Calcium conundrum: What doesn’t kill you makes you stronger?
Evaluation of calcium supplementation on cardiovascular events in postmenopausal women
Isabel Elizabeth Cwikla, PharmD
PGY-1 Pharmacy Resident South Texas Veterans Health Care System
Division of Pharmacotherapy, The University of Texas at Austin College of Pharmacy Pharmacotherapy Education and Research Center, University of Texas Health San Antonio
San Antonio, Texas
February 8, 2019
Objectives
1) Explain physiological changes that occur during menopause and identify the importance of adequatecalcium intake in postmenopausal women
2) Describe potential cardiovascular benefits and risks of calcium supplementation3) Analyze primary literature findings concerning calcium supplementation and cardiovascular safety4) Formulate evidence-based recommendations regarding cardiovascular outcomes associated with
calcium supplementation in postmenopausal women
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I. Menopause1-2
1) Permanent cessation of menses following loss of ovarian follicular activity a) Diagnosed retrospectively upon absence of menses for ≥ 12 months
i) Natural: Part of normal aging process, occurs between 40-58 years old ii) Early: Occurs between 40-45 years old iii) Premature: Induced or precipitated by primary ovarian insufficiency in women < 40 years old
(1) Induced: Bilateral oophorectomy, pelvic radiation, chemotherapy b) Average age of onset in the United States is 52 years old c) By 2025, number of postmenopausal women expected to be ~1.1 billion globally
2) Perimenopause a) Transitional stage immediately preceding menopause b) Characterized by menstrual cycle irregularities and menopausal symptoms c) Lasts 4-8 years, ends one year after final menstrual period (FMP)
3) Pathophysiology a) Menstrual cycle reliant on hypothalamic-pituitary-ovarian axis
(see Figure 1) i) Gonadotropin-releasing hormone (GnRH) stimulates
secretion of follicle-stimulating hormone (FSH) and luteinizing hormone (LH)
ii) Ovarian oocytes produce estradiol and progesterone (1) High estradiol levels suppress FSH and stimulate LH (2) High progesterone levels suppress FSH and LH
iii) Hormonal changes during perimenopause (see Figure 2) (1) Number of ovarian follicles decreases with age (2) Estradiol decreases with follicular cell deterioration (3) Decreased feedback of inhibin and estradiol increases
FSH and LH to stimulate estradiol secretion (4) Menses stop when estradiol levels insufficient to stimulate endometrial proliferation
(a) Results in anovulation, cessation of ovarian estradiol production, and amenorrhea
4) Diagnosis a) No predictive or confirmatory test for perimenopause or menopause
i) Hormonal tests to determine menopause status not indicated (1) FSH concentrations vary during menopause transition, therefore not diagnostic (2) Salivary and urinary hormone tests are expensive and inaccurate
Figure 2. Hormonal fluctuations during menopause https://www.34-menopause-symptoms.com/loss-libido.htm
• FSH o Premenopause: < 10 IU/L o Menopausal transition: ≥ 20 IU/L o Postmenopause: > 30 IU/L
• Estrogen o Decreases by 40-50% between 35-60 years old
• Progesterone o Decreases by 99% between 35-60 years old
Figure 1. Hypothalamic-
pituitary-ovarian axis https://www.researchgate.net/figure/Main-characteristics-of-the-
hypothalamic-pituitary-ovarian-axis-in-female-pigs_fig1_222654045
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ii) Symptomatic changes due to hormonal deficiencies used to diagnose menopause transition
Table 1. Symptoms associated with menopause 1-2
Vasomotor symptoms Non-vasomotor symptoms
• Hot flashes • Night sweats
• Genitourinary syndrome of menopause o Vulvovaginal atrophy (vaginal dryness, discomfort, itching, decreased
libido, dyspareunia) o Lower urinary tract symptoms (urinary frequency, urgency, dysuria)
• Anxiety • Mood changes • Sleep disturbances • Sexual dysfunction
b) Natural menopause i) Stages of Reproductive Aging Workshop (STRAW) + 10 criteria (see Appendix 1)
(1) Gold standard for characterizing stages of reproductive aging c) Premature menopause
i) Primary ovarian insufficiency (1) Amenorrhea ≥ 4 months (2) Estrogen and progesterone deficiency (3) FSH > 20 IU/L on ≥ 2 occasions at least one month apart
(a) Invalid with concomitant use of hormone therapy ii) Chemotherapy-induced
(1) Amenorrhea does not indicate menopause (2) Postmenopausal status confirmed by FSH and/or estradiol levels
5) Physiological changes during menopause a) Increased atherosclerosis risk due to loss of estrogen’s antioxidant effect attributed to higher
level of oxidized low-density lipoprotein cholesterol or angiotensin receptor overexpression i) Cardiovascular disease (CVD) is leading cause of death in women globally ii) Major CVD risk factors in women
(1) Age, hypertension, dyslipidemia, diabetes mellitus, family history of premature CVD, smoking, sedentary lifestyle, poor diet, and history of pregnancy complicated by preeclampsia, gestational diabetes, or hypertension
b) Mediated by estrogen deficiency i) Vaginal atrophy ii) Accelerated bone remodeling 3-4
(1) Bone breakdown exceeds bone formation, increasing osteoporosis risk 5 (a) Bone loss most rapid toward beginning of menopause, then continues at slower rate
