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Selective androgen receptor modulators (SARMs) as pharmacological treatment for muscle wasting in ongoing clinical trials


Abstract and Figures

Introduction Skeletal muscle wasting is a frequent clinical problem encountered in patients with chronic diseases. Its development seems to share a common pathway, characterized by increased levels of inflammatory markers, an imbalance between muscle protein synthesis and degradation, and atrophy from disuse. Although testosterone has long been proposed as a treatment for patients with muscle wasting, undesirable side effects have raised concerns about prostatic hypertrophy in men as well as virilization in women. Selective androgen receptor modulators (SARMs) have demonstrated similar results like testosterone at improving lean body mass (LBM) with less side effects on androgen-dependent tissue. Areas covered This review outlines the ongoing clinical development in the field of SARMs and their effectiveness in improving body composition and physical function. The included articles were collected at and analyzed integrally. Expert opinion There is an unmet clinical need for safe and effective anabolic compounds such as SARMs. Despite the effect on LBM shown by SARMs in phase II clinical trials, results on improved physical function and muscle strength are still lacking and long-term outcomes have to be assessed in these patients. Moreover, there is a need to determine the effect of resistance exercise training and protein intake associated with SARMs in the treatment of patients with muscle wasting.
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Selective androgen receptor modulators (SARMs) as pharmacological treatment for
muscle wasting in ongoing clinical trials
Guilherme Wesley Peixoto Da Fonseca
, Elke Dworatzek
, Nicole Ebner
and Stephan Von Haehling
Heart Institute (Incor), University of São Paulo Medical School, São Paulo, Brazil;
Department of Cardiology and Pneumology, University of
Göttingen Medical Center, Göttingen, Germany;
Institute of Gender in Medicine, Charité - Universitaetsmedizin Berlin, Corporate Member of Freie
Universität Berlin, and Berlin Institute of Health, Berlin, Germany;
Departement of Muscle Physiology, Max-Delbrueck-Center for Molecular
Medicine (MDC) in the Helmholtz Association, Berlin, Germany;
German Center for Cardiovascular Research (DZHK), Partner Site Berlin, Berlin,
German Center for Cardiovascular Research (DZHK), Partner Site Göttingen, Göttingen, Germany
Introduction: Skeletal muscle wasting is a frequent clinical problem encountered in patients with
chronic diseases. Increased levels of inflammatory markers play a role in the imbalance between muscle
protein synthesis and degradation. Although testosterone has long been proposed as a treatment for
patients with muscle wasting, undesirable side effects have raised concerns about prostatic hypertro-
phy in men as well as virilization in women. Selective androgen receptor modulators (SARMs) have
demonstrated similar results like testosterone at improving lean body mass (LBM) with less side effects
on androgen-dependent tissue.
Areas covered: This review outlines the ongoing clinical development in the field of SARMs and their
effectiveness in improving body composition and physical function. The included articles were collected
at and analyzed integrally.
Expert opinion: There is an unmet clinical need for safe and effective anabolic compounds such as
SARMs. Despite the effect on LBM shown by SARMs in phase II clinical trials, results on improved
physical function and muscle strength are still lacking and long-term outcomes have to be assessed in
these patients. Moreover, there is a need to determine the effect of resistance exercise training and
protein intake associated with SARMs in the treatment of patients with muscle wasting.
Received 2 March 2020
Accepted 29 May 2020
Androgen receptor;
cachexia; muscle wasting;
sarcopenia; selective
androgen receptor
modulators; testosterone
1. Introduction
Skeletal muscle wasting, i.e. the reduction in muscle mass, is fre-
quently present in the progression of many chronic diseases, such
as some types of cancer, chronic heart failure, chronic obstructive
pulmonary disease, and chronic kidney disease [14]. The asso-
ciated conditions have been termed cachexia (wasting also invol-
ving tissues other than muscle but leading to a net weight loss) and
sarcopenia (reduction in muscle mass and muscle strength). The
development of both these conditions seems to share a final com-
mon pathway, characterized by increased levels of inflammatory
markers, an imbalance between muscle protein synthesis and
degradation, and atrophy from disuse [5]. Moreover, these altera-
tions in body composition may lead to reduced muscle strength,
frailty, physical disability, and even higher mortality rates [6,7].
Therapies have mainly aimed to increase muscle mass with the
hope to also improve muscle strength. This, however, is a difficult
undertaking, and authorities such as the U.S. Food and Drug
Administration (FDA) and the European Medicines Agency (EMA)
have usually ruled that both parameters have to be improved for
approval of new drugs.
The prototypical anabolic substance applied in this context
is testosterone. Indeed, testosterone replacement therapy and
other anabolic-androgenic steroids have long been proposed
for use in patients with chronic disease with an inflammatory
component [810]. Although they promote significant
increases in muscle and bone mass, undesirable side effects
as a result of the broad tissue activation of testosterone have
raised concerns about prostatic hypertrophy [11] and prostate
cancer in men as well as virilization in women [12].
Additionally, despite lipid profile alterations, hepatotoxicity,
and gynecomastia caused by testosterone use, the cardiovas-
cular risks involved with testosterone replacement are
still debated[13].
In an attempt to overcome the limitations associated with
testosterone, selective androgen receptor modulators (SARMs)
have been developed [14]. SARMs have shown a targeted thera-
peutic effect on the androgen receptor (AR), the word ‘selective’
buttressing the idea of selective binding in skeletal muscle and
bone [15,16]. The binding to AR in the prostate is either antagonistic
or only mildly agonistic, even though the mechanism behind this
tissue selective action is not entirely clear.
Insight into the mechanisms of action has been gained in animal
models, but also in early trials in humans. For instance, the anabolic
and androgenic activity of SARMs has been consistently shown in
orchidectomized male rats by increases in the weight of levator ani
muscle associated with decreased weights in the prostate and
seminal vesicles [1720]. Moreover, SARMs have been
CONTACT Stephan Von Haehling Department of Cardiology and Pneumology, University of Göttingen Medical Center,
Göttingen 37075, Germany
© 2020 Informa UK Limited, trading as Taylor & Francis Group
demonstrated to increase gastrocnemius muscle weight and bone
mineral density as well as bone biomechanical properties in ovar-
iectomized female rats [16].
Clinical trials have demonstrated improvements in lean
body mass (LBM) in healthy men [21] and in postmenopausal
women [22,23] as well as in women with sarcopenia [24] and
in a cancer population [25]. However, the effects of SARMs on
increasing muscle strength and physical function remain
inconclusive [21,24]. The side effect profile of SARMs may
also resemble some aspects of testosterone. Indeed, clinical
trials have reported a decrease in high-density lipoprotein,
hepatotoxicity with increased liver enzymes, and alterations
in the plasma level of anabolic hormones involved in the
hypothalamic-pituitary-gonadal axis [23,25]. These side effects
resemble those reported with testosterone use, but the
degree is much less pronounced.
The aim of this review is to outline the ongoing clinical
development in the field of SARMs and its effects on body
composition and physical function. In addition, we present
ongoing clinical trials that may shed light on the future clinical
applicability of these compounds in patients with muscle
wasting, sarcopenia, or cachexia.
2. The molecular mechanisms of SARMs
The AR is a member of a large family of nuclear receptors. This
family includes receptors that bind estrogen, progesterone,
glucocorticoid, mineralocorticoid, and androgen [26]. The AR
is widely distributed in tissues such as skeletal muscle, cardiac
and smooth muscles, bone, prostate, sebaceous glands, semi-
nal vesicle, male and female genitalia, liver, skin, and brain
[27]. Its structure is composed of an N-terminal domain, a DNA
binding domain, and a ligand-binding domain that is activated
by testosterone and its powerful metabolite dihydrotestoster-
one (DHT) via the action of 5α-reductase [28]. In addition,
a wide range of endogenous and exogenous hormones,
growth factors, and peptides have been shown to bind the
AR [26].
