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Fracture Prevention With Vitamin D Supplementation: A Meta-analysis of Randomized Controlled Trials

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Fracture Prevention With Vitamin D Supplementation: A Meta-analysis of Randomized Controlled Trials

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The role and dose of oral vitamin D supplementation in nonvertebral fracture prevention have not been well established. To estimate the effectiveness of vitamin D supplementation in preventing hip and nonvertebral fractures in older persons. A systematic review of English and non-English articles using MEDLINE and the Cochrane Controlled Trials Register (1960-2005), and EMBASE (1991-2005). Additional studies were identified by contacting clinical experts and searching bibliographies and abstracts presented at the American Society for Bone and Mineral Research (1995-2004). Search terms included randomized controlled trial (RCT), controlled clinical trial, random allocation, double-blind method, cholecalciferol, ergocalciferol, 25-hydroxyvitamin D, fractures, humans, elderly, falls, and bone density. Only double-blind RCTs of oral vitamin D supplementation (cholecalciferol, ergocalciferol) with or without calcium supplementation vs calcium supplementation or placebo in older persons (> or =60 years) that examined hip or nonvertebral fractures were included. Independent extraction of articles by 2 authors using predefined data fields, including study quality indicators. All pooled analyses were based on random-effects models. Five RCTs for hip fracture (n = 9294) and 7 RCTs for nonvertebral fracture risk (n = 9820) met our inclusion criteria. All trials used cholecalciferol. Heterogeneity among studies for both hip and nonvertebral fracture prevention was observed, which disappeared after pooling RCTs with low-dose (400 IU/d) and higher-dose vitamin D (700-800 IU/d), separately. A vitamin D dose of 700 to 800 IU/d reduced the relative risk (RR) of hip fracture by 26% (3 RCTs with 5572 persons; pooled RR, 0.74; 95% confidence interval [CI], 0.61-0.88) and any nonvertebral fracture by 23% (5 RCTs with 6098 persons; pooled RR, 0.77; 95% CI, 0.68-0.87) vs calcium or placebo. No significant benefit was observed for RCTs with 400 IU/d vitamin D (2 RCTs with 3722 persons; pooled RR for hip fracture, 1.15; 95% CI, 0.88-1.50; and pooled RR for any nonvertebral fracture, 1.03; 95% CI, 0.86-1.24). Oral vitamin D supplementation between 700 to 800 IU/d appears to reduce the risk of hip and any nonvertebral fractures in ambulatory or institutionalized elderly persons. An oral vitamin D dose of 400 IU/d is not sufficient for fracture prevention.
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REVIEW
Fracture Prevention With
Vitamin D Supplementation
A Meta-analysis of Randomized Controlled Trials
Heike A. Bischoff-Ferrari, MD, MPH
Walter C. Willett, DrPH
John B. Wong, MD
Edward Giovannucci, ScD
Thomas Dietrich, MPH
Bess Dawson-Hughes, MD
F
RACTURES CONTRIBUTE SIGNIFI-
cantly to morbidity and mortal-
ity of older persons. Hip frac-
tures increase exponentially
with age so that by the ninth decade of
life, an estimated 1 in every 3 women
and 1 in every 6 men will have sus-
tained a hip fracture.
1
With the aging
of the population, the number of hip
fractures is projected to increase world-
wide.
2
The consequences of hip frac-
tures are severe: 50% of older persons
have permanent functional disabili-
ties, 15% to 25% require long-term
nursing home care, and 10% to 20% die
within 1 year.
3-6
Besides the personal
burden, hip fractures account for sub-
stantial health care expenses
3,7
with an-
nual costs in the United States pro-
jected to increase from $7.2 billion in
1990 to $16 billion in 2020.
7
Given the high prevalence, severity,
and cost of osteoporotic fractures, pre-
vention strategies that are effective, low
in cost, and well-tolerated are needed.
One promising prevention strategy may
be oral vitamin D supplementation. Sev-
eral randomized controlled trials
(RCTs) have examined vitamin D
supplements for fracture prevention,
but the results were conflicting. The
goal of our analysis was to determine
Author Affiliations: Department of Nutrition, Har-
vard School of Public Health (Drs Bischoff-Ferrari, Wil-
lett, and Giovannucci); Division of Rheumatology, Im-
munology, and Allergy, The Robert B. Brigham Arthritis
and Musculoskeletal Diseases Clinical Research Cen-
ter, and Division of Aging, Brigham and Women’s Hos-
pital (Dr Bischoff-Ferrari); Department of Epidemiol-
ogy and Channing Laboratory, Brigham and Women’s
Hospital (Drs Willett and Giovannucci); Department
of Medicine, Tufts-New England Medical Center
(Dr Wong); Department of Health Policy and Health
Services Research, Boston University Goldman School
of Dental Medicine (Mr Dietrich); and Jean Mayer US
Department of Agriculture Human Nutrition Re-
search Center on Aging, Tufts University (Dr Dawson-
Hughes), Boston, Mass.
Corresponding Author: Heike A. Bischoff-Ferrari, MD,
MPH, Department of Nutrition, Harvard School of Pub-
lic Health, 651 Huntington Ave, Boston, MA 02115
(hbischof@hsph.harvard.edu).
Context The role and dose of oral vitamin D supplementation in nonvertebral frac-
ture prevention have not been well established.
Objective To estimate the effectiveness of vitamin D supplementation in prevent-
ing hip and nonvertebral fractures in older persons.
Data Sources A systematic review of English and non-English articles using MEDLINE
and the Cochrane Controlled Trials Register (1960-2005), and EMBASE (1991-2005).
Additional studies were identified by contacting clinical experts and searching bibliog-
raphies and abstracts presented at the American Society for Bone and Mineral Research
(1995-2004). Search terms included randomized controlled trial (RCT), controlled clini-
cal trial, random allocation, double-blind method, cholecalciferol, ergocalciferol, 25-
hydroxyvitamin D, fractures, humans, elderly, falls, and bone density.
Study Selection Only double-blind RCTs of oral vitamin D supplementation (cho-
lecalciferol, ergocalciferol) with or without calcium supplementation vs calcium supple-
mentation or placebo in older persons (60 years) that examined hip or nonvertebral
fractures were included.
Data Extraction Independent extraction of articles by 2 authors using predefined
data fields, including study quality indicators.
Data Synthesis All pooled analyses were based on random-effects models. Five RCTs
for hip fracture (n=9294) and 7 RCTs for nonvertebral fracture risk (n=9820) met our
inclusion criteria. All trials used cholecalciferol. Heterogeneity among studies for both hip
and nonvertebral fracture prevention was observed, which disappeared after pooling RCTs
with low-dose (400 IU/d) and higher-dose vitamin D (700-800 IU/d), separately. A vi-
tamin D dose of 700 to 800 IU/d reduced the relative risk (RR) of hip fracture by 26% (3
RCTs with 5572 persons; pooled RR, 0.74; 95% confidence interval [CI], 0.61-0.88) and
any nonvertebral fracture by 23% (5 RCTs with 6098 persons; pooled RR, 0.77; 95%
CI, 0.68-0.87) vs calcium or placebo. No significant benefit was observed for RCTs with
400 IU/d vitamin D (2 RCTs with 3722 persons; pooled RR for hip fracture, 1.15; 95%
CI, 0.88-1.50; and pooled RR for any nonvertebral fracture, 1.03; 95% CI, 0.86-1.24).
Conclusions Oral vitamin D supplementation between 700 to 800 IU/d appears to
reduce the risk of hip and any nonvertebral fractures in ambulatory or institutional-
ized elderly persons. An oral vitamin D dose of 400 IU/d is not sufficient for fracture
prevention.
JAMA. 2005;293:2257-2264 www.jama.com
©2005 American Medical Association. All rights reserved. (Reprinted) JAMA, May 11, 2005—Vol 293, No. 18 2257
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the efficacy of oral vitamin D supple-
mentation in preventing hip and any
nonvertebral fractures among older per-
sons by performing a systematic re-
view of the literature with a meta-
analysis of RCTs.
