Mei Chung, MPH, PhD; Alice M. Tang, SCM, PhD; Zhuxuan Fu, MPH; Ding Ding Wang, MPH; Sydne Jennifer Newberry, MS, PhD
Note: Dr. Newberry contributed her efforts to this manuscript without receiving funding or salary support.
Grant Support: From the NOF.
Disclosures: Authors have disclosed no conflicts of interest. Forms can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M16-1165.
Editors' Disclosures: Christine Laine, MD, MPH, Editor in Chief, reports that she has no financial relationships or interests to disclose. Darren B. Taichman, MD, PhD, Executive Deputy Editor, reports that he has no financial relationships or interests to disclose. Cynthia D. Mulrow, MD, MSc, Senior Deputy Editor, reports that she has no relationships or interests to disclose. Deborah Cotton, MD, MPH, Deputy Editor, reports that she has no financial relationships or interest to disclose. Jaya K. Rao, MD, MHS, Deputy Editor, reports that she has stock holdings/options in Eli Lilly and Pfizer. Sankey V. Williams, MD, Deputy Editor, reports that he has no financial relationships or interests to disclose. Catharine B. Stack, PhD, MS, Deputy Editor for Statistics, reports that she has stock holdings in Pfizer and Johnson & Johnson.
Reproducible Research Statement:Study protocol: Available from Agency for Healthcare Research and Quality (https://effectivehealthcare.ahrq.gov/search-for-guides-reviews-and-reports/?pageaction=displayproduct&productID=1529). Statistical code: See Appendix. Data set: See Supplements 1, 2, 3, 4, and 5.
Address for Single Reprints: Mei Chung, PhD, MPH, Department of Public Health and Community Medicine, School of Medicine, Tufts University, 136 Harrison Avenue, Boston, MA 02111; e-mail, Mei_chun.firstname.lastname@example.org.
Current Author Addresses: Drs. Chung and Tang, Ms. Fu, and Ms. Wang: Department of Public Health and Community Medicine, School of Medicine, Tufts University, 136 Harrison Avenue, Boston, MA 02111.
Dr. Newberry: RAND Corporation, 1776 Main Street, Santa Monica, CA 90407.
Author Contributions: Conception and design: M. Chung.
Analysis and interpretation of the data: M. Chung, A.M. Tang, Z. Fu, D.D. Wang, S.J. Newberry.
Drafting of the article: M. Chung, A.M. Tang, S.J. Newberry.
Critical revision for important intellectual content: M. Chung, S.J. Newberry
Final approval of the article: M. Chung, A.M Tang, Z. Fu, D.D. Wang, S.J. Newberry.
Provision of study materials or patients: M. Chung.
Statistical expertise: M. Chung.
Obtaining of funding: M. Chung.
Administrative, technical, or logistic support: D.D. Wang.
Collection and assembly of data: M. Chung, Z. Fu, D.D. Wang.
Conflicting evidence exists regarding potential cardiovascular risks associated with high levels of calcium intake.
To update and reanalyze 2 systematic reviews to examine the effects of calcium intake on cardiovascular disease (CVD) among generally healthy adults.
MEDLINE; Cochrane Central Register of Controlled Trials; Scopus, including EMBASE; and previous evidence reports from English-language publications from 1966 to July 2016.
Randomized trials and prospective cohort and nested case–control studies with data on dietary or supplemental intake of calcium, with or without vitamin D, and cardiovascular outcomes.
Study characteristics and results extracted by 1 reviewer were confirmed by a second reviewer. Two raters independently assessed risk of bias.
Overall risk of bias was low for the 4 randomized trials (in 10 publications) and moderate for the 27 observational studies included. The trials did not find statistically significant differences in risk for CVD events or mortality between groups receiving supplements of calcium or calcium plus vitamin D and those receiving placebo. Cohort studies showed no consistent dose–response relationships between total, dietary, or supplemental calcium intake levels and cardiovascular mortality and highly inconsistent dose–response relationships between calcium intake and risks for total stroke or stroke mortality.
CVD disease outcomes were secondary end points in all trials. Dose–response metaregression analysis of cohort studies was limited by potential confounding, ecological bias, and imprecise measures of calcium exposures. Data were scarce regarding very high calcium intake—that is, beyond recommended tolerable upper intake levels.
Calcium intake within tolerable upper intake levels (2000 to 2500 mg/d) is not associated with CVD risk in generally healthy adults.
National Osteoporosis Foundation.
Summary of evidence searches and study selection flow.
