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Effectiveness of Nutritional Supplementation

on Muscle Mass in Treatment of Sarcopenia in
Old Age: A Systematic Review

Article in Journal of the American Medical Directors Association · September 2012

Impact Factor: 4.94 · DOI: 10.1016/j.jamda.2012.08.001 · Source: PubMed

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 JAMDA 14 (2013) 10e17

JAMDA
journal homepage: www.jamda.com

Review

Effectiveness of Nutritional Supplementation on Muscle Mass in Treatment

of Sarcopenia in Old Age: A Systematic Review
Vincenzo Malafarina MD a, *, Francisco Uriz-Otano MD a, Raquel Iniesta PhD c, Lucía Gil-Guerrero MD, PhD b
a
Department of Geriatrics, Hospital San Juan de Dios, Pamplona, Spain
b
Department of Internal Medicine, Hospital San Juan de Dios, Pamplona, Spain
c
Servicio de soportes estadístico, Fundació per a la recerca Sant Joan de Deu, Barcelona, Spain

a b s t r a c t

Keywords: Background: Much interest has been focused on nutritional treatment of sarcopenia, loss of muscle mass
Sarcopenia and performance associated to aging; however, its benefits are unclear.
oral supplement Objective: To analyze the relevance of nutritional treatment of sarcopenia and assess the effects of
muscle mass
supplementation on muscle mass and function within the aged population.
fat-free-mass
Methods: We searched Medline and the Cochrane Library for controlled trials published between 1991
and 2012. We have assessed the quality, type of intervention, the cohort used, the way muscle mass was
measured, and the outcomes of the various studies.
Results: We have included 17 studies, with a total of 1287 patients, aged between 65 and 85 on average.
An improvement in muscle mass was proven, whether measured with bioelectrical impedance analysis
or dual energy x-ray absorptiometry, and an improvement in strength was also proven.
Conclusion: Nutritional supplementation is effective in the treatment of sarcopenia in old age, and its
positive effects increase when associated with physical exercise. The main limitation of this treatment
is lack of long-term adherence. A healthy diet associated with a physically active lifestyle and possibly
with aerobic exercise are the basis of healthy aging, which is the aim of all doctors treating aged
people must seek.
Published by Elsevier Inc. on behalf of the American Medical Directors Association, Inc.

Sarcopenia is the loss of muscle mass and function associated with It is not easy to define and identify sarcopenia and all the inter-
aging.1 Its aetiology is not entirely clear. Nevertheless, a number of national groups working on the diagnosis criteria for sarcopenia
factors associated with old age and which contribute to the devel- agree that it must be defined by the decrease of muscle mass and
opment of sarcopenia have been identified. Among these factors, the performance associated to age. The report of the European Working
loss of alpha-motoneurons,2 the increase in inflammatory cy- Group on Sarcopenia in Older People proposed a diagnostic proce-
tokines,3e5 the decrease of physical activity,6 bedrest,7 and humoral dure, but has not achieved consensus on the cut-off points indicating
factors, such as hormone decrease8 (androgen and oestrogen)9 are sarcopenia.14 The special interest groups define sarcopenia as reduced
prominent. muscle mass
2 SD below mean of percentage of muscle mass in
Inadequate food intake may be one of the main causes of sarco- young adults of the same sex and ethnic group, plus impaired muscle
penia and a protein-poor diet determines a compensatory response function as evidenced by 4-meter (m) walking speed of <0.8 m/s.15
characterized by a reduction in lean mass.10,11 The Recommended The International Working Group on Sarcopenia of the Society on
Dietary Allowance of protein of 0.8 g/kg/day is insufficient in aged Sarcopenia, Cachexia and Wasting Disorders, defines sarcopenia on
people for whom a protein allowance of 1.25e1.5 g/kg/day12,13 is the basis of a walking-test result of less than 1 m/s, or less than 400
more advisable. metres covered in the 6-minute-walking test, associated to reduction
of lean mass 7.23 kg/m2 in men and 5.67 kg/m2 in women,
measured with dual energy x-ray absorptiometry (DXA).16,17
The authors have no financial or any other kind of personal conflicts with this Prevalence of sarcopenia differs in the various cohort studies
paper. because of the different methodology applied for diagnosis.18e20
This review was registered at www.crd.york.ac.uk/prospero/prospero.asp Two reviews in Cochrane have shown that there is no correlation
(PROSPERO), as CRD42012002546.
* Address correspondence to Vincenzo Malafarina, MD, Department of Geriatrics,
between nutritional supplementation and reduction of mortality and
Hospital San Juan de Dios, Calle Beloso Alto 3, 31006, Pamplona, Spain. morbidity in older patients with a risk of malnutrition and in older
E-mail address: [email protected] (V. Malafarina). patients with a hip fracture,21,22 but they did show an improvement
1525-8610/$ - see front matter Published by Elsevier Inc. on behalf of the American Medical Directors Association, Inc.
http://dx.doi.org/10.1016/j.jamda.2012.08.001
 V. Malafarina et al. / JAMDA 14 (2013) 10e17 11

