Testosterone treatment improved bone density and anaemia for men over 65 with unequivocally low testosterone, but did not improve cognitive function and did increase plaque buildup in participants’ coronary arteries, found a multi-centre US set of trials.
A team of researchers from the Perelman School of Medicine at the University of Pennsylvania, and twelve other medical centers in the US, in partnership with the National Institute on Ageing, conducted The Testosterone Trials (TTrials), a coordinated group of seven trials, which studied the effects of testosterone treatment for one year as compared to placebo for men 65 and older with low testosterone. The first paper, which reported that testosterone treatment improved sexual function and mood, was published in February 2016. The publication of the Bone, Anemia, Cognition and Cardiovascular Trials conclude the primary results of the study.
Researchers found that testosterone treatment improved bone density and estimated bone strength, as determined by quantitative computed tomography (CT). The treatment also increased hemoglobin concentrations, corrected the anemia of men who had no other identifiable cause of anemia and corrected the anemia of men who had an identifiable cause, such as iron deficiency. While these conclusions proved testosterone to be beneficial to the participants, testosterone treatment did not improve memory or any other measure of cognitive function.
“The paper reporting the results of the first three trials published last year was the first to show there were advantages to giving testosterone treatment to older men with low testosterone levels, and the bone and anemia trial results further support a benefit,” said the principal investigator Dr Peter J Snyder, a professor of medicine in the division of endocrinology, diabetes and metabolism. “However, the increase of plaque buildup in the coronary artery shows that this treatment may also have some risk”
In the cardiovascular trial, researchers assessed coronary artery plaque buildup by CT angiography. That assessment showed more plaque buildup in men treated with testosterone than in men treated with placebo. Nonetheless, in all 788 men in the TTrials, the number of major adverse cardiovascular events was similar in the men treated with testosterone as in the men treated with placebo. However, Snyder added, “treating 788 men for one year is far too few to draw conclusions about the clinical significance of the increase in coronary artery plaque volume and the cardiovascular risk of testosterone treatment.”
The TTrials are now the largest trials to examine the efficacy of testosterone treatment in men 65 and older whose testosterone levels are low due seemingly to age alone. TTrials researchers screened 51,085 men to find 790 who qualified with a sufficiently low testosterone level and who met other criteria. The men enrolled were randomised into two groups: one to take a daily testosterone gel and the other a daily placebo gel, for one year. Efficacy was then evaluated at months three, six, nine and 12.
“Final decisions about testosterone treatment for older men will depend on balancing the results from these seven TTrials with the results from a much larger and longer term trial designed to assess cardiovascular and prostate risk in the future,” said Snyder.
Importance: Recent studies have yielded conflicting results as to whether testosterone treatment increases cardiovascular risk.
Objective: To test the hypothesis that testosterone treatment of older men with low testosterone slows progression of noncalcified coronary artery plaque volume.
Design, Setting, and Participants: Double-blinded, placebo-controlled trial at 9 academic medical centers in the United States. The participants were 170 of 788 men aged 65 years or older with an average of 2 serum testosterone levels lower than 275 ng/dL (82 men assigned to placebo, 88 to testosterone) and symptoms suggestive of hypogonadism who were enrolled in the Testosterone Trials between June 24, 2010, and June 9, 2014.
Intervention: Testosterone gel, with the dose adjusted to maintain the testosterone level in the normal range for young men, or placebo gel for 12 months.
Main Outcomes and Measures: The primary outcome was noncalcified coronary artery plaque volume, as determined by coronary computed tomographic angiography. Secondary outcomes included total coronary artery plaque volume and coronary artery calcium score (range of 0 to >400 Agatston units, with higher values indicating more severe atherosclerosis).
Results: Of 170 men who were enrolled, 138 (73 receiving testosterone treatment and 65 receiving placebo) completed the study and were available for the primary analysis. Among the 138 men, the mean (SD) age was 71.2 (5.7) years, and 81% were white. At baseline, 70 men (50.7%) had a coronary artery calcification score higher than 300 Agatston units, reflecting severe atherosclerosis. For the primary outcome, testosterone treatment compared with placebo was associated with a significantly greater increase in noncalcified plaque volume from baseline to 12 months (from median values of 204 mm3 to 232 mm3 vs 317 mm3 to 325 mm3, respectively; estimated difference, 41 mm3; 95% CI, 14 to 67 mm3; P = .003). For the secondary outcomes, the median total plaque volume increased from baseline to 12 months from 272 mm3 to 318 mm3 in the testosterone group vs from 499 mm3 to 541 mm3 in the placebo group (estimated difference, 47 mm3; 95% CI, 13 to 80 mm3; P = .006), and the median coronary artery calcification score changed from 255 to 244 Agatston units in the testosterone group vs 494 to 503 Agatston units in the placebo group (estimated difference, −27 Agatston units; 95% CI, −80 to 26 Agatston units). No major adverse cardiovascular events occurred in either group.