Cardiovascular death includes death from ischemic heart disease, myocardial infarction, coronary heart disease, and any cardiovascular death. RCTs = randomized, controlled trials.
* Total of 4 unique RCTs in 10 publications.
Appendix Table 1. Characteristics of Randomized, Controlled Trials Examining the Effects of Calcium With or Without Vitamin D Supplementation on CVD Outcomes
Appendix Table 2. Risk-of-Bias Assessment, Background Calcium Intake Levels, and Adherence in the Included Randomized, Controlled Trials
Appendix Table 3. Results From the 10 Randomized, Controlled Trial Publications Examining the Effects of Calcium With or Without Vitamin D Supplementation on CVD
Appendix Table 4. Characteristics of Prospective Cohort and Nested Case–Control Studies Examining the Associations Between Calcium Intake Levels and Risks for CVD
Appendix Table 5. Risk-of-Bias Assessment for 26 Cohort and 1 Nested Case–Control Studies
Results of 15 cohort studies examining the relationships between total (6 studies [top]), dietary (12 studies [middle]), or supplemental (5 studies [bottom]) calcium intake and the risks for CVD, cardiac, or IHD mortality.
CVD = cardiovascular disease; IHD = ischemic heart disease; M = men; W = women.
Risk-of-bias assessment of prospective cohort or nested case–control studies examining the associations between calcium intake and risk for cardiovascular disease.
A. Six studies estimated the associations between total calcium intake levels and risks for cardiovascular or ischemic heart disease death. B. Twelve studies estimated the associations between dietary calcium intake levels and risks for cardiovascular or ischemic heart disease death. C. Five prospective cohort studies estimated the associations between supplemental calcium intake levels and risks for cardiovascular or ischemic heart disease death. D. Five studies estimated the associations between total or dietary calcium intake levels and risks for stroke death. E. Ten studies estimated the associations between total or dietary calcium intake levels and risks for total stroke.
Table. Results of 2-Stage, Hierarchical Random-Effects Model Dose–Response Metaregressions of Prospective Cohort Studies
Reanalysis of 12 cohort studies to examine the risks for CVD, cardiac, or IHD mortality, comparing calcium intake levels 1000 mg/d or greater with those less than 1000 mg/d.
CVD = cardiovascular disease; HR = hazard ratio; IHD = ischemic heart disease; OR = odds ratio; RR = relative risk.
Results of 15 cohort studies examining the relationships between dietary or total calcium intake and the risks for total stroke (10 studies [top]) and stroke mortality (5 studies [bottom]).
HPFS = Health Professionals Follow-up Study; M = men; NHS = Nurses' Health Study; W = women.
Reanalysis of 10 cohort studies to examine the risks for total stroke or stroke mortality, comparing calcium intake levels 1000 mg/d or greater with those less than 1000 mg/d.
HR = hazard ratio; RR = relative risk.
Appendix Table 6. R Codes to Perform Linear and Nonlinear Dose–Response Metaregressions
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Elizabeth (Lisa) Samelson
Harvard Medical School, Beth Israel Deaconess Medical Center, Hebrew SeniorLife
October 26, 2016
Population-based data shows no adverse effect of calcium intake on increased risk of calcification of vascular tissues
Chung and colleagues conducted a robust meta-analysis and found no association between calcium intake and cardiovascular risk. As the authors pointed out, the strength of the evidence linking calcium supplementation with cardiovascular endpoints is weak, and a plausible biological mechanism has not been identified. However, we disagree with the authors that data on the calcification of vascular tissues associated with calcium supplementation for the general population does not exist. We assessed the association between calcium intake and the coronary artery calcification Agatston score, evaluated from CTs, in 1200 women and men the community-based Framingham Heart Study (Am J Clin Nutr 2012;96:1274–80). We found no association between increasing Agatston scores and calcium intake from supplements and/or diet. Our prospective study, conducted in a large, community-based population of women and men, used state-of-the-art CT measures of coronary artery calcification and was able to account for important potential confounders including vitamin D intake, prevalent coronary artery disease, and kidney function. Thus, our study, based on population data, supports the findings of Chung and co-authors, and concludes that calcium supplementation within recommended intake levels does not increase cardiovascular risk.
November 5, 2016
A mistake in text about interaction of personal Ca supplement in women?
