Research

JAMA Internal Medicine | Original Investigation

Association of Long-term Exercise Training With Risk of Falls,

Fractures, Hospitalizations, and Mortality in Older Adults
A Systematic Review and Meta-analysis
Philipe de Souto Barreto, PhD; Yves Rolland, MD, PhD; Bruno Vellas, MD, PhD; Mathieu Maltais, PhD

Invited Commentary
IMPORTANCE Long-term exercise benefits on prevalent adverse events in older populations, Supplemental content
such as falls, fractures, or hospitalizations, are not yet established or known.

OBJECTIVE To systematically review and investigate the association of long-term exercise

interventions (ⱖ1 year) with the risk of falls, injurious falls, multiple falls, fractures,
hospitalization, and mortality in older adults.

DATA SOURCES PubMed, Cochrane Central Register of Controlled Trials, SportDiscus,

PsychInfo, and Ageline were searched through March 2018.

STUDY SELECTION Exercise randomized clinical trials (RCTs) with intervention length
of 1 year or longer, performed among participants 60 years or older.

DATA EXTRACTION AND SYNTHESIS Two raters independently screened articles, abstracted
the data, and assessed the risk of bias. Data were combined with risk ratios (RRs) using
DerSimonian and Laird’s random-effects model (Mantel-Haenszel method).

MAIN OUTCOMES AND MEASURES Six binary outcomes for the risk of falls, injurious falls,
multiple falls (ⱖ2 falls), fractures, hospitalization, and mortality.

RESULTS Forty-six studies (22 709 participants) were included in the review and 40 (21 868
participants) in the meta-analyses (mean [SD] age, 73.1 [7.1] years; 15 054 [66.3%] of
participants were women). The most used exercise was a multicomponent training
(eg, aerobic plus strength plus balance); mean frequency was 3 times per week, about 50
minutes per session, at a moderate intensity. Comparator groups were often active controls.
Exercise significantly decreased the risk of falls (n = 20 RCTs; 4420 participants; RR, 0.88;
95% CI, 0.79-0.98) and injurious falls (9 RTCs; 4481 participants; RR, 0.74; 95% CI,
0.62-0.88), and tended to reduce the risk of fractures (19 RTCs; 8410 participants; RR, 0.84;
95% CI, 0.71-1.00; P = .05). Exercise did not significantly diminish the risk of multiple falls
(13 RTCs; 3060 participants), hospitalization (12 RTCs; 5639 participants), and mortality
(29 RTCs; 11 441 participants). Sensitivity analyses provided similar findings, except the
fixed-effect meta-analysis for the risk of fracture, which showed a significant effect favoring
exercisers (RR, 0.84; 95% CI, 0.70-1.00; P = .047). Meta-regressions on mortality and falls
suggest that 2 to 3 times per week would be the optimal exercise frequency.

CONCLUSIONS AND RELEVANCE Long-term exercise is associated with a reduction in falls, Author Affiliations: Gerontopole of
injurious falls, and probably fractures in older adults, including people with cardiometabolic Toulouse, Institute of Ageing,
Toulouse University Hospital (CHU
and neurological diseases. Toulouse), Toulouse, France
(de Souto Barreto, Rolland, Vellas,
Maltais); UPS/Inserm UMR1027,
University of Toulouse III, Toulouse,
France (de Souto Barreto, Rolland,
Vellas).
Corresponding Author: Philipe
de Souto Barreto, PhD, Gérontopôle
de Toulouse, Institut
du Vieillissement, 37 Allées Jules
JAMA Intern Med. doi:10.1001/jamainternmed.2018.5406 Guesde, F-31000 Toulouse, France
Published online December 28, 2018. (philipebarreto81@yahoo.com.br).

