Outcomes for Tolerable Upper Intake Levels

clipped from July 2009 report

We included only clinical outcomes of tolerable upper intake levels, such as all-cause mortality, cancer (incidence and mortality), soft tissue calcification, renal outcomes, and adverse events reported in RCTs.
Results of all-cause mortality and cancer have been described in previous sections. In brief, we did not find vitamin D and/or calcium associated with an increased risk of mortality. For cancer risk, there were some observational studies reporting high calcium intake may be associated with an increased risk of prostate cancer (see “Prostate cancer” in “Calcium and cancer” section). We did not identify any studies on soft tissue calcification and tolerable upper intake levels.
Renal Outcomes
The WHI trial on women aged 50 to 79 years, examined the effect of vitamin D3 400 IU (the Recommended Dietary Allowance for women aged 50 to 70 years and below the 600 IU recommended intake for women > 70 years) in combination with 1000 mg calcium carbonate versus placebo and found an increase in the risk of renal stones (Hazard Ratio 1.17 95 percent CI 1.02, 1.34), corresponding to 5.7 events per 10,000 person years of exposure.71 It should be noted that women in both groups were allowed to take additional vitamin D supplements up to 600 IU and later 1000 IU per day and calcium supplements up to 1000 mg per day. The baseline total calcium intakes (from foods and supplements) were high: 34 percent consumed less than 800 mg/d, 26 percent consumed 800 to 1200 mg/d, and 40 percent consumed more than 1200 mg/d. A prior publication from WHI trial provided the same data on the risk of renal stones was also included in the Ottawa EPC report.
No studies were identified that evaluated the effect of vitamin D, calcium, or combined vitamin D and calcium on other renal outcomes.
Adverse Events Reported in RCTs.
The reporting of adverse events in RCTs was generally inadequate, and most trials were not adequately powered to detect adverse events. Among the 63 RCTs included in this report, 47 did not report information on adverse events.
Five RCTs (in 6 publications) that enrolled a total of 444 subjects reported no adverse events during the trial periods.35,51,227,238,239 Of these, one RCT administered combination of vitamin D2 (1600 or 3600 IU/d) and vitamin D3 (400 IU/d) supplements for 3 months, two RCTs administered vitamin D supplements (type of vitamin D not reported) with doses ranging from 200 to 2000 IU/d for 3 weeks or 1 year, one RCT used high-dose intermittent vitamin D3 supplement (120,000 IU sachets given 3 times, every 2 weeks, for 6 weeks), and one RCT administered 1200 IU/d vitamin D2 supplement for 5 years.
Eleven RCTs reported at least one adverse event (Table 107). Excessive gas, bloating, and gastrointestinal discomforts were reported to be associated with calcium supplementation (doses ranged from 600 to 1000 mg/d). Other RCTs of vitamin D (doses ranged from 400 to 5714 IU/d vitamin D3 or ranged from 5000 to 10,000 vitamin D2) and/or calcium supplementations (doses ranged from 200 to 1500 mg/d) reported few

cases of gastrointestinal disruption such as constipation, diarrhea, upset stomach, musculoskeletal soreness, primary hyperparathyroidism, hypercalcemia, renal calculi and craniotabes. One RCT reported some adverse events that required hospital admission, including retrosternal pain, a non-ST elevation myocardial infarction and a transient ischemic attack (all 3 cases in vitamin D 400 IU/d plus exercise training group) and one case of acute cholecystitis (in calcium, vitamin D plus exercise training group).80 Another RCT reported that “there were no significant differences between the vitamin D and the control groups in the rate of incident cancer and vascular disease (ischemic heart disease and stroke)” (actual data not provided), and one participant died during the study.98 However, these adverse events may or may not be associated with vitamin D and/or calcium supplementation in this study. Also described earlier in the “Renal outcomes” section, the WHI trial examined the effect of vitamin D3 400 IU in combination with 1000 mg calcium carbonate versus placebo and found an increase in the risk of renal stones (Hazard Ratio 1.17 95 percent CI 1.02, 1.34), corresponding to 5.7 events per 10,000 person years of exposure.71
Ottawa EPC report:
A total of 22 trials reported data on toxicity-related outcomes, 21 of which used doses above 400 IU/d. Toxicity results from trials with intakes of vitamin D above current reference intakes varied and this may have been related to different doses, baseline characteristics of populations or exposure times. Most trials excluded subjects with renal insufficiency or hypercalcemia, were of small sample sizes and had short durations of exposure to vitamin D. Event rates were low across trials in both the treatment and placebo arms.