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Review of vitamin D interaction with drugs – Jan 2014

The Association Between Drugs Frequently Used by the Elderly and Vitamin D Blood Levels: A Review of Observational and Experimental Studies.

Anne Claire B. van Orten-Luiten OrtenW at zgv.nl (1) (2)
André Janse (3)
Rosalie A. M. Dhonukshe-Rutten (4)
Renger F. Witkamp (4)
1. Nutrition Alliance Gelderse Vallei, Hospital Gelderse Vallei, Willy Brandtlaan 10, 6716 RP, Ede, The Netherlands
2. Wageningen University, Wageningen, The Netherlands
3. Department of Geriatry, Hospital Gelderse Vallei, Willy Brandtlaan 10, 6716 RP, Ede, The Netherlands
4. Division of Human Nutrition, Wageningen University, Bomenweg 2, 6703 HD, Wageningen, The Netherlands

The risk of adverse drug reactions (ADRs) rises with increasing age. In the field of ADRs, drug-nutrient interactions (DNIs) are a relatively unexplored area. More knowledge will contribute to the simple prevention of this type of ADR. As the prevalence of vitamin D deficiency in the elderly is high, the primary objective of this review is to evaluate the literature on the relationship between drug use and vitamin D status, focusing on medicines commonly used by the elderly. PubMed was searched for human epidemiological and clinical studies published until early 2013, investigating the relationship between vitamin D blood levels and use of drugs from one of the following groups:

  • proton pump inhibitors (PPIs),
  • biguanides,
  • vitamin K antagonists,
  • platelet aggregation inhibitors,
  • thiazide diuretics,
  • loop diuretics,
  • beta-blocking agents,
  • calcium channel blockers,
  • angiotensin-converting enzyme (ACE) inhibitors,
  • angiotensin-II antagonists,
  • statins,
  • benzodiazepines, and
  • antidepressants.

A total of 63 publications were identified. Thiazide diuretics, statins, and calcium channel blocking agents were the most frequently studied drug groups.

  • Associations between thiazides and vitamin D were mixed (n = 22),
  • statins had no or positive associations (n = 16) and
  • calcium blockers were not associated or were negatively associated with vitamin D (n = 10).

In conclusion, several knowledge gaps exist on the relationship between drug use and vitamin D blood levels. Available data are scarce (particularly for the aged), study characteristics are highly variable, and found associations may be confounded by, amongst other things, the underlying disease. Nonetheless, this review provides a basis for future research on ADRs that contribute to nutrient deficiencies.

