Hypothesis: Magnesium accounts for some of the variation in vitamin D response – Oct 2013

Magnesium deficit ? overlooked cause of low vitamin D status?

BMC Medicine 2013, 11:229 doi:10.1186/1741-7015-11-229
Armin Zittermann, azittermann at hdz-nrw.de
Clinic for Thoracic and Cardiovascular Surgery, Heart Center North Rhine-Westphalia, Ruhr-U. of Bochum, Georgstra?e 11, 32545, Bad Oeynhausen Germany

Like vitamin D deficit, magnesium deficit is considered to be a risk factor for cardiovascular disease. Several steps in the vitamin D metabolism, such as vitamin D binding to its transport protein and the conversion of vitamin D into the hormonal form 1,25-dihydroxyvitamin D by hepatic and renal hydroxylation, depend on magnesium as a cofactor. A new analysis of two National Health and Nutrition Examination Surveys data sets, published in BMC Medicine, investigated potential interactions between magnesium intake, circulating 25-hydroxyvitamin D, which is the generally accepted indicator of vitamin D status, and mortality. Data indicate a reduced risk of insufficient/deficient vitamin D status at high magnesium intake and an inverse association between circulating 25-hydroxyvitamin D and mortality, particularly cardiovascular mortality, among those with magnesium intake above the median. The study provides important findings concerning potential metabolic interactions between magnesium and vitamin D and its clinical relevance. However, results should be considered preliminary since biochemical data on individual magnesium status were lacking, confounding cannot be excluded and questions on the dose?response relationship still remain to be answered.

Please see related research article VitaminDWiki Or : http://www.biomedcentral.com/1741-7015/11/187

Life depends on an energy-consuming complex interplay of organic and inorganic substances to maintain biological structures. Adequate energy and nutrient supply is a prerequisite to guarantee normal functioning of metabolic pathways and thus a healthy life. To become metabolically active, several nutrients require other essential nutrients as cofactors. For example, copper is required for the oxidation of absorbed Fe2+ to Fe3+, which is then bound to transferrin, and riboflavin (vitamin B2) and pyridoxine (vitamin B6) are required to produce niacin (vitamin B3) from dietary tryptophan. Therefore, some nutrition-related illnesses, such as anemia and pellagra, can be caused by multiple nutrient deficits [1,2]. Magnesium (Mg) is a cofactor that is required for the binding of vitamin D to its transport protein. Moreover, conversion of vitamin D by hepatic 25-hydroxlation and renal 1?-hydroxylation into the active, hormonal form 1,25-dihydroxyvitamin D (1,25(OH)2D) is Mg-dependent [3,4]. A study by Deng et al. [5], published in BMC Medicine, investigated potential interactions between Mg intake, vitamin D status and mortality. Still, some questions remain open.

Study results: Deng et al. [5] used two large National Health and Nutrition Examination Surveys data sets to assess interactions between Mg intake, vitamin D status and outcome. According to the Institute of Medicine (IOM) classification, circulating 25-hydroxyvitamin D (25OHD), the generally accepted indicator of vitamin D status, was within the deficit range (<12 ng/ml) in 12% of participants and the insufficiency range (12 to 20 ng/ml) [6] in 30%. Mean energy-adjusted total Mg intake (dietary and supplemental) was clearly below the recommended daily allowance, which is between 310 and 420 mg depending on age and gender [7]. High Mg intake was associated with reduced risk of vitamin D deficit or insufficiency. Data also indicate an inverse association between circulating 25OHD and mortality, particularly cardiovascular mortality, among those with Mg intake above the median.

Vitamin D status and its predictors

The present data are consistent with the assumption that deficient vitamin D levels are an important health issue that may affect not only musculoskeletal health but also a wide range of acute and chronic diseases [8]. The high prevalence of deficient 25OHD blood levels in the population is believed to be primarily due to inadequate vitamin D synthesis in the skin, together with inadequate dietary intake [9]. However, circulating 25OHD levels also depend on body weight and genetic factors, and a significant portion of the variance in circulating 25OHD remains unexplained at present. Therefore, Deng et al. are to be commended for investigating potential interactions between Mg and vitamin D status. Especially with regard to vitamin D, there is still ongoing debate regarding the optimal oral intake and the adequate circulating 25OHD level. The IOM recommends a daily vitamin D intake of 600 international units and considers circulating 25OHD levels of 20 to 50 ng/ml as adequate, and 25OHD levels above 50 ng/ml as potentially harmful [6]. However, according to the Endocrine Society [10], the circulating 25OHD level should be within the range of 30 to 100 ng/ml. To raise the 25OHD level consistently above 30 ng/ml, they recommend a daily vitamin D intake of 1,500 to 2,000 international units.

Open questions

Like vitamin D deficit [11], Mg deficit is considered to be a risk factor for cardiovascular disease [12]. Thus, the presented interactions between Mg, vitamin D and cardiovascular mortality fit well together. Nevertheless, for several reasons, data should be considered preliminary.

