Calcium and Vitamin D Supplementation. Myths and Realities with Regard to Cardiovascular Risk

Author(s): Giovanna Muscogiuri*, Luigi Barrea, Barbara Altieri, Carolina Di Somma, Harjit pal Bhattoa, Daniela Laudisio, Guillaume T. Duval, Gabriella Pugliese, Cédric Annweiler, Francesco Orio, Hana Fakhouri, Silvia Savastano, Annamaria Colao.

Journal Name: Current Vascular Pharmacology

Volume 17 , Issue 6 , 2019

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Graphical Abstract:


Vitamin D and calcium are considered crucial for the treatment of bone diseases. Both vitamin D and calcium contribute to bone homeostasis but also preserve muscle health by reducing the risk of falls and fractures. Low vitamin D concentrations result in secondary hyperparathyroidism and contribute to bone loss, although the development of secondary hyperparathyroidism varies, even in patients with severe vitamin D deficiency. Findings from observational studies have shown controversial results regarding the association between bone mineral density and vitamin D/calcium status, thus sparking a debate regarding optimum concentrations of 25-hydroxyvitamin D and calcium for the best possible skeletal health. Although most of the intervention studies reported a positive effect of supplementation with calcium and vitamin D on bone in patients with osteoporosis, this therapeutic approach has been a matter of debate regarding potential side effects on the cardiovascular (CV) system. Thus, the aim of this review is to consider the current evidence on the physiological role of vitamin D and calcium on bone and muscle health. Moreover, we provide an overview on observational and interventional studies that investigate the effect of vitamin D and calcium supplementation on bone health, also taking into account the possible CV side-effects. We also provide molecular insights on the effect of calcium plus vitamin D on the CV system.

Keywords: Vitamin D, cardiovascular system, calcium, myocardial infarction, stroke, bone health.

Kanis JA, Brazier JE, Stevenson M, Calvert NW, Lloyd JM. Treatment of established osteoporosis: A systematic review and cost-utility analysis. Health Technol Assess 2002; 6: 1-146.
Heaney RP, Weaver CM. Calcium and vitamin D. Endocrinol Metab Clin North Am 2003; 32: 181-94.
Rizzoli R, Stevenson JC, Bauer JM, et al. The role of dietary protein and vitamin D in maintaining musculoskeletal health in postmenopausal women: A consensus statement from the European society for clinical and economic aspects of osteoporosis and osteoarthritis (ESCEO). Maturitas 2014; 79: 122-32.
Kuo IY, Ehrlich BE. Signaling in muscle contraction. Cold Spring Harb Perspect Biol 2015; 7006023
Gehlert S, Bloch W, Suhr F. Ca2+ dependent regulations and signaling in skeletal muscle: From electro-mechanical coupling to adaptation. Int J Mol Sci 2015; 16: 1066-95.
Pfeifer M, Begerow B, Minne HW. Vitamin D and muscle function. Osteoporos Int 2002; 13: 187-94.
Rodman JS, Baker T. Changes in the kinetics of muscle contraction in vitamin D-depleted rats. Kidney Int 1978; 13: 189-93.
Muscogiuri G, Altieri B, Annweiler C, et al. Vitamin D and chronic diseases: The current state of the art. Arch Toxicol 2017; 91: 97-107.
Roux C, Bischoff-Ferrari HA, Papapoulos SE, de Papp AE, West JA, Bouillon R. New insights into the role of vitamin D and calcium in osteoporosis management: An expert roundtable discussion. Curr Med Res Opin 2008; 24: 1363-70.
Reid IR, Bristow SM, Bolland MJ. Cardiovascular complications of calcium supplements. J Cell Biochem 2015; 116: 494-501.
Chalupka S. Associations of dietary calcium intake and calcium supplementation with myocardial infarction, stroke, and overall cardiovascular mortality. Workplace Health Saf 2012; 60: 372.
Thiele I, Linseisen J, Meisinger C, et al. Associations between calcium and vitamin D supplement use as well as their serum concentrations and subclinical cardiovascular disease phenotypes. Atherosclerosis 2015; 241: 743-51.
Block GA, Raggi P, Bellasi A, Kooienga L, Spiegel DM. Mortality effect of coronary calcification and phosphate binder choice in incident hemodialysis patients. Kidney Int 2007; 71: 438-41.
Ross AC, Manson JE, Abrams SA, et al. The 2011 report on dietary reference intakes for calcium and vitamin D from the Institute of Medicine: What clinicians need to know. J Clin Endocrinol Metab 2011; 96: 53-8.
