Effects of calcium on the incidence of recurrent colorectal adenomas: A systematic review with meta-analysis and trial sequential analysis of randomized controlled trials

Abstract

Background: Protective effects of calcium supplementation against colorectal adenomas have been documented in systematic reviews; however, the results have not been conclusive. Our objective was to update and systematically evaluate the evidence for calcium supplementation taking into consideration the risks of systematic and random error and to GRADE the evidence.

Methods: The study comprised a systematic review with meta-analysis and trial sequential analysis (TSA) of randomized controlled trials (RCTs). We searched for RCTs published up until September 2016. Retrieved trials were evaluated using risk of bias. Primary outcome measures were the incidences of any recurrent adenomas and of advanced adenomas. Meta-analytic estimates were calculated with the random-effects model and random errors were evaluated with trial sequential analyses (TSAs).

Results: Five randomized trials (2234 patients with a history of adenomas) were included. Two of the 5 trials showed either unclear or high risks of bias in most criteria. Meta-analysis of good quality RCTs suggest a moderate protective effect of calcium supplementation on recurrence of adenomas (relative risk [RR], 0.88 [95% CI 0.79-0.99]); however, its effects on advanced adenomas did not show statistical significance (RR, 1.02 [95% CI 0.67-1.55]). Subgroup analyses demonstrated a greater protective effect on recurrence of adenomas with elemental calcium dose ≥1600 mg/day (RR, 0.74 [95% CI 0.56-0.97]) compared to ≤1200 mg/day (RR, 0.84 [95% CI 0.73-0.97]). No major serious adverse events were associated with the use of calcium, but there was an increase in the incidence of hypercalcemia (P = .0095). TSA indicated a lack of firm evidence for a beneficial effect. Concerns with directness and imprecision rated down the quality of the evidence to "low."

Conclusion: The available good quality RCTs suggests a possible beneficial effect of calcium supplementation on the recurrence of adenomas; however, TSA indicated that the accumulated evidence is still inconclusive. Using GRADE-methodology, we conclude that the quality of evidence is low. Large well-designed randomized trials with low risk of bias are needed.

Figure 1

Incidence of recurrent adenomas in subjects with a history of adenomas randomized to calcium.

Figure 2

Incidence of recurrent advanced adenomas in subjects with a history of adenomas randomized to calcium.

Figure 3

Trial sequential analysis (TSA) assessing the effect of supplemental calcium on recurrent adenoma incidence. The information size required to demonstrate or reject a 12% relative reduction (low-bias risk trail estimate) based on an assumption of 38.5% of control group event proportion (median proportion of incidence of recurrent adenomas in the control group) with type 1 error of 5% two-sided and type II error of 20% is 3504 patients. The cumulated Z-curve (blue) crosses the traditional boundary but not the trial sequential monitoring boundary indicating the lack of firm evidence for a beneficial effect of 12% relative risk reduction of the intervention when the analysis is adjusted for repetitive testing on accumulating data. There is insufficient information to reject or detect the anticipated intervention effect (12%) as the required information size is not yet reached. TSA = trial sequential analysis.