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Therapeutics
Review: Evidence for the effect of vitamin D supplementation on many patient outcomes was assessed
Theodoratou E, Tzoulaki I, Zgaga L, Ioannidis JP. Vitamin D and multiple health outcomes: umbrella review of systematic reviews and meta-analyses of observational studies and randomised trials. BMJ. 2014;348:g2035.
Clinical impact ratings: F ★★★★★★✩ C ★★★★★✩✩ R ★★★★★✩✩ Question
Review methods
What is the effect of vitamin D supplementation on various outcomes?
MEDLINE and EMBASE/Excerpta Medica (both to Oct 2013) were searched for systematic reviews or meta-analyses of observational studies or randomized controlled trials (RCTs). 107 systematic reviews and 74 meta-analyses of observational studies of plasma vitamin D levels and 87 meta-analyses of RCTs (median number of studies = 4, median n = 446) met selection criteria. Only meta-analyses of RCTs are reported in this abstract. 57 meta-analyses (reported in 19 articles) did not overlap and included CV disease (3); neonatal, infant, or child outcomes (4); pregnancy outcomes (3); skeletal diseases (21); metabolic disorders (7); and other outcomes (18).
Review scope Included studies were English-language meta-analyses of vitamin D supplementation compared with placebo, or vitamin D plus another compound (e.g., calcium) compared with the other compound alone; or meta-analyses of observational studies of vitamin D levels. The studies reported any clinical outcome in any population. Exclusion criteria included meta-analyses of observational studies assessing dietary or supplemental vitamin D intake or ultraviolet B exposure; vitamin D status as the outcome; or prevalence of vitamin D deficiency in certain disease populations. Outcomes included cardiovascular (CV) disease; neonatal, infant, or child outcomes; pregnancy outcomes; skeletal outcomes; and mortality.
Main results
Meta-analyses of RCTs show that vitamin D supplementation reduced risk for low birthweight but did not differ from placebo or no vitamin D for CV disease, mortality, or other outcomes (Table). Some meta-analyses showed that vitamin Vitamin D supplementation vs no supplementation or placebo* D supplementation reduced nonvertebral fractures in Compounds Outcomes Number of trials (n) RRR/RRI (95% CI) older adults; however, in other meta-analyses, suppleVitamin D Cardiovascular disease 2 (NR) RRR 5% (−5 to 14) mentation did not differ from no supplementation for Low birthweight 3 (507) RRR 60% (29 to 77) nonvertebral or vertebral fractures (Table). Small for gestational age 2 (305) RRR 33% (−11 to 60)
Vitamin D2, D3 or active D Vitamin D2, D3 or D
Preterm delivery
2 (529)
RRR 23% (−66 to 65)
Nonvertebral fractures†
9 (7130)
RRR 21% (1 to 37)
Fractures
10 (25 016)
RRI 1% (−7 to 9)
Hip fractures
9 (24 749)
RRI 15% (−1 to 33)
Vertebral fractures
5 (9138)
RRR 10% (−92 to 58)
Vitamin D2
Mortality
8 (17 079)
RRI 4% (−3 to 11)
Vitamin D3
Mortality
9 (12 824)
RRR 9% (−2 to 18)
*NR = not reported; other abbreviations defined in Glossary. RRR, RRI, and CI calculated from relative risks in article.
Conclusion Vitamin D supplementation may improve low birthweight, but results for other outcomes were inconsistent or did not differ from no vitamin D supplementation. Source of funding: No external funding. For correspondence: Dr. E. Theodoratou, University of Edinburgh, Edinburgh, Scotland, UK. E-mail [email protected]. ■
†In older adults.
Commentary Vitamin D is essential for normal bone metabolism. Rickets was a major health problem until the mid-20th century, especially in poor children in northern industrialized cities. Now, with better diets, addition of vitamin D to such foods as milk and breakfast cereals, more exposure to sunlight, and widespread use of multivitamin supplements, rickets has become uncommon. But are vitamin D levels in developed countries still low enough to cause a variety of other health problems, ones that can only be recognized by statistical analyses of rigorous research and not in the examination room? If yes, could these problems be prevented with supplements? Answers probably depend on the baseline nutritional status of the persons studied. If levels of vitamin D are sufficient in most persons, there would be little difference in outcomes between those with relatively low versus relatively high levels and little reason to expect benefit from supplements. It is easy to be overwhelmed by the number of studies published about vitamin D deficiency and the effects of supplementation.