Ross AC, Taylor CL, Yaktine AL, del Valle HB, Eds. Dietary reference intakes for calcium and vitamin D Institute of Medicine. Washington, DC: The National Academies Press 2011.
Lips P. Interaction between vitamin D and calcium. Scand J Clin Lab Invest Suppl 2012; 243: 60-4.
Bolland MJ, Leung W, Tai V, et al. Calcium intake and risk of fracture: Systematic review. BMJ 2015; 351: h4580.
Michaëlsson K. Calcium supplements do not prevent fractures. BMJ 2015; 351: 4825.
Lai JK, Lucas RM, Clements MS, Roddam AW, Banks E. Hip fracture risk in relation to vitamin D supplementation and serum 25-hydroxyvitamin D levels: A systematic review and meta-analysis of randomised controlled trials and observational studies. BMC Public Health 2010; 10: 331.
Chapuy MC, Arlot ME, Duboeuf F, et al. Vitamin D3 and calcium to prevent hip fractures inthe elderly women. N Engl J Med 1992; 327: 1637-42.
Chapuy MC, Pamphile R, Paris E, et al. Combined calcium and vitamin D3 supplementation in elderly women: Confirmation of reversal of secondary hyperparathyreoidism and hip fracture risk: The Decalos II study. Osteoporos Int 2002; 13: 257-64.
Avenell A, Mak JC, O’Connell D. Vitamin D and vitamin D analogues for preventing fractures in post-menopausal women and older men. Cochrane Database Syst Rev 2014; 4CD000227
Holick MF. Vitamin D deficiency. N Engl J Med 2007; 357: 266-81.
Cosman F, de Beur SJ, LeBoff MS, et al. Clinician’s guide to prevention and treatment of osteoporosis. Osteoporos Int 2014; 25: 2359-81.
Bhattoa HP, Konstantynowicz J, Laszcz N, Wojcik M, Pludowski P, Vitamin D. Musculoskeletal health. Rev Endocr Metab Disord 2017; 18: 363-71.
Pludowski P, Holick MF, Grant WB, et al. Vitamin D supplementation guidelines. J Steroid Biochem Mol Biol 2018; 175: 125-35.
Holick MF, Binkley NC, Bischoff-Ferrari HA, et al. Evaluation, treatment, and prevention of vitamin D deficiency: An endocrine society clinical practice guideline. J Clin Endocrinol Metab 2011; 96: 1911-30.
Pludowski P, Karczmarewicz E, Bayer M, et al. Practical guidelines for the supplementation of vitamin D and the treatment of deficits in central Europe - recommended vitamin D intakes in the general population and groups at risk of vitamin D deficiency. Endokrynol Pol 2013; 64: 319-27.
Haq A, Wimalawansa SJ, Pludowski P, Al Anouti F. Clinical practice guidelines for vitamin D in the United Arab Emirates. J Steroid Biochem Mol Biol 2018; 175: 4-11.
Michaëlsson K, Melhus H, Warensjö Lemming E, Wolk A, Byberg L. Long term calcium intake and rates of all cause and cardiovascular mortality: Community based prospective longitudinal cohort study. BMJ 2013; 346: 228.
Ascherio A, Rimm EB, Hernan MA, et al. Intake of potassium, magnesium, calcium, and fiber and risk of stroke among US men. Circulation 1998; 98: 1198-204.
Anagnostis P, Athyros VG, Adamidou F, Florentin M, Karagiannis A. Vitamin D and cardiovascular disease: A novel agent for reducing cardiovascular risk? Curr Vasc Pharmacol 2010; 8: 720-30.
Anagnostis P, Paschou SA, Goulis DG. Vitamin D supplementation and cardiovascular disease risk. JAMA Cardiol 2017; 2: 1281-2.
Van der Vijver LP, Van der Waal MA, Weterings KG, Dekker JM, Schouten EG, Kok FJ. Calcium intake and 28-year cardiovascular and coronary heart disease mortality in Dutch civil servants. Int J Epidemiol 1992; 21: 36-9.
Savanelli MC, Scarano E, Muscogiuri G, et al. Cardiovascular risk in adult hypopituitaric patients with growth hormone deficiency: Is there a role for vitamin D? Endocrine 2016; 52: 111-9.
Samelson EJ, Booth SL, Fox CS, et al. Calcium intake is not associated with increased coronary artery calcification: The Framingham study. Am J Clin Nutr 2012; 96: 1274-80.
Ahmad MI, Chevli PA, Li Y, Soliman EZ. Vitamin D deficiency and electrocardiographic subclinical myocardial injury: Results from national health and nutrition examination survey-III. Clin Cardiol 2018; 41: 1468-73.
