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Letters to the Editor  |   December 2018
Response
Author Notes
  • Lake Erie College of Osteopathic Medicine, Erie, Pennsylvania 
Article Information
Emergency Medicine / Endocrinology / Hypertension/Kidney Disease / Preventive Medicine / Urological Disorders
Letters to the Editor   |   December 2018
Response
The Journal of the American Osteopathic Association, December 2018, Vol. 118, 773-774. doi:10.7556/jaoa.2018.168
The Journal of the American Osteopathic Association, December 2018, Vol. 118, 773-774. doi:10.7556/jaoa.2018.168
I appreciate the opportunity to reemphasize the importance of optimal magnesium balance for maintaining normal cellular and organ functions, including nucleic acid synthesis, cell signaling, energy metabolism, and hormonal activation.1 Hormonal activation of vitamin D is a magnesium-dependent process. Once 1,25-dihydroxyvitamin D is generated, it can increase intestinal magnesium absorption and thereby establish a feed-forward loop to maintain its delicate balance. Of clinical importance, prolonged and disproportionate consumption of vitamin D supplements could induce hyperphosphatemia, hypercalcemia, and hypercalciuria, even without the development of hypervitaminosis D.2 The main reason why vitamin D supplementation is usually considered to be safe is because it rarely increases serum 25-hydroxyvitamin D (25[OH]D) levels to the toxic range, even after repeated intravenous administration of extremely high doses of artificial vitamin D analogs. 
The clinical scenario provided by Mazokopakis and Papadomanolaki3 did not mention the dose of cholecalciferol supplementation used to treat the patients with Hashimoto thyroiditis. The authors found a greater than 200% increase in serum 25(OH)D levels within 4 months of cholecalciferol treatment3; whether supplement-induced high serum levels of 25(OH)D in a relatively shorter period is entirely bioactive or not (in a reduced magnesium microenvironment) is an issue that needs thoughtful consideration. Moreover, despite achieving such high serum levels of 25(OH)D (mean [SD], 45.7 [4.3] ng/mL) after cholecalciferol treatment, the authors3 found that the patients were mostly normocalcemic. The normal range of calcium reflecting reduced bioactivity of the 25(OH)D (due to relatively low magnesium content) is a phenomenon that cannot be ruled out. 
As vitamin D supplement-induced hyperphosphatemia may appear even before changes in serum calcium levels, it would be clinically important to monitor the serum phosphorus levels in these patients. Of significance, phosphorus dysregulation induced by exogenous vitamin D supplementation may lead to tissue and organ damage even without the development of hypervitaminosis D.4,5 Again, by consuming the optimal amount of magnesium, it might be possible to reduce the dependency on vitamin D supplements, which is not always risk-free, particularly when consumed in higher doses or used for prolonged periods.2 According to the Institute of Medicine, serum 25(OH)D levels of more than 50 ng/mL could exert potential harmful effects, and studies have shown that serum levels of 30 to 48 ng/mL can be linked to an increase in all-cause mortality, with more falls and fractures among elderly individuals, higher risk of tumor formation, and cardiovascular disorders.6 In fact, the US Preventive Services Task Force found that the currently available evidence does not justify the recommendation of more than 400 IU per day of a vitamin D3 supplement and more than 1000 mg per day of calcium for the primary prevention of fractures in nonhospitalized postmenopausal women or in men.7 Of note, the task force did not recommend lower doses of vitamin D3 and calcium supplements in general.7 
Mazokopakis and Papadomanolaki3 correctly mentioned the necessity of the assessment of magnesium status in their patient follow-up; however, routinely measured serum magnesium levels do not always reflect total body magnesium status. Therefore, the normal blood magnesium levels might not rule out widespread magnesium deficiency. Because the patients had a normal glomerular filtration rate,3 a magnesium loading test with the estimation of magnesium excretion in 24-hour urine specimens may have been more useful for detecting subclinical magnesium deficiency. Also, the potential risk for nephrolithiasis or vascular calcification developing in patients treated with cholecalciferol3 should have been adequately monitored and addressed by maintaining optimal magnesium balance. 
References
Uwitonze AM, Razzaque MS. Role of magnesium in vitamin D activation and function. J Am Osteopath Assoc. 2018;118(3):181-189. doi: 10.7556 /jaoa.2018.037 [CrossRef] [PubMed]
Razzaque MS. Can adverse effects of excessive vitamin D supplementation occur without developing hypervitaminosis D? J Steroid Biochem Mol Biol. 2018;180:81-86. doi: 10.1016/j.jsbmb.2017.07.006 [CrossRef] [PubMed]
Mazokopakis EE, Papadomanolaki MG. Investigating the influence of vitamin D replacement therapy on magnesium status [letter]. J Am Osteopath Assoc. 2018;118(12):772-773. doi: 10.7556/jaoa.2018.167
Razzaque MS. Phosphate toxicity: new insights into an old problem. Clin Sci (Lond) 2011;120(3):91-97. doi: 10.1042/CS20100377 [CrossRef] [PubMed]
Brown RB, Razzaque MS. Phosphate toxicity and tumorigenesis. Biochim Biophys Acta Rev Cancer. 2018;1869(2):303-309. doi: 10.1016/j.bbcan.2018.04.007 [CrossRef] [PubMed]
Institute of Medicine. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: National Academy Press; 2010.
Moyer VA, LeFevre ML, Siu AL. Vitamin D and calcium supplementation to prevent fractures in adults: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med. 2013;159(12):856-857. doi: 10.7326/0003-4819-159-12-201312170-00016