METHODS
Search Strategy and Data
Extraction
We conducted a systematic review of all
English and non-English articles using
MEDLINE (Ovid, PubMed) and the
Cochrane Controlled Trials Register from
January 1960 to January 2005, and
EMBASE from January 1991 to January
2005. Additional studies were identi-
fied by contacting experts and search-
ing reference lists and abstracts pre-
sented at the American Society for Bone
and Mineral Research from 1995 to 2004.
We used Medical Subject Headings
(MeSH) terms, which included trials
(randomized controlled trial, controlled
clinical trial, random allocation, double-
blind method, single-blind method,orun-
controlled trials), vitamin D (cholecal-
ciferol, ergocalciferol,orvitamin D/blood/
25-hydroxyvitamin D), fractures (hip
fractures, femoral neck fractures, fem-
oral fractures, humeral fractures, ra-
dius fractures,ortibial fractures), hu-
mans, elderly, falls, and bone density.
Eligibility and exclusion criteria were
prespecified. Data extraction was con-
ducted independently by 2 authors
(H.A.B.-F. and T.D.), and consensus
was achieved for all data.
Eligible Studies
We included only double-blind RCTs
that studied oral vitamin D supplemen-
tation (cholecalciferol or ergocalcif-
erol) with a minimum follow-up of 1 year
and required more than a total of 1 frac-
ture in each trial. Trials that included
only 1 fracture were added in a sensitiv-
ity analysis. Because the vitamin D dose
may introduce heterogeneity, we also ex-
amined effect sizes separately for stud-
ies using more than 400 IU/d vitamin D
and those using 400 IU/d or less. To be
included in the primary analysis, we re-
quired that the authors state how frac-
tures were ascertained and that 25-
hydroxyvitamin D levels were measured
during follow-up in the treatment group
or a subset of the treatment group. Be-
cause our target population consisted of
older community-dwelling or institu-
tionalized persons, the mean age of study
participants had to be 60 years or older
to be included (F
IGURE 1).
Ineligible Studies
We excluded uncontrolled trials, ob-
servational studies, and animal stud-
ies. Because health conditions that place
patients at high risk for falls and frac-
tures may confound our analysis, we ex-
cluded studies that focused on pa-
tients following organ transplantation
or stroke, receiving steroid therapy or
care for Parkinson disease, or un-
stable health states, such as after acute
hospitalization.
We excluded RCTs that used active vi-
tamin D metabolites, such as 1,25-
dihydroxyvitamin D or 1--hydroxyvi-
tamin D, because they require
monitoring for hypercalcemia and have
much higher costs, thereby limiting their
public health applicability. We also ex-
cluded trials with intramuscular injec-
tions of vitamin D because it is not avail-
able over the counter, is invasive, and has
resulted in small and variable increases
in 25-hydroxyvitamin D levels.
8
Definitions
Our primary outcome measure was the
relative risk (RR) of a first hip fracture
or any nonvertebral fracture in partici-
pants receiving vitamin D supplemen-
tation with or without calcium supple-
mentation compared with those
participants receiving placebo or cal-
cium supplementation alone.
Quality Assessment
We assessed the following method-
ological features most relevant to the
control of bias: randomization, ran-
dom allocation concealment, masking
of treatment allocation, blinding, and
withdrawals.
9,10
Studies Identified
for Primary Analysis
All studies were identified through our
MeSH term search (TABLE 1).
11-21
Five
RCTs
12,13,16-18
for hip fracture preven-
tion and 7 RCTs
12-18
for nonvertebral
fracture prevention met our inclusion
criteria. All trials had hip or nonverte-
bral fractures as the primary or second-
ary outcome.
Studies Identified
for Sensitivity Analysis
In a sensitivity analysis, we examined the
effect size when including studies meet-
ing less stringent quality criteria for inclu-
sion. Of 3 studies that were identified for
the sensitivity analysis, 1 was retrieved
through our MeSH term search
19
and 2
unpublished studies were identified by
searching through abstract books of the
American Society of Bone and Mineral
Research plus contacting experts in the
field
20,21
(Table 1). Preliminary fracture
Figure 1. QUOROM Flow Diagram
119 Potentially Relevent RCTs
Identified and Screened
for Retrieval
59
Excluded
4 Did Not Have Fracture Outcomes
21 Used Vitamin D in All Participants or
as a Control
1 With Steroid Users Plus Younger Age
12 With Active Vitamin D in the
Control Group
17 With Active Vitamin D
2 With Intramuscular Vitamin D
1 Unblinded With Sun Exposure
(Patients With Stroke)
1 Not Classically Randomized
1 Unpublished
1 in Younger Population (Steroid Users)
50 Excluded
37 Reviews
13 Non-RCTs
69 RCTs Retrieved for More
Detailed Evaluation
10 Potentially Appropriate
for Inclusion
7 RCTs Included in Primary
Analyses
3 Excluded From Primary Analyses
1 Unblinded Pragmatic Trial
2 Unpublished
QUOROM indicates Quality of Reporting of Meta-
analyses; RCTs, randomized controlled trials.
*Vitamin D or active vitamin D compared with treat-
ments other than calcium or placebo.
FRACTURE PREVENTION WITH VITAMIN D SUPPLEMENTATION
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Table 1. Characteristics of Primary Analysis of Both Included and Excluded Trials
Source
No. of
Participants Treatment/d Dwelling
Age,
Mean
(SD), y
Duration,
mo
Baseline and Follow-up
25-Hydroxyvitamin D,
Mean (SD), nmol/L
Treatment Group Control Group
Trials Included in Primary Analysis
Chapuy et al,
11
1992
(Decalyos I)
3270 Women 800-IU cholecalciferol
1200-mg calcium
(tri-calcium phosphate
powder) vs placebo
Ambulatory, living in
nursing homes or
apartments for
elderly persons
84 (6) 18 40 (27.5) to 105
(22.5) at 18-mo
follow-up
32.5 (22.5) to 27.5
(17.5) at 18-mo
follow-up
Chapuy et al,
12
1994
(Decalyos I)
Intention-to-treat
analysis of
2303 women
at 36-mo
report
800-IU cholecalciferol
1200-mg calcium
(tri-calcium phosphate
powder) vs placebo
Ambulatory, living in
nursing homes or
apartments for
elderly persons
84 (6) 36 40 (27.5) to 105
(22.5) at 18-mo
follow-up
32.5 (22.5) to 27.5
(17.5) at 18-mo
follow-up
Lips et al,
13
1996 2578 Persons
(1916 women,
662 men);
no separate
results by sex
400-IU cholecalciferol vs
placebo; participants
asked to consume 3
dairy products daily to
reach a calcium intake
of 800 mg/d
Independent, in
apartments or
homes for elderly
persons
80 (6) 36-41 27 (IQR, 19-36) to
62 (IQR, 52-70)
at 12-mo
follow-up
26 (IQR, 19-37) to
23 (IQR, 17-31)
at 12-mo
follow-up
Dawson-Hughes
et al,
14
1997*
389 Persons
(213 women,
176 men);
no separate
results by sex
700-IU cholecalciferol
500-mg calcium
(calcium citrate malate)
vs placebo; mean
calcium intake at
baseline was about
720 mg/d
Community-dwelling 71 (5) 36 76.5 (37.0) to 112
(36.8) at 36-mo
follow-up
72 (33.1) to 71.7
(30.5) at 36-mo
follow-up
Pfeifer et al,
15
2000*
137 Women 800-IU cholecalciferol
1200-mg calcium vs
1200-mg calcium
Community-dwelling 74 (1) 2 (with treatment)
plus 10 (with
follow-up)
25.7 (13.6) to 66.1
(33.1) at 2-mo
follow-up
24.6 (12.1) to 42.9
(33.1) at 2-mo
follow-up
(baseline was
beginning of
March)
Meyer et al,
16
2002
1144 Persons
(75% women)
400-IU cholecalciferol in
5-mL cod liver oil vs
5-mL cod liver oil alone;
mean calcium intake
from milk and cheese
reported to be about
450 mg/d
Frail nursing home
residents with life
expectancy of 6
mo and not
permanently
bedridden
85 (7) 24 47 (26) to 64 (21)
at 12-mo
follow-up
51 (33) to 46 (20)
at 12-mo
follow-up
Chapuy et al,
17
2002
(Decalyos II)
583 Women 800-IU cholecalciferol
1200-mg calcium
(tri-calcium phosphate)
as fixed or separate
combination vs placebo
Ambulatory, living in
apartment
houses for elderly
persons
85 (7) 24 21.3 (13.3) to 77.5
(ND) from bar
graph at 24-mo
follow-up
22.8 (17.3) to 15
(ND) from bar
graph at 24-mo
follow-up
Trivedi et al,
18
2003
2686 Persons
(649 women,
2037 men)
100 000 IU every 4 mo
(800 IU/d) vs placebo;
mean calcium intake at
4 y was 742 mg/d as
assessed by food
frequency questionnaire
Community-dwelling 75 (5) 60 74.3 (20.7) at a
48-mo
follow-up (no
baseline)
53.4 (21.1) at a
48-mo
follow-up (no
baseline)
Trials Excluded From Primary Analysis
Larsen et al,
19
2004†
7073 Persons
(4256 women,
2817 men)
Patients offered 400-IU/d
cholecalciferol
1000-mg/d calcium vs
no intervention
Community-dwelling 66-103 42 37 (19) to 47 (20)
at 24-mo
follow-up
33 (19) to 38 (18)
at 24-mo
follow-up
Pfeifer et al,
20
2004†
242 Persons
(74% women)
800-IU/d cholecalciferol
1000-mg/d calcium vs
1000-mg/d calcium
Community-dwelling 77 20 (12 with
treatment)
ND ND
Flicker et al,
21
2004†
601 Persons
(53% women)
Ergocalciferol (initially
10 000 IU/wk, then
1000 IU/d) vs
placebo 600-mg
calcium for all
Nursing homes and
assisted-living
facilities
“Elderly” 24 ND ND
Abbreviations: IQR, interquartile range; ND, not determined.
