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Vitamin D - Baseline Status and Effective Dose - Editorial
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Download the PDF here
Download the PDF here
Download the PDF here
original article below -
Robert P. Heaney, M.D.
N Engl J Med July 5 2012
There has been more ink spilled over the efficacy of vitamin D than over that of most nutrients, with the possible exception of sodium. Why is this? Dozens of randomized, controlled trials have been conducted - some large, and many small. Unfortunately, their results have been inconsistent - some positive, some null, and the odd one or two actually negative. Even the many available meta-analyses on the topic have yielded inconsistent results. If vitamin D is actually efficacious, why is there this inconsistency?
In this issue of the Journal, in yet another meta-analysis, Bischoff-Ferrari et al.1 suggest several explanations, including differences in study inclusion criteria and in the handling of adherence to the trial supplement. An even more salient reason is failure to consider the dose-response relation that vitamin D shares with most nutrients. Figure 1shows that in persons whose baseline values differ, an identical nutrient intake may or may not produce a measurable response. Unfortunately, most of the randomized, controlled trials of vitamin D that have been published to date have paid little attention to baseline status. Among the 31,022 patients whose results were analyzed by Bischoff-Ferrari et al., data on baseline concentrations of 25-hydroxyvitamin D were available for only 4383 patients (barely 14%). Instead, the studies focused almost exclusively on the assigned dose.
Figure 1 makes it clear that giving additional amounts of a nutrient to persons who already have enough, or not giving enough to push a person with a deficiency up onto the ascending limb of the response curve, is likely to produce a null response. In this regard, as in several other respects, nutrients are unlike drugs.2 Once an adequate concentration has been achieved, additional intake has no effect. This truism is little more than a restatement of a long-standing skepticism among clinicians about the purported benefits of many nutrient supplements3 and is the explicit basis for the recommendations of the Institute of Medicine.4
Despite the consensus that more is not better, we have continued to conduct trials (and include them in meta-analyses) without regard to ensuring the presence of two key features: baseline status and dose adequacy. For example, two large, randomized, controlled trials5,6 tested the effect of supplemental calcium on the risks of preeclampsia or fracture in patients whose baseline calcium intakes were already at the recommended levels for adequacy. Both trials had null outcomes. But both failed to address the underlying hypothesis that low calcium intake increased the risk of preeclampsia or fracture because neither trial included a group with low calcium intake. Nevertheless, both trials were included in the systematic review7 used by the Institute of Medicine in formulating its intake recommendations for calcium.4 Because of their relatively large samples, both trials heavily weighted the aggregate effect toward the null hypothesis in the corresponding meta-analysis.
The second of the two key considerations, adequacy of dose, was specifically addressed by Bischoff-Ferrari et al., who used individual adherence data to modify the assigned dose. They found that fracture risk was reduced only among persons who were assigned to receive doses of 800 IU per day or higher - a finding that would be more persuasive if it were accompanied by data on the baseline concentration and induced change in the level of 25-hydroxyvitamin D, but very few of the included studies provided this information. Nevertheless, such an intake is consistent with the guidelines for adults that have been issued by the Endocrine Society (1500 to 2000 IU per day).8
The question of how much vitamin D is enough is likely to remain muddled as long as meta-analyses focus on trial methodology rather than on biology. For example, the trial by Sanders et al.,9 which used a single yearly dose (500,000 IU) and was included in the meta-analysis by Bischoff-Ferrari et al., was methodologically sound. Biologically, however, that trial was seriously flawed, with an intertreatment interval that was 12 times as long as the half-life of the agent in the body and a dose that almost certainly induced transient vitamin D intoxication in the 2 to 3 weeks after its administration. If there is a parallel between nutrient repletion and thyroid-replacement therapy, which are both daily matters, then this Stosstherapie (i.e., massive single doses of the vitamin) is not the way to evaluate vitamin D efficacy.
Given the congruence of the findings of this latest meta-analysis with the guidelines from the Endocrine Society, it would appear to be prudent, and probably helpful as well, to ensure an intake at the upper end of the range at which Bischoff-Ferrari et al. found a reduction in fracture risk.
