668

Send Orders for Reprints to reprints@benthamscience.ae

Current Protein and Peptide Science, 2018, 19, 668-672

REVIEW ARTICLE
ISSN: 1389-2037
eISSN: 1875-5550

Beta-Hydroxy-Beta-Methyl Butyrate (HMB): From Experimental Data to Impact

Factor:
2.576

Clinical Evidence in Sarcopenia

BENTHAM
SCIENCE

Alfonso J. Cruz-Jentoft*

Hospital Universitario Ramón y Cajal (Irycis), Madrid, Spain

ARTICLE HISTORY
Received: September 28, 2017
Revised: November 07, 2017
Current Protein & Peptide Science
Abstract: β-hydroxy-β-methylbutyrate (HMB) is a metabolite derived from leucine and its ketoacid al-
pha-ketoisocaproate. Leucine has a role in regulating protein synthesis in muscle cells, and HMB seems
to be a key active metabolite in such regulation. HMB has been shown to modulate muscle protein deg-
radation by inhibiting the ubiquitin-proteasome proteolytic pathway, to up-regulate protein synthesis via
the mTOR pathway, and to stabilize cell membranes via the rate limiting enzyme to cholesterol synthe-
sis HMG- coenzyme A reductase. It can also decrease cell apoptosis, therefore improving cell survival;
and increase proliferation and differentiation of muscle stem cell, via the MAPK/ERK and PI3K/Akt
pathways.
HMB is widely used as an ergogenic supplement by athletes and bodybuilders, usually combined with
exercise training, to increase muscle mass and strength. Some studies have explored the role of HMB in

Accepted: January 23, 2018

DOI:
10.2174/1389203718666170529105026
chronic diseases associated with muscle wasting (cancer, acquired immunodeficiency syndrome, chronic
obstructive pulmonary disease)
This review focuses on the role of HMB in the management of sarcopenia (age or disease-related loss of
muscle mass and function) in older persons. A small number of studies have shown increases in lean
(muscle) mass and some muscle function and physical performance parameters in older people with or
without resistance exercise, and preservation of muscle mass during bed rest. However, heterogeneous
methodological approaches preclude solid conclusions, and more studies are needed to confirm the role
of HMB as a promising agent to treat sarcopenia.

Keywords: Beta-hydroxy-beta-methyl butyrate, elderly, muscle function, muscle mass, muscle wasting, leucine, sarcopenia.

1. INTRODUCTION essential amino acids (EAA) that include around 2.5 g of

Sarcopenia an age-related syndrome characterized by
progressive and generalized loss of skeletal muscle mass and
function [1]. It increases the risk of adverse outcomes such
as physical disability, poor quality of life and death. Preva-
lence of sarcopenia has regional and age-related variations,
but may be as high as 29% in community-dwelling popula-
tions and 33% in long-term care populations [2]. Prevention
and management of sarcopenia may delay death and disabil-
ity in older people.
Multiple factors may be involved in the development of
sarcopenia, with different nutrition related mechanisms in
the front line [1, 3]. It makes sense to think that nutritional
intervention may have an impact on sarcopenia, and at pre-
sent nutrition is considered, together with exercise, as the
standard approach to treating sarcopenia [4]. However, a
recent systematic review of nutrition interventions in sarco-
penia showed that the results of research are still inconclu-
sive [2], especially for protein supplements. Supplements of
*Address correspondence to the author at Servicio de Geriatría, Hospital
Universitario Ramón y Cajal, 28034 Madrid, Spain; Tel: +34 913368172;
E-mail: alfonsojose.cruz@salud.madrid.org
leucine and supplements with β-hydroxy β-methylbutyrate
(HMB) did show some effects in improving muscle mass
and function parameters [2]. Similar findings have been
found in other muscle wasting disorders [5]. This article will
briefly review the role of HMB in the regulation of muscle
proteins and its potential effects in older patients with sarco-
penia.
2. β-HYDROXY-β-METHYLBUTYRATE (HMB)
β-hydroxy-β-methylbutyrate is an amino acid metabolite
derived from leucine and its ketoacid alpha-ketoisocaproate
(KIC). HMB appears naturally in muscle cells and is also
found in some foods (citrus fruits, avocado, and others).
Leucine has a well-defined role in regulating protein synthe-
sis in muscle cells and in muscle wasting diseases [6, 7], and
HMB seems to be a key active metabolite in such regulation.
Most KIC is excreted from muscle and transported to the
liver, where most is metabolized to isovaleryl coenzyme A in
the mitochondria, and only 5% is metabolized to HMB in the
cell cytosol by KIC-dioxygenase. Daily endogenous synthe-
sis has been estimated at around 0.3 to 0.4 g, depending on
the diet. About 60 g of leucine intake would be needed to