In the section of results from RCT "Effects of Calcium Plus Vitamin D Supplementation", second paragraph, the author stated that"Only 2 subgroup analyses revealed statistically significant differences between groups. One showed that use of personal calcium supplementsaltered the effect of calcium and vitamin D on CVD (10). In postmenopausal women receiving calcium supplements, the hazard ratios with calcium and vitamin D were 1.13 to 1.22 for CVD end points. In contrast, among those not taking supplements, the hazard ratios were 0.83 to 1.08.".This indicates an increase risk of intervention in women currently taking personal Ca supplement.However in the original article of ref10, as well as in Appendix Table 3, the interaction is the other way around." In women not taking personal calcium supplements, the hazard ratios with calcium and vitamin D were 1.16 (P=0.04) for the composite end point of clinical myocardial infarction or coronary revascularisation, 1.16 (P=0.05) for clinical myocardial infarction or stroke, 1.22 (P=0.05) for myocardial infarction, and 1.13–1.20 for the other cardiovascular end points. By contrast, in women taking personal calcium supplements, the hazard ratios for these end points with calcium and vitamin D were 0.83–1.08." Just read the last sentence I quoted from both article and see the difference.
Ian R Reid1, Alison Avenell2, Andrew Grey1, Mark J Bolland1
1. Department of Medicine Faculty of Medical and Health Sciences University of Auckland Auckland, New Zealand. 2. Health Services Research Unit University of Aberdeen Aberdeen AB25 2ZD, Scotland
November 21, 2016
Calcium and Cardiovascular Disease
In their review of calcium intake and cardiovascular disease, Chung et al did not carry out a meta-analysis of the randomized controlled trials, as their title suggested.1 They identified only 2 trials reporting the effects of calcium plus vitamin D on cardiovascular events, and 3 trials of calcium alone, whereas we have reported data on myocardial infarction or stroke from 13 studies of calcium with or without vitamin D (4 trials calcium plus vitamin D, 11 trials calcium monotherapy).2 For 6 trials we used individual patient data. As in the Chung report, cardiovascular event rates were not significantly increased in individual trials in our review, but they were when meta-analyzed (relative risk of myocardial infarction or stroke from calcium with or without vitamin D in 9 trials RR 1.15 95%CI 1.03 to 1.27).2 Another meta-analysis of calcium monotherapy (5 trials, 6,333 participants) reported a RR of 1.37 (0.98-1.92) for myocardial infarction.3 Chung provides no comment on why their findings differ from those published previously.Surprisingly, Chung et al do not use the data from the end of each randomized trial, instead substituting data from trial extensions in which participants did not necessarily take trial medications and may have crossed-over to other treatments. On-study analyses are particularly important for examining adverse effects. Having overlooked a considerable body of randomized research, the Chung report relies heavily on extensive analyses of observational studies which are confounded by the consistent observation that higher calcium intakes are associated with indicators of better health. In the setting of a large body of randomized trial evidence (13 trials, 29 277 participants with 1393 incident myocardial infarctions or strokes, and 1857 deaths),2 resorting to lower levels of evidence such as observational studies is neither necessary nor appropriate. The authors suggest that a small increase in adverse events, even if statistically significant, is unlikely to be clinically significant. This is unacceptable for an intervention such as calcium supplements, taken by 30-50% of older people in some Western countries, for which risk must be balanced against the evidence from high quality trials that they do not reduce fracture risk in community-dwelling people.4 In such a setting, a probable risk of any magnitude is unacceptable. Finally, it is unlikely that a significant controversy such as this will be advanced by a review funded by a major producer of calcium supplements, since industry-funded meta-analyses frequently reach different conclusions from non-conflicted reviews.5 References1. Chung M, Tang AM, Fu Z, Wang DD, Newberry SJ. Calcium Intake and Cardiovascular Disease Risk. An Updated Systematic Review and Meta-analysis. Ann Intern Med 2016;doi:10.7326/M16-1165.2. Bolland MJ, Grey A, Avenell A, Gamble GD, Reid IR. Calcium supplements with or without vitamin D and risk of cardiovascular events: reanalysis of the Women’s Health Initiative limited access dataset and meta-analysis. BMJ 2011;342:d2040. doi:10.1136/bmj.d2040.3. Lewis JR, Radavelli-Bagatini S, Rejnmark L, Chen JS, Simpson JM, Lappe JM, Mosekilde L, Prentice RL, Prince RL. The effects of calcium supplementation on verified coronary heart disease hospitalization and death in postmenopausal women: a collaborative meta-analysis of randomized controlled trials. J Bone Miner Res 2015;30(1):165-75.4. Bolland MJ, Leung W, Tai V, Bastin S, Gamble GD, Grey A, Reid IR. Calcium intake and risk of fracture: systematic review. BMJ 2015;351:h4580.5. Jorgensen AW, Hilden J, Gotzsche PC. Cochrane reviews compared with industry supported meta-analyses and other meta-analyses of the same drugs: systematic review. BMJ 2006;333(7572):782-85.