6-7 years after menopause 6 iii) Decreased absorption of calcium and increased urinary excretion of calcium 7
(1) Sustained suboptimal calcium intake in later stages of menopause contributes to secondary hyperparathyroidism, which accelerates bone resorption 5
(2) Hypocalcemia may be exacerbated by medical conditions or medications 8-9 (a) Hypoparathyroidism, achlorhydria, chronic diarrhea, vitamin D deficiency, vitamin K2
deficiency, steatorrhea, sprue, pregnancy and lactation, menopause, pancreatitis, chronic renal failure, alkalosis, hyperphosphatemia, inflammatory bowel disease, celiac disease
(b) Long-term use of systemic corticosteroids, heparin, phenytoin, levothyroxine, methotrexate, cyclosporine, warfarin, thiazide diuretics, or GnRH may inhibit or decrease calcium absorption
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II. Calcium
1) Most abundant mineral in human body 5,10 a) 99% of total body calcium stored in bones and teeth as calcium hydroxyapatite
i) Directly involved in bone remodeling through continuous bone resorption and formation ii) Skeleton serves as reservoir for other essential calcium-dependent functions
b) < 1% of total body calcium supports critical metabolic functions i) Critical roles in circulatory system, extracellular fluid, muscle, and other tissues by mediating
vascular contraction and vasodilatation, muscle function, nerve transmission, intracellular signaling, and hormone secretion
2) Calcium homeostasis
Table 2. Calcium reference range 11
Serum calcium 8.5-10.5 mg/dL Corrected total calcium (mg/dL) Serum calcium (mg/dL) + 0.8 [4 - Serum albumin (g/dL)]
a) Serum calcium tightly regulated by the endocrine system through homeostatic feedback loops mediated by parathyroid hormone (PTH) and calcitonin 5,8
Figure 3. Calcium feedback loops
http://fig.cox.miami.edu/~cmallery/150/physiol/physiology.htm
3) Optimal calcium intake a) On average, Americans consume 750-900 mg/day calcium through diet 8
i) Average dietary calcium intake in adults > 50 years old is 600-700 mg/day 10 b) Guideline recommendations 5,10,12-14
Table 3. Calcium intake recommendations 5,12
Males Females
Age RDA (mg)* UL (mg)** RDA (mg) UL (mg)
0-6 months 200 1,000 200 1,000 7-12 months 260 1,500 260 1,500 1-3 years 700 2,500 700 2,500 4-8 years 1,000 2,500 1,000 2,500 9-18 years 1,300 3,000 1,300 3,000 19-50 years 1,000 2,500 1,000 2,500 51-70 years 1,000 2,000 1,200 2,000 > 71 years 1,200 2,000 1,200 2,000
*Recommended Dietary Allowance (RDA): Average daily intake sufficient to meet requirements of nearly all healthy individuals **Tolerable Upper Intake Level (UL): Maximum daily intake unlikely to cause adverse health effects
• Overall calcium balance maintained at skeletal level through opposing actions of osteoblasts and osteoclasts 5
• 40% ionized, 60% bound to albumin 8 • Serum calcium must be corrected if
albumin stores low (see Table 2) 11
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i) American Association of Clinical Endocrinologists/American College of Endocrinology (AACE/ACE), National Osteoporosis Foundation (NOF), and Institute of Medicine (IOM) guidelines in mutual agreement with recommendations for women > 51 years old
ii) Per NOF and American Society for Preventive Cardiology, dietary and supplemental calcium intake < 2,000-2,500 mg/day is safe from cardiovascular standpoint
iii) U.S. Preventive Services Task Force (USPSTF) recommends against daily supplementation with ≤ 1,000 mg calcium for primary prevention of fractures in non-institutionalized postmenopausal women on basis of evidence of no net benefit
4) Role of vitamin D a) Major role in calcium absorption, bone health, and neuromuscular function 5,10 b) Monitoring via 25-hydroxyvitamin D [25(OH)D] level 11
i) Deficiency: < 20 ng/dL ii) Insufficiency: 20-30 ng/dL iii) Goal: > 30 ng/dL
(1) 30-50 ng/dL for postmenopausal osteoporosis 12 c) Guidelines differ on vitamin D intake recommendations
Table 4. Vitamin D intake recommendations 5,10,12,14 Guideline Recommendation
IOM (2011) < 70 years = 600 IU daily > 70 years = 800 IU daily Safe upper limit = 4,000 IU daily
NOF (2014) < 50 years = 400-800 IU daily > 50 years = 800-1,000 IU daily
AACE/ACE (2016) Only supplement if necessary Supplementation preferred due to limited dietary sources Monitor if supplementing > 2,000 IU/day
USPSTF (2018) Recommends against daily supplementation with ≤ 400 IU vitamin D3 for primary prevention of fractures in non-institutionalized postmenopausal women on basis of evidence of no net benefit
5) Dietary sources (see Appendix 2) 5,8,10,12 a) First-line approach to increasing calcium levels, preferred over supplementation
i) ~30% absorbed from dairy and fortified foods, ~60% absorbed from dark green leafy vegetables 6) Supplementation
a) As of 2000, dietary supplements used by ~50% adults in the United States 15 i) > 60% of middle-aged and older women in the US use calcium supplements regularly 16
b) Indicated when adequate recommended dietary intake cannot be achieved 10 i) Not all calcium salt forms acceptable for supplementation (see Appendix 3)
c) RDA recommendations refer to amount of elemental calcium
Table 5. Calcium salts used for supplementation 8-9,11,17
Formulation Elemental calcium by weight
Calcium carbonate 40% Calcium citrate 21% Calcium glubionate 6.5% Calcium lactate 13%