PMID: 24385337


  1. Onder G, Petrovic M, Tangiisuran B, et al. Development and validation of a score to assess risk of adverse drug reactions among in-hospital patients 65 years or older: the GerontoNet ADR risk score. Arch Intern Med. 2010;170(13):1142–8. CrossRef
  2. van der Hooft CS, Dieleman JP, Siemes C, et al. Adverse drug reaction-related hospitalisations: a population-based cohort study. Pharmacoepidemiol Drug Saf. 2008;17(4):365–71. CrossRef
  3. Boullata JI, Hudson LM. Drug-nutrient interactions: a broad view with implications for practice. J Acad Nutr Diet. 2012;112(4):506–17. CrossRef
  4. Santos CA, Boullata JI. An approach to evaluating drug-nutrient interactions. Pharmacotherapy. 2005;25(12):1789–800. CrossRef
  5. Prentice A, Vitamin D. Deficiency: a global perspective. Nutr Rev. 2008;66(10 Suppl 2):S153–64. CrossRef
  6. Millen AE, Wactawski-Wende J, Pettinger M, et al. Predictors of serum 25-hydroxyvitamin D concentrations among postmenopausal women: the Women’s Health Initiative Calcium plus Vitamin D clinical trial. Am J Clin Nutr. 2010;91(5):1324–35. CrossRef
  7. Murr C, Pilz S, Grammer TB, Kleber ME, et al. Vitamin D deficiency parallels inflammation and immune activation, the Ludwigshafen Risk and Cardiovascular Health (LURIC) study. Clin Chem Lab Med. 2012;50(12):2065–250.
  8. Robien K, Oppeneer SJ, Kelly JA, et al. Drug-vitamin D interactions: a systematic review of the literature. Nutr Clin Pract. 2013;10(28):194–208. CrossRef
  9. Grober U, Kisters K. Influence of drugs on vitamin D and calcium metabolism. Dermatoendocrinol. 2012;4(2):158–66. CrossRef
  10. Sohl E, van Schoor NM, de Jongh RT, et al. The impact of medication on vitamin D status in older individuals. Eur J Endocrinol. 2012;166(3):477–85. CrossRef
  11. van Orten-Luiten ACB. Is use of medication associated with blood levels of micronutrients? A cross-sectional study of a Dutch geriatric hospital population MSc. Wageningen: Wageningen University; 2012.
  12. WHO Collaborating Centre for Drug Statistics Methodology of the Norwegian Institute of Public Health: The ATC/DDD system: The Anatomical Therapeutic Chemical classification system and the Defined Daily Dose. Oslo, Norway: Norwegian Institute of Public Health. Available from: http://www.whocc.no/.
  13. Avgeri M, Papadopoulou A, Platokouki H, et al. Assessment of bone mineral density and markers of bone turnover in children under long-term oral anticoagulant therapy. J Pediatr Hematol Oncol. 2008;30(8):592–7. CrossRef
  14. Seikaly MG, Quigley R, Baum M. Effect of dipyridamole on serum and urinary phosphate in X-linked hypophosphatemia. Pediatr Nephrol. 2000;15(1–2):57–9. CrossRef
  15. Riis B, Christiansen C. Actions of thiazide on vitamin D metabolism: a controlled therapeutic trial in normal women early in the postmenopause. Metabolism. 1985;34(5):421–4. CrossRef
  16. Sakhaee K, Nicar MJ, Glass K, et al. Reduction in intestinal calcium absorption by hydrochlorothiazide in postmenopausal osteoporosis. J Clin Endocrinol Metab. 1984;59(6):1037–43. CrossRef
  17. Manninen A, Wuorela H, Laippala P, et al. Intraplatelet free calcium and calcium-regulating hormones in plasma are not related to the antihypertensive effect of nifedipine in hypertensive pregnancy. Pharmacol Toxicol. 1995;77(5):327–32. CrossRef
  18. Rejnmark L, Vestergaard P, Heickendorff L, et al. Loop diuretics alter the diurnal rhythm of endogenous parathyroid hormone secretion. A randomized-controlled study on the effects of loop- and thiazide-diuretics on the diurnal rhythms of calcitropic hormones and biochemical bone markers in postmenopausal women. Eur J Clin Invest. 2001;31(9):764–72. CrossRef
  19. Adams JS, Song CF, Kantorovich V. Rapid recovery of bone mass in hypercalciuric, osteoporotic men treated with hydrochlorothiazide. Ann Intern Med. 1999;130(8):658–60. CrossRef
  20. Lo Cascio V, Adami S, Tartarotti D, et al. Aberration in vitamin D metabolism during mianserin treatment. Lancet. 1984 Apr 28;1(8383):958–9.
  21. Demir C, Mousa U, Anil C, et al. Effects of atorvastatin and rosuvastatin therapy on serum 25-hydroxyvitamin D levels: a comparative study. In: Abstracts E, editor. European Congress of Endocrinology 2011; 30 April 2011–04 May 2011. Rotterdam: BioScientifica; 2011. p. P548.1.
