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Abstract and Figures

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.
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Nutrients 2019, 11, 2082; doi:10.3390/nu11092082
Health Benefits of β-Hydroxy-β-Methylbutyrate
(HMB) Supplementation in Addition to Physical
Exercise in Older Adults: A Systematic Review with
Javier Courel-Ibáñez
*, Tomas Vetrovsky
, Klara Dadova
, Jesús G. Pallarés
and Michal Steffl
Human Performance and Sports Science Laboratory, Faculty of Sport Sciences, University of Murcia,
30100 Murcia, Spain
Faculty of Physical Education and Sport, Charles University, Prague 16252, Czech Republic
* Correspondence:; 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].
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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 1 Identify the report as a systematic review, meta-analysis, or both. 1
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.
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
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.
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.
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
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.
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.
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
analyses 16 Describe methods of additional analyses (e.g., sensitivity or subgroup analyses,
meta-regression), if done, indicating which were pre-specified. 5
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
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.
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
analysis 23 Give results of additional analyses, if done (e.g., sensitivity or subgroup
analyses, meta-regression (see item 16)). 9
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).
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 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
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Table 2. Search results from electronic databases.
Database Keywords Records
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”))
((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 *))))
Web of
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 *)))
* 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.
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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.
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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
Included Eli
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
(n = 7)
(n = 176)
(n = 474)
Web of Science
(n = 286)
Additional papers
identified from references
(n = 2)
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Table 3. Studies included in the analyses.
Study Length Age Sample Participants Supplementation Compliance SAEs Control Exercise
(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)
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
(2019) 6 weeks 68.5 (1.1) a EG = 8
CG = 8 Healthy men 1.0 g/d HMB-FA in
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)
42.3 ±
20.9 days 85.4 (6.3) EG = 49
CG = 43
Patients with a hip
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
5 × a week, 50-min supervised rehabilitation therapy. Exercises to
strengthen the lower limbs, balance exercises, and walking re-
training in individual or group
(2015) 12 weeks 56.1 (1.3) EG = 15
CG = 15
Patients with non-
cystic fibrosis
60% women
1.5 g/d Ca-HMB in
Ensure Plus Advance
enriched with 25(OH)D
227 IU/100 mL
Exercise: 100% N.R. Standard
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)
(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
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)
(2015) † 12 weeks 72.1 (5.7) EG = 12
CG = 12 Healthy men 3.0 g/d Ca-HMB + 8g/d
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)
(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
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
(2013) *
(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
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
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].
? + + + + !
+ + ? + ? !
+ + + + ? !
? ? ? + ? !
? ? + +
+ + + + ? !
? + + + ? !
? + + +
? + + + ? !
+ + + + ? !
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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)
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
Malafarina 2017
Olveira 2016
Stout 2013
−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°
−4 −3 2 −1 0 1 2
Effect Size
Forest Plot
Studies Effect Size Weig ht
Berton 2015
Din 2019
FFM in training leg DXA
Malafarina 2017
Olveira 2016
Stout 2013
Vukovich 2001
FFM Skinfold
Muscle area CT
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 studys 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
Olveira 2016
Stout 2013
Stout 2015
Abdominal FM DXA
Vukovich 2001
BF % Skinfold
Fat area CT
0 2 4 6
Effect Size
Forest Plot
Studies Effect Size Weight
Berton 2015
Handg rip
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
Olveira 2016
Handg rip
Stout 2013
Handg rip
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
Muscle ar ea CT
−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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... In consideration of the lack of data on HMB supplementation in patients with liver cirrhosis, a pilot study was designed to collect data that can eventually be utilized in the design of future trials. A sample size of 14 subjects for each arm was chosen based on studies previously performed in other patient populations [30]. All clinical, laboratory, and instrumental data of the patients were collected in a pre-established database in accordance with the laws for the protection of privacy. ...
... In accordance with the study by Vallejo et al. [34] on the intracellular metabolic effects of HMB in mouse models and in agreement with the meta-analysis by Holeček et al. [35] on human studies, HMB appears to act mainly on muscle function rather than on muscle mass [30,36,37]. ...