Data Abstraction
in weight and concluded that further research is needed, particularly
into the possible benefits of nutritional supplementation for the
Information was extracted from each included trial on: (1) design
functional state of patients. Our review differs in that we have
of the trial; (2) sample size, drop out and compliance to treatment;
included studies that have assessed both muscle massdwith
(3) age and sex distribution of the population studied; (4) duration of
bioelectrical impedance analysis (BIA) or DXAdand muscle function.
the trial; (5) method used to measure body composition; (6) char-
The main aim of this review is to analyze the importance of
acteristics of the supplementation and control; and (7) main results.
nutritional treatment of sarcopenia and assess the effects of supple-
The data were compiled in Table 1. We also included the following
mentation on muscle mass and performance, in older people. The
aspects: (1) whether the protocol was registered; (2) the type of
secondary objective is to review the types of nutritional supplements
population included, whether it was healthy or with any specific
used and assess their effects on muscle metabolism. In order to do so,
pathologies; (3) body mass index (BMI); (4) comorbidity; (5) the
we have included studies on people with an average age of over 65,
Barthel index; and (6) a cognitive assessment (Table 2).
healthy or otherwise, who received continued nutritional supple-
mentation for at least 8 weeks, compared with those who took
Results
a placebo or no supplementation.

Figure 1 shows the flow chart of the articles we found, the ones we
Methods
discarded, and the ones we included in the review. One hundred sixty-
eight citations came from MEDLINE, 20 came from the search in the
We performed this systematic review in accordance with the
Cochrane Library, and 12 from the references of the included articles,
Preferred Reporting Items for Systematic Reviews and Meta-analyses
from all of which, after removing duplicates, we were left with 176
guidelines for systematic reviews.23 The protocol of this systematic
papers resulted. One hundred fifty-two were discarded because they
review was registered at PROSPERO, as CRD42012002546, which is an
did not fulfill the inclusion criteria set by the design of this review. The
international database of prospectively registered systematic reviews
full text of 24 papers was reviewed. A further seven papers were then
in health and social care. PROSPERO is funded by the UK National
discarded for the following reasons: one because the mean age of
Institute for Health Research (available at: http://www.crd.york.ac.uk/
participants was below 65, three because they did not measure body
PROSPERO/display_record.asp?ID¼CRD42012002546).
composition with BIA or DXA, two for not including nutritional
supplementation, and one because supplementation was administered
Search Strategy intravenously. A total of 17 papers (about trials totalling 1287 patients)
were finally included in the review.
A search for articles published between January 1991 and May
2012 was conducted on the electronic databases MEDLINE and Co- Study Characteristics
chrane library. The following term associations were used: older/
elderly people/adults, sarcopenia, muscle metabolism/ loss/mass, Quality Assessment
nutrition/nutritional/amino acid/beta-hydroxy-beta-methylbutyrate The quality of the trials is summarized in Table 3. The overall mean
treatment/supplementation/supplement, body composition. The score of the studies is 15.2/32 (the range was between 9 and 25) and the
search was restricted to articles that contained the keywords in their score for the design of the study was good, with an average of 7.1/10.
title or abstract. In addition, we reviewed the bibliography of the The general characteristics of the population from which the
selected articles. Papers published in English, Italian, and Spanish patients were recruited were detailed in only a few of the studies. The
were reviewed in detail selecting studies to evaluate the evidence of score for the power of the included studies was low, because of the
therapeutic options and the effectiveness of nutritional outcome in very small number of patients involved and, principally, because of
older sarcopenic patients. the lack of prior calculations to determine the statistic power of the
main variable.
Inclusion and Exclusion Criteria As to the design of the selected studies, one of them was a cohort
study32 and the remaining 16 were randomized controlled trials. Only
We included controlled clinical trials, clinical trials, and random- four studies used the intention-to-treat strategy in order to analyse
ized controlled trials, with orally administered nutritional supple- their results.33,34,36,37
mentation, lasting 8 weeks or longer, in populations with an average
age of 65 of above, which used BIA or DXA to measure body Cohort Characteristics
composition. We considered any preparation that provided an addi- A summary of the main characteristics of the studies can be found
tion of protein, amino acids, or amino acid metabolites to the basic in Table 1. Only one of the studies included people living in nursing
diet as nutritional supplementation. home,33 the rest were carried out within the community, and the
average age is between 65.4 and 85. Four of them was carried out on
Selection and Quality Assessment a healthy population,25e28 two on patients with chronic obstructive
pulmonary disease,29,30 one on diabetic patients,31 and a further one
The titles and abstracts of the articles revealed by the search were on people with a reduced tolerance of glucose.32 The number of
analyzed to assess whether they were valid for the present review subjects included ranged between 12 and 210, as follows: six trials
and those potentially relevant were read in full. with more than 100 patients,33e38 three with between 50 and 100
The quality of the selected papers was determined according to patients,25,31,40 and seven had fewer than 50.26e30,32,39,41 Three of the
the Downs and Black24 criteria. The Downs and Black rating scale is trials were conducted only on women,26,38,40 and a further three only
a validated and reliable instrument for evaluating both randomized on men,28,31,39 one gives no data on the sex distribution of patients,41
and nonrandomized studies. The rating scale has 27 questions and the remainder have a different proportion of men and women.
grouped into five sections: reporting, external validity, internal vali-
dityebias, internal validityeconfounding, and power. The aggregated Definition of Sarcopenia
maximum possible score is 32 with a higher score indicating greater Three trials included sarcopenic patients, but in two of them the
methodological quality. criteria for defining sarcopenia were not specified.29,41 In the trials
Table 1

