Vitamin D is not a substitute for any vaccine — Deplatform Disease

  • Vitamin D is unnecessary.
    Vitamin D is an important hormone and plays critical roles in the regulation of calcium and phosphate metabolism. It is obviously necessary and claiming otherwise is ridiculous and not what I am doing.
  • Diet has no meaningful role in immunological function (this was the subject of an excellent recent review, as well as here).
    The interplay between diet and the immune system is a complex and exciting area in immunology and is the subject of much active research. However, this research is still in its infancy and we are far from being able to make definitive recommendations about dietary changes and a precise immunological effect in humans. Further complicating this are the intersections between this field and the examination of interactions between the microbiota and the immune system. The latter studies are often interesting and valuable but involve so many variables and often require such contrived models that external validity of the studies is an unrealistic claim; this field too, I would argue, is still in its infancy and a ways away from being able to use its findings to make clinical guidances (at least those more granular than “don’t overuse antibiotics”). Nonetheless, the research in these fields is valuable and should be done.
    Principally, the most valuable recommendation regarding diet and immunity is simply to ensure that adequate intake of all nutrients is achieved. The immune system is an extraordinarily complex network of molecules, cells, tissues, and organs and deficiency of any nutrient can potentially be harmful for its optimal function.
  • Vitamin D supplementation is harmful.
    You should consult with your care team before initiating any supplement. However, while vitamin D is fat-soluble and toxicity can be devastating, it is difficult to attain at reasonable doses of the substance, though in particular, it may be an issue in patients who have sarcoidosis or other granulomatous conditions. I do however think that vitamin D supplementation in most circumstances is a waste of money as it doesn’t do much and is often recommended for people who are not actually deficient.
  • Vitamin D deficiency is not necessary to correct.
    There is no good reason to be deficient in any nutrient (or hormone in this case). Physiologic levels of vitamin D are important for health maintenance. Any individual who has evidence of vitamin D deficiency should have it corrected. However, people should be realistic in the benefits associated with that correction.

What is Vitamin D?

Cell Biology and Mechanism of Action

Production, Absorption, Transport, Storage, and Metabolism

D2 vs D3

Virtually all countries fortify food staples with vitamin D to prevent rickets, though a few don’t because of (1) deficiency being very rare e.g. countries near the equator, (2) disputes about whether the cost of fortification should be paid by industry or by the government, or (3) concerns for toxicity, particularly in the very young who are more prone to it. The metabolism of both forms of vitamin D are basically identical, and structurally the molecules are very similar except for a small side chain. In general, reviews of their potency find them to be essentially equivalent, and thus for the purposes of supplementation, in general either one is considered acceptable. However, D3 is shown to raise levels of calcitriol more rapidly than D2, but is also associated with greater toxicity. It is thought that D2 is cleared from the circulation more rapidly than D3 which it is thought helps to prevent toxicity. Despite this, in general, D2 has not been shown to be inferior in pharmacologic quantities at preventing rickets- the hallmark manifestation of vitamin D deficiency.

Vitamin D in Mineral Homeostasis

  1. Calcium ions enter at the apical surface of the intestinal epithelial cell through channel proteins like TRPV5 and TRPV6. Other protein channels are known to play a role here but it is not clear which specific ones.
  2. On entry into the intestinal epithelial cells, the free ions are bound up by calbindin-D9k, which shuttles the ions to the basolateral surface.
  3. The ions are released from the basolateral surface into the body via PMCA1b.
  • Osteoclasts are the major cells that break down bone, releasing calcium and phosphate from the bone mineral matrix into the blood, known as bone resorption. They are derived from monocytes and do not divide (some regard them as the tissue-resident macrophages of the bone). Mature osteoclasts have receptors for calcitonin, but not parathyroid hormone or vitamin D. To break down bone, osteoclasts bind a region and form an adhesive ring which makes contact with a specialized organelle known as a ruffled border, which is essentially a giant lysosome containing proteases like cathepsin K which break down the protein components of the bone and liberate free calcium.
  • Osteoblasts are the major bone-forming (known as bone mineralization) cell. They express receptors for both parathyroid hormone and vitamin D and can lay down matrix called osteoid that gets filled with hydroxyapatite. These cells also secrete large amounts of the alkaline phosphatase enzyme, which is required for bone mineralization. These cells are the major target for parathyroid hormone.
  • Osteoblasts that remain in the bone during the remodeling process become osteocytes. Osteocytes can regulate the functions of osteoblasts through secreted substances. Osteocytes are thought to play a role in the transfer of mineral from the interior of bone to the growth surfaces. A detailed review of osteocyte functions can be found here.