Conversion factor: To convert 25-hydroxyvitamin D to ng/mL, divide values by 2.496.
*This study only included patients with 25-hydroxyvitamin D levels of less than 50 nmol/L. All other trials did not select participants based on baseline 25-hydroxyvitamin D levels.
†None of the studies provided separate data for hip fractures.
FRACTURE PREVENTION WITH VITAMIN D SUPPLEMENTATION
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data from 1 trial was provided by the prin-
cipal investigator.
20
None of the trials pro-
vided separate results for hip fractures,
2 trials included any osteoporotic frac-
ture,
19,21
and 1 trial provided results for
any nonvertebral fracture.
20
Statistical Analyses
Outcomes were analyzed on an inten-
tion-to-treat basis with random-
effects models, as these models pro-
vide a more conservative estimate than
the fixed-effect model by incorporat-
ing both within- and between-study
variation.
22
In addition, we calculated
the risk difference for preventing a frac-
ture to determine the number needed-
to-treat (NNT) to prevent 1 fracture.
Heterogeneity among studies was
evaluated by the Cochran Q test (con-
sidered significant for P.10
23,24
). We ex-
plored heterogeneity by vitamin D dose
by pooling low-dose (400 IU/d) and
higher-dose RCTs (400 IU/d) sepa-
rately. Heterogeneity by vitamin D dose
was also explored visually by plotting the
achieved 25-hydroxyvitamin D levels in
the treatment group of each trial against
the effect size of each trial.
25
In addi-
tion, a random-effects meta-regression
analysis was performed to test whether
higher achieved 25-hydroxyvitamin D
level in the treatment group is a signifi-
cant predictor of antifracture efficacy.
26
This approach was chosen because the
association between vitamin D dose and
change in 25-hydroxyvitamin D is not
linear,
27
and both the starting 25-
hydroxyvitamin D level and the vita-
min D dose determine the achieved 25-
hydroxyvitamin D level in the treatment
group. In the presence of homogeneity,
both fixed and random-effects models
yielded the same results.
As with all meta-analyses, our re-
view has the potential for publication
bias. Despite no evidence for publica-
tion bias in the Begg and Egger test,
28
the
funnel plot suggested a possible ab-
sence of negative studies involving small
sample sizes. However, the trim and fill
analysis
29
did not confirm this sugges-
tion. Statistical analyses were per-
formed with STATA version 7.0 (STATA
Corp, College Station, Tex).
RESULTS
Primary Analyses
Table 1 shows characteristics of the 7
RCTs that were included in the pri-
mary analysis for hip fracture
12,13,16-18
or
any nonvertebral fracture,
12-18
or
both.
12,13,16-18
These trials included 9820
individuals with an approximate mean
age of 79 years, and 68% were women.
All participants were in stable health
states: living in the community,
14,15,18
in
apartments or housing for elderly per-
sons,
13,17
or in nursing homes.
12,16
The vitamin D dose used in 2 RCTs
was 400 IU/d,
13,16
while the other 5 RCTs
used 700 to 800 IU/d. Between 500 mg/
d
14
and 1200 mg/d
12,15,17
of calcium
supplementation was used in combina-
tion with vitamin D supplementation in
4 RCTs. Of the 3 additional trials, 1 rec-
ommended an intake of 3 dairy prod-
ucts per day in all participants to achieve
a calcium intake of at least 800 mg/d,
13
and in the 2 remaining trials, mean cal-
cium intake was between 450
16
and 742
mg/d.
18
Only 1 trial provided calcium
supplementation in the control group.
15
Treatment duration varied between 12
and 60 months.
Two trials reported the method of
randomization,
13,16
2 trials stated that
treatment allocation was concealed
from participants and investiga-
tors,
13,18
all but 1 trial
15
specifically re-
ported performing an intention-to-
treat analysis, and all studies specifically
stated masking of treatment alloca-
tion. The causes for dropout were bal-
anced between treatment and control
groups in all trials and ranged from 7%
15
in community-dwelling participants to
67% in frail institutionalized elderly
persons.
16
Hip Fracture
The pooled RR for any vitamin D dose
preventing hip fractures was 0.88 (95%
confidence interval [CI], 0.69-1.13)
(T
ABLE 2). However, variation be-
tween studies was more than ex-
pected indicating heterogeneity (Q test
P=.09).
Once vitamin D trials with a higher
and a lower dose were pooled sepa-
rately, there was homogeneity (Q test
P=.74 for high-dose trials and P=.68
for low-dose trials). For 3 trials,
12,17,18
including 5572 individuals with 700 to
800 IU/d vitamin D in the treatment
Table 2. Hip and All Nonvertebral Fractures
Citation
No./Total No. of Persons
Effect RR
(95% CI) Total No.Treatment Control
Hip Fractures
Chapuy et al,
12
1994 137/1176 178/1127 0.74 (0.60-0.91) 2303
Lips et al,
13
1996 58/1291 48/1287 1.21 (0.83-1.75) 2578
Dawson-Hughes et al,
14
1997* 0/187 1/202 (389)
Pfeifer et al,
15
2000* 0/70 1/67 (137)
Meyer et al,
16
2002 50/569 47/575 1.08 (0.73-1.57) 1144
Chapuy et al,
17
2002 27/393 21/190 0.62 (0.36-1.07) 583
Trivedi et al,
18
2003 21/1345 24/1341 0.85 (0.47-1.53)† 2686
Total 0.88 (0.69-1.13) 9294
All Nonvertebral Fractures
Chapuy et al,
12
1994 255/1176 308/1127 0.79 (0.69-0.92) 2303
Lips et al,
13
1996 135/1291 122/1287 1.10 (0.87-1.39) 2578
Dawson-Hughes et al,
14
1997 11/202 26/187 0.46 (0.24-0.88) 389
Pfeifer et al,
15
2000 3/70 6/67 0.48 (0.13-1.78) 137
Meyer et al,
16
2002 69/569 76/575 0.92 (0.68-1.24) 1144
Chapuy et al,
17
2002 97/393 55/190 0.85 (0.64-1.13) 583
Trivedi et al,
18
2003 43/1345 62/1341 0.67 (0.46-0.99)† 2686
Total 0.83 (0.70-0.98) 9820
Abbreviations: CI, confidence interval; RR, relative risk.
*Studies were excluded from the pooled analysis of hip fractures due to only 1 observed hip fracture in both trials.
