Health Benefits of β-Hydroxy-β-Methylbutyrate (HMB) Supplementation in Addition to Physical Exercise in Older Adults: A Systematic Review with Meta-Analysis

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.

Full text

Nutrients 2019, 11, 2082; doi:10.3390/nu11092082 www.mdpi.com/journal/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. Pallarés
1
and Michal Steffl
2
1
Human Performance and Sports Science Laboratory, Faculty of Sport Sciences, University of Murcia,
30100 Murcia, Spain
2
Faculty of Physical Education and Sport, Charles University, Prague 16252, Czech Republic
* Correspondence: javier.courel.ibanez@gmail.com; Tel.: +34-655-27-03-15
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 2 of 18
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).
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

Nutrients 2019, 11, 2082 3 of 18
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 5
Indicate 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 18
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 5 of 18
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 1 shows
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 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)

Nutrients 2019, 11, 2082 5 of 18
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) a EG = 8
CG = 8 Healthy 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 x
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) a EG = 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 x 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) a EG = 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 b EG = 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 b EG = 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 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
effects were observed between exercise alone or combined with HMB supplementation in any
physical performance measure except for the 6-min walking test [37].
? + + + + !
+ + ? + ? !
+ + + + ? !
? ? ? + ? !
? ? + + — —
+ + + + ? !
? + + + ? !
? + + + — —
? + + + ? !
+ + + + ? !

Nutrients 2019, 11, 2082 9 of 18
Table 5. Effect of beta-hydroxy-beta-methylbutyrate (HMB) on health parameters.
Outcome Measure Overall effect * Study
Physical performance
SPPB No effect Berton (2015)
No effect
a Deutz (2013)
6-min walking test Positive Berton (2015)
Gait speed No effect Malafarina (2017)
Get-up-and-go No effect Stout (2013)
No effect
a Deutz (2013)
Muscular strength
Isokinetic knee flexion Positive Berton (2015)
No effect Stout (2013)
Isokinetic knee extension Positive Berton (2015)
No effect Stout (2013)
No effect Din (2019)
No effect
a Deutz (2013)
Isometric knee extension Positive Berton (2015)
Handgrip strength
No effect Berton (2015)
No effect Malafarina (2017)
No effect Stout (2013)
Handgrip strength endurance Positive Berton (2015)
Handgrip work index No effect Malafarina (2017)
Knee extension, 1RM No effect Din (2019)
Bench press, 5RM No effect Stout (2013)
Leg press, 5RM No effect Stout (2013)
Leg extensor, 5RM No effect Stout (2013)
Body composition
Fat free mass (DXA)
No effect Berton (2015)
Positive b Stout (2013)
No effect Vukovich (2001)
No effect
a Deutz (2013)
Fat free mass (BIA) Positive Malafarina (2017)
Fat free mass (Skin fold thickness) No effect Vukovich (2001)
ASMMI No effect Berton (2015)
Muscle mass (BIA) Positive Malafarina (2017)
Appendicular lean mass (BIA) Positive Malafarina (2017)
Skeletal muscle mass (BIA) No effect Malafarina (2017)
ASMM (BIA) Positive Malafarina (2017)
Fatty mass (DXA) No effect Stout (2013)
Fatty mass (BIA) No effect Malafarina (2017)
Fatty mass % (Skin fold thickness) Positive Vukovich (2001)
Fatty mass % (DXA) No effect Vukovich (2001)
Leg lean mass (DXA) No effect Stout (2013)
No effect
a Deutz (2013)
Arm lean mass (DXA) Positive b Stout (2013)
Abdominal fat mass (DXA) No effect Berton (2015)
Positive Stout (2015)
Radial muscle density (CT) Positive Berton (2015)
Radial muscle area (CT) No effect Berton (2015)
Radial fat area (CT) No effect Berton (2015)
Radial fat/muscle ratio (CT) Positive Berton (2015)
Tibial muscle density (CT) Positive Berton (2015)
Tibial muscle area (CT) No effect Berton (2015)
Tibial fat area (CT) No effect Berton (2015)
Tibial fat/muscle ratio (CT) No effect Berton (2015)
Fat area (CT) Positive Vukovich (2001)
Muscle area (CT) No effect Vukovich (2001)
Cross-sectional area (VLB) No effect a Standley (2017)
Thigh lean mass (DXA) No effect Din (2019)
Vastus lateralis thickness (DXA) No effect Din (2019)
Others
Muscle quality (Isokinetic knee extension 60°) No effect Stout (2013)
Muscle quality (Isokinetic knee extension 180°) No effect Stout (2013)
Muscle quality (Handgrip strength) No effect Stout (2013)
Proteins expression (histology) Positive a Standley (2017)
* HMB effect compared to CG (p < 0.05); a Bed rest + rehabilitation; b male only; RM—Repetition
maximum; MVC—Maximal voluntary contraction; ASMMI—Appendicular skeletal muscle mass
index; ALM—Appendicular lean mass; ASMM—Appendicular skeletal muscle mass; Muscle