1875-5550/18 $58.00+.00 © 2018 Bentham Science Publishers

Beta-Hydroxy-Beta-Methyl Butyrate (HMB)
produce 3 g of endogenic HMB [8], which is the usual dose
administered in clinical studies. This means that even using
high leucine protein sources (dairy, meat, eggs) the daily
amount needed to reach 3 g/day of HMB is well above that
consumed in a usual diet and may even be risky. Therefore,
supplementation of HMB is needed if the dose generally
used in clinical studies is to be reached [9].
The pharmacokinetics of exogenously administered
HMB has been examined in only a few individuals, at doses
from 1 to 3 g of calcium HMB. Peak plasma concentrations
appear at 1 to 2 h, occurring faster after larger doses, and
plasma half-life is around 2 to 3 hours. Approximately 15-
30% is excreted in urine, and the rest remains in the body.
Baseline blood levels of HMB are reached around 9 h after
ingestion. Recently, a free acid gel presentation showed
quicker and greater plasma concentrations (+185%) and im-
proved clearance (+25%) of HMB from plasma [10].
3. HMB IN THE REGULATION OF MUSCLE PRO-
TEINS
Muscles are important protein stores and have a role in
the regulation of body proteins. Amino acids and leucine in
particular are potent modulators of protein turnover and may
have anabolic effects in skeletal muscle cells via increased
activity of mTORC1, which drives protein synthesis and
growth in healthy individuals [6]. However, despite many
studies showing enhanced acute protein synthesis with
leucine supplements in healthy individuals, it does not seem
to be clearly effective in the long term treatment of muscle
wasting conditions [7].
HMB, as a downstream metabolite of leucine, has been
shown to exert its effect on muscles by different theoretical
mechanisms of action [9, 11-13].
- HMB increases myofibrillar protein synthesis by up-
regulation via the mTOR pathway.
- HMB modulates protein degradation by inhibiting the
ubiquitin-proteasome proteolytic pathway in muscle cells.
Ubiquitin is induced by immobilization and by catabolic
conditions, inducing proteasome expression through the acti-
vation of nuclear factor kappa B (NK-κB), thus promoting
muscle wasting. HMB may inhibit the activity of NK-κB,
attenuating muscle loss in wasting conditions.
- The integrity of cell membranes depends on cholesterol
synthesis from acetyl-CoA. HMB is converted to ß-hydroxy-
ß-methylglutaryl-coenzyme A (HMG-CoA), which is turned
into cholesterol by the HMG-coenzyme A reductase, the
rate-limiting enzyme to cholesterol synthesis. Thus, HMB
supplementation may stabilize cell membranes. HMB itself
seems to be a component of cell membranes.
- HMB may prevent cell apoptosis and enhance muscle
satellite cell survival.
- HMB increases proliferation and differentiation of mus-
cle stem cells, via the MAPK/ERK and PI3K/Akt pathways.
- HMB up-regulates transcription and expression of the
IGF-I gene in skeletal muscle and liver. IGF exerts an ana-
bolic action and causes hypertrophy of skeletal muscle fi-
bers.
Current Protein and Peptide Science, 2018, Vol. 19, No. 7 669
4. EFFICACY OF HMB IN YOUNG ATHLETES
HMB is widely used as an ergogenic supplement by
young athletes. This is based on studies that show that HBM
supplementation, when combined with exercise training,
may lead to increased muscle mass and muscle strength, and
improve endurance in athletes. The effect on muscle mass
and strength may be more pronounced in conditions where
proteolysis is more relevant, as in sedentary individuals start-
ing to exercise. However, there is still conflicting evidence