Extraskeletal Effects of Vitamin D

Immunological Effects of Vitamin D

The Controversies and Misconceptions of Optimal Levels

  • Manaseki-Holland 2010: This was a double-blind 1:1 RCT of 453 children in an inner‐city hospital in Kabul, diagnosed with non‐severe or severe pneumonia at the outpatient clinic. The study is well designed and its principal finding is a significantly lower risk of repeat episodes of pneumonia among the group receiving vitamin D, which looks real to me (45 % in the vitamin D group vs. 58% of the placebo group). Children were excluded from the study if they had evidence of rickets or were known to have received high-dose vitamin D supplementation within 3 months of the study. The randomization looks less than ideal to me but not unreasonable. The principal limitation of this study as I see it is that its subject population is very young children (mean age about 13 months) and it appears to be in a region where vitamin D deficiency is very prevalent which makes me concerned about the external validity of the study.
  • Camargo 2012: A cluster-randomized trial examining 247 Mongolian schoolchildren randomized to vitamin D-fortified milk vs. placebo comparing the incidence of acute respiratory infections as per parental report. One of the major things that jump out in this study is the mean vitamin D level of these patients was 7 ng/mL, which would be universally considered severely deficient. Another potential issue is that it relies on parental reporting which isn’t ideal as it’s subject to a number of biases, but this is mitigated by the randomization process of the trial. The benefit here does also seem real to me, but again, it’s the same problem of external validity: this level of deficiency in places like the US is very rare, and we aren’t principally concerned with schoolchildren in the case of COVID-19.
  • Laaksi 2010: DBPCT of 164 young, Finnish men who received vitamin D supplementation vs. placebo which compared the number of days absent from daily duty. There was a clear benefit for the supplementation group. However, these groups also had pretty significant vitamin D deficiency to start with (~8 ng/mL), so that’s not particularly surprising. The principle is true with vitamins: a health benefit is seen when true deficiency is corrected.
  • Bergman 2012: This is a very interesting study because it examines specifically patients who have diagnosed or possible occult immunological deficiency that predisposes to respiratory infection, and it also followed all 140 patients for 1 year, which is nice (we love a long prospective study). The levels of vitamin D at baseline between the groups are similar but under some classification schemes, the placebo group would be considered mildly/borderline deficient while the treatment group starts out at a level that is sufficient. The major difference was that antibiotic use was rarer in the treatment group than the placebo group, which accounted for the marginally significant result obtained. However, the confidence intervals for this estimate are very wide, which speaks to the study being underpowered as it only has 140 patients. Further, it involves such a specific group of patients that I don’t think it’s very generalizable.
  • Marchisio 2013: 116 children with a history of recurrent middle ear infections were randomized to vitamin D supplementation or placebo for 4 months and the frequency of middle ear infections were monitored for 6 months. The small sample size made randomization difficult, as the gender distribution between the groups is not super well-matched, the number of children that had a symptomatic allergy in the vitamin D group was lower at baseline, and the vitamin D group was also more likely to be breastfed for > 3 months. These differences aren’t huge though. Importantly, the vitamin D levels in both groups were similar and would be considered sufficient under the IOM ranges. Interestingly, the vitamin D levels in the placebo group declined quite a bit throughout the study to a level that would be considered deficient. Vitamin D didn’t seem to affect complicated middle ear infections much, but did show significant reduction in uncomplicated and overall showed a reduction that took about 40 days to manifest. These effects are pretty big though and this meta-analysis does note a relationship between vitamin D levels and otitis media. So I think this might actually possibly be a legitimate benefit for vitamin D supplementation, but middle ear infections are generally a pediatric issue.

