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nutrients
Review
Health Benefits of β-Hydroxy-β-Methylbutyrate
(HMB) Supplementation in Addition to Physical
Exercise in Older Adults: A Systematic Review
with Meta-Analysis
Javier Courel-Ibáñez 1, * , Tomas Vetrovsky 2, Klara Dadova 2, Jesús G. Pallarés1and
Michal Steffl2
1Human Performance and Sports Science Laboratory, Faculty of Sport Sciences, University of Murcia,
30100 Murcia, Spain
2Faculty of Physical Education and Sport, Charles University, 16252 Prague, Czech Republic
*Correspondence: javier.courel.ibanez@gmail.com; Tel.: +34-6-5527-0315
Received: 13 August 2019; Accepted: 29 August 2019; Published: 3 September 2019
Abstract:
Both regular exercise training and beta-hydroxy-beta-methylbutyrate (HMB)
supplementation are shown as effective treatments to delay or reverse frailty and reduce cognitive
impairment in older people. However, there is very little evidence on the true benefits of combining
both strategies. The aim of this meta-analysis was to quantify the effects of exercise in addition to
HMB supplementation, on physical and cognitive health in older adults. Data from 10 randomized
controlled trials (RCTs) investigating the effect of HMB supplementation and physical function in
adults aged 50 years or older were analyzed, involving 384 participants. Results showed that HMB
supplementation in addition to physical exercise has no or fairly low impact in improving body
composition, muscle strength, or physical performance in adults aged 50 to 80 years, compared to
exercise alone. There is a gap of knowledge on the beneficial effects of HMB combined with exercise
to preserve cognitive functions in aging and age-related neurodegenerative diseases. Future RCTs
are needed to refine treatment choices combining HMB and exercises for older people in particular
populations, ages, and health status. Specifically, interventions in older adults aged 80 years or older,
with cognitive impairment, frailty, or limited mobility are required.
Keywords: nutrition; resistance training; leucine; elderly; sarcopenia; neuromuscular function
1. Introduction
Evidence supports the fact that the combination of muscle strength training and protein
supplementation stands as the most effective and easiest intervention to delay or reverse frailty in
primary care [
1
,
2
] and emerges as a plausible treatment to reduce functional and cognitive impairment
in older adults [3].
There is increasing evidence that tailored multicomponent exercise programs benefit both physical
and cognitive health in frail older people [
4
–
8
], to the extent that it is being considered mandatory
for community-dwelling and institutionalized people [
9
]. However, the level of regular physical
activity and resistance training of older ages is likely to be much lower than recommended [
10
].
Physical inactivity in older adults represents a serious health risk as it contributes to the onset of
muscle mass and function decline, which—sometimes irremediably—leads to frailty and derived
short-term and mid-term diseases, hospitalization, disability, and death [
11
–
13
]. Furthermore, physical
inactivity appears to be associated with a higher risk of dementia, Alzheimer’s disease, or mild
cognitive impairment [14].
Nutrients 2019,11, 2082; doi:10.3390/nu11092082 www.mdpi.com/journal/nutrients
Nutrients 2019,11, 2082 2 of 19
In addition to insufficient physical activity, older adults are at high risk for deficient protein intake
due to factors, such as comorbidity, loss of appetite, poor oral health, the loss of autonomy, lack of
economic resources, or limited access to medical and allied health services [
15
,
16
]. Deficits in protein
intake decreases health-related quality of life and accelerate age-related muscle mass waste and the
development of sarcopenia [
17
]. Moreover, malnutrition seems to be related to impaired cognition and
Alzheimer’s disease pathology [
18
]. From an economic perspective, the price of managing patients at
risk of malnutrition is very cost effective, which emphasizes the implementation of strategies focused
on preventing patients from becoming malnourished [19].
One of the most promising nutritional supplements for the preservation of muscle mass in old age
is beta-hydroxy-beta-methylbutyrate (HMB), a bioactive metabolite formed from the decomposition
of leucine, an essential branched-chain amino acid [
20
,
21
]. HMB plays a key nutritional role as
it is considered the most important regulator of muscle protein anabolism, due to its ability to
stimulate the mechanistic Target of Rapamycin (mTOR) signaling pathway, which increases protein
synthesis, and attenuates the proteasome pathway, inducing muscle protein catabolism [
22
,
23
].
Daily HMB supplementation (typically 3 g/day) is demonstrated to have an anti-catabolic effect,
enhance protein synthesis, attenuate proteolysis, increase muscle mass, and decrease muscle damage
in older adults [
20
,
24
,
25
]. Furthermore, animal models have recently suggested that HMB could be
effective in mitigating age-related cognitive deficits [
26
,
27
] and improve the aging neuromuscular
system [
28
]. The optimal dose of HMB cannot be obtained from a standard diet given the low quantities
of HMB available in foods and the low conversion rate of leucine to HMB (~5–10%) [
29
]. Of further
concern, HMB conversion appears to be reduced with age [
30
]. Thus, HMB oral supplementation
stands as a realistic alternative to palliate metabolic diseases, muscle wasting, and functional loss in
older adults.
The implementation of preventive strategies focused on physical and cognitive health maintenance
for frail people through exercise and proper nutrition are required to contribute to lifelong wellbeing
and reduce the extra costs related to physical inactivity and malnutrition. Evidence indicates that
exercise programs and HMB supplementation appear to be effective and affordable strategies as
independent treatments. However, there is very little evidence on the true benefits of combining both
strategies. Therefore, the aim of this meta-analysis was to quantify the effects of exercise in addition to
HMB supplementation on physical and cognitive health in older adults.
2. Materials and Methods
2.1. Search Strategy
We carried out the review in accordance with a protocol that was registered in PROSPERO
(Provisional ID: 147419). The systematic review was conducted according to the PRISMA (Preferred
Reporting Items for Systematic Reviews and Meta-Analyses) statement [
31
]. A compiled PRISMA
checklist is included in Table 1. A literature search was conducted by electronic search for original
papers of three literature databases (Web of Science, Scopus, and PubMed). The search included
original papers written in any language and published before 5 June 2019. Except for minor variations
regarding database mechanisms, we used the same search string in all the databases (Table 2).
Nutrients 2019,11, 2082 3 of 19
Table 1. Checklist of items to include when reporting a systematic review or meta-analysis.
Section/Topic Item Checklist Item Page
TITLE
Title 1 Identify the report as a systematic review, meta-analysis, or both. 1
ABSTRACT
Structured
summary 2
Provide a structured summary including, as applicable: background; objectives; data sources; study
eligibility criteria, participants, and interventions; study appraisal and synthesis methods; results;
limitations; conclusions and implications of key findings; systematic review registration number.