12
Author, Year, Cohort Characteristics, Intervention, and Main Outcomes of Reviewed Studies

Authors Design Sample Size (n) Population Age (y) Duration Measurement Quantity and Type of Main Outcomes
Origin Drop Out (D n) Mean  SD (wk) of Body Intervention
(ITT Analyses) Adherence Rate (AR %) Sex (m/w) Composition
Kim et al 201238 RCT Total n ¼ 155 EþAAS 79.5  2.9 Treatment: BIA E: 60 minute, twice per week. Mass outcomes: legs muscle mass: EþAAS [*CG.
Japan EþAAS n ¼ 38 (D n ¼ 4, AR 70.3%) E 79  2.9 3 mo AAS: packets of powdered, Functional outcomes: walking speed, m/s E and
(No) E n ¼ 39 (D n ¼ 3, AR 80.5%) AAS 79.2  2.8 3 g, two times a day. EþAAS [*CG.
AAS n ¼ 39 (D n ¼ 2, AR 72.2%) CG 78.7  2.8 CG: health education.
CG n ¼ 39 (D n ¼ 2, AR 71.8%) Sex n ¼ 0/155
Leenders et al 201131 RCT Total n ¼ 60 Diabetic Treatment: DXA Leu: 5 capsules, after each Mass outcomes: FM and LBM did not change.
The Netherlands Leu n ¼ 30 (D n ¼ 1) 71  1 6 months main meal Functional outcomes: [* leg strength in
(No) CG n ¼ 30 (D n ¼ 2) Sex n ¼ 60/0 CG: placebo CG and Leu group.
Carlsson et al 201133 RCT Total n ¼ 177 EþProt 84.4  6.3 Treatment: BIS E: 45 minute, 5 times every Mass outcomes: at 6 mo: EþProt and E Y*
Sweden EþProt n ¼ 42 (D n ¼ 11) E 85.3  5.5 3 months. 2weeks. Prot and CG muscle mass and body water.
(Yes) E n ¼ 41 (D n ¼ 15) Prot 82.7  6.4 Follow-up: Prot: 200 mL drink, 5 times Functional outcomes: at 6 mo: EþProt and E [
Prot n ¼ 47 (D n ¼ 10) CG 85.4  7.2 3 months every 2 weeks. Prot and CG Berg Balance Scale.
CG n ¼ 47 (D n ¼ 8) Sex n ¼ 46/131 CG: placebo.
Neelemaat et al RCT Total n ¼ 210 Prot 74.6  9.7 Treatment: BIS Prot: protein enriched Mass outcomes: FFM [ Prot vs CG.
201137 The Netherlands Prot n ¼ 105 (D n ¼ 30, AR 80%) Sex n ¼ 56/49 3 months supplement and VitD3, Functional outcomes: Prot [ CG handgrip
(Yes) CG n ¼ 105 CG 74.4  9.3 once a day. strength.
Sex n ¼ 60/45 CG: no supplement.
Total n ¼ 32 Mass outcomes: EEA [* FFM, LBM T12 vs T0.

