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1 s2.0 S2161831322007840 Main
1 s2.0 S2161831322007840 Main
ABSTRACT
The 2015 Dietary Guidelines Advisory Committee indicated that magnesium was a shortfall nutrient that was underconsumed relative to
the Estimated Average Requirement (EAR) for many Americans. Approximately 50% of Americans consume less than the EAR for magnesium,
and some age groups consume substantially less. A growing body of literature from animal, epidemiologic, and clinical studies has demonstrated
a varied pathologic role for magnesium deficiency that includes electrolyte, neurologic, musculoskeletal, and inflammatory disorders;
osteoporosis; hypertension; cardiovascular diseases; metabolic syndrome; and diabetes. Studies have also demonstrated that magnesium
deficiency is associated with several chronic diseases and that a reduced risk of these diseases is observed with higher magnesium intake
or supplementation. Subclinical magnesium deficiency can exist despite the presentation of a normal status as defined within the current serum
magnesium reference interval of 0.75–0.95 mmol/L. This reference interval was derived from data from NHANES I (1974), which was based on
the distribution of serum magnesium in a normal population rather than clinical outcomes. What is needed is an evidenced-based serum
magnesium reference interval that reflects optimal health and the current food environment and population. We present herein data from an
array of scientific studies to support the perspective that subclinical deficiencies in magnesium exist, that they contribute to several chronic diseases,
and that adopting a revised serum magnesium reference interval would improve clinical care and public health. Adv Nutr 2016;7:977–93.
Keywords: serum magnesium, plasma magnesium, magnesium deficiency, reference interval, chronic disease
ã2016 American Society for Nutrition. Adv Nutr 2016;7:977–93; doi:10.3945/an.116.012765. 977
whether the magnesium biomarkers in serum and/or urine are
consistent across population groups, and 4) identify data gaps
for serum or urinary magnesium in terms of population groups
(specific age, sex, and ethnicity) that are necessary to inform a re-
evaluation of the clinical reference interval for serum magnesium.
Approximately half (48%) of the US population has been
shown to consume less than the daily requirement of magne-
sium from foods (1), partly because of the processing of food,
a lower consumption of whole grains and fruits and vegeta-
bles than recommended, and a greater consumption of fast
food that has a low magnesium content. The 2015 Dietary
Guidelines Advisory Committee found magnesium to be
underconsumed relative to the Estimated Average Require-
ment (EAR) and characterized it as a shortfall nutrient of
public health concern (2). The European Food Safety Author-
ity recently published a scientific opinion on dietary reference
values for magnesium and found that “although the role of
Mg in bone structure and physiology is well established, there
are few quantitative data for using this relation for setting
dietary reference values for magnesium” (3). Nevertheless,
the impact of chronically low magnesium intake on serum
magnesium concentrations and long-term health remains FIGURE 1 Age-specific distributions of serum magnesium in
US adults. Data were derived from NHANES I (1971–1975). Mg,
poorly studied; most trials have been of short duration,
magnesium.
and most observational studies have lacked repeated serum
measures.
Overt signs of clinical magnesium deficiency have not in NHANES was >40 y ago, and given changes in the food
been routinely recognized in the healthy population. How- supply, changes in population distribution, prevalence of
ever, relatively low magnesium intake and/or status has diseases such as obesity and T2D, and so on, the current dis-
been associated with critical health issues, such as but tribution of serum magnesium in the United States is effec-
not limited to hypertension (4–9), cardiovascular disease tively an unknown.