1
INTRODUCTION
Rationale 3 Describe the rationale for the review in the context of what is already known. 2
Objectives 4 Provide an explicit statement of questions being addressed with reference to participants,
interventions, comparisons, outcomes, and study design (PICOS). 2
METHODS
Protocol and
registration 5Indicate if a review protocol exists, if and where it can be accessed (e.g., Web address), and, if
available, provide registration information including registration number. 2
Eligibility criteria 6
Specify study characteristics (e.g., PICOS, length of follow-up) and report characteristics (e.g., years
considered, language, publication status) used as criteria for eligibility, giving rationale. 4
Information
sources 7
Describe all information sources (e.g., databases with dates of coverage, contact with study authors
to identify additional studies) in the search and date last searched. 3
Search 8
Present full electronic search strategy for at least one database, including any limits used, such that
it could be repeated. 3
Study selection 9
State the process for selecting studies (i.e., screening, eligibility, included in systematic review, and,
if applicable, included in the meta-analysis). 3
Data collection
process 10 Describe method of data extraction from reports (e.g., piloted forms, independently, in duplicate)
and any processes for obtaining and confirming data from investigators. 4
Data items 11 List and define all variables for which data were sought (e.g., PICOS, funding sources) and any
assumptions and simplifications made. 4
Risk of bias in
individual studies 12
Describe methods used for assessing risk of bias of individual studies (including specification of
whether this was done at the study or outcome level), and how this information is to be used in any
data synthesis.
5
Summary measures
13 State the principal summary measures (e.g., risk ratio, difference in means). 5
Synthesis of results 14 Describe the methods of handling data and combining results of studies, if done, including
measures of consistency (e.g., I2) for each meta-analysis. 5
Risk of bias across
studies 15
Specify any assessment of risk of bias that may affect the cumulative evidence (e.g., publication bias,
selective reporting within studies). 5
Additional
analyses 16
Describe methods of additional analyses (e.g., sensitivity or subgroup analyses, meta-regression), if
done, indicating which were pre-specified. 5
RESULTS
Study selection 17
Give numbers of studies screened, assessed for eligibility, and included in the review, with reasons
for exclusions at each stage, ideally with a flow diagram. 6
Study
characteristics 18 For each study, present characteristics for which data were extracted (e.g., study size, PICOS,
follow-up period) and provide the citations. 7
Risk of bias within
studies 19
Present data on risk of bias of each study and, if available, any outcome level assessment (see item
12). 6
Results of
individual studies 20
For all outcomes considered (benefits or harms), present, for each study: (a) simple summary data
for each intervention group (b) effect estimates and confidence intervals, ideally with a forest plot.
5
Synthesis of results 21 Present results of each meta-analysis done, including confidence intervals and measures of
consistency. 9
Risk of bias across
studies 22 Present results of any assessment of risk of bias across studies (see Item 15). 7
Additional analysis
23
Give results of additional analyses, if done (e.g., sensitivity or subgroup analyses, meta-regression
(see item 16)). 9
DISCUSSION
Summary of
evidence 24 Summarize the main findings including the strength of evidence for each main outcome; consider
their relevance to key groups (e.g., healthcare providers, users, and policy makers). 13
Limitations 25 Discuss limitations at study and outcome level (e.g., risk of bias), and at review-level (e.g.,
incomplete retrieval of identified research, reporting bias). 14
Conclusions 26
Provide a general interpretation of the results in the context of other evidence, and implications for
future research. 15
FUNDING
Funding 27
Describe sources of funding for the systematic review and other support (e.g., supply of data); role
of funders for the systematic review. 15
Nutrients 2019,11, 2082 4 of 19
Table 1. Cont.
Section/Topic Item Checklist Item Page
TITLE
Title 1 Identify the report as a systematic review, meta-analysis, or both. 1
ABSTRACT
Structured
summary 2
Provide a structured summary including, as applicable: background; objectives; data sources; study
eligibility criteria, participants, and interventions; study appraisal and synthesis methods; results;
limitations; conclusions and implications of key findings; systematic review registration number.
1
INTRODUCTION
Rationale 3 Describe the rationale for the review in the context of what is already known. 2
Objectives 4 Provide an explicit statement of questions being addressed with reference to participants,
interventions, comparisons, outcomes, and study design (PICOS). 2
METHODS
Protocol and
registration 5Indicate if a review protocol exists, if and where it can be accessed (e.g., Web address), and, if
available, provide registration information including registration number. 2
Eligibility criteria 6
Specify study characteristics (e.g., PICOS, length of follow-up) and report characteristics (e.g., years
considered, language, publication status) used as criteria for eligibility, giving rationale. 4
Information
sources 7
Describe all information sources (e.g., databases with dates of coverage, contact with study authors
to identify additional studies) in the search and date last searched. 3
Search 8
Present full electronic search strategy for at least one database, including any limits used, such that
it could be repeated. 3
Study selection 9
State the process for selecting studies (i.e., screening, eligibility, included in systematic review, and,
if applicable, included in the meta-analysis). 3
Data collection
process 10 Describe method of data extraction from reports (e.g., piloted forms, independently, in duplicate)
and any processes for obtaining and confirming data from investigators. 4
Data items 11 List and define all variables for which data were sought (e.g., PICOS, funding sources) and any
assumptions and simplifications made. 4
Risk of bias in
individual studies 12
Describe methods used for assessing risk of bias of individual studies (including specification of
whether this was done at the study or outcome level), and how this information is to be used in any
data synthesis.
5
Summary measures
13 State the principal summary measures (e.g., risk ratio, difference in means). 5
Synthesis of results 14 Describe the methods of handling data and combining results of studies, if done, including
measures of consistency (e.g., I2) for each meta-analysis. 5
Risk of bias across
studies 15
Specify any assessment of risk of bias that may affect the cumulative evidence (e.g., publication bias,
selective reporting within studies). 5
Additional
analyses 16
Describe methods of additional analyses (e.g., sensitivity or subgroup analyses, meta-regression), if
done, indicating which were pre-specified. 5
RESULTS
Study selection 17
Give numbers of studies screened, assessed for eligibility, and included in the review, with reasons
for exclusions at each stage, ideally with a flow diagram. 6
Study
characteristics 18 For each study, present characteristics for which data were extracted (e.g., study size, PICOS,
follow-up period) and provide the citations. 7
Risk of bias within
studies 19
Present data on risk of bias of each study and, if available, any outcome level assessment (see item
12). 6
Results of
individual studies 20
For all outcomes considered (benefits or harms), present, for each study: (a) simple summary data
for each intervention group (b) effect estimates and confidence intervals, ideally with a forest plot.
