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E d i t o r i a l
Myostatin Inhibition: A New Treatment for Androgen
Deprivation-Induced Sarcopenia?
Mathis Grossmann
Department of Medicine Austin Health, University of Melbourne, and Endocrine Unit, Austin Health,
Heidelberg, Victoria 3052, Australia
I
n nonobese individuals, muscle is the largest organ by
mass (40% of body weight) and serves important physical and metabolic functions. Not surprisingly, sarcopenia, defined as age-related loss of muscle mass and function, is a significant public health issue associated with loss
of functional independence and substantial health care
costs (1).
Sarcopenia not only leads to loss of muscle mass and
strength, but is associated with systemic consequences mediated via reciprocal interactions with other tissues, such
as fat and bone. Skeletal muscle plays a prominent role in
insulin-mediated glucose disposal. It also releases biological mediators collectively referred to as myokines that
counteract the effects of proinflammatory adipokines (2).
Therefore, sarcopenia promotes insulin resistance and visceral adiposity. In turn, diabetes and obesity accelerate the
age-related loss of muscle mass and quality (1). Sarcopenia
diminishes bone strength via reduced mechanical load,
reduced secretion of anabolic myokines, and increased
falls and hence fracture risk (3). Sarcopenia therefore plays
a key role in the self-perpetuating cycle of sarcopenic obesity, metabolic dysregulation, and bone decay leading to
frailty.
The pathogenesis of sarcopenia is multifactorial and
involves physical inactivity, systemic inflammation, and
age-associated hormonal changes. In men, androgen deficiency is an important contributory cause. Skeletal muscle is one of the most androgen-responsive somatic tissues.
Randomized controlled trials have consistently shown robust dose-response relationships between circulating T
and muscle mass and strength, ranging from low to supraphysiological T levels, in both young and older men (4,
5). In addition, low T predicts frailty in observational
studies of community-dwelling men (6). The increased risk
of functional decline associated with low T may be mediated through effects on muscle mass and strength (7).
The most common contemporary cause of severe T deficiency is androgen deprivation therapy (ADT) given to men
with prostate cancer (8). Lifetime incidence of prostate cancer is 1:6 in US men and is increasing in prevalence worldwide. Because prostate cancer is an androgen-dependent malignancy, ADT provides effective palliation and, as adjuvant
therapy, improves survival in appropriately selected highrisk men. Evidence for benefit in other settings in more limited, in part because the antitumor effects of ADT are offset
by its toxicities. There is evidence that ADT is overused: 3%
of the US Medicare population currently receives this treatment, or more than 500 000 US men (9).
The 10-year prostate cancer-specific survival exceeds
90% for most men, and therefore survivorship issues become
an important consideration. ADT induces therapeutic hypogonadism with a number of constitutional and somatic side
effects, including profound skeletal muscle loss, obesity, diabetes, and bone architectural decay (10, 11). Although effective medications for diabetes and osteoporosis are available, there is currently no approved pharmacotherapy to
improve skeletal health. Exercise improves muscle strength
and physical performance in clinical trials of men receiving
ADT and should be recommended routinely (12). Implementation and sustainability, however, remain challenging, especially in older men receiving ADT, who commonly have a
substantial comorbid burden and may experience ADT-associated fatigue and low mood.
A variety of pharmacological interventions to improve
skeletal muscle health are currently being explored in early
clinical trials. One such strategy is based on the inhibition
ISSN Print 0021-972X ISSN Online 1945-7197
Printed in U.S.A.
Copyright © 2014 by the Endocrine Society
Received August 24, 2014. Accepted August 25, 2014.
Abbreviation: ADT, androgen deprivation therapy.
