Magnesium as a Calcification Inhibitor

      Vascular calcification (VC) is associated with elevated cardiovascular mortality rates in patients with CKD. Recent clinical studies of patients with advanced CKD have observed an association between low serum magnesium (Mg) levels on one hand and elevated VC and cardiovascular mortality on the other. These findings have stimulated interest in understanding Mg's impact on CKD in general and the associated VC in particular. In vitro and preclinical in vivo data indicate that Mg has the potential to protect vascular smooth muscle cells against calcification via several different molecular mechanisms. Accordingly, data from pilot interventional studies in the clinic suggest that oral Mg supplementation reduces VC in patients with CKD. The present review provides an overview of our current understanding of the impact of Mg on the development of VC in patients with CKD.

      Key Words

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to Advances in Chronic Kidney Disease
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Rennenberg R.J.
        • Kessels A.G.
        • Schurgers L.J.
        • van Engelshoven J.M.
        • de Leeuw P.W.
        • Kroon A.A.
        Vascular calcifications as a marker of increased cardiovascular risk: a meta-analysis.
        Vasc Health Risk Manag. 2009; 5: 185-197
        • Hénaut L.
        • Mentaverri R.
        • Liabeuf S.
        • et al.
        Pathophysiological mechanisms of vascular calcification.
        Ann Biol Clin (Paris). 2015; 73: 271-287
        • Kanbay M.
        • Goldsmith D.
        • Uyar M.E.
        • Turgut F.
        • Covic A.
        Magnesium in chronic kidney disease: challenges and opportunities.
        Blood Purif. 2010; 29: 280-292
        • Spiegel D.M.
        Magnesium in chronic kidney disease: unanswered questions.
        Blood Purif. 2011; 31: 172-176
        • Massy Z.A.
        • Drüeke T.B.
        Magnesium and outcomes in patients with chronic kidney disease: focus on vascular calcification, atherosclerosis and survival.
        Clin Kidney J. 2012; 5: i52-i61
        • Villa-Bellosta R.
        • Millan A.
        • Sorribas V.
        Role of calcium-phosphate deposition in vascular smooth muscle cell calcification.
        Am J Physiol Cell Physiol. 2011; 300: C210-C220
        • Sage A.P.
        • Lu J.
        • Tintut Y.
        • Demer L.L.
        Hyperphosphatemia-induced nanocrystals upregulate the expression of bone morphogenetic protein-2 and osteopontin genes in mouse smooth muscle cells in vitro.
        Kidney Int. 2011; 79: 414-422
        • Boskey A.L.
        • Posner A.S.
        Effect of magnesium on lipid-induced calcification: an in vitro model for bone mineralization.
        Calcif Tissue Int. 1980; 32: 139-143
        • Termine J.D.
        • Peckauskas R.A.
        • Posner A.S.
        Calcium phosphate formation in vitro. II. Effects of environment on amorphous-crystalline transformation.
        Arch Biochem Biophys. 1970; 140: 318-325
        • Contiguglia S.R.
        • Alfrey A.C.
        • Miller N.L.
        • Runnells D.E.
        • Le Geros R.Z.
        Nature of soft tissue calcification in uremia.
        Kidney Int. 1973; 4: 229-235
        • Schlieper G.
        • Aretz A.
        • Verberckmoes S.C.
        • et al.
        Ultrastructural analysis of vascular calcifications in uremia.
        J Am Soc Nephrol. 2010; 21: 689-696
        • Yang H.
        • Curinga G.
        • Giachelli C.M.
        Elevated extracellular calcium levels induce smooth muscle cell matrix mineralization in vitro.
        Kidney Int. 2004; 66: 2293-2299
        • Montes de Oca A.
        • Guerrero F.
        • Martinez-Moreno J.M.
        • et al.
        Magnesium inhibits Wnt/β-catenin activity and reverses the osteogenic transformation of vascular smooth muscle cells.
        PLoS One. 2014; 9: e89525
        • Herencia C.
        • Rodríguez-Ortiz M.E.
        • Muñoz-Castañeda J.R.
        • et al.
        Angiotensin II prevents calcification in vascular smooth muscle cells by enhancing magnesium influx.
        Eur J Clin Invest. 2015; 45: 1129-1144
        • Alesutan I.
        • Tuffaha R.
        • Auer T.
        • et al.
        Inhibition of osteo/chondrogenic transformation of vascular smooth muscle cells by MgCl2 via calcium-sensing receptor.
        J Hypertens. 2017; 35: 523-532
        • Hénaut L.
        • Boudot C.
        • Massy Z.A.
        • et al.
        Calcimimetics increase CaSR expression and reduce mineralization in vascular smooth muscle cells: mechanisms of action.