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 Research Original Investigation Association of Long-term Exercise With Risk of Falls, Fractures, Hospitalizations, and Mortality in Older Adults
E
xercise training is an intervention of utmost impor-
tance for older adults’ health leading to benefits on mul-
tiple systems and functions, including muscle and bone
health, the cardiometabolic system,1,2 as well as physical1,3,4
and potentially cognitive (results still mixed5,6) functions. Re-
cent meta-analyses of randomized clinical trials (RCT) have
shown that exercise reduces the number of incident falls in
older adults,7-9 a major adverse event for this population.
Nevertheless, important gaps about the association of ex-
ercise with decreased risk of developing serious adverse
outcomes still remain unclear. Most studies included in
meta-analyses7-9 were short- to medium-term exercise inter-
ventions, evidencing a paucity of long-term (≥1 year) RCTs.
Other important gaps are: a lack of evidence on exercise ef-
fects on death and hospitalization in diverse older adult popu-
lations, and the best exercise prescription (ie, type, intensity,
frequency, session duration) for decreasing the risk of seri-
ous adverse events. The recent findings of the LIFE study,10
the largest and longest exercise trial performed to date among
older people, showed, unexpectedly, increases in both hospi-
talization and mortality among exercisers compared with con-
trols (differences statistically nonsignificant), raising doubts
about safety issues of exercise for older individuals. Further-
more, meta-analyses have obtained mixed results for the ef-
fects of exercise in preventing fractures.2,11,12 Regarding falls,
to the best of our knowledge, no meta-analyses have investi-
gated the association of long-term exercise with falls-related
outcomes, particularly multiple falls, which are common in
older adults.13
The objectives of this systematic review of RCTs with pre-
planned meta-analysis were to investigate the association of
long-term exercise interventions with the risk of mortality, hos-
pitalization, becoming a faller, a faller with multiple falls, a faller
with injurious falls, and sustaining a fracture.
Methods
This systematic review and meta-analysis was registered in
PROSPERO (CRD42018090757) and follows the PRISMA
guidelines.14 The protocol is available in the Supplement.
Search Strategy and Eligibility Criteria
One author (M.M.) performed the electronic searches be-
tween February 20 and March 5, 2018, using a search strategy
approved by all authors, from inception until the date of search
in the following databases: PubMed, Cochrane Central Regis-
ter of Controlled Trials, SportDiscus, PsychInfo, and Ageline.
Full search strategies are available in the Supplement. Lan-
guage restrictions were not applied. Two authors performed
title/abstract screening independently. After that, the full-
text of potentially eligible studies was accessed by 2 authors
(P.S.B. and M.M.) for finally determining eligibility and, then,
proceeding to data extraction. The reference list of previous
systematic reviews7-9,12,15,16 were scrutinized. Divergences be-
tween authors on articles’ eligibility were resolved in an in-
person meeting (100% consensus on articles’ eligibility was
reached).
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Key Points
Question What is the association of long-term (ⱖ1 year) exercise
with the risk of falls, fractures, hospitalizations and death in older
adults?
Findings In this meta-analysis of 40 long-term randomized
clinical trials (RCTs) of 21 868 participants, exercise significantly
decreased the risk of being a faller and injurious faller but did not
significantly reduce the risk of fractures. Exercise did not diminish
the risk of multiple falls, hospitalization, and mortality.
Meaning Long-term exercise, particularly moderate intensity,
multicomponent training with balance exercises, performed 2 to 3
times per week, appears to be a safe and effective intervention
for reducing the risk of being a faller/injurious faller in older
populations.
To be included in this review, studies had to meet the fol-
lowing criteria: (1) RCT design with exercise length of 1 year
or longer (or ≥12 months or ≥48 weeks); (2) the study com-
pared the effects of at least 1 exercise intervention against a
comparator group (ie, no intervention, attention or active con-
trols). Studies operationalizing cointerventions were eligible
if the sole difference between intervention and comparator was
the exercise training. All kinds of intervention structure
(eg, home-based or group-based) were eligible, with unsuper-
vised exercises being included only when a personalized ex-
ercise plan had been used; (3) participants had to be 60 years
or older at baseline or the mean population age should be 60
years or older.
Outcome Measures
Six binary outcomes including mortality; hospitalization: num-
ber of individuals admitted to the hospital (eg, inpatient hos-
pitalization, ≥24-hour hospitalization); fallers: people who fell
at least once; fallers with multiple falls: people who fell at least
twice; injurious fallers: people who suffered an injurious fall
(eg, fall with wound, head trauma, medical care, fracture, or
hospitalization) according to original investigators; and frac-
tures: number of people who sustained a fracture.
Data Extraction
Two raters (P.S.B. and M.M.) made the data abstraction inde-
pendently using a standard data collection form specifically
designed for this review. Divergences were solved in an in-
person meeting (100% consensus reached). In case of doubts
or insufficient data/information reported, original investiga-
tors were contacted by email.
When extracting data for the meta-analysis, we priori-
tized comparisons in which the sole difference between groups
was the exercise intervention. In studies with multiple exer-
cise groups vs a control group, we selected for the meta-
analysis the group with higher amount of exercise sessions
performed.
Risk of Bias
Two authors (P.S.B. and M.M.) independently coded the risk
of bias in the 7 domains of the Cochrane Collaboration’s tool.17
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 Association of Long-term Exercise With Risk of Falls, Fractures, Hospitalizations, and Mortality in Older Adults
Statistical Analysis
Data on death, people hospitalized, fallers, and people with
fractures were obtained from baseline until the end of the in-
tervention period; data from observational follow-up were not
used. Estimates of the outcomes were combined using the risk
ratio (RR). Regarding fractures, for 5 studies without data on
the number of people with fractures, we assumed the num-
ber of people with fractures was the same as the number of frac-
tures (multiple fractures representing a relatively uncom-
mon outcome, which would not severely bias our estimations);
a sensitivity analysis removing these studies was under-
taken. As prespecified in the review protocol (Supplement),
we employed DerSimonian and Laird’s random-effects model18
(with Mantel-Haenszel method). Heterogeneity was evalu-
ated using the I2 statistics, with an I2 greater than 50% repre-
senting substantial heterogeneity.19 Potential bias was evalu-
ated using the Egger’s test, with P < .10 indicating substantial
asymmetry, and funnel plots. Randomized clinical trials with
attrition rates of more than 40% and those with low compli-
ance (<30%) to the exercise intervention did not enter into the
primary analyses, but were added in sensitivity analyses. Trials
with no data on a given outcome were removed from meta-
analysis of the specific outcome. For cluster RCTs, we used ap-
propriate intracluster correlation (ICC) values (from the study,
from another similar study included in the review, or from ex-
ternal databases20-22) to estimate the effective sample size using
the design effect. If no appropriate estimate was available, we
presented unadjusted estimates and ran a sensitivity analy-
sis by removing cluster RCTs.
Other sensitivity/subgroup analyses were undertaken as
prespecified in the protocol: by using a fixed-effect model when
I2 was less than 50%, by restricting the analysis to RCTs with a
low risk of attrition bias, and by stratifying analysis according to
study population (clinically specific or disease specific vs non-
clinically specific). We further performed analysis restricted to
trials that have randomized more than 203 participants (median
of study population across included RCTs), and by removing the
2 trials23,24 in which the average baseline age of participants was
around 59 to properly address this deviation to the protocol.
When the number of studies was 10 or more, exploratory
metaregressions were undertaken in an attempt to find which
aspects of the exercise regimen would be associated to the effect
size (log-transformed) of the outcomes. The following variables
were tested: exercise frequency (3 times per week or more than
3 times per week compared with twice per week or less) as well
as effective exercise frequency (weekly frequency multiplied by
exercise compliance: between 2-3 times per week or more than
3 times per week compared with less than twice per week), vol-
ume (product of intensity and session duration: between 120 min-
utes per week and 180 minutes per week or 180 or more minutes
