T4DM Trial and its T4Bone Substudy Shed Further Light on Effects of Testosterone Treatment in Middle-Aged and Older Men.

Testosterone is approved for the treatment of classical hypogonadism due to known diseases of the testis, pituitary, and the hypothalamus, but it is not approved for the treatment of age-related decline in testosterone levels. Yet, a majority of testosterone prescriptions in the United States are written for middle-aged and older men who have symptoms that are common to aging and hypogonadism but who do not meet the criteria for hypogonadism. In 2004, an expert panel of the Institute of Medicine (IOM) concluded that there was insufficient evidence of testosterone’s efficacy and safety for the treatment of age-related hypogonadism or for any age-related condition and recommended that randomized trials be conducted first to determine the efficacy of testosterone treatment in older men before proceeding to larger, long-term safety trials. In response to the IOM’s report, the National Institute on Aging funded the Testosterone Trials (TTrials), a set of 7 coordinated trials that have provided a large body of information about the efficacy of testosterone treatment for 1 year in older men with unequivocally low testosterone levels and 1 or more conditions associated with testosterone deficiency (1). The Bone Trial of the TTrials demonstrated that testosterone treatment substantially increased volumetric bone mineral density (vBMD) of the lumbar spine (4). In this issue of the Journal of Clinical Endocrinology & Metabolism, Ng Tang Fui et al (2) describe the findings of the T4Bone trial, a study of the effects of testosterone treatment on bone microarchitecture in middle-aged and older men. The T4Bone trial was a substudy of the T4DM Trial (3), one of the largest randomized testosterone trials completed to-date, whose primary aim was to determine whether testosterone treatment, when administered in conjunction with a community-based lifestyle program, was more efficacious than the lifestyle program alone in preventing progression to or in reversing type 2 diabetes (T2DM). The study participants in the T4DM Trial were men, 50 to 74 years of age, who were at increased risk of T2DM or had newly diagnosed T2DM. The T4DM Trial had several attributes of good trial design, including randomized allocation of subjects, concealed randomization, intent-to-treat analyses, parallel groups, and reasonable retention rates.

Testosterone treatment for 2 years in the T4Bone trial was associated with greater improvements in the cortical and total vBMD and cortical area and thickness at the distal tibia and radius, compared with placebo. Testosterone treatment also significantly increased areal BMD (aBMD) at the lumbar spine and the hip. Testosterone did not affect microarchitecture.

Although the findings of the T4Bone trial are similar in some ways to those of the Bone Trial of the TTrials (4), there also are some salient differences. In both, testosterone treatment, compared with placebo, increased vBMD. The magnitude of the increase of the primary end point (tibial cortical vBMD) in the T4Bone trial was smaller, 3% in 2 years, compared with 7% in 1 year of the primary end point (spine trabecular vBMD) in the Bone Trial. In the T4Bone trial, larger increases were observed in the cortical bone, while the Bone Trial found greater increases in the trabecular bone. The changes in aBMD at the hip and spine were similar in the 2 trials.

What could explain the differences in the vBMD response to testosterone in the 2 trials? The most plausible explanation is that the men in the T4Bone trial were not uniformly hypogonadal. Testosterone threshold for eligibility in the T4DM Trial was 14nmol/L (403 ng/dL), and a majority had baseline testosterone levels in the eugonadal range. In contrast, the baseline mean testosterone levels in the Bone Trial were unequivocally, although modestly, hypogonadal (8.0 nmol/L [229.6 ng/dL]) and 8.3nmol/L [238.8ng/dL] in testosterone and placebo arms, respectively). There were some other differences in the 2 trials, but they are less likely to explain the differences in the results. The men in the T4Bone trial were younger; their mean age was 60 years, compared with the mean age of 72 years in the Bone Trial. The primary endpoint of the T4Bone trial was based on the assessment of appendicular bones—radius and distal tibia—while that of the Bone Trial was based on the assessment of axial bone—the spine and hip. The anatomic site of assessment, however, is not the likely explanation for the differences, since testosterone treatment of men with severe classical hypogonadism profoundly increased the trabecular bone volume fraction at the distal tibia but not the cortical bone volume fraction (5). Differences in the techniques of assessment—quantitative computed tomography in the Bone Trial and high-resolution peripheral quantitative computed tomography in the T4Bone trial—remain a possible explanation.

Estradiol levels above 10 pg/mL and testosterone levels in the range of 200 to 300ng/dL have been considered sufficient to prevent increases in bone resorption and decreases in BMD in men (6). However, it is notable that testosterone treatment of men in the T4Bone trial, who were not hypogonadal, also increased vBMD as well as aBMD, and the magnitude of treatment effect was not dissimilar from that reported in the TTrials that enrolled subjects who were unequivocally hypogonadal.

What are the clinical and research implications of these findings? First, the promising results of the T4Bone and the TTrials provide strong rationale for larger and longer studies to determine whether the improvements in areal and volumetric BMD and bone strength associated with testosterone treatment reduce fracture risk in older hypogonadal men. Second, because no trial has been large enough or long enough to determine testosterone’s effects on bone fractures, and neither the T4Bone nor the Bone Trial required men to have osteoporosis for eligibility, testosterone treatment should not be used alone to treat hypogonadal men at high risk of bone fracture. These men should be treated with a drug approved for the treatment of osteoporosis, consistent with current guidelines (7, 8). In hypogonadal men, who are candidates for testosterone treatment, but who are not at high risk of bone fracture, BMD should be monitored after initiating testosterone treatment (7, 8). The cardiovascular and prostate safety of testosterone remains to be demonstrated. An ongoing randomized trial (TRAVERSE, NCT03518034) designed to determine the effects of testosterone replacement on major adverse cardiovascular events in middle-aged and older hypogonadal men at increased risk of cardiovascular disease will provide important information about testosterone’s cardiovascular safety and also its efficacy in reducing clinical bone fractures.