        Cardiovasc Res. 2014; 101: 256-265
        • Louvet L.
        • Metzinger L.
        • Büchel J.
        • Steppan S.
        • Massy Z.A.
        Magnesium attenuates phosphate-induced deregulation of a MicroRNA signature and prevents modulation of Smad1 and Osterix during the course of vascular calcification [published online June 22, 2016]..
        Biomed Res Int. 2016; 2016 (doi: 10.1155/2016/7419524): 7419524
        • Louvet L.
        • Büchel J.
        • Steppan S.
        • Passlick-Deetjen J.
        • Massy Z.A.
        Magnesium prevents phosphate-induced calcification in human aortic vascular smooth muscle cells.
        Nephrol Dial Transplant. 2013; 28: 869-878
        • Fischer D.C.
        • Behets G.J.
        • Hakenberg O.W.
        • et al.
        Arterial microcalcification in atherosclerotic patients with and without chronic kidney disease: a comparative high-resolution scanning X-ray diffraction analysis.
        Calcif Tissue Int. 2012; 90: 465-472
        • Jiang Q.
        • Uitto J.
        Restricting dietary magnesium accelerates ectopic connective tissue mineralization in a mouse model of pseudoxanthoma elasticum (Abcc6(-/-) ).
        Exp Dermatol. 2012; 21: 694-699
        • Gorgels T.G.
        • Waarsing J.H.
        • de Wolf A.
        • ten Brink J.B.
        • Loves W.J.
        • Bergen A.A.
        Dietary magnesium, not calcium, prevents vascular calcification in a mouse model for pseudoxanthoma elasticum.
        J Mol Med (Berl). 2010; 88: 467-475
        • LaRusso J.
        • Li Q.
        • Jiang Q.
        • Uitto J.
        Elevated dietary magnesium prevents connective tissue mineralization in a mouse model of pseudoxanthoma elasticum (Abcc6(-/-)).
        J Invest Dermatol. 2009; 129: 1388-1394
        • Li Q.
        • Larusso J.
        • Grand-Pierre A.E.
        • Uitto J.
        Magnesium carbonate-containing phosphate binder prevents connective tissue mineralization in Abcc6(-/-) mice-potential for treatment of pseudoxanthoma elasticum.
        Clin Transl Sci. 2009; 2: 398-404
        • van den Broek F.A.
        • Beynen A.C.
        The influence of dietary phosphorus and magnesium concentrations on the calcium content of heart and kidneys of DBA/2 and NMRI mice.
        Lab Anim. 1998; 32: 483-491
        • Schwille P.O.
        • Schmiedl A.
        • Schwille R.
        • et al.
        Media calcification, low erythrocyte magnesium, altered plasma magnesium, and calcium homeostasis following grafting of the thoracic aorta to the infrarenal aorta in the rat–differential preventive effects of long-term oral magnesium supplementation alone and in combination with alkali.
        Biomed Pharmacother. 2003; 57: 88-97
        • Pen J.X.
        • Li L.
        • Wang X.
        • Zhang Y.H.
        • Li X.F.
        • Wu S.Y.
        The effect of the magnesium supplementation on vascular calcification in rats.
        Zhongguo Ying Yong Sheng Li Xue Za Zhi. 2012; 28: 20-23
        • Zelt J.G.
        • McCabe K.M.
        • Svajger B.
        • et al.
        Magnesium modifies the impact of calcitriol treatment on vascular calcification in experimental chronic kidney disease.
        J Pharmacol Exp Ther. 2015; 355: 451-462
        • De Schutter T.M.
        • Behets G.J.
        • Geryl H.
        • et al.
        Effect of a magnesium-based phosphate binder on medial calcification in a rat model of uremia.
        Kidney Int. 2013; 83: 1109-1117
        • Verberckmoes S.C.
        • Persy V.
        • Behets G.J.
        • et al.
        Uremia-related vascular calcification: more than apatite deposition.
        Kidney Int. 2007; 71: 298-303
        • Mak I.T.
        • Dickens B.F.
        • Komarov A.M.
        • Wagner T.L.
        • Phillips T.M.
        • Weglicki W.B.
        Activation of the neutrophil and loss of plasma glutathione during Mg-deficiency–modulation by nitric oxide synthase inhibition.
        Mol Cell Biochem. 1997; 176: 35-39
        • Malpuech-Brugère C.
        • Nowacki W.
        • Daveau M.
        • et al.
        Inflammatory response following acute magnesium deficiency in the rat.
        Biochim Biophys Acta. 2000; 1501: 91-98
        • Matsuzaki H.
        • Katsumata S.
        • Kajita Y.
        • Miwa M.
