The good, the bad, and the ugly of calcium supplementation: a review of calcium intake on human health

Abstract

Calcium is an important integrative component of the human body and critical for human health. It has been well established that calcium intake is helpful in the prevention and treatment of osteoporosis, which has become one of the most serious public health problems across the world. However, community-dwelling adults with and without osteoporosis are rarely concerned or even not aware of the potential side effects of high or inappropriate doses of calcium intake. Some recent studies have revealed that excessive calcium intake might increase the risks of cardiovascular diseases. The purpose of this article was to review the health benefits, costs, and consequences of calcium supplementation on osteoporosis/osteoporotic fractures, cardiovascular events, kidney stones, gastrointestinal diseases, and other important diseases. In the end, we suggest that calcium supplementation should be prescribed and taken cautiously, accounting for individual patients’ risks and benefits. Clearly, further studies are needed to examine the health effects of calcium supplementation to make any solid recommendations for people of different genders, ages, and ethnicities.

Full text

© 2018 Li et al. This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php
and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you
hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission
for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php).
Clinical Interventions in Aging 2018:13 2443–2452
Clinical Interventions in Aging Dovepress
submit your manuscript | www.dovepress.com
Dovepress 2443
REVIEW
open access to scientific and medical research
Open Access Full Text Article
http://dx.doi.org/10.2147/CIA.S157523
The good, the bad, and the ugly of calcium
supplementation: a review of calcium intake on
human health
Kelvin Li,1,* Xia-Fang Wang,2,3,*
Ding-You Li,4 Yuan-Cheng
Chen,2 Lan-Juan Zhao,1 Xiao-
Gang Liu,5 Yan-Fang Guo,6 Jie
Shen,2 Xu Lin,2 Jeffrey Deng,1
Rou Zhou,2 Hong-Wen Deng1,7
1Center for Bioinformatics and Genomics,
Department of Global Biostatistics and
Data Science, Tulane University, New
Orleans, LA 70112, USA; 2Department of
Endocrinology and Metabolism, The Third
Affiliated Hospital of Southern Medical
University, Guangzhou, Guangdong 510630,
People’s Republic of China; 3Department of
Endocrinology and Metabolism, Hengyang
Central Hospital, Hengyang, Hunan 421000,
People’s Republic of China; 4Department
of Gastroe nte rolo gy, Chi ldren’s Merc y
Kansas City, University of Missouri Kansas
City School of Medicine, Kansas City,
MO 64108, USA; 5School of Life Science
and Technology, Xi’an Jiao Tong University,
Xi’an, Shanxi 710049, People’s Republic of
China; 6Institute of Bioinformatics, School
of Basic Medical Science, Southern Medical
University, Guangzhou, Guangdong 510515,
People’s Republic of China; 7School of
Basic Medical Science, National Clinical
Research Center for Geriatric Diseases,
Xiangya Hospital, Central South University,
Changsha, Hunan 410078, People’s Republic
of China
*These authors contributed equally
to this work
Abstract: Calcium is an important integrative component of the human body and critical for
human health. It has been well established that calcium intake is helpful in the prevention and
treatment of osteoporosis, which has become one of the most serious public health problems
across the world. However, community-dwelling adults with and without osteoporosis are
rarely concerned or even not aware of the potential side effects of high or inappropriate doses of
calcium intake. Some recent studies have revealed that excessive calcium intake might increase
the risks of cardiovascular diseases. The purpose of this article was to review the health benefits,
costs, and consequences of calcium supplementation on osteoporosis/osteoporotic fractures,
cardiovascular events, kidney stones, gastrointestinal diseases, and other important diseases. In
the end, we suggest that calcium supplementation should be prescribed and taken cautiously,
accounting for individual patients’ risks and benefits. Clearly, further studies are needed to
examine the health effects of calcium supplementation to make any solid recommendations
for people of different genders, ages, and ethnicities.
Keywords: calcium, osteoporosis, osteoporotic fractures, cardiovascular diseases, kidney
stones, gastrointestinal diseases
Introduction
Calcium supplementation is a widespread practice in different age-groups and has
been promoted widely to improve bone density.1 The public generally believes that
calcium is always good for health, owing largely to successful marketing and various
clinical practice guidelines (Table 1). Based on the published data, 61% of women
aged .60 years received calcium supplements in 2003–2006 in the United States.2
As a result, calcium supplementation has become a billion dollar market in recent
years and has been taken by millions of both men and women, children, adults, and
the elderly wishing to improve their skeletal health.
People may get more calcium from dietary intake or calcium supplementation. Due
to the limited availability of calcium-rich foods and dietary habits, it is not always
possible for people to take more and sufficient dietary calcium. Thus, there is a role
for calcium supplementation for patients with inadequate dietary calcium intake. Initial
studies suggested that dietary calcium had a greater effect on bone building due to its
better absorption than supplemental calcium, but further studies are needed to fully
elucidate whether one is better than the other to improve bone density.3
Recently, increasing concerns have been raised regarding whether indiscriminate
calcium supplementation is safe. A meta-analysis by Bischoff-Ferrari et al demonstrated
Correspondence: Hong-Wen Deng
Center for Bioinformatics and Genomics,
Department of Global Biostatistics and Data
Science, Tulane University, 1440 Canal Street,
Suite 2001, New Orleans, LA 70112, USA
Tel +1 504 988 1310
Fax +1 504 988 1706
Email hdeng2@tulane.edu
Journal name: Clinical Interventions in Aging
Article Designation: Review
Year: 2018
Volume: 13
Running head verso: Li et al
Running head recto: Calcium metabolism and homeostasis
DOI: 157523
This article was published in the following Dove Press journal:
Clinical Interventions in Aging

Clinical Interventions in Aging 2018:13
submit your manuscript | www.dovepress.com
Dovepress
Dovepress
2444
Li et al
an increased hip fracture risk with calcium supplementation.4
A recent meta-analysis of randomized clinical trials showed
that calcium supplementation was not associated with a low
risk of fractures among community-dwelling older adults.5
There has been a concern for a significant increase in the risk
of cardiovascular diseases with high supplemental calcium
intake in men.6–8
Given the emerging dilemma regarding calcium supple-
mentation, the present article reviews discusses the potential
benefits and side effects of calcium supplementation on
health and diseases such as osteoporosis/osteoporotic frac-
tures, cardiovascular events, kidney stones, gastrointestinal
diseases, and others.