5
Synthesis of results 21 Present results of each meta-analysis done, including confidence intervals and measures of
consistency. 9
Risk of bias across
studies 22 Present results of any assessment of risk of bias across studies (see Item 15). 7
Additional analysis
23
Give results of additional analyses, if done (e.g., sensitivity or subgroup analyses, meta-regression
(see item 16)). 9
DISCUSSION
Summary of
evidence 24 Summarize the main findings including the strength of evidence for each main outcome; consider
their relevance to key groups (e.g., healthcare providers, users, and policy makers). 13
Limitations 25 Discuss limitations at study and outcome level (e.g., risk of bias), and at review-level (e.g.,
incomplete retrieval of identified research, reporting bias). 14
Conclusions 26
Provide a general interpretation of the results in the context of other evidence, and implications for
future research. 15
FUNDING
Funding 27
Describe sources of funding for the systematic review and other support (e.g., supply of data); role
of funders for the systematic review. 15
Nutrients 2019,11, 2082 5 of 19
Table 2. Search results from electronic databases.
Database Keywords Records
PubMed
Search (((((HMB)[Title/Abstract] OR
beta-hydroxy-beta-methylbutyrate)[Title/Abstract] OR
β-hydroxy-β-methylbutyrate[Title/Abstract]))) AND (((((elder *) OR
elderly)) OR (((exercise *) OR intervention *) OR training *)) OR ((((sarcopen
*) OR frail *) OR cachexia) OR “muscle weakness”))
176
Scopus
((TITLE-ABS-KEY (β-hydroxy-β-methylbutyrate) OR TITLE-ABS-KEY
(hmb) OR TITLE-ABS-KEY (beta-hydroxy-beta-methylbutyrate) OR
TITLE-ABS-KEY (b-hydroxy-b-methylbutyrate))) AND (((TITLE-ABS-KEY
(elder *) OR TITLE-ABS-KEY (“old * adult *”))) OR ((TITLE-ABS-KEY
(sarcopen *) OR TITLE-ABS-KEY (frail *) OR TITLE-ABS-KEY (cachexia)
OR TITLE-ABS-KEY (“muscle weakness”))) OR ((TITLE-ABS-KEY (exercise
*) OR TITLE-ABS-KEY (intervention *) OR TITLE-ABS-KEY (training *))))
474
Web of Science
TOPIC: (β-Hydroxy-β-Methylbutyrate) OR TOPIC: (hmb) OR TOPIC:
(beta-hydroxy-beta-methylbutyrate) OR TOPIC:
(b-hydroxy-b-methylbutyrate) AND ((TOPIC: (elder *) OR TOPIC: (“old *
adult *”)) OR (TOPIC: (sarcopen *) OR TOPIC: (frail *) OR (TOPIC:
(cachexia) OR TOPIC: (“muscle weakness”)) OR (TOPIC: (exercise *) OR
TOPIC: (intervention *) OR TOPIC: (training *)))
286
* Broadens the search by finding words that start with the same letters.
2.2. Inclusion Criteria
Screening and eligibility of studies were performed independently by two investigators.
Discrepancies were settled by negotiation with a third author. The PICOS (population, interventions,
comparators, outcomes, study design) criteria for the eligibility of studies [
32
] was used to determine
the inclusion and exclusion criteria, as follows:
•
Participants: Studies of participants aged 50 or older. We made no restrictions of participants’
gender, health and socio-economic status, ethnicity or geographical area. We emphasized searching
for studies including people with frailty, sarcopenia, cachexia, or muscle weakness.
•
Intervention: Any intervention combining physical exercise in addition to HMB oral
supplementation. We considered every exercise activity requiring increased energy output without
taking into account frequency or intensity. We considered any HMB dosage, supplementation
form (powders, pills, nutritional drink) and nature (free acid or enriched).
•Comparators: Participants not provided with HMB supplementation (controls or placebo).
•
Outcomes: Clinical outcomes on physical and cognitive health, including (but not restricted to)
changes in physical function, muscular strength, body composition, cognitive impairment, and
quality of life.
•
Study designs: Randomized controlled trials (RCT) were included in order to determine if the
HMB oral supplementation (investigational treatment) was more effective than a control or placebo
group when provided during a physical exercise program. The comprehensive search of RCT was
set to identify gaps in the current evidence.
2.3. Data Collection
The data in the studies were evaluated by one investigator using a predefined data sheet.
The extraction was checked independently by two other authors. First, all potential papers were
downloaded in the citation software EndNote; second, all duplicates were deleted; third, titles and
abstracts were screened to identify studies that potentially met the eligibility criteria; fourth, full
texts were subsequently assessed for eligibility. Additionally, we hand-searched the reference lists
of eligible papers and of several recently published reviews for further studies. Disagreements were
resolved through discussions with the reviewers. For our meta-analyses, we collected the following
data for both the exercise groups and control groups: Group sizes, and the mean differences of selected
outcomes (after–before) with a 95% CI or SD.
Nutrients 2019,11, 2082 6 of 19
2.4. Quality Assessment and Risk of Bias
Risk of bias was assessed independently by two investigators using the latest version of the
Cochrane Collaboration Risk-of-Bias tool (RoB, 2 March 2019) in randomized trials [
33
]. Studies were
assessed in five domains: Bias arising from the randomization process; bias due to deviations from
intended interventions; bias due to missing outcome data; bias in measurement of the outcome; bias
in selection of the reported result. The tool includes algorithms that map responses to signaling
questions onto a proposed risk-of-bias judgement for each domain in three levels: Low risk of bias,
some concerns, and high risk of bias.
2.5. Data Analysis
The effect sizes (ESs) were calculated as the standardized mean differences between the HMB
supplementation and placebo groups. The sample size and mean ES across all studies were used
to calculate the variance around each ES. Meta-analyses were performed using robust variance
estimation (RVE) with small-sample corrections. RVE is a form of random-effects meta-regression for
multilevel data structures, which allows for multiple effect sizes from the same study to be included
in a meta-analysis, even when information on the covariance of these effect sizes is unavailable.
Instead, RVE estimates the variance of meta-regression coefficient estimates using the observed
residuals. It does not require distributional assumptions and does not make any requirements
on the weights [
34
,
35
]. Study was used as the clustering variable to account for correlated effects
within studies. Observations were weighted by the inverse of the sampling variance. A sensitivity
analysis, using alternative correlational values to calculate the standard error, revealed that the choice
of correlational value did not impact the overall results of the meta-analysis. I2 was used to evaluate
between-study heterogeneity. Values of I2 more than 25%, 50%, and 75% were selected to reflect low,
moderate, and high heterogeneity, respectively. All analyses were performed using packages robumeta
(version 2.0) and metafor (version 2.0-0) in R version 3.4.4 (The R Foundation for Statistical Computing,
Vienna, Austria).
3. Results
3.1. Characteristics of Studies
Out of the 936 publications from the database search, we included 10 RCTs [
36
–
45
] on physical
activity and the additional effect of HMB on several measures in the final analysis. Figure 1shows the
PRISMA flow diagram. Across the 10 studies, we extracted data from 384 participants, all over 50
years of age. The majority of studies (n =8) included healthy people. The ethnicity of the subjects was
not mentioned in any study. HMB dosage varied between 1.0 (n =1), 1.5 (n =2), and 3.0 g/d (n =7).