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A Pooled Analysis of Vitamin D Dose Requirements for Fracture Prevention
INTRODUCTION: Approximately 75% of fractures occur in people 65 years of age or older.1 By 2050, the worldwide incidence of hip fractures is expected to increase by 240% among women and 310% among men.2
One strategy to prevent fractures in this population might be universal vitamin D supplementation. However, the results of several study level meta-analyses and one pooled participant-level analysis do not agree. Although one trial-level meta-analysis of double-blind, randomized, controlled trials suggested an 18% reduction in the incidence of hip fracture and a 20% reduction in the incidence of any nonvertebral fracture at a received dose of no less than 482 IU of vitamin D per day,3 three study-level meta-analyses4-6 and one pooled analysis of participant-level data7 from open-design and blinded trials suggested that vitamin D may have no effect on total fractures4 or may reduce hip fracture by 7 to 16%, if combined with calcium supplementation, regardless of the dose of vitamin D.4-7 The discordant findings may be explained, in part, by differences in the criteria for including trials in the analyses, with respect to blinding, vitamin D formulation (oral vs. injectable), or accommodations for nonadherence. Our analysis was designed to estimate the effects of vitamin D supplementation according to the actual intake of each participant, rather than simply the dose to which the participant was randomly assigned.
Background
The results of meta-analyses examining the relationship between vitamin D supplementation and fracture reduction have been inconsistent.
Methods
We pooled participant-level data from 11 double-blind, randomized, controlled trials of oral vitamin D supplementation (daily, weekly, or every 4 months), with or without calcium, as compared with placebo or calcium alone in persons 65 years of age or older. Primary end points were the incidence of hip and any nonvertebral fractures according to Cox regression analyses, with adjustment for age group, sex, type of dwelling, and study. Our primary aim was to compare data from quartiles of actual intake of vitamin D (including each individual participant's adherence to the treatment and supplement use outside the study protocol) in the treatment groups of all trials with data from the control groups.
Results
We included 31,022 persons (mean age, 76 years; 91% women) with 1111 incident hip fractures and 3770 nonvertebral fractures. Participants who were randomly assigned to receive vitamin D, as compared with those assigned to control groups, had a nonsignificant 10% reduction in the risk of hip fracture (hazard ratio, 0.90; 95% confidence interval [CI], 0.80 to 1.01) and a 7% reduction in the risk of nonvertebral fracture (hazard ratio, 0.93; 95% CI, 0.87 to 0.99). By quartiles of actual intake, reduction in the risk of fracture was shown only at the highest intake level (median, 800 IU daily; range, 792 to 2000), with a 30% reduction in the risk of hip fracture (hazard ratio, 0.70; 95% CI, 0.58 to 0.86) and a 14% reduction in the risk of any nonvertebral fracture (hazard ratio, 0.86; 95% CI, 0.76 to 0.96). Benefits at the highest level of vitamin D intake were fairly consistent across subgroups defined by age group, type of dwelling, baseline 25-hydroxyvitamin D level, and additional calcium intake.
Conclusions
High-dose vitamin D supplementation (≥800 IU daily) was somewhat favorable in the prevention of hip fracture and any nonvertebral fracture in persons 65 years of age or older. (Funded by the Swiss National Foundations and others.)
Discussion
This pooled analysis included a large participant-level data sample of double-blind, randomized, controlled trials of vitamin D supplementation that involved persons 65 years of age or older. The findings suggest that only a high intake of vitamin D leads to a significant reduction in the risk of fracture - with a 30% reduction in the risk of hip fracture and a 14% reduction in the risk of any nonvertebral fracture; this reduction is independent of the assigned treatment dose of vitamin D, age group, sex, type of dwelling, and study. Thus, it is possible that the results of typical intention-to-treat analyses of vitamin D supplementation, as replicated in this pooled analysis with a nonsignificant 10% reduction in the risk of hip fracture and a 7% reduction in the risk of any nonvertebral fracture, underestimate the benefit of vitamin D supplementation. Notably, the benefit at the highest actual-intake level of vitamin D was confirmed in the internal validation analysis, which compared the highest actual-intake level with the lowest, regardless of study assignment (treatment or control). A dose-response relationship between vitamin D and fracture risk is further supported by our analysis of baseline levels of 25-hydroxyvitamin D and prospective fracture risk.