per week compared with less than 120 minutes per week), inten-
sity (vigorous compared with moderate), and type (aerobic,
strength, or other exercise type compared with multicomponent
training); given the importance of balance for all outcomes of this
review, we also compared multicomponent training comprising
a balance component vs all other exercise types combined.
All analyses were performed using STATA statistical soft-
ware (version 14, StataCorp).
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Original Investigation Research
Results
Forty-eight articles,10,13,23-68 representing 46 studies, met eligi-
bility criteria and were included in the review. The flowchart for
study selection is provided in the Supplement. The Table pro-
vides the characteristics of the included RCTs. The 46 studies
have randomized 22 709 (median of 203 participants; range from
20 to 6420) participants and have been conducted mainly in
Europe (n = 15), North America (n = 13, with 11 studies in the
United States), and Oceania (n = 10). Participants had a mean age
of 73.1 years, 66.3% were women (2 RCTs included only men45,46
and 11 solely included women13,27,34,37,43,48,49,53,55,56,64); mean
intervention length was 17 months (median, 12 months). Sixteen
trials23,24,29,33,40,41,45,46,50-52,57,58,61,62,64 were conducted in clini-
cally specific or disease specific populations (eg, mild cognitive
impairment or dementia [n = 7] and cardiac diseases [n = 4]).
Thirty-five studies were parallel-group RCTs, whereas 11 were
cluster RCTs30-32,35,36,47,51,52,65,67,68; most of the trials involved
community dwellers (n = 35). Two studies in which participants
had a baseline age of 59 years23 and 59.324 were included because
their follow-up length was among the largest (12023 and 30.124
months, respectively), meaning that the average age increased
to above 60 still at the beginning of the study. Two cluster RCTs
were removed from primary quantitative analysis because very
few participants exercised (26%30) or a very small fraction of ex-
ercise sessions (24%31) were attended.
As for any behavioral intervention, most trials had a high
risk of bias related to blinding participants. The risk of con-
cealment allocation was mostly unclear (n = 24), whereas in-
complete data (n = 15) and blinding of outcome assessors
(n = 11) may have been an issue for several studies (Supple-
ment).
The most used exercise was a multicomponent training
(multiple exercises; eg, aerobic plus strength plus balance train-
ing; 29 RCTs), followed by aerobic (8 RTCs)23,24,28,41,46,49,61,63
and strength (5 RTCs)27,31,38,48,64 training (Supplement). Ex-
ercise regimen was: mean frequency of 3 times per/week,
about 50 minutes per session, at a moderate intensity (n = 35
RCTs). Average compliance was about 65%. Group-based su-
pervised (n = 29) and a mix of group-based supervised and
home-based unsupervised exercises (n = 12) were the most
common format of exercise delivery. Comparator groups were
often active controls, ranging from attention controls to more
intensive interventions (eg, stent angioplasty). Thirteen trials
had more than two study arms,26,27,31,37,38,40,48,52,56,57,62,66,67
all of them with two exercise groups except two studies,27,48
which had three exercise groups. All exercise arms in these
studies have been scrutinized qualitatively. ICC values32,60 for
mortality (ICC = 0.001) and fractures (ICC = 0.03) applied for
cluster-RCTs performed in long-term care facilities (LTCF). No
other suitable ICC values were found.
Original investigators of 28 studies were contacted; 18 re-
sponded, and 9 provided new data and/or information.
Mortality
Thirty-nine studies10,13,23,24,27-52,54,56-58,61-65 provided available
information on death for 19 670 participants. Among them,
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 Research Original Investigation
Table. Characteristics of the Included Studies
Source
Belardinelli et al,23
2012
42
Barnett et al, 2003
Bunout et al,25 2005b
O’Connor et al,24 2009
Campbell et al,13 1997
Dangour et al,31 2011
El-Khoury et al,43 2015
Galvão et al,45 2014
Gianoudis et al,44 2014
Hambrecht et al,46
2004
Hewitt et al,47 2018
Karinkanta et al,48
2007
Kemmler et al,34 2010
King et al,49 2002
Kovács et al,50 2013
51
Lam et al, 2012
Lam et al,52 2015
Lord et al,53 1995
Lord et al,35 2003
Liu-Ambrose et al,27
2010b
MacRae et al,68 1994
36
Merom et al, 2016
Messier et al,40 2013
Munro et al,30 2004
Muscari et al,28 2010b
Mustata et al,41 2011
Nowalk et al,26 2001b
Pahor et al,54 2006
Pahor et al,10 2014
Park et al,55 2008
56 f
Patil et al, 2015
Pitkälä et al,57 2013
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Association of Long-term Exercise With Risk of Falls, Fractures, Hospitalizations, and Mortality in Older Adults
Intervention
Country Study Design, Participants, Groups, and Sample Size Setting Length, mo
Italy Study population: 59 years; chronic heart failure; 22% women; 2 groups: Community dwellersa 120.0
exercise (n = 63), control (n = 60)
Australia Study population: 75 years; 67% women; 2 groups: exercise (n = 83), Community dwellers 12.0
control (n = 80)
Chile Study population: 75 years; 71% women; 2 groups Community dwellers 12.0
United States Study population: 59 years; chronic heart failure; 28% women; 2 groups: Community dwellersa 30.1
/Canada/France exercise (n = 1159), control (n = 1172)
New Zealand Study population: 84 years; 100% women; 2 groups: exercise (n = 116), Community dwellers 12.0
control (n = 117)
Chile Study population: 66 years, 68% women; 4 groups: nutrition supplement Health centers 24.0
(n = 502), nutrition supplement + exercise (n = 516), exercise
(n = 480),c control (n = 504)c
France Study population: 80 years; 100% women; 2 groups: exercise (n = 352), Community dwellers 24.0
control (n = 354)
Australia/New Study population: 72 years; 0% women; prostate cancer; 2 groups: Community dwellersa 12.0
Zealand exercise (n = 50), control (n = 50)
Australia Study population: 68 years; 73% women; 2 groups: exercise (n = 81), Community dwellers 12.0
control (n = 81)
Germany Study population: 61 years; 0% women; coronary heart disease; 2 groups: Community dwellers 12.0
exercise (n = 51), control (n = 50)
Australia Study population: 86 years; 65% women; 2 groups: exercise (n = 113), Institutionalized 12.0
control (n = 108)
Finland Study population: 73 years; 100% women; 4 groups: exercise (n = 37)d, Community dwellers 12.0
control (n = 37)
Germany Study population: 69 years; 100% women; 2 groups: exercise (n = 123), Community dwellers 18.0
control (n = 123)
United States Study population: 63 years; 100% women; 2 groups: exercise (n = 51), Community dwellers 12.0
controls (n = 49)
Hungary Study population:78 years; 81% women; MCI; 2 groups: exercise Institutionalized 12.0
(n = 43), control (n = 43)
Hong Kong Study population: 78 years; 76% women; MCI; 2 groups: exercise Community dwellers 12.0
(n = 171), controls (n = 218) and institutionalized
Hong Kong Study population: 76 years; 39% women; MCI; 4 groups: exercise Community dwellers 12.0
(n = 147),c cognitive (n = 145), cognitive-physical (n = 132), control
(n = 131)c
Australia Study population: 72 years; 100% women; 2 groups: exercise (n = 100), Community dwellers 12.0
control (n = 97)
Australia Study population: 80 years; 86% women; 2 groups: exercise (n = 280), Institutionalized 12.0
controls (n = 271)
Canada Study population: 70 years; 100% women; 3 groups: 2 weekly RT Community dwellers 12.0
sessions (n = 52)c,e, 1 weekly RT session, balance training control
(n = 49)c,e
United States Study population: 71 years; 82% women; 2 groups: exercise (n = 49), Senior centers 12.0
control (n = 48)
Australia Study population: 78 years; 85% women; 2 groups: exercise (n = 279), Institutionalized 12.0
control (n = 251)
United States Study population: 66 years; 72% women; 3 groups: exercise only Community dwellers 18.0
(n = 150), exercise + diet (n = 152)c, diet (n = 152)c
United Kingdom Study population: 75.4 years; 67% women; 2 groups: exercise Community dwellers 24.0
(n = 2283), control (n = 4137)
Italy Study population: 69 years; 52% women; 2 groups: exercise (n = 60), Community dwellers 12.0
control (n = 60)
Canada Study population: 68 years; 55% women; chronic kidney disease; 2 Community dwellers 12.0
groups: exercise (n = 10), controls (n = 10)
United States Study population: 86 years; 85% women; 3 groups: exercise (n = 37),c Institutionalized 24.0
tai-chi (n = 38), control (n = 35)
United States Study population: 77 years; 69% women, 2 groups: exercise (n = 213), Community dwellers 12.0
control (n = 211)
United States Study population: 79 years; 67% women; 2 groups: exercise (n = 818), Community dwellers 31.2
control (n = 817)
South Korea Study population: 68 years; 100% women; 2 groups: exercise (n = 25), Community dwellers 12.0
control (n = 25)
Finland Study population: 74 years, 100% women; 4 groups: exercise (n = 205), Community dwellers 24.0
control (n = 204)
Finland Study population: 78 years; 81% women; Alzheimer disease; 3 groups; Community dwellers 12.0
home-based (n = 70)g, group-based exercise (n = 70), control (n = 70)g
(continued)
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 Association of Long-term Exercise With Risk of Falls, Fractures, Hospitalizations, and Mortality in Older Adults Original Investigation Research

