Calcium supplementation increases heart attack risk in large study
In this enormous real-world study, heart attacks, strokes, and mortality in general were significantly increased by calcium supplementation.
The risks increased even though the subject population consumes a low calcium diet, adding to previous evidence for potential harm. The authors advise caution in prescribing calcium supplements for osteoporosis.
Compelling research just published in the journal Nutrients adds substantial evidence to support earlier concerns about calcium supplementation, followed by important information on the effects of magnesium deficiency that can be made worse by calcium supplementation.
The authors note:
“Calcium supplementation has been advocated for treating and preventing osteoporosis [6]. However, studies have reported negative cardiovascular effects of calcium supplement intake and stated that calcium intake might be related to an increased risk of myocardial infarction [7] and ischemic stroke [8]. Although a previous meta-analysis by Lewis et al. showed no relationship between calcium supplementation and cardiovascular event risk [9], a recent meta-analysis of 13 randomized, double-blind, placebo-controlled trials showed that calcium supplementation increased the risk of cardiovascular diseases [10]. However, most studies were conducted in Western countries with high calcium intake, and evidence regarding populations with low calcium intake is rare…Moreover, few studies have examined the relationship between calcium supplementation and cardiovascular outcomes in real-world settings.”
Enormous study on a low calcium intake population
South Korean governmental public health data management provides an outstanding opportunity to observe the effects of calcium supplementation on a vast scale. Subjects for this study numbered approximately 52 million people over a period of twelve years.
“This study was based on mandatory health insurance claims from the NHIS claims database from 1 January 2007 to 31 December 2018. The NHIS, run by the government of South Korea, covers the entire population of South Korea (i.e., approximately 52 million people) [13]. All healthcare providers are required to submit all treatment data to the NHIS for insurance reimbursement. The NHIS database contains enormous epidemiological and medical service information, including demographics, diagnoses, and prescription records…The database also includes health check-up data with questionnaires on health-related lifestyles and behaviors, collected through a national health examination every other year from office workers aged >40 years and once a year from non-office workers.”
Basically, they were able to observe the effects of calcium supplementation in the entire country of South Korea for primary outcomes of acute myocardial infarction, (heart attack), and all causes of death.
Substantial increase in heart attacks and strokes linked with calcium supplementation
The authors state:
“In this large-scale nationwide cohort study, the cumulative incidence and HR [hazard ratio] for acute myocardial infarction, ischemic stroke, and death events were higher in the calcium supplementation group than in the control group in a Korean population after adjusting for confounding variables. Calcium supplementation was significantly associated with an increased risk of acute myocardial infarction, ischemic stroke, and death in the Korean population...
Our findings are consistent with those of previous studies which showed that calcium supplementation is associated with an increased risk of myocardial infarction [7,10,17], ischemic stroke [8], and death [19] in other populations. Moreover, our findings suggest that calcium supplementation may increase the risk of myocardial infarction and ischemic stroke in Koreans, who are known to have little calcium intake.
In addition, few studies have examined the effects of calcium supplementation on cardiovascular outcomes by using real-world data. This is the first large population-based cohort study to use real-world data to reveal a close relationship between calcium supplementation and the incidence of myocardial infarction and ischemic stroke. Thus, our results confirm earlier findings regarding the association between calcium supplementation and cardiovascular outcomes.”
As for stroke:
“In this study, ischemic stroke occurred faster in the calcium supplementation group compared with that in the control group, and this gap was maintained for the rest of study period.”
Mechanisms, osteoporosis…and the crucial role of magnesium
Osteoporosis is not a calcium-deficiency disorder, it is a failure to maintain the protein matrix of the bone to which minerals attach. This protein mesh gives resilience and elasticity. When the protein ‘scaffolding’ thins, mineral density goes down because there are fewer binding sites. Although there can be ancillary contributing causes, the two major factors that drive osteoporosis are an elevated systemic burden of inflammation and a hormonal milieu that is not sufficiently anabolic (‘building up’) to maintain protein mass in the bone (and elsewhere).
In osteoporosis, activation of inflammatory pathways characterized by Th17 cell polarization (typically associated with an inadequate Th1 response) drives excessive 'osteoclastogenesis’, the production of the osteoclasts whose normal job it is to tear down old bone to make room for the new. Dysbiosis (imbalance of the microbial ecology) in the hollow spaces of the body, is a common contributing cause of Th17 polarization. Conversely, supporting Th1 production of INF-γ (interferon-gamma) promotes osteoblastogenesis (osteoblasts build up new bone). It has been demonstrated that in mice whose ovaries have been removed, the loss of estrogen permitted increased migration of inflammatory Th17 cells from the intestine to the bone.