(CVD) (10–14), type 2 diabetes (T2D) (15–18), and osteo- A simple, rapid, and accurate test to assess total body mag-
porosis (19, 20). In most cases, risk was elevated at serum nesium status is lacking. Although STMC is most commonly
magnesium concentrations higher than the present clinical used to assess the status of patients, >99% of total body mag-
cutoff for deficiency, raising the question of potential sub- nesium (22–26 g in adults) is extravascular, mostly in the
clinical deficiency and chronic latent magnesium deficiency bones (>50%), with only 0.3% in the serum (25). Thus, this
and justifying a review of the current research to evaluate parameter does not necessarily reflect the true total body mag-
contemporary ideas on “healthy” or “normal” serum total nesium content. The serum concentration of ionized magne-
magnesium values. Therefore, this perspective is oriented sium, the biologically active form, may be more reflective of
toward supporting a need for identifying a clinical reference true magnesium status; however, clinical reliance on this mea-
interval of STMC that is needed for optimal health. sure remains controversial (26). Another noninvasive method
STMC is the predominant test used by healthcare pro- is to analyze urinary magnesium excretion. Because renal
viders to assess magnesium status. The current reference magnesium excretion decreases in response to dietary defi-
interval for STMC was determined by measuring serum ciency, this can be an important parameter during the assess-
magnesium in then-representative healthy normal individ- ment of magnesium status (27). The combined determination
uals of NHANES I (1974) (21). The central 95th percentile of the STMC and urinary magnesium excretion are currently
of this measure in 15,820 apparently healthy individuals the most practical tests to assess magnesium status (28), but
aged 18–74 y was defined as the normal range (Figure 1). their reliability as biomarkers needs rigorous evaluation.
This set the reference interval for serum magnesium at Although normal serum magnesium concentrations can
0.75–0.95 mmol/L. It is important to highlight that this ref- be seen in the presence of intracellular magnesium defi-
erence interval was based on the distribution in a normal ciency, once serum magnesium declines, it is unlikely that
population—not the relation between serum magnesium the intracellular magnesium concentration remains nor-
and clinical outcomes. Re-evaluating this reference interval mal. In addition, taking into account that magnesium ho-
while also taking into account health outcomes is therefore meostasis depends on the relation between intake and loss,
justified (22). Physicians may be led to assume that patients a rational approach for a reliable magnesium biomarker
have normal magnesium status when they may have chronic should take into account the relation between intake, serum
latent magnesium deficiency (23, 24). Complicating the pic- concentrations, and urinary concentrations. Available data
ture further, the last time serum magnesium was measured suggest that serum and plasma magnesium concentrations,
compared with 17.1 6 21.0 nmol/L; P = 0.01) than par- 7 studies (49) and 6 case-control studies (50–55). In these
ticipants in the control group. Two mechanisms have been pro- studies, the association between serum magnesium concen-
posed to explain the increase in inflammatory response caused trations in postmenopausal women with osteoporosis compared
by magnesium deficiency or insufficiency. First, reactive oxygen with a healthy control were examined. The 6 case-control studies
species are increased when an individual undergoes a state of were all included in the meta-analysis (49), which suggested that
magnesium deficiency, as measured by serum magnesium sta- serum magnesium concentrations have an inverse relation with
tus. The increase in reactive oxygen species promotes membrane bone mineral density (BMD). Taken together, these studies sug-
oxidation and NF-kB production. Second, the attenuation of the gest low serum magnesium is a plausible risk factor for osteopo-
calcium channel-blocking effect of magnesium during magne- rosis among postmenopausal women. BMD is currently the
sium deficit allows for increased calcium entry within immune- only risk biomarker of osteoporosis considered valid by the
competent cells, stimulating an inflammatory response (46). FDA; however, other markers of bone turnover have also been
These studies support a role for magnesium in the in- used to assess the effect of serum magnesium status in relation
flammation-based etiology of many chronic diseases and to bone health and fracture risk (56, 57). Men, but not women,
suggest a causal role for magnesium in lowering certain enrolled in the European Prospective Investigation into Cancer
markers of inflammation. However, more studies are needed and Nutrition-Norfolk cohort showed significant inverse trends
if magnesium’s role in inflammation can or should be used in fracture risk across serum magnesium concentration groups
to support a revision of reference intervals, especially be- for spine fractures (P = 0.02) and total hip, spine, and wrist frac-
cause many markers of inflammation do not yet have clini- tures (P = 0.02). The mean serum magnesium for men was
cally useful reference intervals. Nevertheless, the relations 0.81 6 0.12 mmol/L (58).