        Magnesium deficiency regulates vitamin D metabolizing enzymes and type II sodium-phosphate cotransporter mRNA expression in rats.
        Magnes Res. 2013; 26: 83-86
        • Rude R.K.
        • Gruber H.E.
        • Norton H.J.
        • Wei L.Y.
        • Frausto A.
        • Kilburn J.
        Reduction of dietary magnesium by only 50% in the rat disrupts bone and mineral metabolism.
        Osteoporos Int. 2006; 17: 1022-1032
        • Matsuzaki H.
        • Kajita Y.
        • Miwa M.
        Magnesium deficiency increases serum fibroblast growth factor-23 levels in rats.
        Magnes Res. 2013; 26: 18-23
        • Matsuzaki H.
        • Fuchigami M.
        • Miwa M.
        Dietary magnesium supplementation suppresses bone resorption via inhibition of parathyroid hormone secretion in rats fed a high-phosphorus diet.
        Magnes Res. 2010; 23: 126-130
        • Meema H.E.
        • Oreopoulos D.G.
        • Rapoport A.
        Serum magnesium level and arterial calcification in end-stage renal disease.
        Kidney Int. 1987; 32: 388-394
        • Ishimura E.
        • Okuno S.
        • Kitatani K.
        • et al.
        Significant association between the presence of peripheral vascular calcification and lower serum magnesium in hemodialysis patients.
        Clin Nephrol. 2007; 68: 222-227
        • Molnar A.O.
        • Biyani M.
        • Hammond I.
        • et al.
        Lower serum magnesium is associated with vascular calcification in peritoneal dialysis patients: a cross sectional study.
        BMC Nephrol. 2017; 18: 129
        • Tzanakis I.
        • Pras A.
        • Kounali D.
        • et al.
        Mitral annular calcifications in haemodialysis patients: a possible protective role of magnesium.
        Nephrol Dial Transplant. 1997; 12: 2036-2037
        • Silva A.P.
        • Gundlach K.
        • Büchel J.
        • et al.
        Low magnesium levels and FGF-23 dysregulation predict mitral valve calcification as well as intima media thickness in predialysis diabetic patients [published online May 18, 2015]..
        Int J Endocrinol. 2015; 2015: 308190
        • Hruby A.
        • O'Donnell C.J.
        • Jacques P.F.
        • Meigs J.B.
        • Hoffmann U.
        • McKeown N.M.
        Magnesium intake is inversely associated with coronary artery calcification: the Framingham Heart Study.
        JACC Cardiovasc Imaging. 2014; 7: 59-69
        • Lee S.Y.
        • Hyun Y.Y.
        • Lee K.B.
        • Kim H.
        Low serum magnesium is associated with coronary artery calcification in a Korean population at low risk for cardiovascular disease.
        Nutr Metab Cardiovasc Dis. 2015; 25: 1056-1061
        • Izawa H.
        • Imura M.
        • Kuroda M.
        • Takeda R.
        Proceedings: effect of magnesium on secondary hyperparathyroidism in chronic hemodialysis: a case with soft tissue calcification improved by high Mg dialysate.
        Calcif Tissue Res. 1974; 15: 162
        • Spiegel D.M.
        • Farmer B.
        Long-term effects of magnesium carbonate on coronary artery calcification and bone mineral density in hemodialysis patients: a pilot study.
        Hemodial Int. 2009; 13: 453-459
        • Tzanakis I.P.
        • Stamataki E.E.
        • Papadaki A.N.
        • Giannakis N.
        • Damianakis N.E.
        • Oreopoulos D.G.
        Magnesium retards the progress of the arterial calcifications in hemodialysis patients: a pilot study.
        Int Urol Nephrol. 2014; 46: 2199-2205
        • Mazzaferro S.
        • Coen G.
        • Bandini S.
        • et al.
        Role of ageing, chronic renal failure and dialysis in the calcification of mitral annulus.
        Nephrol Dial Transplant. 1993; 8: 335-340
        • Bressendorff I.
        • Hansen D.
        • Schou M.
        • Kragelund C.
        • Brandi L.
        The effect of magnesium supplementation on vascular calcification in chronic kidney disease-a randomised clinical trial (MAGiCAL-CKD): essential study design and rationale.
        BMJ Open. 2017; 7: e016795
        • Paravicini T.M.
        • Yogi A.
        • Mazur A.
        • Touyz R.M.
        Dysregulation of vascular TRPM7 and annexin-1 is associated with endothelial dysfunction in inherited hypomagnesemia.
        Hypertension. 2009; 53: 423-429
        • Sherer Y.
        • Shaish A.
        • Levkovitz H.
        • et al.
        Magnesium fortification of drinking water suppresses atherogenesis in male LDL-receptor-deficient mice.