Table. Characteristics of the Included Studies (continued)

Intervention
Source Country Study Design, Participants, Groups, and Sample Size Setting Length, mo
Prescott et al,58 2008 Denmark Study population: 68 years; 21% women; chronic heart failure; 2 groups: Community dwellers 14.0
exercise (n = 36), control (n = 30)
Reinsch et al,67 1992 United States Study population: 75 years, 80% women; 4 groups: exercisec (n = 57), Community dwellers 12.0
cognitive (n = 51), exercise + cognitive (n = 72), controls (n = 50)c
Rejeski et al,38 2017 United States Study population: 67 years, 71% women; overweight/obesity; 3 groups: Community dwellers 18.0
WL+aerobic (n = 86), WL+RT (n = 81)d, controls (n = 82)d
Rolland et al,33 2007 France Study population: 83 years; 75% women; Alzheimer disease; 2 groups: Institutionalized 12.0
exercise (n = 67), controls (n = 67)
Sherrington et al,39 Australia Study population: 81 years; 74% women; 2 groups: exercise (n = 171), Community dwellers 12.0
2014 controls (n = 169)
Suzuki et al,29 2012b Japan Study population: 76 years; 46% women; MCI; 2 groups: exercise Community dwellers 12.0
(n = 25), controls (n = 25)
Underwood et al,32 United Kingdom Study population: 87 years; 76% women; 2 groups: exercise (n = 398), Institutionalized 12.0
2013 controls (n = 493)
van Uffelen et al61 Netherlands Study population: 75 years; 37% women; MCI; 2 groups: exercise Community dwellers 12.0
2008 (n = 86), controls (n = 93)
62
Villareal et al, 2011 United States Study population: 70 years; 63% women; Obese; 4 groups: diet (n = 26), Community dwellers 12.0
exercise (n = 26)c, diet + exercise (n = 28), controls (n = 27)c
Von Stengel et al,37 Germany Study population: 69 years; 100% women; 3 groups: exercise + Community dwellers 18.0
2011 whole-body vibration (n = 50), exercise (n = 50)c, controls (n = 51)c
63
Voukelatos et al, Australia Study population: 73 years; 74% women; 2 groups: exercise (n = 192), Community dwellers 12.0
2015 controls (n = 194)
Winters-Stone et al,64 United States Study population: 62 years; 100% women; breast cancer survivors; Community dwellers 12.0
2011b 2 groups: exercise (n = 52), controls (n = 54)
Wolf et al,65 2003 United States Study population 81 years; 86% women; 2 groups: exercise (n = 158), Institutionalized 12.0
controls (n = 153)
Woo et al,66 2007 Hong Kong Study population: 69 years; 50% women; 3 groups: exercise (n = 60),d Community dwellers 12.0
controls (n = 60), Tai Chi (n = 60)
d
Abbreviations: MCI, mild cognitive impairment; RT, resistance training; We selected the exercise group with the highest attendance.
WL, weight loss. e
We selected the exercise group with highest frequency.
a
Study setting was not clearly mentioned in this study. We assume that these f
We used data from combined exercise groups (exercise alone and exercise
are community dwellers. plus vitamin D supplementation) vs combined nonexercise groups (vitamin D
b
No data available for the quantitative analysis (not usable data or no event supplementation and placebo) because original investigators indicated no
occurring in both exercisers and controls), but the articles were included in the interaction was found between the use of vitamin D and exercise.
qualitative analysis. g
We selected the home-based exercise group instead of the group-base
c
These study groups were selected for the meta-analyses. exercise group because the former had higher exercise adherence.

8 studies27-29,40,41,46,62,64 had no deaths during the trial. Hospitalization

Twenty-nine RCTs 10,13,23,24,32-39,42-45,47-52,54,56-58,61,63,65
were included in the primary analysis (2 excluded owing
to low compliance),30,31 totaling 11 441 participants in the
model; 406 of 5677 (7.1%) and 453 of 5764 (7.9%) people
died in the exercise and control groups, respectively.
Figure 1A10,13,23,24,32-35,37-39,42-45,47-52,54,56-58,61,63,65 displays the
forest plot of the effects of exercise on mortality. Exercise had
no effects on mortality (P = .51). Heterogeneity was low
(I2 = 0%) and Egger’s test suggested no important asymme-
try (P = .76). The funnel plot (Supplement) suggested the pres-
ence of some bias, with small studies presenting inflated RRs
(exercisers at increased risk of death). All sensitivity analyses
provided similar results (Supplement), except analysis re-
stricted to clinically specific or disease-specific populations,
which found that exercise tended to reduce the risk of mor-
tality (10 RCTs; RR, 0.70; 95% CI, 0.49-1.00; P = .05; I2 = 15%).
Meta-regressions found associations for exercise frequency of
3 times per week compared with 2 or fewer times per week
(exp[b], 0.42; standard error [SE], 0.14; P = .01) and effective
frequency of between 2 and 3 times per week compared with
fewer than 2 times per week (exp[b], 0.35; SE, 0.15; P = .03)
with a reduced mortality risk. All the other meta-regressions
found nonsignificant associations.
Fourteen studies10,23,24,30,32,33,38,40,41,46,47,50,54,57 had investigated
hospitalization, but 1 RCT32 had no usable data on the number
of people hospitalized; in this trial, exercisers and controls did
not differ in terms of mean hospitalizations (0.87 vs 0.74, respec-
tively). From the remaining thirteen studies (12 059 participants),
12 (5639 participants) entered into the primary analysis (1 exclu-
sion owing to low compliance30): 1242 of 2822 (44%) and 1257
of 2817 (44.6%) people have been hospitalized in the exercise and
control groups, respectively. Figure 1B23,24,33,38,40,41,46,47,50,54,57,59
shows that exercise has not reduced the risk of being hospital-
ized (P = .51), but heterogeneity was substantial (I2 = 59.2%). Even
though the Egger’s test (P = .39) did not have evidence of small
study effects, the funnel plot (Supplement) showed some asym-
metry, with small studies having exaggerated large RR (increased
risk of hospitalization among exercisers). Sensitivity and sub-
group analyses (Supplement) provided unchanged nonsignifi-
cant findings. All meta-regressions provided nonsignificant
associations of exercise variables with the risk of being hospital-
ized (Supplement).
Fallers and Fallers With Multiple Falls
Twenty-eight studies13,25,26,31,33-44,47,48,50,53,55-57,63,65-68 inves-
tigated falls; 7 had no usable information on the number of