Nutrients 2019, 11, 2082 10 of 18
quality—Muscle strength relative to muscle mass; DXA—Dual X-ray absorptiometry; CT—
Computed tomography; BIA—Bioelectrical impedance analysis; VLB—Vastus lateralis biopsy.
3.4. Meta-Analyses
Out of all the meta-analyses, handgrip strength (Figure 2) was the only outcome close to showing
statistical significance but with a small effect size (ES = 0.19 (95% CI: −0.03 to 0.40) p = 0.067). This
result almost significantly favors the HMB supplementation against placebo with the smallest
heterogeneity possible (I2 = 0%). On the other hand, the effect of HMB was not significantly harmful
to leg strength (ES = −0.78 (95% CI: −3.16 to 1.59) p = 0.291). However, there was very high
heterogeneity, I2 = 91.6% (Figure 3). Almost no effect was found in muscle mass (ES = 0.07 (95% CI
−0.69 to 0.82_ p = 0.833, I2 = 90.6) (Figure 4). A positive non-significant effect of HMB was found in fat
mass (ES = 0.61 (95% CI −0.73 to 1.96) p = 0.293, I2 = 84.1) (Figure 5). When muscle and strength were
calculated together, HMB did not have any effect (ES = −0.06 (95% CI: −0.82 to 0.71) p = 0.853, I2 = 85.8)
(Figure 6).
Figure 2. Effects meta-analysis of HMB on handgrip strength. Squares are effect sizes. The area of
each square is proportional to the study’s weight in the meta-analysis. Vertical line and diamond
indicate the overall measure of effects and confidence intervals.
Forest Plot
Studies Effect Size Weight
Berton 2015
Handgrip
Malafarina 2017
Handgrip
Olveira 2016
Handgrip
Stout 2013
Handgrip
0.271
0.088
0.109
0.303
16.098
18.469
7.489
8.789
−1 −0.5 0 0.5 1
Effect Size

Nutrients 2019, 11, 2082 11 of 18
Figure 3. Effects meta-analysis of HMB on leg strength. Squares are effect sizes. The area of each
square is proportional to the study’s weight in the meta-analysis. Vertical line and diamond indicate
the overall measure of effects and confidence intervals.
Figure 4. Effects meta-analysis of HMB on muscle mass. Squares are effect sizes. The area of each
square is proportional to the study’s weight in the meta-analysis. Vertical line and diamond indicate
the overall measure of effects and confidence intervals.
Forest Plot
Studies Effect Size Weight
Berton 2015
Chair stand
Knee ext isokinet ic
Knee ext isometric
Knee flex isokinetic
Din 2019
Knee ext 1RM
Knee ext isokinetic
Stout 2013
Leg press, 5RM
Leg ext, 5RM
Knee ext isokinetic 60°
Knee flex isokinetic 180°
Knee f lex isokinetic 60°
Knee ext isokinetic 180°
−0.432
0.534
0.548
0.338
−1.682
−1.112
0.572
−0.652
−2.494
−0.888
−2.217
−2.118
0.141
0.141
0.141
0.141
0.247
0.247
0.090
0.090
0.090
0.090
0.090
0.090
−4 −3 − 2 −1 0 1 2
Effect Size
Forest Plot
Studies Effect Size Weig ht
Berton 2015
ASMMI DXA
FFM DXA
Din 2019
FFM in training leg DXA
Malafarina 2017
ASM M BIA
FFM BI A
ASM M BIA
Olveira 2016
FFM DXA
FFMI DXA
Stout 2013
FFM DXA
Vukovich 2001
FFM Skinfold
FFM DXA
Muscle area CT
0.372
0.156
0.257
0.095
0.127
0.095
0.085
0.138
−1.283
2.435
0.487
0.000
0.969
0.969
1.417
0.656
0.656
0.656
0.852
0.852
1.698
0.540
0.540
0.540
−3 −2 −1 0 1 2 3 4
Effec t Size

