Hypoparathyroidism During Magnesium Deficiency or Excess

  • René RizzoliEmail author


In humans, body magnesium content amounts to 25 g, with 66 % located in the bone, 33 % within cells, and only 1 % in the extracellular fluid (ECF), including blood [1–5] (see also Chap.  7). In the bone, magnesium as the divalent cation is adsorbed on the hydroxyapatite crystal and is in equilibrium with magnesium in the ECF. It is the most abundant intracellular cation together with potassium, reaching a concentration of approximately 0.5 mmol/l, which is thus close to that of magnesium in the ECF. Free cytosolic magnesium accounts for 5–10 % of total cellular magnesium. It binds to various organelles, 60 % of which is within mitochondria, where it is involved in phosphate transport, ATP synthesis, and utilization. ATP is synthesized by a magnesium-dependent oxidative phosphorylation process. Magnesium is a cofactor and regulator of a large series of enzymatic reactions, particularly those utilizing magnesium-ATP (glycolysis, oxidative phosphorylation), but also of DNA transcription and protein synthesis [1, 6]. In serum, 30 % of magnesium is protein bound. Circulating magnesium, which is between 0.7 and 1.0 mmol/l, is determined by bidirectional fluxes taking place at the levels of the intestine, kidney, and bone. Ionic magnesium interacts with the calcium-sensing receptor (CaSR) on parathyroid cells, and also on renal tubular cells, with a potency lower than calcium [7].