V. Malafarina et al. / JAMDA 14 (2013) 10e17

Dal Negro et al RCT COPD Treatment: BIA EAA: 4 g, two times a day.
201029 Italy EAA n ¼ 16 EEA 75  7 12 weeks CG: placebo Functional outcomes: EEA [* steps number
(No) CG n ¼ 16 Sex n ¼ 14/2 T12 vs T0.
CG 75  7
Sex n ¼ 11/5
Verhoeven et al RCT Total n ¼ 30 Healthy Treatment: DXA Leu: 5 capsules, after each Mass outcomes: FM and FFM no change.
200928 The Netherlands Leu n ¼ 15 (D n ¼ 0) 71  4 12 weeks main meal (7.5 g day). Functional outcomes: 1RM for leg press and
(No) CG n ¼ 15 (D n ¼ 1) Sex n ¼ 30/0 CG: placebo leg extension no change.
Cornish et al 200925 RCT Total n ¼ 60 Healthy Treatment: DXA E: 3 times/wk. Mass outcomes: FM and total body mass Y*
Canada ALA n ¼ 30 (D n ¼ 5, AR 83.6  14.4%) 65.4  0.8 12 weeks ALA: 30 mL of flaxseed oil in the two groups.
(No) CG n ¼ 30 (D n ¼ 4, 78.2  21%) Sex n ¼ 28/23 (14 g ALA) Functional outcomes: no change (1RM chest
CG: placebo press and leg press).
Baier et al 200934 RCT Total n ¼ 104 Men 76.6  1.3 Treatment: BIA 101 HMB: 1 packet daily. Mass outcomes: FFM [* in HMB vs CG.
USA HMB n ¼ 52 (D n ¼ 12, AR 95%) Women 76.4  1.6 12 months DXA CG: placebo. Functional outcomes: no change G&G test, Y
(Yes) CG n ¼ 52 (D n ¼ 15, AR 95%) Sex n ¼ 50/54 handgrip strength in HMB and CG.
Verdijk et al 200939 RCT Total n ¼ 26 Healthy 12 weeks DXA E: 3 times/wk Mass outcomes: leg lean mass and whole-body
The Netherlands EþProt n ¼ 13 72  2 Prot: 250 mL (10 gr protin) lean mass [* in Prot and CG.
(No) CG n ¼ 13 Sex n ¼ NS before and after exercise Functional outcomes: leg extension [* in Prot
(D n ¼ 2) session. and CG.
CG: placebo
Solerte et al 200841 RCT Total n ¼ 41 Age range: 66e84 4þ4þ8 DXA AAS: snacks, two times a day. Mass outcomes at 8-16 mo: LBM [*.
Open-label AAS n ¼ NS Sex n ¼ NS months
Crossover CG n ¼ NS
Italy
(No)
Børsheim et al 200832 Cohort Total n ¼ 12 Glucose intolerant Treatment: DXA EAA: 11 capsules between Mass outcomes: LMB [* T12 vs T0, [ T16 vs T0.
USA EAA n ¼ 12 (D n ¼ 0) 67  5.6 16 weeks meals (11 gr/day). Functional outcomes: [* walking speed T16 vs T0.
(No) Sex n ¼ 5/7
Flakoll et al 200440 RCT Total n ¼ 57 Study 1 Treatment: BIA 101 HMB: 240 mL (HMB 2 gr), Mass outcomes: FFM [ HMB vs CG.
USA Study 1 HMB 84.2  1.6 12 weeks with breakfast Functional outcomes: handgrip strength [*
(No) HMB n ¼ 15 (D n ¼ 2) CG 81.1  1.8 CG: placebo HMB vs CG.
CG n ¼ 14 (D n ¼ 4) Study 2
Study 2 HMB 71.5  1.5
HMB n ¼ 14 (D n ¼ 0) CG 71.5  1.5
CG n ¼ 14 (D n ¼ 1) Sex n ¼ 0/57
(study 1e2 AR n ¼ 100%)
 V. Malafarina et al. / JAMDA 14 (2013) 10e17 13