The basics: the role of calcium
It is well established that calcium is an extremely important
and integrative component of human body, with 99% of the
body’s calcium being contained within the skeleton.9 Plasma
calcium homeostasis plays a vital role in maintaining human
life activities, such as maintenance of the skeleton, regulation
of hormonal secretion, transmission of nerve impulses, and
vascular activities.10–12 As shown in Figure 1, dietary calcium
is absorbed mainly in the small intestine. Through circulation,
it is mostly deposited into bones. Excessive or unabsorbed
calcium is excreted in urine and feces.10 The homeostasis
of calcium is mainly maintained by both parathyroid hor-
mone (PTH) and calcitonin.13 When serum calcium level
drops, PTH promotes calcium releases from the bones and
stimulates reabsorption of calcium by the kidney tubules. In
addition, PTH indirectly increases calcium absorption in the
intestine via calcitriol, which is produced by the kidney and
is the hormonal form of vitamin D. On the other hand, when
serum calcium level rises, calcitonin would suppress calcium
release from the bones10 and reduce calcium reabsorption by
the kidney tubules.14
Potential benecial effects of
calcium supplementation
Osteoporosis
As calcium is one of the constituents of bone, the major-
ity of researches considered that high calcium intake may
result in higher bone density.1 According to the current
status of our knowledge and understanding, improving
accrual of peak bone mass and slowing the loss of bone
after reaching the peak are two key factors in the prevention
of osteoporosis. Moreover, bone mass grows most quickly
during adolescence;15 thus, the prevention of osteoporosis
should ideally start from this time.16 Importantly, calcium
supplementation, together with vitamin D supplementation,
is supported by the accumulating evidence for patients at
high risk of calcium and vitamin D insufficiency and for
those who receive treatment for osteoporosis.17
Interestingly, some studies illustrated that calcium
supplementation played a protective role for bone health,
improving bone mass density (BMD) and decreasing
morbidity of osteoporosis and osteoporotic fractures in
different genders and age-groups.18 For children or adults,
best evidence (grade A) is available for positive effects of
calcium intake on the prevention of osteoporosis accord-
ing to the National Osteoporosis Foundation (NOF).16 In
addition, the administration of calcium was also shown to
stave off fracture.19 Radford et al investigated the effects
of calcium on fracture incidence and BMD after calcium
supplement discontinuation; they concluded that the frac-
tures in forearm and vertebrae were significantly decreased,
but the positive benefits on BMD observed in the original
Table 1 Calcium intake clinical practice guidelines for osteoporosis in different populations
Source Year published Populations Recommended intake
(mg/day)
References
UK National Osteoporosis
Guideline Group
2017 Postmenopausal women
Old people
700–1,200 68
Osteoporosis New Zealand 2017 Adults 500 69
National Osteoporosis Foundation 2014 Men (aged 50–70 years)
Women aged .51 years
Men aged .71 years
1,000
1,200
1,200
56
None 2012 Adults 700–800 70
None 2012 Adults 1,200 71
Chinese Society of Osteoporosis
and Bone Mineral Research
2011 Adults
Postmenopausal women
Old people
800
1,000
1,000
72
Best Practice Guidelines Committee 2010 People aged .50 years 1,000 73

Clinical Interventions in Aging 2018:13 submit your manuscript | www.dovepress.com
Dovepress
Dovepress
2445
Calcium metabolism and homeostasis
Figure 1 Schema of calcium metabolism and homeostasis in human body.
Notes: Dietary calcium is absorbed mainly in the small intestine and mostly deposited into bones. Excessive or unabsorbed calcium is excreted in urine and feces. Plasma
calcium level is mainly maintained by both PTH and calcitonin. When serum calcium level drops, PTH promotes calcium releases from the bones and stimulates reabsorption
of calcium by the kidney tubules. In addition, PTH indirectly increases calcium absorption in the intestine via calcitriol. On the other hand, when serum calcium level rises,
calcitonin would suppress calcium release from the bones and reduce calcium reabsorption by the kidney tubules.
Abbreviation: PTH, parathyroid hormone.
$EVRUSWLRQ
5HOHDVH
)HFHV
8ULQH
,QWHVWLQHV
%RQH
&DOFLWRQLQ
3ODVPDFDOFLXP
&DOFLWULRO
37+
.LGQH\
&D
&D
3URPRWHV
3URPRWHV
5HDEVRUSWLRQ
,QKLELWV
trial did not persist when the calcium supplementation was
discontinued.19 Taking all the evidence into account, these
studies all suggested that calcium supplementation, either in
the form of calcium supplements or dietary calcium, played
a positive role in people of different ages and genders, even
though those results were obtained from studies of different
sample sizes.
Postmenopausal women
A randomized, double-blind, placebo-controlled study
performed on 1,471 postmenopausal women with 5-year
follow-up, receiving either 1,000 mg/d calcium supplements
or identical placebo, showed that calcium supplements could
decrease bone loss.20 One meta-analysis, which included 29
randomized trials with men and women aged .50 years
(including menopausal women), indicated that adequate
calcium intake with/without vitamin D is associated with
a reduced risk of fractures of any type (the RR =0.88, 95%
CI =0.83–0.95) as well as provided a modest benefit on
reducing the rate of bone loss, with 0.54% reduction of bone
loss in the hip and 1.19% reduction of bone loss in the spine.