Toxicity, Deficiency, and Supplementation

Vitamin D in COVID-19

References

  1. Abrams SA, Coss-Bu JA, Tiosano D. 2013. Vitamin D: effects on childhood health and disease. Nat Rev Endocrinol. 9(3):162–170.
  2. Adams JS, Hewison M. 2008. Unexpected actions of vitamin D: new perspectives on the regulation of innate and adaptive immunity. Nat Clin Pract Endocrinol Metab. 4(2):80–90.
  3. Ahmad N, Mohamed Sobaihi M, Al-Jabri M, Al-Esaei NA, Al Zaydi AM. 2018. Acute respiratory failure and generalized hypotonia secondary to vitamin D dependent rickets type 1A. Int J Pediatr Adolesc Med. 5(2):78–81.
  4. Armstrong D. 2018 Sep 26. The Child-Abuse Contrarian. New Yorker. [accessed 2021 Feb 10]. https://www.newyorker.com/news/news-desk/the-child-abuse-contrarian.
  5. Autier P, Mullie P, Macacu A, Dragomir M, Boniol Magali, Coppens K, Pizot C, Boniol Mathieu. 2017. Effect of vitamin D supplementation on non-skeletal disorders: a systematic review of meta-analyses and randomised trials. Lancet Diabetes Endocrinol. 5(12):986–1004.
  6. Baughman RP, Lower EE. 2014. Goldilocks, vitamin D and sarcoidosis. Arthritis Res Ther. 16(3):111.
  7. Bergman P, Norlin A-C, Hansen S, Rekha RS, Agerberth B, Björkhem-Bergman L, Ekström L, Lindh JD, Andersson J. 2012. Vitamin D3 supplementation in patients with frequent respiratory tract infections: a randomised and double-blind intervention study. BMJ Open. 2(6):e001663.
  8. Bikle D, Christakos S. 2020. New aspects of vitamin D metabolism and action — addressing the skin as source and target. Nat Rev Endocrinol. 16(4):234–252.
  9. Bikle DD. 2014. Vitamin D metabolism, mechanism of action, and clinical applications. Chem Biol. 21(3):319–329.
  10. Bischoff-Ferrari HA, Dawson-Hughes B, Orav EJ, Staehelin HB, Meyer OW, Theiler R, Dick W, Willett WC, Egli A. 2016. Monthly high-dose vitamin D treatment for the prevention of functional decline: A randomized clinical trial. JAMA Intern Med. 176(2):175.
  11. Borel P, Caillaud D, Cano NJ. 2015. Vitamin D bioavailability: state of the art. Crit Rev Food Sci Nutr. 55(9):1193–1205.
  12. Boron WF, Boulpaep EL. 2016. Medical Physiology. 3rd ed. Philadelphia, PA: Elsevier — Health Sciences Division.
  13. Bouillon R. 2017. Comparative analysis of nutritional guidelines for vitamin D. Nature Reviews Endocrinology. 13(8):466–479.
  14. Brown LL, Cohen B, Tabor D, Zappalà G, Maruvada P, Coates PM. 2018. The vitamin D paradox in Black Americans: a systems-based approach to investigating clinical practice, research, and public health — expert panel meeting report. BMC Proc. 12(Suppl 6):6.
  15. Brunton L, Knollman B, Hilal-Dandan R. 2017. Goodman and gilman’s the pharmacological basis of therapeutics, 13th edition. 13th ed. McGraw-Hill Education/Medical.
  16. Camargo CA, Ganmaa D, Frazier AL, Kirchberg FF, Stuart JJ, Kleinman K, Sumberzul N, Rich-Edwards JW. 2012. Randomized trial of vitamin D supplementation and risk of acute respiratory infection in Mongolia. Pediatrics. 130(3):e561-e567.
  17. Cantorna MT, Snyder L, Arora J. 2019. Vitamin A and vitamin D regulate the microbial complexity, barrier function, and the mucosal immune responses to ensure intestinal homeostasis. Crit Rev Biochem Mol Biol. 54(2):184–192.
