In this population of older men with mobility limitations and high burden of chronic diseases, the men assigned to the testosterone arm experienced greater gains in leg-press strength, chest-press strength and power, skeletal muscle mass, and loaded stair-climbing power than those assigned to placebo. Because of early trial cessation, the preplanned enrollment target of 252 randomized men was not met; furthermore, a substantial fraction of randomized participants did not complete the planned 6 months of intervention. In spite of the early cessation of enrollment and earlier than planned discontinuation of intervention in many participants, changes in muscle strength and stair-climbing power associated with randomization to testosterone arm of the study were statistically significant. As a greater proportion of men experienced improvements in leg-press and chest-press strengths and stair-climbing power that exceeded the MID, these treatment effects are patient important and therefore clinically meaningful. Walking speed, a key determinant of mobility, did not change significantly. The improvements in muscle mass and strength without significant improvements in walking speed should be weighed against the greater risk of adverse cardiovascular events observed among men assigned to testosterone arm.
The changes in maximal voluntary strength and loaded stair-climbing power were related to changes in testosterone concentrations. The muscle strength gains were related to gains in skeletal muscle mass, which were related to changes in total and free testosterone concentrations. Changes in stair-climbing power and walking speed were related to changes in leg-press strength, which is an important determinant of stair-climbing power and walking speed. These correlational analyses are consistent with the following mechanistic directionality: increases in testosterone levels → gains in skeletal muscle mass → increase in muscle strength → improved physical function.
Meta-analyses of testosterone trials have reported significant gains in LBM but inconsistent changes in muscle strength and physical function (35
). The trials in these meta-analyses were limited by the small number of participants, shorter treatment durations than the 6-month intervention period used in the TOM Trial, or the failure to include comprehensive assessments of muscle strength and physical function. Some trials used small doses of testosterone that resulted in significantly smaller increments in testosterone levels than were achieved in the TOM Trial (18
). A unique aspect of this trial is the use of MID estimates derived using an anchor within this trial to determine the clinical meaningfulness of the observed treatment effects. Additionally, the trial included a comprehensive assessment of upper and lower extremity function and performance-based as well as self-reported measures.
Most testosterone trials have enrolled healthy older men; this is the first randomized testosterone trial in older men with mobility limitations. A recent important testosterone trial in older men with frailty reported improvements in LBM and some self-reported measures of physical function, but the trial found no significant differences in muscle strength or performance-based measures of physical function between placebo and testosterone arms (14
). A significant fraction of participants in that trial were prefrail. Another trial in frail elderly men also failed to find significant improvement in muscle strength or physical function measures (37
); the testosterone dose in that trial was lower than that used in the TOM Trial. Small testosterone trials in men with congestive heart failure have suggested improvements in exercise capacity with inconsistent changes in muscle mass and strength (38
In spite of substantial gains in muscle mass and maximal voluntary strength in men assigned to testosterone arm, several measures of physical function did not improve significantly beyond the improvements seen in the placebo arm. Other factors, such as neuromuscular integration and functional training, might be required to optimize the translation of muscle mass and strength gains into improved physical function. It is possible that neuromuscular adaptations that result in improved function may require more time than the 6-month duration of our trial. Page and colleagues reported significant improvement in a continuous timed physical performance test after 12 months of testosterone administration (20
), but other studies of 1- to 3-year duration (17
) have failed to note improvements in functional measures.
In our trial, treatment effects for most measures of physical function favored testosterone administration; in general, the measures having the highest ceiling (loaded stair-climb and loaded gait speed) showed greater testosterone effect than unloaded tests with lower ceilings. As substantial numbers of randomized participants did not complete the trial due to early study cessation, this may have reduced statistical power. However, close examination of proportional gains in functional outcomes indicates that variation in the unloaded functional measures was comparable to that in the strength indices. Thus, there were indeed gains in the functional measures among participants in the testosterone arm, but there were comparable gains in function among participants assigned to placebo (whereas participants assigned to placebo evinced little to no gains in strength; ). Thus, the estimated treatment effects (testosterone vs placebo) for unloaded walk, unloaded stair-climb, and late life function and disability index were of modest magnitude. By contrast, proportionate variation in the loaded functional measures—particularly stair-climb power—was somewhat greater than that in the strength measures, so that sizeable estimates of treatment effect (testosterone vs placebo) did not achieve statistical significance due to the large variation. One may postulate that had the trial achieved full enrollment, these differences in the loaded measures would have achieved statistical significance, whereas the available evidence suggests that the unloaded measures would have failed to demonstrate efficacy even under full enrollment.
Several factors merit consideration in weighing the observed improvements in muscle strength and physical function against the increased risk of cardiovascular events in men assigned to the testosterone arm. The number needed to treat has been used to describe the efficacy of health care interventions. In the TOM Trial, the numbers needed to treat to achieve clinically meaningful improvements in leg-press strength and stair-climbing power were 4.0 and 5.5, respectively. However, the gains in skeletal muscle mass and muscle strength were not associated with significant improvements in walking speed. Adjunctive strategies, such as physical activity or other interventions (39
), may be needed to induce neuromuscular, cognitive, and behavioral adaptations that are necessary for translating muscle mass and strength gains induced by testosterone into functional improvements. Also, the testosterone administration at the dose used in the trial was associated with adverse events. Therefore, the clinical application of testosterone as a function promoting anabolic therapy might be predicated upon strategies, which augment the anabolic effects of testosterone and facilitate translation of testosterone-induced gains in muscle mass and strength into functional improvements at lower testosterone concentrations that can be safely administered. Such strategies, which might include physical activity interventions (39
), resistance exercise training, cognitive and behavioral training, or combined administration of testosterone with other anabolic agents, such as recombinant human growth hormone, should be investigated.