Controversies in Nutrition By Alan R. Gaby, M.D..

Controversies in Nutrition

By Alan R. Gaby, M.D.

A Modern Day Tea Party?

Don’t be Mad: Be Responsible

Recent controversies

Does calcium cause heart disease?

Is supplementing with high-dose vitamin D to achieve an “optimal” serum 25(OH)D level safe and beneficial?

Is megadose iodine safe and beneficial?

Does vitamin E increase mortality and cause congestive heart failure?

Recent controversies

Is lowering homocysteine levels with B vitamins beneficial?

Does folic acid cause cancer?

Does vitamin A cause osteoporosis and increase mortality?

Is high-dose strontium safe and effective for osteoporosis?


Meta-analysis of 15 randomized controlled trials: participants who received supplemental calcium as monotherapy (i.e., without other nutrients) had a 30% increase in the incidence of myocardial infarction (p = 0.035 to 0.038).

BMJ 2010;341:c3691


The data were derived from secondary (post hoc) analyses of studies (mainly osteoporosis studies) that were not designed to test the effect of calcium on heart disease risk.

BMJ 2010;341:c3691


Findings of borderline statistical significance from post hoc analyses are more likely to be due to chance than are findings of borderline statistical significance from primary analyses.

Calcium-magnesium interrelationships (Effects of a high-calcium diet in rats and pigs)

Decreased tissue magnesium levelsFed Proc 1986;45:374

Increased magnesium requirementsJ Nutr 1960;70:103-111

Increased severity of magnesium deficiency in animals fed a magnesium-deficient dietAm J Physiol 1951;166:408-12

Calcium-magnesium interrelationships (Effects of high-calcium intake in humans)

2 g/day of calcium (citrate) decreased Mg absorption and plasma Mg levels in healthy volunteers. Clin Sci 1967;32:11-18

Calcium supplementation had no effect on Mg balance in adolescent girls.Am J Clin Nutr 1996;63:950-3

Magnesium: a cardioprotective nutrient

Inhibits platelet aggregation

Vasodilator

Anti-arrhythmic activity

Required for ATP synthesis

Promotes intracellular potassium uptake

Possibly lowers BP and increases HDL-C

Magnesium: a cardioprotective nutrient

Rats fed a Mg-deficient diet developed myocardial necroses. Am J Pathol 1964;45:757-68

In rats, epinephrine-induced myocardial necroses were prevented by Mg. Arzneimittelforschung 1983;33:205-10

Mg prevented myocardial infarction induced by coronary artery ligation in rats. Can Med Assoc J 1960;82:212-3

Mg prevented the development of atherosclerosis in animals fed an atherogenic diet. Proc Natl Acad Sci 1990;87:1840-4

Magnesium intake is frequently low

NHANES 1999-2000: 50% of Caucasians consumed < 75-80% of the RDA; Mg intake was about 25% lower in African-Americans than in Caucasians.J Nutr 2003;133:2879-82

Mean Mg intake by high school and college women was 125 mg/day (60-65% below the RDA)J Am Diet Assoc 1969;55:38-43

Calcium-magnesium interrelationships

In people with low or suboptimal Mg status, administration of calcium without concomitant Mg supplementation could further compromise Mg status, and thereby increase the risk of developing heart disease.

Calcium-silicon interrelationships

In rats, calcium supplementation decreased the silicon content of bone. Fed Proc 1970;29:565

As a cross-linking agent, silicon may help protect arteries from injury. Lancet 1977;1:454-7

Silicon prevented the development of atherosclerosis in rabbits fed an atherogenic diet. Atherosclerosis 1979;33:397-408

Calcium: to supplement or not?

Adequate calcium intake is essential for optimal bone health.

In most instances, calcium supplementation should be accompanied by Mg (usual ratio, approximately 2:1), and possibly by silicon (perhaps 2-5 mg/day, as part of a multi-mineral formula).

High-dose vitamin D:

Is it safe

and effective?

Vitamin D deficiency

Rickets

Osteomalacia, osteoporosis

Weakness, falls

Myalgia

Decreased resistance against infection

Benefits of supplementation

Fewer falls & fractures, better bone density

Greater insulin sensitivity

Prevention of influenza

Prevention of asthma attacks

Improvement of hypertension?

Better mood?

Vitamin D: effective dosages

800-1,200 IU/day generally effective

400 IU/day generally ineffective

New RDA (2010): 600 IU/day for ages 1-70; 800 IU/day for ages ≥ 71

2,000 IU/day was used for prostate cancer: slowed disease progression, decreased pain.

Purported benefits of maintaining “optimal” vitamin D status

“Optimal” outcomes re falls, fractures, insulin sensitivity, BP, mood, etc.