  22. Wright MJ, Sullivan RR, Gaffney-Stomberg E, et al. Inhibiting gastric acid production does not affect intestinal calcium absorption in young, healthy individuals: a randomized, crossover, controlled clinical trial. J Bone Miner Res. 2010;25(10):2205–11. CrossRef
  23. Hansen KE, Jones AN, Lindstrom MJ, Davis LA, et al. Do proton pump inhibitors decrease calcium absorption? J Bone Miner Res. 2010;25(12):2786–95.
  24. Sharara AI, El-Halabi MM, Ghaith OA, et al. Proton Pump inhibitors have no measurable effect on calcium and bone metabolism in healthy young males: a prospective matched controlled study. Metabolism. 2012;62(4):518–26. CrossRef
  25. Sathyapalan T, Shepherd J, Arnett C, et al. Atorvastatin increases 25-hydroxy vitamin D concentrations in patients with polycystic ovary syndrome. Clin Chem. 2010;56(11):1696–700. CrossRef
  26. Kos E, Liszek MJ, Emanuele MA, et al. Effect of metformin therapy on vitamin D and vitamin B12 levels in patients with type 2 diabetes mellitus. Endocr Pract. 2012;18(2):179–84.
  27. Suzuki A, Kotake M, Ono Y, et al. Hypovitaminosis D in type 2 diabetes mellitus: association with microvascular complications and type of treatment. Endocr J. 2006;53(4):503–10. CrossRef
  28. Ragonesi PD, Taddei MT, Ragonesi G, et al. Influence of diabetic treatment regimens on vitamin D metabolism in elderly patients. Arch Gerontol Geriatr. 1996;22(Suppl 1):271–4. CrossRef
  29. Sato Y, Honda Y, Jun I. Long-term oral anticoagulation therapy and the risk of hip fracture in patients with previous hemispheric infarction and nonrheumatic atrial fibrillation. Cerebrovasc Dis. 2010;29(1):73–8. CrossRef
  30. Sato Y, Honda Y, Kunoh H, et al. Long-term oral anticoagulation reduces bone mass in patients with previous hemispheric infarction and nonrheumatic atrial fibrillation. Stroke. 1997;28(12):2390–4. CrossRef
  31. Stenova E, Steno B, Killinger Z, et al. Effect of long-term oral anticoagulant therapy on bone mineral density and bone turnover markers: a prospective 12 month study. Bratisl Lek Listy. 2011;112(2):71–6.
  32. Prie D, Blanchet FB, Essig M, et al. Dipyridamole decreases renal phosphate leak and augments serum phosphorus in patients with low renal phosphate threshold. J Am Soc Nephrol. 1998;9(7):1264–9.
  33. Vestergaard P, Hermann P, Jensen JE, et al. Effects of paracetamol, non-steroidal anti-inflammatory drugs, acetylsalicylic acid, and opioids on bone mineral density and risk of fracture: results of the Danish Osteoporosis Prevention Study (DOPS). Osteoporos Int. 2012;23(4):1255–65. CrossRef
  34. Cigolini M, Iagulli MP, Miconi V, et al. Serum 25-hydroxyvitamin D3 concentrations and prevalence of cardiovascular disease among type 2 diabetic patients. Diabetes Care. 2006;29(3):722–4. CrossRef
  35. Rejnmark L, Vestergaard P, Pedersen AR, et al. Dose-effect relations of loop- and thiazide-diuretics on calcium homeostasis: a randomized, double-blinded Latin-square multiple cross-over study in postmenopausal osteopenic women. Eur J Clin Invest. 2003;33(1):41–50. CrossRef
  36. Rejnmark L, Vestergaard P, Heickendorff L, et al. Effects of thiazide- and loop-diuretics, alone or in combination, on calcitropic hormones and biochemical bone markers: a randomized controlled study. J Intern Med. 2001;250(2):144–53. CrossRef
  37. Reid IR, Ames RW, Orr-Walker BJ, et al. Hydrochlorothiazide reduces loss of cortical bone in normal postmenopausal women: a randomized controlled trial. Am J Med. 2000;109(5):362–70. CrossRef
  38. Insogna KL, Ellison AS, Burtis WJ, et al. Trichlormethiazide and oral phosphate therapy in patients with absorptive hypercalciuria. J Urol. 1989;141(2):269–74.
  39. Nowack R, Hofner MC, Reichel H, et al. Subacute effects of thiazide administration on renal hemodynamics and calcium metabolism. Clin Investig. 1992;70(8):686–91. CrossRef
  40. Calo L, Cantaro S, Marchini F, et al. Is hydrochlorothiazide-induced hypocalciuria due to inhibition of prostaglandin E2 synthesis? Clin Sci (Lond). 1990;78(3):321–5.
  41. Krause U, Zielke A, Schmidt-Gayk H, et al. Direct tubular effect on calcium retention by hydrochlorothiazide. J Endocrinol Invest. 1989;12(8):531–5.
  42. Zerwekh JE, Pak CY. Selective effects of thiazide therapy on serum 1 alpha,25-dihydroxyvitamin D and intestinal calcium absorption in renal and absorptive hypercalciurias. Metabolism. 1980;29(1):13–7. CrossRef