demonstrated to date on the role of magnesium and inflam- Postmenopausal women with osteoporosis had consis-
mation suggest that this and accruing evidence could sup- tently lower serum magnesium concentrations across studies
port a disease and/or optimal health-based re-evaluation than their healthy controls (49). In addition, RBC magnesium
of the current serum magnesium reference interval. concentrations have been shown to be lower in postmeno-
pausal women with osteoporosis than a healthy control
Are Skeletal Studies Informative for Redefining (59). These data are consistent with other studies that have in-
the Reference Range for Serum Magnesium? dicated that the dietary intake of magnesium is inversely asso-
Magnesium consists of ;0.5–1.0% bone ash and plays an im- ciated with DXA bone status measurements (60). A recent
portant role in bone and mineral homeostasis. Several animal analysis of the Women’s Health Initiative Observational
studies have demonstrated that magnesium deficiency results Study, which did not assess serum or urine magnesium, sug-
in bone loss (47, 48). The small body of clinical evidence sug- gested that lower dietary magnesium intake is associated with
gesting that long-term low dietary intakes of magnesium influ- lower BMD of the hip and whole body but not with an in-
ence bone mass, bone turnover, bone-related hormones, and creased risk of fractures (61). Magnesium intake has been
cytokine concentrations has been previously reviewed (37). shown to have a positive association with BMD in both
There is growing evidence that magnesium may not only affect cross-sectional studies that used dietary recalls (20, 62–65)
bone cell function and hydroxyapatite crystal formation but and clinical studies of supplemental intake (66–68).
may also be an important factor in quantitative changes of The limited evidence to date, primarily in the form of
the bone matrix that predict fragility. Magnesium has been case-control studies, points to an inverse relation between
evaluated with respect to bone health in a meta-analysis of serum magnesium and osteoporosis, a relation further
CVD risk factors given either magnesium supplementation 3 studies collected all 3 status markers. No studies collected
or a placebo in studies that lasted 28 d to 12 mo. These stud- urinary magnesium data alone, but 2 collected urinary data
ies evaluated magnesium status via serum and/or urine and along with dietary data.
the impact of magnesium supplement or placebo upon bio- Together, these population-based cross-sectional studies
markers of insulin resistance, glycemic control, blood lipids, and clinical trials indicate that some 10–30% of a given pop-
and/or inflammation. ulation, considered healthy, may have serum magnesium
Very few studies enrolled exclusively men or exclusively concentrations below typically used cutoffs (<0.80 mmol/L).
women. Only one study—the Trial of Hypertension Preven- This points to several potential realities and questions. If, in
tion, which was the largest of the studies—reported serum fact, serum magnesium concentrations are clinically low in
values separately for men, women, blacks, and whites as much as a third of any given population, such a reality
(100). Data from 13 different countries are represented in would warrant considerable attention and potential inter-
this healthy RCT data set. The 20–39- and 40–59-y age vention, not to mention additional research (notably trials)
groups were the predominant groups studied; 2 studies on the causes of such a high incidence of hypomagnese-
were identified with participants aged <18 y, and 4 studies mia and the potential effects of magnesium intake in
enrolled participants $75 y. Serum and plasma magnesium reducing or preventing chronic disease. Of course, as
was collected in 23 studies. Dietary data were collected in highlighted elsewhere, the possibility remains that existing
5 of these studies, urinary data were collected in 4, and clinical cutoffs are too low. If so, the proportion of the
population with suboptimal serum magnesium concentra- measurements of serum and/or urinary magnesium (Sup-
tions, along with any associated adverse health conse- plemental References). Of these 65 trials, 44 were RCTs, 9
quences, may be even higher. were non-RCTs, and 12 were noncontrolled trials. Of the
44 RCTs, 30 reported serum magnesium measurements. Ta-
How Do Oral Magnesium Studies in Participants ble 2 shows the range of baseline serum and plasma magne-
with Elevated BP Inform a Reference Range for sium reported in these 30 RCTs on normotensive and
Serum Magnesium? hypertensive participants.