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Background and aim: Sarcopenia is considered an important risk factor for morbidity and mortality in liver cirrhosis. Beta-hydroxy-beta-methylbutyrate (HMB) has the potential to increase muscle mass and performance by stimulating protein synthesis and reducing muscle catabolism. The present study aimed at evaluating the effect of HMB supplementation on muscle mass and function in patients with liver cirrhosis. Changes in frailty during the study were also estimated, and the safety of HMB supplementation was verified. Methods: This is a randomized, single-blind, placebo-controlled pilot trial. Twenty-four patients (14 HMB and 10 placebo) affected by liver cirrhosis were enrolled in the study. Each patient received dedicated counseling, which included nutrition and physical activity recommendations for chronic liver disease patients. Patients were randomized to receive 3 g/day of HMB or placebo (sorbitol powder) for 12 consecutive weeks. A diet interview, anthropometry, electrical bioimpedance analysis (BIA), quadriceps ultrasound, physical performance battery, Liver Frailty Index (LFI), and cognitive tests were completed at enrolment (T0), at 12 weeks (T1), and 24 weeks after enrolment (T2). Results: At baseline, the two groups were similar in demography, severity of liver disease, muscle mass, muscle function, and cognitive tests. LFI at baseline was higher in patients in the HMB group vs. those in the placebo group (4.1 ± 0.4 vs. 3.4 ± 0.6, p < 0.01). After treatment, a statistically significant increase in muscle function was seen in the HMB group (chair stand test: 14.2 ± 5 s vs. 11.7 ± 2.6 s, p < 0.05; six-minute walk test: 361.8 ± 68 m vs. 409.4 ± 58 m, p < 0.05). Quadriceps muscle mass measured by ultrasound also increased (4.9 ± 1.8 vs. 5.4 ± 1.8 mm, p < 0.05) after HMB, while LFI decreased (4.1 ± 0.4 vs. 3.7 ± 0.4, p < 0.05). HMB was well tolerated by patients, and no adverse events were documented. Conclusions: Our study suggests the efficacy of 12-week beta-hydroxy-beta-methylbutyrate supplementation in promoting improvements in muscle performance in compensated cirrhotic patients. LFI was also ameliorated. Further studies with a greater number of patients are required to reinforce this hypothesis.
... A recent meta-analysis has suggested that the addition of HMB supplementation to exercise is particularly effective in promoting recovery from exercise and optimizing it in older adults with muscle-wasting conditions (30). Thus, we designed this trial expecting to detect synergistic effects of exercise and HMB on changes in muscle mass parameters in older women with low muscle mass, but no significant main effects or interactions were observed ( Table 2). ...
... The per-protocol analysis showed that HMB increased upper-extremity muscle mass by 0.06 kg, which is within the measurement error because it is difficult for the Inbody 720 to accurately detect very small changes. Several RCTs have reported that adding HMB supplementation to exercise increases muscle mass more than exercise alone (7,8); however, recent meta-analyses have concluded that, compared with exercise alone, combining HMB supplementation with exercise has no effect or an exceedingly small effect on increasing muscle mass in older adults (30,31). Our results are consistent with these metaanalyses. ...
Background: The interaction between exercise and nutritional supplementation is unclear among older adults at risk of sarcopenia. Objectives: We aimed to examine if β-hydroxy-β-methylbutyrate (HMB) supplementation enhances the effects of exercise on muscle mass, strength, and physical performance and observe potential residual effects in older women with low muscle mass. Methods: This 12-wk, randomized, double-blind, placebo-controlled, 2 × 2 factorial design (exercise-only, HMB-only, both, and none) trial included 156 women aged 65-79 y with skeletal muscle index <5.7 kg/m2, and was followed by a 12-wk observational period. Resistance training twice weekly or education programs every 2 wk and calcium-HMB (1500 mg) or placebo supplements daily were provided. The primary outcome was the change in muscle mass from baseline to postintervention. Secondary outcomes included changes in muscle strength and physical performance. Results: In total, 149 and 144 participants completed the assessment at weeks 12 and 24, respectively. ANOVAs based on the intention-to-treat principle showed no significant interactions between exercise and HMB on any primary outcomes. The main-effect analyses revealed that exercise improved the usual and maximal gait speed by 0.16 m/s (95% CI: 0.10, 0.21 m/s) and 0.15 m/s (95% CI: 0.09, 0.22 m/s), respectively; the knee extensor and hip adductor strength by 22.0 N (95% CI: 10.1, 33.9 N) and 21.8 N (95% CI: 12.9, 30.7 N), respectively; and timed up-and-go and sit-to-stand time by -0.5 s (95% CI: -0.7, -0.3 s) and -1.7 s (95% CI: -2.1, -1.3 s), respectively, relative to education. HMB improved usual gait speed by 0.06 m/s (95% CI: 0.01, 0.11 m/s) relative to placebo. Most improvements disappeared during the subsequent 12-wk observation period. Conclusions: HMB additively improved gait performance with negligible benefit and provided no enhancements in the effects of exercise on other outcomes. Exercise appeared to be the only effective intervention to improve outcomes in older women with low muscle mass.This trial was registered at UMIN000028560.