  18. Carpenter TO, Shaw NJ, Portale AA, Ward LM, Abrams SA, Pettifor JM. 2017. Rickets. Nat Rev Dis Primers. 3(1):17101.
  19. Carroll A. 2016. Why take vitamin D supplements if they don’t improve health? JAMA Health Forum. A5(1). doi:10.1001/jamahealthforum.2016.0013. [accessed 2021 Jan 23]. https://jamanetwork.com/channels/health-forum/fullarticle/2760179.
  20. Cereda E, Bogliolo L, Lobascio F, Barichella M, Zecchinelli AL, Pezzoli G, Caccialanza R. 2021. Vitamin D supplementation and outcomes in coronavirus disease 2019 (COVID-19) patients from the outbreak area of Lombardy, Italy. Nutrition. 82(111055):111055.
  21. cew. 2014 Jun 2. Child Abuse Pediatrics Certification. Abp.org. [accessed 2021 Feb 10]. https://www.abp.org/content/child-abuse-pediatrics-certification.
  22. Christakos S, Dhawan P, Verstuyf A, Verlinden L, Carmeliet G. 2016. Vitamin D: Metabolism, molecular mechanism of action, and pleiotropic effects. Physiol Rev. 96(1):365–408.
  23. Clinical lipidology: A companion to braunwald’s heart disease. 2014. 2nd ed. Philadelphia, PA: Saunders.
  24. Dallas SL, Prideaux M, Bonewald LF. 2013. The osteocyte: an endocrine cell … and more. Endocr Rev. 34(5):658–690.
  25. Deeks ED. 2018. Denosumab: A review in postmenopausal osteoporosis. Drugs Aging. 35(2):163–173.
  26. Degirolamo C, Sabbà C, Moschetta A. 2016. Therapeutic potential of the endocrine fibroblast growth factors FGF19, FGF21 and FGF23. Nat Rev Drug Discov. 15(1):51–69.
  27. Denburg MR, Hoofnagle AN, Sayed S, Gupta J, de Boer IH, Appel LJ, Durazo-Arvizu R, Whitehead K, Feldman HI, Leonard MB, et al. 2016. Comparison of two ELISA methods and mass spectrometry for measurement of vitamin D-binding protein: Implications for the assessment of bioavailable vitamin D concentrations across genotypes: Comparison of Elisa and LC-ms/ms methods for measurement of dbp. J Bone Miner Res. 31(6):1128–1136.
  28. Franceschi C, Garagnani P, Parini P, Giuliani C, Santoro A. 2018. Inflammaging: a new immune-metabolic viewpoint for age-related diseases. Nat Rev Endocrinol. 14(10):576–590.
  29. Ganmaa D, Uyanga B, Zhou X, Gantsetseg G, Delgerekh B, Enkhmaa D, Khulan D, Ariunzaya S, Sumiya E, Bolortuya B, et al. 2020. Vitamin D supplements for prevention of tuberculosis infection and disease. N Engl J Med. 383(4):359–368.
  30. Gittoes NJL. 2016. Vitamin D — what is normal according to latest research and how should we deal with it? Clin Med. 16(2):171–174.
  31. Goldring SR. 2015. The osteocyte: key player in regulating bone turnover. RMD Open. 1(Suppl 1):e000049.
  32. Griffin G, Hewison M, Hopkin J, Kenny R, Quinton R, Rhodes J, Subramanian S, Thickett D. 2020. Vitamin D and COVID-19: evidence and recommendations for supplementation. R Soc Open Sci. 7(12):201912.
  33. Hansdottir S, Monick MM, Lovan N, Powers L, Gerke A, Hunninghake GW. 2010. Vitamin D decreases respiratory syncytial virus induction of NF-kappaB-linked chemokines and cytokines in airway epithelium while maintaining the antiviral state. J Immunol. 184(2):965–974.
  34. Hansen KE, Johnson MG. 2016. An update on vitamin D for clinicians. Curr Opin Endocrinol Diabetes Obes. 23(6):440–444.