Our findings suggest that some previous high-quality trials of vitamin D supplementation either showed no benefit owing to lower-than-intended doses of vitamin D or showed an unexpected benefit owing to higher-than-intended doses. For example, the RECORD trial by Grant et al.16 was designed with an intended dose of 800 IU per day, but the actual intake of vitamin D was lower, with a mean intake of 539 IU per day in the group that received vitamin D combined with calcium and 613 IU per day in the group that received vitamin D alone. Conversely, the Women's Health Initiative trial by Jackson et al.17 was designed with an intended dose of 400 IU per day, but the actual intake of vitamin D and the proportion of participants in the highest intake range were higher, which may in part explain the reduced risk of fracture that was observed in the older participants in that trial.
Previous meta-analyses have suggested that the benefits of vitamin D may be limited to older persons who live in institutions.4,6 Our subgroup analyses suggest that at the highest actual-intake level, the risk of hip fracture is reduced among all persons 65 years of age or older, whether they live in the community or in an institution. Our data further suggest that persons who are most vulnerable to vitamin D deficiency - those 85 years of age or older and those with very low baseline levels of 25-hydroxyvitamin D - benefit from vitamin D supplementation at least as much as others do. However, because of the reduced sample size and power, we are not able to determine whether this benefit is greater or simply equivalent.
Several previous meta-analyses suggested that the dose of vitamin D is irrelevant when vitamin D is combined with calcium.4-7 In contrast, our pooled subgroup analyses of the eight double-blind, randomized, controlled trials that used vitamin D combined with calcium indicate that with combined supplementation, the risk of fracture is reduced only at the highest actual-intake level of vitamin D. Furthermore, our data suggest that at the highest actual-intake level of vitamin D, a smaller amount of calcium supplementation (<1000 mg per day), as compared with a larger amount (≥1000 mg per day), may be more beneficial in reducing the risk of fracture - a finding that is consonant with epidemiologic studies.23,24
Our sensitivity analysis suggests that the vitamin D dosing interval may be relevant for reducing the risk of fracture. When we included in our sensitivity analysis the trial by Sanders et al.,11 in which one annual dose of vitamin was administered, the risk reduction was attenuated. Similarly, another study of annual supplementation with injectable vitamin D showed a null effect on the risk of fracture.25 In contrast, a trial from which the source data set could not be retrieved showed that a dose of 100,000 IU of vitamin D taken orally every 4 months was associated with a 33% reduction in the risk of a first hip, wrist, or forearm fracture, suggesting that the 4-month dosing interval is satisfactory.8 More frequent dosing (daily or weekly) in adequate amounts is supported by our analysis as a means of lowering the risk of both hip and nonvertebral fractures.
The strengths of our pooled analysis are the large sample, the assessment of fracture risk by actual intake of vitamin D, and the consistency of the primary findings and the internal validation study. The principal limitation of our analysis is the unavailability of source data for 2 of the 14 qualifying trials8,9; however, inclusion of the trial-level data from these studies in a random-effects meta-analysis did not alter our findings. A further limitation is that we could not assess the effect of the highest quartile of actual intake of vitamin D (792 to 1000 IU per day) without additional calcium, because all trials that gave higher doses of vitamin D (≥800 IU per day with good adherence) also gave calcium. The threshold assessment of fracture was limited because baseline levels of 25-hydroxyvitamin D were available for only a subset of participants and because the assays used to measure 25-hydroxyvitamin varied among the studies. However, after adjustment for this variation and all other covariates, the dose-response relationship remained significant.
Our findings support the most recent recommendation from the Institute of Medicine26 that persons 65 years of age or older receive 800 IU of vitamin D per day, but suggest that a 25-hydroxyvitamin D level of more than 60 nmol per liter may be most beneficial for reducing the risk of fractures. Furthermore, although our data did not allow us to determine whether the actual-intake level of a calcium supplement influenced the effect of vitamin D at the highest actual-intake level, it would be important for future studies to consider the possibility that a calcium-supplement intake of 1000 mg per day or more, combined with high-dose vitamin D (≥800 IU per day) may be harmful. Calcium supplements without vitamin D have been reported to increase the risk of hip fracture.27
In conclusion, our data suggest that high-dose vitamin D supplementation (≥800 IU per day) may reduce the risk of hip fracture in persons 65 years of age or older, independently of type of dwelling, age, and sex. Furthermore, our data support a 25-hydroxyvitamin D level above 60 nmol per liter for the prevention of fractures.
