Re:Fall prevention with Vitamin D. Clarifications needed.
In response to Dr. Jose AP da Silva: Fall prevention with Vitamin D.
Clarifications needed.
1,2Bischoff-Ferrari HA, 3Willett WC, 4Orav JE, 5Kiel DP, 6Dawson-
Hughes B
1Center on Aging and Mobility, University of Zurich, Switzerland;
2Dept. of Rheumatology, University Hospital Zurich, Zurich, Switzerland,
3Department of Nutrition, Harvard School of Public Health, Boston, USA;
4Department of Biostatistics, Harvard School of Public Health, Boston,
USA; 5Hebrew Senior Life Institute for Aging Research, Harvard Medical
School, Boston, USA; 6USDA Human Nutrition Research Center on Aging, Tufts
University, Boston, USA
We agree with Prof. da Silva, and wish to clarify the three issues
raised by the recent IOM report1 concerning our 2009 meta-analysis on
vitamin D and fall prevention2 (A). In addition, we comment on the overall
recommendation of the IOM (B) on vitamin D and fall prevention1.
(A) Rebuttal on the issues raised by the IOM - regarding our 2009
meta-analysis on vitamin D supplementation and fall prevention:
1. It was stated that our inclusion/exclusion criteria for the
selection of trials were problematic for two studies. Of 8 studies
included in the primary analysis, the IOM questioned the inclusion of Broe
et al.3, which did not pre-specify falls as a primary or secondary
outcome. While this did violate our inclusion criteria, the Broe trial
took advantage of a high-quality fall assessment at the trial site
throughout the course of the trial. In all other regards: blinding,
randomization and fall ascertainment methodology; the Broe trial qualified
for the primary analysis.
The IOM also questioned the omission of Law et al4. The Law study was
excluded appropriately because it was not blinded as required. When the
Law trial was included in a sensitivity analysis along with 6 other
additional trials that did not meet our inclusion criteria, the benefit of
vitamin D on fall prevention remained significant.
2. It was stated that the dose-response relationship in our Figure 3
was inappropriately presented. Our intent was simply to summarize the
findings at varying levels of vitamin D and achieved 25(OH)D in the
treatment groups. The figure was used to visually identify a threshold at
which vitamin D, and 25(OH)D, appeared efficacious (i.e. the RR dropped
below 1), these threshold levels were then used in formal meta-regressions
to explain the significant heterogeneity. Unfortunately, our intentions
were not sufficiently clear and the Figure 3 was misinterpreted as
representing the actual meta-regression. We therefore present Figure 3
without the trend line through the RRs which may have led to the
misinterpretation. For our actual published meta-regression, the RRs were
analyzed on a log scale, looking for a difference between low (< 700 IU
vitamin D per day) and high dose (700 to 1000 IU vitamin D per day) as
identified in Figure 3, and not a linear trend, and individual studies
were included separately and not aggregated in dosage level.
3. Finally, it was stated that one trial (Broe et al.) which had 5
arms (4 different doses of vitamin D versus a common placebo) was
incorrectly treated in our meta-regression as 4 independent meta-analysis
entries. We agree that there are stochastic dependencies (correlations)
between the corresponding risk ratios which refer to the same placebo arm.
Therefore, we converted the published summary results into a pooled
patient-level database and re-ran the analyses as a random effects
logistic regression, allowing for between-patient correlation within all
arms of the Broe study. In this re-analysis, when treatment is the only
predictor (regardless of dose level), there is a significant reduction in
the odds of falling based on our primary analysis: OR=0.73 [.62, .87];
p=.0004. When the model is expanded to capture the impact of both high
dose and low dose treatment, high dose vitamin D (700 to 1000 IU vitamin
D per day) reduces the odds of falling (OR=0.66 [.53, .82] p=.0002),
while low dose vitamin D does not (OR=1.14 [.69, 1.87]; p=.61).
However, different than the reported result, the interaction term does not
reach significance (p = 0.06), but this does not invalidate the overall
significant result or the significantly lower risk with doses of 700 IU or
larger.