  35. Hastie CE, Pell JP, Sattar N. 2021. Vitamin D and COVID-19 infection and mortality in UK Biobank. Eur J Nutr. 60(1):545–548.
  36. Heaney RP, Dowell MS, Hale CA, Bendich A. 2003. Calcium absorption varies within the reference range for serum 25-hydroxyvitamin D. J Am Coll Nutr. 22(2):142–146.
  37. Henderson CM, Fink SL, Bassyouni H, Argiropoulos B, Brown L, Laha TJ, Jackson KJ, Lewkonia R, Ferreira P, Hoofnagle AN, et al. 2019. Vitamin D-binding protein deficiency and homozygous deletion of the GC gene. N Engl J Med. 380(12):1150–1157.
  38. Hewison M. 2011. Antibacterial effects of vitamin D. Nat Rev Endocrinol. 7(6):337–345.
  39. Jameson JL, De Groot LJ. 2015. Endocrinology: Adult and pediatric, 2-volume set. 7th ed. Philadelphia, PA: Saunders.
  40. Jameson JL, Fauci AS, Kasper DL, Hauser SL, Longo DL, Loscalzo J. 2018. Harrison’s Principles of Internal Medicine 20th Edition. 20th ed. Columbus, OH: McGraw-Hill Education.
  41. Jesus JE, Landry A. 2012. Chvostek’s and Trousseau’s Signs. N Engl J Med. 367(11):e15.
  42. Kahwati LC, Weber RP, Pan H, Gourlay M, LeBlanc E, Coker-Schwimmer M, Viswanathan M. 2018. Vitamin D, calcium, or combined supplementation for the primary prevention of fractures in community-dwelling adults: Evidence report and systematic review for the US Preventive Services Task Force. JAMA. 319(15):1600–1612.
  43. Ketha H, Wadams H, Lteif A, Singh RJ. 2015. Iatrogenic vitamin D toxicity in an infant — a case report and review of literature. J Steroid Biochem Mol Biol. 148:14–18.
  44. Kim D, Nguyen QT, Lee J, Lee SH, Janocha A, Kim S, Le HT, Dvorina N, Weiss K, Cameron MJ, et al. 2020. Anti-inflammatory roles of glucocorticoids are mediated by Foxp3+ regulatory T cells via a miR-342-dependent mechanism. Immunity. 53(3):581–596.e5.
  45. Laaksi I, Ruohola J-P, Mattila V, Auvinen A, Ylikomi T, Pihlajamäki H. 2010. Vitamin D supplementation for the prevention of acute respiratory tract infection: a randomized, double-blinded trial among young Finnish men. J Infect Dis. 202(5):809–814.
  46. Lee AH, Dixit VD. 2020. Dietary regulation of immunity. Immunity. 53(3):510–523.
  47. Li H-B, Tai X-H, Sang Y-H, Jia J-P, Xu Z-M, Cui X-F, Dai S. 2016. Association between vitamin D and development of otitis media: A PRISMA-compliant meta-analysis and systematic review. Medicine (Baltimore). 95(40):e4739.
  48. Li YC. 2011. Vitamin D and the Renin-Angiotensin System. In: Vitamin D. Elsevier. p. 707–723.
  49. Maestro MA, Molnár F, Carlberg C. 2019. Vitamin D and its synthetic analogs. J Med Chem. 62(15):6854–6875.
  50. Majak P, Olszowiec-Chlebna M, Smejda K, Stelmach I. 2011. Vitamin D supplementation in children may prevent asthma exacerbation triggered by acute respiratory infection. J Allergy Clin Immunol. 127(5):1294–1296.
  51. Manaseki-Holland S, Qader G, Isaq Masher M, Bruce J, Zulf Mughal M, Chandramohan D, Walraven G. 2010. Effects of vitamin D supplementation to children diagnosed with pneumonia in Kabul: a randomised controlled trial: Vitamin D supplement during childhood pneumonia. Trop Med Int Health. 15(10):1148–1155.
  52. Marchisio P, Consonni D, Baggi E, Zampiero A, Bianchini S, Terranova L, Tirelli S, Esposito S, Principi N. 2013. Vitamin D supplementation reduces the risk of acute otitis media in otitis-prone children. Pediatr Infect Dis J. 32(10):1055–1060.
