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Articles in PresS. J Appl Physiol (October 24, 2003). 10.1152/japplphysiol.00808.2003
Treatment with Oxandrolone and the Durability of Effects in Older Men
E. Todd Schroeder, PhD
1, 4
Ling Zheng, MS
2
Kevin E.Yarasheski, PhD
3
Dajun Qian, PhD
2
Yolanda Stewart
2
Carla Flores
2
Carmen Martinez, MS, RD
2
Michael Terk, MD
4,5
Fred R. Sattler, MD
1, 2, 4
Running Title: Androgen Supplementation and Durability of Effects
Department of Medicine and Division of Infectious Diseases
1
, General Clinical Research
Center
2
, and the Department of Radiology
5
of the Keck School of Medicine
and the Department of Biokinesiology and Physical Therapy
4
of the University of Southern California, Los Angeles, California
and
Department of Internal Medicine, Divisions of Metabolism, Endocrinology and Lipid Research
and Cell Biology and Physiology
3
,
Washington University School of Medicine, St. Louis, Missouri
Address for inquiries and Reprints:
Fred Sattler, MD
University of Southern California
Departments of Medicine and Biokinesiology & Physical Therapy
1540 East Alcazar St. CHP-155
Los Angeles, CA 90033
Phone: 323-442-2498
Facsimile: 323-442-1515
Email:
fsattler@usc.edu
Copyright (c) 2003 by the American Physiological Society.
ABSTRACT
We investigated the effects of the anabolic androgen, oxandrolone, on lean body mass (LBM),
muscle size, fat, and maximum voluntary muscle strength, and determined the durability of
effects after stopping treatment. Thirty-two healthy 60-87 year old men were randomized to
receive 20 mg oxandrolone/day (n = 20) or placebo (n = 12) for 12 weeks. Body composition
(DEXA, MRI and D
2
O dilution) and muscle strength (1-repetition maximum; 1-RM) were
evaluated at baseline and after 12 weeks of treatment; body composition (DEXA) and 1-RM
strength were then assessed 12 week after discontinuing treatment (week 24). At week 12,
oxandrolone increased LBM 3.0±1.5kg (P<0.001), total body water 2.9±3.7kg (P=0.002),
proximal thigh muscle area 12.4±8.4cm
2
(P<0.001); these increases were greater (P<0.003) than
in the placebo group. Oxandrolone increased 1-RM strength for leg press 6.7±6.4% (P<0.001),
leg flexion 7.0±7.8% (P<0.001), chest press 9.3±6.7% (P<0.001), and latissimus pull-down
5.1±9.1% (P=0.02) exercises; these increases were greater than placebo. Oxandrolone reduced
total (-1.9±1.0kg) and trunk fat (-1.3
±0.6kg;
P<0.001) and these decreases were greater
(P<0.001) than placebo. Twelve weeks after discontinuing oxandrolone (week 24), the
increments in LBM and muscle strength were no longer different from baseline (P>0.15).
However, the decreases in total and trunk fat were sustained (-1.5±1.8, P=0.001 and -1.0±1.1kg,
P<0.001, respectively). Thus, oxandrolone induced short-term improvements in lean body mass,
muscle area, and strength, while reducing whole-body and trunk adiposity. Anabolic
improvements were lost 12 weeks after discontinuing oxandrolone, while improvements in fat
mass were largely sustained.
Key Words:
Oxandrolone, Lean Body Mass, Muscle Mass, DEXA, MRI
2
INTRODUCTION:
Advancing age is associated with a progressive loss of muscle mass (sarcopenia), skeletal muscle
strength, and physical function (2, 3, 10, 14, 19). Sarcopenia increases the risk for frailty, falls,
fractures, dependency and depression (34, 36). Advancing age is also associated with increases
in fat mass, particularly central adiposity, which increases the risk for insulin resistance,
hypertension, dyslipidemia, and impaired fibrinolysis (Metabolic Syndrome) (37). The Metabolic
Syndrome predisposes older persons to accelerated atherosclerosis and type II diabetes.
The contribution of age-associated hormonal alterations to these adverse health consequences is
unclear. Both cross-sectional (15, 28, 51) and longitudinal (17, 30) studies have shown that
serum total and free concentrations of testosterone decline with advancing age in men.