Nutrients 2019, 11, 2082 12 of 18
Figure 5. Effects meta-analysis of HMB on fat mass. Squares are effect sizes. The area of each square
is proportional to the study’s weight in the meta-analysis. Vertical line and diamond indicate the
overall measure of effects and confidence intervals.
Figure 6. Effects meta-analysis of HMB on muscle mass and strength. Squares are effect sizes. The
area of each square is proportional to the study’s weight in the meta-analysis. Vertical line and
diamond indicate the overall measure of effects and confidence intervals.
Forest Plot
Studies Effect Size Weight
Berton 2015
Abdominal FM DXA
Malafarina 2017
FM BIA
Olveira 2016
FM DXA
Stout 2013
FM DXA
Stout 2015
Abdominal FM DXA
Vukovich 2001
BF % Skinfold
FM DXA
Fat area CT
−0.291
−0.426
−0.016
1.125
0.501
2.829
1.704
5.449
0.884
0.889
0.831
0.834
0.806
0.235
0.235
0.235
0 2 4 6
Effect Size
Forest Plot
Studies Effect Size Weight
Berton 2015
Handg rip
ASMMI DXA
FFM DXA
Chair st and
Knee ext isokinetic
Knee ext isometric
Knee flex isokinetic
Din 2019
FFM in training leg DXA
Knee ext 1RM
Knee ext isokinetic
Malafarina 2017
Handg rip
ASM M BIA
FFM BIA
ASM M BIA
Olveira 2016
Handg rip
FFM DXA
FFMI DXA
Stout 2013
Handg rip
FFM DXA
Leg press, 5RM
Leg ext, 5RM
Knee ext isokinetic 60°
Knee flex isokinetic 180°
Knee flex isokinetic 60°
Knee ext isokinetic 180°
Vukovich 2001
FFM Skinfold
FFM DXA
Muscle ar ea CT
0.271
0.372
0.156
−0.432
0.534
0.548
0.338
0.257
−1.682
−1.112
0.088
0.095
0.127
0.095
0.109
0.085
0.138
0.303
−1.283
0.572
−0.652
−2.494
−0.888
−2.217
−2.118
2.435
0.487
0.000
0.191
0.191
0.191
0.191
0.191
0.191
0.191
0.341
0.341
0.341
0.338
0.338
0.338
0.338
0.407
0.407
0.407
0.151
0.151
0.151
0.151
0.151
0.151
0.151
0.151
0.393
0.393
0.393
−4 −2 0 2 4
Effect Size

Nutrients 2019, 11, 2082 13 of 18
4. Discussion
The results from this review with meta-analysis suggest 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. These findings
reinforce the effectiveness of supervised and controlled exercise, alone or combined with HMB
supplementation, to enhance health and functionality in older adults. Whereas the nutritional
supplementation strategy was very similar among studies (3 g/d of HMB), the heterogeneity of the
exercise programs (type, frequency, volume, and intensity) render the comparison between
interventions difficult, which encourages replication. Finally, we identified an important gap in the
literature relating to the combination of HMB and exercise and its impact to reduce cognitive
impairment, as well as limited studies examining physical performance variables and including frail
people, over 80 years and with very limited or no mobility.
Previous reviews have evidenced that the oral supplementation of HMB is an effective
nutritional therapy to mitigate the decline in muscle mass and preserve muscle function in older
adults and frail people, especially during hospital rehabilitation and recovery [20,24,25,46,47].
However, to the best of our knowledge, this is the first time comparing the impact of HMB as a
nutritional strategy to optimize physical exercise interventions. Our findings revealed no critical
differences in favor of HMB supplementation compared to placebo in muscle mass and strength
improvements, when provided during an exercise training program. Whereas this does not
contradict the promising benefits of HMB supplementation to improve lean muscle mass and
preserve muscle strength in older adults, it seems to indicate that physical exercise may produce
similar—and likely more—benefits to improve muscle and strength in healthy older people,
especially if including a properly designed resistance training program [48,49].
The length of studies varied from 3 to 24 weeks. The majority of interventions included
resistance training as the main part of the exercise program and lasted 8 weeks with a frequency of 2
to 3 sessions per week. Interestingly, from the five studies showing positive effects of HMB
supplementation (Table 3), one was the shortest in duration (40 ± 20 days), but the one with the
highest training frequencies (5 days a week) [44], another was the longest (24 weeks) [43], and the
other three included an 8-week program, two with 2 sessions/week [37,41] and one with 3 sessions
per week after a bed rest period [39]. While all these studies provided an optimal HMB dosage and
met the general recommendations of resistance training in older adults, the particular adaptations in
the program (frequency, intensity, and exercise modifications) to specific individual needs and
capabilities of each older adult (e.g., frailty, mobility limitations, or osteoporosis) may account for the
greater effects on health [48,49].
It is important to note that there is very limited information relating to the effects of combining
HMB and exercise in frail people or with reduced mobility. In the current review, only two studies
explored people with physical limitations, such as hip fracture [44] and non-cystic fibrosis
bronchiectasis [36], both showing greater muscle and strength improvements after HMB
supplementation. The fact that one short intervention on patients with a hip fracture found benefits
in body composition after less than 6 weeks of a high frequency exercise intervention may indicate a
potential positive effect of acute HMB supplementation during rehabilitation programs to help old
people in recovering functional capacity after a fall. Previous interventions in older adults who
underwent orthopedic surgery found that HMB accelerated wound healing, reduced dependence on
bed and immobilization period, and increased muscle strength [50]. Furthermore, a pilot non-
randomized control trial on sarcopenic patients with gastric cancer found that a preoperative home-
based, daily exercise program (handgrip training, walking, and resistance training), with nutritional
support including HMB, reduced sarcopenia and postoperative complications [51]. HMB has
antioxidant and anti-inflammatory properties that ameliorate muscle loss by stimulating protein
synthesis and by decreasing proteolysis [20,52,53]. Thus, it seems that HMB supplementation in
addition to exercise would be particularly effective to optimize physical rehabilitation treatments and
accelerate mobility recovery in frail people and muscle wasting conditions. Although evidence
supporting the positive impact of HMB to enhance exercise training adaptations and increase health

