Benefit-risk assessment of vitamin D supplementation

Abstract

Current intake recommendations of 200 to 600 IU vitamin D per day may be insufficient for important disease outcomes reduced by vitamin D.

Introduction: This study assessed the benefit of higher-dose and higher achieved 25-hydroxyvitamin D levels [25(OH)D] versus any associated risk.

Methods and results: Based on double-blind randomized control trials (RCTs), eight for falls (n = 2426) and 12 for non-vertebral fractures (n = 42,279), there was a significant dose-response relationship between higher-dose and higher achieved 25(OH)D and greater fall and fracture prevention. Optimal benefits were observed at the highest dose tested to date for 700 to 1000 IU vitamin D per day or mean 25(OH)D between 75 and 110 nmol/l (30-44 ng/ml). Prospective cohort data on cardiovascular health and colorectal cancer prevention suggested increased benefits with the highest categories of 25(OH)D evaluated (median between 75 and 110 nmol/l). In 25 RCTs, mean serum calcium levels were not related to oral vitamin D up to 100,000 IU per day or achieved 25(OH)D up to 643 nmol/l. Mean levels of 75 to 110 nmol/l were reached in most RCTs with 1,800 to 4,000 IU vitamin D per day without risk.

Conclusion: Our analysis suggests that mean serum 25(OH)D levels of about 75 to 110 nmol/l provide optimal benefits for all investigated endpoints without increasing health risks. These levels can be best obtained with oral doses in the range of 1,800 to 4,000 IU vitamin D per day; further work is needed, including subject and environment factors, to better define the doses that will achieve optimal blood levels in the large majority of the population.

Figure 1

Evidence from controlled RCTs: Trend-plots on benefit (fall and non-vertebral fracture prevention) and risk (mean achieved serum calcium levels) by dose of vitamin D and achieved 25(OH)D levels Figure 1A – by dose of vitamin D Figure 1B – by achieved 25(OH)D level Blackcircles represent relative risks (RRs) from 12 double-blind RCTs on vitamin D supplementation and non-vertebral fracture risk as summarized in a 2009 meta-analysis (Bischoff-Ferrari et al; Archives of Internal Medicine 2009[1]). Trendline is based on series of effect sizes (circles). For any non-vertebral fractures, anti-fracture efficacy increased significantly with higher received dose (meta-regression: Beta = - 0.0007; p = 0.003; Figure 1 A) and higher achieved 25-hydroxyvitamin D levels (meta-regression: Beta = - 0.005; p = 0.04; Figure 1 B). Black triangles represent relative risks (RRs from 8 double-blind RCTs on vitamin D supplementation and fall risk as summarized in a 2009 meta-analysis (Bischoff-Ferrari et al; in press British Medical Journal[2]). Trendline is based on series of effect sizes (triangles). A meta-regression, which included 2426 individuals from 8 RCTs, indicated a significant inverse relationship between higher treatment dose and the risk of sustaining at least one fall (Beta-estimate for dose: 700 IU or higher compared to less = - 0.337; p = 0.02; Figure 1 A). A meta-regression, which included 1447 individuals from 6 RCTs with reported 25(OH)D levels, indicated a significant inverse relationship between higher achieved 25(OH)D level in the treatment group and the risk of sustaining at least one fall (Beta-estimate for a 25(OH)D of 60 nmol/l or higher compared to lower = - 0.586; p = 0.005; Figure 1 B). Grey squares represent mean calcium levels in the treatment group from 25 vitamin D supplementation trials (28 data points; one trial with separate report from community-dwelling and hospitalized older individuals[45]). Trendline is based on series of mean serum calcium levels (grey squares). The doses of vitamin D applied in these trials ranged from 400 to 100'000 IU vitamin D per day. There was flat trend line for mean serum calcium levels with higher dose of vitamin D (Figure 1 A) and higher achieved 25-hydroxyvitamin D levels (Figure 1 B).