In addition, there was a 24% risk reduction in osteoporotic
fractures in people with high compliance rate for calcium
supplementation. Furthermore, this study also suggested
that a minimum dose of 1,200 mg/d calcium with 800 IU/d
vitamin D was the best treatment for osteoporosis.21 Most
studies involving postmenopausal women did not conduct
data stratification to address whether calcium supplementa-
tion had similar or different effects in those women with or
without osteoporosis. A Spanish study demonstrated a high
prevalence of low calcium intake and vitamin D deficiency
in postmenopausal women with osteoporosis.22 Further stud-
ies are needed to determine whether higher dose of calcium
supplementation would be beneficial in this patient popula-
tion. In one study performed exclusively in the postmeno-
pausal women with no history of osteoporosis, 187 women
aged .65 years were enrolled in a descriptive cross-sectional
trial, revealing that adequate calcium intake along with
proper exercise can effectively prevent osteoporosis.23 The
recommended dosage of calcium supplementation for post-
menopausal women with or without osteoporosis has been
supported by the results of some large studies; 36,282 post-
menopausal women were randomized into various groups
with 1,000 mg/d calcium and vitamin D or placebo and
followed for 7 years in the largest study, suggesting that hip
bone density was improved with calcium supplements.24

Clinical Interventions in Aging 2018:13
submit your manuscript | www.dovepress.com
Dovepress
Dovepress
2446
Li et al
Premenopausal women
The current evidence is not sufficient to recommend calcium
supplementation for the primary prevention of fractures
in community-dwelling, asymptomatic premenopausal
women.25 However, for those with a history of osteoporotic
fractures, a diagnosis of osteoporosis, vitamin D deficiency,
or a high risk for osteoporosis (eg, primary ovarian insuf-
ficiency), calcium supplementation may be considered.26,27
Pregnant and lactating women
There is still a lack of clinical data to recommend calcium
supplementation in pregnant or lactating women for the
skeletal health of fetus and mother. A Cochrane database
systemic review found that calcium supplementation dur-
ing pregnancy did not have any clear additional benefits in
the prevention of preterm birth or low infant birthweight.28
However, in pregnant and lactating women with low calcium
intakes, calcium supplementation may be considered.29
Interestingly, in a study in pregnancy women in Gambia,
West Africa, with low calcium intakes, calcium supplement
resulted in significantly lower bone mineral content, bone
area, and BMD at the hip throughout 12-month lactation.
The women also had greater decreases in bone mineral dur-
ing lactation at the lumbar spine and distal radius and had
biochemical changes consistent with greater bone mineral
mobilization.30
Men
Although the evidence for preventing osteoporosis and
improving BMD has been mostly generated in studies of
postmenopausal women, a study back in 2008 compared
the effects of two dosages of calcium citrate (600 mg/d,
1,200 mg/d, or placebo) on BMD in healthy men. The
double-blind, randomized controlled trial performed on 323
healthy men aged .40 years for a 2-year period revealed that
the 1,200 mg/d group showed increased BMD; however, it
needs to be noted that urine calcium tended to increase by
57% correspondingly.31 In one study recently performed in
Korean subjects, including 5,955 men, 1,256 premenopausal
women and 4,494 postmenopausal women, it was revealed
that increasing dietary calcium intake significantly improved
BMD in both men and women.32
Children
In a study conducted in rural Gambian children accustomed
to a low-calcium diet, calcium supplementation resulted in
higher bone mineral content and BMD.33 For healthy chil-
dren, there has been no recommendation for routine calcium
supplementation. In clinical practice, children with a high
risk of osteoporosis (eg, celiac disease, inflammatory bowel
disease, or congenital bone disorder) or low calcium intake
may benefit from calcium supplementation.
Cardiovascular disease
There is evidence suggesting that cardiovascular disease
might be protected by calcium supplementation. A prospec-
tive cohort study conducted among an elderly Chinese popu-
lation indicated that dietary calcium intake (mean =600 mg/d)
could reduce the risk of death from all causes and cardiovas-
cular diseases.34 Despite the limitations (a self-administered
questionnaire was used), its results added to the body of
evidence that calcium supplementation decreases the mor-
tality risk of cardiovascular diseases. Another prospective
cohort study in Europe indicated that a daily administration
of a mean of 820 mg dietary calcium has an effect of up
to a 30% decrease in the risk of myocardial infarction.35
Similarly, in a prospective cohort study performed exclu-
sively in .34,000 postmenopausal women, both the high
intake of dietary and supplemental calcium were associated
with a decrease in the mortality of ischemic heart disease.36 It
was even observed that adverse cardiovascular effects were
stopped after calcium supplements discontinued.19 Findings
of these studies are likely to suggest that positive effects
between calcium and cardiovascular diseases exist and that
there is generally favorable evidence to imply that calcium
influences cardiovascular disease occurrence. Calcium may
slightly adjust lipid profiles and reduce blood pressure and –
more importantly – the risk of developing hypertension.37,38
In prospective studies, the risks for developing hyperten-
sion were reduced with calcium supplements in men and
women.39,40 In addition, preeclampsia is characterized by
hypertension and would lead to perinatal morbidity and
mortality of both mothers and infants.41 In 2013, the World
Health Organization published a strong recommendation that
pregnant women should take calcium supplements to prevent
preeclampsia.42 A randomized controlled trial in women
suggested that calcium supplementation .1,000 mg/d
is associated with a significant reduction in the risk of
preeclampsia.43
Gastrointestinal disease
The effect of dietary calcium intake on the colorectal cancer
and a comparison with the effect of higher and lower level
of dietary calcium have been investigated by Galas et al.44
They concluded that an increase of 100 mg dietary cal-
cium intake per day lowered by 5% the risk of colorectal

Clinical Interventions in Aging 2018:13 submit your manuscript | www.dovepress.com
Dovepress
Dovepress
2447
Calcium metabolism and homeostasis
cancer (OR =0.95, 95% CI =0.92–0.99), and an increase of
1,000 mg/d dietary calcium consumption decreased incidence
by 37% of colorectal cancer and the risk of colon cancer
by 50%. Simultaneously, dietary calcium .1,000 mg/d
decreased 46% incidence of colon cancer by 46% and the
risk of colorectal cancer by 30%.44 A prospective cohort study
revealed that the greatest benefits were observed with subjects
who had highest dietary calcium intake (median =914 mg/d)
compared with subjects who had lowest calcium intakes at
a median level of 486 mg/day.45
A similar effect was observed with calcium supplement.