†Age-adjusted.
FRACTURE PREVENTION WITH VITAMIN D SUPPLEMENTATION
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groups, the pooled RR was 0.74 (95%
CI, 0.61-0.88), suggesting that 700 to
800 IU/d vitamin D reduces hip frac-
ture risk by 26% (F
IGURE 2). The
pooled risk difference was 2% (95% CI,
1%-4%; P.001), so the NNT was 45
(95% CI, 28-114) for a treatment
duration of 24 to 60 months. For 2
trials,
13,16
which included 3722 indi-
viduals and a vitamin D dose of 400
IU/d, the pooled RR was 1.15 (95% CI,
0.88-1.50), suggesting that 400 IU/d vi-
tamin D supplementation does not re-
duce hip fracture risk.
We also examined the achieved level
of serum 25-hydroxyvitamin D in re-
lation to reduction in hip fracture risk
(F
IGURE 3). A greater reduction in hip
fractures was observed with higher
achieved 25-hydroxyvitamin D levels
in the treatment group (meta-
regression P=.02).
When we included the 2 trials each
with only 1 hip fracture report in a sen-
sitivity analysis, the corresponding
pooled results were as follows for 7 trials
with 9820 individuals and hip frac-
ture by vitamin D supplementation be-
tween 400 to 800 IU/d (RR, 0.87; 95%
CI, 0.70-1.09), hip fracture by vita-
min D supplementation between 700
to 800 IU/d (RR, 0.73; 95% CI, 0.61-
0.88), and hip fracture by vitamin D
supplementation of 400 IU/d (RR, 1.15;
95% CI, 0.88-1.50).
Any Nonvertebral Fracture
The pooled RR for any vitamin D dose
preventing nonvertebral fractures was
0.83 (95% CI, 0.70-0.98). However,
variation between studies was more
than expected indicating heterogene-
ity (Q test P=.07).
After stratifying trials by vitamin D
dose, there was homogeneity (Q test
P=.41 for high-dose trials and P=.36 for
low-dose trials). For 5 trials,
12,14,15,17,18
which included 6098 individuals and a
vitamin D dose of 700 to 800 IU/d, the
pooled RR was 0.77 (95% CI, 0.68-
0.87), suggesting that 700 to 800 IU/d
vitamin D supplementation reduces
nonvertebral fracture risk by 23%
(Figure 2). The pooled risk difference
was 4% (95% CI, 2%-5%), P=.02); there-
fore, the NNT was 27 (95% CI, 19-49)
for a treatment duration of 12 to 60
months. For 2 trials,
13,16
which in-
cluded 3722 individuals and a vitamin
D dose of 400 IU/d, the pooled RR was
Figure 2. Forest Plots Comparing the Risk of Hip and Nonvertebral Fractures Between Vitamin D (700-800 IU/d and 400 IU/d) and Control
Groups
Hip Fracture
Favors Vitamin D
Nonvertebral Fracture
Favors Control Favors Vitamin D Favors Control
Source
1.00.2
Relative Risk (95% CI) Relative Risk (95% CI)
1.00.2 0.50.5 5.05.0
1.00.2 1.00.2 0.50.5 5.05.0
Meyer et al,
16
2002
Pooled
Source
Pooled
Vitamin D 700-800 IU/d Vitamin D 700-800 IU/d
Vitamin D 400 IU/d Vitamin D 400 IU/d
Pooled Pooled
Chapuy et al,
17
2002
Chapuy et al,
12
1994
Trivedi et al,
18
2003
Lips et al,
13
1996
Lips et al,
13
1996
Meyer et al,
16
2002
Trivedi et al,
18
2003
Dawson-Hughes et al,
14
1997
Chapuy et al,
12
1994
Chapuy et al,
17
2002
Pfeifer et al,
15
2000
Squares represent relative risks (RRs) and size of squares is proportional to the size of the trials. Error bars represent 95% confidence intervals (CIs). Trials are sorted by
trial duration ranging from 24 to 60 months for hip fracture and 12 to 60 months for nonvertebral fracture. For 3 trials with hip fractures,
12,17,18
which included 5572
individuals with a vitamin D dose of 700 to 800 IU/d, the pooled RR was 0.74 (95% CI, 0.61-0.88; Q test P= .74). For 5 trials with nonvertebral fractures,
12,14,15,17,18
which included 6098 individuals with a vitamin D dose of 700 to 800 IU/d, the pooled RR was 0.77 (95% CI, 0.68-0.87; Q test P=.41). For the 2 trials,
13,16
with a
vitamin D dose of 400 IU/d, trial duration ranged from 24 months to 36 to 41 months.
FRACTURE PREVENTION WITH VITAMIN D SUPPLEMENTATION
©2005 American Medical Association. All rights reserved. (Reprinted) JAMA, May 11, 2005—Vol 293, No. 18 2261
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1.03 (95% CI, 0.86-1.24), suggesting
that 400 IU/d vitamin D supplementa-
tion has no significant benefit on reduc-
ing the risk of sustaining a nonverte-
bral fracture.
The achieved level of serum
25-hydroxyvitamin D in relation to
reduction in nonvertebral fracture risk
is shown in Figure 3.
30
A greater
reduction i n nonvertebral fractures
was observed with the higher achieved
25-hydroxyvitamin D levels in the
treatment group (meta-regression
P=.03). Rather than omitting studies
with different assays, we cross-
calibrated to the widely used DiaSorin
assay (DiaSorin, Stillwater, Minn).
31
DiaSorin equivalent values for each of
the studies were 54 nmol/L (Lips et
al
13
); DiaSorin equivalent values not
available, as reported
32
(Meyer et al
16
and Pfeifer et al
15
); 63 nmol/L (Deca-
lyos II study
17
); 75 nmol/L (Decalyos I
study
12
); 74 nmol/L (Trivedi et al
18
);
and 99 nmol/L (Dawson-Hughes et
al
14
).
Sensitivity Analysis of Trials That
Did Not Meet Quality Criteria
for Inclusion
Including 3 additional studies
19-21
in the
pooled analysis for any nonvertebral
fracture doubled the total number of par-
ticipants to 17 736 (Table 1). The pooled
RR for any vitamin D dose preventing
any nonvertebral fracture was 0.83 (95%
CI, 0.73-0.94; Q test P=.13). In trials that
provided 700 to 800 IU/d cholecalcif-
erol or 1000 IU/d ergocalciferol in the
treatment groups (n=6941 individu-
als), the pooled RR was 0.77 (95% CI,
0.67-0.87; Q test P=.40). In trials that
provided 400 IU/d vitamin D (n=10 795
individuals), the pooled RR was 0.93
(95% CI, 0.76-1.12; Q test P=.12).
Subgroup Analyses
Additional Calcium Supplementation.
We could not examine separately the
effect of additional calcium supplemen-
tation because the 2 low-dose vitamin
D trials
13,16
were also the trials that did
not provide calcium supplements, and
the high-dose vitamin D trials did pro-
vide supplementation with 1 excep-
tion, the Trivedi trial, which gave the
equivalent of 800 IU/d vitamin D with-
out calcium.
18
The other 4 high-dose vi-
tamin D trials provided 500 to 1200 mg
of calcium in the treatment group.
Sex. For hip fracture prevention, only
3 studies provided separate results by
sex. The pooled RR was 0.73 (95% CI,
0.61-0.89) for 3 studies involving 5838
women,
12,17,18
and the RR was 0.76 (95%
CI, 0.35-1.67) for the 1 study involv-
ing 2037 men.
18
For any nonvertebral fracture pre-
vention, only 4 studies provided sepa-
rate results by sex. The pooled RR was
0.80 (95% CI, 0.70-0.91) for 4 studies
involving 5975 women,
12,15,17,18
and the
RR was 0.70 (95% CI, 0.40-1.20) for the
1 study involving 2037 men.
18
Length of Follow-up. When stud-
ies were sorted by length of treatment
and follow-up, we were unable to dis-
cern a clear difference in the effect of
vitamin D for both hip and any non-
vertebral fractures (Figure 2).