Wang H, Xia N, Yang Y, Peng DQ. Influence of vitamin D supplementation on plasma lipid profiles: A meta-analysis of randomized controlled trials. Lipids Health Dis 2012; 11: 42.
Savastano S, Barrea L, Savanelli MC, et al. Low vitamin D status and obesity: Role of nutritionist. Rev Endocr Metab Disord 2017; 18: 215-25.
Barrea L, Savastano S, Di Somma C, et al. Low serum vitamin D-status, air pollution and obesity: A dangerous liaison. Rev Endocr Metab Disord 2017; 18: 207-14.
Muscogiuri G, Barrea L, Scannapieco M, et al. The lullaby of the sun: The role of vitamin D in sleep disturbance. Sleep Med 2018; 54: 262-5.
Di Somma C, Scarano E, Barrea L, et al. Vitamin D and neurological diseases: An endocrine view. Int J Mol Sci 2017; 18 pii:E2482
Barrea L, Savanelli MC, Di Somma C, et al. Vitamin D and its role in psoriasis: An overview of the dermatologist and nutritionist. Rev Endocr Metab Disord 2017; 18: 195-205.
Dan Q, Xiao-lu N, Shouling W, Jun C. Vitamin D and hypertension: Prospective study and meta-analysis. PLoS One 2017; 12e0174298
Scragg R, Stewart AW, Waayer D, et al. Effect of monthly high-dose vitamin d supplementation on cardiovascular disease in the vitamin d assessment study: A randomized clinical trial. JAMA Cardiol 2017; 2: 608-16.
Manson JE, Cook NR, Lee IM, et al. Vitamin d supplements and prevention of cancer and cardiovascular disease. N Engl J Med 2019; 380: 33-44.
Knox EG. Ischaemic-heart-disease mortality and dietary intake of calcium. Lancet 1973; 1: 1465-7.
Bostick RM, Kushi LH, Wu Y, Meyer KA, Sellers TA, Folsom AR. Relation of calcium, vitamin D, and dairy food intake to ischemic heart disease mortality among postmenopausal women. Am J Epidemiol 1999; 149: 151-61.
Iso H, Stampfer MJ, Manson JE, et al. Prospective study of calcium, potassium, and magnesium intake and risk of stroke in women. Stroke 1999; 30: 1772-9.
Shah S, Chiang C, Sikaris K, et al. Serum 25-hydroxyvitamin D insufficiency in search of a bone disease. J Clin Endocrinol Metab 2017; 102: 2321-8.
Reid IR, Ames R, Mason B, et al. Effects of calcium supplementation on lipids, blood pressure and body composition in healthy older men: A randomized controlled trial. Am J Clin Nutr 2010; 91: 131-9.
Trautvetter U, Ditscheid B, Jahreis G, Glei M. Habitual intakes, food sources and excretions of phosphorus and calcium in three german study collectives. Nutrients 2018; 10:pii: E171..
Chang AR, Lazo M, Appel LJ, Gutiérrez OM, Grams ME. High dietary phosphorus intake is associated with all-cause mortality: Results from NHANES III. Am J Clin Nutr 2014; 99: 320-7.
Van Mierlo LA, Arends LR, Streppel MT, et al. Blood pressure response to calcium supplementation: A meta-analysis of randomized controlled trials. J Hum Hypertens 2006; 20: 571-80.
Gallo L, Faniello MC, Canino G, et al. Serum calcium increase correlates with worsening of lipid profile: An observational study on a large cohort from south Italy. Medicine 2016; 95e2774
Radwan SF, Ghada II, Gamal AE, Osama AA, Mohamad TM. High dietary calcium and weight regulation in mature and premature rats. Med J Cairo Univ 2012; 80: 715-23.
De Abajo FJ, Rodríguez-Martín S, Rodríguez-Miguel A, Gil MJ. Risk of ischemic stroke associated with calcium supplements with or without vitamin D: A nested case-control study. J Am Heart Assoc 2017; 6 pii: e005795
Hagen G, Wisloff T, Kristiansen IS. The predicted lifetime costs and health consequences of calcium and vitamin D supplementation for fracture prevention-the impact of cardiovascular effects. Osteoporos Int 2016; 27: 2089-98.
Kern J, Kern S, Blennow K, et al. Calcium supplementation and risk of dementia in women with cerebrovascular disease. Neurology 2016; 87: 1674-80.
Bolland MJ, Avenell A, Baron JA, et al. Effect of calcium supplements on risk of myocardial infarction and cardiovascular events: meta-analysis. BMJ 2010; 341: c3691.