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 Research Original Investigation Association of Long-term Exercise With Risk of Falls, Fractures, Hospitalizations, and Mortality in Older Adults

Figure 1. Association of Exercise on the Risk of Mortality and Hospitalization

A Mortality

Favors Favors Weight,

Study RR (95% CI) Exercise Control %
Belardinelli et al,23 2012 0.38 (0.13-1.15) 1.26
Barnett et al,42 2003 0.14 (0.01-2.63) 0.18
O’Connor et al,24 2009 0.96 (0.80-1.16) 46.50
Campbell et al,13 1997 0.50 (0.09-2.70) 0.55
El−Khoury et al,43 2015 0.84 (0.26-2.72) 1.11
Galvão et al,45 2014 3.00 (0.13-71.92) 0.15
Gianoudis et al,44 2014 1.00 (0.06-15.72) 0.20
Hewitt et al,47 2018 1.02 (0.52-2.03) 3.30
Karinkanta et al,48 2007 0.33 (0.01-7.93) 0.15
Kemmler et al,34 2010 0.33 (0.01-8.10) 0.15
King et al,49 2002 0.32 (0.01-7.68) 0.15
Kovács et al,50 2013 0.40 (0.14-1.17) 1.33
Lam et al,51 2012 0.64 (0.06-7.05) 0.27
Lam et al,52 2015 0.30 (0.03- 2.82) 0.30
Lord et al,35 2003 4.84 (0.55-42.33) 0.33
Merom et al,63 2015 1.36 (0.22-8.23) 0.48
Pahor et al,54 2006 0.99 (0.14-6.97) 0.40
Pahor et al,10 2014/Gill et al,59 2016 1.14 (0.76-1.71) 9.50
Patil et al,56 2015 0.11 (0.01-2.04) 0.18
Pitkälä et al,57 2013 0.25 (0.06-1.14) 0.67
Prescott et al,58 2008 0.42 (0.08-2.12) 0.58
Rejeski et al,38 2017 0.34 (0.01-8.16) 0.15
Rolland et al,33 2007 0.88 (0.34-2.28) 1.69
Sherrington et al,39 2014 1.10 (0.46-2.63) 2.01
Underwood et al,32 2013 1.06 (0.84-1.35) 27.50
Van Uffelen et al,61 2008 0.36 (0.01-8.72) 0.15
von Stengel et al,37 2011 0.34 (0.01-8.15) 0.15
Voukelatos et al,63 2015 9.09 (0.49-167.75) 0.18
Wolf et al,65 2003 0.97 (0.14-6.86) 0.40
Overall effect: I2 = 0% (P = .68) 0.96 (0.85-1.09) 100.00

0.01 0.1 1 10 100

RR (95% CI)

B Hospitalization
Favors Favors Weight,
Study RR (95% CI) Exercise Control %
Belardinelli et al,23 2012 0.30 (0.15-0.62) 4.87
O’Connor et al,24 2009 0.97 (0.91-1.03) 29.99
Hambrecht et al,46 2004 0.16 (0.02-1.31) 0.66
Hewitt et al,47 2018 0.64 (0.27-1.50) 3.56
Kovács et al,50 2013 2.00 (0.19-21.21) 0.52
Messier et al,40 2013 8.54 (0.46-157.06) 0.34
Mustata et al,41 2011 0.33 (0.02-7.32) 0.30
Pahor et al,54 2006 0.99 (0.68-1.44) 12.62
Pahor et al,10 2014/Gill et al,59 2016 1.10 (0.99-1.22) 27.92
Pitkala et al,57 2013 0.78 (0.55-1.12) 13.30
Rejeski et al,38 2017 3.04 (0.13-73.46) 0.29
Rolland et al,33 2007 1.82 (0.95-3.49) 5.63
Overall effect: I2 = 59.2% (P = .005) 0.94 (0.80-1.12) 100.00
Association of exercise with risk of
0.01 0.1 1 10 100 mortality (A) and hospitalization (B).
RR (95% CI) Weights are from random effects
analysis.

fallers,25,26,33,34,36-38 with 5 studies finding nonsignificant dif-
ferences in number of falls across study groups, 134 showing
significant effects favoring the exercise group, and 1 having
no event across groups.38 Twenty-one studies contributed in-
formation on the number of fallers for 5220 participants.
Of the 4420 people included in the primary analysis (20
RCTs13,35,39-44,47,48,50,53,55-57,63,65-68; 1 excluded31 owing to low
compliance), 951 of 2207 (43.1%) and 1066 of 2213 (48.2%) be-
came a faller in the exercise and control groups, respectively.
As shown in Figure 2A,13,35,39-44,47,48,50,53,55-57,63,65-68 exercis-
ers had a reduced risk of 12% to become a faller compared with
controls (P = .02); heterogeneity was moderate (I2 = 50.7%).