COMMENT
For both hip and nonvertebral fracture
prevention by vitamin D, our pooled
results indicated variation between stud-
ies that was resolved when low- and high-
dose vitamin D (cholecalciferol) trials
were pooled separately. For trials using
700 to 800 IU/d oral vitamin D with or
without calcium supplementation, we
found a significant 26% reduction in risk
of sustaining a hip fracture and a signifi-
cant 23% reduction in risk of sustaining
any nonvertebral fracture vs calcium or
placebo. The pooled risk difference indi-
cated that 45 persons would need to be
treated with 700 to 800 IU/d vitamin D
to prevent 1 person from sustaining a hip
fracture, and 27 persons would need to
be treated to prevent 1 person from sus-
taining any nonvertebral fracture. In con-
trast, 400 IU/d vitamin D did not appre-
ciably reduce hip or nonvertebral
fractures in older persons compared with
placebo or calcium.
There are 2 physiological explana-
tions for the beneficial effect of vitamin
D on fracture risk in older persons. First,
Figure 3. Hip and Nonvertebral Fracture Efficacies by Achieved 25-Hydroxyvitamin D Levels
in 400 IU/d and 700-800 IU/d Vitamin D–Treated Groups
Hip Fracture Nonvertebral Fracture
Relative Risk (95% CI)
2.0
1.5
13
16
18
17
12
1.0
0.5
0
50 64 98 106 12072
Achieved 25-Hydroxyvitamin D Level, nmol/L Achieved 25-Hydroxyvitamin D Level, nmol/L
Relative Risk (95% CI)
2.0
1.5
1.0
0.5
0
50 64 98 106 12072
Vitamin D Dose
700-800 IU/d
400 IU/d
12
14
17
18
15
13
16
Circles and squares represent relative risks (RRs) and error bars represent 95% confidence intervals. Trendline
is based on series of effect sizes (open circles and squares). All trials identified for the primary analyses for both
fractures are shown as a reference number outside each circle or square. A meta-regression, which included
9294 individuals, indicated a significant inverse relationship between higher achieved 25-hydroxyvitamin D
levels in the treatment group and hip fracture risk (=–0.009; P=.02; log RR of hip fracture is estimated to
decrease by 0.009 per 1-nmol/L increase in 25-hydroxyvitamin D). A meta-regression, which included 9820
individuals, indicated a significant inverse relationship between higher achieved 25-hydroxyvitamin D levels in
the treatment group and nonvertebral fracture risk (=−0.006; P=.03; log RR of nonvertebral fracture is es-
timated to decrease by 0.006 per 1-nmol/L of 25-hydroxyvitamin D achieved in the treatment group). To
convert 25-hydroxyvitamin D to ng/mL, divide values by 2.496.
FRACTURE PREVENTION WITH VITAMIN D SUPPLEMENTATION
2262 JAMA, May 11, 2005—Vol 293, No. 18 (Reprinted) ©2005 American Medical Association. All rights reserved.
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the well-described decrease in bone loss
in older persons
14,33
; and second, vita-
min D appears to have a beneficial effect
on muscle strength
34
and balance
15
me-
diated through highly specific recep-
tors in muscle tissue.
35,36
Furthermore,
vitamin D has been associated with a sig-
nificant 22% reduction in the risk of fall-
ing in older individuals.
37
As both bone
loss and falls are important risk factors
for fractures in older persons,
38,39
it is
plausible that vitamin D supplementa-
tion in a sufficient dose reduces the risk
of fracture in older persons.
The pooled results suggest that for hip
and nonvertebral fracture prevention 700
to 800 IU/d of vitamin D is better than
400 IU/d. Our finding that a higher dose
of vitamin D supplementation and ac-
companying higher serum 25-hydroxyvi-
tamin D levels are advantageous for frac-
ture prevention is consistent with 2
previous findings. First, in a national US
survey among adults aged 50 years or
older, we found that bone mineral den-
sity increased monotonically with higher
25-hydroxyvitamin D levels up to at least
80 nmol/L.
40
Second, in our previous
meta-analysis of falls, vitamin D supple-
mentation at a dose of 800 IU/d re-
duced fall risk by 35%, although 400 IU/d
was not effective in reducing falls.
37
This range of 700 to 800 IU/d vita-
min D shown to be effective in frac-
ture prevention is higher than the cur-
rent vitamin D intake recommendation
of between 400 to 600 IU/d in middle-
aged and older adults. In the current un-
certainty about vitamin D intake rec-
ommendations, our results support
increasing the suggested dose.
40-44
Among the high-dose trials, some of
the variation in achieved 25-hydroxyvi-
tamin D levels in the treatment group
may be explained by the difference in
starting levels of 25-hydroxyvitamin D,
45
which may relate to type of dwelling
(lower levels in nursing home resi-
dents), latitude (higher levels in more
southern latitudes), or food fortifica-
tion with vitamin D.
46-48
Optimal frac-
ture prevention appeared to occur in
trials with achieved mean 25-hydroxyvi-
tamin D level of approximately 100
nmol/L. This level was reached in 2 high-
dose trials with baseline 25-hydroxyvi-
tamin D levels of between 40
12
to 77
nmol/L,
14
whereas participants in 2 other
high-dose trials with baseline levels be-
tween 21
17
to 26 nmol/L
15
did not achieve
25-hydroxyvitamin D levels of more than
100 nmol/L. Thus, it cannot be ex-
cluded that optimal fracture prevention
may require more than 700 to 800 IU/d
vitamin D in populations with low base-
line 25-hydroxyvitamin D levels.
Another source of variation in
achieved 25-hydroxyvitamin D levels
may be interlaboratory differences in as-
says for 25-hydroxyvitamin D.
30
How-
ever, there would still be a similar trend
between higher achieved 25-hydroxyvi-
tamin D levels and fracture efficacy if
the different assays were transformed
into DiaSorin equivalent values.
None of the studies that were in-
cluded in the primary analysis tested oral
ergocalciferol as the intervention; there-
fore, our findings used only cholecalcif-
erol. Previous studies, however, re-
ported that the potency of ergocalciferol
may be less than one third that of cho-
lecalciferol in the same dose.
49,50
Because calcium was administered in
combination with vitamin D in all but
1 of the higher-dose vitamin D trials,
the independent effect of vitamin D
could not be clearly determined. In the
Trivedi trial,
18
which used 100 000 IU
every 4 months (equivalent to 800 IU/d)
without additional calcium, the RR was
similar to high-dose studies in which
500 to 1200 mg/d calcium was used in
combination with vitamin D (RR, 0.67
vs pooled RR plus calcium, 0.77
12,14,15,17
).
Thus, additional calcium supplemen-
tation may not be critical for nonver-
tebral fracture prevention once 700 to
800 IU of vitamin D are provided. How-
ever, in the Trivedi trial,
18
the mean total
calcium intake was 742 mg/d; there-
fore, we cannot determine if lower di-
etary calcium intakes with high-dose vi-
tamin D would prevent fractures.
Although the data in men were lim-
ited, we did not find evidence that the
benefit of vitamin D differed by sex. Also,
we did not find evidence that the effect
of vitamin D supplementation in-
creased with duration of trial, which may
be explained by the early benefits (within
2-3 months) of vitamin D on strength
and falls observed in previous stud-
ies.
15,34,51
However, benefits from start-
ing supplementation earlier in life or con-
tinuing beyond 5 years cannot be
excluded. All trials were performed in
primarily white populations, so our meta-
analysis cannot address vitamin D ef-
fects in other racial or ethnic groups.
We performed a sensitivity analysis by
including 3 RCTs that did not meet our
inclusion criteria
19
or were only pub-
lished in abstract form.
20,21
The inclu-
sion of these RCTs would have nearly
doubled the number of individuals
pooled from 9820 to 17 736. Adding the
3 studies to the primary analysis for any
nonvertebral fracture, the pooled RR re-
mained 0.83 and was significant for all
10 studies; in addition, the pooled RR
was 0.77 and significant for the higher-
dose vitamin D supplementation trials.
For the low-dose vitamin D trials, the RR
was 0.93 without gaining significance.
Thus, our sensitivity analysis is largely
consistent with the primary analysis.