A randomized, double-blind trial performed on people with
a history of colorectal adenomas, receiving either 1,200 mg/d
elemental calcium or placebo, revealed a significant reduction
in the risk of recurrent colorectal adenomas with calcium
supplementation.46 The explanation behind those findings
is the ability of calcium to combine with bile acids in the
intestines, reducing the rectal epithelial proliferation rate.47
Most of the risk reduction benefit was achieved by calcium
intake of at least 900 mg/day. Lower calcium intake was
reported to increase the risk of colorectal cancer in Korean
individuals with the CC genotype of the CASR gene in
the single nuclear polymorphism of rs2270916, compared
with those in higher calcium intake with the TT genotype
(OR =2.11, 95% CI =1.27–3.51).48
Kidney stone
Kidney stones are a common disease of the urinary system
and are partially formed by calcium phosphate and calcium
oxalate. Taylor and Curhan reported a relationship between
calcium intake and urinary oxalate levels in a cross-sectional
study. They concluded that high intake of dietary calcium
or supplemental calcium (.500 mg/d) could lower urinary
oxalate levels, subsequently decreasing the risk of kidney
stones formation.49 Interestingly, a 12-year prospective
study of 91,731 women without a history of kidney stones
with 12-year follow-up suggested that high dietary calcium
could reduce the risk of kidney stones, whereas the risk would
be increased in women with high supplemental calcium.50
The mechanism of the different results caused by different
types of calcium on kidney stones has not been definitively
determined, but it is likely that dietary calcium decreases
the absorption of oxalate and is probably associated with
the timing of calcium ingestion relative to the amount of
oxalate consumed. Consequently, it is reasonable to specu-
late that the effect of supplemental calcium on kidney stone
risk depends on whether supplements are received with or
between meals.
Aside from its beneficial roles on people, calcium is
also used in the management of hypoparathyroidism and
osteomalacia. Calcium supplements are considered a standard
treatment for hypocalcemia associated with postsurgical
hypoparathyroidism and achieves better clinical results.51
Potential adverse effects of calcium
supplementation
Despite the abovementioned studies providing powerful evi-
dence for beneficial health-related effects of taking calcium,
some recent evidence has implied that calcium supplementa-
tion might increase the risk for cardiovascular diseases and
malignancy. What is more notable about these adverse effects
is that, under the recommended dosage, calcium would pro-
duce some unwelcome reactions; therefore, a more detailed
consideration of the safety and health benefits of calcium
supplementation would be warranted. A number of adverse
events are possibly influenced by calcium supplementation;
these include myocardial infarction, constipation, colorectal
neoplasms, and kidney stone. For example, in the Kuopio
Osteoporosis Study, where 10,555 women were followed for
7 years, the HR for coronary heart disease in those who were
taking calcium was 1.24 compared with nonusers.52 Thus, a
doubt was for the first time raised in the beneficial effects of
calcium supplementation on bone due to its adverse cardio-
vascular effects by this randomized control study. Moreover,
a total of 1,460 postmenopausal women were randomized to
taking calcium or a placebo and followed over 5 years, and
the HR was found to be 1.12 for incident ischemic heart dis-
ease (95% CI =0.77–1.64).53 These surprising findings from
the large related studies provide a stimulus for evaluating
the effects of calcium on some disease events in other trials,
which we describe below.
Osteoporosis
Although most studies indicate that calcium supplementation
has a beneficial effect on osteoporosis and fractures, this state-
ment is not confirmed by some other researches. Warensjö
et al found that dietary calcium intake ,751 mg/d raised
the risk of osteoporosis-related fractures and osteoporosis;
meanwhile, intake .1,137 mg/d would increase the risk of
hip fractures in women.54 A meta-analysis with seven cohorts
totaling 170,991 women reported that calcium supplemen-
tation does not reduce the risk of hip fractures, and on the
contrary, an increase in risk is possible.4 From these studies,
the benefits of calcium supplementation become unclear, and
there may be a therapeutic window where the greatest benefits
on skeletal health are gained. Further research is needed to

Clinical Interventions in Aging 2018:13
submit your manuscript | www.dovepress.com
Dovepress
Dovepress
2448
Li et al
clarify this, with respect to dietary intake, ethnicity, race,
age, and gender.
Cardiovascular diseases
The side effects of calcium have long been focused on car-
diovascular diseases as the principal concern. Cardiovascular
diseases, especially myocardial infarction and myocardial
ischemia, are among the leading causes of death around the
world. It is estimated by a meta-analysis (including eleven
randomized controlled trials) that calcium supplements
have up to 30% increase risk for myocardial infarction.55 It
was noteworthy that men or women aged .50 years were
recommended to take $1,000 mg/d calcium according to
the guidelines;56 however, the risk of cardiovascular diseases
appears to be particularly increased when those doses are
actually used. A prospective study found that supplemental
calcium intake of .1,000 mg/d may raise the risk of death
from cardiovascular diseases among men, but not among
women.6 A randomized, placebo controlled trial performed
on a population of 1,471 postmenopausal healthy women,
with a follow-up that lasting 5 years, revealed that 1,000 mg/d
elemental calcium supplements increased the incidence of
cardiovascular events.57 In addition, a prospective observa-
tional study suggested that the use of calcium supplements in
a long term would raise the risk of hospitalization in patients
with chronic heart failure; for patients with diabetes, that
risk was doubled.58 It is a remarkable fact that the effects of
cardiovascular diseases between dietary and supplements
of calcium lead to disparate results. A study indicated that
the risk of myocardial infarction remarkably increased by
taking calcium supplements compared with nonusers of any
supplements (HR =1.86, 95% CI =1.17–2.96).35 The finding
of an adverse trend in cardiovascular diseases with calcium
supplementation is not necessarily surprising, as calcium
supplements potentially contribute to elevated serum cal-
cium levels and possibly accelerated cardiovascular calcifica-
tion in the long run,59 which is predictive of cardiovascular
event rates.60 Because of the high incidence of cardiovascular
disease, any effects of calcium supplements on vascular
health could be as important in terms of their effects on
morbidity and mortality as their effects on osteoporosis
or bone health.61 As these adverse effects are confirmed, a
comprehensive reappraisal of taking calcium supplements
may be required.
