Despite the multiple systematic reviews and meta-analyses accumulating evidence on the preventive effect of calcium supplementation for colorectal cancer, most of the associated adverse effects are not systematically analyzed. The aim of the study is evaluating adverse events associated with calcium supplementation for colorectal cancer prevention through a systematic meta-analysis. We searched Medline, PubMed Central, EMBASE (Excerpta Medica database), Scopus, Cochrane Central Register of Controlled Trials, and Web of Science published in English from database inception up to 31 July 2019. In the current systematic meta-analysis, we included human studies (including cohort studies, clinical trials, case-control studies) on supplementation of calcium in patients with or at risk of colorectal cancer. Assessment of the quality of included studies was performed by Jadad score. Information on the patient population, number of enrolled subjects in each group, dose of calcium supplementation, duration of calcium supplementation, and reported adverse events were gathered. The data were pooled for incidence rates for any adverse event during the study period regardless of causality association. We identified 6 studies, comprising 4583 participants that met the inclusion criteria. Meta-analysis on pooled incidence rates for adverse event during study period showed no statistically significant increased risk for cancer (OR = 0.92, 95% CI: 0.70–1.21,
Colorectal cancer incidence varies markedly worldwide. Globally, it is the third most common detected cancer in males and the second in females (
Different interventions are suggested for modifying the colorectal cancer risk (
Calcium is an essential molecule to maintain human body health. Calcium is needed for different physiologic functions in human body including skeletal, neurologic, cardiologic, and muscular system functions (
Calcium supplementation is largely studied for its effect on colorectal cancer risk reduction in patients at risk, with promising results. These studies vary on the level of evidence and include case controls, cohorts, and clinical trials (
Despite the beneficial preventive effects of calcium supplementation on colorectal cancer, some studies suggested health risks and adverse events associated with calcium supplementation. In a randomized controlled trial on 1471 postmenopausal women receiving calcium supplementation, the adjusted rate of myocardial infarction in the calcium group was significantly higher than the rate in the placebo group (RR: 2.12, 95% CI: 1.01–4.47) (
Despite the multiple systematic reviews and meta-analyses accumulating evidence on the preventive effect of supplementation of calcium on the risk of colorectal cancer, the associated adverse events were not systematically reviewed. The aim of this study to evaluates the adverse events associated with calcium supplementation for colorectal cancer prevention in a systematic meta-analysis.
A comprehensive search was performed to retrieve any reported adverse event associated with calcium supplementation in patients with or at risk of colorectal cancer from published literature. The following databases were searched since initiation up to 31 July 2019; Medline, PubMed Central, EMBASE (Excerpta Medica database), Scopus, Cochrane Central Register of Controlled Trials, and Web of Science. Keywords including “trial”, “cohort”, “case-control”, “observational”, “interventional”, “patients” were added to “colorectal”, “colon” plus “calcium” and were used for database search. Our search was limited to studies reported in the English language.
To meet the study objectives, human studies (including cohort studies, clinical trials, and case-control studies) on supplementation of calcium in patients with or at risk of colorectal cancer were included. To be included in the meta-analysis, studies should include information on the observed adverse events in two study groups (the active group receiving calcium supplementation and the control group not receiving calcium supplementation) (
Participants | Patients with or at risk of colorectal cancer |
---|---|
Interventions | Calcium supplementation |
Comparisons | Not receiving calcium supplementation |
Outcomes | Any reported adverse event |
Study design | A systematic review of human studies |
The following studies were excluded: (1) non-original reports; (2) experimental models and
Bibliographic information of all manuscripts retrieved through database search was transferred to Endnotes V.X6. Data extraction was performed by two independent reviewers. Disagreements were resolved by a third reviewer.
Data were documented in predefined forms. Information on the patient population, numbers in each study group, dose of calcium supplementation, duration of calcium supplementation, reported adverse events in each group were extracted from each included study. The data were pooled for incidence rates for any adverse event during the study period regardless of causality association.
Assessment of the quality of included studies was performed by Jadad score.
A comparison of reported adverse events was made between interventions by collecting data from studies by direct meta-analysis technique. Meta-analysis of the available data was performed using Review Manager (RevMan V.5.1) software. Dichotomous outcomes were summarized as risk (relative) ratios.