HMB supplementation was administered in its calcium salt form (Ca-HMB) in nine studies, whilst only
one provided the free acid form (HMB-FA). Exercise interventions lasted from 3 to 24 weeks, with a
frequency between 1 to 3 days a week. HMB administration was the same as the exercise intervention
except for one study [
40
], in which participants consumed HMB 5 days prior to bed rest and was
continued until the end of the rehabilitation period. All the interventions included resistance exercises,
but the routine and intensity of the programs differed. A summary of the studies included is presented
in Table 3.
Nutrients 2019,11, 2082 7 of 19
Nutrients 2019, 11, x FOR PEER REVIEW 6 of 18
Figure 1. Flowchart illustrating the different phases of the search and study selection, according to
the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) statements.
Records identified through database searching
Screenin
g
Included Eli
g
ibilit
y
Identification
Records after duplicates removed
(n = 551)
Records excluded
(n = 517)
Full-text articles assessed
for eligibility
(
n = 34
)
Full-text articles excluded
(n = 26)
Studies included in
qualitative synthesis
(
n = 10
)
Studies included in
quantitative synthesis
(meta-analysis)
(n = 7)
PubMed
(n = 176)
Scopus
(n = 474)
Web of Science
(n = 286)
Additional papers
identified from references
(n = 2)
Figure 1.
Flowchart illustrating the different phases of the search and study selection, according to the
PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) statements.
Nutrients 2019,11, 2082 8 of 19
Table 3. Studies included in the analyses.
Study Length Age Sample Participants Supplementation Compliance SAEs Control Exercise
Berton (2015) 8 weeks 69.5 (5.3) EG =32
CG =34 Healthy women
1.5 g/d Ca-HMB in
Ensure Plus Advance
enriched with
25(OH)D 227 IU/100
mL
HMB: 96 ±6%
Exercise: N.R.
Abdominal pain,
constipation (n =2)
and itching (n =1)
Standard diet
2
×
a week, mild fitness program at public gyms. Aerobic
exercises to improve speed of muscle contraction, and a
small part dedicated to resistance exercises, essentially to
improve handgrip strength
Din (2019) 6 weeks 68.5 (1.1) aEG =8
CG =8Healthy men 1.0 g/d HMB-FA in
BetaTOR®
HMB: 99%
Exercise: N.R. N.R. Placebo
3×a week, supervised unilateral progressive resistance
training. Leg extension of the dominant leg (6 sets, 8 rep,
75% 1-RM, adjusted each 10 days)
Malafarina
(2017)
42.3 ±20.9
days 85.4 (6.3) EG =49
CG =43
Patients with a hip
fracture
73.8% women
3.0 g/d Ca-HMB in
Ensure Plus Advance
enriched with
25(OH)D 227 IU/100
mL
HMB: >80%
Exercise: N.R. N.R. Standard diet
5×a week, 50-min supervised rehabilitation therapy.
Exercises to strengthen the lower limbs, balance exercises,
and walking re-training in individual or group
Olveira (2015) 12 weeks 56.1 (1.3) EG =15
CG =15
Patients with
non-cystic fibrosis
bronchiectasis
60% women
1.5 g/d Ca-HMB in
Ensure Plus Advance
enriched with
25(OH)D 227 IU/100
mL
HMB: N.R.
Exercise:
100%
N.R. Standard diet
2×a week, 60-min supervised exercise program at a
hospital and 1 ×30-min unsupervised session. Cycle
ergometer and treadmill (30 min, 75–80% VO2max),
upper and lower limb strength (8 min, 1 set, 8–10 rep),
breathing retraining (15 min), and stretching and
relaxation (7 min)
Stout (2013) †24 weeks 73.0 (1.0) aEG =16
CG =20
Healthy older adults
54.2% women
3.0 g/d Ca-HMB +8
g/d carbohydrate
HMB: >67%
Exercise:
>60%
N.R. Placebo
3×a week, supervised resistance training. Bench press,
leg press, leg extension (1–3 sets, 8–12 rep, 80% 1RM,
adjusted), lat pulldown hack squat (1–3 sets, 8–12 rep,
2–5 min rest)
Stout (2015) †12 weeks 72.1 (5.7) EG =12
CG =12 Healthy men 3.0 g/d Ca-HMB +
8g/d carbohydrate
HMB: >67%
Exercise:
>60%
N.R. Placebo
3×a week, supervised resistance training. Bench press,
leg press, leg extension (1–3 sets, 80% 1RM, adjusted), lat
pulldown hack squat (1–3 sets, 8–12 rep, 2–5 min rest)
Vukovich
(2001) 8 weeks 70 (1.0) EG =14
CG =17
Healthy older adults
54.6% women 3.0 g/d Ca-HMB
HMB: 100%
Exercise:
100%
No adverse reaction
or medical
complication
Placebo
2×a week, supervised resistance training and 3 ×
walking (40 min self-paced) and stretching (10 min).
Overhead press, bench press, l at pulldown, elbow
extension and flexion, leg flexion/extension, and leg press
(2 sets, 8–12 reps. 70% 1RM, adjusted each 2 weeks)
After bed rest
Deutz (2013) *
Standley
(2017) *
8 weeks 67.4 (1.4) aEG =11
CG =8
Healthy older adults
78.9% women 3.0 g/d Ca-HMB HMB >67%
Exercise >60%
No serious adverse
events Placebo
3×a week, 1-h resistance training rehabilitation after a
10-day bed rest. 1-h circuit training for combined hip and
knee extensors and flexors, light upper body exercises (3
sets, 8–10 rep, 80% 1RM) and self-paced walking
Results were not showed separately for old people
Nissen (2000) 8 weeks 63–81 bEG =18
CG =18 Healthy older adults 3.0 g/d Ca-HMB N.R.
Less diarrhea and less
loss of appetite Placebo
3×a week, supervised resistance training. Alternated
exercising of either the upper or lower body during each
exercise session
8 weeks 62–79 bEG =16
CG =18 Healthy older adults 3.0 g/d Ca-HMB N.R.
Less diarrhea and less
loss of appetite Placebo
2
×
a week resistance training +3
×
60-min walking and
stretching
a
Mean age of the whole sample was not reported; therefore, the mean age of the experimental group is presented;
b
Range of the experimental group; * the same population;
†
part of the
same population; EG: experimental group; CG: control group; Ca-HMB: calcium beta-hydroxy-beta-methylbutyrate; HMB-FA: beta-hydroxy-beta-methylbutyrate free acid SAEs: serious
adverse events; N.R.: not reported.
