ARTHRITIS & RHEUMATOLOGY

Vol. 67, No. 6, June 2015, pp 14651473

DOI 10.1002/art.39100
C 2015, American College of Rheumatology
V

Lack of Association of Oral Calcium Supplementation With

Coronary Artery Calcification in Rheumatoid Arthritis
Laura Geraldino-Pardilla, Shanthi Dhaduvai, Jon T. Giles, and Joan M. Bathon
Objective. To investigate the association between
oral calcium supplementation and coronary artery
calcification among rheumatoid arthritis (RA) patients
without known cardiovascular disease (CVD).
Methods. This study was conducted as a nested,
prospective cohort study of RA patients without known
CVD. The daily supplemental calcium dose was ascertained from each patients list of prescription and over-thecounter medications at baseline and at visit 2 (median 20
months postbaseline). The coronary artery calcium (CAC)
score, a measure of coronary atherosclerosis, was assessed
by cardiac multidetector row computed tomography at
baseline and at visit 3 (median 39 months postbaseline).
The association between calcium supplementation and
CAC was explored.
Results. Among the 145 RA patients studied, 42
(28%) were taking 1,000 mg/day of supplemental calcium at baseline. A CAC score of >100 units was seen in
44 patients (30%) at baseline and 50 patients (34%) at
followup. Baseline CAC scores of >100 units were significantly less frequent in patients receiving the higher dosage (1,000 mg/day) of supplemental calcium than in
those receiving the lower dosage (<1,000 mg/day) (odds
ratio [OR] 0.28, 95% confidence interval [95% CI] 0.11
0.74); this association remained significant after adjustment for relevant confounders (adjusted OR 0.30, 95% CI
0.090.93). Similarly, at the third study visit, CAC scores
of >100 units were less frequent in the higher supplemen-

tal calcium dose group compared to the lower dose group

(OR 0.41, 95% CI 0.180.95); however, after adjustment
for relevant confounders, the statistical significance of
this association was lost (adjusted OR 0.39, 95% CI 0.14
1.12). No effect of sex heterogeneity was seen in the association of calcium supplementation with coronary artery
calcification, and no change in the CAC score over time
was observed.
Conclusion. Higher levels of oral calcium supplementation were not associated with an increased risk of
coronary atherosclerosis, as measured by the CAC
score, in this RA cohort.
Despite substantial therapeutic advancements
over the past few decades, standardized mortality rates
still remain up to 3 times higher in rheumatoid arthritis
(RA) patients when compared to the general population
(1). Cardiovascular disease (CVD) is the leading cause of
premature deaths in RA (2,3). Therefore, identification
of contributing factors to this excess risk is of utmost
interest. RA poses an increased risk for the development
of accelerated atherosclerosis, myocardial infarction, and
heart failure (1,4,5), with RA itself being an independent
risk factor for the development of CVD (6).
Levels of coronary artery calcium (CAC), a noninvasive measure of coronary artery atherosclerosis, are
increased in RA patients relative to non-RA controls (7),
and CAC levels have strong predictive value in determining the risk of incident CVD events in the general population (8). Results of recent studies in the general
population have suggested an association between use of
calcium supplementation and risk of CVD (914), presumably by worsening vascular calcification. The use of calcium
supplements has been reported to increase overall
cardiovascular-related deaths by ;20% (14), with an
increased risk of myocardial infarction as high as 2231%
(1012). This raises a relevant concern in the clinical management of RA patients, to whom calcium supplements
are routinely given for osteoporosis prevention. Chronic

Supported by the NIH (National Institute of Arthritis and

Musculoskeletal and Skin Diseases grant AR-050026-01 to Dr. Bathon).
Laura Geraldino-Pardilla, MD, MSc, Shanthi Dhaduvai,
MD, Jon T. Giles, MD, MPH, Joan M. Bathon, MD: Columbia
University College of Physicians & Surgeons, New York, New York.
Drs. Geraldino-Pardilla and Dhaduvai contributed equally to
this work.
Address correspondence to Laura Geraldino-Pardilla, MD,
MSc, Division of Rheumatology, Columbia University College of
Physicians & Surgeons, 630 West 168th Street, P&S 10-445, New
York, NY 10032. E-mail: Lbg2124@columbia.edu.
Submitted for publication June 30, 2014; accepted in revised
form February 26, 2015.
1465