i) Do not exceed 500-600 mg per dose for optimal absorption 12 ii) Concurrent use of some medications requires dose separation 11
(1) Levothyroxine, cations, specific antibiotics
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III. Health implications of calcium supplementation
1) Benefits of supplementation a) Maintenance of bone density
i) > 54% of older men and > 64% of older women take calcium supplements to prevent osteoporosis and bone fractures 18
b) Cardiovascular effects i) Decreased cholesterol levels 19-21
(1) Decreased fat absorption mediated by intestinal binding with fatty acids and bile acids (2) Increased ratio of high density lipoprotein cholesterol to low density lipoprotein
cholesterol by almost 20% in healthy postmenopausal women ii) Decreased blood pressure 22-27
(1) Downregulation of renin-angiotensin-aldosterone system and improved sodium-potassium balance
(2) Per meta-analysis, long-term calcium supplementation reduced systolic blood pressure by 2.63 mmHg and diastolic blood pressure by 1.30 mmHg
iii) Anthithrombotic effects 28 (1) Inhibition of platelet aggregation and prevention of intravascular thrombosis
iv) Vasorelaxation 29 (1) Promotes opening of calcium-activated potassium channels, which increases sensitivity
to nitric oxide and decreases superoxide production 2) Risks of supplementation
a) Gastrointestinal effects 11 i) Constipation, bloating, flatulence
b) Renal effects i) Nephrolithiasis 30
(1) Per Women’s Health Initiative (WHI) trial, 17% increased risk of kidney stones in postmenopausal women taking 1,000 mg calcium and vitamin D vs. placebo
c) Cardiovascular effects i) Myocardial infarction (MI)
(1) Meta-analysis including 15 trials with > 500 mg/day calcium supplementation, mean age > 40 years old, and study duration > 1 year found 27% increased risk of MI 31
(2) Reanalysis of WHI calcium and vitamin D study limited access dataset and incorporation in meta-analysis with eight other studies evaluating postmenopausal women found 24% increased risk of MI 32
ii) Vascular and valvular calcification (1) Coronary artery calcification (CAC) strongly related to atherosclerosis and predictive for
future cardiac events 33-34 (a) Established risk factor for CVD 35
(2) Age and gender dependent prevalence 36-37 (a) Affects 67% of women and 90% of men > 70 years old
(3) Organized, regulated processes similar to bone formation and remodeling 35,38-39 (a) Mechanism not fully identified despite multiple existing theories 40
(i) Imbalance between calcium and phosphate distribution (ii) Induction of bone formation via vascular bone and cartilage-like cells (iii) Apoptic body presence, circulating nucleational complexes, and loss of inhibitions
(b) Leads to decreased vascular compliance, abnormal vasomotor responses, and impaired myocardial perfusion 41-42
(c) Potentiates atherosclerosis and increases risk of coronary events 43-44
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(4) Conflicting findings in literature (a) High serum calcium levels linked to CAC 44
(i) Potential association between supplementation and cardiovascular events (b) Calcium supplementation associated with 22% increased risk for incident CAC 45 (c) In systematic reviews and meta-analyses, calcium intake showed no significant
adverse or beneficial effect on vascular calcification and cardiovascular endpoints 46 (d) Calcium intake not associated with increased CAC in Framingham Offspring study,
with findings similar for dietary and supplement intake 47 (e) Substudy of WHI calcium and vitamin D trial found no difference in CAC scores after
7 years in women receiving 1,000 mg elemental calcium + vitamin D3 400 IU daily vs. placebo 48
IV. Clinical question
Does calcium supplementation increase cardiovascular events in postmenopausal women? 1) Several observational studies investigating association between dietary calcium +/- vitamin D and
CVD mortality, coronary heart disease (CHD) mortality, and stroke in postmenopausal women report inconsistent results (see Appendix 4) 15-16, 49-58 a) More studies found no association between dietary calcium intake and CVD risk b) Secondary analyses of multiple trials report mixed results regarding CVD events
2) Initial concern regarding increased cardiovascular risk associated with calcium supplementation originally raised by Auckland Calcium Study (see Table 6) a) Two-fold increase in MI risk in postmenopausal women taking calcium supplements vs. placebo
3) Controversy intensified with publication of additional studies suggesting calcium supplementation increases CVD risk 31-32 a) Potential limitations
i) Post-hoc analyses of randomized controlled trials (RCTs) not designed to evaluate effects of calcium supplements on CVD
ii) Small number of reported CVD events iii) Most CVD events not adjudicated iv) Most individual trials within meta-analyses did not report significant difference in CVD
events between the calcium and placebo groups v) Use of published and unpublished data vi) Non-adherence to study protocols by study participants vii) Lack of covariate information for many participants
Table 6. Bolland MJ, Barber PA, Doughty RN, et al. Vascular events in healthy older women receiving calcium
supplementation: randomized controlled trial. BMJ. 2008;336:262-266.