For article see page E1967
doi: 10.1210/jc.2014-3290
J Clin Endocrinol Metab, October 2014, 99(10):3625–3628
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Grossmann
Myostatin Inhibition and Androgen Deprivation
of myostatin, a highly conserved member of the TGF superfamily. As the name implies, myostatin is a strong negative regulator of skeletal muscle mass. Myostatin signals
through the activin type IIB receptor to regulate genes
involved in the differentiation and proliferation of skeletal
muscle precursor cells and in the regulation of protein
turnover in mature myocytes. Genetic inactivation of
myostatin is associated with marked hypermuscularity in
mammalian species including humans (13), and its transgenic overexpression or systemic delivery leads to muscle
atrophy in adult mice. Myostatin also modulates adipose
tissue and metabolic functions: myostatin knockout mice
display reduced body fat mass and are resistant to fat accumulation and to the development of insulin resistance
(14).
In this issue of the JCEM, a team of leading clinical
prostate cancer researchers collaborating with Amgen
present results of one of the first trials using a myostatin
inhibitor in humans. In this phase I study, Padhi et al (16)
report on the tolerability and pharmacodynamic effects of
the antimyostatin peptibody AMG 745, previously characterized in mice (15), in men with nonmetastatic prostate
cancer receiving ADT. The rationale of this study is based
on preclinical data suggesting that the myogenic actions of
androgen are mediated, at least in part, through inhibition
of myostatin expression, although not all studies concur
(17). Men with prostate cancer receiving ADT are a logical
cohort to study. First, given that increasing age and insulin
resistance are risk factors for prostate cancer, they have a
high baseline prevalence of sarcopenic obesity and reduced bone mass even before ADT is commenced (18).
Second, T is anabolic not only to muscle but also, either
directly or via its metabolite estradiol, to bone, and it reduces fat mass and insulin resistance. ADT therefore exacerbates sarcopenic obesity and bone decay and accelerates the age-related frailty cycle (8).
In this multicenter, randomized, double-blind, placebo-controlled, multiple-dose phase I study (16), men with
prostate cancer without documented metastatic disease
treated with ADT for at least 6 months were allocated to
receive weekly doses of AMG 745 (n ⫽ 25, including six
men participating in a dose-escalation study) or placebo
(n ⫽ 23) for 4 weeks (16). Participants had a good performance status, were body composition matched, and
maintained castrate T levels throughout the study. Adverse effects were more common in men receiving AMG
745 compared to placebo and included fatigue (13 vs 4%),
diarrhea (13 vs 9%), and contusion (10 vs 0%). Although
numbers were small, among men receiving AMG 745, all
but two of the 12 adverse events occurred in men receiving
the maximum 3 mg/kg dose of AMG 745. All adverse events
were reported as mild or moderate, except for one event of
J Clin Endocrinol Metab, October 2014, 99(10):3625–3628
syncope associated with electrocardiogram changes occurring 19 days after the last dose of AMG 745 3 mg/kg. One
subject required discontinuation of AMG 745 because of
erythema, and one participant developed anti-AMG 745
binding antibodies.
Change in lean body mass, a prespecified pharmacodynamic endpoint, was evaluated by DEXA in a subgroup
of 38 participants randomized in a 1:1 allocation to the
maximum 3 mg/kg dose of AMG 745 or placebo. Remarkably, given the short duration of the study, AMG 745
modestly, but significantly, increased lean body mass by
2.2 ⫾ 0.8% vs placebo (P ⫽ .008) and, in an exploratory
analysis, decreased fat mass by ⫺2.5 ⫾ 1.0% (P ⫽ .02) at
study end (day 29). Lower extremity muscle size, assessed
by computed tomography scanning, increased significantly in AMG 745 subjects (between-group difference,
⫹2.8 ⫾ 1.0%; P ⫽ .007) at 1 month after study end.
No significant between-group differences in muscle
strength or physical performance were seen, which is not
unexpected given the small study size, the use of relative
insensitive methodology (knee extension strength and
short physical performance battery test), and the high
baseline functional status of the participants (16). In addition, there were no significant changes in fasting glucose,
insulin, or lipid levels.