        Pathobiology. 1999; 67: 207-213
        • Yamaguchi Y.
        • Kitagawa S.
        • Kunitomo M.
        • Fujiwara M.
        Preventive effects of magnesium on raised serum lipid peroxide levels and aortic cholesterol deposition in mice fed an atherogenic diet.
        Magnes Res. 1994; 7: 31-37
        • Altura B.T.
        • Brust M.
        • Bloom S.
        • Barbour R.L.
        • Stempak J.G.
        • Altura B.M.
        Magnesium dietary intake modulates blood lipid levels and atherogenesis.
        Proc Natl Acad Sci U S A. 1990; 87: 1840-1844
        • Kupetsky E.A.
        • Rincon F.
        • Uitto J.
        Rate of change of carotid intima-media thickness with magnesium administration in Abcc6⁻/⁻ mice.
        Clin Transl Sci. 2013; 6: 485-486
        • Tzanakis I.
        • Virvidakis K.
        • Tsomi A.
        • et al.
        Intra- and extracellular magnesium levels and atheromatosis in haemodialysis patients.
        Magnes Res. 2004; 17: 102-108
        • Zaher M.M.
        • Abdel-Salam M.
        • Abdel-Salam R.
        • Sabour R.
        • Morsy A.A.
        • Gamal D.
        Serum magnesium level and vascular stiffness in children with chronic kidney disease on regular hemodialysis.
        Saudi J Kidney Dis Transpl. 2016; 27: 233-240
        • Salem S.
        • Bruck H.
        • Bahlmann F.H.
        • et al.
        Relationship between magnesium and clinical biomarkers on inhibition of vascular calcification.
        Am J Nephrol. 2012; 35: 31-39
        • Fragoso A.
        • Silva A.P.
        • Gundlach K.
        • Büchel J.
        • Neves P.L.
        Magnesium and FGF-23 are independent predictors of pulse pressure in pre-dialysis diabetic chronic kidney disease patients.
        Clin Kidney J. 2014; 7: 161-166
        • Kanbay M.
        • Yilmaz M.I.
        • Apetrii M.
        • et al.
        Relationship between serum magnesium levels and cardiovascular events in chronic kidney disease patients.
        Am J Nephrol. 2012; 36: 228-237
        • Van Laecke S.
        • Maréchal C.
        • Verbeke F.
        • et al.
        The relation between hypomagnesaemia and vascular stiffness in renal transplant recipients.
        Nephrol Dial Transpl. 2011; 26: 2362-2369
        • Liao F.
        • Folsom A.R.
        • Brancati F.L.
        Is low magnesium concentration a risk factor for coronary heart disease? The Atherosclerosis Risk in Communities (ARIC) Study.
        Am Heart J. 1998; 136: 480-490
        • Ma J.
        • Folsom A.R.
        • Melnick S.L.
        • et al.
        Associations of serum and dietary magnesium with cardiovascular disease, hypertension, diabetes, insulin, and carotid arterial wall thickness: the ARIC study. Atherosclerosis Risk in Communities Study.
        J Clin Epidemiol. 1995; 48: 927-940
        • Hashimoto T.
        • Hara A.
        • Ohkubo T.
        • et al.
        Serum magnesium, ambulatory blood pressure, and carotid artery alteration: the Ohasama study.
        Am J Hypertens. 2010; 23: 1292-1298
        • Turgut F.
        • Kanbay M.
        • Metin M.R.
        • Uz E.
        • Akcay A.
        • Covic A.
        Magnesium supplementation helps to improve carotid intima media thickness in patients on hemodialysis.
        Int Urol Nephrol. 2008; 40: 1075-1082
        • Mortazavi M.
        • Moeinzadeh F.
        • Saadatnia M.
        • Shahidi S.
        • McGee J.C.
        • Minagar A.
        Effect of magnesium supplementation on carotid intima-media thickness and flow-mediated dilatation among hemodialysis patients: a double-blind, randomized, placebo-controlled trial.
        Eur Neurol. 2013; 69: 309-316
        • Joris P.J.
        • Plat J.
        • Bakker S.J.
        • Mensink R.P.
        Effects of long-term magnesium supplementation on endothelial function and cardiometabolic risk markers: a randomized controlled trial in overweight/obese adults.
        Sci Rep. 2017; 7: 106
        • Pagès N.
        • Gogly B.
        • Godeau G.
        • Igondjo-Tchen S.
        • Maurois P.
        • Durlach J.
        • et al.
        Structural alterations of the vascular wall in magnesium-deficient mice. A possible role of gelatinases A (MMP-2) and B (MMP-9).
        Magnes Res. 2003; 16: 43-48