The fundamental feature of cardiovascular disease is inflammation of the blood vessels with damage to the inner protective barrier or ‘lining’ called the glycocalyx. An inflammatory lesion that generates vulnerable (soft) plaque can precipitate a heart attack or ischemic stroke when the plaque ruptures and forms a clot.
“Cardiovascular disease and osteoporosis…share pathogenic mechanisms, including inflammation and imbalance in mineral metabolism and the renin–angiotensin–aldosterone system [20,21]. Studies have indicated a relationship between cardiovascular disease and low bone mass [22,23,24].
Several possible mechanisms can be attributed to the significantly increased risk of myocardial infarction and ischemic stroke through calcium supplementation. Although dietary calcium has smaller effects on circulating calcium concentration, calcium supplementation could abruptly increase serum calcium concentration [25,26,27]…Furthermore, elevated serum calcium elevates blood pressure, possibly mediated by extracellular and intracellular calcium changes, altering the renin–angiotensin–aldosterone system and regulating vascular smooth muscle contraction [30,31,32].”
Regrettably, the authors neglect to mention the crucial role of magnesium. Magnesium is nature’s calming, anti-inflammatory, blood vessel relaxing mineral. Calcium competes with magnesium absorption and supplementation increases the ratio of calcium to magnesium, opposing its function. Suboptimal magnesium levels are extremely common, resulting in increased inflammation and elevated blood pressure.
Subclinical magnesium deficiency: a principal driver of cardiovascular disease and a public health crisis, published in Open Heart, an official journal of the British Cardiovascular Society and the BMJ, describes the scope and significance of suboptimal levels of magnesium for cardiovascular health.
“‘Hypomagnesemia is a relatively common occurrence in clinical medicine. That it often goes unrecognized is due to the fact that magnesium levels are rarely evaluated since few clinicians are aware of the many clinical states in which deficiency, or excess, of this ion may occur’.28”
Only a tiny percentage of magnesium is in the blood serum making the usual serum tests for magnesium misleading.
“Extracellular magnesium accounts for only ∼1% of total body magnesium, which is found primarily in serum and red blood cells’.1
…despite renal conservation, magnesium can be pulled from the bone (as well as muscles and internal organs) in order to maintain normal serum magnesium levels when intakes are low.7 8 Thus, a normal serum magnesium level does not rule out magnesium deficiency, which predisposes to osteopaenia, osteoporosis and fractures.”
Practitioners must be astute in investigating for subclinical magnesium and other deficiencies which have great clinical consequences:
There are two types of nutrient deficiencies, frank deficiencies (such as scurvy from ascorbic acid deficiency or goitre from iodine deficiency) and subclinical deficiencies (a clinically silent reduction in physiological, cellular and/or biochemical functions). It is the latter that is most concerning as it is hard to diagnose and predisposes to numerous chronic diseases. And while both result in negative health consequences, the former has obvious symptoms (hence frank deficiency), whereas the latter may have negative or variable health effects that are not so apparent (eg, vascular calcification). The evidence in the literature suggests that subclinical magnesium deficiency is rampant and one of the leading causes of chronic diseases including cardiovascular disease and early mortality around the globe, and should be considered a public health crisis.12–14
The most recent published review on magnesium concluded: ‘Approximately 50% of Americans consume less than the Estimated Average Requirement (EAR) for magnesium, and some age groups consume substantially less’.2…And since many individuals may be consuming below 320 mg/day of magnesium, this poses a major public health threat.
Moreover, the great majority of clinicians are not paying attention:
“Based on 183 peer-reviewed studies published from 1990 to 2008, one group of authors concluded: ‘The perception that ‘normal’ serum magnesium excludes deficiency is common among clinicians. This perception is probably enforced by the common laboratory practice of highlighting only abnormal results. A health warning is therefore warranted regarding potential misuse of ‘normal’ serum magnesium because restoration of magnesium stores in deficient patients is simple, tolerable, inexpensive and can be clinically beneficial’.48
‘The existence of subacute or chronic magnesium deficiency is difficult to diagnose. Because the tissues damaged by magnesium depletion are those of the cardiovascular, renal and the neuromuscular systems, early damage is not readily detectable. It is postulated that long-term suboptimal intakes of magnesium may participate in the pathogenesis of chronic diseases of these systems’.88
‘Abnormalities of serum Mg may be the most underdiagnosed serum electrolyte abnormality in clinical practice today.”