JC4
© 2014 American College of Physicians
The reviews by Theodoratou and colleagues and Chowdhury and colleagues help us see the big picture. In the populations studied, which were mainly in North America and Europe, lower vitamin D levels were associated with few health effects, even on bone mineral density and fractures. In observational studies, relative risks for high versus low vitamin D levels for various outcomes were small enough that they may be a result of bias or uncontrolled confounding. Similarly, RCTs of vitamin D supplementation report only a few small effects, including only modest, if any, benefit for preventing fractures. Observational studies tended to show larger effects than RCTs with the same outcomes, which is generally attributed to confounding from healthier lifestyles and better health outcomes in persons who choose to eat well or take vitamins. We have seen this before when observational studies consistently found that low vitamin E was a risk factor for CV disease, but RCTs of supplements found no effect (1). What about the few outcomes that showed statistical improvements with vitamin D? Of those measuring clinical outcomes, the (continued on page 5) 15 July 2014 | ACP Journal Club | Volume 161 • Number 2
Downloaded From: http://annals.org/pdfaccess.ashx?url=/data/journals/aim/930510/ by a NYU Medical Center Library User on 03/09/2017
Therapeutics
Review: Vitamin D3 supplementation may reduce mortality in adults; vitamin D2 does not
Chowdhury R, Kunutsor S, Vitezova A, et al. Vitamin D and risk of cause specific death: systematic review and meta-analysis of observational cohort and randomised intervention studies. BMJ. 2014;348:g1903.
Clinical impact ratings: F ★★★★★✩✩ C ★★★★★✩✩ G ★★★★★★✩ O ★★★★★✩✩ Question Does vitamin D supplementation affect mortality compared with placebo or no treatment?
Review scope Included studies assessed associations of circulating 25-hydroxyvitamin D levels with cause-specific or all-cause mortality in general populations or disease-specific populations of adults or compared vitamin D supplements with placebo or no treatment in adults. Outcomes included all-cause mortality.
Review methods MEDLINE, EMBASE/Excerpta Medica, and Cochrane databases (all to Aug 2013) were searched for observational studies or randomized controlled trials (RCTs). 73 cohort studies and 22 RCTs (n = 30 716, mean age range 56 to 85 y, follow-up range 0.4 to 7 y) met selection criteria. RCT results are reported in this abstract. All RCTs had low risk for bias for randomization, 20 for
concealed allocation, 18 for blinding of participants and personnel, 8 for blinded outcome assessments, and 12 for adequate follow-up. 14 RCTs assessed vitamin D3, and 8 assessed vitamin D2. Subgroup analyses by form of vitamin D (D2 or D3) were done.
Main results Meta-analyses show that, overall, vitamin D supplementation did not differ from placebo for mortality; vitamin D3 did reduce mortality more than placebo, but vitamin D2 did not (Table).
Conclusion In adults, vitamin D3 supplementation may reduce mortality; vitamin D2 supplementation does not. Source of funding: No external funding. For correspondence: Dr. R. Chowdhury, University of Cambridge, Cambridge, England, UK. E-mail [email protected]. ■
Vitamin D supplementation vs placebo in adults* Outcome
Number of trials (n)
All-cause mortality
22 (30 716)
Weighted event rates
At 0.4 to 7 y
Vitamin D Placebo NR
RRR (CI)
NNT (CI)
NR
2% (−2 to 6)
NS
17%
11% (1 to 20)
53 (29 to 579)
Vitamin D3 14 (13 637)
15%
Vitamin D2 8 (17 079)
17%
RRI (CI) 16%
4% (−3 to 11)
NS
*NR = not reported; NS = not significant; other abbreviations defined in Glossary. RRR, RRI, NNT, and CI calculated from control event rates and relative risks in article using a randomeffects model.