Prevention of some cancers

Prevention of some autoimmune diseases

Better dental health

Vitamin D: new definition of deficiency

Traditional definition: deficiency = serum 25(OH) < 10-15 ng/ml (< 25-37.5 nmol/L)

New definition: deficiency = serum 25(OH)D < 20 ng/ml (< 50 nmol/L)

insufficiency = < 30 ng/ml (< 75 nmol/L)

Vitamin D: new definition of “optimal”

A review article concluded that a protective effect with respect to various outcomes began at a serum 25(OH)D level of 30 ng/ml (75 nmol/L) and that the best outcomes were seen in people with levels of 36-40 ng/ml (90-100 nmol/L).

Am J Clin Nutr 2006;84:18-28

Dosage requirements for new “adequate” and “optimal”

Only 50% of people will achieve “adequacy” (≥ 30 ng/ml) with 1,000 IU/day.

1,644-3,440 IU/day (depending on the study) will achieve “adequacy” in nearly all healthy adults.

Even larger doses (4,000-10,000 IU/day?) needed to achieve “optimal” levels.

Tolerable Upper Intake Level = 4,000 IU/day (recently increased from 2,000 IU/day)

Examining the evidence

Is routine use of vitamin D in dosages greater than 2,000 IU per day beneficial?

Is it safe?

My conclusions

Serum 25(OH)D is not always a reliable indicator of vitamin D status.

The new definitions of vitamin D deficiency and insufficiency may not be valid for some populations and some individuals.

Evidence supporting the benefit of pushing 25(OH)D to an “optimal” level is weak.

My conclusions

Evidence supporting the long-term safety of dosages > 2,000/day is weak.

The safety and efficacy of vitamin D supplementation cannot be inferred from data regarding the safety and efficacy of sunlight exposure.

Assessment of vitamin D status

Serum vitamin D: unreliable; serum half-life is only 24 hours.

Serum 1,25-dihydroxyvitamin D: unreliable; may be normal or elevated in people with vitamin D deficiency. Am J Clin Nutr 2004;79:362-371

Serum 25-hydroxyvitamin D: serum half-life is 3 weeks; more reliable than vitamin D itself.

Assessment of vitamin D status

Serum 25-hydroxyvitamin D

↓ ?

Serum 25-hydroxyvitamin D

Accuracy of 25(OH)D measurement

Substantial variations from one lab to another and with different assay methods

With nearly identical serum samples, one lab found that 90% were below 32 ng/ml; another lab found that only 17% were below 32 ng/ml.

Am J Clin Nutr 2008;87:1087S-91S

Validity of 25(OH)D measurement

25(OH)D is only one of more than 50 vitamin D metabolites identified.

Vitamin D nutritional status may be a function of complex interactions between many different vitamin D metabolites.

Different people may have different serum 25(OH)D “set points” for adequate or “optimal” vitamin D nutritional status.

Validity of 25(OH)D measurement

Serum 25(OH)D may be even less reliable as an indicator of vitamin D status when vitamin D doses are greater than 2,000 IU/day, because 25-hydroxylases become saturated at those dosages. Storage of large amounts of unmetabolized vitamin D may not be reflected in serum 25(OH)D measurements.

Am J Clin Nutr 2008;87:1738-42

New definition of deficiency: is it valid?

Definition is based on biochemical markers:

As 25(OH)D levels go up, parathyroid levels tend to go down and fractional calcium absorption tends to increase.


Vitamin D sufficiency is inferred when a further increase in serum 25(OH) does not further depress parathyroid hormone levels or further increase fractional calcium absorption. In population studies, the average 25(OH)D level at which vitamin D sufficiency occurred was around 30 ng/ml (75 nmol/L).

N Engl J Med 2007;357:266-81


In the absence of severe vitamin D deficiency, the associations between serum 25(OH), parathyroid hormone, and fractional calcium absorption do not seem to apply to all population groups, nor to all individuals.


Of 93 young adults living in Hawaii who had sun exposure a mean of 29 hours a week, 25-51% had a 25(OH)D level < 30 ng/ml and 3-8% had a level < 20 ng/ml. There was no correlation between 25(OH)D and parathyroid hormone levels.

J Clin Endocrinol Metab 207;92:2130-5


Those findings suggest either that the cut-off level for 25(OH)D used to define vitamin D sufficiency is either inappropriately high for some groups or that 25(OH)D is not always a reliable indicator of vitamin D nutritional status.



In the late 1990s, the standard RIA for 25(OH)D was changed. The new method decreased measured values by 4 ng/ml (10 nmol/L). Am J Clin Nutr 2008;88:1519-27

The new cut-off points for deficiency and insufficiency were based in part on studies done prior to the late 1990s.

New definition of “optimal”: is it valid?

Evidence is derived mainly from observational studies in which serum 25(OH)D was correlated with health outcomes. Findings conflicting.