• First, associations are based on oral Mg intake. The assessment of oral Mg intake does not take into account inter-individual differences in intestinal Mg absorption and renal and cutaneous Mg loss. It would have been more appropriate to use biochemical data, such as plasma Mg levels (levels of 0.79 to 0.76 mmol/l have been classified as inadequate and levels <0.76 mmol/l as deficient), to assess individual Mg status. Unfortunately, plasma levels of Mg are still rarely assessed, whereas measurement of circulating 25OHD levels has exploded in the clinical setting in recent years [13].
• Second, total Mg intake, 25OHD status and physical activity level were clearly interrelated [5]. High Mg intake may thus only be an indicator for high physical activity, which is known to influence 25OHD status (and cardiovascular mortality). Even adjustment for physical activity may not completely solve the problem of potential bias.
• Third, no data on circulating levels of the biologically active form of vitamin D, 1,25(OH)2D, were presented.

Circulating 1,25(OH)2D is probably a better predictor of total mortality compared with circulating 25OHD, at least if mid-term mortality is assessed [14]. Circulating 1,25(OH)2D declines significantly (and parathyroid hormone levels increase substantially) at 25OHD levels below 10 ng/ml, whereas levels of both hormones seem to plateau at 25OHD levels of 20 ng/ml [15]. Notably, three out of the four 25OHD categories in the mortality analysis of the present investigation were above 20 ng/ml, and none covered the range that the IOM has classified as deficient. It would have been interesting to see whether the combination of inadequate Mg intake with 25OHD levels below 12 ng/ml is associated with a further mortality increase.

Conclusion

The present study must be praised for bringing potential interactions between individual nutrients into the focus of interest. Because the intake of Mg is often inadequate and several other factors are also known to impair Mg supply (for example, diuretics use, diabetes mellitus, chronic alcohol consumption, stress factors) [16-18], more attention should in future be paid to possible consequences of insufficient or deficient Mg supply in the general population. Further studies on the interactions between Mg supply and vitamin D status should include a more detailed assessment of individual Mg status (for example, by measuring biochemical parameters of Mg status or by adjusting statistical analysis for stress factors, diuretics use, alcohol consumption and concomitant diagnoses such as diabetes); a more detailed investigation of different components of the vitamin D-parathyroid hormone axis in general populations; clarification of the dose/response relationship; and the realization of randomized controlled trials to verify whether oral Mg is indeed able to improve vitamin D status and survival.

Competing interests
The author declares that he has received speaker honoraria from Abbott, Germany, and DiaSorin, Germany, two companies that provide test kits for the measurement of circulating 25-hydroxyvitamin D.

Author information
AZ is a nutritionist, whose main research focuses on human vitamin D status, including the prevalence and consequences of vitamin D insufficiency or deficit. He is head of the study center at the Clinic for Thoracic and Cardiovascular Surgery at the Heart Center North-Rhine Westphalia, Ruhr-University of Bochum, Germany.