... Another physiological change related to aging is a gradual loss of motor neurons, which promotes a decline in muscle fiber number and size, resulting in impaired mechanical muscle performance, including reduction in muscle strength [1]. To compensate these age-induced losses, resistance training plays a key role in promoting adaptive changes in muscle and nervous system function that reflect in increased muscle strength [1,4,39,40]. Thereby, resistance training is considered the most potent non-pharmacological stimulus to improve muscle strength. ...
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Background: There are some controversial findings regarding the benefits of combining protein supplementation with resistance training in order to optimize adaptations to training in older adults. Objective: The aim of this review was to summarize the evidence from meta-analyses assessing the effects of protein supplementation combined with resistance training on body composition and muscle strength in the older population. Methods: We included systematic reviews with meta-analyses of randomized clinical trials that examined the effects of protein and/or amino acid supplementation associated with resistance training compared with resistance training alone on lean body mass, muscle mass, and muscle strength in older people. The search was performed using the MEDLINE (PubMed), Embase, Cochrane Database of Systematic Reviews, Google Scholar, and OpenGrey databases. Methodological quality was assessed using the Assessing the Methodological Quality of Systematic Reviews 2 checklist, and the quality of evidence was determined using the Grading of Recommendations Assessment, Development and Evaluation system. The pooled effect estimates were computed from the standardized mean difference and the 95% confidence interval achieved by each meta-analysis, using random effects models. Results: Five reviews were included, all of moderate methodological quality. In the analyses, protein supplementation combined with resistance training was associated with greater increases in lean body mass and muscle mass when compared with resistance training alone. However, no differences were observed between the interventions on muscle strength increases. The quality of evidence ranged from moderate to very low. Conclusion: Protein supplementation associated with resistance training induces greater increases in lean body mass compared with resistance training alone. In addition, it is suggested that the use of protein supplementation enhances gains in muscle mass but does not promote greater increases in muscle strength.
... This has led to HMB being increasingly used in clinical practice 42 . However, several studies have concluded that HMB supplementation could not markedly improve body composition or performance in young adults and older adults who loves sports 43,44 . Still, increasing evidence suggests that HMB treatment can improve muscle mass in patients with chronic diseases such as chronic obstructive pulmonary disease, cancer, and malnutrition 45 . ...
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Objectives: To evaluate the efficacy of resistance training (RT) combined with beta-hydroxy-beta-methylbutyric acid (HMB) in the treatment of elderly patients with sarcopenia after hip replacement. Methods: From January 1, 2018 to December 31, 2018, 200 elderly patients (68 men, mean age 76.3 years and 137 women, mean age 79.1 years) who experienced femoral neck fracture with sarcopenia after hip arthroplasty were assigned to four groups: RT + HMB group, RT group, HMB group, and negative control group. Baseline data, body composition, grip strength, Barthel index (BI), Harris hip score (HHS), and visual analog scale score (VAS) were compared among the four groups before and 3 months after surgery. Results: A total of 177 participants completed the trial, including 43 in the HMB + RT group, 44 in the HMB group, 45 in the RT group, and 45 in the negative control group. At the 3-month follow-up, the body composition and grip strength of the HMB + RT group and RT group were significantly improved compared with those before operation. The HMB group had no significant change, while the measures in the negative control group significantly decreased. Postoperative BI and HSS did not reach pre-injury levels in any of the four groups, but postoperative VAS score was significantly improved. However, there was no significant difference in BI, HSS, or VAS among the four groups. Conclusion: RT, with or without HMB supplementation, can effectively improve body composition and grip strength in elderly patients with sarcopenia after hip replacement at short-term follow-up. Simultaneously, use of exclusive HMB supplementation alone may also help to prevent decreases in muscle mass and grip strength in these patients.