1466

GERALDINO-PARDILLA ET AL

systemic inflammation, glucocorticoid use, and reduced

physical activity in RA patients together contribute a 2fold increased risk of reduced bone mineral density as
compared to that in the general population (15). Therefore, calcium supplementation is widely recommended for
RA patients, to increase bone mineral density and possibly
reduce fracture risk (1618).
Besides being an integral component of the skeleton, calcium is critical for mediating vascular contraction
and vasodilatation, muscle function, nerve transmission,
intracellular signaling, and hormonal secretion (19). The
Institute of Medicine recommends an intake of at least
1,000 mg of calcium daily for individuals over the age of
18 years (20). It is estimated that $20% of adult US citizens have intakes that exceed the recommendations,
with calcium supplements serving as the main contributor to the excess (20,21). It remains unknown whether
large bolus intakes of calcium supplements contribute to
arterial calcification in patients without renal failure.
Although the Framingham Study did not find an
increase in CAC scores with high total dietary or supplementary calcium intake (22), the findings from several
large studies have suggested an association between high
intake of calcium supplementation and myocardial
infarction (1012).
The possible contribution of supplemental calcium to CAC and the risk of CVD in RA has not been
explored to date. We therefore investigated the association of calcium supplementation with CAC scores in a
cohort of RA patients without known CVD. We
hypothesized that higher intake of calcium supplements
may be associated with higher levels of CAC.
PATIENTS AND METHODS
Patients. Study participants were enrollees in the
Evaluation of Subclinical Cardiovascular Disease and Predictors of Events in Rheumatoid Arthritis (ESCAPE-RA) study,
a prospective cohort study that investigated subclinical CVD
in patients with RA, as has been previously described in
detail (7). All participants were ages 4584 years, met the
American College of Rheumatology 1987 classification criteria for RA (23), and had a duration of RA of $6 months.
Exclusion criteria were as follows: known CVD at baseline
(defined as self-reported, physician-diagnosed myocardial
infarction, heart failure, coronary artery revascularization,
angioplasty, peripheral vascular disease, implanted pacemaker or defibrillator devices, and/or current atrial fibrillation), weight exceeding 300 pounds (limit required because of
imaging equipment restrictions), and underwent computed
tomography (CT) scanning of the chest within 6 months prior
to enrollment (allowing us to limit radiation exposure).
A total of 145 patients had complete longitudinal data
on calcium supplementation use, obtained at baseline and at
visit 2 (median time from baseline 20 months), and had 2 car-