Hypocalcemia Hypokalemia Renal handling Malabsorption 


  1. 1.
    Walser M (1961) Ion association. VI. Interactions between calcium, magnesium, inorganic phosphate, citrate and protein in normal human plasma. J Clin Invest 40:723–730CrossRefPubMedCentralPubMedGoogle Scholar
  2. 2.
    Wacker WE, Parisi AF (1968) Magnesium metabolism. N Engl J Med 278(14):772–776 concl, Epub 1968/04/04CrossRefPubMedGoogle Scholar
  3. 3.
    Wacker WE, Parisi AF (1968) Magnesium metabolism. N Engl J Med 278(13):712–717, Epub 1968/03/28CrossRefPubMedGoogle Scholar
  4. 4.
    Wacker WE, Parisi AF (1968) Magnesium metabolism. N Engl J Med 278(12):658–663, Epub 1968/03/21CrossRefPubMedGoogle Scholar
  5. 5.
    Rude RK, Singer FR, Gruber HE (2009) Skeletal and hormonal effects of magnesium deficiency. J Am Coll Nutr 28(2):131–141, Epub 2009/10/16CrossRefPubMedGoogle Scholar
  6. 6.
    Rude RK (1998) Magnesium deficiency: a cause of heterogeneous disease in humans. J Bone Miner Res 13(4):749–758, Epub 1998/04/29CrossRefPubMedGoogle Scholar
  7. 7.
    Brown EM, MacLeod RJ (2001) Extracellular calcium sensing and extracellular calcium signaling. Physiol Rev 81(1):239–297, Epub 2001/01/12PubMedGoogle Scholar
  8. 8.
    Board IoMFaN (1997) Dietary references intakes: calcium, phosphorus, magnesium, vitamin D and fluoride. National Academic Press, Washington, DCGoogle Scholar
  9. 9.
    Fine KD, Santa Ana CA, Porter JL, Fordtran JS (1991) Intestinal absorption of magnesium from food and supplements. J Clin Invest 88(2):396–402, Epub 1991/08/01CrossRefPubMedCentralPubMedGoogle Scholar
  10. 10.
    Schmulen AC, Lerman M, Pak CY, Zerwekh J, Morawski S, Fordtran JS et al (1980) Effect of 1,25-(OH)2D3 on jejunal absorption of magnesium in patients with chronic renal disease. Am J Physiol 238(4):G349–G352, Epub 1980/04/01PubMedGoogle Scholar
  11. 11.
    Karbach U (1989) Cellular-mediated and diffusive magnesium transport across the descending colon of the rat. Gastroenterology 96(5 Pt 1):1282–1289, Epub 1989/05/01PubMedGoogle Scholar
  12. 12.
    Brannan PG, Vergne-Marini P, Pak CY, Hull AR, Fordtran JS (1976) Magnesium absorption in the human small intestine. Results in normal subjects, patients with chronic renal disease, and patients with absorptive hypercalciuria. J Clin Invest 57(6):1412–1418CrossRefPubMedCentralPubMedGoogle Scholar
  13. 13.
    Schlingmann KP, Weber S, Peters M, Niemann Nejsum L, Vitzthum H, Klingel K et al (2002) Hypomagnesemia with secondary hypocalcemia is caused by mutations in TRPM6, a new member of the TRPM gene family. Nat Genet 31(2):166–170, Epub 2002/05/29CrossRefPubMedGoogle Scholar
  14. 14.
    Lainez S, Schlingmann KP, van der Wijst J, Dworniczak B, van Zeeland F, Konrad M et al (2014) New TRPM6 missense mutations linked to hypomagnesemia with secondary hypocalcemia. Eur J Hum Genet 22(4):497–504, Epub 2013/08/15CrossRefPubMedGoogle Scholar
  15. 15.
    Houillier P (2014) Mechanisms and regulation of renal magnesium transport. Annu Rev Physiol 76:411–430, Epub 2014/02/12CrossRefPubMedGoogle Scholar
  16. 16.
    Agus ZS (1999) Hypomagnesemia. J Am Soc Nephrol 10(7):1616–1622, Epub 1999/07/15PubMedGoogle Scholar
  17. 17.
    de Rouffignac C, Quamme G (1994) Renal magnesium handling and its hormonal control. Physiol Rev 74(2):305–322, Epub 1994/04/01PubMedGoogle Scholar
  18. 18.
    Voets T, Nilius B, Hoefs S, van der Kemp AW, Droogmans G, Bindels RJ et al (2004) TRPM6 forms the Mg2+ influx channel involved in intestinal and renal Mg2+ absorption. J Biol Chem 279(1):19–25, Epub 2003/10/25CrossRefPubMedGoogle Scholar
  19. 19.
    Bailly C, Roinel N, Amiel C (1985) Stimulation by glucagon and PTH of Ca and Mg reabsorption in the superficial distal tubule of the rat kidney. Pflugers Arch 403(1):28–34, Epub 1985/01/01CrossRefPubMedGoogle Scholar
  20. 20.
    Groenestege WM, Hoenderop JG, van den Heuvel L, Knoers N, Bindels RJ (2006) The epithelial Mg2+ channel transient receptor potential melastatin 6 is regulated by dietary Mg2+ content and estrogens. J Am Soc Nephrol 17(4):1035–1043, Epub 2006/03/10CrossRefPubMedGoogle Scholar
  21. 21.
    Cholst IN, Steinberg SF, Tropper PJ, Fox HE, Segre GV, Bilezikian JP (1984) The influence of hypermagnesemia on serum calcium and parathyroid hormone levels in human subjects. N Engl J Med 310(19):1221–1225, Epub 1984/05/10CrossRefPubMedGoogle Scholar
  22. 22.
    Mayer GP, Hurst JG (1978) Comparison of the effects of calcium and magnesium on parathyroid hormone secretion rate in calves. Endocrinology 102(6):1803–1814, Epub 1978/06/01CrossRefPubMedGoogle Scholar