  53. Mark A. Sperling, MD, Joseph A. Majzoub, MD Ram K. Menon, MD, FRCP Constantine A. Stratakis, MD, D(MED)Sc, PhD(hc). 2021. Sperling Pediatric Endocrinology 5th Edition. Philadelphia: Elsevier.
  54. Martineau AR, Jolliffe DA, Hooper RL, Greenberg L, Aloia JF, Bergman P, Dubnov-Raz G, Esposito S, Ganmaa D, Ginde AA, et al. 2017. Vitamin D supplementation to prevent acute respiratory tract infections: systematic review and meta-analysis of individual participant data. BMJ.:i6583.
  55. Mason RS, Rybchyn MS, Abboud M, Brennan-Speranza TC, Fraser DR. 2019. The role of skeletal muscle in maintaining vitamin D status in winter. Curr Dev Nutr. 3(10):nzz087.
  56. Mazidi M, Rezaie P, Vatanparast H, Kengne AP. 2017. Effect of statins on serum vitamin D concentrations: a systematic review and meta-analysis. Eur J Clin Invest. 47(1):93–101.
  57. Meaning of elevated procalcitonin unclear in COVID-19. 2020 Apr 20. Massgeneral.org. [accessed 2021 Feb 15]. https://advances.massgeneral.org/research-and-innovation/article.aspx?id=1174.
  58. Medicines evidence commentary Commentary on important new evidence from medicines awareness weekly Vitamin D supplementation for preventing intensive care admissions in people with COVID-19 associated pneumonia. 2020 Sep. Nhs.uk. [accessed 2021 Feb 15]. http://arms.evidence.nhs.uk/resources/hub/1069281/attachment.
  59. Meltzer DO, Best TJ, Zhang H, Vokes T, Arora V, Solway J. 2020. Association of vitamin D status and other clinical characteristics with COVID-19 test results. JAMA Netw Open. 3(9):e2019722.
  60. Mendel CM. 1989. The free hormone hypothesis: a physiologically based mathematical model. Endocr Rev. 10(3):232–274.
  61. Moriyama M, Hugentobler WJ, Iwasaki A. 2020. Seasonality of respiratory viral infections. Annu Rev Virol. 7(1):83–101.
  62. &na; 2007. Dangers of indoor tanning. Nursing. 37(11):66.
  63. Naot D, Musson DS, Cornish J. 2019. The activity of peptides of the calcitonin family in bone. Physiol Rev. 99(1):781–805.
  64. National Heart, Lung, and Blood Institute PETAL Clinical Trials Network, Ginde AA, Brower RG, Caterino JM, Finck L, Banner-Goodspeed VM, Grissom CK, Hayden D, Hough CL, Hyzy RC, et al. 2019. Early high-dose vitamin D3 for critically ill, vitamin D-deficient patients. N Engl J Med. 381(26):2529–2540.
  65. Newman CB, Preiss D, Tobert JA, Jacobson TA, Page RL 2nd, Goldstein LB, Chin C, Tannock LR, Miller M, Raghuveer G, et al. 2019. Statin safety and associated adverse events: A scientific statement from the American heart association. Arterioscler Thromb Vasc Biol. 39(2):e38-e81.
  66. Nielsen R, Christensen EI, Birn H. 2016. Megalin and cubilin in proximal tubule protein reabsorption: from experimental models to human disease. Kidney Int. 89(1):58–67.
  67. Norman PE, Powell JT. 2014. Vitamin D and cardiovascular disease. Circ Res. 114(2):379–393.
  68. de Oliveira C, Biddulph JP, Hirani V, Schneider IJC. 2017. Vitamin D and inflammatory markers: cross-sectional analyses using data from the English Longitudinal Study of Ageing (ELSA). J Nutr Sci. 6(e1):e1.
  69. Orimo H. 2010. The mechanism of mineralization and the role of alkaline phosphatase in health and disease. J Nippon Med Sch. 77(1):4–12.