Nutrients 2019,11, 2082 9 of 19
3.2. Quality of Studies and Risk of Bias
No study was considered as low risk of bias in all categories. The greatest biases were found in
the concealment, randomization, and selection of the reported results. Two studies showed high risk
of bias in the selection of the reported results due to important discrepancies with the pre-registered
trial. Four studies did not provide a trial pre-registration or publication. Two studies showed partial
results from the pre-specified plan. A summary of the risk of bias assessment is shown in Table 4.
Table 4. Risk of bias of included studies.
Randomization
Process
Deviations
from
Intended
Interventions
Missing
Outcome
Data
Measurement
of the
Outcome
Selection of
the
Reported
Result
Overall Bias
Berton (2016)
Nutrients 2019, 11, x FOR PEER REVIEW 8 of 18
3.2. Quality of Studies and Risk of Bias
No study was considered as low risk of bias in all categories. The greatest biases were found in
the concealment, randomization, and selection of the reported results. Two studies showed high risk
of bias in the selection of the reported results due to important discrepancies with the pre-registered
trial. Four studies did not provide a trial pre-registration or publication. Two studies showed partial
results from the pre-specified plan. A summary of the risk of bias assessment is shown in Table 4.
Table 4. Risk of bias of included studies.
Randomization Process
Deviations from
Intended Interventions
Missing Outcome Data
Measurement of the
Outcome
Selection of the Reported
Result
Overall Bias
Berton (2016)
Deutz (2013)
Din (2019)
Malafarina (2017)
Olveira (2015)
Standley (2017)
Stout (2013)
Stout (2015)
Vukovich (2001)
Nissen (2000)
Low risk of bias; Unclear risk of bias; High risk of bias.
3.3. Studies’ Outcomes and Results
Seven studies included data from the mean differences between control and HMB groups after
exercise training on different health measures, showing controversial results (Table 5). Body
composition was the most studied outcome [37–41,43,44], followed by muscular strength
[37,38,40,43,44] and physical performance [37,40,43,44]. No study included cognitive outcomes.
Studies shared 11 out of the 40 measures analyzed. Body composition was examined using dual-
energy X-ray absorptiometry (DXA), bioelectrical impedance analysis (BIA), and computed
tomography (CT). Two studies [43,44] found positive effects in fat free mass using different
techniques, whilst three studies [37,40,41] found no differences between HMB and controls. HMB
supplementation had no effects on fatty mass in absolute terms when using DXA and BIA exams
[41,43,44]; in turn, the % of body fat loss after HMB supplementation increased when using skinfold
analysis [41]. Two studies [37,43] examined the abdominal fat mass with contradictory results.
Muscular strength included handgrip, knee flexion/extension by isokinetic, isometric and one
maximum repetition (1RM) measures, and bench/leg press exercises. Out of the five RCTs exploring
muscular strength, only one study [37] found positive effects of HMB supplementation in comparison
with controls. Physical performance was tested using the short physical performance battery (SPPB)
and its three component parts (sit-to-stand, gait speed 6 m, and get-up-and-go tests). No treatment
? + + + + !
+ + ? + ? !
+ + + + ? !
? ? ? + ? !
? ? + + — —
+ + + + ? !
? + + + ? !
? + + + — —
? + + + ? !
+ +
+
+ ? !
Nutrients 2019, 11, x FOR PEER REVIEW 8 of 18
3.2. Quality of Studies and Risk of Bias
No study was considered as low risk of bias in all categories. The greatest biases were found in
the concealment, randomization, and selection of the reported results. Two studies showed high risk
of bias in the selection of the reported results due to important discrepancies with the pre-registered
trial. Four studies did not provide a trial pre-registration or publication. Two studies showed partial
results from the pre-specified plan. A summary of the risk of bias assessment is shown in Table 4.
Table 4. Risk of bias of included studies.
Randomization Process
Deviations from
Intended Interventions
Missing Outcome Data
Measurement of the
Outcome
Selection of the Reported
Result
Overall Bias
Berton (2016)
Deutz (2013)
Din (2019)
Malafarina (2017)
Olveira (2015)
Standley (2017)
Stout (2013)
Stout (2015)
Vukovich (2001)
Nissen (2000)
Low risk of bias; Unclear risk of bias; High risk of bias.
3.3. Studies’ Outcomes and Results
Seven studies included data from the mean differences between control and HMB groups after
exercise training on different health measures, showing controversial results (Table 5). Body
composition was the most studied outcome [37–41,43,44], followed by muscular strength
[37,38,40,43,44] and physical performance [37,40,43,44]. No study included cognitive outcomes.
Studies shared 11 out of the 40 measures analyzed. Body composition was examined using dual-
energy X-ray absorptiometry (DXA), bioelectrical impedance analysis (BIA), and computed
tomography (CT). Two studies [43,44] found positive effects in fat free mass using different
techniques, whilst three studies [37,40,41] found no differences between HMB and controls. HMB
supplementation had no effects on fatty mass in absolute terms when using DXA and BIA exams
[41,43,44]; in turn, the % of body fat loss after HMB supplementation increased when using skinfold
analysis [41]. Two studies [37,43] examined the abdominal fat mass with contradictory results.
Muscular strength included handgrip, knee flexion/extension by isokinetic, isometric and one
maximum repetition (1RM) measures, and bench/leg press exercises. Out of the five RCTs exploring
muscular strength, only one study [37] found positive effects of HMB supplementation in comparison
with controls. Physical performance was tested using the short physical performance battery (SPPB)
and its three component parts (sit-to-stand, gait speed 6 m, and get-up-and-go tests). No treatment
? + + + + !
+ + ? + ? !
+ + + + ? !
? ? ? + ? !
? ? + + — —
+ + + + ? !
? + + + ? !
? + + + — —
? + + + ? !
+ +
+
+ ? !
Nutrients 2019, 11, x FOR PEER REVIEW 8 of 18
3.2. Quality of Studies and Risk of Bias
No study was considered as low risk of bias in all categories. The greatest biases were found in
the concealment, randomization, and selection of the reported results. Two studies showed high risk
of bias in the selection of the reported results due to important discrepancies with the pre-registered
trial. Four studies did not provide a trial pre-registration or publication. Two studies showed partial
results from the pre-specified plan. A summary of the risk of bias assessment is shown in Table 4.
Table 4. Risk of bias of included studies.
Randomization Process
Deviations from
Intended Interventions
Missing Outcome Data
Measurement of the
Outcome
Selection of the Reported
Result
Overall Bias
Berton (2016)
Deutz (2013)
Din (2019)
Malafarina (2017)
Olveira (2015)
Standley (2017)
Stout (2013)
Stout (2015)
Vukovich (2001)
Nissen (2000)
Low risk of bias; Unclear risk of bias; High risk of bias.
3.3. Studies’ Outcomes and Results
Seven studies included data from the mean differences between control and HMB groups after
exercise training on different health measures, showing controversial results (Table 5). Body
composition was the most studied outcome [37–41,43,44], followed by muscular strength
[37,38,40,43,44] and physical performance [37,40,43,44]. No study included cognitive outcomes.