... Our study found that pre-frail individuals accounted for about half of the elderly inpatients. Data showed that pre-frail patients were more likely to progress to frailty (25), while certain interventions may delay or even reverse the decline (26). This suggests that clinical workers should pay close attention to pre-frail patients, as their early identification and intervention is more consequential than that of frail patients. ...
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Background: Coronary heart disease (CHD) is a common chronic disease in the elderly. Frailty can accelerate the development of CHD and lead to adverse health outcomes. Risk prediction and decision-making for frailty are crucial. The peripheral hemoglobin-to-red blood cell distribution width ratio (HRR) is a novel biomarker of inflammation. Our purpose was to explore the correlation between HRR and frailty in elderly patients with CHD. Methods: This cross-sectional study evaluated 245 Chinese hospitalized patients with CHD. Blood parameters measured upon admission were obtained via the hospital electronic information medical record system. The Fried Frailty Phenotype Scale was used to evaluate the frailty status of the participants. The Receiver operating characteristic curve was used to determine the optimal cut-off values of HRR. We used univariate analysis to examine the potential factors affecting frailty. Kendall's tau-b grade correlation was used to analyze the correlation between HRR and frailty. The ordered logistic regression model was used to analyze the relationship between HRR and frailty. Results: A total of 233 elderly patients with CHD were included in our study. Among the patients, 33.48% (78) were in a state of frailty. The optimal cut-off values of HRR was 9.76. The area under the curve (AUC) for HRR in the frailty patients was 0.652, exceed Hb (AUC = 0.618) and RDW (AUC = 0.650). Kendall's tau-b grade correlation analysis showed that HRR (K = −0.296, P < 0.001) was negatively correlated with frailty. The ordered logistic regression analysis determined that lower HRR was associated with frailty ( P < 0.05) after adjusted for age, body mass index, number of drugs, comorbidity index, heart failure, red blood cells, albumin, total cholesterol, triglyceride, high density lipoprotein cholesterol, and low density lipoprotein cholesterol. Conclusion: Lower HRR is an independent risk factor for frailty in elderly hospitalized patients with CHD. HRR was a more powerful prognostic indicator for frailty than either Hb or RDW alone. Clinicians should focus on timely identification of the risk of frailty in order to improve patient quality of life and to reduce the risk of complications.
... Leucine supplementation, as well as vitamin D, in association with physical exercise increased skeletal muscle mass and muscle strength (96). Furthermore, the supplementation of betahydroxy-beta-methyl butyrate is associated with preservation of muscle tissue during short period of bed rest and increased muscle mass and strength, particularly in combination with resistance training (97)(98)(99). ...
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Sarcopenia represents a major health burden in industrialized country by reducing substantially the quality of life. Indeed, it is characterized by a progressive and generalized loss of muscle mass and function, leading to an increased risk of adverse outcomes and hospitalizations. Several factors are involved in the pathogenesis of sarcopenia, such as aging, inflammation, mitochondrial dysfunction, and insulin resistance. Recently, it has been reported that more than one third of inflammatory bowel disease (IBD) patients suffered from sarcopenia. Notably, the role of gut microbiota (GM) in developing muscle failure in IBD patient is a matter of increasing interest. It has been hypothesized that gut dysbiosis, that typically characterizes IBD, might alter the immune response and host metabolism, promoting a low-grade inflammation status able to up-regulate several molecular pathways related to sarcopenia. Therefore, we aim to describe the basis of IBD-related sarcopenia and provide the rationale for new potential therapeutic targets that may regulate the gut-muscle axis in IBD patients.