In conclusion, this meta-analysis sug-
gests that oral vitamin D supplementa-
tion in the range of 700 to 800 IU/d
should reduce the risk of hip or any non-
vertebral fracture by approximately 25%.
The role of additional calcium supple-
mentation together with 700 to 800 IU/d
vitamin D could not be clearly defined,
but dietary calcium intakes of more than
700 mg/d may be necessary for nonver-
tebral fracture prevention. Given the
NNT of 27 to 45 for any nonvertebral and
hip fracture prevention, and the high
morbidity, mortality, and cost of frac-
tures, our results are compelling for gen-
eral vitamin D supplementation in the
range of 700 to 800 IU/d in elderly per-
sons. Future research should focus on
comparative vitamin D supplementa-
tion trials testing higher doses of vita-
min D. Another question to be ad-
dressed in future research is whether and
in what dose calcium is adding value to
the fracture efficacy of vitamin D.
Author Contributions: Dr Bischoff-Ferrari had full ac-
cess to all of the data in the study and takes respon-
sibility for the integrity of the data and the accuracy
of the data analysis.
FRACTURE PREVENTION WITH VITAMIN D SUPPLEMENTATION
©2005 American Medical Association. All rights reserved. (Reprinted) JAMA, May 11, 2005—Vol 293, No. 18 2263
Downloaded From: http://jama.jamanetwork.com/ on 02/25/2013
Study concept and design: Bischoff-Ferrari, Willett,
Giovannucci, Dawson-Hughes.
Acquisition of data: Bischoff-Ferrari, Dietrich.
Analysis and interpretation of data: Bischoff-Ferrari,
Willett, Wong, Giovannucci, Dietrich, Dawson-
Hughes.
Drafting of the manuscript: Bischoff-Ferrari, Dawson-
Hughes.
Critical revision of the manuscript for important in-
tellectual content: Bischoff-Ferrari, Willett, Wong,
Giovannucci, Dietrich, Dawson-Hughes.
Statistical analysis: Bischoff-Ferrari, Willett, Wong,
Giovannucci, Dietrich, Dawson-Hughes.
Obtained funding: Bischoff-Ferrari.
Administrative, technical, or material support:
Dawson-Hughes.
Financial Disclosures: Dr Wong receives funding from
federal agencies, Schering Plough, and Centocor for
work unrelated to studies of vitamin D or falls and frac-
tures. No other authors reported financial disclo-
sures.
Funding/Support: This study was supported by grants
from the Medical Foundation (Charles H. Farns-
worth Trust; US Trust Company; Trustee and the
Charles A. King Trust; Fleet National Bank) and the
James Knox Memorial Foundation.
Role of the Sponsors: No sponsors participated in the
design and conduct of the study; in the collection,
analysis, and interpretation of the data; or in the prepa-
ration, review, or approval of the manuscript.
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much less effective than vitamin D3 in humans. J Clin
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FRACTURE PREVENTION WITH VITAMIN D SUPPLEMENTATION
2264 JAMA, May 11, 2005—Vol 293, No. 18 (Reprinted) ©2005 American Medical Association. All rights reserved.
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... Vitamin E plays a critical role in promoting and maintaining reproductive function, promoting follicle development and progesterone secretion, and also has strong antioxidant capacity (5). Vitamin D maintains calcium homeostasis and prevents fractures (6). Therefore, fat-soluble vitamin deficiency causes a decline in fertility and immunity, and causes a series of diseases such as xerophthalmia, anemia, and rickets. ...
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Fat-soluble vitamin malabsorption may occur due to low dietary fat content, even in the presence of an adequate supply of fat-soluble vitamins. Bile acids (BAs) have been confirmed as emulsifiers to promote fat absorption in high-fat diets. However, there are no direct evidence of exogenous BAs promoting the utilization of fat-soluble vitamins associated with fat absorption in vitro and in vivo. Therefore, we chose laying hens as model animals, as their diet usually does not contain much fat, to expand the study of BAs. BAs were investigated in vitro for emulsification, simulated intestinal digestion, and release rate of fat-soluble vitamins. Subsequently, a total of 450 healthy 45-week-old Hy-Line Gray laying hens were chosen for an 84-day feeding trial. They were divided into five treatments, feeding diets supplemented with 0, 30, 60, 90, and 120 mg/kg BAs, respectively. No extra fat was added to the basic diet (crude fat was 3.23%). In vitro, BAs effectively emulsified the water-oil interface. Moreover, BAs promoted the hydrolysis of fat by lipase to release more fatty acids. Although BAs increased the release rates of vitamins A, D, and E from vegetable oils, BAs improved for the digestion of vitamin A more effectively. Dietary supplementation of 60 mg/kg BAs in laying hens markedly improved the laying performance. The total number of follicles in ovaries increased in 30 and 60 mg/kg BAs groups. Both the crude fat and total energy utilization rates of BAs groups were improved. Lipase and lipoprotein lipase activities were enhanced in the small intestine in 60, 90, and 120 mg/kg BAs groups. Furthermore, we observed an increase in vitamin A content in the liver and serum of laying hens in the 60, 90, and 120 mg/kg BAs groups. The serum IgA content in the 90 and 120 mg/kg BAs groups was significantly improved. A decrease in serum malondialdehyde levels and an increase in glutathione peroxidase activity were also observed in BAs groups. The present study concluded that BAs promoted the absorption of vitamin A by promoting the absorption of fat even under low-fat diets, thereupon improving the reproduction and health of model animals.
... A 2019 Oxford meta-analysis found that while daily or bolus dosing of Vitamin D3 alone was not sufficient to reduce the risk of fractures in elderly patients, daily supplementation of 400-800 IU of Vitamin D with 1000-1200 mg calcium reduced fracture risk by 6% [23]. This is further corroborated by a 2005 Harvard study showing that 700-800 IU/day Vitamin D3 supplementation significantly reduced he risk of non-vertebral fractures in institutionalized elderly patients [24]. However, dosing of Vitamin D3 and calcium supplementation is important as this regimen comes with side effects such as risk of nephrolithiasis [25]. ...
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Vitamin D plays a critical role in various physiologic processes throughout the body including metabolism, immune support, and bone formation and mineralization. Vitamin D is chemically modified by enzymatic reactions in the liver and kidney before it can be used by the rest of the body. The process of how Vitamin D is absorbed and metabolically activated is important in understanding how to diagnose and treat patients with low Vitamin D levels. While Vitamin D toxicity can occur, Vitamin D deficiency is more common and can result in increased risk of fractures in the elderly. Vitamin D deficiency can occur because of malabsorption, poor diet, inadequate sun exposure and a variety of other causes. The purpose of this manuscript was to explore the different functions of Vitamin D in the body and significant clinical effects if these levels are below normal limits.
... The vast discrepancy of various studies may be attributed to multiple complex confounders such as sex and gender, etc. One notable confounder is that the consumption of cod liver oil rich in vitamins A and D was likely to exert influence to some degree on bone health (48,49). Some researchers attempt to explain this phenomenon with more objective and more profound mechanisms, such as circulating fatty acids. ...
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Background This Mendelian randomization (MR) study aimed to explore the causal relationship between polyunsaturated fatty acids (PUFAs) and bone mineral density (BMD). Methods We conducted a two-sample MR analysis to figure out if there is any causal effect of PUFAs on BMD through the summary data from the genome-wide association study (GWAS). Relationships were evaluated through inverse variance weighted (IVW), MR-Egger, weighted median, and maximum likelihood methods. The MR Pleiotropy RESidual Sum and Outlier (MR-PRESSO) test was performed to detect the horizontal pleiotropy. Results Our findings revealed that omega-6 fatty acids were negatively related to the TB-BMD (beta-estimate: −0.0515; 95% confidence interval [CI]: −0.0911 to −0.0119; standard error [SE]: 0.0201; p-value: 0.0106). The reverse direction MR analysis showed that TB-BMD was linked to the omega-6 FAs (beta-estimate: −0.0699; 95% CI: −0.1304 to −0.0095; SE: 0.0308; p-value: 0.0265). No statistically significant correlations between PUFAs and BMD were observed after adjusting the interactions between metabolites. Conclusion This two-sample MR analyses produced strong and new genomic evidence that there was a causal relationship between omega-6 FAs and BMD. Further investigations are still required to elucidate the potential mechanism.