Commentary (continued from page 4) systematic reviews suggest, but do not establish beyond reasonable doubt, small effects of vitamin D on birthweight, rate of falls, nonvertebral fractures, muscle strength, and dental caries in children. In RCTs, vitamin D3 reduced overall mortality among older adults, whereas vitamin D2 did not. A possible difference in effectiveness of vitamins D2 and D3 supplements is worth more study but is not yet ready for clinical application because the effects of vitamin D3 were in the context of multiple comparisons and the results were only borderline significant. Studies with P values around 0.05 are often not statistically significant at the 0.05 level when repeated or augmented with additional data (2). Despite weak effects of vitamin D in developed countries, clinicians should be alert for the occasional patient who is at increased risk for vitamin D deficiency (e.g., those with fat malabsorption or severe osteoporosis) who could benefit from supplements. However, for most patients, testing for vitamin D levels or recommending individually tailored supplements goes beyond the evidence. True, the prevalence of laboratory-defined vitamin D
15 July 2014 | ACP Journal Club | Volume 161 • Number 2
deficiency is high, especially in the elderly, but the small-toabsent effects of supplementation on a wide variety of health outcomes call into question the clinical validity of the laboratory definition of “normal.” Nevertheless, if one wanted to give vitamin D supplements the benefit of the doubt, it is not unreasonable to recommend small doses (e.g., 600 IU/d) to unselected patients on the grounds that these supplements are likely safe (3) and may have some small beneficial effects. Robert H. Fletcher, MD, MSc Harvard Medical School Boston, Massachusetts, USA References 1. Yusuf S, Dagenais G, Pogue J, Bosch J, Sleight P. Vitamin E supplementation and cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators. N Engl J Med. 2000;342:154-60. 2. Wood J, Freemantle N, King M, Nazareth I. Trap of trends to statistical significance: likelihood of near significant P value becoming more significant with extra data. BMJ. 2014;348:g2215. 3. Otten JJ, Hellwig JP, Meyers LD, eds. Dietary reference intakes: the essential guide to nutrient requirements. Washington: National Academies Press; 2006.
© 2014 American College of Physicians
Downloaded From: http://annals.org/pdfaccess.ashx?url=/data/journals/aim/930510/ by a NYU Medical Center Library User on 03/09/2017
JC5
Therapeutics
Review: Evidence for the effect of vitamin D supplementation on many patient outcomes was assessed
Theodoratou E, Tzoulaki I, Zgaga L, Ioannidis JP. Vitamin D and multiple health outcomes: umbrella review of systematic reviews and meta-analyses of observational studies and randomised trials. BMJ. 2014;348:g2035.
Clinical impact ratings: F ★★★★★★✩ C ★★★★★✩✩ R ★★★★★✩✩ Question
Review methods
What is the effect of vitamin D supplementation on various outcomes?
MEDLINE and EMBASE/Excerpta Medica (both to Oct 2013) were searched for systematic reviews or meta-analyses of observational studies or randomized controlled trials (RCTs). 107 systematic reviews and 74 meta-analyses of observational studies of plasma vitamin D levels and 87 meta-analyses of RCTs (median number of studies = 4, median n = 446) met selection criteria. Only meta-analyses of RCTs are reported in this abstract. 57 meta-analyses (reported in 19 articles) did not overlap and included CV disease (3); neonatal, infant, or child outcomes (4); pregnancy outcomes (3); skeletal diseases (21); metabolic disorders (7); and other outcomes (18).
Review scope Included studies were English-language meta-analyses of vitamin D supplementation compared with placebo, or vitamin D plus another compound (e.g., calcium) compared with the other compound alone; or meta-analyses of observational studies of vitamin D levels. The studies reported any clinical outcome in any population. Exclusion criteria included meta-analyses of observational studies assessing dietary or supplemental vitamin D intake or ultraviolet B exposure; vitamin D status as the outcome; or prevalence of vitamin D deficiency in certain disease populations. Outcomes included cardiovascular (CV) disease; neonatal, infant, or child outcomes; pregnancy outcomes; skeletal outcomes; and mortality.