  70. Pachter L. 2020 Nov 17. Mathematical analysis of “mathematical analysis” of a vitamin D COVID-19 trial. liorpachter.wordpress.com. [accessed 2021 Feb 17]. https://liorpachter.wordpress.com/2020/11/17/mathematical-analysis-of-mathematical-analysis-of-a-vitamin-d-covid-19-trial/.
  71. Passeron T, Bouillon R, Callender V, Cestari T, Diepgen TL, Green AC, van der Pols JC, Bernard BA, Ly F, Bernerd F, et al. 2019. Sunscreen photoprotection and vitamin D status. Br J Dermatol. 181(5):916–931.
  72. ‘Patchen BK, Clark AG, Hancock DB, Gaddis N, Cassano PA. 2021. Genetically predicted serum vitamin D and COVID-19: a Mendelian randomization study. bioRxiv. doi:10.1101/2021.01.29.21250759. https://www.medrxiv.org/content/10.1101/2021.01.29.21250759v1.full.pdf.
  73. Pham H, Waterhouse M, Baxter C, Duarte Romero B, McLeod DSA, Armstrong BK, Ebeling PR, English DR, Hartel G, Kimlin MG, et al. 2021. The effect of vitamin D supplementation on acute respiratory tract infection in older Australian adults: an analysis of data from the D-Health Trial. Lancet Diabetes Endocrinol. 9(2):69–81.
  74. Pike JW, Christakos S. 2017. Biology and mechanisms of action of the vitamin D hormone. Endocrinol Metab Clin North Am. 46(4):815–843.
  75. Pilz S, Verheyen N, Grübler MR, Tomaschitz A, März W. 2016. Vitamin D and cardiovascular disease prevention. Nat Rev Cardiol. 13(7):404–417.
  76. Rak K, Bronkowska M. 2018. Immunomodulatory effect of vitamin D and its potential role in the prevention and treatment of type 1 diabetes mellitus-A narrative review. Molecules. 24(1):53.
  77. Rooney MR, Harnack L, Michos ED, Ogilvie RP, Sempos CT, Lutsey PL. 2017. Trends in use of high-dose vitamin D supplements exceeding 1000 or 4000 international units daily, 1999–2014. JAMA. 317(23):2448–2450.
  78. Rosen CJ, Taylor CL. 2013. Common misconceptions about vitamin D-implications for clinicians. Nat Rev Endocrinol. 9(7):434–438.
  79. Ross AC, Taylor CL, Yaktine AL, Del Valle HB, editors. 2011. Dietary reference intakes for calcium and vitamin D. Washington, D.C., DC: National Academies Press.
  80. Rubin R. 2021. Sorting out whether vitamin D deficiency raises COVID-19 risk. JAMA. 325(4):329–330.
  81. Santos RAS, Sampaio WO, Alzamora AC, Motta-Santos D, Alenina N, Bader M, Campagnole-Santos MJ. 2018. The ACE2/angiotensin-(1–7)/MAS axis of the renin-angiotensin system: Focus on angiotensin-(1–7). Physiol Rev. 98(1):505–553.
  82. Shah A, Aeddula NR. 2020. Renal Osteodystrophy. In: StatPearls. Treasure Island (FL): StatPearls Publishing.
  83. Shoback D, Rosen CJ, Black DM, Cheung AM, Murad MH, Eastell R. 2020. Pharmacological Management of osteoporosis in Postmenopausal Women: An endocrine society guideline update. J Clin Endocrinol Metab. 105(3):587–594.
  84. Silva MC, Furlanetto TW. 2018. Intestinal absorption of vitamin D: a systematic review. Nutr Rev. 76(1):60–76.
  85. Sparks MA, Crowley SD, Gurley SB, Mirotsou M, Coffman TM. 2014. Classical Renin-Angiotensin system in kidney physiology. Compr Physiol. 4(3):1201–1228.
  86. Stipanuk MH, Caudill MA. 2012. Biochemical, physiological, and molecular aspects of human nutrition. 3rd ed. London, England: W B Saunders.