Evidence is also derived from controlled trials in which vitamin D-supplemented patients who achieved higher 25(OH) levels had better outcomes than did supplemented patients whose 25(OH)D levels were lower.

Limitations of observational studies

Failure to control for confounders such as age, BMI, co-morbidities

High 25(OH)D levels result mainly from sunlight exposure. People who spend time in the sun differ from those who do not.

If sun exposure is beneficial, the effect may not be due entirely (or even primarily) to vitamin D.

Findings from controlled trials

Clinical trials did not compare higher-dose versus lower-dose vitamin D.

Instead they assessed outcomes as a function of the serum 25(OH)D response to vitamin D supplementation. That measurement might simply be identifying differences in body chemistry, rather than an effect of vitamin D supplementation.

Findings from controlled trials

A higher serum 25(OH)D response to supplementation might reflect:

More efficient nutrient absorption in general

More efficient 25-hydroxylation of vitamin D

Hepatic hydroxylase enzymes

Four different cytochrome P450 enzymes are thought to be capable of 25-hydroxylating vitamin D. Trends Biochem Sci 2004;29:664-73

Cytochrome P450 enzymes also help detoxify xenobiotic chemicals.

Hydroxylase enzymes also play a role in the synthesis of DHEA and estriol, both of which may have health benefits.

Extra-hepatic hydroxylase enzymes

Human testis (androgen-producing Leydig cells) and possibly ovary are also capable of 25-hydroxylating vitamin D.

25(OH)D levels were 60% lower in young men with h/o orchiectomy for bilateral testicular cancer than in matched controls.

Lancet 2010;376:1301

Extra-hepatic hydroxylase enzymes

Observational studies on 25(OH)D levels and health outcomes may be confounded by differences in levels of testosterone and DHEA. Both of these androgenic hormones may have positive influences on health.

Is high-dose vitamin D safe?

Tolerable Upper Intake Level for adults is 4,000 IU per day (recently increased from 2,000 IU/day).

Some investigators have argued that up to 10,000 IU per day is safe for most adults.

Basis of the argument that long-term use of 10,000 IU/day of vitamin D safe

Hypercalcemia uncommon with 10,000 IU/day

Whole-body sun exposure results in production of at least 10,000 IU/day without causing vitamin D toxicity.

Weaknesses of the argument

1. High-dose supplementation studies were of short duration.

2. Absence of hypercalcemia is not proof of safety.

3. Unclear whether human skin really can produce 10,000 IU/day of vitamin D

4. Physiological effects of sunlight exposure differ from those of vitamin D supplementation.

High-dose supplementation studies were of short duration

10,000 IU/day was given for a maximum of 20 weeks. As a fat-soluble nutrient, vitamin D can accumulate with continued administration.

Absence of hypercalcemia is not proof of safety

An increase in urinary calcium excretion (even within the normal range) might increase the risk of developing kidney stones.

3 of 45 elderly individuals who received 5,000 IU/day of vitamin D for 12 months showed evidence of hypercalciuria. Am J Clin Nutr 2009;89:1132-7

Absence of hypercalcemia is not proof of safety

Swine fed human equivalent of 11,500 IU/day of vitamin D3 developed pathological changes in the aorta that were indistinguishable from human atherosclerosis. Am J Clin Nutr 1979;32:58-83

Increasing vitamin D3 intake only modestly (equivalent to a total of 917 IU/day for humans) exacerbated atherosclerosis in swine induced by a diet high in butterfat. Nutr Rep Int 1983;28:1111-8

Can human skin can produce 10,000 IU/day?

This claim is based in part on a study in which UV irradiation of 5% of body surface area was equivalent to oral administration of 400 IU/day.J Bone Miner Res 1998;13:1238-42

No evidence that it is appropriate to extrapolate this finding to full-body irradiation


One-time exposure to 1 minimal erythemal dose of UV irradiation was equivalent to oral administration of 10,000-25,000 IU of vitamin D2.

This finding is of doubtful relevance to long-term vitamin D homeostasis.


Repeated sun exposure results in photodegradation of vitamin D that has not yet entered the circulation. Am J Clin Nutr 1995;61(Suppl):638S-45S

Therefore, net vitamin D production may be substantially lower on subsequent days than on the first day.

UV light and oral vitamin D are not the same

One photodegradation product of vitamin D (5,6-trans-vitamin D) has effects similar to 1,25-dihdroxyvitamin D, but is 20-40 times less potent.Biochemistry 1972;11:2715-9

5,6-trans-Vitamin D might compete with 1,25(OH)2D and thereby function as a regulator of vitamin D activity.

UV light and oral vitamin D are not the same

Sunlight (but not vitamin D):

Produces photodegradation products

Produces corticotropin-releasing hormone

May directly influence hypothalamic and pituitary function through the retina

What to make of it all

RDAs of 400-600 IU/day are not sufficient to promote optimal health. 800-1,200 IU/day is more effective than 400 IU/day.