Joshua R. Lewis1,2 and Richard L. Prince2
Children's Hospital at Westmead, University of Western Australia School of Medicine and Pharmacology
November 30, 2016
We read the recent meta-analysis by Chung et al (1) and National Osteoporosis Foundation and American Society for Preventative Cardiology guidelines (2) with interest and agree that there is only moderate quality evidence that calcium supplements with or without vitamin D do not effect cardiovascular and cerebrovascular disease, mortality, or all-cause mortality in generally healthy adults exists. It is important to note that this recommendation acknowledges that a future high-quality study or several studies with limitations are likely to impact our confidence in the estimates based on the current evidence. Given the widespread use of these supplements and the clinical uncertainty, further high-quality studies are warranted.Of interest is the recent publication by Baron and colleagues (3) reporting the effects of 3 to 5 years of daily calcium supplements in a partial 2×2 randomized factorial trial with either; none, 1200 mg day of calcium or 1000IU of vitamin D3 or both on the risk of recurrent colorectal adenomas. In addition to the primary outcome, major adverse events adjudicated by two physicians blinded to treatment were also reported. In the no calcium group (none or vitamin D) there were 9 participants with one or more myocardial infarctions out of 835 participants (1.1%) compared to 2 participants with one or more myocardial infarctions out of 840 participants (0.2%) in the calcium supplemented group, P=0.03. These conflicting findings once again highlight the problems associated with interpreting post hoc findings from trials underpowered to determine true effects. The editorial (4) on calcium and cardiovascular disease on what clinicians and patients need to know provides helpful advice to a confused and confusing area of clinical practice that only a few years ago was considered to be resolved after 100 years of careful research. There are however some additional insights relevant to the debate. Using mean values of calcium intake and vitamin D status, commonly reported in RCT’s, ignores the fact that unlike pharmaceuticals, the control group is exposed to some level of dietary calcium and vitamin D. So the real question being examined is what are the health benefits or risks of increasing calcium intake and vitamin D status rather than a simple yes/no exposure. However in this regard the use of meta-regression to consider the effect of high calcium intake is reassuring in that no evidence of increased risk was identified. Calcium supplements with or without vitamin D continue to be strongly supported by expert groups for the prevention of age-related bone loss, particularly in elderly women where recommended dietary intakes often cannot be reached from food sources alone (5). These recommendations remain despite claims by the Auckland group that such expert groups are controlled by pharmaceutical companies and financial self-interest (6). Contrary to this viewpoint, it is more likely the claims of adverse effects have not been taken up by professional bodies due to the inconsistent evidence for harm as well as the approach chosen by this group including; cherry picking certain classes of adverse event (7), inconsistent validation of endpoints (8), and post hoc splitting of clinical trial data that fundamentally undermines the role of randomization (9) leading to uncertainty over whether the reported findings are real or due to chance or bias. Perhaps these latest data will allow a more rational and less emotive evidence-based view of an important public health initiative.References1. Chung M, Tang AM, Fu Z, Wang DD, Newberry SJ. Calcium Intake and Cardiovascular Disease Risk: An Updated Systematic Review and Meta-analysis. Ann Intern Med. 2016.2. Kopecky SL, Bauer DC, Gulati M, Nieves JW, Singer AJ, Toth PP, et al. Lack of Evidence Linking Calcium With or Without Vitamin D Supplementation to Cardiovascular Disease in Generally Healthy Adults: A Clinical Guideline From the National Osteoporosis Foundation and the American Society for Preventive Cardiology. Ann Intern Med. 2016.3. Baron JA, Barry EL, Mott LA, Rees JR, Sandler RS, Snover DC, et al. A Trial of Calcium and Vitamin D for the Prevention of Colorectal Adenomas. N Engl J Med. 2015;373(16):1519-30.4. Margolis KL, Manson JE. Calcium Supplements and Cardiovascular Disease Risk: What Do Clinicians and Patients Need to Know? Ann Intern Med. 2016.5. Institute of Medicine. Dietary reference intakes for calcium and vitamin D. Washington DC; 2011.6. Grey A, Bolland M. Web of industry, advocacy, and academia in the management of osteoporosis. BMJ. 2015;351:h3170.7. Cordoba G, Schwartz L, Woloshin S, Bae H, Gotzsche PC. Definition, reporting, and interpretation of composite outcomes in clinical trials: systematic review. BMJ. 2010;341:c3920.8. Lewis JR, Radavelli-Bagatini S, Rejnmark L, Chen JS, Simpson JM, Lappe JM, 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. J Bone Miner Res. 2015;30(1):165-75.9. Prentice RL, Jackson RD, Rossouw JE. Calcium supplements and cardiovascular risk in the Women's Health Initiative: response to Bolland et al. Osteoporos Int. 2013;24(8):2373-4.