BP is an extremely easy physiologic marker to measure, and This large number of clinical trials that used oral magne-
hypertension is an established and reliable risk factor for sium for BP in adults provides a rich source of data on se-
CVD morbidity and mortality. Meta-analyses of clinical trials rum and urinary magnesium with changes in BP during a
of oral magnesium therapy and BP have also shown varying re- stated supplemental oral magnesium dose. All of these stud-
sults (4–8) depending on the meta-analysis inclusion and ex- ies, both those on normotensive as well as hypertensive par-
clusion criteria. Overall, however, these meta-analyses have ticipants, show increases in serum and urinary magnesium
established a statistically significant effect of oral magnesium with oral magnesium supplementation along with variable
in lowering high BP. In a recent meta-analysis that investi- results on BP (analyzed in the section that follows).
gated oral magnesium supplementation, Zhang et al. (9)
showed a mean rise of 0.05 mmol/L in serum magnesium How Do Cohort Studies of CVD Outcomes Inform
in 27 trials in a median time of 87 d and found significance a Reference Range for Serum Magnesium?
(P < 0.001). Magnesium is believed to be linked to CVD risk through a
broad range of physiologic roles, several of which have
Clinical studies been described in the previous sections; e.g., low circulating
Our search of magnesium in BP and hypertension resulted in concentrations have been associated with impaired glucose
80 studies (53 clinical trials and 6 cohort, 3 case-control, and homeostasis and insulin action, elevated BP, chronic inflam-
18 cross-sectional studies) (Supplemental References) that mation, impaired vasomotor tone and peripheral blood
included measurements of serum and/or urinary magne- flow, and electrocardiogram abnormalities (4, 15, 144,
sium, 2 of which were in adolescents (1 RCT in those aged 145). To date, no RCT to our knowledge has explored
14–18 y and 1 cohort study in those aged 12–14 y). The re- whether magnesium supplementation is related to lower
maining 78 studies were conducted in adults, of which 5 in- CVD risk. However, prospective observational studies in ini-
cluded some elderly participants aged $75 y. Our search tially generally healthy populations have linked low circulat-
returned no studies on young children or infants. Thus, there ing magnesium to a higher risk of CVD morbidity and
are considerable gaps in the data for the understanding of mortality. Many of these observational studies were included
magnesium and BP in children, infants, teens, and the el- in one or both of the 2 meta-analyses (10, 146) published in
derly. In the vast majority of prospective and cross-sectional 2013. Del Gobbo et al. (10) estimated that per 0.2-mmol/L
studies, serum, urinary, and dietary magnesium were in- increment in circulating magnesium, the risk of total CVD
versely associated with hypertension and BP, except in one was 30% lower (RR: 0.70; 95% CI: 0.56, 0.88), the risk of is-
study in teens. In general, these studies show that when uri- chemic heart disease was 17% lower (RR: 0.83; 95% CI:
nary, serum, and/or dietary magnesium goes up, both sys- 0.65, 1.05), and the risk of fatal ischemic heart disease
tolic and diastolic BP go down. (e.g., fatal myocardial infarction) was 39% lower (RR: 0.61;
95% CI: 0.37, 1.00). Results were similar, albeit slightly
Intervention trials weaker, in the meta-analysis from Qu et al. (146) for total
Our search resulted in 53 publications that reported 65 hu- CVD events (RR: 0.91; 95% CI: 0.85, 0.97 per 0.05 mmol/L).