AAS, amino acid supplement; ALA, alpha-linoleic acid supplement; AR, attendance rate; BIA, bioelectrical impedance analysis; BIS, bioelectrical impedance spectroscopy; CG, control group; CT, controlled trial; D, drop-out; DXA,

analyses; LBM, lean body mass; Leu, leucin supplement; Prot, protein supplement; RCT, randomized controlled trial; RM, repetition maximum; [, improvement (P
.05); [*, significant improvement (P < .05); Y, decreased (P

dual energy x-ray absorptiometry; E, exercise; EAA, essential amino acid supplement; FFM, fat free mass; FM, fat mass; G&G, Get-up-and-Go test; HMB, beta-hydroxy-beta-methylbutyrate supplement; ITT, intention-to-treat
conducted by Kim et al38 sarcopenia was defined by appendicular
muscle mass values 6.42 kg/m2 or a BMI below 22 kg/m2, associated
Functional outcomes: grip strength no change.

Functional outcomes: leg curl [* HMB vs CG.

to one of the following two indexes: knee extension strength 1.01

Functional outcomes: walking capacity no

Nm/kg, or walking speed 1.22 m/s.

Functional outcomes: 1RM no change.

Mass outcomes: LBM [* in EAA vs CG.
Mass outcomes: FFM [* EAA vs CG.
Mass outcomes: FFM [ HMB vs CG.

Intervention Characteristics
Mass outcomes: FFM no change.

Mass outcomes: FFM no change.

When we analyzed the intervention carried out in the various

change in E group, Y* CG.

trials, we found that they differed greatly in terms of the supplements
used, the duration of the trials, adherence to treatment and methods
used to measure muscle mass.
In seven of the trials, supplementation was associated with phys-
ical exercise. In the trials conducted by Bunout et al35 and Kim et al38
the population was split into four groups, exercise plus supplement,
only exercise, only supplement, or nothing at all, and in the trial by
Carlsson et al,33 the split was the same, although the control group
was given a placebo. In the remaining four trials, physical exercise was
Prot: 125 mL, two times a day

EAA: 20 capsules, twice a day.

associated with supplements as follows: in Baldi et al30 with essential

HMB: 4 capsules, after each

EAA: 200 mL twice a day

E: 1 hour, twice a week.

amino acids and the control group with no supplement; in Vucowich

Prot: soup or porridge,
main meal (3 g day).

et al27 with beta-hydroxy-beta-methylbutyrate and the control group

E: 2 sessions a day of

CG: no supplement

CG: no exercise, no
E: 5 days per week

was given a placebo, in Cornish et al25 with alpha linoleic acid and the
twice a daily.

control group was given a placebo; and in Verdijk et al39 with proteins
supplement
30 minutes.
CG: placebo

CG: placebo

CG: placebo

and the control group was given a placebo.

Two trials used a protein supplement, in Wouters et al36 checking
it against a placebo and in Neelemaat et al37 the control group took
no supplement.
Five of the trials used an essential amino acid-rich supplement, in
four cases26,28,29,31 confronting it with a placebo and in Borsheim
et al32 there was no control group.
DXA

DXA

DXA

DXA
BIA

In Flakoll et al 40 and in Baier et al, 34 a beta-hydroxy-beta-

methylbutirate-rich supplement was used, comparing it with a
18 months
6 months

3 months
12 weeks
Treatment:

Treatment:

Treatment:

Treatment:

Treatment:

placebo.
8 weeks

In Solerte et al,41 an amino acid-rich supplement was used but the

characteristics of the population in the control group were not
specified.
EAA Sex n ¼ 12/2

In 11 of the trials, the duration of the treatment was between 8

EþProt n ¼ 9/22
CG Sex n ¼ 8/6
Prot n ¼ 13/21

Prot n ¼ 10/16
Sex n ¼ 15/16

and 12 weeks, three of the trials lasted between 12 and 24 weeks and
CG n ¼ 16/18

CG n ¼ 13/12
Sex n ¼ 0/14

E n ¼ 4/12

in a further three the treatment lasted over 24 weeks.