Gastrointestinal diseases
The second major safety concern with respect to calcium
has been gastrointestinal diseases. The conclusion regarding
the effects of calcium supplements on the gastrointestinal
diseases is not totally consistent. Calcium supplements may
increase the incidence of constipation, severe diarrhea, and
abdominal pain.1,62 It highlights that calcium carbonate is more
often associated with gastrointestinal side effects, including
constipation, flatulence, and bloating.18 Of the 92,000 adverse
events recorded, the occurrence of constipation was increased
with calcium carbonate treatment (1,200 mg/d) in a 5-year,
double-blind, placebo-controlled study.53 Moreover, some
studies demonstrated a negative correlation between the
intake of calcium and colorectal adenoma. A meta-analysis
of 24 studies exploring the relationship between calcium
supplementation and colorectal adenoma implied that the
pooled RR was 1.13 for the occurrence of colorectal adenoma
(95% CI =0.91–1.39).63 As stated previously, these findings
are inconsistent as other research has shown reduction in the
risk of colorectal cancer with calcium supplements.
Kidney stone
The third major concern regarding the safety of calcium has
been the occurrence of kidney stones. Despite that calcium
has positive effects on kidney stones by some researches, the
literature is not consistent regarding the relationship between
calcium and kidney stone formation. It was found that the
abnormality of urinary supersaturation is one of the main fac-
tors for the formation of kidney stones.64 Specifically, levels
of supersaturation above 1 can easily result in crystal deposits
and growth and are considered a high-risk factor in kidney
stone formation. The formation of urinary calcium oxalate
stones is probably related to abnormal oxalate metabolism.52
Of note, people lacking adequate calcium intake should
carefully consider the intake of oxalate-rich foods, such as
spinach, chocolates, and teas.53 While studies indicate the
potential beneficial effects of dietary calcium intake on the
reduction of the risk of kidney stones, individuals who con-
sumed any amount of supplemental calcium had an increased
risk for kidney stones compared with individuals who did
not consume supplemental calcium.50 A study performed in
53 postmenopausal women with 1,000 mg/d calcium (with
400 IU/d vitamin D) for 1 year showed a weak relationship
with kidney stones formation; only one patient with urinary
calculi was proved by ultrasonography. However, the small
sample size and short clinical trial duration may contribute
to lack of significant findings in this study.65 Nonetheless, a
study conducted in 2006, including 36,282 postmenopausal
women aged 50–70 years followed up for an average of
7 years, receiving either 1,000 mg/d elemental calcium or
placebo, found a 17% increased risk of developing kidney

Clinical Interventions in Aging 2018:13 submit your manuscript | www.dovepress.com
Dovepress
Dovepress
2449
Calcium metabolism and homeostasis
stones, with 449 women reporting kidney stones in the
calcium with vitamin D group vs 381 women in the placebo
group.24 Normally, stone formation in a normal kidney is
relatively rare and is probably due to a combination of fac-
tors, such as health condition, urinary acidity, dietary habit,
and variation in intake of calcium supplements (calcium
oxalate, calcium citrate, and calcium carbonates). Dietary
calcium is more beneficial for health in the aspect of kidney
stone development.66
Other diseases
In addition, adverse effects of calcium on other diseases
such as age-related macular degeneration (AMD) and
metabolic syndrome were reported. A recent cross-sectional
study found that .800 mg/d of calcium consumption in
people aged .67 years may increase the risk of AMD
compared with those who do not take calcium (OR =2.63,
95% CI =1.52–4.54).67 A study in Korea found that men
taking dietary calcium .1,200 mg/d had increased the
prevalence of metabolic syndrome compared with those
taking ,1,200 mg/d, but no similar correlation was found
in women.32
For ease of reference, we summarized the above
most salient points for the benefits and adverse effects in
Table 2.
Conclusion
The issue of safety in people receiving calcium has long
been a matter of debate. There is an abundance of data for
beneficial effects and side effects in the literature on the role
of calcium. All taken together, it is important to balance the
advantages and disadvantages of calcium supplementation
on human health. Based the literature, calcium supplementa-
tion is a double-edged sword in promoting bone formation
or preventing osteoporosis, as it also may have a potential
negative impact.
Many factors could account for the inconsistencies in
earlier studies. First, different dosages of calcium may induce
different results. Second, dietary calcium may have beneficial
effects than calcium supplements. Third, different popula-
tions and sample sizes may affect the results of studies. In the
reported studies, sample sizes vary from several hundreds
to several thousands. Last, there are still some unknown
mechanisms affecting the results. Therefore, further experi-
mental studies are necessary to decipher the mechanisms of
the calcium intake affecting those diseases. As for the types
of calcium to consume, a thorough search of the literature
on calcium studies suggested that dietary calcium is more
beneficial for health than calcium supplements and that it is
also easier to absorb.
However, there is no denying that the favorable role
of calcium is evident in people of all ages, not only in the
postmenopausal women and elderly population but also in
childhood and adolescence. For children and adolescents, suf-
ficient calcium intake is important for building strong bone.
For adults, sufficient calcium intake is necessary to prevent
or delay the incidence of osteoporosis. The expert from NOF
recommended 1,200 mg/d of calcium intake for women
aged .51 years and men aged .71 years and 1,000 mg/d
for men aged .50 years,56 but based on the abovementioned
literature, the proper dosages of calcium supplementation
for people are actually not clear, especially when consider-
ing its adverse health effects. Is it suitable for people with
some diseases to take calcium, such as those at a high risk
for heart failure as cardiovascular diseases are one of the top
three causes of mortality currently? And if taking calcium is
necessary for those people, what is the proper dosage? There
appears to be no clear answer to questions like these. There-
fore, we recommend that calcium supplementation should be
prescribed cautiously and take into account the health status
of individuals. Of note, the patients with hypercalcemia
should avoid taking calcium supplements.
Osteoporosis is a systemic metabolic disease that severely
impacts the quality of life in the middle-aged and elderly,
which has gradually grown into one of the most serious
problems in public health. The two studies demonstrated
that calcium could prevent osteoporosis and osteoporotic
fracture or improve BMD, but simultaneously also revealed
the increase of the occurrence of cardiovascular diseases19
and increase in urine calcium level and subsequently in the
risk of urinary calculi.24 The results stimulated our attention
to evaluate whether the beneficial role in bone is greater than
its side effects. Therefore, calcium is a double-edged sword,
which may be both potentially crucial and perilous.