There are many causes of magnesium deficiency, including:
“Supplementing with calcium can lead to magnesium deficiency due to competitive inhibition for absorption,84 and oversupplementing with vitamin D may lead to magnesium deficiency via excessive calcium absorption and hence increase the risk of arterial calcifications.85”
Consequences of magnesium deficiency
Magnesium deficiency is a cause of hypertension, atherosclerosis and arteriosclerosis, arrhythmias, and coronary artery disease.
Because excitability of the neuromuscular junction (the connection between nerve and muscle) is controlled by the balance between calcium and magnesium there which becomes hyper excitable as calcium goes up and magnesium goes down:
“Common signs of magnesium deficiency in include spontaneous muscle cramps which can occur during the day and in bed at night.”
Regarding the treatment of hypertension:
Hypertension (high blood pressure)
“Magnesium status has a direct effect upon the relaxation capability of vascular smooth muscle cells and the regulation of the cellular placement of other cations important to blood pressure…This can cause vasoconstriction of venous smooth muscles and arteries causing hypertension.”
Regarding the treatment of hypertension:
“Many patients with hypertension are treated with thiazide and loop diuretics, both of which deplete the body of magnesium,99 and giving patients with hypertension who are receiving long-term thiazide diuretics oral magnesium supplementation significantly reduces blood pressure.99 In fact, the high intracellular calcium induced by magnesium deficiency may induce both insulin resistance and hypertension.100”
Nitric oxide produced by a healthy endothelium (innermost lining of the blood vessel) is crucial for vessel function and dilation (phosphodiesterase type 5 inhibitors like Viagra® work by increasing nitric oxide availability).
“Hypomagnesaemia can impair the release of nitric oxide from the coronary endothelium,105 while magnesium therapy can improve endothelium-dependent vasodilation in patients with coronary artery disease.105 Since nitric oxide is both a vasodilator and an inhibitor of platelet aggregation, this makes magnesium supplementation a promising therapy in the treatment of hypertension and coronary artery disease.”
Atherosclerosis and abnormal calcification
Magnesium deficiency contributes to arterial plaque formation and abnormal calcium deposition in other tissues.
“A greater intake of magnesium is associated with having a lower risk of an elevated coronary artery calcification score,110 and supplementing with magnesium has been found to improve endothelial function in patients with coronary artery disease.111
Magnesium deficiency and magnesium depletion in soft tissues can cause calcifications in the heart, liver and skeletal muscles.107
…eating a diet deficient in magnesium predisposes to atherosclerosis, calcification of the aorta, degeneration of myocardial muscle fibres and inflammatory connective tissue throughout the body. This study suggests that low magnesium intake increases inflammation…Magnesium deficiency may enhance vascular endothelial injury, promoting the development and progression of atherosclerosis.120
Magnesium deficiency may supersaturate bodily fluids with octacalcium phosphate calcifying soft tissues, whereas magnesium therapy may stop or even prevent soft tissue calcifications.121 [I have seen this in many x-ray exams.]
Thus, magnesium deficiency predisposes to lipoprotein peroxidation and atherosclerosis. Perhaps most importantly, patients in the intensive cardiac care unit have been noted to have low blood mononuclear cell magnesium levels.125 The authors summarised their findings as the following: ‘We conclude that the incidence of intracellular Mg deficiency in patients with cardiovascular disease is much higher than the serum magnesium would lead one to suspect, and may contribute to clinical cardiovascular morbidity’.125”
Cardiac arrhythmias
Various types of cardiac arrhythmias can occur due to low magnesium.
“…the lack of routine serum Mg analysis as part of the ‘electrolyte panel’ impedes the diagnosis of clinical Mg deficiency…Life-threatening cardiac arrhythmias and seizures represent the most serious manifestation of clinical hypomagnesemia and Mg depletion.
Thus, it appears that low dietary intake of magnesium or low magnesium levels can predispose to arrhythmias. Diuretics and digoxin also cause magnesium depletion, making the heart more susceptible to the development of arrhythmias.131…A meta-analysis of 19 randomised trials using magnesium orotate found a significant reduction in first-degree mitral valve prolapse, grade 1 regurgitation, supraventricular and ventricular premature contraction, and paroxysmal supraventricular tachycardia.134”
Just 42–64 days on a diet low in magnesium (~101 mg/day) produced atrial fibrillation and flutter in three of five postmenopausal women (ages 47–75 years). Moreover, the arrhythmias responded quickly to magnesium supplementation.