70.1  5.8

74.1  3.4
73.1  6
Healthy

Healthy

Seven of the papers specified adherence to treatment, which was

70  1

68  2
82  7

COPD

below 50% in one case,35 between 50% and 75% in another38 and
Sex:

Sex:

above 75% in the remaining five.25,34,36,37,40

Six of the studies used BIA, nine used DXA, and one used both
Prot n ¼ 52 (D n ¼ 18, AR 85  36%)
CG n ¼ 49 (D n ¼ 15, AR 94  24%)

(Table 1).

Outcomes
EþProt n ¼ 42 (D n ¼ 11)

Prot n ¼ 42 (D n ¼ 16
EAA n ¼ 14 (D n ¼ 1)
CG n ¼ 14 (D n ¼ 1)

CG n ¼ 33 (D n ¼ 8)
E n ¼ 32 (D n ¼ 16)

Muscle Mass
Prot Ar 49% 6 mo

Kim et al38 demonstrated a significant increase of leg muscle mass

E Ar 63% 6 mo
Total n ¼ 101

Total n ¼ 149
HMB n ¼ 14
Total n ¼ 31

Total n ¼ 28

Total n ¼ 14

in the group treated with physical exercise and supplementation

44% 18 mo

43% 18 mo
EAA n ¼ 7
CG n ¼ 17

CG n ¼ 7

compared with the group without treatment (P ¼ .007), they also

proved an increase of appendicular muscle mass in the same group,
although the difference was not significant (P ¼ 0.26).
In the trials conducted by Leenders et al31 and Verhoeven et al,28
The Netherlands

the effect of leucine supplementation in association to physical

.05); Y*, significant decreased (P < .05).

exercise was assessed, with no change in fat free mass and fat-mass
(measured with DXA) observed in the supplemented groups over
(Yes)

Chile
(No)

(No)

(No)

(No)
Italy
USA

USA
RCT

RCT

RCT

RCT

RCT

those using a placebo.

Bunout et al35 showed that fat free mass (FFM) measured with
Vukovich et al 200127

DXA suffered no changes following physical exercise and supple-

Bunout et al 200135
Wouters-Wesseling

Dillon et al 200926
Baldi et al 201030

mentation, compared with the group with no treatment. Neele-

maat et al37 could not find significant differences due to
et al 200336

treatment.
Dal Negro et al29 and Baldi et al30 proved a significant increase
(P ¼ 0.05) of FFM in the group supplemented with essential amino
acids but the difference was not significant compared with the
 14
Table 2
Baseline Characteristics of the Studies Patients

Authors Criteria

Inclusion Exclusion Population Trial BMI kg/m2 Barthel MMSE Depression

characteristics registered (mean  SD) (mean  SD) (mean  SD) (%)
Kim et al 201238 Women Severe knee or back pain, impaired mobility, cognition, NS No 18.3  2.5 NS NS NS
Aged
75 years unstable cardiac conditions, musculoskeletal conditions.
Leenders et al 201131 Men Cardiac or peripheral vascular disease, orthopedics Diabetic Yes 27.3  0.4 NS NS NS
limitations, impaired renal function. NIH
33
Carlsson et al 2011 Aged
65 years Pacemaker, unable to perform BIS on right side Residential care No 24.9  4.4 NS 17.2  5.1 63%
Dependent in
one ADL
Able to stand up from a chair,
10
on MMSE
Neelemaat et al 201137 Aged
60 years Senile dementia, not understand Dutch language, not able NS Yes  20: 55.2 % NS NS NS
Length admission >2 days to give informed consent NTR 20-25: 30.5%
BMI 20 kg/m2 or weight loss
5%
25: 14.3 %
in previous month or
10%