Table 2 The effects of calcium supplementation in diseases
Potential benecial effects of calcium supplementation
Diseases References
Osteoporosis 19, 20, 21, 24, 32
Cardiovascular disease 34–36, 43
Gastrointestinal diseases 44–46, 48
Kidney stones 49, 50
Potential adverse effects of calcium supplementation
Osteoporosis 4, 54
Cardiovascular disease 6, 35, 55, 57
Gastrointestinal diseases 53, 63
Kidney stones 24, 50

Clinical Interventions in Aging 2018:13
submit your manuscript | www.dovepress.com
Dovepress
Dovepress
2450
Li et al
Questions remain as to whether taking extra calcium as
calcium supplements is helpful to the general population.
What is the real value of calcium intake by supplements per
day for different individuals? Could it do more harm rather
than good, particularly taking into consideration the increased
risk of other diseases? More studies are needed to examine
these effects for making better recommendations in different
genders, ages, and ethnicities.
Acknowledgments
HWD and LJZ were partially supported by grants from the
National Institutes of Health (AR069055, U19 AG055373,
R01 MH104680, R01AR059781 and P20GM109036), the
Edward G. Schlieder Endowment fund and the Tsai and Kung
endowment fund to Tulane University.
Author contributions
HWD contributed to study conception, initiation, general
development, and design. KL, XFW, YCC, YFG, and RZ col-
lected data. XFW, DYL, YCC, XGL, LJZ, and YFG drafted
the manuscript. KL, XFW, DYL, YCC, XGL, LJZ, JS, and
HWD revised the final manuscript. All authors contributed
to data analysis, drafting and revising the article, gave final
approval of the version to be published, and agree to be
accountable for all aspects of the work.
Disclosure
The authors report no conflicts of interest in this work.
References
1. Reid IR. Should we prescribe calcium supplements for osteoporosis
prevention? J Bone Metab. 2014;21(1):21–28.
2. Gahche J, Bailey R, Burt V, et al. Dietary supplement use among U.S.
adults has increased since NHANES III (1988–1994). NCHS Data Brief.
2011;61:1–8.
3. Booth A, Camacho P. A Closer look at calcium absorption and the ben-
efits and risks of dietary versus supplemental calcium. Postgrad Med.
2013;125(6):73–81.
4. Bischoff-Ferrari HA, Dawson-Hughes B, Baron JA, et al. Calcium intake
and hip fracture risk in men and women: a meta-analysis of prospec-
tive cohort studies and randomized controlled trials. Am J Clin Nutr.
2007;86(6):1780–1790.
5. Zhao JG, Zeng XT, Wang J, Liu L. Association Between Calcium or
Vitamin D Supplementation and Fracture Incidence in Community-
Dwelling Older Adults: A Systematic Review and Meta-analysis. JAMA.
2017;318(24):2466–2482.
6. Xiao Q, Murphy RA, Houston DK, Harris TB, Chow WH, Park Y. Dietary
and supplemental calcium intake and cardiovascular disease mortality:
the National Institutes of Health-AARP diet and health study. JAMA
Intern Med. 2013;173(8):639–646.
7. Tankeu AT, Ndip Agbor V, Noubiap JJ. Calcium supplementation and
cardiovascular risk: A rising concern. J Clin Hypertens. 2017;19(6):
640–646.
8. Reid IR, Birstow SM, Bolland MJ. Calcium and Cardiovascular Disease.
Endocrinol Metab. 2017;32(3):339–349.
9. Emkey RD, Emkey GR. Calcium metabolism and correcting cal-
cium deficiencies. Endocrinol Metab Clin North Am. 2012;41(3):
527–556.
10. Institute of Medicine (US) Committee to Review Dietary Reference
Intakes for Vitamin D and Calcium. Dietary Reference Intakes for
Calcium and Vitamin D. (Ross AC, Taylor CL, Yaktine AL, Del Valle
HB, eds.). Washington, DC: National Academies Press; 2011. Avail-
able from: http://www.ncbi.nlm.nih.gov/books/NBK56070/. Accessed
September 13, 2018.
11. Brini M, Calì T, Ottolini D, Carafoli E. Intracellular calcium homeo-
stasis and signaling. Met Ions Life Sci. 2013;12:119–168.
12. Krebs J, Agellon LB, Michalak M. Ca(2+) homeostasis and endoplasmic
reticulum (ER) stress: An integrated view of calcium signaling. Biochem
Biophys Res Commun. 2015;460(1):114–121.
13. Kleeman CR, Massry SG, Coburn JW. The clinical physiology of cal-
cium homeostasis, parathyroid hormone, and calcitonin. I. Calif Med.
1971;114(3):16–43.
14. Blaine J, Chonchol M, Levi M. Renal control of calcium, phos-
phate, and magnesium homeostasis. Clin J Am Soc Nephrol. 2015;
10(7):1257–1272.
15. Watts NB, Bilezikian JP, Camacho PM, et al; AACE Osteoporosis
Task Force. American Association of Clinical Endocrinologists Medi-
cal Guidelines for Clinical Practice for the diagnosis and treatment of
postmenopausal osteoporosis. Endocr Pract. 2010;16(Suppl 3):1–37.
16. Weaver CM, Gordon CM, Janz KF, et al. The National Osteoporosis
Foundation’s position statement on peak bone mass development and
lifestyle factors: a systematic review and implementation recommenda-
tions. Osteoporos Int. 2016;27(4):1281–1386.
17. Harvey NC, Biver E, Kaufman JM, et al. The role of calcium supplemen-
tation in healthy musculoskeletal ageing: An expert consensus meeting
of the European Society for Clinical and Economic Aspects of Osteo-
porosis, Osteoarthritis and Musculoskeletal Diseases (ESCEO) and
the International Foundation for Osteoporosis (IOF). Osteoporos Int.
2017;28(2):447–462.
18. Straub DA. Calcium supplementation in clinical practice: a review of
forms, doses, and indications. Nutr Clin Pract. 2007;22(3):286–296.
19. Radford LT, Bolland MJ, Mason B, et al. The Auckland calcium study:
5-year post-trial follow-up. Osteoporos Int. 2014;25(1):297–304.