Bolland MJ, Grey A, Avenell A, Gamble GD, Reid IR. Calcium supplements with or without vitamin D and risk of cardiovascular events: Reanalysis of the women’s health initiative limited access dataset and meta-analysis. BMJ 2011; 342: 2040.
Brazier M, Grados F, Kamel S, et al. Clinical and laboratory safety of one year’s use of a combination calcium + vitamin D tablet in ambulatory elderly women with vitamin D insufficiency: Results of a multicenter, randomized, double-blind, placebo-controlled study. Clin Ther 2005; 27: 1885-93.
Fang J, Alderman MH. Serum uric acid and cardiovascular mortality the NHANES I epidemiologic follow-up study, 1971-1992. National health and nutrition examination survey. JAMA 2000; 283: 2404-10.
Julien M, Magne D, Masson M, et al. Phosphate stimulates matrix Gla protein expression in chondrocytes through the extracellular signal regulated kinase signaling pathway. Endocrinology 2007; 148: 530-7.
David V, Dai B, Martin A, Huang J, Han X, Quarles DL. Calcium regulates FGF-23 expression in bone. Endocrinology 2013; 154: 4469-82.
Alam M, Kirton JP, Wilkinson FL, et al. Calcification is associated with loss of functional calcium-sensing receptor in vascular smooth muscle cells. Cardiovasc Res 2009; 81: 260-8.
House M, Kohlmeier L, Chattopadhyay N, et al. Expression of an extracellular calcium-sensing receptor in human and mouse bone marrow cells. J Bone Miner Res 1997; 12: 1959-70.
Lewis JR, Radavelli-Bagatini S, Rejnmark L, et al. The effects of calcium supplementation on verified coronary heart disease hospitalization and death in postmenopausal women: A collaborative meta-analysis of randomized controlled trials. J Bone Miner Res 2015; 30: 165-75.
Weaver CM. Calcium supplementation: Is protecting against osteoporosis counter to protecting against cardiovascular disease? Curr Osteoporos Rep 2014; 12: 211-8.
Harvey NC, Biver E, Kaufman JM, et al. The role of calcium supplementation in healthy musculoskeletal ageing: An expert consensus meeting of the European society for clinical and economic aspects of osteoporosis, osteoarthritis and musculoskeletal diseases (ESCEO) and the international foundation for osteoporosis (IOF). Osteoporos Int 2017; 28: 447-62.
Chin K, Appel LJ, Michos ED. Vitamin D, calcium, and cardiovascular disease: A “D” vantageous or “D” etrimental? An Era of Uncertainty. Curr Atheroscler Rep 2017; 19: 5.
Guessous I, Bochud M, Bonny O, Burnier M. Calcium, vitamin D and cardiovascular disease. Kidney Blood Press Res 2011; 34: 404-17.
Hsia J, Heiss G, Ren H, et al. Calcium/vitamin D supplementation and cardiovascular events. Circulation 2007; 115: 846-54.
Avenell A, MacLennan GS, Jenkinson DJ, et al. Long-term follow-up for mortality and cancer in a randomized placebo-controlled trial of vitamin D3 and/or calcium (RECORD trial). J Clin Endocrinol Metab 2012; 97: 614-22.
NC, D'Angelo S, Paccou J, et al.Calcium and vitamin D supplementation are not associated with risk of incident ischemic cardiac events or death: Findings from the UK biobank cohort. J Bone Miner Res 2018; 33: 803-11.
Annweiler C, Legrand E, Souberbielle JC. Vitamin D in adults: Update on testing and supplementation. Geriatr Psychol Neuropsychiatr Vieil 2018; 16: 7-22.
Simpson RU, Thomas GA, Arnold AJ. Identification of 1, 25-dihydroxy vitamin D3 receptors and activities in muscle. J Biol Chem 1985; 260: 8882-91.
Bischoff HA, Borchers M, Gudat F, et al. In situ detection of 1, 25-dihydroxyvitamin D3 receptor in human skeletal muscle tissue. Histochem J 2001; 33: 19-24.
Fraga C, Blanco M, Vigo E, Segura C, García-Caballero T, Pérez-Fernández R. Ontogenesis of the vitamin D receptor in rat heart. Histochem Cell Biol 2002; 117: 547-50.
Chen S, Glenn DJ, Ni W, et al. Expression of the vitamin d receptor is increased in the hypertrophic heart. Hypertension 2008; 52: 1106-12.
David GG, Songcang C, Denis JG. Vitamin D and the heart. Am J Physiol Regul Integr Comp Physiol 2013; 305: 969-77.
