact, a new cancer treatment is designed to actually create a localized deficiency of Vitamin B1 to enable chemotherapy drugs greater time to kill more tumor cells and prevent residual cancer cells from returning to life later. ref  ref ref

From an animal study, giving moderately high doses of Vitamin B1 at 25 times RDA (about 30 mg for Adults) resulted in a 164% increase in tumor growth, while paradoxically, at super mega dosages of 2500X RDA, a 35% reduction occurred (only under medical care). This super mega effect is not understood yet! But it is the 25X level and even less that is of concern since many supplements are available with amounts at this level. ref  To find out if this also occurs in humans needs immediate clarification. Here is a reference that mentions how the mega high dose B1 takes out cancer cells. ref ref

Check this important information. ref  It also has the abstract vital pieces for the B1 tumor connection. They are still controversial. This B1 connection may only take effect for certain cancers or at certain stages of the disease process. Very limited human research on this critical topic. 

SIDEBAR: In some cancers, vitamin B1 is found in greater amounts in urine but measures low in blood plasma. This indicates that the body has lost the ability to convert vitamin B1 into the proper form. Cancer cells may play a role in this lost ability. They want vitamin B1 for themselves. B1 offers protection for cancer cells against the actions of some chemo-drugs. Vitamin B1 is found in greater concentrations in cancer tumors where it helps generate energy for the growing tumor, even though overall the body is deficient.

Return periodically for any updates.