Objective • Determine effect of calcium supplementation on myocardial infarction (MI), stroke, and sudden death in
healthy postmenopausal women Methods
Study Design • Secondary analysis of randomized, placebo controlled trial conducted in urban academic medical center
in New Zealand
Patient
Population
Inclusion criteria:
• Women > 55 years old • Postmenopausal > 5 years • Life expectancy > 5 years
Exclusion criteria:
• Active treatment for osteoporosis or taking calcium supplements • Major ongoing disease o Hepatic, renal, or thyroid dysfunction; malignancy; metabolic
bone disease • Serum 25-hydroxyvitamin D levels < 25 nmol/L
Intervention
• Participants received 1 g elemental calcium citrate or identical placebo o 2 tablets before breakfast, 3 tablets in the evening (1 tablet = 200 mg elemental calcium)
• Validated food frequency questionnaire (FFQ) used to assess dietary calcium intake • Compliance assessed by tablet counts • Participants followed every 6 months for 5 years
Outcomes
• Adverse cardiovascular events over 5 years o Death, sudden death, MI, angina, other chest pain, stroke, transient ischemic attack (TIA), and
composite end point of MI, stroke, or sudden death
Statistical
Analysis
• Student’s t test compared groups for continuous variables • Fisher’s exact tested for number of women experiencing an event • Kaplan-Meier survival analysis compared proportion of women in each group with an event over time • Poisson regression completed to determine whether effect of treatment on number of events per
participant was independent of age and glomerular filtration rate; history of ischemic heart disease, stroke, hypertension, dyslipidemia, and diabetes; and compliance with study drug
• NNT or NNH calculated as inverse of absolute difference in event rates between groups • Significance defined as p < 0.05, all tests two-tailed • Intention-to-treat analysis for all outcomes unless otherwise specified
Results
Baseline
Characteristics
• n = 1,471 (mean age 74 years old) o Calcium supplementation group = 732, placebo group = 739 § 336 participants from calcium group and 296 participants from placebo group stopped study drug due
to “health reasons” before 5-year endpoint § 90% of participants had complete follow-up with 85% compliance rate in each 6-month period
• Baseline characteristics similar between groups o By end of 5-year follow-up, significant changes found in weight, systolic blood pressure, and high and
low density lipoprotein cholesterol levels, however these did not differ between groups
Outcomes
Potential vascular events self-reported by participants or family members
Calcium group n (# of events)
Placebo group n (# of events)
P-value RR (95% CI)
Angina 50 (88) 71 (99) 0.058 0.71 (0.50-1.01) Death 34 29 0.52 1.18 (0.73-1.92) MI 31 (45) 14 (19) 0.01 2.24 (1.20-4.17) Other chest pain 16 (18) 15 (16) 0.86 1.08 (0.54-2.16)
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Stroke 40 (52) 28 (34) 0.14 1.44 (0.90-2.31) Sudden death 4 1 0.22 4.04 (0.45-36.0) TIA 33 (42) 21 (27) 0.10 1.59 (0.93-2.72) Angina, chest pain, MI, or sudden death
87 (155) 93 (135) 0.68 0.94 (0.72-1.24)
Composite end point 69 (101) 42 (54) 0.008 1.66 (1.15-2.40)
Verified vascular events self-reported by participants or family members
Calcium group n (# of events)
Placebo group n (# of events)
P-value RR (95% CI)
MI 21 (24) 10 (10) 0.047 2.12 (1.01-4.47) Stroke 31 (34) 22 (23) 0.21 1.42 (0.83-2.43) Sudden death 3 3 1.00 1.01 (0.20-4.99) Composite end point 51 (61) 35 (36) 0.076 1.47 (0.97-2.23)
Verified vascular events self-reported by participants or family members including unreported
events from national database of hospital admissions in New Zealand
Calcium group n (# of events)
Placebo group n (# of events)
P-value RR (95% CI) Rate ratio P-value
MI 31 (36) 21 (22) 0.16 1.49 (0.86-2.57)
1.67 (0.98-2.87) 0.058
Stroke 34 (37) 25 (26) 0.23 1.37 (0.83-2.28)
1.45 (0.88-2.49) 0.15
Sudden death 3 6 0.51 0.51 (0.13-2.01)
0.51 (0.10-2.04) 0.36
Composite end point 60 (76) 50 (54) 0.32 1.21
(0.84-1.74) 1.43
(1.01-2.04) 0.043
• NNH to cause event during 5 years: MI = 44, stroke = 56, cardiovascular event = 29 Discussion
Critique
Strengths:
• Findings based off randomized, placebo controlled trial with appropriate blinding
• Use of highly bioavailable calcium supplement
• High rate of complete follow-up
Limitations:
• Post-hoc analysis of previous trial with non-CVD end points • Small sample size for study with cardiovascular end points • Limited external validity since single center study • Limited extrapolation to U.S. and non-Caucasians • High discontinuation rate and dependence on self-reports
limit validity and extrapolation of findings
Conclusions
Authors:
• Calcium supplementation in healthy postmenopausal women is associated with upward trends in cardiovascular event rates
Reviewer:
• Cardiovascular events occurring in very small subset of patients overinflate results; statistical significance decreased with additional verification of vascular events
• Study results inconclusive and do not allow for definitive conclusions due to attenuation of calcium effect through assessment of unreported events from national database
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Table 7. Lewis JR, Radavelli-Bagatini S, Rejnmark L, et al. The effects of calcium supplementation on verified coronary
heart disease hospitalization and death in postmenopausal women: a collaborative meta-analysis of randomized
controlled trials. JBMR. 2014;30(1):165-175.