diac CT scans, the first obtained at baseline and another

obtained at visit 3 (median time from baseline 39 months).
Patients were recruited from the Johns Hopkins Arthritis
Center or recruited by referral from community rheumatologists. The study was approved by the Johns Hopkins Hospital,
with all participants providing written informed consent prior
to enrollment (October 2004 through May 2006).
Assessment of coronary artery calcification as the
primary outcome. All participants underwent cardiac multidetector row CT scanning, as previously described (7). CAC
was quantified using the Agatston method (24). All scans
were transmitted to a central CT reading center for interpretation. We observed a high intraobserver agreement between
CT scans (k 5 0.93) and a high interobserver agreement
between CT assessors (k 5 0.90) with regard to CAC scores
(7). The primary outcome was the CAC score at baseline and
at the third visit (median time from baseline 39 months).
CAC was dichotomized using an Agatston score of 100 units
as the cutoff value, since a CAC score of .100 units has been
validated as a strong predictor of future cardiovascular clinical events (8).
Assessment of covariates. Calcium supplementation
assessment. Data on the use of calcium supplements were
derived from each patients medication list, which was ascertained from the prescription and nonprescription bottles
brought by the patients to the first and second study visits.
Based on the common use of the Institute of Medicine
recommendations for minimum daily intake of calcium
($1,000 mg) and the study by Xiao et al demonstrating an
increased risk of CVD events among patients taking
.1,000 mg of supplemental calcium daily (14), we dichotomized the average daily calcium supplement doses as ,1,000 mg
and $1,000 mg.
Sociodemographic covariates. Information on demographics, physical activity, and education was self-reported and
collected from standardized study questionnaires. The body
mass index (BMI) was calculated as weight (in kg) divided
by height (in m2).
Cardiovascular risk factors. Resting blood pressure
(BP), obtained while the patient was seated, was measured
3 times, and the mean value of the last 2 measurements
was used in the analyses. Hypertension was defined as a
systolic BP of $140 mm Hg, a diastolic BP of $90 mm Hg,
or use of antihypertensive medications. Diabetes was
defined as a fasting serum glucose level of $126 mg/dl or
use of diabetes medications. Smoking history was assessed
by self-report.
RA-specific covariates. The duration of RA was calculated based on self-reported duration of disease from the time
of diagnosis by a physician. RA activity was calculated using
the Disease Activity Score in 28 joints with C-reactive protein
(CRP) level (25). Current and past use of glucocorticoids, biologic and nonbiologic disease-modifying antirheumatic drugs
(DMARDs), and bisphosphonates were ascertained by chart
review and patient interview.
Laboratory covariates. Levels of high-sensitivity CRP
and interleukin-6 were measured as previously described (26).
Levels of plasma lipids and glucose were measured by standard
assays; low-density lipoprotein cholesterol was estimated using
the Friedewald equation. Presence of rheumatoid factor (RF)
was assessed by enzyme-linked immunosorbent assay (ELISA),
with seropositivity set at $40 ELISA units. Presence of anti

CALCIUM AND CAC ASSOCIATION IN RA

Table 1.

1467

Characteristics of the patients at baseline (n 5 145)*

Demographics
Age, mean 6 SD years
Female, no. (%)
White, no. (%)
Education (college or higher), no. (%)
RA characteristics
Disease duration, median (IQR) years
DAS28-CRP, mean 6 SD
RF or anti-CCP positivity, no. (%)
IL-6, median (IQR) pg/ml
CRP, median (IQR) mg/liter
HAQ score, median (IQR) (scale 03)
Nonbiologic DMARD use, no. (%)
Biologic DMARD use, no. (%)
Current
Ever
Glucocorticoid use, no. (%)
Current
Ever
Cumulative prednisone dose, median (IQR) gm
Cardiovascular risk factors
Diabetes, no. (%)
Systolic blood pressure, mean 6 SD mm Hg
Diastolic blood pressure, mean 6 SD mm Hg
Antihypertensive use, no. (%)
Total cholesterol, mean 6 SD mg/dl
LDL cholesterol, mean 6 SD mg/dl
HDL cholesterol, mean 6 SD mg/dl
Triglycerides, median (IQR) mg/dl
Lipid medication use, no. (%)
NSAID use, no. (%)
Ever or current smoking, no. (%)
Body mass index, mean 6 SD kg/m2
Physical activity measures
Exercise time, median (IQR) minutes/day
Television watching time, median (IQR) minutes/day
Bisphosphonate use, no. (%)
Calcium dosage, median (IQR) mg/day

Calcium $1,000 mg/day

(n 5 42)

Calcium ,1,000 mg/day

(n 5 103)

60 6 8
34 (81)
34 (81)
37 (88)

59 6 8
55 (53)
93 (90)
76 (74)

0.64
0.002
0.12
0.06

9 (417)
3.7 6 0.8
31 (74)
4.2 (1.88.1)
2.5 (1.08.2)
0.75 (0.121.25)
38 (90)

8 (415)
3.5 6 1.1
74 (72)
3.1 (1.45.9)
2.1 (1.05.3)
0.62 (01.25)
91 (89)

0.57
0.40
0.81
0.22
0.38
0.38
1.0

23 (55)
27 (64)

39 (38)
45 (44)

0.07
0.03

17 (40)
33 (88)
4.8 (0.913.1)

34 (33)
76 (74)
2.7 (07.8)

0.39
0.06
0.08

3 (7)
128 6 19
74 6 8
17 (40)
197 6 36
118 6 31
56 6 17
95 (60145)
5 (12)
32 (78)
24 (57)
28 6 6

