The Brave New World of Function-Promoting Anabolic Therapies: Testosterone and Frailty

Abstract

Physical function is an excellent marker of an individual’s health (1). Limitations in physical function are an important public health problem because of their high prevalence and their association with adverse health outcomes, including the increased risk of disability, poor quality of life, hospitalization, and mortality (2, 3). In the USA alone, 12–14% of the noninstitutionalized population—approximately 35–38 million people—have a disability due to a chronic health condition (4). For people over age 65 yr, 35 to 40% experience activity limitations or disability. Because the U.S. population is aging, the percentage of population aged 65 yr or over will increase from 12% in 2000 to 20% in 2030—to more than 69 million. The number of people 85 or older is expected to grow from 3 million (2.1%) to 6.2 million (3.4%) in the United States alone. The majority of individuals who reach this age will experience some limitation in function (4, 5). The costs of support services, lost productivity associated with disabling conditions, and the impact of disability on an individual’s quality of life will have enormous societal consequences (6). Currently, the practicing physicians have few therapeutic choices for the treatment of older individuals with functional limitations and physical disability. Exercise, physical rehabilitation, and behavioral modalities have had limited impact at a population level. Therefore, there is growing need for developing pharmacological function promoting therapies for the treatment of functional limitations. It has become apparent that a small number of intersecting signaling pathways are crucial for regulating muscle growth through their effects on ribosomal protein translation (AkT/mammalian target of rapamycin pathway), mesenchymal progenitor cell differentiation (Wnt and Smad signaling), and muscle protein degradation (ubiquitin-proteasome pathway and the FoXo family of transcription factors). Pharmacophores that selectively modulate these signaling pathways, such as androgens, myostatin antagonists, and GH/IGF-I mimetics are being explored for their potential as function-promoting anabolic therapies; of these, androgens are the farthest along in development. The idea that androgens have anabolic effects on the skeletal muscle is not new. Athletes and recreational body builders who abuse androgens do so because of the widely held perception that androgens increase muscle mass, muscle strength, and athletic performance. However, systematic investigations of androgens as function-promoting therapies have been limited largely to the past 15 yr (7). Epidemiological studies have shown that circulating testosterone levels are associated with skeletal muscle mass, muscle strength, and self-reported as well as performancebased measures of physical function (8–10). Cawthon et al. (11) reported in a recent issue of the Journal that low levels of bioavailable testosterone in men participating in the Osteoporotic Fractures in Men Study (MrOS) were associated independently with worse frailty status. In longitudinal analysis, the men in the lowest quartile of bioavailable testosterone levels had approximately 1.5-fold higher odds of greater frailty status 4.1 yr later (11). However, neither total nor free testosterone levels were associated with frailty status. Mohr et al. (12) in a separate analysis of the data from the Massachusetts Male Aging Study (MMAS) also found no significant association of