Figure 1

Evidence from controlled RCTs: Trend-plots on benefit (fall and non-vertebral fracture prevention) and risk (mean achieved serum calcium levels) by dose of vitamin D and achieved 25(OH)D levels Figure 1A – by dose of vitamin D Figure 1B – by achieved 25(OH)D level Blackcircles represent relative risks (RRs) from 12 double-blind RCTs on vitamin D supplementation and non-vertebral fracture risk as summarized in a 2009 meta-analysis (Bischoff-Ferrari et al; Archives of Internal Medicine 2009[1]). Trendline is based on series of effect sizes (circles). For any non-vertebral fractures, anti-fracture efficacy increased significantly with higher received dose (meta-regression: Beta = - 0.0007; p = 0.003; Figure 1 A) and higher achieved 25-hydroxyvitamin D levels (meta-regression: Beta = - 0.005; p = 0.04; Figure 1 B). Black triangles represent relative risks (RRs from 8 double-blind RCTs on vitamin D supplementation and fall risk as summarized in a 2009 meta-analysis (Bischoff-Ferrari et al; in press British Medical Journal[2]). Trendline is based on series of effect sizes (triangles). A meta-regression, which included 2426 individuals from 8 RCTs, indicated a significant inverse relationship between higher treatment dose and the risk of sustaining at least one fall (Beta-estimate for dose: 700 IU or higher compared to less = - 0.337; p = 0.02; Figure 1 A). A meta-regression, which included 1447 individuals from 6 RCTs with reported 25(OH)D levels, indicated a significant inverse relationship between higher achieved 25(OH)D level in the treatment group and the risk of sustaining at least one fall (Beta-estimate for a 25(OH)D of 60 nmol/l or higher compared to lower = - 0.586; p = 0.005; Figure 1 B). Grey squares represent mean calcium levels in the treatment group from 25 vitamin D supplementation trials (28 data points; one trial with separate report from community-dwelling and hospitalized older individuals[45]). Trendline is based on series of mean serum calcium levels (grey squares). The doses of vitamin D applied in these trials ranged from 400 to 100'000 IU vitamin D per day. There was flat trend line for mean serum calcium levels with higher dose of vitamin D (Figure 1 A) and higher achieved 25-hydroxyvitamin D levels (Figure 1 B).

Figure 2

Trend-plots on benefit from observational studies (cardiovascular disease prevention and colorectal cancer prevention) and risk (case reports of hypercalcemia) by achieved 25(OH)D level Dashed lines relate to data from epidemiologic studies on the RR of incident hypertension[4], all-cause[90] and cardiovascular[90] mortality and colorectal cancer [91] based on categories of median 25-hydroxyvitamin D levels. For colorectal cancer, we included a quantitative meta-analysis of 5 studies[91]. Based on this summary of non-skeletal endpoints of public health significance, there was a dose-response of better health status with higher median 25(OH)D levels. By visual inspection, the desirable median serum 25(OH)D level to be achieved for all endpoints was approximately 100 nmol/l. The solid grey diamonds relate to 24 case-reports of hypercalcemia with corresponding 25(OH)D levels. 22 of 24 cases of hypercalcemia were reported at 25(OH)D levels beyond 240 nmol/l 25(OH)D.

Figure 3

Dose of vitamin D and achieved 25(OH)D levels based on RCTs with a duration of at least 4 weeks Figure 3 A: Lower dose trials (double-blind fall and fracture RCTs) This graph summarizes data from identified RCTs (as illustrated in Figure 1) with oral doses of vitamin D of less than 10,000 IU vitamin D per day and a treatment duration of at least 4 weeks. Dots either represent the mean 25(OH)D level from a single trial or the mean and the range of several trials. There were 3 RCTs with 400 IU vitamin D per day with a mean increase in 25(OH)D levels to 56.7 nmol/l (range: 44 to 64 nmol/l) after a mean treatment duration of 653 days (range: 140 to 1148 days). The trial with 700 IU vitamin D and achieved mean serum levels close to 100 nmol/l ay be an outlier due to the high starting levels documented in the trial (84 nmol/l in men and 72 nmol/l in women age 65 and older[26]). There were 9 RCTs for 800 IU per day with a mean increase in 25(OH)D levels to 75 nmol/l (range: 60 to 105 nmol/l) after a mean treatment duration of 697 days (range: 56 to 1680 days). There were 7 RCTs with 2000 IU vitamin D per day with a mean increase in 25(OH)D levels to 87 nmol/l (range: 71 to 103 nmol/l) after a mean treatment duration of 146 days (range: 42 to 365 days).There were 3 RCTs for 4000 IU per day with a mean increase in 25(OH)D levels to 120 nmol/l (range: 85.5 to 160 nmol/l) after a mean treatment duration of 168 days (range: 56 to 365 days). And there were 4 trials with a treatment dose between 5720 and 7600 IU vitamin D per day with a mean increase in 25(OH)D levels to 128 nmol/l (range: 120–147 nmol/l). From this summary of available dose-response data from RCTs, most trials among healthy younger and older adults reached a mean value in the target range of 75 to 110 nmol/l with 1800 IU to 4000 IU vitamin D3 per day treated for at least 42 days.