V. Malafarina et al. / JAMDA 14 (2013) 10e17

in previous 6 month
Dal Negro et al 201029 > 40, FEV1 50% predicted, Asthma, interstitial pulmonary disease, neoplasm, life COPD No 20.2  1.8 NS 19.1  4.6 NS
FEV1/FVC 70%, BMI 23 kg/m2 expectancy < 1 year, mental deterioration, acute
exacerbation of COPD in the last 4 wk.
Verhoeven et al 200928 NS Cardiac or peripheral vascular disease, orthopedic Healthy Yes 26.3  0.6 NS NS NS
limitations, type 2 diabetes. NIH 25.9  0.6
25
Cornish et al 2009
60 years Medication that affect inflammation, inflammatory Healthy No NS NS NS NS
disease, consumption of flaxseed products, resistance
training
2 times per week
Baier et al 200934
65 years, G&G test >10 but <20 seg. Treatment for liver or kidney disease, uncontrolled NS No NS NS NS NS
hypertension, diabetes, morbidly obese.
Verdijk et al 200939 NS Cardiac or peripheral vascular disease, orthopedics Healthy Yes 26.5  1 NS NS NS
limitations. NIH
41
Solerte et al 2008 Diagnosis of sarcopenia NS NS No NS NS NS NS
Børsheim et al 200832 Impaired glucose tolerance Heart, kidney or liver disease, hyperlipidemia. Impaired glucose No NS NS NS NS
tolerance
Flakoll et al 200440 Women Treatment for liver or kidney disease, uncontrolled NS No NS NS NS NS
hypertension, diabetes.
Wouters-Wesseling Caucasian,
65 years, BMI 25 kg/m2, Cancer, gastrointestinal disorders, mentally unable to Residence in a No 23.4  2.4 NS NS NS
Et al 200336 sheltered housing. answer study questions. home for the
elderly
Vukovich et al 200127 No contraindications to exercise, no Uncontrolled hypertension, cardiovascular or kidney Volunteered No NS NS NS NS
medications, physician approval. disease, diabetes.
Baldi et al 201030 Weight loss >5% of body weight over Malignancy, gastrointestinal disorders, severe endocrine COPD No 19.9  2.8 NS NS NS
previous 6 months. disorders, recent surgery, respiratory tract infection,
edema or use of diuretics.
Dillon et al 200926 NS Metabolically unstable medical condition, vascular disease, Volunteered No NS NS NS NS
hypertension, cardiac abnormality, estrogen women
supplementation, exercise trained.
Bunout et al 200135 NS Cancer, chronic infections, severe organ failure, diabetes. NS No NS NS 26.2  3 NS

ADL, activities of daily living; BMI, body mass index; COPD, chronic obstructive pulmonary disease; FEV1, forced expiratory volume in one second; FVC, forced vital capacity; G&G, get-up-and-go test; MMSE, Mini Mental State
Examination; NIH, U.S. National Institutes of Health (clinicaltrials.gov); NS, not specified; NTR, Netherlands Trial Register (www.trialregister.nl).
 V. Malafarina et al. / JAMDA 14 (2013) 10e17 15

Identification
Potentially relevant citation: Bibliography of selected articles:
PubMed n=168 N=12
Cochrane Library n=20

Screening After duplicates removed: n=176

Records excluded: n=152

Records screened: 176 No BIA/DXA: n=58
No supplement/no oral: n=84
Supplement <8wk: n=1
<65 years: n=2
Cancer: n=6
No RCT: n=1
Eligibility

Full-text articles assessed for

eligibility: n=24 Full-text articles excluded: n=7
Mean age < 65 years: n=1
No BIA/DXA: n=3
Studies included in qualitative No supplements: n=2
Included

synthesis: n=17 Intravenous supplement: n=1

Studies included in quantitative

synthesis: 0

Fig. 1. Flowchart of literature search. BIA, bioelectrical impedance analysis; DXA, dual energy x-ray absorptiometry; RCT, randomized controlled trial.

control group. The trial run by Baier et al34 demonstrated a significant Leenders et al31 found a statistically significant (P < .001) increase
increase of FFM in the group supplemented with beta-hydroxy-beta- of thigh strength after a 6-month follow-up in both the supple-
methylbutyrate compared with the control group. mented and the control group, but the difference between them was
not significant. The same outcome was observed by Verhoeven et al.28
Muscle Function Carlsoon et al33 found an improvement in measurements with the
Analyzing the various trials we find that adding a nutritional Berg Balance Scale, but did not specify whether this improvement
supplement may not only restore or increase muscle mass, but may was significant. Bunout et al35 proved that walking ability decreased
also improve muscle function, in terms of the following parameters: in a significant way in the control group compared with the sup-
(1) walking speed; (2) handgrip strength; (3) leg strength; (4) plemented group.
balance; and (5) climbing stairs. Neelemaat et al37 found there was a tendency to reduce functional
The trial by Kim et al38 showed a significant increase of walking limitations, although this outcome was not statistically significant.
speed in the groups treated with physical exercise, compared with They also observed improvement of handgrip-strength in the sup-
the group with no treatment (P ¼ .007). plemented group compared with the control group.