... However, there has been no consensus reached, and different results have been reported. For instance, Bischoff-Ferrari et al. [79] suggested that the effect was positive on hip and any non-vertebral fractures. In contrast, Lai et al. reported that varying doses of vitamin D supplementation were effective in preventing a hip fracture [27]. ...
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Background Chronic kidney disease (CKD) and end-stage renal diseases, has high global morbidity and mortality. Objective We aimed to investigate the antioxidant and anti-inflammatory properties of curcumin and its impact on kidney biochemical parameters associated with kidney disease among CKD and hemodialysis (HD) patients. Methods The intended keywords were used in the literature search. Clinical trial studies from the very beginning to December 25th, 2021, indexed in the Institute for Scientific Information (ISI), Scopus, and PubMed databases were included in the review. Records with no accessible full texts, non-English language articles, and studies that were not related to the study aim were excluded. The agreement for exclusion required all authors to concur. Finally, after reviewing all available literature, 27 articles were included in this systematic review. Results Curcumin supplementation increased antioxidant capacity by improving catalase (CAT) activity, free radical scavenging activity, and, nuclear factor erythroid 2–related factor 2 (Nrf2). It also reduced hs-CRP, IL-6, and, TNF-a levels in patients with CKD and HD patients. Different results were reported regarding the effect of curcumin on kidney-related biochemical parameters. But mostly the results showed that there are no significant changes were seen in glomerular filtration (GFR), albumin (Alb), serum creatinine (sCr), proteinuria (PRO), and blood urea nitrogen (BUN) in these patients. Conclusion Although it seems curcumin improved antioxidant capacity and decreased inflammatory cytokines in CKD and HD patients, it did not affect renal biochemical parameters. More clinical studies with larger sample sizes appear to be needed.
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Objetivo: avaliar a eficácia da utilização da terapia combinada de alendronato de sódio e vitamina D no metabolismo ósseo de mulheres em tratamento de osteoporose pós-menopausa.Métodos: trata-se de uma revisão sistemática, a qual foram pesquisados ensaios clínicos randomizados (ECR) indexados nas bases de dados BVS, ISI Web of Science, PubMed, SciELO, ScienceDirect e Scopus que comparavam a associação de alendronato sódico e vitamina D com a monoterapia de alendronato de sódio. Resultados: um total de seis ECR contemplou os critérios para serem inclusos nesse estudo, compreendendo um total de 4164 participantes e seus respectivos dados. Os estudos avaliaram diferentes domínios do metabolismo ósseo, como níveis séricos de vitamina D, paratormônio, densidade mineral óssea e marcadores de turnover ósseo. A terapia combinada produziu melhora significativa nos marcadores metabólicos ósseos. Conclusão: a terapia combinada de alendronato de sódio com vitamina D promove melhora no metabolismo ósseo de mulheres com osteoporose pós-menopausa.
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This book discusses the global prevalence as well as the geographic distribution of HIV-1 and HIV-2 infections and updates on recent shared global initiatives. The demographic trends in HIV in the United States, especially regarding gender, sexuality, race, ethnicity, age, injection-drug use, socioeconomic status, and recent initiatives are reviewed. Special attention is paid to HIV among communities of color, as well as women, children, and adolescences. The role of HIV in men who have sex with men and the transgender community is reviewed in detail. HIV Testing and Counselling lists and describes the various types of HIV testing available. The book also presents an overview of HIV counselling. HIV testing terminology and algorithms are presented to the reader along with descriptive figures. Laboratory markers for HIV are reviewed. The chapter describes who should be tested, as well as pre and post-test counselling elements. A section of the chapter is dedicated to special populations and environments (blood supply screening, prenatal screening, testing settings) Strategies to improve uptake of HIV testing are discussed.
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Kas iskelet sisteminin sağlıklı ve sürdürebilir şe-kilde işlev görmesi için vücudumuzun temel ih-tiyaçlarından biri de D vitaminidir. Sanayi devrimi ile birlikte kırsaldan şehir hayatına geçişin artması beraberinde gelişim geriliği, kemiklerde kısalık ve iskelet deformiteleriyle seyreden bir hastalık olan raşitizmin insidansında artışa yol açmıştır. Bu durum o döneme ait bilim insanlarının da ilgisini çekmiş olup, raşitizmin tanı ve tedavisi yoğun ilgi görmüştür. Raşitizm ile güneş ışınlarının ilişkisi ilk olarak 1822 yılında bildirilmiştir. Güneş ışınların-dan mahrum kalan bölgelerde yaşayan çoçuk-larda raşitizm sıklığının artması bilim insanlarının dikkatini çekmiştir. Bu nedenle raşitik çoçukların tedavisinde sistematik olarak güneş banyosu yapılması önerilmiş ve rutin tedavide de kullanıl-mıştır.(1) İlerleyen yıllarda raşitizmin tedavisi için besin replasmanı yapılması gündeme gelmiş ve yüksek oranda başarı elde edilmiştir. 1827'de Bre-tonneau, akut raşitizmli 15 aylık bir çocuğu mori-na karaciğeri yağı ile beslenmesini sağlayarak te-davi etmiştir. Hastalığın bu şekilde besin takviyesi tedavisine hızlı yanıt vermesi döneminde epey dikkat çekmiştir. İlerleyen yıllarda farklı türde su memelilerinin karaciğerlerinden elde edilen çe-şitli mama ve gıdalar raşitizm ve osteomalazi te-davisinde aktif olarak kullanılmaya başlanmıştır.(2) Başlangıçta balık karaciğerindeki iyileştirici etke-nin A vitamini olduğu düşünülmekteydi. Bununla birlikte Mc Collum ve arkadaşları bu etkenin A vi-tamininden farklı bir etken olduğunu bildirmişler-dir. Sonraki çalışmalarda bu etken D vitamini ola-rak adlandırılmıştır.(1) İlerleyen dönemde bilimsel çalışmaların artması ve bilgi birikiminin katlanarak artması sonucu D vitamin eksikliğinin çoçuklarda rikets erişkinlerde osteomalazi oluşturduğu ve bu hastalıkların güneş ışınları alma ve besin takviyesi ile tedavi edilebileceği anlaşılmıştır. 1970'lerde D vitamini üzerinden yapılan yeni araştırmalar, D vi-tamininin vitaminden öte bir hormon olduğunu ortaya koymuştur.(3) Son 40 yılda yapılan bilimsel çalışmalar sonucunda D vitaminin sadece kemik hastalıkları değil kanser, romatizmal hastalıklar, otoimmün hastalıklar, enfeksiyon hastalıkları, nörolojik hastalıklar, kalp hastalıklarında da aktif rol aldığı ortaya çıkmıştır.
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Hip fractures have a huge impact in reducing the quality of life and increasing mortality. This review aims to assess the impact of daily oral supplementation of vitamin D3 plus calcium on the incidence of hip fracture in people over 65 years. PRISMA guidelines were followed and RCTs that evaluated the effectiveness of daily oral supplementation of vitamin D3 plus calcium in preventing hip fracture in adults over 65 years were included in the study. The databases such as Cochrane Library, Embase, Medline, PubMed, CINAHL, Web of Science and Scopus were searched from October 2019‐ January 2020.The Cochrane risk of bias tool was used to check the quality of the included studies. A meta‐analysis with fixed effect model using Review Manager (Revman 5.3) was used to analyse the data. The meta‐analysis of seven RCTs on vitamin D3 plus calcium supplementation and hip fracture (n = 12,620) identified odds ratio (OR) of 0.75; 95% Confidence interval (CI): 0.64, 0.87; p = .0003. Daily oral supplementation of 800 IU of Vitamin D3 plus 1200 mg of calcium was found more effective (n = 5676 participants; OR = 0.69; 95% CI: 0.58, 0.82; p < .0001) than daily oral supplementation of 800 IU of Vitamin D3 plus 1000 mg of calcium (n = 6555,OR = 1.08; 95% CI: 0.74, 1.56; p = .70) in reducing hip fracture. A meta‐analysis of the seven RCTs to identify the incidence of non‐vertebral fracture gave the OR of 0.80; 95% CI: 0.72, 0.89; p < .0001. A meta‐analysis of three RCTs on femoral neck bone mineral density (BMD) (n = 483) gave a mean difference of 1.21; 95% CI: ‐0.79, 3.20; p = .24. Daily oral supplementation 800 IU of vitamin D3 plus 1200 mg of calcium reduces hip fracture and non‐vertebral fracture in older people. Administering vitamin D3 and calcium supplements had no effect in increasing the femoral neck BMD. Even though it is evident from the review that optimal daily intake of vitamin D3 plus calcium supplementation help in the prevention of fracture, it is only one essential element in fracture prevention. Also, people who are on dietary supplements should be compliant with same for better result. Efforts to prevent bone loss and osteoporosis should begin from an early age. It includes maintaining a healthy lifestyle, optimal intake of calcium and vitamin D3, proper nutrition, adequate exposure to sunlight, exercise etc. Proper education on healthy lifestyle, avoiding risk factors like smoking, caffeine, alcohol and awareness of bone health should continue throughout life with emphasis during menopause when increased bone loss is expected.