6 (6)
125 6 16
76 6 9
42 (41)
197 6 42
117 6 32
55 6 21
104 (75141)
19 (18)
65 (62)
59 (57)
28 6 5

0.72
0.44
0.30
0.97
0.94
0.88
0.83
0.52
0.34
0.13
0.99
0.92

34 (9494)
120 (111180)
16 (38)
1,200 (1,2001,500)

29 (7381)
120 (120180)
22 (21)
0 (0500)

0.70
0.30
0.04
,0.0001

* P values less than or equal to 0.05 were considered significant. RA 5 rheumatoid arthritis; IQR 5 interquartile range; DAS28-CRP 5 Disease
Activity Score in 28 joints with C-reactive protein level; RF 5 rheumatoid factor; anti-CCP 5 anticyclic citrullinated peptide; IL-6 5 interleukin6; HAQ 5 Health Assessment Questionnaire; DMARD 5 disease-modifying antirheumatic drug; LDL 5 low-density lipoprotein; HDL 5 highdensity lipoprotein; NSAID 5 nonsteroidal antiinflammatory drug.
Diabetes was defined as a fasting serum glucose level of $126 mg/dl or use of diabetes medications.

cyclic citrullinated peptide (anti-CCP) antibodies was assessed

by ELISA, with seropositivity defined as $60 units.
Statistical analysis. Baseline characteristics and clinical data were summarized as the mean 6 SD for normally
distributed continuous variables, and as the median (interquartile range) for nonnormally distributed continuous variables, and comparisons between groups were made using
Students t-test and Wilcoxons rank sum test, respectively.
Counts and percentages were calculated for categorical variables and compared using the chi-square or Fishers exact test,
as appropriate. The daily doses of calcium supplements being
taken by the patients at baseline and the second study
visit were averaged and dichotomized as ,1,000 mg and
$1,000 mg. Correspondingly, CAC scores from baseline
and the third study visit were dichotomized as #100 units and
.100 units. The association between the average daily intake

of calcium supplementation (in mg/day) with the CAC score

was assessed using ordinal logistic regression. Subsequently,
multivariable logistic regression models were constructed to
adjust for potential relevant confounders. Goodness of fit was
evaluated using the Hosmer and Lemeshow goodness-of-fit
test. In all tests, P values less than or equal to 0.05 were considered significant. Statistical calculations were performed
using SAS software (version 9.4; SAS Institute).

RESULTS
Characteristics of the study participants. In
total, 145 RA patients for whom complete longitudinal
data were available were studied, and 71 patients
(49%) were taking calcium supplementation. Forty-two

1468

Figure 1. Association of daily supplemental calcium dose

($1,000 mg versus ,1,000 mg) with coronary artery calcification,
measured as a coronary artery calcium (CAC) score of .100 units, at
baseline (A) and the third study visit (B), in crude analyses and analyses adjusted for sex, age, body mass index, presence of hypertension,
and bisphosphonate use. Bars show the mean percentage of patients
and the 95% confidence interval (95% CI). A, At baseline, crude
odds ratio (OR) 0.28 (95% CI 0.110.74) and adjusted OR 0.30 (95%
CI 0.090.93) (P 5 0.09 by Hosmer-Lemeshow test). B, At third visit,
crude OR 0.41 (95% CI 0.180.95) and adjusted OR 0.39 (95% CI
0.141.12) (P 5 0.21 by Hosmer-Lemeshow test).

patients (29%) were taking an average calcium supplement dose of at least 1,000 mg daily (median daily dose
1,200 mg), while 103 patients (71%) were taking