The safety and efficacy of using high doses (such as > 2,000 IU/day) for the sole purpose of achieving a target 25(OH)D level has not been established.

What to make of it all

Doses greater than 2,000 IU per day may be considered in selected cases, but the potential benefits should be weighed against the risks.

Sunlight 5-15 min 2-3 times a week between 10 a.m. and 3 p.m. in spring, summer, and autumn is usually sufficient for skin types II and III. Am J Clin Nutr 2004;80(Suppl):1678S-88S

Iodine facts (µg/day)

Adult RDA 150

Median urinary [I] in US adults 168

Tolerable Upper Intake Level 1,100

Iodine: adverse effects

Very high doses 700-4,500 mg/day)

Thyroid dysfunction (mainly hypo-thyroidism), burning mouth, increased salivation, parotid and submandubular swelling, severe headache, acneiform eruptions, pulmonary edema, angioedema, heart failure, and death.


Moderately high doses (3-6 mg/day)

10.9% of 1,365 women treated for fibrocystic breast changes experienced side effects including acne, nausea, diarrhea, thinning hair, skin rash, headache, hypothyroidism (0.3%), and hyperthyroidism (0.1%). Can J Surg 1993;36:453-60


Modestly high doses (> 500 µg/day?)

Autoimmune thyroiditisHypothyroidismGoiter or increased thyroid volume

N Engl J Med 2006;354:2783-93; Thyroid 2003;13:561-7; Clin Endocrinol 1991;34:413-6; Lancet 1987;2:257-9; Am J Clin Nutr 2005;81:840-4

Iodine:A Lot

to Swallow

“Orthoiodosupplementation”(Guy Abraham, M.D.)

According to Abraham, the optimal dietary iodine intake is 13.8 mg/day, which is 92 times the RDA and more than 12 times the Tolerable Upper Intake Level.

http://www.optimox.com/pics/Iodine/IOD-02/IOD_02.htm

Basis of the claim

Japanese people consume an average of 13.8 mg/day of iodine, and are among the healthiest people in the world.

High-doses are needed to fully saturate the tissues, as demonstrated by an iodine-load test.

But it doesn’t make sense!

Of the many criticisms I had of Abraham’s theory, one was related to evolution: We have evolved in an iodine-poor environment. Our thyroid glands have developed a powerful mechanism to concentrate iodine, and some thyroid glands (or other tissues) might not function properly if iodine intake is increased by 90-fold.

To which Abraham replied . . .

“It is understandable why someone who believes in the theory of evolution has a problem with such high requirements for iodine in an environment depleted of this element. According to the biblical narrative, the Creator declared planet earth and everything in it perfect. Therefore, the original planet earth contained a topsoil rich in iodine, and all elements required for perfect health of Adam, Eve, and their descendants.”

To which Abraham replied . . .

“A sequence of events followed, culminating in the worldwide flood 4,500 years ago. Following this episode, the receding waters washed away the topsoil with all its elements into oceans and seas. The new topsoil became deficient in iodine . . .”

Townsend Letter for Doctors & Patients, October 2005

That doesn’t make sense either!

Humans have a powerful mechanism to concentrate iodine in the thyroid gland. In an iodine-rich antediluvian world, that mechanism would have been an imperfection, so the Creator could not have declared everything perfect.

Other statements by Abraham . . .

“Following World War II, there was a systematic attempt to remove iodine from the food supply of Christian America. Iodophobic misinformation, well synchronized with the introduction of alternatives to iodine supplementation in medical practice, strongly suggest a well planned conspiracy by agents of foreign powers planted at strategic positions in academia and the regulatory agencies.”

http://www.optimox.com/pics/Iodine/pdfs/IOD16.pdf. Accessed 10/10/10

Other statements by Abraham . . .

“In the early 1960’s, potassium iodate was added to bread as a dough conditioner . . . . This was an oversight by the agents of foreign powers . . . . One slice of bread contained the full RDA of 150 mcg. This amount of the dezombifier iodine in a major staple food of Christian America could not be tolerated for long.”

http://www.optimox.com/pics/Iodine/pdfs/IOD16.pdf. Accessed 10/10/10

Foreign agents plotting deiodination of America

Do Japanese people consume 13.8 mg/day?

Claim based on a misinterpretation of a 1967 paper. Average seaweed consumption in Japan = 4.6 g/day. Seaweed contains average of 0.3% iodine.

4,600 mg x 0.003 = 13.8 mg

However, 4.6 g/day of seaweed was wet weight, whereas 0.3% iodine was based on dry weight.


Amount of iodine consumed in Japan

In studies in the 1990s that specifically looked at iodine intake in Japan, mean dietary iodine (estimated from urinary iodine excretion) was 330-500 µg/day, which is 25-fold lower than 13.8 mg/day.