Revised Figure 3 without trend line through RRs and showing all
trials individually:
Legend Figure 3: Markers filled indicate trials with oral vitamin D3
(cholecalciferol) and markers unfilled indicate trials with oral vitamin
D2 (ergocalciferol)
(B) Comment on the overall recommendation of the IOM regarding
vitamin D and fall
prevention
The IOM did a thorough review on the effect of vitamin D on fall
prevention. Their synopsis is that the evidence of vitamin D on fall
prevention is inconsistent, which is in contrast to the 2011 assessment of
the Agency for Healthcare Research and Quality (AHRQ) for the U.S.
Preventive Services Task Force5 , the 2010 American Geriatric
Society/British Geriatric Society Clinical Practice Guideline6, and to the
2010 assessment by the IOF7, all 3 of which identified vitamin D as an
effective intervention to prevent falling in older adults. Here are the
primary results that were published in the IOM report (omitting the
analyses restricted to the two studies of injectable vitamin D and
sensitivity analyses):
In summary, both the overall analysis and the majority of the subset
analyses support the use of vitamin D in the prevention of falling. A few
of the analyses that were non-significant (1A + B and 2) showed effect
sizes comparable to the overall pooled findings and the lack of
significance is likely due to reduced sample size and power. The set of
analyses which showed no benefit (4, 4A+B) were based on 4 studies, which
either used low dose vitamin D8, had less than 50% adherence9, had a low-
quality fall assessment10 or used one large bolus dose of vitamin D among
seniors in unstable health11. Thus, we would argue that the main
inconsistency raised by the IOM is based on 4 studies that cannot be
considered reliable indicators of true treatment efficacy, and that these
do not invalidate the overall findings.
2. Bischoff-Ferrari HA, Dawson-Hughes B, Staehelin HB, et al. Fall
prevention with supplemental and active forms of vitamin D: a meta-
analysis of randomised controlled trials. Bmj 2009;339:b3692.
3. Broe KE, Chen TC, Weinberg J, Bischoff-Ferrari HA, Holick MF, Kiel
DP. A higher dose of vitamin d reduces the risk of falls in nursing home
residents: a randomized, multiple-dose study. J Am Geriatr Soc 2007;55:234
-9.
4. Law M, Withers H, Morris J, Anderson F. Vitamin D supplementation
and the prevention of fractures and falls: results of a randomised trial
in elderly people in residential accommodation. Age Ageing 2006;35:482-6.
5. Michael YL, Whitlock EP, Lin JS, Fu R, O'Connor EA, Gold R.
Primary care-relevant interventions to prevent falling in older adults: a
systematic evidence review for the u.s. Preventive services task force.
Ann Intern Med;153:815-25.
7. Dawson-Hughes B, Mithal A, Bonjour JP, et al. IOF position
statement: vitamin D recommendations for older adults. Osteoporos Int.
8. Graafmans WC, Ooms ME, Hofstee HM, Bezemer PD, Bouter LM, Lips P.
Falls in the elderly: a prospective study of risk factors and risk
profiles. Am J Epidemiol 1996;143:1129-36.
9. Grant AM, Avenell A, Campbell MK, et al. Oral vitamin D3 and
calcium for secondary prevention of low-trauma fractures in elderly people
(Randomised Evaluation of Calcium Or vitamin D, RECORD): a randomised
placebo-controlled trial. Lancet 2005;365:1621-8.
10. Trivedi DP, Doll R, Khaw KT. Effect of four monthly oral vitamin
D3 (cholecalciferol) supplementation on fractures and mortality in men and
women living in the community: randomised double blind controlled trial.
BMJ 2003;326:469.
11. Latham NK, Anderson CS, Lee A, Bennett DA, Moseley A, Cameron ID.
A randomized, controlled trial of quadriceps resistance exercise and
vitamin D in frail older people: the Frailty Interventions Trial in
Elderly Subjects (FITNESS). J Am Geriatr Soc 2003;51:291-9.
Rapid Response:
Re:Fall prevention with Vitamin D. Clarifications needed.
In response to Dr. Jose AP da Silva: Fall prevention with Vitamin D.
Clarifications needed.