  23. 23.
    Rude RK, Oldham SB, Singer FR (1976) Functional hypoparathyroidism and parathyroid hormone end-organ resistance in human magnesium deficiency. Clin Endocrinol (Oxf) 5(3):209–224, Epub 1976/05/01CrossRefGoogle Scholar
  24. 24.
    Fuss M, Cogan E, Gillet C, Karmali R, Geurts J, Bergans A et al (1985) Magnesium administration reverses the hypocalcaemia secondary to hypomagnesaemia despite low circulating levels of 25-hydroxyvitamin D and 1,25-dihydroxy vitamin D. Clin Endocrinol (Oxf) 22(6):807–815, Epub 1985/06/01CrossRefGoogle Scholar
  25. 25.
    Rude RK, Oldham SB, Sharp CF Jr, Singer FR (1978) Parathyroid hormone secretion in magnesium deficiency. J Clin Endocrinol Metab 47(4):800–806, Epub 1978/10/01CrossRefPubMedGoogle Scholar
  26. 26.
    Fatemi S, Ryzen E, Flores J, Endres DB, Rude RK (1991) Effect of experimental human magnesium depletion on parathyroid hormone secretion and 1,25-dihydroxyvitamin D metabolism. J Clin Endocrinol Metab 73(5):1067–1072, Epub 1991/11/01CrossRefPubMedGoogle Scholar
  27. 27.
    Rude RK, Adams JS, Ryzen E, Endres DB, Niimi H, Horst RL et al (1985) Low serum concentrations of 1,25-dihydroxyvitamin D in human magnesium deficiency. J Clin Endocrinol Metab 61(5):933–940, Epub 1985/11/01CrossRefPubMedGoogle Scholar
  28. 28.
    Estep H, Shaw WA, Watlington C, Hobe R, Holland W, Tucker SG (1969) Hypocalcemia due to hypomagnesemia and reversible parathyroid hormone unresponsiveness. J Clin Endocrinol Metab 29(6):842–848, Epub 1969/06/01CrossRefPubMedGoogle Scholar
  29. 29.
    Freitag JJ, Martin KJ, Conrades MB, Bellorin-Font E, Teitelbaum S, Klahr S et al (1979) Evidence for skeletal resistance to parathyroid hormone in magnesium deficiency. Studies in isolated perfused bone. J Clin Invest 64(5):1238–1244, Epub 1979/11/01CrossRefPubMedCentralPubMedGoogle Scholar
  30. 30.
    Suh SM, Tashjian AH Jr, Matsuo N, Parkinson DK, Fraser D (1973) Pathogenesis of hypocalcemia in primary hypomagnesemia: normal end-organ responsiveness to parathyroid hormone, impaired parathyroid gland function. J Clin Invest 52(1):153–160, Epub 1973/01/01CrossRefPubMedCentralPubMedGoogle Scholar
  31. 31.
    Rosler A, Rabinowitz D (1973) Magnesium-induced reversal of vitamin-D resistance in hypoparathyroidism. Lancet 1(7807):803–804, Epub 1973/04/14CrossRefPubMedGoogle Scholar
  32. 32.
    Medalle R, Waterhouse C, Hahn TJ (1976) Vitamin D resistance in magnesium deficiency. Am J Clin Nutr 29(8):854–858, Epub 1976/08/01PubMedGoogle Scholar
  33. 33.
    Wong ET, Rude RK, Singer FR, Shaw ST Jr (1983) A high prevalence of hypomagnesemia and hypermagnesemia in hospitalized patients. Am J Clin Pathol 79(3):348–352, Epub 1983/03/01PubMedGoogle Scholar
  34. 34.
    Ryzen E, Wagers PW, Singer FR, Rude RK (1985) Magnesium deficiency in a medical ICU population. Crit Care Med 13(1):19–21, Epub 1985/01/01CrossRefPubMedGoogle Scholar
  35. 35.
    Petrelli F, Borgonovo K, Cabiddu M, Ghilardi M, Barni S (2012) Risk of anti-EGFR monoclonal antibody-related hypomagnesemia: systematic review and pooled analysis of randomized studies. Expert Opin Drug Saf 11(Suppl 1):S9–S19, Epub 2011/08/17CrossRefPubMedGoogle Scholar
  36. 36.
    Furlanetto TW, Faulhaber GA (2011) Hypomag-nesemia and proton pump inhibitors: below the tip of the iceberg. Arch Intern Med 171(15):1391–1392, Epub 2011/05/11Google Scholar
  37. 37.
    Hoorn EJ, van der Hoek J, de Man RA, Kuipers EJ, Bolwerk C, Zietse R (2010) A case series of proton pump inhibitor-induced hypomagnesemia. Am J Kidney Dis 56(1):112–116, Epub 2010/03/02CrossRefPubMedGoogle Scholar
  38. 38.
    Drueke TB (2004) Modulation and action of the calcium-sensing receptor. Nephrol Dial Transplant 19(Suppl 5):V20–V26, Epub 2004/07/31CrossRefPubMedGoogle Scholar
  39. 39.
    Whang R, Flink EB, Dyckner T, Wester PO, Aikawa JK, Ryan MP (1985) Magnesium depletion as a cause of refractory potassium repletion. Arch Intern Med 145(9):1686–1689, Epub 1985/09/01CrossRefPubMedGoogle Scholar
  40. 40.
    Ryzen E, Elbaum N, Singer FR, Rude RK (1985) Parenteral magnesium tolerance testing in the evaluation of magnesium deficiency. Magnesium 4(2–3):137–147, Epub 1985/01/01PubMedGoogle Scholar

Copyright information

© Springer-Verlag Italia 2015

Authors and Affiliations

  1. 1.Division of Bone Diseases, Faculty of MedicineGeneva University HospitalsGeneva 14Switzerland

Personalised recommendations