Objective • Determine if calcium supplementation +/- vitamin D increases CHD risk in elderly women Methods
Study Design • Collaborative meta-analysis of randomized controlled trials comparing calcium supplementation +/-
vitamin D with placebo or no-treatment control groups
Patient
Population
Inclusion criteria:
• Randomized controlled trials where groups differed only by calcium supplementation +/- vitamin D or calcium supplementation +/- vitamin D with a factor unlikely to affect CHD
• Mean cohort age > 50 yrs
Exclusion criteria:
• Observational studies • Total calcium dose < 0.5g daily • Groups differed by factor considered to mediate CVD • Mean cohort age < 50 yrs • Study duration < 1 yr
Intervention
• 2 authors completed data collection and trial selection independently • Authors contacted investigators of eligible trials for unpublished data if necessary for study inclusion
(for studies reporting outcomes for males and females, lead investigators were contacted to provide data solely for females)
• 3 eligible trials contributed to missing data due to lack of response or refusal, accounting for 258 female participants eligible for inclusion in CHD outcome analysis and 775 female participants eligible for inclusion in all-cause mortality analysis
Outcomes
• Primary o CHD (MI, angina pectoris including acute coronary syndrome, chronic CHD) o All-cause mortality
• Secondary o MI, angina pectoris including acute coronary syndrome, chronic CHD
Statistical
Analysis
• Trial data combined using random-effects meta-analysis to calculate pooled relative risk • Significance defined as p < 0.05 for primary outcomes, all tests two tailed • Post hoc power calculations determined adequate power to detect relative risk changes in previously
reported results • Analysis of results repeated using different measures of effect size (risk ratio, odds ratio, etc.) and
different statistical models (fixed-effect and random-effects models) • Bonferroni multiple testing corrections applied for 3 tests for secondary outcomes (p < 0.0167) as well
as for 24 tests for prespecified subgroup and sensitivity tests (p < 0.002) with uncorrected p values • Heterogeneity identified by visual inspection of the forest plots, standard chi-square test with
significance level of 0.1, and I2 statistics • Publication bias assessed using funnel plots
Results
Baseline
Characteristics
• 18 randomized controlled trials (13 = published data, 5 = unpublished data) o n = 63,563
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Outcomes
Outcome Events Pooled RR (95% CI) P-value I2
CHD (5 trials) 3,390 1.02 (0.96–1.09) 0.51 0% All-cause mortality (17 trials) 4,157 0.96 (0.91-1.02) 0.18 0% MI (7 trials) 1,123 1.08 (0.93-1.25) 0.32 8% Angina pectoris and ACS (4 trials) 876 1.09 (0.95-1.24) 0.22 0% Chronic coronary heart disease (4 trials) 1,506 0.92 (0.73-1.15) 0.46 38%
Sensitivity analysis results based on type of supplementation Outcome Intervention RR (95% CI) P-value
CHD Calcium 1.15 (0.88-1.50) 0.30 Calcium + vitamin D 1.01 (0.95-1.08) 0.69
All-cause mortality Calcium 1.03 (0.88-1.21) 0.68 Calcium + vitamin D 0.95 (0.89-1.01) 0.11
MI Calcium 1.37 (0.98-1.92) 0.07 Calcium + vitamin D 1.03 (0.91-1.16) 0.65
Discussion
Critique
Strengths:
• Multifaceted control for bias • Presence of primary and secondary
outcomes verified by clinical review, hospital record, or death certificate provides stronger evidence than self-reports as is common with other studies investing cardiovascular outcomes associated with calcium
• Relative risk calculation mitigates possibility of type II error
• Low heterogeneity
Limitations:
• Included studies do not have primary endpoints designed to analyze cardiovascular outcomes
• Only 7 of 18 studies included calcium-only intervention • Calcium salts utilized in included studies not uniform,
total daily elemental calcium intake not controlled • Variability in calcium intake among studies • Reliance on correct entry of ICD-10 codes in original
studies • Main analysis did not control for vitamin D inclusion
Conclusions
Authors:
• Calcium supplementation +/- vitamin D does not increase CHD or all-cause mortality risk in elderly women
Reviewer:
• No statistically significant association between calcium +/- vitamin D supplementation and cardiac outcomes
• Despite sensitivity analysis suggesting calcium alone increases MI risk, calcium alone group made up only ~12% of analyzed patients taking calcium +/- vitamin D
• Additional studies with larger sample size and analyzing solely calcium with uniformity in supplementation warranted to better evaluate cardiovascular risks
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Table 8. Paik JM, Curhan GC, Sun Q, et al. Calcium supplement intake and risk of cardiovascular disease in women.
Osteoporos Int. 2014;25:2047-2056.