Nippon Naibunpi Gakkai Zasshi 1994;70:1093-1100; Nippon Naibunpi Gakkai Zasshi 1992;68:550-6

Amount of iodine consumed in Japan

According to a 2008 study, average iodine intake in Japan from seaweed was 1.2 mg/day in 2006 and 1.7 mg/day in 1986, which is 88-93% less than 13.8 mg/day.

Thyroid 2008;18:667

Abraham’s iodine load test

Patient ingests 50 mg of iodine/iodide. Patient considered iodine-deficient if < 90% is excreted in the urine over the next 24 hours.

92-98% of patients taking the test have been found to be deficient.

Abraham’s iodine load test

The validity of the test depends on the assumption that the average person can absorb at least 90% of a 50-mg dose.

No research in humans; proponents have not measured fecal iodine levels. In cows fed supraphysiological doses of iodine, 50% appeared in the feces. J Dairy Sci 1996;79:254-9

Adverse effects of “orthoiodosupplementation”

Toxic multinodular goiterGraves’ diseaseAutoimmune thyroiditisHypothyroidismSevere headachesDeep acneHair loss, agitation, sweatingEsophagitis

Megadose iodine: conclusion

3-6 mg/day may be considered for fibrocystic breast changes that do not improve with methylxanthine avoidance, vitamin E, etc.

As an antimicrobial agent, iodine may produce clinical benefit in selected patients by killing intestinal pathogens.

Beneficial for some other conditions, such as erythema nodosum and possibly some types of cysts.


Iodine is not indicated as a treatment for hypothyroidism except in cases of dietary iodine deficiency. High iodine intake can make hypothyroidism worse.


There is no credible evidence that routinely giving high-dose iodine based on an iodine load test or on a misunderstanding of human iodine requirements is either safe or beneficial.

Side effects of high-dose iodine are common, and in a small proportion of cases side effects are severe and/or persistent.

Does vitamin E cause heart failure?

In a double-blind study of patients with vascular disease or diabetes, treatment with 400 IU/day of alpha-tocopherol for 7 years resulted in a significant 19% increase in the incidence of heart failure compared with placebo.

JAMA 2005;293:1338-47

Does vitamin E increase mortality?

Meta-analysis of 19 randomized controlled trials found that long-term supplementation with ≥ 400 IU/day of vitamin E was associated with a significant 4% increase in all-cause mortality compared with placebo. In contrast, < 400 IU/day was associated with a nonsignificant decrease in all-cause mortality.

Ann Intern Med 2005;142;37-46

Vitamin E and heart failure: possible explanation

The study used pure alpha-tocopherol, whereas vitamin E as it occurs naturally in food consists of 4 isomers: alpha-, beta-, gamma-, and delta-tocopherol. Supplemen-tation with large doses of alpha-tocopherol (AT) can deplete gamma-tocopherol (GT).

J Nutr 2003;133:3137-40

Importance of gamma-tocopherol (GT)

GT is metabolized largely to 2,7,8-tri-methyl-2-(beta-carboxyethyl)-6-hydroxy-chroman (gamma-CEHC), which may function as a natriuretic hormone, since it is involved in the body’s response to sodium-induced plasma volume expansion.

J Pharmacol Exp Ther 1997;282:657-62; Proc Natl Acad Sci 1996;93:6002-7; J Nutr Sci Vitaminol 2004;50:277-82

Importance of gamma-tocopherol (GT)

GT depletion might lead to impaired regulation of sodium and water balance, potentially increasing the risk for heart failure.

If high-dose AT does adversely affect heart function in some people, one might reasonably expect that mixed tocopherols (which contain AT and GT) would not have the same negative effect, and might even be beneficial.

Vitamin E and mortality: study flaws

Three of the 19 studies in the meta-analysis, which included a total of 27,000 participants (two-thirds of all of the patients in the pooled analysis) had major weaknesses.


First study (n = 20,536): Patients, most of whom had heart disease, received beta-carotene in addition to vitamin E. Presumably, a large proportion were smokers. Beta-carotene increases incidence of lung cancer in smokers.

Lancet 2002;360:23-33; N Engl J Med 1994;330:1029-35


Second study (n = 3,640): In addition to receiving vitamin E, patients received 80 mg/day of zinc for an average of 6.3 years.Arch Ophthalmol 2001;119:1417-36

Long-term use of high-dose zinc can cause copper deficiency, which can lead to heart disease. Copper was given, but as cupric oxide, which is not absorbable.


Third study (n = 2,002): Vitamin E and placebo groups were not comparable at baseline. Vitamin E group had significantly higher serum cholesterol and significantly higher prevalence of hypertension, diabetes, smoking, and severe coronary artery disease.