Conclusions and Relevance: Among older men with symptomatic hypogonadism, treatment with testosterone gel for 1 year compared with placebo was associated with a significantly greater increase in coronary artery noncalcified plaque volume, as measured by coronary computed tomographic angiography. Larger studies are needed to understand the clinical implications of this finding.
Matthew J Budoff; Susan S Ellenberg; Cora E Lewis; Emile R Mohler III; Nanette K Wenger; Shalender Bhasin; Elizabeth Barrett-Connor; Ronald S Swerdloff; Alisa Stephens-Shields; Jane A Cauley; Jill P Crandall; Glenn R Cunningham; Kristine E Ensrud; Thomas M Gill; Alvin M Matsumoto; Mark E Molitch; Rine Nakanishi; Negin Nezarat; Suguru Matsumoto; Xiaoling Hou; Shehzad Basaria; Susan J Diem; Christina Wang; Denise Cifelli; Peter J Snyder
Importance: As men age, they experience decreased serum testosterone concentrations, decreased bone mineral density (BMD), and increased risk of fracture.
Objective: To determine whether testosterone treatment of older men with low testosterone increases volumetric BMD (vBMD) and estimated bone strength.
Design, Setting, and Participants: Placebo-controlled, double-blind trial with treatment allocation by minimization at 9 US academic medical centers of men 65 years or older with 2 testosterone concentrations averaging less than 275 ng/L participating in the Testosterone Trials from December 2011 to June 2014. The analysis was a modified intent-to-treat comparison of treatment groups by multivariable linear regression adjusted for balancing factors as required by minimization.
Interventions: Testosterone gel, adjusted to maintain the testosterone level within the normal range for young men, or placebo gel for 1 year.
Main Outcomes and Measures: Spine and hip vBMD was determined by quantitative computed tomography at baseline and 12 months. Bone strength was estimated by finite element analysis of quantitative computed tomography data. Areal BMD was assessed by dual energy x-ray absorptiometry at baseline and 12 months.
Results: There were 211 participants (mean [SD] age, 72.3 [5.9] years; 86% white; mean [SD] body mass index, 31.2 [3.4]). Testosterone treatment was associated with significantly greater increases than placebo in mean spine trabecular vBMD (7.5%; 95% CI, 4.8% to 10.3% vs 0.8%; 95% CI, −1.9% to 3.4%; treatment effect, 6.8%; 95% CI, 4.8%-8.7%; P < .001), spine peripheral vBMD, hip trabecular and peripheral vBMD, and mean estimated strength of spine trabecular bone (10.8%; 95% CI, 7.4% to 14.3% vs 2.4%; 95% CI, −1.0% to 5.7%; treatment effect, 8.5%; 95% CI, 6.0%-10.9%; P < .001), spine peripheral bone, and hip trabecular and peripheral bone. The estimated strength increases were greater in trabecular than peripheral bone and greater in the spine than hip. Testosterone treatment increased spine areal BMD but less than vBMD.
Conclusions and Relevance: Testosterone treatment for 1 year of older men with low testosterone significantly increased vBMD and estimated bone strength, more in trabecular than peripheral bone and more in the spine than hip. A larger, longer trial could determine whether this treatment also reduces fracture risk.
Peter J Snyder; David L Kopperdahl; Alisa J Stephens-Shields; Susan S Ellenberg; Jane A Cauley; Kristine E Ensrud; Cora E Lewis; Elizabeth Barrett-Connor; Ann V Schwartz; David C Lee; Shalender Bhasin; Glenn R Cunningham; Thomas M Gill; Alvin M Matsumoto; Ronald S Swerdloff; Shehzad Basaria; Susan J Diem; Christina Wang; Xiaoling Hou; Denise Cifelli; Darlene Dougar; Bret Zeldow; Douglas C Bauer; Tony M Keaveny