due to variability in study design and many other methodo-
logical issues [13]. A recent meta-analysis including 394
subjects from 9 studies found small benefits in the lower
body and average muscle strength, but not in the upper body,
and these gains were only observed in untrained lifters; no
relevant changes in body composition were found [14].
HMB may also prevent muscle damage. A recent sys-
tematic review confirmed the effectiveness of HMB in pre-
venting exercise-related muscle damage in healthy trained
and untrained individuals as well as muscle loss during
chronic diseases [15].
A Position Statement issued by the International Society
of Sports Nutrition (ISSN), after a critical analysis of the
literature on the use of calcium HMB as a nutritional sup-
plement supported its use to enhance recovery in trained and
untrained populations, and to enhance skeletal muscle hyper-
trophy, strength, and power in untrained and trained popula-
tions together with the appropriate exercise prescription [16].
This Society recommends consuming the supplement in
close proximity to the physical workout, starting 2 weeks
prior to an exercise bout.
Some studies are exploring the use of HMB together with
other ergogenic substances. For instance, supplementation
with adenosine-5'-triphosphate (ATP) and HMB for 12
weeks, in combination with resistance exercise training, im-
proved muscle mass, strength and power in well-trained in-
dividuals [17].
5. HMB IN AGED INDIVIDUALS WITH SARCO-
PENIA
Growing use of HMB in younger individuals and evi-
dence from basic science that some age-related and disease-
related muscle wasting mechanisms may be counteracted by
this substance have prompted research on the role of HMB in
sarcopenia. There is some evidence that HMB supplementa-
tion may be useful for clinical muscle wasting conditions,
including AIDS, cancer, bed-rest, and during periods of ca-
loric deficits [13].
5.1. Bed Rest and Bedridden Patients
Bed rest causes a rapid loss of muscle mass in older peo-
ple, both in health and disease. This loss of muscle mass may
explain the loss of functional capacity after hospital admis-
sion [18]. Deutz et al. [19] carried out a randomized con-
trolled study of the role of HMB in the prevention of muscle
loss in healthy older adults in complete bed rest. They en-
rolled 24 healthy older adults (60 to 74 years old, 20 women,
with normal physical performance assessed with the Short
Physical Performance Battery [SPPB]) and confined them to
complete bed rest for ten days. After that period, resistance
670 Current Protein and Peptide Science, 2018, Vol. 19, No. 7
training rehabilitation was started for eight weeks. This set-
ting simulates a standard hospital admission, after which
many older patients need rehabilitation to recover their base-
line functional status. Subjects in the experimental group
were treated with calcium HMB (3 g/day) starting 5 days
before bed rest and until the end of rehabilitation, and control
subjects received a placebo. Of the 19 subjects evaluable at
the end of the bed rest period, those in the control group had
a significant decrease in total lean body mass (measured by
DXA) of 2.05 kg (-4.9% of baseline), while lean body mass
in those treated with HMB did not change significantly (loss
of 0.17 kg, -0.04%). No significant changes were found in
muscle strength or physical performance measurements. Six-
hours muscle protein fractional synthesis rate (FSR) was
measured in 18 subjects. Those in the control group had a
non-significant decrease in FSR by 21% (p=0.14), while in