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Objective: Funnel plots (plots of effect estimates against sample size) may be useful to detect bias in meta-analyses that were later contradicted by large trials. We examined whether a simple test of asymmetry of funnel plots predicts discordance of results when meta-analyses are compared to large trials, and we assessed the prevalence of bias in published meta-analyses. Design: Medline search to identify pairs consisting of a meta-analysis and a single large trial (concordance of results was assumed if effects were in the same direction and the meta-analytic estimate was within 30
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Exploring the possible reasons for heterogeneity between studies is an important aspect of conducting a meta-analysis. This paper compares a number of methods which can be used to investigate whether a particular covariate, with a value defined for each study in the meta-analysis, explains any heterogeneity. The main example is from a meta-analysis of randomized trials of serum cholesterol reduction, in which the log-odds ratio for coronary events is related to the average extent of cholesterol reduction achieved in each trial. Different forms of weighted normal errors regression and random effects logistic regression are compared. These analyses quantify the extent to which heterogeneity is explained, as well as the effect of cholesterol reduction on the risk of coronary events. In a second example, the relationship between treatment effect estimates and their precision is examined, in order to assess the evidence for publication bias. We conclude that methods which allow for an additive component of residual heterogeneity should be used. In weighted regression, a restricted maximum likelihood estimator is appropriate, although a number of other estimators are also available. Methods which use the original form of the data explicitly, for example the binomial model for observed proportions rather than assuming normality of the log-odds ratios, are now computationally feasible. Although such methods are preferable in principle, they often give similar results in practice. Copyright © 1999 John Wiley & Sons, Ltd.
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1. Eleven patients with the bone loss of ageing were treated with the vitamin D analogue 1α-hydroxycholecalciferol and calcium for 3–6 months. 2. Muscle biopsies were taken from the vastus lateralis before and after the treatment and the activity of several enzymes was measured. Succinate dehydrogenase and total phosphorylase activities, which are a measure of the oxidative capacity, were low and increased significantly with the treatment. The lactate dehydrogenase activity, which can be taken as a measure of the anaerobic metabolism, was normal and did not change with treatment. The phosphagen stores, ATP and creatine phosphate were low and increased to normal with treatment. 3. Histochemical classification of the fibre composition revealed that the treatment induced an increase in the relative number of fast-twitch a (FTa or type II A) fibres accompanied by a reduction of the fast-twitch b (FTb or type II B) fibres. The cross-sectional area of the FTa fibres also increased with the treatment. 4. The present findings indicate that treatment with the active vitamin D analogue, 1α-hydroxycholecalciferol, and calcium improves the myopathy associated with the bone loss of ageing.
Article
Hypovitaminosis D and a low calcium intake contribute to increased parathyroid function in elderly persons. Calcium and vitamin D supplements reduce this secondary hyperparathyroidism, but whether such supplements reduce the risk of hip fractures among elderly people is not known. We studied the effects of supplementation with vitamin D3 (cholecalciferol) and calcium on the frequency of hip fractures and other nonvertebral fractures, identified radiologically, in 3270 healthy ambulatory women (mean [+/- SD] age, 84 +/- 6 years). Each day for 18 months, 1634 women received tricalcium phosphate (containing 1.2 g of elemental calcium) and 20 micrograms (800 IU) of vitamin D3, and 1636 women received a double placebo. We measured serial serum parathyroid hormone and 25-hydroxyvitamin D (25(OH)D) concentrations in 142 women and determined the femoral bone mineral density at base line and after 18 months in 56 women. Among the women who completed the 18-month study, the number of hip fractures was 43 percent lower (P = 0.043) and the total number of nonvertebral fractures was 32 percent lower (P = 0.015) among the women treated with vitamin D3 and calcium than among those who received placebo. The results of analyses according to active treatment and according to intention to treat were similar. In the vitamin D3-calcium group, the mean serum parathyroid hormone concentration had decreased by 44 percent from the base-line value at 18 months (P < 0.001) and the serum 25(OH)D concentration had increased by 162 percent over the base-line value (P < 0.001). The bone density of the proximal femur increased 2.7 percent in the vitamin D3-calcium group and decreased 4.6 percent in the placebo group (P < 0.001). Supplementation with vitamin D3 and calcium reduces the risk of hip fractures and other nonvertebral fractures among elderly women.
Article
The study goal was to use population-based data to model aspects of lifetime osteoporosis impact not previously studied, specifically: (1) to estimate person-years of fracture-related functional impairment against the trajectory of functional status in the general population; (2) jointly to consider hip, vertebral, and Colles' fractures in estimating the percent of women who will ever fracture; and (3) to estimate the lifetime number of fractures expected in a cohort of 10,000 50-year-old white postmenopausal women. The model estimates that 54% of 50-year-old women will sustain osteoporosis-related fractures during their remaining lifetimes. Beyond the functional impairment expected in similarly aged, unfractured women, osteoporosis-related fractures are estimated to cause 6.7% of women to become dependent in basic activities of daily living; 7.8% are expected to require nursing home care for an average of 7.6 years.
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An annual intramuscular injection of ergocalciferol (150,000 IU) normalized low serum (25(OH)D concentrations in elderly people for 1 year. The treatment had a slight effect on serum 24,25(OH)2D levels but no effect on 1,25(OH)2D levels.
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Although even in the elderly most falls are not associated with fractures, over 90 percent of hip fractures are the result of a fall. Few studies have assessed whether the risk factors for falls are also important risk factors for hip fracture. To examine the importance of risk factors for falls in the epidemiology of hip fracture, we performed a case-control study of 174 women (median age, 80 years) admitted with a first hip fracture to 1 of 30 hospitals in New York and Philadelphia. Controls, matched to the case patients according to age and hospital, were selected from general surgical and orthopedic surgical hospital services. Information was obtained by direct interview. As measured by the odds ratio, increased risks for hip fracture were associated with lower-limb dysfunction (odds ratio = 1.7; 95 percent confidence interval, 1.1 to 2.8), visual impairment (odds ratio = 5.1; 95 percent confidence interval, 1.9 to 13.9), previous stroke (odds ratio = 2.0; 95 percent confidence interval, 1.0 to 4.0), Parkinson's disease (odds ratio = 9.4; 95 percent confidence interval, 1.2 to 76.1), and use of long-acting barbiturates (odds ratio = 5.2; 95 percent confidence interval, 0.6 to 45.0). Of the controls, 44 (25 percent) had had a recent fall. The case patients were more likely than these controls to have fallen from a standing height or higher (odds ratio = 2.4; 95 percent confidence interval, 1.0 to 5.7). Of those with hip fracture the younger patients (less than 75 years old) were more likely than the older ones (greater than or equal to 75 years old) to have fallen on a hard surface (odds ratio = 1.9; 95 percent confidence interval, 1.04 to 3.7). A number of factors that have been identified as risk factors for falls are also associated with hip fracture, including lower-limb dysfunction, neurologic conditions, barbiturate use, and visual impairment. Given the prevalence of these problems among the elderly, who are at highest risk, programs to prevent hip fracture should include measures to prevent falls in addition to measures to slow bone loss.