Table 3
Assessment of Methodological Quality of the Studies Included in the Systematic Review

Reporting (10) External Internal Internal Validitye Power (5) Total (32)
Validity (3) Validity e Bias (7) Confounding (6)
Kim et al 201238 9 3 4 5 1 22
Leenders et al 201131 6 0 5 2 0 13
Carlsson et al 201133 6 0 5 2 1 14
Neelemaat et al 201137 10 3 5 5 2 25
Dal Negro et al 201029 5 0 6 2 0 13
Verhoeven et al 200928 7 1 5 2 0 15
Cornish et al 200925 6 0 5 2 0 13
Baier et al 200934 6 0 6 3 1 16
Verdijk el al 200939 8 0 4 2 0 14
Solerte et al 200841 5 0 3 1 0 9
Børsheim et al 200832 9 0 3 2 0 14
Flakoll et al 200440 6 0 4 2 0 12
Wouters-Wesseling et al 200336 9 0 5 5 1 20
Vukovich et al 200127 9 0 5 4 0 18
Baldi et al 201030 8 1 4 4 0 17
Dillon et al 200926 5 0 5 3 0 13
Bunout et al 200135 6 0 3 1 0 10
16 V. Malafarina et al. / JAMDA 14 (2013) 10e17

Conclusion
In the trials by Dal Negro et al29 a statistically significant increase
of the functional state of the supplemented group, expressed as an
We found two papers assessing the effects of nutritional supple-
increase of steps climbed (P ¼ .01), was observed.
mentation on muscle mass and function in patients with hip fractures
Baier et al34 found a decrease of handgrip strength in both the
that were published in the “Journal” last month.53,54 These further
supplemented and control groups, whereas Flakoll et al40 observed
support our conclusions. Some of the papers reviewed did not
a statistically significant improvement (P ¼ .04) of this parameter in
achieve positive results, but showed negative effects on untreated
the supplemented group. The trials by Vukovich et al27 showed
groups, which may be an indirect indication of the protective effect of
a significant improvement of leg curl in the supplemented group
nutritional supplementation in terms of the consequences of ageing.
compared with the control group.
The right kind of diet and a physically active lifestyle are two
In persons with chronic obstructive pulmonary disease, van We-
important factors to counterbalance the development of sarcopenia
tering et al42 found that nutritional therapy increased average power,
with old age and condition ongoing independence and autonomy in
6-minute walk distance, cycle endurance time, and peak exercise
older people.55e57
capacity.
The relatively small number of papers falling within our inclusion
criteria was the main limitation of this review. A further shortcoming,
Discussion unrelated to the paper selection criteria, stems from the differences in
the studied populationsdwomen only, men only, trials for specific
All the papers reviewed refer to sarcopenia in their introduction pathologies such as chronic obstructive pulmonary disease or dia-
and mention sarcopenia often in the discussion but only three of the betesdand the broad range of supplementation used and the
trials included sarcopenic patients. In one of them, the criteria used to considered outcomes.
define sarcopenia differ from those accepted by international Nutritional therapy has generated great expectations, but further
consensus and the other two do not specify the criteria used. randomized clinical trials are needed, with a more rigorous design,
Patients with a BMI higher than 20 kg/m2 were included in 53% combining the current definitions of sarcopenia with nutritional
of the trials and 30% included patients with a BMI above 27 kg/m2. intervention. It would be interesting to assess the effects of nutri-
Despite the severe limitations the said index undergoes in older tional supplementation on inpatients of hospitals, rather than on
people, it is fair to assume that the subjects of these trials were healthy people living in the community, as the former is a population
well-nourished people or presented a relatively low risk of with a high risk of under nourishment, sarcopenia, and functional
malnutrition.43,44 We believe that supplementing well-nourished deterioration with a view to reinstate the levels of autonomy enjoyed
people is one of the main shortcomings of the trials reflected in before the acute process.
these papers, as this could limit the margin of improvement we It is time for an international consensus on the diagnostic criteria
could expect. for sarcopenia, to which all trials dealing with sarcopenia should
Despite the fact that the groups studied in the included papers adhere in the future.
were homogenous originally, the relatively low number of patients
prevents a correction of the analysis of the outcomes because of the
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