the HMB group FSR was maintained. This study shows that
in healthy older adult, HMB supplementation may preserve
muscle mass during 10 days of bed rest. These results are
encouraging, but need to be confirmed by other groups.
Malnutrition and sarcopenia are common in bed-ridden
nursing home residents. Hsieh et al. [20] investigated the
effects of HMB on body composition and protein metabo-
lism in bedridden older subjects who were already receiving
tube feeding. They were assigned to usual nasogastric tube
feeding protocols, adding 2 g/day of calcium HMB in the
experimental group (n = 39) and not in the placebo group (n
= 40). Anthropometric measurements and blood/urine tests
were performed at baseline and 14 days; roughly half of the
subjects continued in the study for additional 14 days. Body
weight, BMI and a number of anthropometric measurements
did not change significantly in either group, with very few
exceptions (waist and calf circumference improved with
HMB at 28 days). Blood urea and urine urea nitrogen excre-
tion, two very indirect measures of muscle breakdown,
tended to decrease in the HMB group at some points, and
showed a trend to increase in the control group. The results
of this trial are mostly inconclusive.
5.2. HMB with Exercise
The effects of HMB may be additive to those of exercise
in muscle mass and function. Vukovich et al. [21] compared
the effects of 8 weeks of HMB supplementation on fat-free
mass and muscle strength in 70-year-old men and women
along with exercise and resistance training 5 days per week.
Fourteen subjects received calcium HMB 3 g/d and 17 con-
trols received a similar placebo. Skinfold thickness was
measured in all patients as a measure of body composition.
Lean body mass was measured using skinfold, computerized
tomography (CT) and dual x-ray absorptiometry (DXA);
muscle strength was measured with a one-repetition maxi-
mum (1-RM) test of different muscle groups. HMB supple-
mentation increased fat-free mass by 0.8 kg (measured by
skinfold thickness), while those on placebo did not change.
No changes were found in DXA measurements. The HMB
group experienced an 8% decrease in fat mass measured by
CT, but no differences in lean mass change were observed.
At the end of 8 weeks, upper body strength increased by
nearly 15% and lower body strength increased approximately
20% in both groups, but there was no statistically significant
difference between the groups. In conclusion, some changes
Alfonso J. Cruz-Jentoft
in body composition can be observed with HMB supplemen-
tation in 70-year old adults participating in a strength-
training program. The small sample size and the choice of
muscle strength measures may have limited the power of this
study to detect differences.
More recently, Stout et al. [22] evaluated the effects of
24 weeks of supplementation with 3 g of calcium HMB and
resistance training (3 days a week) or calcium HMB supple-
mentation only in 54 ambulatory males and females over 65
years old (mean age 72 years) at risk for malnutrition in a
double-blind, placebo-controlled trial. The study had two
phases: phase I consisted of two non-exercise groups: (a)
placebo and (b) 3 g of calcium HMB divided into two doses.
Phase II consisted of two resistance exercise groups: (a) pla-
cebo and resistance exercise and (b) HMB and resistance
exercise. In phase I with no exercise, changes in body com-
position were not different in the HMB group and the pla-
cebo group. Improvements were found in the HMB group on
some measures of muscle strength (knee flexion and exten-