For AR activation, the ligand diffuses through the cell mem-
brane and binds to an available receptor located within the
cytoplasm. The efficacy of the ligand, in this case SARMs, in
the activation process is determined by its binding affinity and
its ability to replace the corresponding endogenous hormone (i.
e. testosterone) [28]. The AR, in an inactive state, is bound to
heat shock proteins (HSPs), such as HSP40, 60, 70, and 90, and,
when activated, these HSPs are involved in the folding/unfold-
ing process of proteins and immune response. Subsequently,
HSP is uncoupled from AR in the presence of a ligand so that
forming the AR-ligand complex that translocates into the
nucleus where it binds to the androgen response element
(ARE) regulating gene expression (Figure 1) [29].
Following the concept of tissue-specific AR activation to
avoid detrimental side-effects, the idea of selective AR activators
was born. This concept originated from the development of
selective estrogen receptor modulators (SERMs) in the 1990 s,
now widely used in the treatment of breast cancer. SARMs were
initially formulated in 1998 from a class of molecules called
bicalutamides [30]. Other pharmacophores commonly used to
synthetize SARMs have emerged along the years, for instance
arylpropionamide, quinolinone, pyrrolidinyl-benzonitrile, diaryl-
hydantoin, indole, phenyloxadiazole, and steroids (Figure 2) [31].
The term ‘modulator’ was given to these compounds because of
their capability to range from full agonists in some tissues to
partial agonists or full antagonists in others. SARMs are delivered
orally and can have a half-life of hours or even days. Although
their biological response may vary according to sex, age and
hormonal status [22], some types of SARMs have been shown to
have an anabolic/androgenic ratio of 20:1 in comparison to
testosterone, which has a ratio of 1:1 [32]. However, given the
variety of co-regulators that converge on the androgen-
signaling pathway and produce distinct androgenic and ana-
bolic responses [29], the mechanisms of SARMs-action are still
not clear and most of the knowledge about SERMs has been
transferred to SARMs.
3. Facts and figures about SARMs in experimental
and clinical studies
In the following section, we give an overview about the
current SARMs, which are under development by several com-
panies so far and their impact on body composition/physical
performance outcomes in preclinical and clinical studies. In
addition, we present an overview of the available data in the
public domain about clinical trials (Table 1) and published
(Table 2) clinical trials assessing these parameters.
3.1. Enobosarm
Enobosarm, also known as GTx-024, ostarine, MK-2866 and/or
S-22, is an oral, non-steroidal SARM that has been developed
by GTx Inc., since June 2019 under the name Oncternal
Therapeutics. This compound was patented by James
T. Dalton, Duane D. Miller and Karen A. Veverka in 2005
(WO2005120483A2) and since then it has been under devel-
opment to treat patients with muscle wasting. In
November 2007, GTx and Merck announced a 3-year
Article highlights
Debatable cardiovascular risks and undesirable side effects of testos-
terone have encouraged the development of alternative therapies to
treat declines in muscle mass and muscle function;
Selective androgen receptor modulators (SARMs), similar to testoster-
one in action, has received the term ‘modulators’ due to their cap-
ability to range from full agonists in some tissues (e.g. muscle and
bone) to partial agonists or full antagonists in others (e.g. reproduc-
tive organs);
SARMs have shown to improve total lean body mass, but there is still
inconclusive finding with regards to improvement in muscle strength
and physical function.
Although the side effect profile of SARMs may resemble some aspects
of testosterone (reduced HDL, hepatotoxicity and hypothalamic-
pituitary-gonadal axis suppression), these alterations occur to
a much lesser extent degree than testosterone;
There is still a need to determine the effect of resistance exercise
training and protein intake, well-known interventions to promote
changes in muscle strength and muscle mass, in the treatment of
patients with muscle wasting.
This box summarizes key points contained in the article.
agreement for research and development of enobosarm [33].
According to GTx Inc., there have been 25 studies with eno-
bosarm conducted, which enrolled over 1,700 subjects [34]. In
a statement dated 4 April 2014, the company estimated that
35 million US dollars had been invested in the development of
enobosarm [35].
The dosages of enobosarm administered orally under study
have ranged from 1–18 mg in ongoing phase II and III clinical
Figure 1. Testosterone and DHT (dihydrotestosterone), as well as SARMs (selective androgen receptor modulators), are ligands that exert anabolic action on tissues.
Firstly, they diffuse through the cell membrane and bind to an available AR (androgenic receptor) located in the cytoplasm of skeletal muscle, cardiac and smooth
muscle, bone, and reproductive organs. Then, the AR, initially in an inactive state coupled with HSP (heat shock protein), is bound to SARMs, while uncouples the
HSP forming the AR-complex that is able to translocate into the nucleus and bind to ARE (androgen response element). Finally, ARE regulates the expression of
mRNA (messenger ribonucleic acid) in AR-targeted gene that promotes protein synthesis in these tissues.
Figure 2. Chemical structure of the basic molecules (on the left side) used to synthetize the selective androgen receptor modulators (on the right side). The
structural changes added on the basic molecule are highlighted in red.
trials. These seem to be well tolerated, presenting little risk of
interacting with other drugs as shown by in vitro studies [36].
Enobosarm promotes a similar anabolic response com-
pared with DHT via muscle AR activation, and its effect may
be also intermediated by non-muscle cell pathways that con-
tribute to the anabolic response [37]. In a recent study with
ovariectomized mice, the weight of the musculus gastrocne-
mius has been shown to be higher in all groups treated with
ostarine as well as bone mineral density and bone biomecha-
nical properties [16]. Moreover, the stimulation of reproduc-
tive organs with enobosarm seems to be less pronounced
compared to testosterone administration [38] due to its partial
agonist and antagonist effect on other androgen-dependent
tissues such as prostate and seminal vesicles [39].
In the POWER trials (POWER 1, NCT01355484 and POWER 2,
NCT01355497; Table 1), double-blind, placebo-controlled, and
multi-center phase III studies [40], patients with non-small-cell
lung cancer were given 3 mg of enobosarm or placebo for five
months. Despite a lower rate of decline in body weight in the
group treated with enobosarm in POWER 1, patients increased
LBM at day 84 and day 147 in POWER 1 (+0.41 kg) and POWER
2 (+0.47 kg) compared with patients receiving placebo.
However, no physical function improvement has been
reported in both studies [41].
To date, in spite of its preeminence as a potentially clinical
SARM, enobosarm is not approved for human use in any
country. It has been in the prohibited list for competition
purpose by the World Anti-Doping Agency since 2008
(WADA) [42]. For illegal use, however, it is available from
internet suppliers in the black market [43].
3.2. GSK 2881078
Glaxo-Smith-Kline (GSK) developed another non-steroidal
SARM that has provisionally been named GSK 2881078
(WO2015110958), which is the most successful drug in
a series of SARMs including GSK 971086 (NCT00540553), GSK
2849866 and GSK 2849466 (NCT01696604; Table 1). The
dosages under study for this compound have ranged from
0.1 mg to 10 mg daily.
GSK 2881078 has demonstrated improved anabolic
responses in skeletal muscle of orchiectomized rodents com-
pared with DHT, while producing minor increases in prostate
weight (unpublished data cited by reference 21) [22].
Moreover, the anabolic effect attributed to this compound
seems to be due to its half-life of nearly 7.5 days, which may
lead to more sustained anabolic responses caused by the time
exposure of the drug [44].
To date, GSK 2881078 has only been studied in a phase Ib
clinical trial showing to be safe and well tolerated in healthy
men aged ≥50 years and postmenopausal women [22].
A multi-center, randomized clinical trial in phase II is currently
underway in patients with chronic obstructive pulmonary dis-
ease (NCT03359473), including body composition and muscle
function assessments (Table 1).
3.3. GLPG-0492
GLPG-0492, also named DT-200, was developed by Galapagos
NV in 2010 as a clinical candidate drug for the treatment of
cachexia and muscular dystrophy [45]. The doses under study
have ranged from 0.5 mg to 120 mg administered daily.