Nutrients 2019, 11, 2082 14 of 18
benefits in frail or sarcopenic people is lacking, the results of ongoing clinical trials [54–56] will likely
provide additional evidence in the near future to support treatment choices for older people.
We found no study examining the effects of HMB and exercise to reduce older adults’ cognitive
impairment. Since the appearance of HMB in the brain was detected [57], there is growing interest in
its beneficial cognitive effects in aging [26–28,58–60]. Animal models suggest that HMB promotes
neurite outgrowth in vitro, which is related to neuronal survival and differentiation [60], and
ameliorates age-related cognitive deficits [27,58,59]. These findings encourage ongoing research into
the benefits of HMB and its mechanism of action on the neuromuscular system in aging [28].
This meta-analysis has some limitations that should be noted. Although overall the quality of
the studies was sufficient, some trials included in this review were at some risk of bias and should be
treated with caution. Only one study examined a women sample, with the majority including both
men and women with no gender distinction, which makes comparisons impossible. Furthermore, the
studies included employed a variety of measures and techniques, which may provide different
results and, thus, make comparisons between data sets difficult, encouraging replication.
Nevertheless, all of them used standard protocols and high-quality equipment. While all the studies
provided a similar dosage of HMB and included resistance training as a main part of the exercise
interventions, there was substantial differences in the type, frequency, volume, and intensity of the
programs. Future studies should investigate the effects of HMB and exercise through tailored,
evidence-based resistance training for older adults, with a particular interest in adapted programs
for people with frailty, mobility limitations, cognitive impairment, or other chronic conditions.
5. Conclusions
Physical exercise and HMB supplementation are two effective treatments to reduce muscle
wasting and maintain or improve muscle mass in older people. This is the first systematic review and
meta-analysis of RCTs examining the health benefits of combining HMB in addition to physical
training in older adults. HMB seems to produce no extra improvements to exercise in physical
performance, muscular strength and body composition in people aged 50 to 80 years. There is no
study to date exploring 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
these findings to particular populations, ages, and health status. Specifically, results from
interventions of HMB combined with exercise in older people with frailty, limited mobility, and/or
cognitive impairment are required.
Author Contributions: Conceptualization, J.C.I. and M.S.; methodology, T.V., and M.C.; formal analysis, T.V.
and M.C.; investigation, J.C.I., K.D., and J.G.P.; writing—original draft preparation, J.C.I. and M.C.; writing—
review and editing, all authors.
Funding: This meta-analysis was supported by the research grants of Charles University, Czech Republic
(PRIMUS/19/HUM/012 and the project Q41) and by the Autonomous Community of the Region of Murcia,
Regional Program for the Promotion of Scientific and Technical Research (Action Plan 2018), Seneca Foundation-
Agency of Science and Technology, Region of Murcia (ID: 20872/PI/18).
Conflicts of Interest: The authors declare no conflict of interest. The funders had no role in the design of the
study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to
publish the results.
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