Objective • Examine independent associations between calcium supplement use and CVD risk Methods
Study Design • Prospective cohort study of Nurses’ Health Study (1984-2008)
Patient
Population
Inclusion criteria:
• Completion of 1984 dietary questionnaire
Exclusion criteria:
• CVD at baseline • Cancer at baseline • Cerebrovascular diseases due to infection, trauma, or malignancy • Silent or undetermined strokes
Intervention
• Participants followed for 24 years with calcium intake assessed every 4 years (1984, 1986, 1990, 1994, 1998, 2002, 2006) o Semi-quantitative FFQs used to assess dietary and calcium supplement intake during previous year o Participants categorized into 5 categories based on calcium supplement intake
• FFQ responses used to construct Dietary Approaches to Stop Hypertension (DASH) score, with results classified into quintiles based on intake ranking
• Outcomes confirmed via medical record review
Outcomes • Incident CHD (nonfatal or fatal MI) • Stroke (ischemic or hemorrhagic)
Statistical
Analysis
• Analysis used period-specific categories of calcium supplement intake • Mantel extension test evaluated linear trends across calcium supplement intake categories • Cox proportional hazards regression adjusted for CVD risk factors • Multivariable adjustment for age, BMI, dietary calcium, vitamin D intake, and other CVD risk factors • All p-values two tailed
Results
Baseline
Characteristics
• n = 74,245
Baseline characteristics
Calcium intake (mg/day)
n Mean age (years)
Post-menopause (%)
Dietary calcium intake (mg/day)
Supplemental calcium intake (mg/day)
0 51,623 49.6 +/- 7.2 58.3 708 +/- 251 0 1-100 11,617 48.9 +/- 7.2 57 726 +/- 239 52 +/- 34 101-500 14,699 51.8 +/- 6.8 63.4 720 +/- 247 350 +/- 152 501-1,000 4,516 52 +/- 6.6 64.3 733 +/- 265 893 +/- 170 > 1,000 1,790 52.4 +/- 6.5 67.2 730 +/- 269 1,408 +/- 209
o 4,565 CVD cases confirmed § 2,709 CHD events (2,151 nonfatal, 558 fatal) § 1,856 strokes (1,449 ischemic, 407 hemorrhagic)
• 30.5% of participants used calcium supplements at baseline, which increased to 80% by 2004 o Higher physical activity levels, lower trans fat intake, and less smoking among women who took
calcium supplements o Higher supplemental calcium intake associated with higher mean age, total vitamin D intake,
postmenopausal hormone use, self-reported hyperlipidemia, and physical activity as well as lower percentage of current smokers
o > 97.5% Caucasian across all quintiles
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Outcomes
• For calcium supplement intake > 1,000 mg/day o No independent associations between supplemental calcium and risk of incident CDH and stroke o No association between duration of calcium supplement use o No association between calcium supplement use and CVD after adjustment for menopausal status
Event RR after multivariate adjustment (95% CI) P-value for trend
Total CVD 0.82 (0.74-0.92) < 0.001 Total CHD 0.71 (0.61-0.83) < 0.001 -Nonfatal 0.77 (0.65-0.91) < 0.001 -Fatal 0.71 (0.50-1.00) 0.06 Total stroke 1.03 (0.87-1.21) 0.61 -Ischemic 0.96 (0.79-1.16) 0.22 -Hemorrhagic 1.32 (0.94-1.87) 0.24
Discussion
Critique
Strengths:
• Large sample size and large number of events allowed for sufficient analysis
• Confirmation of events via medical record review
• Assessment of calcium use enabled examination of dose-response relationship
• Assessment and inclusion of CVD risk factors as covariates
• Long-term follow-up • High follow-up rate of > 90% • Adjustment of analyses and subgroup
analyses
Limitations:
• Possibility of residual confounding and/or confounding by unknown or unmeasured factors
• Use of FFQ not fully reliable as supplementation may be incorrectly reported and assessed
• FFQs completed every 4 years, however assessed dietary and calcium supplement intake during previous year
• Calcium salts utilized and vitamin D intake by participants unknown
• Limited extrapolation to non-Caucasian women • Socioeconomic factors not included, participants may
have higher health literacy as all were registered nurses
Conclusions
Authors:
• Calcium supplement intake does not increase CVD risk in women
• Calcium supplement use inversely associated with CHD risk
Reviewer:
• Significant data gaps with calcium intake based on FFQ completion
• More consistent follow up and controlled study design warranted to better control for calcium and vitamin D intake and draw conclusions
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V. Conclusion
1) Current literature provides inconsistent and inconclusive findings i) Limitations
(1) No trials designed primarily to evaluate effect of calcium supplementation on cardiovascular outcomes (a) Increased potential for false-positive findings
(2) Observational data provides highest quality of evidence due to unethical nature of evaluating cardiovascular safety via RCT study design
(3) Outcome data heavily reliant upon self-reports, hospital codes, and death certificates (a) High possibility of misinformation and/or misclassification of cardiovascular events
2) No randomized trials performed to date focus on effects of calcium supplementation alone on cardiovascular outcomes as a primary endpoint, especially in postmenopausal women a) Existing data primarily consists of post-hoc analyses, observational prospective studies, or meta-
analyses of above b) Majority of literature includes men and women, with very limited focus on highly susceptible
postmenopausal population c) Limited literature available studying effects of calcium monotherapy without vitamin D
i) Difficult to evaluate effects of calcium monotherapy as many dietary sources also contain vitamin D
d) Unclear if concomitant administration of vitamin D, calcium dose, or type of calcium salt influences cardiovascular safety outcomes
VI. Recommendation
1) Utilize resources to evaluate estimated dietary calcium intake prior to considering calcium supplementation
2) Obtain as much calcium from dietary sources as possible, supplement only when necessary 3) Due to inconclusive findings with weak evidence in available literature, target recommended
calcium RDA of 1,200 mg upon entering menopause, not to exceed maximum of 2,500 mg daily a) No additional benefits associated with higher doses
VII. Future direction
1) No follow-up studies ongoing at present 2) More studies warranted highlighting postmenopausal women 3) For definitive guidance, randomized controlled trial warranted though potentially unethical
a) Adequately powered with high adherence and follow-up rates b) Large sample size with long-term follow-up to evaluate cardiovascular endpoints appropriately c) Control for elemental calcium and/or calcium salt formulations d) Evaluate calcium monotherapy and calcium + vitamin D to denote differences e) Appropriate cardiovascular event ascertainment
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VIII. References
1) Barnes KN, Yancey AM. PSAP 2016 Book 3 Women’s and Men’s Health. Lenexa (KS): American College of Clinical Pharmacy; 2016. Perimenopause and menopause; p. 83-105.