20. Reid IR, Mason B, Horne A, et al. Randomized controlled trial of
calcium in healthy older women. Am J Med. 2006;119(9):777–785.
21. Tang BM, Eslick GD, Nowson C, Smith C, Bensoussan A. Use of
calcium or calcium in combination with vitamin D supplementation
to prevent fractures and bone loss in people aged 50 years and older: a
meta-analysis. Lancet. 2007;370(9588):657–666.
22. Quesada-Gómez JM, Diaz-Curiel M, Sosa-Henriquez M, et al.
Low calcium intake and inadequate vitamin D status in postmeno-
pausal osteoporotic women. J Steroid Biochem Mol Biol. 2013;136:
175–177.
23. Swaim RA, Barner JC, Brown CM. The relationship of calcium intake
and exercise to osteoporosis health beliefs in postmenopausal women.
Res Social Adm Pharm. 2008;4(2):153–163.
24. Jackson RD, LaCroix AZ, Gass M, et al; Women’s Health Initiative
Investigators. Calcium plus vitamin D supplementation and the risk of
fractures. N Engl J Med. 2006;354(7):669–683.
25. US Preventive Services Task Force, Grossman DC, Curry SJ, et al.
Vitamin D, Calcium, or Combined Supplementation for the Primary
Prevention of Fractures in Community-Dwelling Adults: US Preven-
tive Services Task Force Recommendation Statement. JAMA. 2018;
319(15):1592–1599.
26. Islam MZ, Shamim AA, Viljakainen HT, et al. Effect of vitamin D,
calcium and multiple micronutrient supplementation on vitamin D and
bone status in Bangladeshi premenopausal garment factory workers with
hypovitaminosis D: a double-blinded, randomised, placebo-controlled
1-year intervention. Br J Nutr. 2010;104(2):241–247.
27. Marino R, Misra M. Bone health in primary ovarian insufficiency.
Semin Reprod Med. 2011;29(4):317–327.

Clinical Interventions in Aging 2018:13 submit your manuscript | www.dovepress.com
Dovepress
Dovepress
2451
Calcium metabolism and homeostasis
28. Buppasiri P, Lumbiganon P, Thinkhamrop J, Ngamjarus C,
Laopaiboon M. Calcium supplementation (other than for preventing or
treating hypertension) for improving pregnancy and infant outcomes.
Cochrane Database Syst Rev. 2011;10(10):CD007079.
29. Thomas M, Weisman SM. Calcium supplementation during pregnancy
and lactation: effects on the mother and the fetus. Am J Obstet Gynecol.
2006;194(4):937–945.
30. Jarjou LM, Laskey MA, Sawo Y, Goldberg GR, Cole TJ, Prentice A.
Effect of calcium supplementation in pregnancy on maternal bone
outcomes in women with a low calcium intake. Am J Clin Nutr. 2010;
92(2):450–457.
31. Reid IR, Ames R, Mason B, et al. Randomized controlled trial of calcium
supplementation in healthy, nonosteoporotic, older men. Arch Intern
Med. 2008;168(20):2276–2282.
32. Noe EB, Chon SJ, Kim MK, et al. Associations between dietary
calcium intake with prevalence of metabolic syndrome and changes
in bone mineral density among Korean population. Maturitas. 2015;
81(1):171.
33. Dibba B, Prentice A, Ceesay M, Stirling DM, Cole TJ, Poskitt EM.
Effect of calcium supplementation on bone mineral accretion in
gambian children accustomed to a low-calcium diet. Am J Clin Nutr.
2000;71(2):544–549.
34. Chan R, Leung J, Woo J. A prospective cohort study examining the
associations of dietary calcium intake with all-cause and cardiovascular
mortality in older Chinese community-dwelling people. PLoS One.
2013;8(11):e80895.
35. Li K, Kaaks R, Linseisen J, Rohrmann S. Associations of dietary calcium
intake and calcium supplementation with myocardial infarction and
stroke risk and overall cardiovascular mortality in the Heidelberg cohort
of the European Prospective Investigation into Cancer and Nutrition
study (EPIC-Heidelberg). Heart. 2012;98(12):920–925.
36. 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(2):151–161.
37. Reid IR, Mason B, Horne A, et al. Effects of calcium supplementation
on serum lipid concentrations in normal older women: a randomized
controlled trial. Am J Med. 2002;112(5):343–347.
38. Reid IR, Horne A, Mason B, Ames R, Bava U, Gamble GD. Effects of
calcium supplementation on body weight and blood pressure in normal
older women: a randomized controlled trial. J Clin Endocrinol Metab.
2005;90(7):3824–3829.
39. Witteman JC, Willett WC, Stampfer MJ, et al. A prospective study of
nutritional factors and hypertension among US women. Circulation. 1989;
80(5):1320–1327.
40. Ascherio A, Rimm EB, Giovannucci EL, et al. A prospective study
of nutritional factors and hypertension among US men. Circulation.
1992;86(5):1475–1484.
41. Duhig KE, Shennan AH. Recent advances in the diagnosis and manage-
ment of pre-eclampsia. F1000 Prime Rep. 2015;7:24.
42. World Health Organization. Guideline: Calcium Supplementation in
Pregnant Women. Geneva: World Health Organization; 2013. Avail-
able from: http://www.ncbi.nlm.nih.gov/books/NBK154180/. Accessed
September 13, 2018.
43. Hofmeyr GJ, Atallah AN, Duley L. Calcium supplementation during
pregnancy for preventing hypertensive disorders and related problems.
Cochrane Database Syst Rev. 2006;3(3):CD001059.
44. Galas A, Augustyniak M, Sochacka-Tatara E. Does dietary calcium
interact with dietary fiber against colorectal cancer? A case-control
study in Central Europe. Nutr J. 2013;12:134.
45. Terry P, Baron JA, Bergkvist L, Holmberg L, Wolk A. Dietary calcium
and vitamin D intake and risk of colorectal cancer: a prospective cohort
study in women. Nutr Cancer. 2002;43(1):39–46.
46. Baron JA, Beach M, Mandel JS, et al. Calcium supplements for the
prevention of colorectal adenomas. Calcium Polyp Prevention Study
Group. N Engl J Med. 1999;340(2):101–107.