References

1. Karthikeyan K, Thappa DM: Pellagra and skin, Int J Dermatol 2002, 41:476-481. PubMed Abstract | Publisher Full Text OpenURL
2. Sharp P: The molecular basis of copper and iron interactions, Proc Nutr Soc 2004, 63:563-569. PubMed Abstract | Publisher Full Text OpenURL
3. Reddy V, Sivakumar B: Magnesium-dependent vitamin-D-resistant rickets. Lancet 1974, 1:963-965. PubMed Abstract | Publisher Full Text OpenURL
4. Rude RK, Adams JS, Ryzen E, Endres DB, Niimi H, Horst RL, Haddad JG Jr, Singer FR: Low serum concentrations of 1,25-dihydroxyvitamin D in human magnesium deficiency. J Clin Endocrinol Metab 1985, 61:933-940. PubMed Abstract | Publisher Full Text OpenURL
5. Deng X, Song Y, Manson JE, Signorello LB, Zhang SM, Shrubsole M, Ness RM, Seidner D, Dai Q: Magnesium, vitamin D status and mortality: results from US National Health and Nutrition Examination Survey (NHANES) 2001 to 2006 and NHANES III, BMC Med 2013, 11:187. PubMed Abstract | BioMed Central Full Text | PubMed Central Full Text OpenURLVitaminDWiki
6. Ross AC, Manson JE, Abrams SA, Aloia JF, Brannon PM, Clinton SK, Durazo-Arvizu RA, Gallagher JC, Gallo RL, Jones G, Kovacs CS, Mayne ST, Rosen CJ, Shapses SA: The 2011 report on dietary reference intakes for calcium and vitamin D from the Institute of Medicine: what clinicians need to know. J Clin Endocrinol Metab 2011, 96:53-58. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL
7. Standing Committee on the Scientific Evaluation of Dietary Reference Intakes, Food and Nutrition Board, Institute of Medicine: Dietary reference intakes for calcium, phosphorus, magnesium, vitamin D, and fluoride. Washington D.C: National Academy Press; 1997. OpenURL
8. Hossein-nezhad A, Holick MF: Optimize dietary intake of vitamin D: an epigenetic perspective. Curr Opin Clin Nutr Metab Care 2012, 15:567-579. PubMed Abstract | Publisher Full Text OpenURL
9. Tsiaras WG, Weinstock MA: Factors influencing vitamin D status. Acta Derm Venereol 2011, 91:115-124. PubMed Abstract | Publisher Full Text OpenURL
10. Holick MF, Binkley NC, Bischoff-Ferrari HA, Gordon CM, Hanley DA, Heaney RP, Murad MH, Weaver CM, Endocrine Society: Evaluation, treatment, and prevention of vitamin D deficiency: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 2011, 96:1911-1930. PubMed Abstract | Publisher Full Text OpenURL
11. Pilz S, Kienreich K, Tomaschitz A, Lerchbaum E, Meinitzer A, M?rz W, Zittermann A, Dekker JM: Vitamin D and cardiovascular disease: update and outlook. Scand J Clin Lab Invest Suppl 2012, 243:83-91. PubMed Abstract OpenURL
12. Seelig M: Cardiovascular consequences of magnesium deficiency and loss: pathogenesis, prevalence and manifestations?magnesium and chloride loss in refractory potassium repletion. Am J Cardiol 1989, 63:4G-21G. PubMed Abstract | Publisher Full Text OpenURL
13. Shahangian S, Alspach TD, Astles JR, Yesupriya A, Dettwyler WK: Trends in laboratory test volumes for Medicare part B reimbursements, 2000-2010. Arch Pathol Lab Med 2013. [Epub ahead of print] OpenURL
14. Zittermann A, Schleithoff SS, Frisch S, G?tting C, Kuhn J, Koertke H, Kleesiek K, Tenderich G, Koerfer R: Circulating calcitriol concentrations and total mortality. Clin Chem 2009, 55:1163-70. PubMed Abstract | Publisher Full Text OpenURL
15. Zittermann A: Vitamin D, and disease prevention with special reference to cardiovascular disease. Prog Biophys Mol Biol 2006, 92:39-48. PubMed Abstract | Publisher Full Text OpenURL
16. Abbott L, Nadler J, Rude RK: Magnesium deficiency in alcoholism: possible contribution to osteoporosis and cardiovascular disease in alcoholics. Alcohol Clin Exp Res 1994, 18:1076-1082. PubMed Abstract | Publisher Full Text OpenURL
17. Barbagallo M, Belvedere M, Dominguez LJ: Magnesium homeostasis and aging. Magnes Res 2009, 22:235-246. PubMed Abstract | Publisher Full Text OpenURL
18. Weber KT, Bhattacharya SK, Newman KP, Soberman JE, Ramanathan KB, McGee JE, Malik KU, Hickerson WL: Stressor states and the cation crossroads. J Am Coll Nutr 2010, 29:563-574. PubMed Abstract | Publisher Full Text OpenURL

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See also VitaminDWiki

• Overview Magnesium and vitamin D
• Response to vitamin D increased 30 percent with Magnesium - Nov 2018
• If at high risk of vitamin D deficiency, get a higher response if take more Magnesium – Sept 2013
• Magnesium and Vitamin D very synergistic – Aug 2013
• Magnesium and Vitamin D - similar, different and synergistic which has the following chart as of Oct 2013

They are also synergistic, that is, increasing one helps the other

	Magnesium	not Magnesium
Vitamin D	Magnesium or Vitamin D Aging, Amytrophic Lateral Sclerosis, Alzheimer's Disease; Asthma, Attention Deficit Disorder; Autism, Cancer, Cerebrovascular, Chronic Fatigue, Diabetes, Hearing Loss, Heart Disease. Heart Attack, Atherosclerosis, Cardiovascular Disease, HIV, AIDS; Hypertension; Kidney Stones, Migraine Headache, Multiple Sclerosis, Obesity, Osteoporosis; Peripheral vascular disease; Pregnancy-related problems,Rheumatoid Arthritis; Sports-related problems,	Vitamin D only Acne, Allergy, Autoimmune, Bone, Breathing, Celiac, Cognition, Colds and Flu, Cystic Fibrosis, Dental, Fertility, Hyperparathyroid, Immunity, Kidney, Liver, Lupus, Osteoarthritis, Pain - chronic, Parkinson, Psoriasis, Rickets, Strokes, Sarcoidosis, Thyroid, Parathyroid, Tuberculosis, Vision, Hair, Skin, Sports
Not Vitamin D	Magnesium only Aggressive Behavior, Alcoholism, Arrhythmia, Cerebral Palsy, Chemical Sensitivity, Cluster Headaches; Cocaine-related Stroke; Constipation, Cramps, Fluoride Toxicity; Head Injuries, Central Nervous System Injuries, Magnesium Deficiency; Menopause, Mitral Valve Prolapsee, Nystagmus, Psychiatric Disorders; Repetitive Strain Injury, Sickle Cell Disease, SIDS, Stress, Stuttering, Tetanus; Tinnitis, Sound Sensitivity; TMJ; Toxic Shock; Violence	Neither ALL OTHER DISEASES

Vitamin D Council review of Mg deficiency, starting with the Zittermann article

Nice overview of Magnesium and how hard it is to measure
Wonder if a new test will be able to indirectly measure Mg? One test to estimate Vitamin D, A, Cu, Se, etc : measure proteins in blood – Oct 2013
behind a $5 a month paywall.