2) The North American Menopause Society [Internet]. Pepper Pike (OH): The North American Menopause Society; c2019 [cited 2019 Jan 13]. Available from: http://www.menopause.org/home
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Appendix 1. STRAW + 10 criteria
https://www.menopause.org/docs/default-document-library/straw10.pdf?sfvrsn=2
Appendix 2. Selected food sources of calcium
http://www.ars.usda.gov/ba/bhnrc/ndl
Appendix 3. Calcium salt formulations Table 9. Calcium product availability 11,17
Formulation PO/IV Uses Supplementation Dosing Miscellaneous Calcium acetate à25% elemental
PO • Control of hyperphosphatemia in end-stage renal disease
• N/A • Brand names: Calphron, Phoslyr • Do not provide additional calcium supplementation
Calcium carbonate à40% elemental
PO • Supplementation • Antacid • Hyperphosphatemia in CKD (off-label)
• 500-4,000 mg daily in 1-3 divided doses
• Brand names: Cal-Carb Forte, Cal-Gest, Cal-Mint, Calci-Chew, Calci-Mix, Caltrate, Florical, Maalox, Oysco, Titralac, Tums
• Highest amount of elemental calcium • Absorption is acid-dependent • Insoluble salt, must be taken with food • Most constipating • Least expensive
Calcium chloride à27% elemental
IV • Hypocalcemia • Cardiac arrest or cardiotoxicity in presence of
hyperkalemia, hypocalcemia, or hypermagnesemia • Beta-blocker overdose with shock refractory to
other measures (off-label) • Calcium channel blocker overdose (off-label)
• N/A • Routine use in cardiac arrest not recommended due to lack of improved survival
Calcium citrate à21% elemental
PO • Supplementation • 200-4,000 mg daily in 1-3 divided doses
• Brand names: Cal-Citrate, Calcitrate • Absorption is NOT acid-dependent o Preferred in patients taking PPIs or H2RAs
• Soluble salt, improved absorption if taken without meals Calcium glubionate à6.5% elemental
PO • Supplementation • 15 mL TID • Pregnant/lactating: 15
mL QID
• Brand names: Calcionate • Available as syrup for children
Calcium gluconate à9% elemental
PO IV
• Hypocalcemia • Cardiac arrest or cardiotoxicity in presence of
hyperkalemia, hypocalcemia, or hypermagnesemia • Parenteral nutrition, maintenance requirement • Beta-blocker overdose (off-label) • Calcium channel blocker overdose (off-label) • Treatment of hydrofluoric acid burns (off-label)
• N/A • Brand names: Cal-Glu • Routine use in cardiac arrest not recommended due to lack
of improved survival o Preferred over IV calcium chloride in non-emergent
hypocalcemia due to potential for more severe extravasation with calcium chloride
• Soluble salt Calcium lactate à13% elemental
PO • Supplementation • 252 mg daily • Brand names: Cal-Lac • Soluble salt
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Appendix 4. Studies evaluating calcium/calcium + vitamin D and cardiovascular events in women Table 10. Studies evaluating calcium and cardiovascular events in women 15-16,49-53
Author (Year) Design Calcium doses Patient population Outcomes Results Bostick, et al (1999)
Analysis of data from prospective cohort study (Iowa Women’s Health Study)
0 mg 1-500 mg > 500 mg
34,486 postmenopausal women (55-69 years old) without history of ischemic heart disease (IHD) followed for 8 years
CHD mortality No risk of fatal CHD with ≥ 500 mg/day calcium supplements vs. none
Iso, et al (1999)
Analysis of data from prospective cohort study (Nurse’s Healthy Study)
0 mg < 400 mg ≥ 400 mg
85,764 women (34-59 years old) free of cancer and CVD followed for 14 years
Incident stroke Independent inverse relationship between highest vs. lowest quintile of calcium intake and incidence of ischemic stroke
Prince, et al (2006)
Randomized, double-blind, placebo controlled study
Calcium carbonate 1,200 mg (divided into 2 doses) vs. placebo
1,460 women (> 70 years old) followed for 5 years -730 calcium -730 placebo
Clinical incident osteoporotic fractures, vertebral deformity, and adverse events (includes IHD)
No significant difference in IHD between calcium vs. placebo
Larsson, et al (2011)
Analysis of data from population-based prospective cohort study (Swedish Mammography Cohort)
Unspecified 34,670 women (49-83 years old) without history of stroke, CHD, or cancer followed for mean of 10.4 years
Incident stroke No overall association between calcium intake and risk of any stroke or cerebral infarction
Lewis, et al (2011)