47. Welberg JWM, Kleibeuker JH, Dermeer RV, Mulder NH, de Vries EGE,
Vries E. Calcium and the Prevention of Colon Cancer. Scand J Gas-
troenterol. 1991;26(Sup 188):52–59.
48. Kim KZ, Shin A, Kim J, et al. Association between CASR polymor-
phisms, calcium intake, and colorectal cancer risk. PLoS One. 2013;
8(3):e59628.
49. Taylor EN, Curhan GC. Determinants of 24-hour urinary oxalate excre-
tion. Clin J Am Soc Nephrol. 2008;3(5):1453–1460.
50. Curhan GC, Willett WC, Speizer FE, Spiegelman D, Stampfer MJ.
Comparison of dietary calcium with supplemental calcium and other
nutrients as factors affecting the risk for kidney stones in women. Ann
Intern Med. 1997;126(7):497–504.
51. Khan MI, Waguespack SG, Hu MI, Mi H. Medical management of post-
surgical hypoparathyroidism. Endocr Pract. 2011;17(Suppl 1):18–25.
52. Pentti K, Tuppurainen MT, Honkanen R, et al. Use of calcium supple-
ments and the risk of coronary heart disease in 52–62-year-old women:
The Kuopio Osteoporosis Risk Factor and Prevention Study. Maturitas.
2009;63(1):73–78.
53. Prince RL, Devine A, Dhaliwal SS, Dick IM. Effects of calcium supple-
mentation on clinical fracture and bone structure: results of a 5-year,
double-blind, placebo-controlled trial in elderly women. Arch Intern
Med. 2006;166(8):869–875.
54. Warensjö E, Byberg L, Melhus H, et al. Dietary calcium intake and
risk of fracture and osteoporosis: prospective longitudinal cohort study.
BMJ. 2011;342:d1473.
55. 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.
56. Cosman F, de Beur SJ, LeBoff MS, et al; National Osteoporosis Founda-
tion. Clinician’s Guide to Prevention and Treatment of Osteoporosis.
Osteoporos Int. 2014;25(10):2359–2381.
57. Bolland MJ, Barber PA, Doughty RN, et al. Vascular events in healthy
older women receiving calcium supplementation: randomised controlled
trial. BMJ. 2008;336(7638):262–266.
58. Drozd M, Cubbon R, Gierula J, et al. 54 Calcium Supplementa-
tion in Patients with Chronic Heart Failure: Is it Safe? Heart. 2014;
100(Suppl 3):A31.
59. West SL, Swan VJ, Jamal SA. Effects of calcium on cardiovascular
events in patients with kidney disease and in a healthy population. Clin
J Am Soc Nephrol. 2010;5(Suppl 1):S41–S47.
60. Meier C, Kränzlin ME. Calcium supplementation, osteoporosis and
cardiovascular disease. Swiss Med Wkly. 2011;141:w13260.
61. 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:f228.
62. Lewis JR, Zhu K, Prince RL. Adverse events from calcium supplemen-
tation: relationship to errors in myocardial infarction self-reporting in
randomized controlled trials of calcium supplementation. J Bone Miner
Res. 2012;27(3):719–722.
63. Bergsma-Kadijk JA, van’t Veer P, Kampman E, Burema J. Calcium
does not protect against colorectal neoplasia. Epidemiology. 1996;
7(6):590–597.
64. Worcester EM, Coe FL. Clinical practice. Calcium kidney stones.
N Engl J Med. 2010;363(10):954–963.
65. Haghighi A, Samimagham H, Gohardehi G. Calcium and vitamin D
supplementation and risk of kidney stone formation in postmenopausal
women. Iran J Kidney Dis. 2013;7(3):210–213.
66. Favus MJ. The risk of kidney stone formation: the form of calcium
matters. Am J Clin Nutr. 2011;94(1):5–6.
67. Kakigi CL, Singh K, Wang SY, Enanoria WT, Lin SC. Self-reported
Calcium Supplementation and Age-Related Macular Degeneration.
JAMA Ophthalmol. 2015;133(7):746–754.
68. Compston J, Cooper A, Cooper C, et al. UK clinical guideline for
the prevention and treatment of osteoporosis. Arch Osteoporos.
2017;12(1):43.

Clinical Interventions in Aging
Publish your work in this journal
Submit your manuscript here: http://www.dovepress.com/clinical-interventions-in-aging-journal
Clinical Interventions in Aging is an international, peer-reviewed journal
focusing on evidence-based reports on the value or lack thereof of treatments
intended to prevent or delay the onset of maladaptive correlates of aging
in human beings. This journal is indexed on PubMed Central, MedLine,
CAS, Scopus and the Elsevier Bibliographic databases. The manuscript
management system is completely online and includes a very quick and fair
peer-review system, which is all easy to use. Visit http://www.dovepress.
com/testimonials.php to read real quotes from published authors.
Clinical Interventions in Aging 2018:13
submit your manuscript | www.dovepress.com
Dovepress
Dovepress
Dovepress
2452
Li et al
69. Osteoporosis.org.nz. Guidance on the Diagnosis and Management
of Osteoporosis in New Zealand. Available from: http://osteoporosis.
org.nz/resources/health-professionals/clinical-guidance/. Accessed
September 13, 2018.
70. Orimo H, Nakamura T, Hosoi T, et al. Japanese 2011 guidelines for
prevention and treatment of osteoporosis – executive summary. Arch
Osteoporos. 2012;7(1–2):3–20.
71. Makras P, Vaiopoulos G, Lyritis GP. 2011 guidelines for the diagnosis
and treatment of osteoporosis in Greece. J Musculoskelet Neuronal
Interact. 2012;12(1):38–42.
72. Chinese Society of Osteoporosis and Bone Mineral Research. Guideline
of diagnosis and treatment of primary osteoporosis. Chin J Osteoporos
Bone Miner Res. 2011;4(1):2–17.
73. Papaioannou A, Morin S, Cheung AM, et al. 2010 clinical practice
guidelines for the diagnosis and management of osteoporosis in Canada:
summary. Can Med Assoc J. 2010;182(17):1864–1873.