In a mouse model of unilateral hindlimb immobilization,
GLPG-0492 has shown to prevent muscle atrophy in the
immobilized hindlimb in a dose-dependent manner, while
increasing gastrocnemius muscle weight in the contralateral
hindlimb at a dose of 3 mg/kg/d. The mechanisms behind
these adaptations were attributed to suppression/inhibition of
gene expression caused by GLPG-0492 in key muscle genes
(muscle RING (really interesting new gene) Finger-1, MurF-1;
forkhead box O1, FoxO1 and myogenin) and reduced inflam-
mation markers (tumor necrosis factor, TNF and interleukin 1β,
IL1β), similar to testosterone therapy in magnitude [46].
However, in a mouse model of Duchenne muscular dystrophy,
GLPG-0492 has shown improvements in strength and
Table 1. The available data in the public domain about clinical trials with SARMs and body composition/physical function outcomes.
Name Manufacturer Condition Phase of development CT identifier Current status
GTx-024 GTx Inc. Muscle wasting in Non-Small Cell Lung Cancer
Completed NCT01355484 On-going
GTx-024 GTx Inc. Muscle wasting in Non-Small Cell Lung Cancer
Completed NCT01355497 On-going
GTx-024 GTx Inc. Breast cancer Phase
Completed NCT02746328 On-going
LY2452473 Eli Lilly Prostate cancer Phase
Active, not
NCT02499497 On-going
GSK2881078 Glaxo-Smith-Kline Healthy older men and postmenopausal women Phase
Completed NCT02567773 On-going
GSK2881078 Glaxo-Smith-Kline Chronic obstructive pulmonary disease Phase
Active, not
NCT03359473 On-going
GSK2881078 Glaxo-Smith-Kline Healthy men (18–50 years) Phase
Completed NCT02045940 On-going
GSK2849466 Glaxo-Smith-Kline Healthy men (18–50 years) Phase
Completed NCT01696604 Unknown
VK-5211 Viking Therapeutics
Patients recovering from hip fracture Phase
Completed NCT02578095 On-going
GLPG0492 Galapagos NV Healthy older men and postmenopausal women Phase
Completed NCT01538420 Discontinued
MK-0773 Merck postmenopausal women with osteoporosis Phase
Completed NCT01011725 Discontinued
Table 2. Published clinical trials with SARMs and body composition/physical function outcomes.
period Outcomes Results
Adverse events (vs.
placebo) Reference
GTx-024 (0.1 mg, 0.3 mg, 1 mg or 3 mg) 86 days BC measured by DXA;
Physical function assessed by the
SCT (12 steps).
LBM by 1.3 kg in the 3-mg (p < 0.001) and 0.7 kg
in the 1-mg group vs. placebo (p = 0.055);
TFM by 0.3 kg in the 3-mg (p = 0.049) and
0.3 kg in the 1-mg group vs. placebo (p = 0.085);
SCT time by 0.8 sec in the 3-mg group vs.
placebo (p = 0.08);
SCT time by 0.6 sec in the 0.1-mg group vs.
placebo (p = 0.010);
SCT power by 50 watts in the 3-mg group vs.
placebo (p = 0.049);
SCT power by 17 watts in the 0.1-mg group vs.
placebo (p = 0.012).
ALT elevation (7% vs. 0%)
Urinary tract infection
(1% vs. 0%);
J Cachexia Sarcopenia Muscle.
2011; 2:153–161.
GTx-024 (1 mg or 3 mg) 113 days BC measured by DXA;
Physical function assessed by the
SCT (12 steps) and 6-min walking
Muscle strength measured by
hand grip.
LBM by 1.5 kg in the 1-mg (p = 0.0012) and 1.3 kg
in the 3-mg group vs. placebo (p = 0.046);
TFM for 1-mg (p = 0.210) and 3-mg group vs.
placebo (p = 0.328);
SCT time by 1.63 sec in the 1-mg (p = 0.0019)
and 2.22 sec in the 3-mg group vs. placebo
(p = 0.0065);
SCT power by 14 watts in the 1-mg
(p = 0.0008) and 17 watts in the 3-mg group vs.
placebo (p = 0.0006);
6-min walking test for 1-mg (p = 0.068) and
3-mg group vs. placebo (p = 0.987);
Grip strength for 1-mg (p = 0.222) and 3-mg
group vs. placebo (p = 0.747).
Anemia (6% vs. 4%);
Malignant neoplasm
progression (11% vs.
Thrombocytopenia (2%
vs. 6%).
Lancet Oncol. 2013;
GSK2881078 [0.35 mg in the first 28 days then 1.5 mg
until 56
day (for women) and 1.0 mg, 1.5 mg or 4 mg
(for men)]
56 days BC measured by DXA;
Thigh muscle volume measured
by MRI.
LBM by 3.39 kg (for women) and 1.76 kg (for
men) at the end of the higher dosage;
ALM by 1.83 kg (for women) and 1.21 kg (for
men) at the end of the higher dosage;
Thigh muscle volume by 80.4 ml (for women)
and 96.6 ml (for men) at the end of the higher
ALT elevation (3% vs. 0%). J Clin Endocrinol Metab.
LGD-4033 (0.1 mg, 0.3 mg or 1.0 mg) 21 days BC measured by DXA;
Physical function assessed by the
SCT (12 steps);
MVC measured by 1-RM leg
LBM by 1.21 kg in the 1-mg group (p = 0.047);
ALM for all groups (p = 0.078);
TFM for all groups (p = 0.261);
1-RM leg press for all groups (p = 0.203).
No drug-related severe or
serious adverse events
J Gerontol A Biol Sci Med Sci.
MK-0773 (50 mg) in only female participants 6 months BC measured by DXA;
Physical function assessed by the
SCT (4 steps) and SPPB test;
MVC measured by 1-RM leg
LBM by 1.26 kg vs. placebo (p < 0.001);
ALM by 0.72 kg vs. placebo (p < 0.001);
TFM by 0.84 kg vs. placebo (p = 0.186);
BMC by 0.2 kg vs. placebo (p = 0.137);
SCT power by 20 watts vs. placebo (p = 0.224);
Gait speed by 6.24 cm/sec vs. placebo
(p = 0.581);
1-RM leg press by 17.42lb vs. placebo
(p = 0.269).
ALT elevation (6% vs. 1%);
AST elevation (5% vs.
Acne (1% vs. 1%)
J Nutr Health Aging. 2013;
1-RM, one-repetition maximum; ALM, appendicular lean mass; ALT, alanine aminotransferase; AST, aspartate aminotransferase; BC, body composition; BMC, bone mineral content; DXA, dual energy X-ray absorptiometry; LBM,
lean body mass; MRI, magnetic resonance imaging; MVC, maximal voluntary contraction; SCT, stair climb test; SARMs, selective androgen receptor modulators; SPPB, short physical performance battery; TFM, total fat mass.
resistance to exercise fatigue without histological changes in
fiber diameter and muscle mass [47].
Moreover, GLPG-0492 has shown a clear dissociation
between anabolic and androgenic responses in a classic
model of orchiectomized male mice [45]. Apart from its indi-
cation for cachexia, GLPG-0492 has been the only SARM can-
didate proposed for the treatment of patients with muscular
dystrophy, however, even after three phase I clinical trials, this
compound has not advanced to phase II.
In March 2013, GLPG-0492 was renamed DT-200 after its acqui-
sition by DART Therapeutics, which later, in June 2014, became
Akashi Therapeutics. To date, DT-200 is still in phase I clinical trial
and is at the forefront of the company’s pipeline list [48].
3.4. Ligandrol
Ligandrol, also referred to as LGD-4033 or VK5211, is a tissue-
selective AR and is now under development by Viking
Therapeutics Inc. LG121071 was the precursor molecule of
Ligandrol discovered by Ligand Pharmaceuticals Inc. in 1999
[49]. On 22 May 2014 Viking Therapeutics Inc. obtained an
exclusive worldwide license from Ligand Pharmaceuticals Inc.
for VK5211, which the company intended to advance into
mid-to-late stage clinical trials [50].
In a model of gonadectomized mice, increases in the weight of
levator ani muscle (a skeletal muscle with a high density of AR) and
gastrocnemius muscle have been reported to occur in a dose-
dependent manner with the administration of LGD-3303 [51,52].