After retrieving data from various international databases, 210 articles were retrieved. Omitting duplicate articles, 162 articles were remained which sent for evaluation of the topics and abstracts. Passing this stage, 69 articles entered the full texts review and finally, 6 eligible articles entered the final analysis. It should be noted that the references of the included articles were also reviewed to add relevant studies. The flowchart of the included studies is displayed in
The characteristics of the studies included in the meta-analysis are presented in
Trial | Dose (mg elemental Ca/day) | Treatment duration | Number in the calcium group | Number in the control group | Reported adverse events | Randomization | Randomization method | Blinding | Blinding method | Excluded described | ||
---|---|---|---|---|---|---|---|---|---|---|---|---|
( |
1200 | 55 ± 15 months | 760 | 745 | Calcium | Control | Observational | |||||
Death | 15 | 16 | ||||||||||
Myocardial Infarction | 9 | 6 | ||||||||||
Coronary revascularization | 12 | 12 | ||||||||||
Stroke | 7 | 13 | ||||||||||
Transient ischemic attack | 5 | 1 | ||||||||||
Cancer | 45 | 46 | ||||||||||
Urolithiasis | 16 | 14 | ||||||||||
Fracture | 37 | 31 | ||||||||||
( |
1200 | 3–5 years | 840 | 835 | Calcium | Control | Yes | Yes | Yes | No | No | |
Death | 13 | 12 | ||||||||||
Myocardial Infarction | 2 | 9 | ||||||||||
Coronary revascularization | 12 | 8 | ||||||||||
Stroke | 3 | 5 | ||||||||||
Transient ischemic attack | 0 | 3 | ||||||||||
Cancer | 46 | 46 | ||||||||||
Urolithiasis | 20 | 15 | ||||||||||
Fracture | 37 | 43 | ||||||||||
Hypercreatininemia | 58 | 40 | ||||||||||
Hypercalcemia | 17 | 5 | ||||||||||
( |
1200 | 4 years | 464 | 466 | Calcium | Control | Yes | Yes | Yes | Yes | Yes | |
Death | 25 | 22 | ||||||||||
Hospitalization | 172 | 164 | ||||||||||
Cardiac disease | 50 | 46 | ||||||||||
Stroke | 12 | 11 | ||||||||||
Gastrointestinal disease | 38 | 32 | ||||||||||
Cancer | 15 | 21 | ||||||||||
Stop treatment due to perceived toxicity | 12 | 13 | ||||||||||
( |
2000 | 3 years | 176 | 178 | All adverse events |
26 | 12 | Yes | Yes | No | No | Yes |
( |
600 | 12 weeks | 14 | 13 | No adverse event observed | Yes | No | Yes | No | No | ||
( |
2000 | 6 months | 46 | 46 | No adverse event observed | Yes | Yes | Yes | Yes | Yes |
Among the included studies, three randomized controlled trials (RCTs) assessed the risk of development of cancer in patients receiving calcium supplementation. Meta-analysis revealed less incidence of cancer in intervention group compared to placebo group, but these findings were not statistically significant (OR = 0.92, 95% CI: 0.70–1.21,
Three studies reported risk of coronary revascularization. No overall significant effect was observed in the intervention compared to control group (OR = 1.12, 95% CI: 0.79–1.59.
Among the included studies, two RCTs assessed the risk of myocardial infarction. Meta-analysis revealed lower incidence of myocardial infarction in patients receiving calcium supplementation compared to control, but these findings were not statistically significant (OR = 0.81, 95% CI: 0.34–1.91,
Three studies assessed the risk of stroke in studied patients. Pooled effect of intervention compared to control showed not significant association (OR = 0.75, 95% CI: 0.42–1.33,
Two studies assessed the effect of calcium supplementation on the risk of TIA. Despite the increased risk, the statistical analysis indicated no significant effect of calcium supplement compared to control (OR = 1.37, 95% CI: 0.28– 6.51,
Two studies reported this adverse event in patients who received calcium supplementation. No overall significant effect was observed in the intervention compared to control group (OR = 1.23, 95% CI: 0.75–2.01,
Two studies assessed the effect of calcium supplementation on the risk of fractures. The results indicated no significant effect of calcium supplementation compared to control (OR = 0.98, 95% CI: 0.70–1.37,
Three studies assessed the risk of death in the patient population. Pooled effect of intervention compared to control showed no significant association (OR = 1.05, 95% CI: 0.71–1.56,
Based on the results of the Egger test, publication bias was not observed among the included studies (
Calcium homeostasis play important roles in different systems of our body, including skeletal, hormonal, cardiovascular, neurologic, and gastrointestinal systems (
The preventive effect of calcium in colorectal cancer is considered to be through extracellular calcium-sensing receptors (CaSR) in the colon. The CaSR is involved in cell proliferation and differentiation. Accumulating evidence suggests that the CaSR might play a protective role against colorectal cancer. CaSR expression was shown to be reduced in colorectal cancer (
Different mechanisms are proposed for the potential adverse effects of calcium supplementation. Transiently elevated calcium levels by calcium supplements may contribute to cardiovascular risk. This risk is considered to be associated with calcium-sensing receptors on platelets that are activated with elevated serum calcium and cause increased blood coagulability. (
Notwithstanding the proposed mechanisms for adverse events associated with calcium supplementation, our results demonstrated no significant increase in the mentioned side effects in patients receiving calcium supplementation for colorectal cancer prevention compared to control groups.
The main strength of this study was its novelty. Despite the popular use of calcium supplementation in patients at the risk of colorectal cancer, no research has previously accumulated the evidence for potential risks of this intervention. This study has evaluated the risk of calcium supplementation in this population of patients for the first time. The use of the meta-analysis method was another important point of study which let us accumulate the observed adverse events in 2300 patients of 6 different human studies and compare it with 2283 controls. The use of control patients for statistical comparison made it possible to evaluate the potential causality of observed adverse events to calcium supplementation. The use of control comparison in the evaluation of adverse effects is of special importance in high-risk patient populations like patients with colorectal cancer which different adverse events may be observed in them without a causal relationship with the specific intervention.
There are some limitations to this systematic study. The majority of studies on calcium supplementation in colorectal cancer did not report information on adverse events. Studies included in this review were not similar in follow-up duration and the dose of calcium supplementation. The interaction between calcium and other supplementation used in colorectal cancer prevention like vitamin D, folic acid, pyridoxine, garlic, and fish oil was not evaluated in this study. Publication bias is another source of bias in the meta-analysis. Studies with a higher rate of adverse events are more prone not to be published in the literature. Language limitation of included studies is another potential source of bias in this systematic review.
A meta-analysis of human studies reporting adverse events associated with calcium supplementation for the prevention of colorectal cancer demonstrated no statistically significant increased risk for the development of adverse events compared to control groups.
The authors extend their appreciation to the College of Applied Medical Sciences Research Center and the Deanship of Scientific Research, King Saud University, Riyadh, Saudi Arabia for their kind support.
Excerpta Medica database
population, intervention, control, outcome, study
calcium-sensing receptors
preferred reporting items for systematic reviews and meta-analyses
randomized controlled trials
review manager