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 Association of Long-term Exercise With Risk of Falls, Fractures, Hospitalizations, and Mortality in Older Adults Original Investigation Research

Figure 2. Association of Exercise on the Risk of Becoming a Faller and a Faller With Multiple Falls

A Faller

Favors Favors Weight,

Study RR (95% CI) Exercise Control %
Barnett et al,42 2003 0.71 (0.49-1.04) 4.68
Campbell et al,13 1997 0.86 (0.66-1.12) 7.04
El−Khoury et al,43 2015 0.86 (0.75-0.97) 10.86
Gianoudis et al,44 2014 1.16 (0.75-1.80) 3.87
Hewitt et al,47 2018 0.65 (0.51-0.84) 7.47
Karinkanta et al,48 2007 0.88 (0.35- 2.17) 1.17
Kovács et al,50 2013 0.75 (0.49-1.15) 3.97
Lord et al,53 1995 0.99 (0.65-1.50) 4.16
Lord et al,35 2003 0.90 (0.74-1.09) 8.85
MacRae et al,68 1994 0.79 (0.42-1.49) 2.20
Messier et al,40 2013 3.79 (0.43-33.50) 0.22
Mustata et al,41 2011 0.20 (0.01-3.70) 0.12
Park et al,55 2008 0.80 (0.24-2.64) 0.70
Patil et al,56 2015 0.99 (0.87-1.13) 10.72
Pitkälä et al,57 2013 0.83 (0.58-1.19) 4.93
Reinsch et al,67 1992 1.14 (0.68-1.88) 3.12
Sherrington et al,39 2014 1.38 (1.11-1.73) 8.10
Voukelatos et al,63 2015 0.90 (0.67-1.20) 6.45
Wolf et al,65 2003 0.79 (0.64-0.98) 8.21
Woo et al,66 2007 0.48 (0.29-0.80) 3.16
Overall effect: I2 = 50.7% (P = .005) 0.88 (0.79-0.98) 100.00

0.01 0.1 1 10 100

RR (95% CI)

B Multiple faller
Favors Favors Weight,
Study RR (95% CI) Exercise Control %
Barnett et al,42 2003 0.43 (0.20-0.93) 5.83
Campbell et al,13 1997 0.65 (0.41-1.05) 9.58
Gianoudis et al,44 2014 2.17 (0.87-5.42) 4.61
Hewitt et al,47 2018 0.52 (0.35-0.77) 10.76
Karinkanta et al,48 2007 0.25 (0.03-2.13) 1.11
Kovács et al,50 2013 0.67 (0.24-1.88) 3.87
Lord et al,53 1995 0.84 (0.36-1.94) 5.19
Lord et al,35 2003 0.73 (0.50-1.05) 11.20
Patil et al,56 2015 1.06 (0.86-1.31) 13.88
Reinsch et al,67 1992 1.75 (0.64-4.79) 4.05
Sherrington et al,39 2014 1.58 (1.01-2.49) 9.87
Voukelatos et al,63 2015 1.01 (0.62-1.66) 9.20
Wolf et al,66 2003 0.76 (0.52-1.13) 10.85
Overall effect: I2 = 60.2% (P = .003) 0.86 (0.68-1.08) 100.00
Association of exercise with risk of
0.01 0.1 1 10 100 becoming a faller (A) and becoming a
RR (95% CI) multiple faller (B). Weights are from
random effects analysis.

Although the Egger’s test did not evidence small study ef-
fects (P = .92), the funnel plot (Supplement) showed some
asymmetry, with small studies having exaggeratedly large RRs
(increased risk to be a faller in the exercise group). Sensitivity
and subgroup analyses (Supplement) provided similar find-
ings, with RRs for exercisers varying from 0.81 to 0.91, even if
most of them did not reach statistical significance. All meta-
regressions provided nonsignificant associations, except that
exercise frequency (exp[b], 1.35; SE, 0.19; P = .05) as well as
effective frequency (exp[b], 1.60; SE, 0.25; P = .01) more than
3 times per week were associated with increased risk of be-
coming a faller.
For fallers of multiple falls, 13 studies (3060
participants)13,35,39,42,44,47,48,50,53,56,63,65,67 composed the primary
analysis: 329 of 1526 (21.5%) and 374 of 1534 (24.4%) individu-
als have fallen at least twice in the exercise and control
groups, respectively. Exercise had no significant effect
(Figure 2B)13,35,39,42,44,47,48,50,53,56,63,65,67 in decreasing the risk
of being a faller with multiple falls (P = .20); heterogeneity was
moderate (I2 = 60.2%). Egger’s test did not find small study ef-
fects (P = .96), but the funnel plot (Supplement) showed that
small studies had inflated RRs (increased risk to be a multiple
faller in the exercise group). Sensitivity analysis provided simi-
lar results. Meta-regressions found no significant associations.

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 Research Original Investigation Association of Long-term Exercise With Risk of Falls, Fractures, Hospitalizations, and Mortality in Older Adults

Figure 3. Association of Exercise on the Risk of Becoming an Injurious Faller and Sustaining a Fracture

A Injurious falls

Favors Favors Weight,

Study RR (95% CI) Exercise Control %
Barnett et al,42 2003 0.77 (0.48-1.21) 10.08
Campbell et al,13 1997 0.67 (0.45-1.00) 12.08
El−Khoury et al,43 2015 0.90 (0.78-1.05) 26.83
Hewitt et al,47 2018 0.58 (0.42-0.81) 14.89
MacRae et al,68 1994 0.16 (0.01-2.92) 0.35
Pahor et al,10 2014/Gill et al,59 2016 0.89 (0.66-1.20) 16.91
Patil et al,56 2015 0.51 (0.31-0.84) 8.80
Pitkälä et al,57 2013 0.65 (0.39-1.09) 8.53
Reinsch et al,67 1992 1.46 (0.37-5.81) 1.52
Overall effect: I2 = 40.2% (P =.10) 0.74 (0.62-0.88) 100.00

0.01 0.1 1 10 100

RR (95% CI)

B Fractures
Favors Favors Weight,
Study RR (95% CI) Exercise Control %
Belardinelli et al,23 2012 0.19 (0.01-3.89) 0.34
O’Connor et al,24 2009 0.60 (0.32-1.11) 8.13
El−Khoury et al,43 2015 0.88 (0.62-1.25) 24.39
Gianoudis et al,44 2014 3.00 (0.12-72.57) 0.30
Hewitt et al,47 2018 0.80 (0.20-3.11) 1.65
Karinkanta et al,48 2007 1.00 (0.15-6.73) 0.84
Kemmler et al,34 2010 0.49 (0.19-1.25) 3.42
Kovács et al,50 2013 3.00 (0.13-71.56) 0.30
Lam et al,51 2012 1.27 (0.06-28.95) 0.31
Pahor et al,10 2014/Gil et al,59 2016 0.87 (0.63-1.19) 30.74
Patil et al,56 2015 0.66 (0.28-1.59) 4.00
Pitkälä et al,57 2013 1.00 (0.26-3.84) 1.69
Reinsch et al,67 1992 0.45 (0.04-4.78) 0.54
Rolland et al,33 2007 2.50 (0.50-12.44) 1.19
Sherrington et al,39 2014 0.92 (0.46-1.85) 6.29
Underwood et al,32 2013 1.05 (0.63-1.74) 11.79
Villareal et al,62 2011 0.52 (0.05-5.39) 0.56
von Stengel et al,37 2011 0.58 (0.18-1.87) 2.25
Wolf et al,66 2003 0.78 (0.17-3.67) 1.27
Overall effect: I2 = 0% (P =.97) 0.84 (0.71-1.00) 100.00
Association of exercise with risk of
0.01 0.1 1 10 100 becoming an injurious faller (A) and
RR (95% CI) sustaining a fracture (B). Weights are
from random effects analysis.