Another compound, LGD-2226, has shown similar results in muscle
cells, but also in prostatic tissue associated with enhanced sexual
function and motivation in a preclinical model [53]. Moreover, ingu-
inal fat has been shown to decrease with LGD-3303, while bone
mineral density, femur bending load and lumbar spine compression
load were increased in female rats. Thus, the increase reported in
body weight associated with Ligandrol may be due to muscle and
bone mass accrual combined with reduced fat mass [52].
Although the tissue concentration of LGD-3303 has been
reported to be higher in prostate than in muscles, ventral
prostate weight did not continue to increase above gonadal
levels in oral or continuous infusion of LGD-3303, showing
that the interaction of SARMs at the level of AR in prostatic
tissue may be different in relation to testosterone [51].
Moreover, in male cyomolgus monkeys, LGD-2941 showed to
upregulate gene expression for insulin like growth factor bind-
ing protein 3 (IGFBP3) while downregulating cathepsin L and
calpain 3, which are genes related to muscle synthesis and
degradation, respectively [54].
To date, there is only a phase II clinical trial completed with
VK5211 in patients suffering from hip fracture (NCT02578095; Table
1) and the disclosure of the results will eventually add information
on the impact of Ligandrol on body composition.
3.5. MK-0773
Merck has developed MK-0773, originally known as PF-05314882, in
association with GTx Inc. in 2007. MK-0773 is a 4-aza-steroid that
binds to AR, but it does not seem to interact with other steroid
receptors like glucocorticoid or progesterone receptors, increasing
the availability of this compound for AR [55]. For example, an
experimental study demonstrated MK-0773 to improve bone for-
mation and LBM to a similar degree like DHT, whilst showing minor
effects on the reproductive tracts and sebaceous glands in female
and male mice [55].
The collaboration between GTx Inc. and Merck to develop
MK-0773 ended on 17 March 2010, soon after Merck merged
with Schering-Plow Corporation, causing the discontinuation
of this candidate drug. Therefore, there is one clinical study
published with this compound (Table 2) and two other clinical
trials without reposted results in healthy older men
(NCT01017458) and postmenopausal women (NCT01011725;
Table 1). Merk has recently developed a new SARM termed
MK-4541, but its status has not been publicly disclosed [56].
3.6. BMS-564929
Another company in the SARM race is Bristol-Myers Squibb, which
has developed BMS-564929. In an experimental model of mature
castrated rats, BMS-564929 has shown similar affinity to binding
sites of AR compared to DHT. Moreover, this candidate drug has
been shown to be 200 times more potent in stimulating muscle
and 80 times more selective for skeletal muscle than prostatic tissue
[32]. However, to our knowledge, there is not currently a clinical trial
underway involving this compound.
3.7. RAD140
RAD140, commercially known as Testolone, is a non-steroidal AR
agonist developed by Radius Health Inc. in 2010 [57]. It has shown
to suppress genes related to estrogen receptor, such as estrogen
receptor 1 (ESR1), and activate AR in breast cancer cells [58].
Although RAD140 has been shown to increase LBM in
primates in a dose-dependent fashion within a short period
of time with no changes in fat mass, these results need to be
interpreted with caution, because there were only 3 monkeys
tested in each dosage group [57].
In an Alzheimer’s disease model, despite an increase in the
levator ani muscle weight, RAD140 has also increased prostate
and seminal vesicles weight, though these increases were
lower than the rats exposed to testosterone. In addition,
knowing that testosterone can also exert a central action on
neural cells, RAD140 was shown to decrease neural cell death
and promote neuroprotection to a similar extent like the
group treated with testosterone [59].
However, there is no published study with RAD140 in
humans yet and the first clinical trial in phase I is currently
underway recruiting postmenopausal women with breast can-
cer to test safety and tolerability (NCT03088527). Unfortunately,
this study does not include endpoints related to body composi-
tion and physical function.
3.8. Other compounds
The past two decades have witnessed the development of
a series of non-steroidal SARMs from globally-acting pharma-
ceutical companies and many SARMs are still in an early stage
of development.
Several candidates, such as JNJ-28330835 [60], JNJ-
37654032 [20], S-1 [61], S-4 [62], and S-40503 [63], have not
advanced to phase I clinical trials. The progression of other
compounds, such as S-23, BMS-564929, TFM-4 AS-1 and YK-11,
is still unknown, while other compounds, including LGD-2226,
LGD-2941, GLPG-0492, PF-06260414 [64], and MK-0773 have
been discontinued after preclinical or phase I clinical studies
(Table 1) [31]. However, there is still limited information about
the action and applicability of these SARMs. Interestingly, new
routes of administration of SARMs have been recently
explored by Eli Lilly, which developed patches containing
a compound termed LY305 [65].
4. Clinical trials investigating SARMs
Several companies have developed a considerable number of
SARMs. Although SARMs have attracted attention as
a potential treatment for patients with muscle wasting, there
are currently only few published papers focused on body
composition and physical function adaptation.
In a double-blind, placebo controlled phase II clinical trial,
enobosarm has shown a dose-dependent increase in total
LBM for the 1-mg group (0.7 ± 0.3 kg; p = 0.055) and the
3-mg group (1.3 ± 0.3 kg; p < 0.001). Fat mass decreased on
average in healthy men aged ≥60 years and postmenopausal
women about 0.6 kg in comparison to controls [23]. Moreover,
in the 3-mg group, there was a positive impact on physical
performance measured by the stair climbing power test (Table
2) [23]. A large randomized phase II clinical trial in men
(>45 years) and postmenopausal women with cancer, part of
the POWER trial program, reported an improvement in LBM in
the 1-mg (1.5 ± 2.7 kg; p = 0.0012) and 3-mg group (1.3 ± 3.5;
p = 0.046) compared with patients on placebo [25].
Additionally, the stair climbing test was improved in both
groups submitted to the intervention, without any difference
for placebo patients (Table 2) [25].
Results from the AUSTRID study, a phase II clinical trial
assessing the safety and effectiveness of GTx-024 in postme-
nopausal women with stress urinary incontinence
(NCT02658448), have shown an improvement in the diameter
of pelvic muscles. In addition, in a study with GSK 2881078
after 8 weeks of treatment, healthy men ≥50 years old and
postmenopausal women showed a dose-related increase in
LBM and appendicular lean mass (ALM). Interestingly, the
female participants were more sensitive to the compound
compared to males [3.39 ± 0.406 kg vs. 1.76 ± 0.767 kg for
LBM, respectively], showing a sex-related effect with the
administration of this SARM [22]. Although GSK 2881078 was
the only SARM to report significant differences in LBM
between men and women, the effect of SARMs on sex-
dependent outcomes is still unknown.
On the other hand, the SARM-induced improvement in
LBM may not always reflect physical function enhancement.
In a double blind, placebo-controlled study in healthy young
men (21–50 years), LGD-4033 increased on average 1.21 kg of
LBM (p = 0.047 vs. placebo), also showing a positive correla-
tion with the dosage increase. Although stair-climbing speed,
power and strength showed a trend toward dose-related
improvement, there was no statistical difference for these
variables when compared to placebo [21]. The age of the
subjects in this study may have limited the results on
parameters of performance, since this age group is not likely
to present substantial reductions in physical performance.
In a multi-center study that enrolled women ≥65 years old
with sarcopenia, the participants were randomly submitted to
a 6-month intervention with MK-0773 (n = 81) or placebo
(n = 89), both conditions associated with protein and vitamin
D supplementation. Although there was an increase in LBM
(1.26 ± 1.09 vs. 0.29 ± 1.29; p < 0.001) and ALM (0.72 ± 0.55 vs.
0.15 ± 0.69; p < 0.001) with MK-0773, these changes in body
composition were not associated with improvements in mus-
cle strength and physical performance that could be deemed
clinically relevant. However, participants with milder mobility
disability (short physical performance battery score ≥8; SPPB)
showed a greater response to MK-0773 than those with
reduced disability [24].