  43. Laroche M, Mazieres B. Beneficial effect of a thiazide diuretic on bone mineral density in male osteoporosis with hypercalciuria. Clin Exp Rheumatol. 1998;16(1):109–10.
  44. Coe FL, Parks JH, Bushinsky DA, et al. Chlorthalidone promotes mineral retention in patients with idiopathic hypercalciuria. Kidney Int. 1988;33(6):1140–6. CrossRef
  45. Lemann J Jr, Gray RW, Maierhofer WJ, et al. Hydrochlorothiazide inhibits bone resorption in men despite experimentally elevated serum 1,25-dihydroxyvitamin D concentrations. Kidney Int. 1985;28(6):951–8. CrossRef
  46. Dawson-Hughes B, Harris S. Thiazides and seasonal bone change in healthy postmenopausal women. Bone Miner. 1993;21(1):41–51. CrossRef
  47. Kokot F, Pietrek J, Srokowska S, et al. 25-hydroxyvitamin D in patients with essential hypertension. Clin Nephrol. 1981;16(4):188–92.
  48. Drinka PJ, Krause PF, Nest LJ, et al. Determinants of parathyroid hormone levels in nursing home residents. J Am Med Dir Assoc. 2007;8(5):328–31. CrossRef
  49. Sowers MR, Wallace RB, Hollis BW. The relationship of 1,25-dihydroxyvitamin D and radial bone mass. Bone Miner. 1990;10(2):139–48. CrossRef
  50. Perry HM 3rd, Jensen J, Kaiser FE, et al. The effects of thiazide diuretics on calcium metabolism in the aged. J Am Geriatr Soc. 1993;41(8):818–22.
  51. Rejnmark L, Vestergaard P, Heickendorff L, et al. Loop diuretics increase bone turnover and decrease BMD in osteopenic postmenopausal women: results from a randomized controlled study with bumetanide. J Bone Miner Res. 2006;21(1):163–70. CrossRef
  52. Rejnmark L, Vestergaard P, Heickendorff L, et al. Effects of long-term treatment with loop diuretics on bone mineral density, calcitropic hormones and bone turnover. J Intern Med. 2005;257(2):176–84. CrossRef
  53. Reichel H, Deibert B, Geberth S, et al. Frusemide therapy and intact parathyroid hormone plasma concentrations in chronic renal insufficiency. Nephrol Dial Transplant. 1992;7(1):8–15.
  54. Calo L, Cantaro S, Piccoli A, et al. Effect of nifedipine on urinary excretion of calcium and calcium-controlling hormones in essential hypercalciuria. Cardiovasc Drugs Ther. 1990;4(Suppl 5):983–6. CrossRef
  55. Resnick LM, Nicholson JP, Laragh JH. The effects of calcium channel blockade on blood pressure and calcium metabolism. Am J Hypertens. 1989;2(12 Pt 1):927–30.
  56. Resnick LM, Nicholson JP, Laragh JH. The antihypertensive effects of calcium channel blockade: role of sodium and calcium metabolism. J Cardiovasc Pharmacol. 1988;12(Suppl 6):S114–6. CrossRef
  57. Townsend R, DiPette DJ, Evans RR, et al. Effects of calcium channel blockade on calcium homeostasis in mild to moderate essential hypertension. Am J Med Sci. 1990;300(3):133–7. CrossRef
  58. Hughes GS Jr, Cowart TD, Oexmann MJ, et al. Verapamil-induced natriuretic and diuretic effects: dependency on sodium intake. Clin Pharmacol Ther. 1988;44(4):400–7. CrossRef
  59. Riegel W, Horl WH, Heidland A. Long-term effects of nifedipine on plasma levels of 25 hydroxyvitamin D and 1,25 dihydroxyvitamin D in hypertensive hemodialyzed patients. Klin Wochenschr. 1986;64(24):1291. CrossRef
  60. Albers MM, Johnson W, Vivian V, et al. Chronic use of the calcium channel blocker nifedipine has no significant effect on bone metabolism in men. Bone. 1991;12(1):39–42. CrossRef
  61. Perez-Castrillon JL, Justo I, Sanz A, et al. Effect of angiotensin converting enzyme inhibitors on 1.25-(OH)2 D levels of hypertensive patients. Relationship with ACE polymorphisms. Horm Metab Res. 2006;38(12):812–6. CrossRef
  62. Perez-Castrillon JL, Silva J, Justo I, et al. Effect of quinapril, quinapril-hydrochlorothiazide, and enalapril on the bone mass of hypertensive subjects: relationship with angiotensin converting enzyme polymorphisms. Am J Hypertens. 2003;16(6):453–9. CrossRef
  63. Perez-Castrillon JL, Vega G, Abad L, Sanz A, Chaves J, et al. Effects of Atorvastatin on vitamin D levels in patients with acute ischemic heart disease. Am J Cardiol. 2007;99(7):903–5. CrossRef
  64. Doorenbos CR, de Cuba MM, Vogt L, et al. Antiproteinuric treatment reduces urinary loss of vitamin D-binding protein but does not affect vitamin D status in patients with chronic kidney disease. J Steroid Biochem Mol Biol. 2012;128(1–2):56–61. CrossRef