Background: Aging, which is accompanied by loss of muscle mass, strength, and function, may contribute to the development of frailty and fractures in older people. Interventions such as β-hydroxy-β-methyl butyrate (HMB) treatment and resistance exercise training (RET) have been well established independently to attenuate muscle loss in previous researches. Nevertheless, no consensus exists on whether the combination of HMB intervention and RET could obtain an additional benefit to the older population. Our aim was to systematically quantify whether HMB supplementation combined with RET has a synergistic effect on improving muscle mass, strength, and function in older adults. Methods: A systematic search was performed using the electronic databases Medline, Embase, Cochrane Library, and Web of Science from inception of the study until Oct 30, 2021. The articles included were all randomized controlled trials and met the inclusion. A fixed or randomized (if data were heterogeneous) effects metaanalysis was performed using Stata. Results: A total of 256 articles were screened, with eight studies matching the eligibility criteria, which enrolled 333 subjects (≥ 65 years old). A meta-analysis was conducted, and the results showed no significant difference between the groups in lean mass, fat mass, or physical performance. In the subgroup analysis regarding the differences in muscle strength between appendicular muscles, HMB supplementation combined with RET contributed to significantly improving the muscle strength of the lower limbs (n = 6, SMD: 0.55, 95% confidence interval: 0.06 to 1.04). Conclusion: A combination of HMB supplementation and RET in older people has an additional benefit for muscle strength, especially in the lower limbs, instead of muscle function and physical performance. Further studies are needed to demonstrate the mechanism. Keywords: PHMB, muscle mass, resistance exercise training, elderly
With the aging of the world’s population, a large proportion of patients seen in cardiovascular practice are older adults, but many patients also exhibit signs of physical frailty. Cardiovascular disease and frailty are interdependent and have the same physiological underpinning that predisposes to the progression of both disease processes. Frailty can be defined as a phenomenon of increased vulnerability to stressors due to decreased physiological reserves in older patients and thus leads to poor clinical outcomes after cardiovascular insults. There are various pathophysiologic mechanisms for the development of frailty: cognitive decline, physical inactivity, poor nutrition, and lack of social supports; these risk factors provide opportunity for various types of interventions that aim to prevent, improve, or reverse the development of frailty syndrome in the context of cardiovascular disease. There is no compelling study demonstrating a successful intervention to improve a global measure of frailty. Emerging data from patients admitted with heart failure indicate that interventions associated with positive outcomes on frailty and physical function are multidimensional and include tailored cardiac rehabilitation. Contemporary cardiovascular practice should actively identify patients with physical frailty who could benefit from frailty interventions and aim to deliver these therapies in a patient-centered model to optimize quality of life, particularly after cardiovascular interventions.
The problem of population aging in developed countries poses new challenges for the medical community. Sarcopenia is one of the most common problems that decrease the quality of life of older people and increase the risk of disability and death. Currently, several dietary approaches to the prevention and correction of sarcopenia have been developed. Hydroxymethyl butyrate is one of the innovative substances designed to optimize the diet of elderly patients, primarily those with a sedentary lifestyle or on bed rest.
Objectives: We aimed to determine whether the benefits of long (24 weeks) and short (4 weeks) training programs persisted after short (6 weeks) and long (14 weeks) periods of inactivity in elderly nursing home residents with sarcopenia. Design: Multicenter randomized trial. Intervention: The Vivifrail tailored, multicomponent exercise programme ( was conducted to individually prescribe exercise for frail older adults, depending on their functional capacity. The training included four levels combining strength/power, balance, flexibility and cardiovascular endurance exercises. Setting and Participants: Twenty-four institutionalized older adults (87.1±7.1 years, 58.3% women) diagnosed with sarcopenia were allocated into two groups: the Long Training-Short Detraining (LT-SD) group completed 24 weeks of supervised Vivifrail training followed by 6 weeks of detraining; the Short Training-Long Detraining (ST-LD) group completed 4 weeks of training and 14 weeks of detraining. Measures: Changes in functional capacity and strength were evaluated at baseline, and after short and long training and detraining periods. Results: Benefits after short and long exercise interventions persisted when compared with baseline. Vivifrail training was highly effective in the short term (4 weeks) in increasing functional and strength performance (effects size=0.32–1.44, p<0.044) with the exception of handgrip strength. Continued training during 24 weeks produced 10–20% additional improvements (p<0.036). Frailty status was reversed in 36% of participants, with 59% achieving high self-autonomy. Detraining resulted in a 10–25% loss of strength and functional capacity even after 24 weeks of training (effects size=0.24–0.92, p<0.039). Conclusions and Implications: Intermittent strategies such as 4 weeks of supervised exercise 3 times yearly with no more than 14 weeks of inactivity between exercise periods appears as an efficient solution to the global challenge of maintaining functional capacity and can even reverse frailty in vulnerable institutionalized older adults.