Randomized, double-blinded, placebo controlled trial using data from Calcium Intake Fracture Outcome Study
Calcium carbonate 1,200 mg vs placebo
1,460 women (75.1 +/- 2.7 years old) followed for 5 years + 4.5 year follow-up
Combined outcome of atherosclerotic vascular mortality of first hospitalization
No significant difference between placebo vs. calcium after 5 years or 9.5 year follow-up
Mursu, et al (2011)
Analysis of data from prospective cohort study (Iowa Women’s Health Study)
0 mg 1-500 mg > 500 mg
38,772 postmenopausal women (55-69 years old) followed for 11 years
Total mortality Calcium inversely related to total mortality, no dose-response relationship observed
Michaelsson, et al (2013)
Prospective longitudinal cohort study in Sweden
< 600 mg 600-999 mg 1,000-1,399 mg ≥ 1,400 mg
38,984 women (49-84 years old) followed for median of 19 years
Death from all causes, CVD, IHD, and stroke
Calcium intake > 1,400 mg/day associated with higher death rates from all causes, CVD, and IHD, but not from stroke
Supplementation not associated with all-cause or cause-specific mortality, but those with dietary calcium > 1,400 mg/day who also used supplements had higher CVD mortality
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Table 11. Studies evaluating calcium + vitamin D and cardiovascular events in women 54-58
Author (Year) Design Calcium doses Patient population Outcomes Results Brazier, et al (2005)
Multicenter, randomized, double-blind, placebo controlled study
Calcium carbonate 1,000 mg + vitamin D3 800 IU daily (divided into 2 doses) vs. placebo
192 women (> 65 years old) with vitamin D insufficiency followed for 1 year -95 calcium + vitamin D -96 placebo
Primary endpoint of bone mineral density and biochemical markers on bone formation and resorption
Secondary endpoint of clinical and laboratory safety
No significant difference between calcium + vitamin D vs. placebo (6 adverse cardiovascular events in treatment group vs. 5 in placebo group)
Hsia, et al (2007)
Randomized, controlled trial using data from WHI calcium-vitamin D trial
Calcium carbonate 1,000 mg + vitamin D3 400 IU daily (divided into 2 doses) vs. placebo
36,282 postmenopausal women (50-79 years old) followed for 7 years -18,176 calcium + vitamin D -18,106 placebo
Primary endpoint of fracture incidence
CVD as pre-specified secondary efficacy outcome
No significant difference between calcium + vitamin D vs. placebo
Lappe, et al (2008)
Randomized controlled trial
Calcium citrate 1,400 mg or calcium carbonate 1,500 mg alone or calcium + vitamin D 1,100 IU vs. placebo
1,179 women (> 55 years old) followed for 4 years -445 calcium only -446 calcium + vitamin D -288 placebo
Primary skeletal endpoint No significant difference between calcium + vitamin D vs. placebo
Lower rates of vascular events when 2 calcium groups compared with placebo
LaCroix, et al (2009)
Randomized, controlled trial using data from WHI calcium-vitamin D trial
1,000 mg elemental calcium carbonate + vitamin D3 400 IU daily vs. placebo
36,282 postmenopausal women (50-79 years old) followed for 7 years -18,176 calcium + vitamin D -18,106 placebo
Total and cause-specific mortality by age and adherence
No statistically significant effect of supplementation on mortality rates, but findings support possibility that supplements may reduce total and CVD mortality rates in postmenopausal women < 70 years old
Prentice, et al (2013)
Analysis of participants in WHI randomized controlled trial (RCT) and WHI prospective observational study (OS)
WHI RCT: 1,000 mg of elemental calcium carbonate and 400 IU of vitamin D3 daily or placebo with average follow-up of 7.0 years
WHI OS: ≥ 500 mg calcium daily + ≥ 400 IU vitamin D
WHI RCT: 36,282 postmenopausal women (50-79 years old) followed for 7 years -18,176 calcium + vitamin D -18,106 placebo
WHI OS: 46,892 postmenopausal women (50-79 years old) followed for 7 years -15,476 calcium + vitamin D -5,941 calcium only -23,561 supplement non-users
Fractures, invasive cancers, CVD, and total mortality
No significant association of MI, CHD, total heart disease, stroke or total CVD among women taking calcium supplements alone (OS) or calcium + vitamin D (RCT, OS, and combined RCT and OS analysis)
Suggested reduction in total heart disease and total CVD risk in supplement users