sion at 60º) but not in other (knee flexion and extension at
180º, grip strength), and both groups had similar improve-
ment in physical performance (timed up and go test). In
phase II, with resistance exercise, both groups improved sig-
nificantly with exercise with an increase in most measures of
muscle mass, muscle strength and physical performance.
However, no significant differences were found between the
placebo and the HMB group in any of these variables.
5.3. HMB with Other Amino Acids
Flakoll et al. [23] investigated the effects of supplemen-
tation with calcium HMB (2 g) together with 5 g of arginine
and 1.5 g of lysine in two parallel studies in 57 female pa-
tients 62 to 90 years old, recruited from senior centers and
assisted care facilities. Subjects were randomly assigned to
receive the active supplement (n = 27), or placebo (n = 23)
for 12 weeks, without an exercise intervention. Seven sub-
jects did not finish the study for different reasons; compli-
ance was confirmed by plasma HMB levels. Body composi-
tion was measured either by bioelectrical impedance or
plethysmography. A borderline 0.7 kg increase in fat-free
mass was observed (P = 0.08) in the active group, compared
with no change in the placebo group. This result was mostly
based on changes measured by plethysmography, a method
with no studies on sensitivity to change after interventions.
Muscle strength measured by handgrip strength tended to
improve in the active group (+0.6 kg) compared with the
control group (-1.1 kg, p = 0.07), and knee extensor and
flexor forces (only measured in roughly half of the subjects)
improved significantly in the active group compared with the
placebo group. The most relevant changes were found in
physical performance, measured with the timed up-and-go
test: the active group improved their time in 2.3 seconds
(baseline 10.1 s), with no change in the placebo group (p =
0.007). Finally, rates of protein metabolism were measured
in some subjects at the end of the study. Whole body protein
synthesis improved around 20% in the active group, but this
group tended to increase proteolysis, and the net protein gain
was similar in both groups. Two findings are relevant in this
study: improvement of physical performance, and the ability
to promote this change with no physical exercise. However,
Beta-Hydroxy-Beta-Methyl Butyrate (HMB)
not only HMB but also two other amino acids were used, so
assessment of the effect of each of them is needed.
The same group of researchers [24] later investigated the
effects of this combination (HMB, arginine, and lysine) over
a 1-year period in 104 men and women recruited from senior
citizen centers and assisted living and care facilities. Mean
age was around 75 years. The dose of the supplement was
adjusted to body weight, with a maximum of 3 g of calcium
HMB, based on previous research [25]. The control group
did not receive placebo, but an isonitrogenous, isocaloric
drink with non-essential amino acids (alanine, glutamic acid,
glycine, serine). 77 subjects completed the one-year follow-
up. Body composition was measured both with bioelectrical
impedance analysis (BIA) and DXA. Fat-free mass measured
by BIA increased linearly in the active group (0.88 kg at one
year, compared with no change in the control group), and
lean mass measured with DXA increased quadratically (0.55
kg, again no change in the control group). Muscle strength
(handgrip and leg strength) was gradually reduced in both
groups, with no significant difference. Physical performance