  87. Szabo L. 2018 Aug 20. The man who sold America on vitamin D — and profited in the process. Khn.org. [accessed 2021 Feb 10]. https://khn.org/news/how-michael-holick-sold-america-on-vitamin-d-and-profited/.
  88. Tangpricha V. Vitamin D Deficiency and Related Disorders. Medscape.com. [accessed 2021 Feb 17]. https://emedicine.medscape.com/article/128762-overview#a6.
  89. Taylor CL, Thomas PR, Aloia JF, Millard PS, Rosen CJ. 2015. Questions about vitamin D for Primary Care practice: Input from an NIH conference. Am J Med. 128(11):1167–1170.
  90. Tebben PJ, Singh RJ, Kumar R. 2016. Vitamin D-mediated hypercalcemia: Mechanisms, diagnosis, and treatment. Endocr Rev. 37(5):521–547.
  91. Tripkovic L, Lambert H, Hart K, Smith CP, Bucca G, Penson S, Chope G, Hyppönen E, Berry J, Vieth R, et al. 2012. Comparison of vitamin D2 and vitamin D3 supplementation in raising serum 25-hydroxyvitamin D status: a systematic review and meta-analysis. Am J Clin Nutr. 95(6):1357–1364.
  92. Vaeth M, Feske S. 2018. Ion channelopathies of the immune system. Curr Opin Immunol. 52:39–50.
  93. Vitamin D. Nih.gov. [accessed 2021a Feb 10]. https://ods.od.nih.gov/factsheets/Vitamin%20D-HealthProfessional/.
  94. Vitamin D & iron supplements for babies: AAP recommendations. Healthychildren.org. [accessed 2021b Feb 17]. https://www.healthychildren.org/English/ages-stages/baby/feeding-nutrition/Pages/Vitamin-Iron-Supplements.aspx.
  95. Voet D, Voet JG. 2010. Biochemistry 4th Edition. Chichester, England: John Wiley & Sons.
  96. Vogiatzi MG, Jacobson-Dickman E, DeBoer MD, Drugs, and Therapeutics Committee of The Pediatric Endocrine Society. 2014. Vitamin D supplementation and risk of toxicity in pediatrics: a review of current literature. J Clin Endocrinol Metab. 99(4):1132–1141.
  97. Wade KH, Hall LJ. 2020. Improving causality in microbiome research: can human genetic epidemiology help? Wellcome Open Res. 4(199):199.
  98. Waldron JL, Ashby HL, Cornes MP, Bechervaise J, Razavi C, Thomas OL, Chugh S, Deshpande S, Ford C, Gama R. 2013. Vitamin D: a negative acute phase reactant. J Clin Pathol. 66(7):620–622.
  99. Wein MN, Kronenberg HM. 2018. Regulation of bone remodeling by parathyroid hormone. Cold Spring Harb Perspect Med. 8(8). doi:10.1101/cshperspect.a031237. http://perspectivesinmedicine.cshlp.org/cgi/pmidlookup?view=long&pmid=29358318.
  100. Yavuz B, Ertugrul DT. 2012. Statins and vitamin D: A hot topic that will be discussed for a long time: A hot topic that will be discussed for a long time. Dermatoendocrinol. 4(1):8–9.
  101. Zimmerman L, McKeon B. 2020. Osteomalacia. In: StatPearls. Treasure Island (FL): StatPearls Publishing.
  102. Neale RE, Khan SR, Lucas RM, Waterhouse M, Whiteman DC, Olsen CM. 2019. The effect of sunscreen on vitamin D: a review. Br J Dermatol. 181(5):907–915
  103. Vitamin D. Aad.org. [accessed 2021 Apr 24]. https://www.aad.org/media/stats-vitamin-d.

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Edward Nirenberg

Edward Nirenberg

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I write about vaccines here. You can find me on Twitter @enirenberg and at deplatformdisease.com (where I publish the same content without a paywall)