Studies shared 11 out of the 40 measures analyzed. Body composition was examined using dual-
energy X-ray absorptiometry (DXA), bioelectrical impedance analysis (BIA), and computed
tomography (CT). Two studies [43,44] found positive effects in fat free mass using different
techniques, whilst three studies [37,40,41] found no differences between HMB and controls. HMB
supplementation had no effects on fatty mass in absolute terms when using DXA and BIA exams
[41,43,44]; in turn, the % of body fat loss after HMB supplementation increased when using skinfold
analysis [41]. Two studies [37,43] examined the abdominal fat mass with contradictory results.
Muscular strength included handgrip, knee flexion/extension by isokinetic, isometric and one
maximum repetition (1RM) measures, and bench/leg press exercises. Out of the five RCTs exploring
muscular strength, only one study [37] found positive effects of HMB supplementation in comparison
with controls. Physical performance was tested using the short physical performance battery (SPPB)
and its three component parts (sit-to-stand, gait speed 6 m, and get-up-and-go tests). No treatment
? + + + + !
+ + ? + ? !
+ + + + ? !
? ? ? + ? !
? ? + + — —
+ + + + ? !
? + + + ? !
? + + + — —
? + + + ? !
+ +
+
+ ? !
Nutrients 2019, 11, x FOR PEER REVIEW 8 of 18
3.2. Quality of Studies and Risk of Bias
No study was considered as low risk of bias in all categories. The greatest biases were found in
the concealment, randomization, and selection of the reported results. Two studies showed high risk
of bias in the selection of the reported results due to important discrepancies with the pre-registered
trial. Four studies did not provide a trial pre-registration or publication. Two studies showed partial
results from the pre-specified plan. A summary of the risk of bias assessment is shown in Table 4.
Table 4. Risk of bias of included studies.
Randomization Process
Deviations from
Intended Interventions
Missing Outcome Data
Measurement of the
Outcome
Selection of the Reported
Result
Overall Bias
Berton (2016)
Deutz (2013)
Din (2019)
Malafarina (2017)
Olveira (2015)
Standley (2017)
Stout (2013)
Stout (2015)
Vukovich (2001)
Nissen (2000)
Low risk of bias; Unclear risk of bias; High risk of bias.
3.3. Studies’ Outcomes and Results
Seven studies included data from the mean differences between control and HMB groups after
exercise training on different health measures, showing controversial results (Table 5). Body
composition was the most studied outcome [37–41,43,44], followed by muscular strength
[37,38,40,43,44] and physical performance [37,40,43,44]. No study included cognitive outcomes.
Studies shared 11 out of the 40 measures analyzed. Body composition was examined using dual-
energy X-ray absorptiometry (DXA), bioelectrical impedance analysis (BIA), and computed
tomography (CT). Two studies [43,44] found positive effects in fat free mass using different
techniques, whilst three studies [37,40,41] found no differences between HMB and controls. HMB
supplementation had no effects on fatty mass in absolute terms when using DXA and BIA exams
[41,43,44]; in turn, the % of body fat loss after HMB supplementation increased when using skinfold
analysis [41]. Two studies [37,43] examined the abdominal fat mass with contradictory results.
Muscular strength included handgrip, knee flexion/extension by isokinetic, isometric and one
maximum repetition (1RM) measures, and bench/leg press exercises. Out of the five RCTs exploring
muscular strength, only one study [37] found positive effects of HMB supplementation in comparison
with controls. Physical performance was tested using the short physical performance battery (SPPB)
and its three component parts (sit-to-stand, gait speed 6 m, and get-up-and-go tests). No treatment
? + + + + !
+ + ? + ? !
+ + + + ? !
? ? ? + ? !
? ? + + — —
+ + + + ? !
? + + + ? !
? + + + — —
? + + + ? !
+ +
+
+ ? !
Nutrients 2019, 11, x FOR PEER REVIEW 8 of 18
3.2. Quality of Studies and Risk of Bias
No study was considered as low risk of bias in all categories. The greatest biases were found in
the concealment, randomization, and selection of the reported results. Two studies showed high risk
of bias in the selection of the reported results due to important discrepancies with the pre-registered
trial. Four studies did not provide a trial pre-registration or publication. Two studies showed partial
results from the pre-specified plan. A summary of the risk of bias assessment is shown in Table 4.
Table 4. Risk of bias of included studies.
Randomization Process
Deviations from
Intended Interventions
Missing Outcome Data
Measurement of the
Outcome
Selection of the Reported
Result
Overall Bias
Berton (2016)
Deutz (2013)
Din (2019)
Malafarina (2017)
Olveira (2015)
Standley (2017)
Stout (2013)
Stout (2015)
Vukovich (2001)
Nissen (2000)
Low risk of bias; Unclear risk of bias; High risk of bias.
3.3. Studies’ Outcomes and Results
Seven studies included data from the mean differences between control and HMB groups after
exercise training on different health measures, showing controversial results (Table 5). Body
composition was the most studied outcome [37–41,43,44], followed by muscular strength
[37,38,40,43,44] and physical performance [37,40,43,44]. No study included cognitive outcomes.
Studies shared 11 out of the 40 measures analyzed. Body composition was examined using dual-
energy X-ray absorptiometry (DXA), bioelectrical impedance analysis (BIA), and computed
tomography (CT). Two studies [43,44] found positive effects in fat free mass using different
techniques, whilst three studies [37,40,41] found no differences between HMB and controls. HMB
supplementation had no effects on fatty mass in absolute terms when using DXA and BIA exams
[41,43,44]; in turn, the % of body fat loss after HMB supplementation increased when using skinfold
analysis [41]. Two studies [37,43] examined the abdominal fat mass with contradictory results.
Muscular strength included handgrip, knee flexion/extension by isokinetic, isometric and one
maximum repetition (1RM) measures, and bench/leg press exercises. Out of the five RCTs exploring
muscular strength, only one study [37] found positive effects of HMB supplementation in comparison
with controls. Physical performance was tested using the short physical performance battery (SPPB)
and its three component parts (sit-to-stand, gait speed 6 m, and get-up-and-go tests). No treatment
? + + + + !
+ + ? + ? !
+ + + + ? !
? ? ? + ? !
? ? + + — —
+ + + + ? !
? + + + ? !
? + + + — —
? + + + ? !
+ +
+
+ ? !
Nutrients 2019, 11, x FOR PEER REVIEW 8 of 18
3.2. Quality of Studies and Risk of Bias
No study was considered as low risk of bias in all categories. The greatest biases were found in
the concealment, randomization, and selection of the reported results. Two studies showed high risk
of bias in the selection of the reported results due to important discrepancies with the pre-registered
trial. Four studies did not provide a trial pre-registration or publication. Two studies showed partial
results from the pre-specified plan. A summary of the risk of bias assessment is shown in Table 4.