Lancet 1996;347:781-6

If vitamin E does increase mortality

Possible explanations:

Use of synthetic (all-rac, or DL), as opposed to “natural” (RRR or D), alpha-tocopherol.

Use of alpha-tocopherol instead of mixed tocopherols

Vitamin E: synthetic vs. natural

Synthetic (all-rac, or DL): Only 1 of the 8 isomers is found naturally in the body.

In the only high-dose study in the meta-analysis (other than the flawed studies) that used “natural” (RRR, or D) alpha-tocopherol, the mortality rates in the vitamin E and placebo groups were identical.

N Engl J Med 2000;342:154-160

Vitamin E: alpha vs. mixed tocopherols

High-dose AT may deplete GT.

In addition to functioning as a natriuretic hormone, GT was more effective than AT in inhibiting platelet aggregation, prostate cancer cell growth, and oxidative DNA damage, and in increasing superoxide dismutase activity.

J Nutr 2003;133:3137-40; J Am Coll Cardiol 1999;34:1208-15

Vitamin E: alpha vs. mixed tocopherols

GT was more effective than AT as a scavenger of peroxynitrite (a mutagenic nitrating and oxidizing agent formed during the activation of phagocytes. Peroxynitrite is believed to play a role in the pathogenesis of cardiovascular disease, cancer, and neurodegenerative diseases.

Proc Natl Acad Sci 1997;94:3217-22

Vitamin E and mortality

If high-dose alpha-tocopherol (synthetic or natural) does increase mortality slightly, one might reasonably expect that the same adverse effect would not occur with mixed tocopherols, which contains both alpha- and gamma-tocopherol.

Is lowering homocysteine beneficial?

Homocysteine is a byproduct of methionine metabolism.

Oral or parenteral administration of homocysteine thiolactone (a precursor to homocysteine) caused atherosclerosis in rabbits.

Atherosclerosis 1975;22:215-227

Homocysteine: adverse effects

Individuals with homozygous homocystinuria (a rare inborn error of metabolism) develop early-onset osteoporosis, premature atherosclerosis, and thromboembolism, and usually die by age 13.

Homocysteine: observational studies

Hyperhomocysteinemia has been associated with an increased incidence of atherosclerosis, thromboembolism, stroke, osteoporosis, recurrent miscarriage, and age-related cognitive decline.

Homocysteine: genetic factors

The 677C→T variant of methylenetetra-hydrofolate reductase (which is associated with hyperhomocysteinemia) is associated with increased risk of heart disease, stroke, dementia, miscarriage, osteoporosis. This suggests that the association of hyper-homocysteinemia with these diseases is causal.

Homocysteine: positive clinical trials

In hyperhomocysteinemic stroke patients, 5 mg/day of folic acid plus 1,500 µg/day of vitamin B12 for 2 years reduced hip fracture incidence by 78%, compared with placebo.

No difference in incidence of falls or in metacarpal bone density, suggesting that the reduced fracture incidence was due to improved bone quality.

JAMA 2005;293:1082-8


In an uncontrolled trial, supplementation with folic acid, vitamin B6, and vitamin B12 appeared to reverse carotid athero-sclerosis in hyperhomocysteinemic patients.

Lancet 1998;351:263.


Meta-analysis of 8 randomized controlled trials found that folic acid supplementation significantly reduced the risk of stroke by 18%.

Lancet 2007;369:1876-1882

Homocysteine: negative clinical trials

Numerous randomized controlled trials have found that homocysteine-lowering regimens failed to reduce various endpoints including all-cause mortality, myocardial infarction, heart disease-related death, and venous thrombosis, and failed to slow the progression of Alzheimer’s disease.

Homocysteine: negative clinical trials

Because many trials have produced negative results, some researchers have pronounced the homocysteine theory of disease “dead.”

Possible explanations for negative results

Nutrient imbalances from supplementing with just a few nutrients (e.g., exacerbation of magnesium deficiency)

Is postprandial homocysteine more important than the fasting level?J Am Coll Cardiol 1985;6:725-30

Possible explanations for negative results

Betaine (and presumably choline) appear to be more effective than folic acid, B12, and B6 for lowering postprandial (i.e., post methionine load) homocysteine levels.Arterioscler Thromb Vasc Biol 2005;25:379-385.

Potential benefits of betaine and choline were not investigated in clinical trials.

Betaine and choline:recommended doses

Betaine: 500 mg/day to 2,000 mg 3 times per day

Choline: 500-1,000 mg/day

Does folic acid cause cancer?

Double-blind study: 1 mg/day for 3-8 years was associated with a higher incidence of prostate cancer (9.7% vs. 3.3% for placebo) in patients with recent colorectal adenoma. J Natl Cancer Inst 2009;101:432-435

Double-blind JAMA study: 0.8 mg/day was associated with a significant 21% increase in cancer incidence, 38% increase in cancer deaths.