This dissociation between LBM gains and physical function
improvement may be attributed to bioenergetics adaptation
reported with SARM administration, such as increases in inter-
mediates of the Krebs cycle and oxidative metabolism, show-
ing that physical performance may be related to metabolic
adaptation instead of morphological alterations in the muscle
[46]. These metabolic adaptations may reflect an improvement
in handgrip strength and tests related to physical performance
like SPPB and stair climbing test. Additionally, the lack of
strong association between increased LBM and physical func-
tion may also be due to confounding factors, such as age,
baseline physical function, stage of the disease, associated
comorbidities, type of SARM administered [66] and treatment
exposure to other drugs.
Therefore, the ideal SARM for the treatment of muscle
wasting in patients with chronic diseases is still under devel-
opment and seems to be an oral compound, although new
transdermal compounds have been developed [65]. The effect
on body composition, increasing muscle/bone mass and
decreasing fat mass, has been demonstrated with different
compounds, but the clinical impact on muscle strength and
physical function of these morphological adaptations is still
inconsistent and we do not know the long-term outcomes of
these drugs.
5. Side effects of SARMs
Despite the consistent effect demonstrated by SARMs on LBM
accrual, reductions in high-density lipoprotein (HDL) with even
lower doses seem to be an important concern with these
compounds, though it occurs to a lesser extent compared to
testosterone [21,23,44]. For instance, to proceed with enobo-
sarm into a phase III clinical trial in patients with sarcopenia,
the FDA requested a cardiovascular safety study, which the
manufacturer refused to undertake due to considerable costs
and decided to test enobosarm in cancer cachexia patients in
whom the FDA was more tolerant to the long-term cardiovas-
cular side effects [67].
The suppression of the hypothalamic-pituitary-gonadal axis is
another concern involving SARMs. A study with LGD-4033 in
healthy men (21–50 years) reported a dose-related suppression
in total testosterone and sex hormone-binding globulin levels
after 21 consecutive days of administration, though the hormone
levels return to baseline by day 56 after discontinuation [21].
Furthermore, SARMs administration has also been related
to hepatotoxicity and some compounds have shown liver
enzymes alterations, the most common adverse events being
increases in alanine transaminase and aspartate transaminase.
However, these changes affected 9 out of 81 participants
(11%) in a study with a daily dosage of 50 mg of MK-0773
[24] and 7 out of 96 participants (7%) in another study with
3 mg of enobosarm [23].
6. Expert opinion
Increased LBM and improved physical performance have been
associated with better prognosis and quality of life in patients
with chronic diseases and muscle wasting disorder. Although
SARMs have been shown to increase LBM in phase II clinical
trials, its implementation on clinical practice is still debatable
due to inconsistent results on physical function improvement.
A complete understanding of the mechanisms involved in
synthesis and degradation of skeletal muscle is the base to
start thinking about an effective intervention. Even though the
development of muscle wasting may share a common path-
way associated with increased levels of inflammatory markers,
decreased protein synthesis, elevated protein degradation and
atrophy from disuse, the physiological mechanisms behind
these changes are still not clear.
SARMs, a proposed treatment that tackles the anabolic side
of the wasting spectrum, are in early stage of development so
that the inclusion of new compounds, apart from those cited
in their specific sections, in this class of drug is still fully
opened. Although oral administration has been mostly used
in clinical trials, transdermal patches have been recently devel-
oped and it may allow a more sustained anabolic response
due to a steady release of the compound into the circulation.
In our point of view, the evolvement of SARMs may follow
what we have witnessed with testosterone treatment, which
evolved from injection to gel administration. Despite the
required improvement on physical function imposed by the
FDA for approval, the compounds that may progress into
clinical practice are those with higher anabolic action and
lower androgenic activation.
The inconsistent results reported with SARMs may also lie on
differences in prescription (type, dosage, time exposure and
frequency of administration), like any other drug. In addition,
age, disease stage, baseline muscle mass as well as physical
function, and association with other pharmacological treat-
ments are the other confounders to explain the disconnection
between increased LBM and physical function enhancement.
Thus, to improve the efficacy of SARMs, future clinical trials
should focus on endpoints that tackle these questions.
Moreover, taking into consideration that the development
of muscle wasting is multifactorial, so should be the approach
to prevention and treatment. In this perspective, administra-
tion of SARMs in future clinical trials should be concomitantly
done with nutrition interventions and exercise training to
optimize the gains in LBM and physical function as it has
been proposed in clinical trials with other drugs [68].
Furthermore, along with SARMs, anamorelin [69,70], an
agonist of ghrelin receptor, and espindolol [71],
a nonselective β-blocker, are other leading candidates to
treat patients with muscle wasting, but these compounds,
just like SARMs, are still lacking improvement on clinical out-
comes, such as handgrip strength and physical performance.
Although the accretion of contractile component (more mus-
cle mass) plays an important role in muscle function, the lack
of improvement on muscle strength reported with all these
drugs may be related to their limited capability to affect motor
unit recruitment as well as metabolic patterns. Moreover,
increases in LBM may not necessarily result only in muscle
mass accrual, considering that other structure, such as con-
junctive tissue, can be part of this gain. The specificity of
physical function assessment, focused on lower or upper
limb (e.g. stair climbing test and handgrip strength) and
whole body function (i.e. SPPB), also plays a role in this dis-
connection with LBM.
Indeed, considering the limitations to be addressed in
future studies and the treatment potential of drug-related
muscle wasting, we may see some of these compounds
advancing into clinical practice in the presence of allied thera-
pies, like positive protein intake, exercise training or even
neuromuscular electrical stimulation.
7. Conclusion and perspectives for future research
In summary, there are no currently approved pharmacological
therapies for the prevention or treatment of muscle wasting in
chronic diseases, although there is an unmet clinical need for
safe and effective anabolic compounds such as SARMs. Despite
the effect on LBM shown by these compounds in phase II clinical
trials, results on improved muscle strength and physical function
are still lacking and long-term outcomes have to be assessed,
not only in patients with sarcopenia/cachexia, but also in
patients with muscular dystrophy. Moreover, there is a need to
determine the effect of resistance exercise training and protein
intake, as recently recommended by the Society on Sarcopenia,
Cachexia and Wasting Disorders [72], associated with SARMs in
the treatment of patients with muscle wasting.
The preparation of this manuscript was nanced in part by the
Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - Brazil
(CAPES) - Finance Code 001 and by the German Center for Cardiovascular
Research (DZHK).
Declaration of interest
S von Haehling has been a paid consultant and/or received fees for
lectures from Bayer, Boehringer Ingelheim, BRAHMS/Thermo Fisher,
Chugai Pharma, Grünenthal, Helsinn, Novartis, Pharmacosmos,
Respicardia, Roche, Servier, and Vifor. The authors have no other relevant
affiliations or financial involvement with any organization or entity with
a financial interest in or financial conflict with the subject matter or
materials discussed in the manuscript apart from those disclosed.
Reviewer disclosures
Peer reviewers on this manuscript have no relevant financial relationships
or otherwise to disclose.
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... However, in contrast to AASs, SARMS have decreased activity on nontargeted tissues such as the heart, prostate, and liver. 1 Additionally, lack of the 5α-reductase metabolism of SARMs prevents androgenic side effects such as virilization, androgenic alopecia, or prostatic hyperplasia. [2][3][4][5] Furthermore, many AASs cannot be delivered orally because of rapid hepatic clearance. 5,6 That has led to the development of 17α-alkylated AASs which reduce hepatic metabolism but increase the risk of liver toxicity. ...
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Selective androgen receptor modulators (SARMs) are a class of nonsteroidal drugs that are favored over anabolic an-drogenic steroids (AASs) for their tissue-selectivity and improved side-effect profile. These drugs have been evaluated for treatment of various diseases including muscle-wasting disorders, osteoporosis, and breast cancer. Despite lacking approval for therapeutic use, SARMs are widely used recreationally as performance enhancing drugs by bodybuilders and athletes. In recent years, cases of drug-induced liver injury (DILI) secondary to SARMs have begun to emerge, but little is known regarding their hepatotoxicity. In this review , we provide current knowledge regarding DILI from SARMs. A literature search was conducted regarding SARMs and liver injury to evaluate relevant cases and information. SARMs have been associated with a cholestatic syndrome congruent with that of DILI from AASs, and it consists of a bland cholestasis in which there is minimal bile duct injury, inflammation, or necrosis. Patients present with an insidious onset of jaundice with marked hyperbilirubinemia and mild hepatic enzyme elevations. No clear treatment exists, although patients typically show improvement with cessation of the offending SARM. Given the novelty of these drugs, further study is necessary to understand diagnosis, management , and complications of SARM-related DILI.