Table 4. Risk of bias of included studies.
Randomization Process
Deviations from
Intended Interventions
Missing Outcome Data
Measurement of the
Outcome
Selection of the Reported
Result
Overall Bias
Berton (2016)
Deutz (2013)
Din (2019)
Malafarina (2017)
Olveira (2015)
Standley (2017)
Stout (2013)
Stout (2015)
Vukovich (2001)
Nissen (2000)
Low risk of bias; Unclear risk of bias; High risk of bias.
3.3. Studies’ Outcomes and Results
Seven studies included data from the mean differences between control and HMB groups after
exercise training on different health measures, showing controversial results (Table 5). Body
composition was the most studied outcome [37–41,43,44], followed by muscular strength
[37,38,40,43,44] and physical performance [37,40,43,44]. No study included cognitive outcomes.
Studies shared 11 out of the 40 measures analyzed. Body composition was examined using dual-
energy X-ray absorptiometry (DXA), bioelectrical impedance analysis (BIA), and computed
tomography (CT). Two studies [43,44] found positive effects in fat free mass using different
techniques, whilst three studies [37,40,41] found no differences between HMB and controls. HMB
supplementation had no effects on fatty mass in absolute terms when using DXA and BIA exams
[41,43,44]; in turn, the % of body fat loss after HMB supplementation increased when using skinfold
analysis [41]. Two studies [37,43] examined the abdominal fat mass with contradictory results.
Muscular strength included handgrip, knee flexion/extension by isokinetic, isometric and one
maximum repetition (1RM) measures, and bench/leg press exercises. Out of the five RCTs exploring
muscular strength, only one study [37] found positive effects of HMB supplementation in comparison
with controls. Physical performance was tested using the short physical performance battery (SPPB)
and its three component parts (sit-to-stand, gait speed 6 m, and get-up-and-go tests). No treatment
? + + + + !
+ + ? + ? !
+ + + + ? !
? ? ? + ? !
? ? + + — —
+ + + + ? !
? + + + ? !
? + + + — —
? + + + ? !
+ +
+
+ ? !
Deutz (2013)
Nutrients 2019, 11, x FOR PEER REVIEW 8 of 18
3.2. Quality of Studies and Risk of Bias
No study was considered as low risk of bias in all categories. The greatest biases were found in
the concealment, randomization, and selection of the reported results. Two studies showed high risk
of bias in the selection of the reported results due to important discrepancies with the pre-registered
trial. Four studies did not provide a trial pre-registration or publication. Two studies showed partial
results from the pre-specified plan. A summary of the risk of bias assessment is shown in Table 4.
Table 4. Risk of bias of included studies.
Randomization Process
Deviations from
Intended Interventions
Missing Outcome Data
Measurement of the
Outcome
Selection of the Reported
Result
Overall Bias
Berton (2016)
Deutz (2013)
Din (2019)
Malafarina (2017)
Olveira (2015)
Standley (2017)
Stout (2013)
Stout (2015)
Vukovich (2001)
Nissen (2000)
Low risk of bias; Unclear risk of bias; High risk of bias.
3.3. Studies’ Outcomes and Results
Seven studies included data from the mean differences between control and HMB groups after
exercise training on different health measures, showing controversial results (Table 5). Body
composition was the most studied outcome [37–41,43,44], followed by muscular strength
[37,38,40,43,44] and physical performance [37,40,43,44]. No study included cognitive outcomes.
Studies shared 11 out of the 40 measures analyzed. Body composition was examined using dual-
energy X-ray absorptiometry (DXA), bioelectrical impedance analysis (BIA), and computed
tomography (CT). Two studies [43,44] found positive effects in fat free mass using different
techniques, whilst three studies [37,40,41] found no differences between HMB and controls. HMB
supplementation had no effects on fatty mass in absolute terms when using DXA and BIA exams
[41,43,44]; in turn, the % of body fat loss after HMB supplementation increased when using skinfold
analysis [41]. Two studies [37,43] examined the abdominal fat mass with contradictory results.
Muscular strength included handgrip, knee flexion/extension by isokinetic, isometric and one
maximum repetition (1RM) measures, and bench/leg press exercises. Out of the five RCTs exploring
muscular strength, only one study [37] found positive effects of HMB supplementation in comparison
with controls. Physical performance was tested using the short physical performance battery (SPPB)
and its three component parts (sit-to-stand, gait speed 6 m, and get-up-and-go tests). No treatment
? + + + + !
+ + ? + ? !
+ + + + ? !
? ? ? + ? !
? ? + + — —
+ + + + ? !
? + + + ? !
? + + + — —
? + + + ? !
+ +
+
+ ? !
Nutrients 2019, 11, x FOR PEER REVIEW 8 of 18
3.2. Quality of Studies and Risk of Bias
No study was considered as low risk of bias in all categories. The greatest biases were found in
the concealment, randomization, and selection of the reported results. Two studies showed high risk
of bias in the selection of the reported results due to important discrepancies with the pre-registered
trial. Four studies did not provide a trial pre-registration or publication. Two studies showed partial
results from the pre-specified plan. A summary of the risk of bias assessment is shown in Table 4.
Table 4. Risk of bias of included studies.
Randomization Process
Deviations from
Intended Interventions
Missing Outcome Data
Measurement of the
Outcome
Selection of the Reported
Result
Overall Bias
Berton (2016)
Deutz (2013)
Din (2019)
Malafarina (2017)
Olveira (2015)
Standley (2017)
Stout (2013)
Stout (2015)
Vukovich (2001)
Nissen (2000)
Low risk of bias; Unclear risk of bias; High risk of bias.
3.3. Studies’ Outcomes and Results
Seven studies included data from the mean differences between control and HMB groups after
exercise training on different health measures, showing controversial results (Table 5). Body
composition was the most studied outcome [37–41,43,44], followed by muscular strength
[37,38,40,43,44] and physical performance [37,40,43,44]. No study included cognitive outcomes.
Studies shared 11 out of the 40 measures analyzed. Body composition was examined using dual-
energy X-ray absorptiometry (DXA), bioelectrical impedance analysis (BIA), and computed
tomography (CT). Two studies [43,44] found positive effects in fat free mass using different
techniques, whilst three studies [37,40,41] found no differences between HMB and controls. HMB
supplementation had no effects on fatty mass in absolute terms when using DXA and BIA exams
[41,43,44]; in turn, the % of body fat loss after HMB supplementation increased when using skinfold
analysis [41]. Two studies [37,43] examined the abdominal fat mass with contradictory results.
Muscular strength included handgrip, knee flexion/extension by isokinetic, isometric and one
maximum repetition (1RM) measures, and bench/leg press exercises. Out of the five RCTs exploring
muscular strength, only one study [37] found positive effects of HMB supplementation in comparison
with controls. Physical performance was tested using the short physical performance battery (SPPB)
and its three component parts (sit-to-stand, gait speed 6 m, and get-up-and-go tests). No treatment
? + + + + !