Coronary artery disease
Low magnesium levels in heart tissue contribute to death from heart attacks.
“Autopsy studies have revealed lower magnesium content in both infarcted and non-infarcted heart muscle in those who have died of a myocardial infarction.131…This suggests that patients who have lower than normal magnesium concentrations in their heart muscle may be more likely to die suddenly after a myocardial infarction. Indeed, there are numerous studies indicating an increased rate of death from heart disease in low-magnesium drinking water areas.131
Administration of magnesium salts has been shown to reverse many of the changes in animal models of heart disease…There is also good evidence from some animal studies that pretreatment with magnesium salts protects against many of the changes in the heart caused by anoxia…’ In other words, consuming a diet high in magnesium may prevent the harms from an acute ischaemic events.
Considering that around 25% of all myocardial infarctions are not due to atherosclerotic plaque rupture, coronary artery spasm induced by magnesium deficiency may explain some of these events.
Magnesium treatment has been found to inhibit thrombus formation (as measured by platelet-dependent thrombosis) in patients with stable coronary artery disease by 35%.105…the molecular basis for these effects is likely modulated via reduction of intracellular calcium mobilization’.105 Thus, magnesium may prevent thrombotic events and may also protect cardiac cells against ischaemia.139
Possible cardiovascular manifestations of magnesium deficiency
The authors list proven effects of suboptimal magnesium levels. Bear in mind that calcium too high in relation to magnesium drives these adverse effects.
Hypertension.
Arrhythmias.
Calcifications.
Atherosclerosis.
Heart failure.
Increased platelet reactivity and thrombosis.
Myocardial infarction.
Stroke.
Sudden cardiac death.
The authors sum it up nicely in their conclusion:
“Subclinical magnesium deficiency is a common and under-recognised problem throughout the world. Importantly, subclinical magnesium deficiency does not manifest as clinically apparent symptoms and thus is not easily recognised by the clinician. Despite this fact, subclinical magnesium deficiency likely leads to hypertension, arrhythmias, arterial calcifications, atherosclerosis, heart failure and an increased risk for thrombosis. This suggests that subclinical magnesium deficiency is a principal, yet under-recognised, driver of cardiovascular disease. A greater public health effort is needed to inform both the patient and clinician about the prevalence, harms and diagnosis of subclinical magnesium deficiency.”
A lower magnesium-to-calcium ratio increases risk of death from COVID
Finally, recently published research, also in the journal Nutrients, shows that a magnesium-to-calcium ratio ≤ 0.20 is strongly associated with mortality from severe COVID-19.
“Obesity, type 2 diabetes, arterial hypertension, decrease in immune response, cytokine storm, endothelial dysfunction, and arrhythmias, which are frequent in COVID-19 patients, are associated with hypomagnesemia [low blood magnesium]. Given that cellular influx and efflux of magnesium and calcium involve the same transporters, we aimed to evaluate the association of serum magnesium-to-calcium ratio with mortality from severe COVID-19. The clinical and laboratory data of 1064 patients, aged 60.3 ± 15.7 years, and hospitalized by COVID-19 from March 2020 to July 2021 were analyzed…The ROC curve showed that the best cut-off point of the magnesium-to-calcium ratio for identifying individuals at high risk of mortality from COVID-19 was 0.20.
Interestingly, several of the well-known COVID-19 risk factors and some co-morbidities such as acute renal failure, arterial and venous thrombosis, cardiac failure, and arrhythmias are linked to magnesium deficiency [4,5]. Therefore, we hypothesized that hypomagnesemia might play an important role in the pathophysiology and mortality from COVID-19 [5,6].
Hypomagnesemia is associated with a decrease synthesis and activation in vitamin D, an increase in oxidative stress and cytotoxic activity of T lymphocytes, and with the triggering of cytokine storm [7,8]. Hypomagnesemia is also related to abnormal platelet aggregation, coagulation abnormalities [9,10], endothelial dysfunction [11], and myocardial damage [12], entities frequently identified in severely ill COVID-19 patients [5,13,14].
…patients discharged per death had lower serum magnesium levels, a finding suggesting that hypomagnesemia could be a biomarker of a poor outcome from COVID-19. Findings supported the hypothesis by Iotti et al. [34], which states that a low magnesium status might be related to the critical clinical manifestations of COVID-19.”
In conclusion, our results show that the magnesium-to-calcium ratio ≤ 0.20 is strongly associated with mortality from severe COVID-19.”
