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

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 performance-based 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 total or free testosterone levels with overall frailty status. However, in the MMAS, total testosterone levels were associated with some frailty components—grip strength and physical activity—but not with other components such as exhaustion, slow walking, or weight loss (12). In light of the known effects of testosterone on muscle mass and strength, it is not surprising that testosterone levels would be associated with frailty components that are more tightly linked to skeletal muscle mass and strength. Undoubtedly, frailty is a heterogeneous construct, and not all of its components share a common biological or pathophysiological basis or have the same prognostic significance (13). In this issue of the Journal, Srinivas-Shankar et al. (14) report the results of the first randomized clinical trial of the effects of testosterone therapy in older men with one or more components of the frailty syndrome, total testosterone less than 12 nmol/liter, or free testosterone less than 250 pmol/liter. The study had several features of good clinical trial design: randomization, blinding of subjects and investigators, parallel group design, and inclusion of a placebo group as the reference for comparison (14). Unlike some other important studies that did not achieve robust increments in testosterone concentrations (15, 16), Srinivas-Shankar et al. (14) adjusted the testosterone dose to achieve testosterone concentrations in the target range. Testosterone therapy was associated with greater improvements in isokinetic knee extension peak torque and lean body mass (14). Although performance-based measures of physical function did not improve to a greater extent than placebo, in secondary analysis, physical function improved in subsets of older and frailer men. Importantly, somatic and sexual symptoms improved to a greater extent with testosterone therapy than with placebo. The overall frequency of adverse events was relatively low given the age and frail status of the participants. It is important to recognize that frailty was not an efficacy outcome of this trial. There is much to be learned from this pioneering study by Srinivas-Shankar et al. (14), which represents the first randomized clinical trial of testosterone in men with frailty or intermediate frailty. This trial reaffirmed a common theme emerging from previous testosterone trials: that testosterone therapy is associated with improvements in skeletal muscle mass and maximal voluntary muscle strength (7), but that the improvements in muscle mass and strength during testosterone therapy are not consistently translated into functional improvements (17). The improvements in muscle strength in testosterone-treated men in this trial, although statistically significant, were relatively small, and it is debatable whether they were clinically meaningful. Testosterone therapy raised serum testosterone concentrations into the mid to normal range. Because gains in skeletal muscle mass and strength are correlated with testosterone dose and testosterone concentrations (17, 18), it may be necessary to raise serum testosterone concentrations to even higher levels than those achieved in this trial to realize clinically meaningful gains in muscle mass and strength; the long-term safety of such an approach remains to be demonstrated. Also, translation of muscle mass and strength gains into physical function improvements may require additional neuromuscular, cognitive, and behavioral adaptations that are not induced by testosterone administration alone. It is possible that concurrent functional training may be required to induce such adaptations. Although strength training is known to augment the anabolic effects of testosterone on muscle mass and strength, functional training protocols may need to incorporate additional cognitive, behavioral and task-specific training components. The field of function-promoting therapies has become stymied by a number of regulatory uncertainties. One major issue is how to operationalize the clinical indications for which efficacy trials of function promoting therapies should be conducted. A therapeutic indication should ideally be a condition that is recognized by clinicians, affects health outcomes, and can be ascertained precisely and accurately by self-reported or performance-based measures. Additionally, there should be some mechanistic plausibility that the drug being tested would improve the condition for which the indication is being sought. As an example, mobility limitation is a common condition in older individuals, widely recognized by geriatricians as an important clinical condition that renders the affected individual at higher risk of disability, hospitalization, and death (1–3). Mobility limitation can be ascertained by self-reported difficulty in walking and verified by measuring the gait speed. Testosterone levels have been associated with gait speed. Therefore, one could argue that mobility limitation is a good indication for promyogenic function-promoting molecules such as testosterone, other androgens, or selective androgen receptor modulators. Fried et al. (19) have defined frailty as a syndrome consisting of three or more of the following: unintentional weight loss, self-reported exhaustion, weakness, slow walking speed, and low physical activity. Frailty, defined by these criteria, is predictive of adverse health outcomes. Although geriatricians quibble about the definition of frailty, there is agreement that frailty is an important geriatric syndrome. The problem with frailty operationalized in this manner is that it is a heterogeneous construct not unified by a common pathophysiological mechanism. Neither MrOS nor MMAS epidemiological studies revealed an association of total or free testosterone with frailty phenotype (11, 12). MMAS data suggested that testosterone levels may be associated with some frailty components, such as strength and physical activity, but not others (12). Therefore, it is possible that testosterone therapy may improve some, but not other components of the frailty syndrome. A large fraction of participants in the frailty trial by Srinivas-Shankar et al. (14) met only one criterion of the five-component frailty definition—most frequently only exhaustion. This trial illustrates the conceptual as well as practical difficulties inherent in using frailty as an indication for efficacy trials of promyogenic function-promoting therapies. The remarkable momentum in the discovery of novel, promyogenic function-promoting therapies, such as selective androgen receptor modulators, myostatin antagonists, and GH secretagogues, contrasts sharply with the near paralysis of pharmaceutical efforts in conducting efficacy trials of candidate molecules. Regulatory uncertainty about the appropriate approvable indications, efficacy outcomes, and clinical trial design issues has stifled clinical development of candidate function-promoting molecules. A collaborative effort of academia, industry, and regulatory agencies is needed to facilitate a consensus resolution of these complex issues and to jump-start the clinical development of function-promoting anabolic therapies. Disclosure Summary: The author has nothing to declare.