Limitations of the study include the short duration and
small size inherent to a phase I clinical trial. Physical activity levels were not recorded, and actual evidence demonstrating that myostatin was in fact inhibited in AMG
745-treated participants was not provided. Men who received ADT for less than 6 months, the period during
which the most rapid loss of muscle associated with ADT
occurs (11), were not enrolled in the study. Therefore, it
remains plausible that myostatin inhibition may be particularly effective if used in a preventative, rather than in
a restorative, fashion.
The study by Padhi et al (16) provides justification for
further clinical trials of myostatin inhibition for ADT-associated sarcopenia, a central component of frailty for
which currently no approved pharmacological therapy exists. Given that the clinical experience with myostatin inhibitors is currently very limited and is restricted to mostly
ongoing phase I-II studies (19), important questions regarding safety and efficacy remain. Cardiovascular safety
is particularly important, given that men with prostate
cancer commonly have cardiovascular disease. Myostatin
is expressed in cardiac muscle, and preclinical studies have
reported both beneficial and adverse effects of myostatin
on the heart (20). The syncopal event with associated electrocardiogram changes in one subject, although occurring
almost 3 weeks after the last dose of AMG 735, is of potential concern. Cardiotoxicity has not been reported in
doi: 10.1210/jc.2014-3290
other early clinical studies of myostatin inhibition, although very few have been completed (19). Myostatin
peptibody-associated fatigue, if confirmed in larger studies, may reduce engagement in regular physical exercise.
The observed improvements in body composition after
only 4 weeks of AMG 745 treatment are intriguing, although the between-group differences may have been amplified by greater than expected (11) adverse changes in
body composition occurring in the placebo-treated men.
Nevertheless, similar increases in muscle mass with myostatin inhibition have also been observed in other human trials
(19). Of central importance is the question of whether myostatin inhibition will improve muscle function and lead to
clinically meaningful improvements in physical performance. In rodent models of myostatin inhibition, the increase
in muscle mass was not necessarily matched by a proportional increase in muscle force and function, resulting in a
relative strength deficit (21). By contrast, exercise increases
muscle strength well before a noticeable increase in muscle
mass occurs, emphasizing that improvement of muscle quality is important for functional outcomes.
If confirmed, the decrease in fat mass observed with
AMG 745 may prove to be an important additional benefit
of myostatin inhibition. Although it is unclear whether
this simply reflects the increase in metabolically active lean
mass or is due to direct actions related to low levels of
myostatin expression in adipose tissue, this raises the possibility that myostatin inhibition has the potential to improve glucose metabolism and cardiometabolic health
(22). This is of particular relevance for men with prostate
cancer receiving ADT who are more likely to die from
cardiovascular events than their underlying malignancy
(8).
In summary, given the central role of sarcopenia in the
frailty cycle, more effective treatments to improve skeletal
muscle health are needed. This is important not only for
men with prostate cancer receiving ADT, who may be
particularly vulnerable to the consequences of sarcopenia,
but also for the wider aging population. Innovative and
even more potent forms of ADT, some of which require
glucocorticoid cotreatment, have been shown to improve
prognosis but may further accelerate the sarcopeniafrailty cycle (23). Clearly, sarcopenia is a complex multifactorial condition, and optimal treatment will require a
multifaceted approach with tailored physical exercise as
the cornerstone. Padhi et al (16) provide early evidence
that myostatin inhibition may be a potentially promising
approach. However, myostatin inhibition is at a very early
stage of clinical development, and clearly further evidence
is required to clarify whether this treatment is safe and
whether it meaningfully improves physical performance
and other patient-important health outcomes.
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Acknowledgments
Address all correspondence and requests for reprints to: Associate
Professor Mathis Grossmann, Department of Medicine Austin
Health, The University of Melbourne, 145 Studley Road, Heidelberg, Victoria 3084, Australia. E-mail: [email protected].
M.G. is supported by a National Health and Medical Research Council of Australia Career Development Fellowship (no.
1024139).
Disclosure Summary: The author has nothing to disclose.
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