(timed get up and go tests) remained unchanged during the
study in both groups. The rates of protein turnover signifi-
cantly increased in the active group and decreased in the
controls at 3 and 12 months. Both protein synthesis and pro-
tein breakdown increased in the active group, so protein bal-
ance remained the same for both groups. The findings of this
study are quite conflicting with the former and, from a clini-
cal perspective; the absence of changes in muscle function
(muscle strength and physical performance) is disappointing.
This led Fuller et al. [26] to perform additional analysis.
They considered that the lack of an exercise protocol to-
gether with the nutritional supplement might have contrib-
uted to the lack of changes in muscle function, but they hy-
pothesized that poor vitamin D intake and vitamin D status
could have played a role. They classified the subjects by
vitamin D status (serum OH-vitamin D3 levels below or over
30 ng/mL) and found that vitamin D status did not have any
impact on the reported gain in fat-free mass. However, they
did find an increase in muscle strength (combined knee ex-
tension and flexion) in the active group with sufficient vita-
min D levels. Individual findings for knee extension and
flexion are not reported, and grip strength and physical per-
formance are never mentioned, so the outcome measure used
was not pre-defined in the protocol. This finding has to be
considered only as hypothesis generator and not face value.
6. SAFETY OF HMB
HMB seems to be safe in humans. A report summarizing
data from nine studies in humans, using 3 g doses of HMB
for up to two months, including some older subjects (up to
81 years old) did not find any safety concern in blood tests,
tolerance or mood [27, 28]. In fact, HMB reduced total cho-
lesterol, LDL cholesterol, and systolic blood pressure.
These findings have been confirmed in those clinical tri-
als that included both healthy and frail older adults and pro-
spectively collected safety parameters, were no adverse
events could be attributed to the use of HMB [22, 24].
Current Protein and Peptide Science, 2018, Vol. 19, No. 7 671
CONCLUSION
Sarcopenia is a disabling condition that leads to depend-
ence in old age, and nutritional deficits, especially those re-
lated to proteins, have a key role in the pathogenesis of sar-
copenia. Experimental research suggests that HMB has many
effects that may counteract sarcopenia, and this is confirmed
by the use of HMB in younger athletes. However, research
on the effects of HBM in sarcopenia is limited by the small
number of studies, heterogeneous methodological ap-
proaches, lack of agreement on what are significant outcome
measures, and issues on the interaction of HMB with other
nutrients and with exercise. Some findings suggest that, at
least in some settings, HMB may prevent muscle mass loss
or improve muscle mass, and increase muscle function and
physical performance. However, limitations in research pre-
clude solid conclusions, and more studies are needed to con-
firm the role of HMB as a promising agent to treat sarco-
penia.
CONSENT FOR PUBLICATION
Not applicable.
CONFLICT OF INTEREST
The author has received research funds or speaker funds
from Abbott Nutrition, Novartis, Nutricia and Regeneron
Pharmaceuticals, companies that are developing products for
the treatment of sarcopenia. This article was not funded.
ACKNOWLEDGEMENTS
Declared none.
REFERENCES
[1] Cruz-Jentoft, A.J.; Baeyens, J.P.; Bauer, J.M.; Boirie, Y.; Ceder-
holm, T.; Landi, F.; Martin, F.C.; Michel, J.P.; Rolland, Y.;