Results
Characteristics of the Participants
The clinical characteristics of 31,022 participants from 11 trials are shown in Table 1. Of 4383 participants with baseline measurements of 25-hydroxyvitamin D, 24% had levels of less than 30 nmol per liter, 62% had levels of less than 50 nmol per liter, and 88% had levels of less than 75 nmol per liter. Appendix 1 in the Supplementary Appendix, available with the full text of this article at NEJM.org, shows the assigned treatment doses and actual-intake amounts in each trial.
Primary Analyses
The intention-to-treat analysis showed a nonsignificant 10% reduction in the risk of hip fracture (hazard ratio, 0.90; 95% confidence interval [CI], 0.80 to 1.01), which did not differ according to assigned treatment dose. On the basis of our primary comparison of actual intake, however, there was a significant 30% reduction in the incidence of hip fracture at the highest actual-intake level (792 to 2000 IU per day) in treated participants, as compared with controls (Table 2) with a similar finding for the adherence-adjusted dose, which did not include supplements outside the study protocol (29% reduction). Notably, there was no reduction in the risk of hip fracture at any actual-intake level lower than 792 IU per day.
In the internal validation analysis, regardless of study assignment, the reduction in the risk of hip fracture was 30% and was significant at the highest actual-intake level (792 to 2000 IU per day), as compared with the lowest actual-intake level (0 to 360 IU per day), suggesting a dose-response relationship. Such a relationship was also suggested by the threshold assessment of hip-fracture risk according to quartile of baseline 25-hydroxyvitamin D level in the 4383 participants for whom serum measurements were available (Figure 1A).
The intention-to-treat analysis showed a 7% overall reduction in the risk of nonvertebral fracture (hazard ratio, 0.93; 95% CI, 0.87 to 0.99), with no risk reduction at doses of 400 IU per day or less (hazard ratio, 0.96; 95% CI, 0.89 to 1.05), and an 11% reduction at doses higher than 400 IU per day (hazard ratio, 0.89; 95% CI, 0.80 to 0.98). In the primary comparison of actual intake, the pattern was largely the same as that observed for hip fracture (Table 2). For prevention of nonvertebral fracture, a dose-response relationship was supported by the internal validation analysis (Table 2) and by the threshold assessment of baseline 25-hydroxyvitamin D level (Figure 1B). Primary findings at the highest actual-intake level were robust when individual trials were excluded (Appendixes 2A and 2B in the Supplementary Appendix).
Sensitivity Analyses
When we included the trial-level findings for the two trials with missing source data8,9 (treatment doses, 800 IU and 833 IU per day) at the highest actual-intake level, results were unchanged for hip fracture (relative risk, 0.70; 95% CI, 0.59 to 0.84) and any nonvertebral fracture (relative risk, 0.84; 95% CI, 0.74 to 0.95). The inclusion of the trial by Sanders et al.,11 in which a high annual dose of vitamin D was administered, attenuated the findings in the intention-to-treat analysis (Appendix 3 in the Supplementary Appendix) and at the highest actual-intake level (Appendixes 2A and 2B in the Supplementary Appendix). The results of additional sensitivity analyses were robust (data not shown), and there was homogeneity among trials at the quartile level of actual intake of vitamin D (Figure 2A and 2B).
Subgroup Analyses
There were no significant interactions, after Bonferroni adjustment, between the highest actual intake of vitamin D and subgroups defined by age, type of dwelling, baseline level of 25-hydroxyvitamin D, and additional calcium intake (Table 3). This suggests that the effect of the highest actual intake of vitamin D was relatively consistent across these subgroups. However, reduced power, especially in the subset of participants for whom baseline levels of 25-hydroxyvitamin D were available and the subset with additional calcium intake, may have masked some true differences. There was a suggestion that the highest actual-intake level of vitamin D was less beneficial for the prevention of nonvertebral fracture in participants living in community dwellings than in those living in institutions (P=0.02), with the P value indicating a significant difference on the basis of the conventional threshold for significance but not the Bonferroni-adjusted threshold.
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