  65. Perez-Castrillon JL, De Luis D, Inglada L, et al. Telmisartan effect’s on remodelling bone markers in hypertensive patients. Nutr Hosp. 2012;27(1):276–80.
  66. Aloia JF, Li-Ng M, Pollack S. Statins and vitamin D. Am J Cardiol. 2007;100(8):1329. CrossRef
  67. Rejnmark L, Vestergaard P, Heickendorff L, et al. Simvastatin does not affect vitamin d status, but low vitamin d levels are associated with dyslipidemia: results from a randomised, controlled trial. Int J Endocrinol. 2010;2010:957174. CrossRef
  68. Sathyapalan T, Shepherd J, Atkin SL, et al. The effect of atorvastatin and simvastatin on vitamin D, oxidative stress and inflammatory marker concentrations in patients with type 2 diabetes: a crossover study. Diabetes Obes Metab. 2013;15(8):767–9.
  69. Liberopoulos EN, Makariou SE, Moutzouri E, et al. Effect of simvastatin/ezetimibe 10/10 mg versus simvastatin 40 mg on serum vitamin D levels. J Cardiovasc Pharmacol Ther. 2013;2:1–5.
  70. Ertugrul DT, Yavuz B, Cil H, et al. STATIN-D study: comparison of the influences of rosuvastatin and fluvastatin treatment on the levels of 25 hydroxyvitamin D. Cardiovascular Ther. 2011;29(2):146–52.
  71. Ismail F, Corder CN, Epstein S, et al. Effects of pravastatin and cholestyramine on circulating levels of parathyroid hormone and vitamin D metabolites. Clin Ther. 1990;12(5):427–30.
  72. Montagnani M, Lore F, Di Cairano G, et al. Effects of pravastatin treatment on vitamin D metabolites. Clin Ther. 1994;16(5):824–9.
  73. Dobs AS, Levine MA, Margolis S. Effects of pravastatin, a new HMG-CoA reductase inhibitor, on vitamin D synthesis in man. Metabolism. 1991;40(5):524–8. CrossRef
  74. Ott C, Raff U, Schneider MP, et al. 25-hydroxyvitamin D insufficiency is associated with impaired renal endothelial function and both are improved with rosuvastatin treatment. Clin Res Cardiol. 2013 ;102(4) :299–304.
  75. Makariou SE, Liberopoulos EN, Agouridis AP, et al. Effect of rosuvastatin monotherapy and in combination with fenofibrate or omega-3 fatty acids on serum vitamin D levels. J Cardiovasc Pharmacol Ther. 2012;17(4):382–6. CrossRef
  76. Yavuz B, Ertugrul DT, Cil H, et al. Increased levels of 25 hydroxyvitamin D and 1,25-dihydroxyvitamin D after rosuvastatin treatment: a novel pleiotropic effect of statins? Cardiovasc Drugs Ther. 2009;23(4):295–9.
  77. Verhoeven V, Vanpuyenbroeck K, Lopez-Hartmann M, et al. Walk on the sunny side of life–epidemiology of hypovitaminosis D and mental health in elderly nursing home residents. J Nutr Health Aging. 2012;16(4):417–20. CrossRef
  78. Jones G. Metabolism and biomarkers of vitamin D. Scand J Clin Lab Invest Suppl. 2012;243:7–13.
  79. Bugel S, Vitamin K. Vitamin K and bone health in adult humans. Vitam Horm. 2008;78:393–416.
  80. Zhou SF, Xue CC, Yu XQ, et al. Clinically important drug interactions potentially involving mechanism-based inhibition of cytochrome P450 3A4 and the role of therapeutic drug monitoring. Ther Drug Monit. 2007;29(6):687–710. CrossRef
  81. Chonchol M, Scragg R. 25-Hydroxyvitamin D, insulin resistance, and kidney function in the Third National Health and Nutrition Examination Survey. Kidney Int. 2007;71(2):134–9. CrossRef
  82. Gama R, Waldron JL, Ashby HL, et al. Hypovitaminosis D and disease: consequence rather than cause? BMJ. 2012;345:e5706.
  83. Ding C, Parameswaran V, Blizzard L, et al. Not a simple fat-soluble vitamin: changes in serum 25-(OH)D levels are predicted by adiposity and adipocytokines in older adults. J Intern Med. 2010;268(5):501–10. CrossRef
  84. Querfeld U. Vitamin D and inflammation. Pediatr Nephrol. 2012;28(4):605–10.
  85. Milaneschi Y, Hoogendijk W, Lips P, et al. The association between low vitamin D and depressive disorders. Mol Psychiatry. Epub 2013 Apr 9.
  86. Riegel W, Horl WH, Heidland A. Long-term effects of nifedipine on carbohydrate and lipid metabolism in hypertensive hemodialyzed patients. Klin Wochenschr. 1986;64(21):1124–30. CrossRef

Summary by VitaminDWiki

Drug Increase Vitamin D Neutral Decrease Vitamin D
Thiazide Increase Drug affect Increases Drug affect (negative)
Statin Increase Drug affect Neutral
Calcium blocker Neutral Increases Drug affect (negative)

See also VitaminDWiki

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