Schneider, S.M.; Topinková, E.; Vandewoude, M.; Zamboni, M.;
European Working Group on Sarcopenia in Older People. Sarco-
penia: European consensus on definition and diagnosis: Report of
the European Working Group on Sarcopenia in Older People. Age
Ageing, 2010, 39, 412-423.
[2] Cruz-Jentoft, A.J.; Landi, F.; Schneider, S.M.; Zuniga, C.; Arai, H.;
Boirie, Y.; Chen, L.-K.; Fielding, R.A.; Martin, F.C.; Michel, J.-P.;
Sieber, C.; Stout, J.R.; Studenski, S.A.; Vellas, B.; Woo, J.; Zam-
boni, M.; Cederholm, T. Prevalence of and interventions for sarco-
penia in ageing adults: A systematic review. Report of the Interna-
tional Sarcopenia Initiative (EWGSOP and IWGS). Age Ageing,
2014, 43, 748-759.
[3] Laviano, A.; Gori, C.; Rianda, S. Sarcopenia and nutrition. Adv.
Food Nutr. Res., 2014, 71, 101-136.
[4] Walston, J.D. Sarcopenia in older adults. Curr. Opin. Rheumatol.,
2012, 24, 623-627.
[5] Wandrag, L.; Brett, S.J.; Frost, G.; Hickson, M. Impact of supple-
mentation with amino acids or their metabolites on muscle wasting
in patients with critical illness or other muscle wasting illness: A
systematic review. J. Hum. Nutr. Diet. Off. J. Br. Diet. Assoc. 2015,
28(4), 313-330.
[6] Van Loon, L.J.C. Leucine as a pharmaconutrient in health and
disease. Curr. Opin. Clin. Nutr. Metab. Care, 2012, 15, 71-77.
[7] Ham, D.J.; Caldow, M.K.; Lynch, G.S.; Koopman, R. Leucine as a
treatment for muscle wasting: A critical review. Clin. Nutr. Edinb.
Scotl., 2014, 33, 937-945.
[8] Wilson, J.M.; Lowery, R.P.; Joy, J.M.; Andersen, J.C.; Wilson,
S.M.C.; Stout, J.R.; Duncan, N.; Fuller, J.C.; Baier, S.M.; Naimo,
M.A.; Rathmacher, J. The effects of 12 weeks of beta-hydroxy-
beta-methylbutyrate free acid supplementation on muscle mass,
strength, and power in resistance-trained individuals: A random-
672 Current Protein and Peptide Science, 2018, Vol. 19, No. 7
ized, double-blind, placebo-controlled study. Eur. J. Appl. Physiol.,
2014, 114, 1217-1227.
[9] Fitschen, P.J.; Wilson, G.J.; Wilson, J.M.; Wilund, K.R. Efficacy
of β-hydroxy-β-methylbutyrate supplementation in elderly and
clinical populations. Nutrition, 2013, 29, 29-36.
[10] Fuller, J.C.; Sharp, R.L.; Angus, H.F.; Baier, S.M.; Rathmacher,
J.A. Free acid gel form of β-hydroxy-β-methylbutyrate (HMB) im-
proves HMB clearance from plasma in human subjects compared
with the calcium HMB salt. Br. J. Nutr., 2011, 105, 367-372.
[11] Portal, S.; Eliakim, A.; Nemet, D.; Halevy, O.; Zadik, Z. Effect of
HMB supplementation on body composition, fitness, hormonal
profile and muscle damage indices. J. Pediatr. Endocrinol. Metab.,
2010, 23, 641-650.
[12] Zanchi, N.E.; Gerlinger-Romero, F.; Guimarães-Ferreira, L.; de
Siqueira Filho, M.A.; Felitti, V.; Lira, F.S.; Seelaender, M.;
Lancha, A.H. HMB supplementation: Clinical and athletic per-
formance-related effects and mechanisms of action. Amino Acids,
2011, 40, 1015-1025.
[13] Wilson, G.J.; Wilson, J.M.; Manninen, A.H. Effects of beta-
hydroxy-beta-methylbutyrate (HMB) on exercise performance and
body composition across varying levels of age, sex, and training
experience: A review. Nutr. Metab., 2008, 5, 1.
[14] Rowlands, D.S.; Thomson, J.S. Effects of beta-hydroxy-beta-
methylbutyrate supplementation during resistance training on
strength, body composition, and muscle damage in trained and un-
trained young men: A meta-analysis. J. Strength Cond. Res. Natl.
Strength Cond. Assoc., 2009, 23, 836-846.
[15] Molfino, A.; Gioia, G.; Rossi Fanelli, F.; Muscaritoli, M. Beta-
hydroxy-beta-methylbutyrate supplementation in health and dis-
ease: A systematic review of randomized trials. Amino Acids, 2013,