... SARMs work with the androgen receptors in various tissues to deliver a focused, therapeutic impact. They have proven to ameliorate body composition, increase muscle mass and decrease fat composition in various clinical studies [68,69]. ...
Sarcopenia is an illness of the elderly defined by a widespread and gradual decline of skeletal muscle mass and function, with the possibility of negative effects such as poor physical performance, decreased quality of life, and death. Sarcopenia has complicated and multiple pathogeneses. The shift in pathways necessary for muscle regeneration, inflammatory process, and protein synthesis appears to be one of the leading causes of loss of strength and muscle due to age. Researchers have discussed the effects of hypothalamic-pituitary dysfunction in this condition. Lifestyle factors like diet and exercise significantly influence body composition, physical function, and metabolic consequences. The effectiveness and tolerability of hormone replacement in treating sarcopenia will be determined through large-scale clinical trials. In this article, we present a summary of our current knowledge regarding the role of the endocrine system in sarcopenia and an overview of hormonal therapy to address endocrine abnormalities.
... However, its clinical use is limited by its possible side effects (increased risk of cardiovascular events and skin diseases). Selective androgen receptor modulators (SARMs) have been shown to have similar results to testosterone with fewer side effects in androgen-dependent tissues, but their implementation in clinical practice remains controversial (Fonseca et al., 2020). ...
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Chronic obstructive pulmonary disease (COPD) is a common pulmonary disease characterized by persistent respiratory symptoms and airflow obstruction. In addition to lung diseases, chronic obstructive pulmonary disease (COPD) is often associated with other organ diseases, and sarcopenia is one of the common diseases. In recent years, multiple factors have been proposed to influence muscle dysfunction in COPD patients, including systemic and local inflammation, oxidative stress, hypoxia, hypercapnia, protein synthesis, catabolic imbalance, nutritional changes, disuse, ageing, and the use of medications such as steroids. These factors alone or in combination can lead to a reduction in muscle mass and cross-sectional area, deterioration of muscle bioenergy metabolism, defects in muscle repair and regeneration mechanisms, apoptosis and other anatomical and/or functional pathological changes, resulting in a decrease in the muscle’s ability to work. This article reviews the research progress of possible pathogenesis of sarcopenia in COPD.
... Few pharmacotherapies have been developed specifically for sarcopenia, with most being used to attenuate muscle wasting and weakness associated with conditions such as muscle trauma, metabolic and neuromuscular disease(s) and cancer. Available reviews include results from trials on anabolic approaches to increase muscle (lean) mass and improve muscle strength, such as testosterone replacement, targeting myostatin with neutralizing antibodies, targeting the activin receptor with an antagonist, or treating with selective androgen receptor modulators (141). Despite preclinical studies showing potential of these approaches for attenuating muscle loss or enhancing lean mass, translation to clinical trials is modest and fails to meet clinically relevant outcomes related to muscle strength and physical performance or frailty (142,143). ...
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Sarcopenia and frailty are highly prevalent conditions in older hospitalized patients, which are associated with a myriad of adverse clinical outcomes. This paper, prepared by a multidisciplinary expert working group from the Australian and New Zealand Society for Sarcopenia and Frailty Research (ANZSSFR), provides an up-to-date overview of current evidence and recommendations based on a narrative review of the literature for the screening, diagnosis, and management of sarcopenia and frailty in older patients within the hospital setting. It also includes suggestions on potential pathways to implement change to encourage widespread adoption of these evidence-informed recommendations within hospital settings. The expert working group concluded there was insufficient evidence to support any specific screening tool for sarcopenia and recommends an assessment of probable sarcopenia/sarcopenia using established criteria for all older (≥65 years) hospitalized patients or in younger patients with conditions (e.g., comorbidities) that may increase their risk of sarcopenia. Diagnosis of probable sarcopenia should be based on an assessment of low muscle strength (grip strength or five times sit-to-stand) with sarcopenia diagnosis including low muscle mass quantified from dual energy X-ray absorptiometry, bioelectrical impedance analysis or in the absence of diagnostic devices, calf circumference as a proxy measure. Severe sarcopenia is represented by the addition of impaired physical performance (slow gait speed). All patients with probable sarcopenia or sarcopenia should be investigated for causes (e.g., chronic/acute disease or malnutrition), and treated accordingly. For frailty, it is recommended that all hospitalized patients aged 70 years and older be screened using a validated tool [Clinical Frailty Scale (CFS), Hospital Frailty Risk Score, the FRAIL scale or the Frailty Index]. Patients screened as positive for frailty should undergo further clinical assessment using the Frailty Phenotype, Frailty Index or information collected from a Comprehensive Geriatric Assessment (CGA). All patients identified as frail should receive follow up by a health practitioner(s) for an individualized care plan. To treat older hospitalized patients with probable sarcopenia, sarcopenia, or frailty, it is recommended that a structured and supervised multi-component exercise program incorporating elements of resistance (muscle strengthening), challenging balance, and functional mobility training be prescribed as early as possible combined with nutritional support to optimize energy and protein intake and correct any deficiencies. There is insufficient evidence to recommend pharmacological agents for the treatment of sarcopenia or frailty. Finally, to facilitate integration of these recommendations into hospital settings organization-wide approaches are needed, with the Spread and Sustain framework recommended to facilitate organizational culture change, with the help of ‘champions’ to drive these changes. A multidisciplinary team approach incorporating awareness and education initiatives for healthcare professionals is recommended to ensure that screening, diagnosis and management approaches for sarcopenia and frailty are embedded and sustained within hospital settings. Finally, patients and caregivers’ education should be integrated into the care pathway to facilitate adherence to prescribed management approaches for sarcopenia and frailty.
Repeated, episodic bouts of skeletal muscle contraction undertaken frequently as structured exercise training is a potent stimulus for physiological adaptation in many organs. Specifically in skeletal muscle, remarkable plasticity is demonstrated by the remodeling of muscle structure and function in terms of muscular size, force, endurance, and contractile velocity as a result of the functional demands induced by various types of exercise training. This plasticity, and the mechanistic basis for adaptations to skeletal muscle in response to exercise training, is underpinned by activation and/or repression of molecular pathways and processes induced in response to each individual acute exercise session. These pathways include the transduction of signals arising from neuronal, mechanical, metabolic, and hormonal stimuli through complex signal transduction networks, which are linked to a myriad of effector proteins involved in the regulation of pre- and post-transcriptional processes, and protein translation and degradation processes. This review therefore describes acute exercise-induced signal transduction and the molecular responses to acute exercise in skeletal muscle including emerging concepts such as epigenetic pre- and post-transcriptional regulation, and the regulation of protein translation and degradation. A critical appraisal of methodological approaches and the current state of knowledge informs a series of recommendations offered as future directions in the field.
Although the main bishydroxylated long-term metabolite of the WADA-banned anabolic agent ligandrol (LGD-4033) is an important metabolic marker, it is not readily available in sufficient quantities to facilitate the development...
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Androgens are an important and diverse group of steroid hormone molecular species. They play varied functional roles, such as the control of metabolic energy fate and partition, the maintenance of skeletal and body protein and integrity and the development of brain capabilities and behavioral setup (including those factors defining maleness). In addition, androgens are the precursors of estrogens, with which they share an extensive control of the reproductive mechanisms (in both sexes). In this review, the types of androgens, their functions and signaling are tabulated and described, including some less-known functions. The close interrelationship between corticosteroids and androgens is also analyzed, centered in the adrenal cortex, together with the main feedback control systems of the hypothalamic–hypophysis–gonads axis, and its modulation by the metabolic environment, sex, age and health. Testosterone (T) is singled out because of its high synthesis rate and turnover, but also because age-related hypogonadism is a key signal for the biologically planned early obsolescence of men, and the delayed onset of a faster rate of functional losses in women after menopause. The close collaboration of T with estradiol (E2) active in the maintenance of body metabolic systems is also presented Their parallel insufficiency has been directly related to the ravages of senescence and the metabolic syndrome constellation of disorders. The clinical use of T to correct hypoandrogenism helps maintain the functionality of core metabolism, limiting excess fat deposition, sarcopenia and cognoscitive frailty (part of these effects are due to the E2 generated from T). The effectiveness of using lipophilic T esters for T replacement treatments is analyzed in depth, and the main problems derived from their application are discussed.