Injurious Fallers sensitivity and subgroup analyses (Supplement) provided un-

Fourteen RCTs13,37-43,47,56,57,59,67,68 provided information on in-
jurious falls, with 2 having no usable data for meta-analysis. These
2 studies found mixed results, with 1 showing more falls39 and
the other37 reporting an average number of falls lower in exer-
cisers compared with controls. Twelve RCTs gave data for 4972
participants, with 3 trials38,40,41 having no injurious fallers. Nine
studies (n = 4481)13,42,43,47,56,57,59,67,68 composed the primary
analysis, with 370 of 2192 (16.9%) and 471 of 2289 (20.6%) inju-
rious fallers in the exercise and control groups, respectively. As
displayed in Figure 3A,13,42,43,47,56,57,59,67,68 exercisers had a re-
duced risk of 26% to becoming injurious fallers compared with
controls (P = .001); heterogeneity was moderate, but not substan-
tial (I2 = 40%). Egger’s test (P = .22) and the funnel plot (Supple-
ment) did not evidence any substantial asymmetry, even if there
was a lack of small-to-medium scale studies collecting informa-
tion on injurious falls (suggesting potential publication bias). All
changed results (except analysis restricted to disease-specific
population; 1 RCT), with significant RRs favoring exercisers
(range, 0.74-0.79). All 9 studies included in the primary analy-
sis have operationalized a moderate-intensity, multicomponent
training comprising balance exercises.
Fractures
Twenty-three RCTs10,23,24,31-34,37-41,43,44,47,48,50,51,56,57,62,65,67
had information on fractures for 9701 individuals. Nineteen
trials10,23,24,32-34,37,39,43,44,47,48,50,51,56,57,62,65,67 (no events oc-
curred in 3 trials38,40,41 and 1 study was excluded owing to low
compliance31) were entered into the primary analysis (8410 par-
ticipants): 221 of 4138 (5.3%) and 270 of 4272 (6.3%) people in
the exercise and control groups, respectively, have sustained
a fracture. Figure 3B10,23,24,32-34,37,39,43,44,47,48,50,51,56,57,62,65,67
shows that exercise was not effective in reducing the number

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 Association of Long-term Exercise With Risk of Falls, Fractures, Hospitalizations, and Mortality in Older Adults
of fractures (P = .054). Heterogeneity was low (I2 = 0%), and
the Egger’s test (P = .34) and funnel plot (Supplement) did not
evidence any substantial asymmetry. Sensitivity analysis using
a fixed-effect model found a significant effect of exercise for
reducing the number of people with fractures by 16% (RR, 0.84;
95% CI, 0.70-1.00; P = .047). Excluding studies for which we
assumed the number of fractures was equivalent to the num-
ber of people sustaining a fracture provided similar results
(RR, 0.85; 95% CI, 0.71-1.03; P = .10). All the other analysis
(Supplement) provided similar findings (favoring exercisers
without reaching statistical significance). Meta-regressions
found no significant association of exercise-related variables
with this outcome.
Discussion
This systematic review and meta-analysis showed that long-
term exercise had modest but significant association with re-
duced risk of becoming a faller and an injurious faller, but not
a faller with multiple falls, in older adults. Moreover, exercise
was associated with a nonsignificant reduction in the risk of
sustaining a fracture. Exercise benefits occurred without in-
creasing the risk of mortality and hospitalization.
This is the first meta-analysis focusing on the benefits of long-
term exercise (≥1 year), which may potentially lead to longer-term
positive effects, against major adverse events in older adult popu-
lations. Our findings corroborate the results of recent meta-
analyses focusing on falls that showed exercise (any interven-
tion length) benefited several fall-related outcomes.7-9,16,69 The
magnitude of associations for the risk of becoming a faller in
our study (RR, 0.88; 95% CI, 0.80-0.98) was small but consistent
with those (RR, 0.89; 95% CI, 0.81-0.97 and RR, 0.83; 95% CI,
0.70-0.99) recently reported by Guirguis-Blake et al69 and Tricco
et al,16 respectively; the similarities in the findings across these
meta-analyses represents compelling evidence of the positive
effects of exercise against fall-related outcomes because in the
present work we have used different eligibility criteria (particu-
larly regarding intervention length ≥1 year), leading, then, to the
inclusion of different studies. Furthermore, our study further ex-
tends current knowledge by examining for the first time the as-
sociation of exercise with the risk of being a faller with multiple
falls: we did not evidence a positive association of exercise with
this outcome. However, multiple falls were not reported in some
of the largest, well-conducted original studies (because it was not
an endpoint of those RCTs) that provided data on fallers and in-
jurious fallers,43,59 resulting in a small number of participants in
the analysis; this issue, alongside the asymmetry found in the
funnel plot, suggest publication bias could have affected estima-
tions. For injurious fallers, we provide herein the most compre-
hensive evidence on the topic, gathering information from
more than 4000 people in 9 RCTs, going beyond previous
meta-analyses16,43,69; we consistently (across sensitivity and sub-
group analysis) found that exercise decreased the risk of injuri-
ous falls by about 26%. Regarding fractures, our study contrib-
utes to this still not well-established field by showing that exercise
seems to protect against fractures; although the primary find-
ing was not statistically significant, the absence of both hetero-
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Original Investigation Research
geneity across studies and asymmetry (small study effects and
publication bias), alongside the positive results from the fixed
effect, suggest that long-term exercise might lead to a reduction
in the risk of fractures. Even though we overcame a major issue
of previous meta-analyses,2,11,12,16,69 which have included only
a small number of studies and participants, analysis incorporat-
ing data from future well-conducted long-term RCTs is still
needed before solid conclusions can be drawn on the protective
effects of exercise against fractures in older adults. To our knowl-
edge, our study is the largest meta-analysis ever done on the as-
sociation of long-term exercise with mortality and the first one
reporting about the association of exercise with hospitalization
in older populations. Exercise had no statistically significant as-
sociation with mortality or hospitalizations, which corroborates
the mortality findings of Guirguis-Blake et al69; this may
mean that mortality and hospitalizations are difficult-to-change
outcomes, probably because they are determined by multidimen-
sional parameters that may be beyond the scope of exercise-
induced benefits. Lack of power may also have affected our re-
sults for mortality. Importantly, exercise tended to decrease
mortality risk in clinical populations (mostly people with cog-
nitive decline or cardiac disease), which reinforces the role of ex-
ercise as a core therapeutic element for treating prevalent dis-
eases in older people.
Meta-regressions found that vigorous-intensity is as safe
as moderate-intensity exercise. Exercise frequency of be-
tween twice and thrice a week was associated with decreased
mortality, whereas more than 3 times per week was associ-
ated with increased risk of being a faller; therefore, the best
exercise frequency seems to be 2 to 3 times per week, lower
frequencies probably resulting in less effective outcomes
whereas higher frequencies would augment the risk of ad-
verse events. The association between exercise frequency and
risk of becoming faller might be dependent on the fall-related
vulnerability of the population, with higher risks in more vul-
nerable participants70; indeed, among studies with exercise
frequency of 4 or more times per week, whereas Sherrington
et al39 showed a higher risk of being a faller in the exercise group
in people at increased risk of falling (mean age about 81 years,
about 70% had fallen in the past 12 months), Kemmler et al34
found that exercise reduced fall rates in a population at lower
risk for falls (young women aged on average 69 years) and
Von Stengel et al37 found a trend in fall rates favoring exercis-
ers in a similar low-risk population. It is possible that the dose-
response idea implying that “more exercise is always better”
might not fully apply for the most vulnerable older adults. The
potential mechanisms involved require further investiga-
tion, but it could be related to overtraining: excessive exer-
cise leads to diminished immunity and energy metabolism ac-
cording with animal models71 and is associated with reduced
calorie intake, worse sleep, and negative psychological pat-
terns in young and middle-aged adults.72 Our findings on the
best exercise frequency, alongside the observation that all RCTs
included in the injurious falls analysis had a similar exercise
structure, suggests that the best exercise regimen for protect-
ing older people against diverse adverse events would be mod-
erate-intensity, multicomponent training comprising bal-
ance exercises, performed 2 to 3 times per week; a session
(Reprinted) JAMA Internal Medicine Published online December 28, 2018 E9
 Research Original Investigation Association of Long-term Exercise With Risk of Falls, Fractures, Hospitalizations, and Mortality in Older Adults