Main results
Meta-analyses of RCTs show that vitamin D supplementation reduced risk for low birthweight but did not differ from placebo or no vitamin D for CV disease, mortality, or other outcomes (Table). Some meta-analyses showed that vitamin Vitamin D supplementation vs no supplementation or placebo* D supplementation reduced nonvertebral fractures in Compounds Outcomes Number of trials (n) RRR/RRI (95% CI) older adults; however, in other meta-analyses, suppleVitamin D Cardiovascular disease 2 (NR) RRR 5% (−5 to 14) mentation did not differ from no supplementation for Low birthweight 3 (507) RRR 60% (29 to 77) nonvertebral or vertebral fractures (Table). Small for gestational age 2 (305) RRR 33% (−11 to 60)
Vitamin D2, D3 or active D Vitamin D2, D3 or D
Preterm delivery
2 (529)
RRR 23% (−66 to 65)
Nonvertebral fractures†
9 (7130)
RRR 21% (1 to 37)
Fractures
10 (25 016)
RRI 1% (−7 to 9)
Hip fractures
9 (24 749)
RRI 15% (−1 to 33)
Vertebral fractures
5 (9138)
RRR 10% (−92 to 58)
Vitamin D2
Mortality
8 (17 079)
RRI 4% (−3 to 11)
Vitamin D3
Mortality
9 (12 824)
RRR 9% (−2 to 18)
*NR = not reported; other abbreviations defined in Glossary. RRR, RRI, and CI calculated from relative risks in article.
Conclusion Vitamin D supplementation may improve low birthweight, but results for other outcomes were inconsistent or did not differ from no vitamin D supplementation. Source of funding: No external funding. For correspondence: Dr. E. Theodoratou, University of Edinburgh, Edinburgh, Scotland, UK. E-mail [email protected]. ■
†In older adults.
Commentary Vitamin D is essential for normal bone metabolism. Rickets was a major health problem until the mid-20th century, especially in poor children in northern industrialized cities. Now, with better diets, addition of vitamin D to such foods as milk and breakfast cereals, more exposure to sunlight, and widespread use of multivitamin supplements, rickets has become uncommon. But are vitamin D levels in developed countries still low enough to cause a variety of other health problems, ones that can only be recognized by statistical analyses of rigorous research and not in the examination room? If yes, could these problems be prevented with supplements? Answers probably depend on the baseline nutritional status of the persons studied. If levels of vitamin D are sufficient in most persons, there would be little difference in outcomes between those with relatively low versus relatively high levels and little reason to expect benefit from supplements. It is easy to be overwhelmed by the number of studies published about vitamin D deficiency and the effects of supplementation.
JC4
© 2014 American College of Physicians
The reviews by Theodoratou and colleagues and Chowdhury and colleagues help us see the big picture. In the populations studied, which were mainly in North America and Europe, lower vitamin D levels were associated with few health effects, even on bone mineral density and fractures. In observational studies, relative risks for high versus low vitamin D levels for various outcomes were small enough that they may be a result of bias or uncontrolled confounding. Similarly, RCTs of vitamin D supplementation report only a few small effects, including only modest, if any, benefit for preventing fractures. Observational studies tended to show larger effects than RCTs with the same outcomes, which is generally attributed to confounding from healthier lifestyles and better health outcomes in persons who choose to eat well or take vitamins. We have seen this before when observational studies consistently found that low vitamin E was a risk factor for CV disease, but RCTs of supplements found no effect (1). What about the few outcomes that showed statistical improvements with vitamin D? Of those measuring clinical outcomes, the (continued on page 5) 15 July 2014 | ACP Journal Club | Volume 161 • Number 2
Downloaded From: http://annals.org/pdfaccess.ashx?url=/data/journals/aim/930510/ by a NYU Medical Center Library User on 03/09/2017
Therapeutics
Review: Vitamin D3 supplementation may reduce mortality in adults; vitamin D2 does not
Chowdhury R, Kunutsor S, Vitezova A, et al. Vitamin D and risk of cause specific death: systematic review and meta-analysis of observational cohort and randomised intervention studies. BMJ. 2014;348:g1903.
Clinical impact ratings: F ★★★★★✩✩ C ★★★★★✩✩ G ★★★★★★✩ O ★★★★★✩✩ Question Does vitamin D supplementation affect mortality compared with placebo or no treatment?
Review scope Included studies assessed associations of circulating 25-hydroxyvitamin D levels with cause-specific or all-cause mortality in general populations or disease-specific populations of adults or compared vitamin D supplements with placebo or no treatment in adults. Outcomes included all-cause mortality.