Herein, a green dispersive liquid-liquid microextraction (DLLME) based on hydrophilic and hydrophobic deep eutectic solvents (DESs) was developed for the enrichment of bicalutamide (BIC) from water and spiked human plasma. Six hydrophobic and three hydrophilic DESs were synthesized and evaluated. The hydrophilic DES, composed of tetrabutylammonium bromide and acetic acid in a molar ratio of 1:2, was used as a dispersive solvent. Moreover, the hydrophobic DES, composed of borneol and capric acid in a molar ratio of 1:2, was applied as an extracting solvent. Significant factors affecting the extraction efficiency were investigated through the one-factor-at-a-time (OFAT) strategy. The optimized method was validated in terms of linearity, limits of detection and quantitation, accuracy, precision, and matrix effect. Good linearity with an excellent correlation coefficient (r² > 0.9999 and 0.9987) was achieved as well as low limits of detection of 0.022 and 0.048 μg/mL and preconcentration up to 53.2 and 92.1 folds for water and plasma, respectively. The proposed DLLME method was coupled with spectrophotometric detection and applied for the analysis of BIC in river water and spiked human plasma with satisfactory recoveries (92.54–99.39%). Finally, the greenness of the developed procedure was evaluated using Complex Green Analytical Procedure Index (ComplexGAPI) and Analytical GREEnness (AGREEprep) tools, exhibiting excellent greenness in comparison to the previously reported methods.
Osteosarcopenia is a growing healthcare challenge. This is compounded by a lack of pharmacological strategies to treat both muscle and bone simultaneously. While there are no approved medications for osteosarcopenia, there are some compounds that are known to have a dual role in the treatment of muscle and bone. This chapter discusses the relevant literature, the efficacy, and the challenges surrounding these agents, as well as identifying avenues of future research. Agents of the androgen and endocrine axes repurposed antifracture medications, and factors involved in the crosstalk in muscle and bone are discussed. While there are a number of promising opportunities for future research, as yet there is no clear front-runner in the race to a treatment. More research into the relationship between muscle and bone is required to identify key components of their intertwined physiologies in order to identify the critical factors and pathways that might regulate the disease.
Osteoporosis is a common disease in which the risk of fracture increases due to decreased bone mass and qualitative skeletal changes. Selective androgen receptor modulators (SARMs) are agonists with tissue selectivity, which act as partial or weak androgen receptor (AR) agonists in androgenic tissues, but mainly as complete AR agonists in synthetic metabolic tissues. In the recent 20 years, many scaffolds of SARMs have been reported, among which several molecules are promising and are undergoing clinical trial evaluation. However, it is still a challenge to discover SARMs with high activity and reduced side effects. In this review, not only are structure of SARMs reported in the literatures systematically collected and classified but also the structure-activity relationships (SAR) are systematically summarized. Furthermore, the advances in SARMs as potential treatment for osteoporosis are also updated.
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Non-steroidal selective androgen receptor modulators, including ostarine, have been developed as an alternative to steroidal hormones. Ostarine has shown a beneficial effect on bone in experimental studies, but no data regarding the effect of ostarine on bone healing have yet been reported. We investigated effects of ostarine on bone healing in ovariectomized rats. Sprague-Dawley rats (3 months old) were ovariectomized (Ovx, n = 46) or left intact (Non-Ovx, n = 10). After 8 weeks, an osteotomy of the tibia metaphysis was created in all rats, and the Ovx rats were divided into four groups: untreated Ovx (n = 10) and three Ovx groups (each of 12 rats) treated with ostarine at doses of 0.04, 0.4, or 4 mg/kg BW (OS-0.04, OS-0.4, and OS-4 groups). Five weeks later, bone healing was analyzed. The OS-4 dose enhanced callus formation, increased callus density, accelerated bridging time of the osteotomy, and elevated alkaline phosphatase gene expression in callus and its protein expression in serum. In the Ovx group, most of the callus parameters were diminished. All OS treatments increased the weight of the gastrocnemius muscle, but only partly enhanced uterus weight in OS-0.4 and OS-4. Serum cholesterol level was reduced, and serum phosphorus was elevated in OS-0.04 and OS-4. Ostarine appeared to have a positive effect on early bone healing in ovariectomized rats. Considering its favorable effect on non-osteotomized bone and muscle, this treatment could be further explored as a therapy for osteoporosis. However, possible metabolic side effects should first be evaluated.
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The term sarcopenia was introduced in 1988. The original definition was a “muscle loss” of the appendicular muscle mass in the older people as measured by dual energy x‐ray absorptiometry (DXA). In 2010, the definition was altered to be low muscle mass together with low muscle function and this was agreed upon as reported in a number of consensus papers. The Society of Sarcopenia, Cachexia and Wasting Disorders supports the recommendations of more recent consensus conferences, i.e. that rapid screening, such as with the SARC‐F questionnaire, should be utilized with a formal diagnosis being made by measuring grip strength or chair stand together with DXA estimation of appendicular muscle mass (indexed for height2). Assessments of the utility of ultrasound and creatine dilution techniques are ongoing. Use of ultrasound may not be easily reproducible. Primary sarcopenia is aging associated (mediated) loss of muscle mass. Secondary sarcopenia (or disease‐related sarcopenia) has predominantly focused on loss of muscle mass without the emphasis on muscle function. Diseases that can cause muscle wasting (i.e. secondary sarcopenia) include malignant cancer, COPD, heart failure, and renal failure and others. Management of sarcopenia should consist of resistance exercise in combination with a protein intake of 1 to 1.5 g/kg/day. There is insufficient evidence that vitamin D and anabolic steroids are beneficial. These recommendations apply to both primary (age‐related) sarcopenia and secondary (disease related) sarcopenia. Secondary sarcopenia also needs appropriate treatment of the underlying disease. It is important that primary care health professionals become aware of and make the diagnosis of age‐related and disease‐related sarcopenia. It is important to address the risk factors for sarcopenia, particularly low physical activity and sedentary behavior in the general population, using a life‐long approach. There is a need for more clinical research into the appropriate measurement for muscle mass and the management of sarcopenia. Accordingly, this position statement provides recommendations on the management of sarcopenia and how to progress the knowledge and recognition of sarcopenia.
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Background: Gait speed (GS) and handgrip strength (HGS), both factors associated with frailty and sarcopenia, are reportedly associated with CV events in the general population. However, little is known about the impact of these factors on the outcome of patients on dialysis. This study aimed to evaluate whether evaluation of GS and HGS could be associated the onset of fatal/non-fatal cardiovascular (CV) events in patients on haemodialysis (HD). Methods: One-hundred-eighty-two patients with end-stage renal disease (ESRD) undergoing HD at four dialysis clinics in April 2015 provided written informed consent to participate in the study. We excluded patients who had physical disability, were unable to walk without help, or had recently experienced CV events. Usual GS over a 4-m walk and HGS were measured at baseline, and 173 patients (men, 124; women, 49) were divided into sex-specific quartiles according to GS and HGS and were followed-up for fatal/non-fatal CV events for a median of 2 years. We examined the association of GS and HGS with CV events and determined cut-off values using Cox regression analysis adjusted for age, sex, HD duration, history of CVD, and diabetes. Results: During the follow-up period, 46 CV events occurred. Both physical performance factors were significantly associated with CV events. Low GS (< 0.82 m/s for men and 0.81 m/s for women) and weak HGS (< 29.0 kg for men and 19.7 kg for women) were associated with CV events. For low vs. high GS, the hazard ratio (HR) for CV events was 2.29 [95% confidence interval (CI): 1.20-4.33; P = 0.01], and for low vs. high HGS, the HR was 2.15 [95% CI: 1.00-5.04; P < 0.05]. These HRs remained significant after adjusting for confounding factors, such as sex, age, dialysis vintage, history of CV disease, and diabetes. Conclusions: Slow GS and weak HGS in patients on HD were suggested to be independent predictors of fatal/non-fatal CV events.