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Background: Evidence supports the fact that multicomponent exercise and HMB supplementation are, separately, effective in improving older adult's health and palliate functional metabolic diseases in older people. However, the true effect of HMB supplementation combined with a tailored exercise program in frail older adults is still unknown. Thus, the aim of the HEAL (HMB + Exercise = Adults Living longer) study is to assess the effects of the combination of a daily multicomponent exercise and resistance training (VIVIFRAIL program) intervention in addition to HMB supplementation on older adults' health. Methods/design: A 24-week cluster randomized, double-blind, placebo-controlled study will be conducted on 104 adults ≥70 years. Nursing homes will be randomized to either of four groups: Ex-HMB (exercise intervention with HMB), Ex-Plac (exercise intervention with placebo), NoEx-HMB (no exercise intervention with HMB), and Controls (No exercise and no HMB). Intervention groups which include exercise will complete the individualized multicomponent (strength, balance and cardiovascular exercises) training program VIVIFRAIL. Intervention groups which include HMB supplementation will receive a 3 g/daily dose of free acid HMB in powder form. The primary outcome measure is the functional capacity. Secondary outcome measures are muscle strength and power, frailty and fall risk, body composition, biochemical analyses and cardiometabolic risk factor, disability and comorbidity, cognitive function and depression. Discussion: The findings of the HEAL study will help professionals from public health systems to identify cost-effective and innovative actions to improve older people's health and quality of life, and endorse exercise practice in older adults and people living in nursing homes. Trial registration: NCT03827499 ; Date of registration: 01/02/2019.
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As malnutrition is common in patients with Alzheimer’s disease (AD), we evaluated nutritional status and body composition of patients with AD, mild cognitive impairment (MCI) and controls, and studied associations of AD biomarkers and cognitive performance with nutritional status and body composition. We included 552 participants, of which 198 patients had AD, 135 patients had MCI and 219 controls. We assessed nutritional status (mini nutritional assessment (MNA)) and body composition (body mass index (BMI), fat-free mass (FFM) and waist circumference). Linear regression analyses (adjusted for age, gender and education where appropriate) were applied to test associations of AD biomarkers and cognitive performance on five domains with nutritional parameters (dependent). Patients with MCI and AD had a lower BMI and MNA score than controls. Worse performance in all cognitive domains was associated with lower MNA score, but not with body composition. AD biomarkers were associated with MNA score, BMI and waist circumference, and associations with MNA score remained after adjustment for cognitive performance. Both AD biomarkers and cognitive performance were associated with nutritional status, associations with AD biomarkers remained after adjustment for cognition. Our data suggest that malnutrition is not only related to impaired cognition but also to AD pathology.
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Introduction Resistance training (RT) and nutritional supplementation seem to have beneficial effects on muscle properties and physical performance in older adults. However, the reported effects of specific RT programmes and supplementation prescriptions vary among studies. The present study aims to examine the acute and residual effects of RT and/or beta-hydroxy-beta-methylbutyrate (HMB) supplementation on muscle mass, muscle strength and physical performance in older women with reduced muscle mass. Methods and analysis This is a randomised, double-blind, placebo-controlled trial. Older women fitting the eligibility criteria were recruited in February 2018 from a population-based sample identified via screening conducted in October 2017. In March 2018, 156 participants were randomly allocated to undergo one of four interventions (RT + HMB, RT + placebo, education + HMB and education + placebo) for 12 weeks. Supervised RT consisted of body weight, elastic band, ankle weight and machine-based exercises two times per week at the Tokyo Metropolitan Institute of Gerontology (TMIG). Each participant ingested HMB (1200 mg) or placebo supplements once daily. Sessions of education not associated with sarcopenia treatment were conducted every 2 weeks. Post-intervention follow-up will be conducted for 12 weeks, until September 2018. The study includes assessments conducted in March (baseline), June (post-intervention) and September 2018 (follow-up). The primary outcome is the longitudinal change in muscle mass. Secondary outcomes include the longitudinal changes in muscle strength, physical performance, muscle thickness, muscle quality, blood counts, blood biochemistry, calf circumference, skin viscoelasticity, habitual dietary intake, habitual physical activity levels, functional capacity and health-related quality of life. Intention-to-treat analyses will be conducted. Ethics and dissemination The study protocol was approved by the Ethics Committee of the TMIG, Japan. The study is being conducted according to the principles of the Declaration of Helsinki. The findings will be presented at international academic congresses and published in peer-reviewed international journals. Trial registration number UMIN000028560; Post-results.