1,2Bischoff-Ferrari HA, 3Willett WC, 4Orav JE, 5Kiel DP, 6Dawson-
Hughes B
1Center on Aging and Mobility, University of Zurich, Switzerland;
2Dept. of Rheumatology, University Hospital Zurich, Zurich, Switzerland,
3Department of Nutrition, Harvard School of Public Health, Boston, USA;
4Department of Biostatistics, Harvard School of Public Health, Boston,
USA; 5Hebrew Senior Life Institute for Aging Research, Harvard Medical
School, Boston, USA; 6USDA Human Nutrition Research Center on Aging, Tufts
University, Boston, USA
We agree with Prof. da Silva, and wish to clarify the three issues
raised by the recent IOM report1 concerning our 2009 meta-analysis on
vitamin D and fall prevention2 (A). In addition, we comment on the overall
recommendation of the IOM (B) on vitamin D and fall prevention1.
(A) Rebuttal on the issues raised by the IOM - regarding our 2009
meta-analysis on vitamin D supplementation and fall prevention:
1. It was stated that our inclusion/exclusion criteria for the
selection of trials were problematic for two studies. Of 8 studies
included in the primary analysis, the IOM questioned the inclusion of Broe
et al.3, which did not pre-specify falls as a primary or secondary
outcome. While this did violate our inclusion criteria, the Broe trial
took advantage of a high-quality fall assessment at the trial site
throughout the course of the trial. In all other regards: blinding,
randomization and fall ascertainment methodology; the Broe trial qualified
for the primary analysis.
The IOM also questioned the omission of Law et al4. The Law study was
excluded appropriately because it was not blinded as required. When the
Law trial was included in a sensitivity analysis along with 6 other
additional trials that did not meet our inclusion criteria, the benefit of
vitamin D on fall prevention remained significant.
2. It was stated that the dose-response relationship in our Figure 3
was inappropriately presented. Our intent was simply to summarize the
findings at varying levels of vitamin D and achieved 25(OH)D in the
treatment groups. The figure was used to visually identify a threshold at
which vitamin D, and 25(OH)D, appeared efficacious (i.e. the RR dropped
below 1), these threshold levels were then used in formal meta-regressions
to explain the significant heterogeneity. Unfortunately, our intentions
were not sufficiently clear and the Figure 3 was misinterpreted as
representing the actual meta-regression. We therefore present Figure 3
without the trend line through the RRs which may have led to the
misinterpretation. For our actual published meta-regression, the RRs were
analyzed on a log scale, looking for a difference between low (< 700 IU
vitamin D per day) and high dose (700 to 1000 IU vitamin D per day) as
identified in Figure 3, and not a linear trend, and individual studies
were included separately and not aggregated in dosage level.
3. Finally, it was stated that one trial (Broe et al.) which had 5
arms (4 different doses of vitamin D versus a common placebo) was
incorrectly treated in our meta-regression as 4 independent meta-analysis
entries. We agree that there are stochastic dependencies (correlations)
between the corresponding risk ratios which refer to the same placebo arm.
Therefore, we converted the published summary results into a pooled
patient-level database and re-ran the analyses as a random effects
logistic regression, allowing for between-patient correlation within all
arms of the Broe study. In this re-analysis, when treatment is the only
predictor (regardless of dose level), there is a significant reduction in
the odds of falling based on our primary analysis: OR=0.73 [.62, .87];
p=.0004. When the model is expanded to capture the impact of both high
dose and low dose treatment, high dose vitamin D (700 to 1000 IU vitamin
D per day) reduces the odds of falling (OR=0.66 [.53, .82] p=.0002),
while low dose vitamin D does not (OR=1.14 [.69, 1.87]; p=.61).
However, different than the reported result, the interaction term does not
reach significance (p = 0.06), but this does not invalidate the overall
significant result or the significantly lower risk with doses of 700 IU or
larger.
Revised Figure 3 without trend line through RRs and showing all
trials individually:
Legend Figure 3: Markers filled indicate trials with oral vitamin D3
(cholecalciferol) and markers unfilled indicate trials with oral vitamin
D2 (ergocalciferol)
(B) Comment on the overall recommendation of the IOM regarding
vitamin D and fall
prevention
The IOM did a thorough review on the effect of vitamin D on fall
prevention. Their synopsis is that the evidence of vitamin D on fall
prevention is inconsistent, which is in contrast to the 2011 assessment of
the Agency for Healthcare Research and Quality (AHRQ) for the U.S.