GERALDINO-PARDILLA ET AL

,1,000 mg daily (median daily dose 0 mg). The baseline characteristics of the participants in each group
are summarized in Table 1. In the higher calcium supplement dose group, significantly larger proportions of
patients were female, and significantly more patients
had ever been treated with biologic DMARDs or were
currently receiving bisphosphonates, as compared to
patients in the lower dose group. Physical activity
measures did not differ between the calcium dose
groups. Similarly, cardiovascular risk factors and RA
disease activity and disease severity measures were similar between the 2 groups.
Association of calcium supplementation with a
lower frequency of moderate-to-severe coronary calcification. Associations between the daily dose of calcium
supplementation and the CAC score are depicted in
Figure 1. A CAC score of .100 units was observed in 44
patients (30%) at baseline and 50 patients (34%) at followup. At baseline, CAC scores of .100 units were significantly less frequent in patients receiving the higher
calcium supplement dosage ($1,000 mg/day) when compared to those receiving the lower calcium supplement
dosage (,1,000 mg/day) (odds ratio [OR] 0.28, 95%
confidence interval [95% CI] 0.110.74). This association remained significant after adjustment for sex, age,
BMI, hypertension, and bisphosphonate use (OR 0.30,
95% CI 0.090.93) (Figure 1A).
Similarly, at the third study visit, CAC scores of
.100 units were significantly less frequent in the group
taking an average daily calcium supplement dose of
$1,000 mg when compared to those taking ,1,000 mg
(OR 0.41, 95% CI 0.180.95). When the analysis was
adjusted for relevant covariates, the association was no
longer statistically significant (OR 0.39, 95% CI 0.14
1.12) (Figure 1B).
Lack of sex heterogeneity in the association of
calcium supplementation with coronary artery calcification. The prevalence of a CAC score of .100 units was
higher in men when compared to women at both time
points and in both calcium supplement dose groups
(Figures 2AC). At baseline, in the crude and adjusted
analyses, 17% and 16% of women, respectively, had a
CAC score of .100 units, compared to 52% and 45% of
men, respectively (P 5 0.0001 and P 5 0.0003, respectively). Similarly, at study visit 3, the frequency of a CAC
score of .100 units was 24% among women compared to
52% among men in the crude model (P 5 0.0007), and
25% among women compared to 47% among men in the
adjusted model (P 5 0.004). Interestingly, a CAC score of
.100 units was significantly more common in men taking
,1,000 mg of calcium daily compared to those taking
$1,000 mg of calcium daily, both at baseline and at the

CALCIUM AND CAC ASSOCIATION IN RA

1469

Lack of association of calcium intake with the

change in CAC score over time. Change in CAC score
over time between the baseline and third study visits
was not significantly different between the 2 calcium
supplement dose groups (results not shown). Only 1
patient with a CAC score of .100 units at baseline had
a lower CAC score at the third visit. Otherwise, 98% of
patients with a CAC score of .100 units at baseline
had persistently elevated CAC scores (.100 units) at
visit 3. Among patients receiving the lower dosage of
calcium (,1,000 mg/day) and having a baseline CAC
score of #100 units, 6% had a CAC score of .100
units at the third followup visit, while among patients
receiving the higher dosage of calcium ($1,000 mg/
day) and having a baseline CAC score of #100 units,
8% had a CAC score of .100 units at the third followup visit (P 5 0.7 between dose groups).
Lack of differences in the associations of calcium supplementation with CAC scores according to
strata of other patient characteristics. No associations
were found between the daily dose of calcium supplementation and a CAC score of .100 units according to
the level of education, bisphosphonate use, presence of
moderate-to-severe RA, or RF/anti-CCP antibody status
at baseline or visit 3 (Tables 2 and 3). Similarly, the association between calcium supplementation and CAC
score did not vary according to categories of these variables (P . 0.05 for all interaction terms, both at baseline
and at the third study visit).

DISCUSSION

Figure 2. Association of daily supplemental calcium dose ($1,000 mg

versus ,1,000 mg) with coronary artery calcification, measured as a
coronary artery calcium (CAC) score of .100 units, stratified by sex in
crude analyses and analyses adjusted for sex, age, body mass index,
presence of hypertension, and bisphosphonate use. Bars show the
mean percentage of patients and the 95% confidence interval among
women at baseline (A) and the third study visit (B), and among men at
the third study visit (C).

third study visit (Figure 2C). Nonetheless, no interaction

between the calcium supplement dose and sex was
observed at baseline (interaction term P 5 0.5) or at the
third study visit (interaction term P 5 0.3).