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Background: Recommendations for routine frailty screening in general practice are increasing as frailty prevalence grows. In England, frailty identification became a contractual requirement in 2017. However, there is little guidance on the most effective and practical interventions once frailty has been identified. Aim: To assess the comparative effectiveness and ease of implementation of frailty interventions in primary care. Design and setting: A systematic review of frailty interventions in primary care. Method: Scientific databases were searched from inception to May 2017 for randomised controlled trials or cohort studies with control groups on primary care frailty interventions. Screening methods, interventions, and outcomes were analysed in included studies. Effectiveness was scored in terms of change of frailty status or frailty indicators and ease of implementation in terms of human resources, marginal costs, and time requirements. Results: A total of 925 studies satisfied search criteria and 46 were included. There were 15 690 participants (median study size was 160 participants). Studies reflected a broad heterogeneity. There were 17 different frailty screening methods. Of the frailty interventions, 23 involved physical activity and other interventions involved health education, nutrition supplementation, home visits, hormone supplementation, and counselling. A significant improvement of frailty status was demonstrated in 71% (n = 10) of studies and of frailty indicators in 69% (n=22) of studies where measured. Interventions with both muscle strength training and protein supplementation were consistently placed highest for effectiveness and ease of implementation. Conclusion: A combination of muscle strength training and protein supplementation was the most effective intervention to delay or reverse frailty and the easiest to implement in primary care. A map of interventions was created that can be used to inform choices for managing frailty.
Fragala, MS, Cadore, EL, Dorgo, S, Izquierdo, M, Kraemer, WJ, Peterson, MD, and Ryan, ED. Resistance training for older adults: position statement from the national strength and conditioning association. J Strength Cond Res XX(X): 000-000, 2019-Aging, even in the absence of chronic disease, is associated with a variety of biological changes that can contribute to decreases in skeletal muscle mass, strength, and function. Such losses decrease physiologic resilience and increase vulnerability to catastrophic events. As such, strategies for both prevention and treatment are necessary for the health and well-being of older adults. The purpose of this Position Statement is to provide an overview of the current and relevant literature and provide evidence-based recommendations for resistance training for older adults. As presented in this Position Statement, current research has demonstrated that countering muscle disuse through resistance training is a powerful intervention to combat the loss of muscle strength and muscle mass, physiological vulnerability, and their debilitating consequences on physical functioning, mobility, independence, chronic disease management, psychological well-being, quality of life, and healthy life expectancy. This Position Statement provides evidence to support recommendations for successful resistance training in older adults related to 4 parts: (a) program design variables, (b) physiological adaptations, (c) functional benefits, and (d) considerations for frailty, sarcopenia, and other chronic conditions. The goal of this Position Statement is to a) help foster a more unified and holistic approach to resistance training for older adults, b) promote the health and functional benefits of resistance training for older adults, and c) prevent or minimize fears and other barriers to implementation of resistance training programs for older adults.
An individualized, multicomponent exercise training program may be an effective therapy for improving cognitive function (i.e., executive function and verbal fluency domains) in very old patients 3 60 during acute hospitalization. These findings support the need for a shift from the traditional (bed-rest based) hospitalization to one that recognizes the important role of maintaining functional capacity and cognitive function in older adults, key components of intrinsic capacity.
Background: Loss of skeletal muscle mass and muscle weakness are common in a variety of clinical conditions with both wasting and weakness associated with an impairment of physical function. β-Hydroxy-β-methylbutyrate (HMB) is a nutrition supplement that has been shown to favorably influence muscle protein turnover and thus potentially plays a role in ameliorating skeletal muscle wasting and weakness. Objectives: The aim of this study was to investigate the efficacy of HMB alone, or supplements containing HMB, on skeletal muscle mass and physical function in a variety of clinical conditions characterized by loss of skeletal muscle mass and weakness. Methods: A systematic review and meta-analysis of randomized controlled trials reporting outcomes of muscle mass, strength, and physical function was performed. Two reviewers independently performed screening, data extraction, and risk-of-bias assessment. Outcome data were synthesized through meta-analysis with the use of a random-effects model and data presented as standardized mean differences (SMDs). Results: Fifteen randomized controlled trials were included, involving 2137 patients. Meta-analysis revealed some evidence to support the effect of HMB alone, or supplements containing HMB, on increasing skeletal muscle mass (SMD = 0.25; 95% CI: -0.00, 0.50; z = 1.93; P = 0.05; I2 = 58%) and strong evidence to support improving muscle strength (SMD = 0.31; 95% CI: 0.12, 0.50; z = 3.25; P = 0.001; I2 = 0%). Effect sizes were small. No effect on bodyweight (SMD = 0.16; 95% CI: -0.08, 0.41; z = 1.34; P = 0.18; I2 = 67%) or any other outcome was found. No study was considered to have low risk of bias in all categories. Conclusion: HMB, and supplements containing HMB, increased muscle mass and strength in a variety of clinical conditions, although the effect size was small. Given the bias associated with many of the included studies, further high-quality studies should be undertaken to enable interpretation and translation into clinical practice. The trial was registered on PROSPERO as CRD42017058517.