JAMA 2009;302:2119-2126

Does folic acid cause cancer?Study weaknesses

1) Post-hoc analyses of earlier research that was designed to ask a different question.

2) Studies used folic acid alone or folic acid plus a few other nutrients. Effect might be different when part of a comprehensive nutritional program.

3) No increase in cancer incidence in the US since folic acid fortification of food began in 1998.JAMA 2009;302:2152-2153

Does folic acid prevent cancer?

Double-blind studies: folic acid supplementation for 3.0-7.3 years associated with a nonsignificant decrease in cancer risk in health professionals.

JAMA 2008;300:2012-2021; Am J Clin Nutr 2009;90:1623-1631

Observational studies: Folic acid supplementation or higher dietary folate intake was associated with decreased incidence of cancer.

Folic acid prevented cancer in some animal studies.

Benefits of folic acid

Prevention of neural tube defects

Prevention of strokes (Lancet 2007;369:1876-1882)

Along with B12, prevention of hip fractures in stroke patients (JAMA 2005;293:1082-1088)

Migraine prophylaxis in patients with elevated homocysteine levels (Headache 2007;47:1342-1344)

Folic acid and cancer: conclusion

Effect of folic acid on cancer risk and cancer mortality remains uncertain.

There does not appear to be any compelling reason to recommend that the general public avoid folic acid supplementation.

Folate supplements: synthetic vs. “natural”

Most supplements contain synthetic folic acid (pteroylglutamic acid; PGA).

PGA is metabolized in vivo to methylfolate, the form in which the vitamin is normally transported in the body.


Administration of large doses of PGA (> 400 µg/day?) might lead to the presence of large amounts of unmetabolized PGA, which could theoretically have an anti-folate effect through competitive inhibition of folate-dependent enzymes.


However, aside from that theoretical concern, there is no obvious reason to believe that synthetic folic acid is harmful. In addition, there is no evidence that other commercially available forms of supplemental folate (such as methylfolate, folinic acid, or 5-methyltetrahydrofolate) are safer than PGA.


Virtually all of the research demonstrating a beneficial effect of folate has been done using synthetic folic acid. Other forms of folate have not been shown to prevent neural tube defects, strokes, migraines, or osteoporotic fractures. Synthetic folic acid would therefore seem to be preferable to other folate preparations in most circumstances.

Does vitamin A increase mortality?

A review of 5 randomized controlled trials, which included a total of 21,677 participants, concluded that vitamin A supplementation increased the risk of death significantly by 16%, compared with placebo.

JAMA 2007;297:842-857.

Does vitamin A increase mortality?

Three of those trials, which included 96% of the pooled participants, are described in the following slides.

First vitamin A study

N = 18,314 (84.5% of the pooled participants). Participants were smokers, ex-smokers, or workers exposed to asbestos.

Intervention: Placebo or beta-carotene plus vitamin A. Beta-carotene has been shown to cause lung cancer in this population group.

N Engl J Med 1996;334:1150-1155

First vitamin A study

Even if vitamin A did contribute to the increase in mortality, the effect may not apply to non-smokers.

There might be a toxic interaction between vitamin A and tobacco smoke, analogous to the toxic interaction demonstrated between vitamin A and chronic alcohol consumption.

Alcohol Clin Exp Res 1983;7:15-21

Second vitamin A study

N = 2,297 (mean age, 63 years; 10.6% of pooled participants). 25,000 IU/day or placebo for ≤ 5 years.

Death rate during the study: vitamin A, 2.07%; placebo, 2.11%

Death rate including treatment period plus post-treatment follow-up: vitamin A, 5.4%; placebo, 4.6%

25,000 IU/day may be too high for some older people. Findings may not apply to general population.

Third vitamin A study

N = 109. Elderly nursing home residents: 200,000 IU of vitamin A (single dose) or placebo. During follow-up, death rate higher with vitamin A than with placebo (11.3% vs. 7.1%)

Vitamin A group on average of 4.8 years older than placebo group.

Should we be giving frail old people such a massive dose of vitamin A?

The other two “vitamin A” studies

Elderly people received a multivitamin-multimineral preparation containing 16 or 17 components (including a small dose of vitamin A (2,667 IU/day). No significant difference in mortality between groups.

Does vitamin A cause osteoporosis?

Observational studies: higher intake of vitamin A or higher serum vitamin A levels were associated with lower bone mineral density (BMD) or increased fracture risk.

Adverse effect seen even at low intake levels (≥ 6,667 IU/day; RDA = 2,333 IU/day).


Other observational studies: no association between vitamin A intake or serum vitamin A levels and BMD or fracture risk.

One study: higher serum vitamin A levels were associated with a nonsignificant decrease in fracture risk.