+ + ? + ? !
+ + + + ? !
? ? ? + ? !
? ? + + — —
+ + + + ? !
? + + + ? !
? + + + — —
? + + + ? !
+ +
+
+ ? !
Nutrients 2019, 11, x FOR PEER REVIEW 8 of 18
3.2. Quality of Studies and Risk of Bias
No study was considered as low risk of bias in all categories. The greatest biases were found in
the concealment, randomization, and selection of the reported results. Two studies showed high risk
of bias in the selection of the reported results due to important discrepancies with the pre-registered
trial. Four studies did not provide a trial pre-registration or publication. Two studies showed partial
results from the pre-specified plan. A summary of the risk of bias assessment is shown in Table 4.
Table 4. Risk of bias of included studies.
Randomization Process
Deviations from
Intended Interventions
Missing Outcome Data
Measurement of the
Outcome
Selection of the Reported
Result
Overall Bias
Berton (2016)
Deutz (2013)
Din (2019)
Malafarina (2017)
Olveira (2015)
Standley (2017)
Stout (2013)
Stout (2015)
Vukovich (2001)
Nissen (2000)
Low risk of bias; Unclear risk of bias; High risk of bias.
3.3. Studies’ Outcomes and Results
Seven studies included data from the mean differences between control and HMB groups after
exercise training on different health measures, showing controversial results (Table 5). Body
composition was the most studied outcome [37–41,43,44], followed by muscular strength
[37,38,40,43,44] and physical performance [37,40,43,44]. No study included cognitive outcomes.
Studies shared 11 out of the 40 measures analyzed. Body composition was examined using dual-
energy X-ray absorptiometry (DXA), bioelectrical impedance analysis (BIA), and computed
tomography (CT). Two studies [43,44] found positive effects in fat free mass using different
techniques, whilst three studies [37,40,41] found no differences between HMB and controls. HMB
supplementation had no effects on fatty mass in absolute terms when using DXA and BIA exams
[41,43,44]; in turn, the % of body fat loss after HMB supplementation increased when using skinfold
analysis [41]. Two studies [37,43] examined the abdominal fat mass with contradictory results.
Muscular strength included handgrip, knee flexion/extension by isokinetic, isometric and one
maximum repetition (1RM) measures, and bench/leg press exercises. Out of the five RCTs exploring
muscular strength, only one study [37] found positive effects of HMB supplementation in comparison
with controls. Physical performance was tested using the short physical performance battery (SPPB)
and its three component parts (sit-to-stand, gait speed 6 m, and get-up-and-go tests). No treatment
? + + + + !
+ + ? + ? !
+ + + + ? !
? ? ? + ? !
? ? + + — —
+ + + + ? !
? + + + ? !
? + + + — —
? + + + ? !
+ +
+
+ ? !
Nutrients 2019, 11, x FOR PEER REVIEW 8 of 18
3.2. Quality of Studies and Risk of Bias
No study was considered as low risk of bias in all categories. The greatest biases were found in
the concealment, randomization, and selection of the reported results. Two studies showed high risk
of bias in the selection of the reported results due to important discrepancies with the pre-registered
trial. Four studies did not provide a trial pre-registration or publication. Two studies showed partial
results from the pre-specified plan. A summary of the risk of bias assessment is shown in Table 4.
Table 4. Risk of bias of included studies.
Randomization Process
Deviations from
Intended Interventions
Missing Outcome Data
Measurement of the
Outcome
Selection of the Reported
Result
Overall Bias
Berton (2016)
Deutz (2013)
Din (2019)
Malafarina (2017)
Olveira (2015)
Standley (2017)
Stout (2013)
Stout (2015)
Vukovich (2001)
Nissen (2000)
Low risk of bias; Unclear risk of bias; High risk of bias.
3.3. Studies’ Outcomes and Results
Seven studies included data from the mean differences between control and HMB groups after
exercise training on different health measures, showing controversial results (Table 5). Body
composition was the most studied outcome [37–41,43,44], followed by muscular strength
[37,38,40,43,44] and physical performance [37,40,43,44]. No study included cognitive outcomes.
Studies shared 11 out of the 40 measures analyzed. Body composition was examined using dual-
energy X-ray absorptiometry (DXA), bioelectrical impedance analysis (BIA), and computed
tomography (CT). Two studies [43,44] found positive effects in fat free mass using different
techniques, whilst three studies [37,40,41] found no differences between HMB and controls. HMB
supplementation had no effects on fatty mass in absolute terms when using DXA and BIA exams
[41,43,44]; in turn, the % of body fat loss after HMB supplementation increased when using skinfold
analysis [41]. Two studies [37,43] examined the abdominal fat mass with contradictory results.
Muscular strength included handgrip, knee flexion/extension by isokinetic, isometric and one
maximum repetition (1RM) measures, and bench/leg press exercises. Out of the five RCTs exploring
muscular strength, only one study [37] found positive effects of HMB supplementation in comparison
with controls. Physical performance was tested using the short physical performance battery (SPPB)
and its three component parts (sit-to-stand, gait speed 6 m, and get-up-and-go tests). No treatment
? + + + + !
+ + ? + ? !
+ + + + ? !
? ? ? + ? !
? ? + + — —
+ + + + ? !
? + + + ? !
? + + + — —
? + + + ? !
+ +
+
+ ? !
Nutrients 2019, 11, x FOR PEER REVIEW 8 of 18
3.2. Quality of Studies and Risk of Bias
No study was considered as low risk of bias in all categories. The greatest biases were found in
the concealment, randomization, and selection of the reported results. Two studies showed high risk
of bias in the selection of the reported results due to important discrepancies with the pre-registered
trial. Four studies did not provide a trial pre-registration or publication. Two studies showed partial
results from the pre-specified plan. A summary of the risk of bias assessment is shown in Table 4.
Table 4. Risk of bias of included studies.
Randomization Process
Deviations from
Intended Interventions
Missing Outcome Data
Measurement of the
Outcome
Selection of the Reported
Result
Overall Bias
Berton (2016)
Deutz (2013)
Din (2019)
Malafarina (2017)
Olveira (2015)
Standley (2017)
Stout (2013)
Stout (2015)
Vukovich (2001)
Nissen (2000)
Low risk of bias; Unclear risk of bias; High risk of bias.
3.3. Studies’ Outcomes and Results
Seven studies included data from the mean differences between control and HMB groups after
exercise training on different health measures, showing controversial results (Table 5). Body
composition was the most studied outcome [37–41,43,44], followed by muscular strength
[37,38,40,43,44] and physical performance [37,40,43,44]. No study included cognitive outcomes.
Studies shared 11 out of the 40 measures analyzed. Body composition was examined