man clinical trials of oral magnesium therapy for BP with The studies included in the meta-analyses and 4 additional
median duration of 2 mo (weighted mean difference: 0.03 mmol/L; The Case for Transitioning STMC to an Evidence-
95% CI: 0.01, 0.05; P < 0.0001). Dose- and time-response Based Reference Interval
analyses indicated that serum and plasma magnesium con- Modern medicine has chosen STMC to evaluate magnesium
centrations were elevated immediately after magnesium status, but it represents only ;0.3% of the total body magne-
supplementation and gradually peaked at a dose of 500 mg/d sium content and is not in equilibrium with other body tissues
(Supplemental Figure 2) over a duration of 25 wk (Supple- except nominally with the bone. As noted earlier, the reference
mental Figure 3). In addition, serum and plasma magnesium interval for STMC was determined in a US population as part
changes did not significantly vary by age, sex, magnesium for- of NHANES I with the use of atomic absorption spectrometry.
mulation (organic or inorganic magnesium supplements), The identified reference interval (central 95th percentile) was
cardiometabolic health status (participants free of or with di- 0.75–0.95 mmol/L with a mean concentration of 0.85 mmol/L
abetes, CVD, and/or hypertension), trial sample size, or trial (21) and followed a normal Gaussian distribution curve.
quality (P-interaction > 0.05 for all).
This quantitative assessment of available RCT data shows
similarly substantial dose and time responses of serum and Can the clinical laboratory accurately and precisely
plasma magnesium concentrations to oral magnesium sup- measure STMC?
plementation. These results provide direct evidence that A reference system for accurately determining STMC has
both serum and plasma magnesium are useful for their effec- been established (174). The definitive method for magne-
tiveness in reflecting long-term magnesium status (i.e., 25 wk sium is isotope dilution/MS as indicated by the National In-
for serum and 15 wk for plasma magnesium measurements), stitute of Standards and Technology. The clinical laboratory
although the sensitivity and specificity of serum and plasma reference method for magnesium is flame atomic absorp-
magnesium concentrations in determining magnesium sta- tion spectrometry. Reference materials for magnesium are
tus need to be reliably calibrated in well-designed and rigor- available from the National Institute of Standards and Tech-
ously conducted RCTs with the gold-standard measure nology. Standard reference material (SRM) 929 is a prepara-
of magnesium status, i.e., the magnesium loading test. In ad- tion of magnesium gluconate dihydrate, and SRM 3131a is a
dition, further studies are needed to fully explore potential stock solution of magnesium at a concentration of 10 g/L
biological modifiers of serum and plasma magnesium and 10% HNO3. Furthermore, SRM 909 is a human serum
concentrations. with certified values for many analytes, including magnesium.
mortality) support adverse risk at serum magnesium concen- conference was held at the NIH that established the upper
trations <0.80 mmol/L. Several animal studies have docu- limit of the reference interval for serum total cholesterol
mented this relation (43, 180–183). Furthermore, based on of 200 mg/dL (185). We now recommend a similar consen-
this mechanism, there is an increased risk for T2D, which sus conference with subject experts to establish an evidence-
we also discussed previously. In addition, in clinical settings, based reference interval for STMC (Figure 5) that reflects the
serum magnesium concentrations of 0.75–1.0 mmol/L have US population.
been shown to prolong QTc intervals on electrocardiograms, Based on the review of literature presented herein, we
increasing the risk of cardiac arrhythmias. A recent retro- propose adopting an evidenced-based reference interval
spective hospital chart review in 3200 participants (free for STMC $0.85 mmol/L to reduce the risk of CVD, T2D,
of medications that would alter the electrocardiogram) dem- and other diseases (Figure 6). We further propose a program
onstrated a mean QTc of 465.4 6 1.1 ms with serum magne-
sium >1.0 mmol/L, whereas the mean serum magnesium
of <1.0 mmol/L had a longer QTc that averaged 470.1 +
0.99 ms (P < 0.001) (184), suggesting an increased risk in vul-
nerable population groups even when serum STMC may be
within or above the upper limit of the reference interval.