J Bone Miner Res 2005;20:913-920


Vitamin A at a human-equivalent dosage of 2.4 million IU/day caused bone abnormal-ities in rats, but the equivalent of 470,000 IU/day had no adverse effect. Bone 2003;31:685-689

Healthy men: 25,000 IU/day for 6 weeks had no effect on serum markers of bone turnover.

J Nutr 2002;132:1169-1172

Observational studies:confounding factors

Main dietary sources of vitamin A, aside from liver, are fortified breakfast cereals (usually with added sugar), fortified milk, and fortified margarine. Higher vitamin A intake may simply be a marker of increased consumption of these foods.

Diet and osteoporosis

Refined sugar: Adverse effect according to animal studies and observational studies.

Milk: effect unclear. Associated with increased fracture incidence on one study.Am J Public Health 1997;87:992-997

Margarine: Butter contains vitamin K2. Margarine contains hydrogenated vitamin K2 (dihydrophylloquinine), which is inactive.

Diet and osteoporosis

Liver: Accumulates lead and cadmium (both of which can cause osteoporosis). Also may accumulate various xenobiotic chemicals that could promote bone loss by inhibiting androgen activity.

J Endocrinol 1998;158:327-338

Strontium and bone: to dose or to megadose?

Typical diet provides 1-3 mg/day of strontium

Significant amounts lost in refining of flour

Strontium has high affinity for bone; promotes mineralization of bones and teeth

Stimulates bone formation, inhibits bone resorption

Two-year strontium clinical trial

Strontium % change in Incidence of newdose lumbar BMD vertebral fractures

Placebo +0.50 54.7%

170 mg/day +1.35% 38.8%

340 mg/day +1.65% 56.7%

680 mg/day +2.97% 42.0%

Study of 353 postmenopausal women with osteoporosis and a history of at least one vertebral fracture. J Clin Endocrinol Metab 2002;87:2060-2066.

Three-year strontium clinical trial

1,649 postmenopausal women, 680 mg/day of strontium for 3 years. Top half: % increase in BMD. Bottom half: % reduction in fracture risk.

Adapted from N Engl J Med 2004;350:459-68.

Potential adverse effectsof high-dose strontium on bone

• Syndrome resembling rickets in animals fed 1.5-3.0% strontium

• Bone mineralization defects in young rats at diet concentrations of 0.19% or greater in (equivalent to approximately 800 mg/day for humans). Rat diet contained 0.5% calcium. Bone 1990;11:313-9.

• High soil strontium concentrations associated with increased prevalence of rickets in Turkish children

Arch Dis Child 1996;75:524-6.

Other potential adverse effects of high-dose strontium

• Increased thyroid weight in rats fed 395 ppm of strontium

• Decreased pituitary weight in rats fed 98.7 ppm or 1,580 ppm, but not 395 ppm.

• Estimated no-observed-adverse-effect level = 98.7 ppm, equivalent to 41.1 mg/day for humans (calculation based on 2,000 kcal/day, 30% fat = 417 g/day of food, dry weight)

Toxicology 1977;7:11-21.

Adverse effects of strontium in 3-year clinical trial

Elevated CPK in 3.4% of patients receiving strontium, 1.8% of those receiving placebo. Elevations usually transient.

No mineralization defects found, but only mature (lamellar) bone was biopsied, whereas adverse effects would presumably be most pronounced in new bone.

N Engl J Med 2004;350:459-468.

Three-year strontium clinical trial

1,649 postmenopausal women, 680 mg/day of strontium for 3 years. Top half: % increase in BMD. Bottom half: % reduction in fracture risk.

Adapted from N Engl J Med 2004;350:459-68.

Two-year strontium clinical trial

Strontium % change in Incidence of newdose lumbar BMD vertebral fractures

Placebo +0.50 54.7%

170 mg/day +1.35% 38.8%

340 mg/day +1.65% 56.7%

680 mg/day +2.97% 42.0%

Study of 353 postmenopausal women with osteoporosis and a history of at least one vertebral fracture. J Clin Endocrinol Metab 2002;87:2060-2066.

Distribution of strontium in bone

At high doses, most strontium is incorporated by exchange onto the crystal surface. This strontium, which may promote bone formation and inhibit bone resorption, is rapidly lost from bone and excreted in the urine when supplementation is stopped.

A few strontium atoms are incorporated into the crystal lattice; this strontium may enhance bone quality, and appears to persist in bone after supplementation is stopped.

Bone 2001;28:446-453

Strontium and bone: my opinion

For established osteoporosis, high-dose strontium (170-680 mg/day) appears to be appropriate for 1-3 years. Thereafter, consider “nutritional” doses (such as 2-6 mg/day) for longer-term use. Long-term clinical trials (> 3-5 years) needed to deter-mine safety and efficacy of high-dose strontium.

For osteoporosis prevention, “nutritional” doses may be most appropriate.

Controversies in Nutrition By Alan R. Gaby, M.D..

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