Wang GF, Nikovits W, Schleinitz M, Stockdale FE. Atrial chamber-specific expression of the slow myosin heavy chain 3 gene in the embryonic heart. J Biol Chem 1996; 271: 19836-45.
Tishkoff DX, Nibbelink KA, Holmberg KH, Dandu L, Simpson RU. Functional vitamin D receptor (VDR) in the t-tubules of cardiac myocytes: VDR knockout cardiomyocyte contractility. Endocrinology 2007; 149: 558-64.
Weber KT, Weglicki WB, Simpson RU. Macro-and micronutrient dyshomeostasis in the adverse structural remodelling of myocardium. Cardiovasc Res 2009; 81: 500-8.
Timms PM, Mannan N, Hitman GA, et al. Circulating MMP9, vitamin D and variation in the TIMP-1 response with VDR genotype: Mechanisms for inflammatory damage in chronic disorders? QJM 2002; 95: 787-96.
Berk BC, Fujiwara K, Lehoux S. ECM remodeling in hypertensive heart disease. J Clin Invest 2007; 117: 568-75.
Oh J, Weng S, Felton SK, et al. 25 (OH) 2 vitamin D inhibits foam cell formation and suppresses macrophage cholesterol uptake in patients with type 2 diabetes mellitus. Circulation 2009; 120: 687-98.
Weishaar RE, Simpson RU. Vitamin D3 and cardiovascular function in rats. J Clin Invest 1987; 79: 1706-12.
Weishaar RE, Kim SN, Saunders DE, Simpson RU. Involvement of vitamin D3 with cardiovascular function. III. Effects on physical and morphological properties. Am J Physiol 1990; 258: 134-42.
Oconnell TD, Simpson RU. 25-Dihydroxyvitamin D3 regulation of myocardial growth and C-MYC levels in the rat heart. Biochem Biophys Res Commun 1995; 213: 59-65.
Gezmish O, Tare M, Parkington HC, et al. Maternal vitamin D deficiency leads to cardiac hypertrophy in rat offspring. Reprod Sci 2010; 17: 168-76.
Li YC, Kong J, Wei M, Chen ZF, Liu SQ, Cao LP. 25-Dihydroxyvitamin D3 is a negative endocrine regulator of the renin-angiotensin system. J Clin Invest 2002; 110: 229-38.
Xiang W, Kong J, Chen S, et al. Cardiac hypertrophy in vitamin D receptor knockout mice: Role of the systemic and cardiac renin-angiotensin systems. Am J Physiol Endocrinol Metab 2005; 288: 125-32.
Yuan W, Pan W, Kong J, et al. 25-dihydroxyvitamin D3 suppresses renin gene transcription by blocking the activity of the cyclic AMP response element in the renin gene promoter. J Biol Chem 2007; 282: 29821-30.
Simpson RU, Hershey SH, Nibbelink KA. Characterization of heart size and blood pressure in the vitamin D receptor knockout mouse. J Steroid Biochem Mol Biol 2007; 103: 521-4.
Rahman A, Hershey S, Ahmed S, Nibbelink K, Simpson RU. Heart extracellular matrix gene expression profile in the vitamin D receptor knockout mice. J Steroid Biochem Mol Biol 2007; 103: 416-9.
Heaney RP, Kopecky S, Maki KC, Hathcock J, Mackay D, Wallace TC. A review of calcium supplements and cardiovascular disease risk. Adv Nutr 2012; 3: 763-71.
Yacowitz H, Fleischman A, Bierenbaum M, Kritchevsky D. Calcium and lipid metabolism: effects of increased dietary calcium on atherosclerosis in rabbits. Trans N Y Acad Sci 1971; 33: 344-50.
Fleischman A, Yacowitz H, Hayton T, Bierenbaum M. Effects of dietary calcium upon lipid metabolism in mature male rats fed beef tallow. J Nutr 1966; 88: 255-60.
Draznin B, Sussman K, Kao M, Lewis D, Sherman N. The existence of an optimal range of cytosolic free calcium for insulin-stimulated glucose transport in rat adipocytes. J Biol Chem 1987; 262: 14385-8.
Wright DC, Hucker KA, Holloszy JO, Han DH. Ca2+ and AMPK both mediate stimulation of glucose transport by muscle contractions. Diabetes 2004; 53: 330-5.
Jolma P, Kalliovalkama J, Tolvanen J-P, et al. High-calcium diet enhances vasorelaxation in nitric oxide-deficient hypertension. Am J Physiol Heart Circ Physiol 2000; 279: 1036-43.

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Year: 2019
Page: [610 - 617]
Pages: 8
DOI: 10.2174/1570161117666190408165805
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