Frailty syndrome encompasses several physical hallmarks such as loss of muscle strength, power output and mass, which leads to poor gait ability, fatigue, falls and overall difficulty to perform activities of daily living. On the other hand, physical exercise interventions induce marked improvements in frailty physical hallmarks (e.g., gait ability, muscle strength, balance and falls). In addition, because cognitive impairment is closely related to frailty syndrome, exercise is an effective intervention to counteract the physical consequences of mild cognitive impairment and dementia. Moreover, exercise and early rehabilitation programs are among the interventions through which functional decline is prevented in older patients during acute hospitalization. This narrative review provides a summary of the effectiveness of different exercise interventions in the hallmarks of frailty. Furthermore, this review addresses special considerations on exercise in frail older with cognitive impairment. Also, we review the role of exercise interventions in acute hospitalized older patients. There is strong evidence that exercise training is an effective intervention for improving muscle strength, muscle mass, incidence of falls, and gait ability in frail older adults. In addition, it seems that multicomponent exercise intervention programs including resistance, gait and balance training is the best strategy for improving the frailty hallmarks, as well as for reducing the rate of falls in frail individuals, and so maintaining their functional capacity during aging. This training modality also proved to be safe and effective to revert the functional decline and cognitive impairment in acutely hospitalized older adults of advanced age. Based on the association between muscle power output and physical function, explosive resistance training should be included in the exercise intervention in order to optimize the functional outcomes in frail older adults.
Background Beta-hydroxy-beta-methylbutyrate (HMB) has been shown to be effective and superior to other types of protein supplements to attenuate loss of muscle mass, strength and function, however, its benefits in sarcopenic and frail older people remain unclear. Objective We seek to determine the effect of HMB on muscle mass, strength and function in older people with sarcopenia or frailty by reviewing results from available randomized controlled trials (RCTs). Design This review was registered at PROSPERO (University of York) with registration number CRD42018088462 and conducted according to the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) guidelines. Using a pre-determined e-search strategy, we searched PubMed, Medline, EMBASE, CINAHL, LILACS, Web of Science, Cochrane and Scopus databases. Our inclusion criteria were RCTs that assessed the effect of HMB on muscle mass, strength and function in older people with sarcopenia and frailty aged ≥60 years. The main outcomes were lean body mass, handgrip, leg press strength, and Short Physical Performance Battery (SPPB) score. Results Three studies matched our eligibility criteria which enrolled 203 subjects through a variety of definitions of sarcopenia or frailty. Lean body mass increased and muscle strength and function were preserved following HMB supplementation. Conclusion HMB improves lean muscle mass and preserves muscle strength and function in older people with sarcopenia or frailty.
Purpose of review Given the role of leucine as a major regulator of muscle protein turnover, the consumption of protein sources enhanced with this essential amino acid, or its metabolite beta-hydroxy-beta-methylbutyrate (HMB), is assumed to give the greatest benefit in terms of maintenance of muscle mass and function during aging. The aim of this review is to discuss recent literature about HMB metabolism, its pharmacokinetics compared with the metabolite leucine, effectiveness of HMB to improve outcomes in older adults, and novel approaches for HMB use. Recent findings Overall, this review article highlights the potential relationship between HMB dietary supplementation and parameters related to maintenance of muscle mass and strength in older people. However, there are limitations in the studies conducted so far, including low number of participants per study group, heterogeneity of study designs, methodologies, and outcomes. The combination of HMB with other amino acids or supplements limits the ability to determine the direct impact of HMB alone. Summary It is proposed that HMB may be utilized to protect or rebuild muscle mass in older people with reduced lean body mass.