Chronic kidney disease (CKD), a chronic catabolic condition, is characterized by muscle wasting and decreased muscle endurance. Many insights into the molecular mechanisms of muscle wasting in CKD have been obtained. A persistent imbalance between protein degradation and synthesis in muscle causes muscle wasting. During muscle wasting, high levels of reactive oxygen species (ROS) and inflammatory cytokines are detected in muscle. These increased ROS and inflammatory cytokine levels induce the expression of myostatin. The myostatin binding to its receptor activin A receptor type IIB stimulates the expression of atrogenes such as atrogin-1 and muscle ring factor 1, members of the muscle-specific ubiquitin ligase family. Impaired mitochondrial function also contributes to reducing muscle endurance. The increased protein-bound uremic toxin, parathyroid hormone, glucocorticoid, and angiotensin II levels that are observed in CKD all have a negative effect on muscle mass and endurance. Among the protein-bound uremic toxins, indoxyl sulfate, an indole-containing compound has the potential to induce muscle atrophy by stimulating ROS-mediated myostatin and atrogenes expression. Indoxyl sulfate also impairs mitochondrial function. Some potential therapeutic approaches based on the muscle wasting mechanisms in CKD are currently in the testing stages. Graphical Abstract Fullsize Image
Androgen receptor (AR) is a steroid hormone nuclear receptor which upon binding its endogenous androgenic ligands (agonists), testosterone and dihydrotestosterone (DHT), alters gene transcription producing a diverse range of biological effects. Anti-androgens, such as the pharmaceuticals bicalutamide and hydroxyflutamide, act as agonists in the absence of androgens and as antagonists in their presence or in high concentration. The atomic level mechanism of action by agonists and antagonists of AR is less well characterized. Therefore, in this study, multiple 1 µs molecular dynamics (MD), docking simulations and perturbation-response analyses were performed to more fully explore the nature of interaction between agonist or antagonist and AR and the conformational changes induced in the AR upon interaction with different ligands. We characterized the mechanism of the ligand entry/exit and found that Helix-12 and nearby structural motifs respond dynamically in that process. Modeling showed that the agonist and antagonist/agonist form a hydrogen bond with Thr877/Asn705 and that this interaction is absent for antagonists. Agonist binding to AR increases mobility of residues at allosteric sites and co-activator binding sites, while antagonist binding decreases mobility at these important sites. A new site was also identified as a potential surface for allosteric binding. These results shed light on the effect of agonists and antagonists on the structure and dynamics of AR.
The prevalence of malnutrition in patients with cancer has frequently been shown to be one of the highest of all hospital patient groups. Weight loss is a frequent manifestation of malnutrition in patients with cancer. Several large-scale studies over the last 35 years have reported that involuntary weight loss affects 50-80% of these patients with the degree of weight loss dependent on tumour site, type and stage of disease. This review will focus on the consequences of malnutrition, weight loss and muscle wasting in relation to chemotherapy tolerance, post-operative complications, quality of life and survival in oncology patients. The prognostic impact of weight loss on overall survival has long been recognised with recent data suggesting losses as little as 2.4% predicts survival independent of disease, site, stage or performance score. Recently the use of gold-standard methods of body composition assessment, including computed tomography, have led to an increased understanding of the importance of muscle abnormalities, such as low muscle mass (sarcopenia), and more recently low muscle attenuation, as important prognostic indicators of unfavourable outcomes in patients with cancer. Muscle abnormalities are highly prevalent (ranging from 10-90%, depending on cancer site and the diagnostic criteria used). Both low muscle mass and low muscle attenuation have been associated with poorer tolerance to chemotherapy; increased risk of postoperative complications; significant deterioration in a patients' performance status, and poorer psychological well-being, overall quality of life, and survival.
Selective androgen receptor modulators comprise compounds that bind as ligands to the androgen receptor and possess tissue-selective activities. Ideally, they show agonistic properties in anabolic target tissues, while inducing antagonistic or only weak agonistic effects in reproductive organs. Due to their myoanabolic effects, selective androgen receptor modulators are included in the list of prohibited substances and methods of the World Anti-Doping Agency. In the current investigation, the androgenic potential of RAD-140, GSK-2881078 and GLPG0492 was comparably investigated in two different in vitro bioassays. In the yeast androgen screen, the androgenic effects were lower than in the reporter gene assay in prostate carcinoma cells (e.g. for GSK-2881078, the EC 50 values were 4.44 × 10 ⁻⁶ M in the yeast screen and 3.99 × 10 ⁻⁹ M in the prostate cells respectively). For future investigations, it is of importance whether the yeast androgen screen, which has been proven to detect androgenic compounds in urine, can detect an abuse of the selective androgen receptor modulators. Molecular modeling of the binding to the androgen receptor ligand binding domain suggests slight differences in the binding modes of RAD-140, GSK-2881078 and GLPG0492. In conclusion, androgenic activity of the three non-steroidal compounds in the two different in vitro test systems confirmed the results of the in silico modeling of the androgen receptor binding.
GSK2881078 is a non-steroidal, selective androgen receptor modulator (SARM) under investigation by GlaxoSmithKline (GSK) for treatment of reduced mobility and other functional limitation in men and women with muscle weakness associated with chronic and acute illnesses. Objective This was a phase 1b study intended to explore across a dose range the pharmacokinetic (PK) - pharmacodynamic (PD) relationship and further safety and tolerability data for GSK2881078. This study also evaluated effects of CYP3A4 inhibition on pharmacokinetics (PK) of GSK2881078. Methods This was a randomized, placebo controlled, parallel group, repeat dose, dose-escalation study in healthy older males and post-menopausal females. A total of 3 cohorts of males and 3 cohorts of females were studied. Dosing at each dose level was twice daily (BID) for the first 3 days followed by once daily for up to 53 days Repeated dual energy X-Ray absorptiometry (DXA) and magnetic resonance imaging (MRI) cross-sectional thigh scans were performed. The effect of CYP3A4 inhibition on GSK2881078 PK was evaluated in a separate cohort. Results GSK2881078 was generally well tolerated and no serious adverse events (SAEs) were reported. Compared to placebo, there was greater lean mass accrual with all dose levels of GSK2881078. Females exhibited a greater response at lower doses than males. Transient elevations of ALT were observed. The effect of CYP3A4 inhibition on GKS2881078 pharmacokinetics was unlikely to be of clinical significance. Conclusions GSK2881078 yielded dose-dependent increases in lean mass with evidence of enhanced sensitivity in women. The compound was well tolerated.
We have identified a non-steroidal selective androgen receptor modulator (SARM), termed LY305, that is bioavailable through a transdermal route of administration while highly cleared via hepatic metabolism to limit parent compound exposure in the liver. Selection of this compound and its transdermal formulation was based on the optimization of skin absorption properties using both in vitro and in vivo skin models that supported PBPK modeling for human PK predictions. This molecule is an agonist in perineal muscle while being a weak partial agonist in the androgenic tissues such as prostate. When LY305 was tested in animal models of skeletal atrophy it restored the skeletal muscle mass through accelerated repair. In a bone fracture model, LY305 remained osteoprotective in the regenerating tissue and void of deleterious effects. Finally, in a small cohort of healthy volunteers, we assessed the safety and tolerability of LY305 when administered transdermally. LY305 showed a dose-dependent increase in serum exposure and was well tolerated with minimal adverse effects. Notably, there were no statistically significant changes to hematocrit or HDL after 4-week treatment period. Collectively, LY305 represents a first of its kind de novo development of a non-steroidal transdermal SARM with unique properties which could find clinical utility in hypogonadal men.