duration of 30 to 60 minutes (average of 50 minutes, accord-
ing to studies on injurious falls analysis) should be safe and
effective.
Limitations
This review has limitations. First, several studies have not
clearly reported exercise adherence, which impeded us to
calculate the exact exercise volume performed by partici-
pants. Second, for examining the effects of long-term exer-
cise, we arbitrarily established the 1-year length as the mini-
mum intervention follow-up, which could lead to losing
important studies that employed shorter follow-ups. A lon-
ger follow-up length would probably result in more precise
data, particularly on less frequent events such as fractures,
but it would have undermined the feasibility of the meta-
analysis by reducing the number of eligible studies to 13.
Third, owing to the several analyses performed, multiplicity
may have elevated the chances of type I error. Finally, a high
heterogeneity in terms of study population was found (from
people with Alzheimer disease to overall healthy partici-
pants), but the small number of studies for most outcomes
prevented us from performing stringent subgroup analysis.
In an attempt to reduce such a bias, we performed subgroup
analyses separately for populations with and without clini-
cally and disease-specific profiles.
Conclusions
Exercise is associated with a modest decrease in the risk of be-
coming a faller, an injurious faller, and potentially sustaining
a fracture in older adults. Exercise should be performed 2 to 3
times per week. Studies showing positive effects of exercise
for reducing the risk of becoming an injurious faller opera-
tionalized moderate intensity, multicomponent training with
balance exercises (eg, balance, strength training for the lower
limbs, and aerobic exercise [eg, walking]), for about 50 min-
utes per session.

ARTICLE INFORMATION REFERENCES 9. Sherrington C, Michaleff ZA, Fairhall N, et al.

Accepted for Publication: August 16, 2018.
Published Online: December 28, 2018.
doi:10.1001/jamainternmed.2018.5406
Author Contributions: Drs Philipe de Souto
Barreto and Mathieu Maltais had full access to all of
the data in the study and take responsibility for the
integrity of the data and the accuracy of the data
analysis.
Study concept and design: Barreto, Rolland, Maltais.
Acquisition, analysis, or interpretation of data:
All authors.
Drafting of the manuscript: Barreto, Rolland, Vellas.
Critical revision of the manuscript for important
intellectual content: Rolland, Maltais.
Statistical analysis: Barreto.
Study supervision: Rolland, Vellas, Maltais.
Conflict of Interest Disclosures. Dr Rolland reports
grants from Novartis and Lactalis and fees from
Nestlé and Daxter. Dr Vellas reports Scientific Board
Memberships for Acadia, Accera, Alzhéon, Biogen,
Lilly, Lundbeck, MSD, Nestlé, Roche, Sanofi,
Transition Therapeutics, Takeda, Otsuka, and
Schwabe; and also Gerontopôle Research Grants
from Abbvie, Lilly, Lundbeck, MSD, Otsuka,
Pierre-Fabre, Régénéron, Roche, Sanofi, Alzheon,
Astra-Zénéca, LPG Systems, and Nestlé. No other
conflicts are reported.
Additional Contributions: We thank the following
investigators who contributed additional data or
information to this study: Kaisu Pitkala (MD, PhD,
University of Helsinki), Jennifer Hewitt (BAppSc,
MHealthSc, University of Sydney), Jack Rejeski
(PhD, Wake Forest University), Stefan Mustata (MD,
University of Calgary), Stephen R. Lord (PhD,
Neuroscience Research Australia), Stephen Messier
(PhD, Wake Forest University), Kirsti Uusi-Rasi
(PhD, UKK Institute for Health Promotion Research),
Saija Karinkanta (PhD, UKK Institute for Health
Promotion Research), Ari Heinonen (PhD, UKK
Institute for Health Promotion Research).
They were not compensated.
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