Karl Michaëlsson, Liisa Byberg
Department of Surgical Sciences, Uppsala University, Uppsala, Sweden
January 5, 2017
Calcium intake and cardiovascular disease risk
A blunt study design within a research field with at most modestly strong associations and a probable U-shaped biological relationship will result in null findings. This comes as no surprise. Presently many have the view that the most robust observational evidence is derived from meta-analysis of prospective studies but the results is naturally dependent on the researchers’ ability to uncover strengths and shortcomings of the individual included studies. There is a danger that meta-analyses produce very precise but equally spurious results. More is gained by carefully examining possible sources of heterogeneity between the results from observational studies (1). Mixing studies with poor and good study designs will dilute associations substantially and a true 30- to 50-fold higher risk can be reduced to a combined weak association (2). As with any exposure assessment, self-reported recall of what you have eaten will lead to misclassification of the true dietary exposure. Repeated measurements of long term dietary intake reduce measurement error and offer opportunities to investigate changes in intake over time. Regression calibration, by use of data from a validation study, is another way to further improve accuracy of the exposure. Moreover, some studies have complete outcome identification during follow-up. Mixing studies (3) of different quality will result in diluted associations.Since individual data was not used in their meta-analysis, Chung et al (3) instead tried to circumvent this shortcoming by a meta-regression analytical approach. However, the main dose-response meta-regression compared calcium dose categories greater than 1000 mg/day with those less than 1000 mg/day. The result of such a comparison is likely to be null given the normal distribution of calcium intake in most Western populations. A more fruitful analysis, if there is a wish to detect an excess risk with high or low calcium intakes, is to examine the risk in lowest or highest category of intake compared with the risk in a category consisting of a modest/normal intake. The result of analysis of a quadratic term by meta-regression modeling is reliant on whether the nadir in risk appears at the same calcium exposure level in different populations The calcium need, however, differ by ethnicity and by type of dietary pattern (4). A uniform risk curve with calcium intake in different populations is thus probably not the case. Indeed, differences in the position of the nadir can be readily observed in Figure 1 and Figure 3 (3). There are several additional indications that Chung et al did not perform an in depth analysis of the individual strengths and shortcomings of the included studies. One example is that body mass index is claimed to be not reported in references 41, 47 and 55 despite the fact that body mass index is presented by exposure category in all these studies, an approach recommended by the STROBE guideline for observational studies. Another example is the statement by that no individual study investigated the interaction between calcium and vitamin D intake in relation to CVD outcomes. This is not a correct description (5). Finally and importantly, Chung did not consider or discuss dietary calcium source in their analysis of observational studies. Type of dietary calcium source might have a larger impact on health than the amount of calcium ingested. Fermented and non-fermented dairy products, both rich calcium sources, can affect health in different directions. References1. Egger M, Schneider M, Davey Smith G. Spurious precision? Meta-analysis of observational studies. BMJ. 1998;316(7125):140-4.2. Gedmintas L, Solomon DH, Kim SC. Bisphosphonates and risk of subtrochanteric, femoral shaft, and atypical femur fracture: a systematic review and meta-analysis. J Bone Miner Res. 2013;28(8):1729-37.3. Chung M, Tang AM, Fu Z, Wang DD, Newberry SJ. Calcium Intake and Cardiovascular Disease Risk: An Updated Systematic Review and Meta-analysis. Ann Intern Med. 2016;165(12):856-66.4. Adeva MM, Souto G. Diet-induced metabolic acidosis. Clin Nutr. 2011;30(4):416-21.5. Michaelsson K, Melhus H, Warensjo 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.
Chung M, Tang AM, Fu Z, Wang DD, Newberry SJ. Calcium Intake and Cardiovascular Disease Risk: An Updated Systematic Review and Meta-analysis. Ann Intern Med. 2016;165:856-866. doi: 10.7326/M16-1165
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Published: Ann Intern Med. 2016;165(12):856-866.
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