To our knowledge, this is the first study to explore

the association of oral calcium supplementation with coronary artery atherosclerosis in RA patients. Contrary to
our hypothesis, we found that both at baseline and at the
third study visit ;3 years later, CAC scores of .100 units
were significantly less frequent in the higher calcium
supplement dosage group ($1,000 mg/day) when compared to the lower calcium supplement dosage group
(,1,000 mg/day). After adjusting for pertinent covariates,
this inverse association remained statistically significant
at baseline, but not at study visit 3.
In addition to improving skeletal bone mineral
density, calcium supplementation has been associated
with a modest decrease in blood pressure (27) and an
increase in the ratio of high-density lipoprotein cholesterol to low-density lipoprotein cholesterol of almost 20%
in healthy postmenopausal women (28). Forty-three percent of the US population and up to 70% of elderly
women take dietary supplements containing calcium, with

1470

GERALDINO-PARDILLA ET AL

Table 2. Associations of calcium supplementation dose with a CAC score of .100 units according to
strata of other patient and disease characteristics at baseline*
Calcium
$1,000 mg/day
Sex
Male
Female
Bisphosphonates
Use
Nonuse
Education
College or higher
Less than college
DAS28-CRP
Score .3.2
Score #3.2
RF and/or anti-CCP
Positive
Negative

Calcium
,1,000 mg/day

P for interaction
term with calcium dose

2 (25)
4 (12)

0.3

11 (20)
27 (56)

0.0001

0.5

3 (19)
3 (11)

0.6

6 (27)
32 (39)

0.3

0.3

6 (16)
0 (0)

1.0

27 (35)
11 (41)

0.6

0.3

4 (12)
2 (20)

0.6

21 (36)
17 (39)

0.7

0.7

5 (16)
1 (9)

0.6

31 (42)
7 (24)

0.09

0.9

* Values are the number (%) of patients with a coronary artery calcium (CAC) score of .100 units in
the 2 calcium supplementation dose categories, analyzed per strata of sex, bisphosphonate use, education level, rheumatoid arthritis disease activity measured using the Disease Activity Score in 28 joints
with C-reactive protein level (DAS28-CRP), and rheumatoid factor (RF) and/or anticyclic citrullinated
peptide (anti-CCP) antibody positivity at baseline. P values for all interaction terms are .0.05, indicating that there is no interaction between the different patient and disease characteristics and calcium
supplementation.

.20% of the population reported to be taking doses that

exceed the national recommendations (20,21).
However, several prospective studies in non-RA
populations investigating the effects of supplemental
calcium on the development of CVD have raised concerns with regard to an increased risk of CVD (914),

especially in the incidence of myocardial infarction. In

contrast, other studies have demonstrated no effect of
calcium supplementation on the rates of CVD (22,
2932). No randomized clinical trial has been conducted to test this association as the primary end
point. Most available data are derived from secondary

Table 3. Associations of calcium supplementation dose with a CAC score of .100 units according to
strata of other patient and disease characteristics at the third visit*
Calcium
$1,000 mg/day
Sex
Male
Female
Bisphosphonates
Use
Nonuse
Education
College or higher
Less than college
DAS28-CRP
Score .3.2
Score #3.2
RF and/or anti-CCP
Positive
Negative

Calcium
,1,000 mg/day

P for interaction
term with calcium dose

2 (25)
7 (21)

1.0

27 (56)
14 (25)

0.001

0.3

4 (25)
5 (19)

0.7

8 (36)
33 (41)

0.7

0.6

7 (19)
2 (40)

0.3

31 (41)
10 (37)

0.7

0.3

6 (19)
3 (30)

0.7

23 (39)
18 (41)

0.8

0.6

6 (19)
3 (27)

0.7

32 (43)
9 (31)

0.2

0.3

* Values are the number (%) of patients with a coronary artery calcium (CAC) score of .100 units in
the 2 calcium supplementation dose categories, analyzed per strata of sex, bisphosphonate use, education level, rheumatoid arthritis disease activity measured by the Disease Activity Score in 28 joints with
C-reactive protein level (DAS28-CRP), and rheumatoid factor (RF) and/or anticyclic citrullinated
peptide (anti-CCP) antibody positivity at the third study visit. P values for all interaction terms are
.0.05, indicating that there is no interaction between the different patient and disease characteristics
and calcium supplementation.