Review methods MEDLINE, EMBASE/Excerpta Medica, and Cochrane databases (all to Aug 2013) were searched for observational studies or randomized controlled trials (RCTs). 73 cohort studies and 22 RCTs (n = 30 716, mean age range 56 to 85 y, follow-up range 0.4 to 7 y) met selection criteria. RCT results are reported in this abstract. All RCTs had low risk for bias for randomization, 20 for
concealed allocation, 18 for blinding of participants and personnel, 8 for blinded outcome assessments, and 12 for adequate follow-up. 14 RCTs assessed vitamin D3, and 8 assessed vitamin D2. Subgroup analyses by form of vitamin D (D2 or D3) were done.
Main results Meta-analyses show that, overall, vitamin D supplementation did not differ from placebo for mortality; vitamin D3 did reduce mortality more than placebo, but vitamin D2 did not (Table).
Conclusion In adults, vitamin D3 supplementation may reduce mortality; vitamin D2 supplementation does not. Source of funding: No external funding. For correspondence: Dr. R. Chowdhury, University of Cambridge, Cambridge, England, UK. E-mail [email protected]. ■
Vitamin D supplementation vs placebo in adults* Outcome
Number of trials (n)
All-cause mortality
22 (30 716)
Weighted event rates
At 0.4 to 7 y
Vitamin D Placebo NR
RRR (CI)
NNT (CI)
NR
2% (−2 to 6)
NS
17%
11% (1 to 20)
53 (29 to 579)
Vitamin D3 14 (13 637)
15%
Vitamin D2 8 (17 079)
17%
RRI (CI) 16%
4% (−3 to 11)
NS
*NR = not reported; NS = not significant; other abbreviations defined in Glossary. RRR, RRI, NNT, and CI calculated from control event rates and relative risks in article using a randomeffects model.
Commentary (continued from page 4) systematic reviews suggest, but do not establish beyond reasonable doubt, small effects of vitamin D on birthweight, rate of falls, nonvertebral fractures, muscle strength, and dental caries in children. In RCTs, vitamin D3 reduced overall mortality among older adults, whereas vitamin D2 did not. A possible difference in effectiveness of vitamins D2 and D3 supplements is worth more study but is not yet ready for clinical application because the effects of vitamin D3 were in the context of multiple comparisons and the results were only borderline significant. Studies with P values around 0.05 are often not statistically significant at the 0.05 level when repeated or augmented with additional data (2). Despite weak effects of vitamin D in developed countries, clinicians should be alert for the occasional patient who is at increased risk for vitamin D deficiency (e.g., those with fat malabsorption or severe osteoporosis) who could benefit from supplements. However, for most patients, testing for vitamin D levels or recommending individually tailored supplements goes beyond the evidence. True, the prevalence of laboratory-defined vitamin D
15 July 2014 | ACP Journal Club | Volume 161 • Number 2
deficiency is high, especially in the elderly, but the small-toabsent effects of supplementation on a wide variety of health outcomes call into question the clinical validity of the laboratory definition of “normal.” Nevertheless, if one wanted to give vitamin D supplements the benefit of the doubt, it is not unreasonable to recommend small doses (e.g., 600 IU/d) to unselected patients on the grounds that these supplements are likely safe (3) and may have some small beneficial effects. Robert H. Fletcher, MD, MSc Harvard Medical School Boston, Massachusetts, USA References 1. Yusuf S, Dagenais G, Pogue J, Bosch J, Sleight P. Vitamin E supplementation and cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators. N Engl J Med. 2000;342:154-60. 2. Wood J, Freemantle N, King M, Nazareth I. Trap of trends to statistical significance: likelihood of near significant P value becoming more significant with extra data. BMJ. 2014;348:g2215. 3. Otten JJ, Hellwig JP, Meyers LD, eds. Dietary reference intakes: the essential guide to nutrient requirements. Washington: National Academies Press; 2006.
© 2014 American College of Physicians
Downloaded From: http://annals.org/pdfaccess.ashx?url=/data/journals/aim/930510/ by a NYU Medical Center Library User on 03/09/2017
JC5