Testosterone regulates muscle and fat mass, but the relationship between gonadal hormone status
and age-associated alterations in body composition, skeletal muscle strength, and metabolic
disorders in older persons is uncertain. There is some evidence that bioavailable testosterone
levels (free and the fraction loosely bound to albumin) correlate with skeletal muscle mass and
muscle strength in different ethnic populations (4, 35).
Testosterone treatment in hypogonadal young men increases lean tissue (5, 8, 20, 45, 53, 54),
and muscle strength (5, 54) and decreases fat mass (5, 20, 54). Despite evidence that
supplemental testosterone increases myofibrillar protein synthesis rate in older men (11, 52), its
effects on body composition and muscle function in these men are less clear (22, 31, 44, 46, 50,
51). In the largest studies, in which older relatively hypogonadal older men received testosterone
replacement for one and three years, respectively, lean body mass (LBM) was only modestly
increased (1.0 and 1.9 kg, respectively) (22, 46) and the effects on muscle strength were variable.
3
Only three studies have shown increases in lower extremity maximum voluntary force (11, 22,
52). By contrast, in a controlled study of 108 older men randomized to receive placebo or
testosterone (46), upper extremity grip strength and lower extremity isokinetic strength were
unchanged with testosterone (50). Likewise, the effects of testosterone on fat mass have been
variable with either no change or only modest reductions achieved (11, 21, 31, 46, 51, 52).
The variability in outcomes in older men may be related to the different delivery strategies for
testosterone (intramuscular versus transdermal delivery), dose (200 mg biweekly versus 5
mg/day), change in testosterone levels in response to therapy, duration of treatment (four weeks
versus three years), different methods to assess body composition (bioelectrical impedance
analysis, DEXA, MRI, hydrostatic weighing) as well as measures of muscle strength (hand held
dynamometers, isokinetic dynamometers, free weights or pneumatic resistance devices).
Moreover, with one exception, these studies did not directly assess changes in muscle mass or
muscle cross-sectional area.
Oxandrolone is a potent, oral anabolic androgen that is approved for the treatment of weight loss
due to known medical or unexplained causes (43, 48). We evaluated whether the licensed dose of
oxandrolone increases muscle mass and muscle strength, and reduces body fat mass in older men
at risk for sarcopenia and metabolic complications. Moreover, we followed these men for 12
weeks after discontinuing oxandrolone to evaluate the durability of the alterations in body
composition and muscle strength. We hypothesized that oxandrolone would increase lean mass,
muscle area, and muscle strength, and reduce whole-body and central adiposity in older men and
that these benefits would not be fully sustained.
4
METHODS:
Study Design
This was a single center, investigator initiated, double blind, placebo-controlled investigation to
determine the magnitude and durability of effects of a potent, convenient to administer anabolic
androgen, oxandrolone (Oxandrin ). The study was performed at the University of Southern
California NCRR-funded General Clinical Research Center with the exception that skeletal
muscle strength was assessed at the Clinical Exercise Research Center in the Department of
Biokinesiology and Physical Therapy of the University. The study design and informed consent
were approved and annually reviewed by the Institutional Review Board of the Los Angeles
County-University of Southern California Medical Center.
Study Population
Men >60 years old were recruited from the Los Angeles communities surrounding the University
of Southern California Health Sciences Campus. To be eligible for the study, subjects had to
have a body mass index (BMI)
prostate specific antigen (PSA)
35 kg/m
2
, repeated resting blood pressure <180/95 mm Hg,
4.1 ng/ml, serum hematocrit
50%, alanine aminotransferase
(ALT) less than three times the upper limit of normal (ULN), and serum creatinine < 2 mg/dL.
Subjects with untreated endocrine abnormalities (e.g. diabetes, hypothyroidism), active
inflammatory conditions, or cardiac problems (heart failure, myocardial infarction, or angina) in
the proceeding three months were excluded. An incremental treadmill exercise test with 12-lead
electrocardiogram and blood pressure monitoring to achieve a heart rate 85% of age predicted
maximum was administered prior to resistance exercise testing to identify subjects at possible
risk for exercise induced ischemia, abnormalities in cardiac rhythm, or abnormal blood pressure
responses.
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