Preventive Services Task Force5 , the 2010 American Geriatric
Society/British Geriatric Society Clinical Practice Guideline6, and to the
2010 assessment by the IOF7, all 3 of which identified vitamin D as an
effective intervention to prevent falling in older adults. Here are the
primary results that were published in the IOM report (omitting the
analyses restricted to the two studies of injectable vitamin D and
sensitivity analyses):
In summary, both the overall analysis and the majority of the subset
analyses support the use of vitamin D in the prevention of falling. A few
of the analyses that were non-significant (1A + B and 2) showed effect
sizes comparable to the overall pooled findings and the lack of
significance is likely due to reduced sample size and power. The set of
analyses which showed no benefit (4, 4A+B) were based on 4 studies, which
either used low dose vitamin D8, had less than 50% adherence9, had a low-
quality fall assessment10 or used one large bolus dose of vitamin D among
seniors in unstable health11. Thus, we would argue that the main
inconsistency raised by the IOM is based on 4 studies that cannot be
considered reliable indicators of true treatment efficacy, and that these
do not invalidate the overall findings.
References:
1. Institute of Medicine. Dietary Reference Ranges for Calcium and
Vitamin D. http://wwwiomedu/Reports/2010/Dietary-Reference-Intakes-for-
Calcium-and-Vitamin-D/Report-Briefaspx 2010.
2. Bischoff-Ferrari HA, Dawson-Hughes B, Staehelin HB, et al. Fall
prevention with supplemental and active forms of vitamin D: a meta-
analysis of randomised controlled trials. Bmj 2009;339:b3692.
3. Broe KE, Chen TC, Weinberg J, Bischoff-Ferrari HA, Holick MF, Kiel
DP. A higher dose of vitamin d reduces the risk of falls in nursing home
residents: a randomized, multiple-dose study. J Am Geriatr Soc 2007;55:234
-9.
4. Law M, Withers H, Morris J, Anderson F. Vitamin D supplementation
and the prevention of fractures and falls: results of a randomised trial
in elderly people in residential accommodation. Age Ageing 2006;35:482-6.
5. Michael YL, Whitlock EP, Lin JS, Fu R, O'Connor EA, Gold R.
Primary care-relevant interventions to prevent falling in older adults: a
systematic evidence review for the u.s. Preventive services task force.
Ann Intern Med;153:815-25.
6. American Geriatric Society/British Geriatric Society Guidelines on
Fall Prevention in older Persons 2010.
http://wwwamericangeriatricsorg/files/documents/health_care_pros/FallsSu...
7. Dawson-Hughes B, Mithal A, Bonjour JP, et al. IOF position
statement: vitamin D recommendations for older adults. Osteoporos Int.
8. Graafmans WC, Ooms ME, Hofstee HM, Bezemer PD, Bouter LM, Lips P.
Falls in the elderly: a prospective study of risk factors and risk
profiles. Am J Epidemiol 1996;143:1129-36.
9. Grant AM, Avenell A, Campbell MK, et al. Oral vitamin D3 and
calcium for secondary prevention of low-trauma fractures in elderly people
(Randomised Evaluation of Calcium Or vitamin D, RECORD): a randomised
placebo-controlled trial. Lancet 2005;365:1621-8.
10. Trivedi DP, Doll R, Khaw KT. Effect of four monthly oral vitamin
D3 (cholecalciferol) supplementation on fractures and mortality in men and
women living in the community: randomised double blind controlled trial.
BMJ 2003;326:469.
11. Latham NK, Anderson CS, Lee A, Bennett DA, Moseley A, Cameron ID.
A randomized, controlled trial of quadriceps resistance exercise and
vitamin D in frail older people: the Frailty Interventions Trial in
Elderly Subjects (FITNESS). J Am Geriatr Soc 2003;51:291-9.
Competing interests: No competing interests