CALCIUM AND CAC ASSOCIATION IN RA

analyses of cohort studies in elderly, postmenopausal

women, in whom chronic kidney disease and vascular
calcification are more prevalent (33). Nonetheless, this
is of potential concern for RA patients, in whom a
higher prevalence of coronary artery calcification and
higher incidence rates of CV events, including fatal
and nonfatal myocardial infarctions, have been reported when compared to age- and sex-matched controls (7,34).
Calcium supplementation has been speculated
to increase CVD risk by prompting transient increases
in the serum levels of calcium, thus exerting direct
effects on arterial stiffness, influencing extracellular
calcium-sensing receptors in arterial endothelial cells,
inducing hypercoagulable states (35,36), and facilitating
the deposition of calcium in the arterial walls (37). A
direct relationship between vascular calcification and
low bone mineral density has been demonstrated in
epidemiologic studies (3840). The pathophysiology of
vascular calcification is now understood to resemble
osteogenesis and bone mineralization, with chronic
inflammation as a suggested risk factor. Interestingly,
contrary to the observed effects of supplemental calcium, dietary calcium intakes have been shown to be
protective against cardiovascular events in large prospective trials (4143).
Similar to our results, studies in the general
population that have specifically assessed CAC have
failed to show an association between high intake of
calcium supplements and Agatston scores (22,29,32),
both in the Framingham observational cohort (22) and
in randomized placebo-controlled trials (29,32).
Although individuals who take dietary supplements tend to have a healthier lifestyle and lower risk
profile for CVD (44), our study patients in both calcium dose groups had similar physical activity levels as
well as CVD risk factors. In addition, the possibility of
a protective cardiovascular effect with the use of
bisphosphonates has been proposed (45), and more
patients in the higher calcium supplement dose group
were taking bisphosphonates when compared to the
lower calcium supplement dose group. However, we
found no association between the use of bisphosphonates and CAC scores; furthermore, no interaction
between the use of bisphosphonates and the calcium
dose categories was observed.
Our study has notable strengths. The ESCAPERA cohort, created to define the prevalence, incidence,
and risk factors of subclinical atherosclerosis in RA (7),
is a unique resource, in that the participants were phenotyped with regard to measures of CV risk and subclinical atherosclerosis, as well as RA disease activity,

1471

RA severity, and physical activity levels. This allowed

for adjustment for most variables that could be deemed
potentially important to our outcome of interest.
Limitations of our study include the absence of
information on duration of calcium supplementation
use prior to the baseline visit; therefore, the potential
benefit of high doses of calcium supplementation
beyond 39 months is unclear. Similarly, we did not
measure dietary calcium or serum calcium levels, which
might have impacted the CAC scores (4143,46).
Because the vitamin D supplementation dose was not
collected, we cannot infer whether vitamin D intake
would have impacted the outcome. However, prior
studies have suggested that coadministration of vitamin
D does not appear to alter the association of calcium
supplementation with an increased risk of myocardial
infarction (11). Although the association between calcium supplement intake and lower CAC scores at the
third study visit lost statistical significance in our
adjusted analyses, it is possible that the sample size was
too small to detect a difference between the groups.
Finally, because the ESCAPE-RA cohort was predominantly white, the results may not be generalizable to
other racial and ethnic groups.
In conclusion, the pathophysiology of, and contributing factors to, coronary artery atherosclerosis and
CVD in RA remain poorly understood. However, our
study suggests that calcium supplementation at dosages
of $1,000 mg/day was not associated with a higher risk
of CAC, a measure of coronary atherosclerosis. Further
studies in larger and more diverse RA cohorts are
warranted.

AUTHOR CONTRIBUTIONS
All authors were involved in drafting the article or revising it
critically for important intellectual content, and all authors approved
the final version to be published. Dr. Geraldino-Pardilla had full
access to all of the data in the study and takes responsibility for the
integrity of the data and the accuracy of the data analysis.
Study conception and design. Geraldino-Pardilla, Dhaduvai, Giles,
Bathon.
Acquisition of data. Geraldino-Pardilla, Dhaduvai, Giles, Bathon.
Analysis and interpretation of data. Geraldino-Pardilla, Dhaduvai,
Giles, Bathon.

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