45, 1273-1292.
[16] Wilson, J.M.; Fitschen, P.J.; Campbell, B.; Wilson, G.J.; Zanchi,
N.; Taylor, L.; Wilborn, C.; Kalman, D.S.; Stout, J.R.; Hoffman,
J.R.; Ziegenfuss, T.N.; Lopez, H.L.; Kreider, R.B.; Smith-Ryan,
A.E.; Antonio, J. International Society of Sports Nutrition Position
Stand: Beta-hydroxy-beta-methylbutyrate (HMB). J. Int. Soc.
Sports Nutr., 2013, 10, 6.
[17] Lowery, R.P.; Joy, J.M.; Rathmacher, J.; Baier, S.M.; Fuller, J.;
Shelley, M.C.; Jäeger, R.; Purpura, M.; Wilson, S.M.C.; Wilson,
J.M. Interaction of beta-hydroxy-beta-methylbutyrate free acid
(HMB-FA) and adenosine triphosphate (ATP) on muscle mass,
strength, and power in resistance trained individuals. J. Strength
Cond. Res., 2016, 30(7), 1843-1854.
[18] Merino Martín, S.; Cruz-Jentoft, A.J. Impact of hospital admission
on functional and cognitive measures in older subjects. Eur. Geri-
atr. Med., 2011, 3, 208-212.
Alfonso J. Cruz-Jentoft
[19] Deutz, N.E.P.; Pereira, S.L.; Hays, N.P.; Oliver, J.S.; Edens, N.K.;
Evans, C.M.; Wolfe, R.R. Effect of β-hydroxy-β-methylbutyrate
(HMB) on lean body mass during 10 days of bed rest in older
adults. Clin. Nutr., 2013, 32, 704-712.
[20] Hsieh, L.C.; Chow, C.J.; Chang, W.C.; Liu, T.H.; Chang, C.K.
Effect of beta-hydroxy-beta-methylbutyrate on protein metabolism
in bed-ridden elderly receiving tube feeding. Asia Pac. J. Clin.
Nutr., 2010, 19, 200-208.
[21] Vukovich, M.D.; Stubbs, N.B.; Bohlken, R.M. Body composition
in 70-year-old adults responds to dietary beta-hydroxy-beta-
methylbutyrate similarly to that of young adults. J. Nutr., 2001,
131, 2049-2052.
[22] Stout, J.R.; Smith-Ryan, A.E.; Fukuda, D.H.; Kendall, K.L.; Moon,
J.R.; Hoffman, J.R.; Wilson, J.M.; Oliver, J.S.; Mustad, V.A. Effect
of calcium β-hydroxy-β-methylbutyrate (CaHMB) with and with-
out resistance training in men and women 65+yrs: A randomized,
double-blind pilot trial. Exp. Gerontol., 2013, 48, 1303-1310.
[23] Flakoll, P.; Sharp, R.; Baier, S.; Levenhagen, D.; Carr, C.; Nissen,
S. Effect of beta-hydroxy-beta-methylbutyrate, arginine, and lysine
supplementation on strength, functionality, body composition, and
protein metabolism in elderly women. Nutrition, 2004, 20, 445-
451.
[24] Baier, S.; Johannsen, D.; Abumrad, N.; Rathmacher, J.A.; Nissen,
S.; Flakoll, P. Year-long changes in protein metabolism in elderly
men and women supplemented with a nutrition cocktail of beta-
hydroxy-beta-methylbutyrate (HMB), L-arginine, and L-lysine. J.
Parenter. Enter. Nutr., 2009, 33, 71-82.
[25] Gallagher, P.M.; Carrithers, J.A.; Godard, M.P.; Schulze, K.E.;
Trappe, S.W. Beta-hydroxy-beta-methylbutyrate ingestion, Part I:
Effects on strength and fat free mass. Med. Sci. Sports Exerc.,
2000, 32, 2109-2115.
[26] Fuller, J.C.; Baier, S.; Flakoll, P.; Nissen, S.L.; Abumrad, N.N.;
Rathmacher, J.A. Vitamin D status affects strength gains in older
adults supplemented with a combination of -hydroxy- -
methylbutyrate, arginine, and lysine: A cohort study. J. Parenter.
Enter. Nutr., 2011, 35, 757-762.
[27] Nissen, S.; Sharp, R.L.; Panton, L.; Vukovich, M.; Trappe, S.;
Fuller, J.C. Beta-hydroxy-beta-methylbutyrate (HMB) supplemen-
tation in humans is safe and may decrease cardiovascular risk fac-
tors. J. Nutr., 2000, 130, 1937-1945.
[28] Rathmacher, J.A.; Nissen, S.; Panton, L.; Clark, R.H.; Eubanks
May, P.; Barber, A.E.; D’Olimpio, J.; Abumrad, N.N. Supplemen-
tation with a combination of beta-hydroxy-beta-methylbutyrate
(HMB), arginine, and glutamine is safe and could improve hemato-
logical parameters. J. Parenter. Enteral Nutr., 2004, 28, 65-75.