Effect of Testosterone Treatment on Volumetric Bone Density and Strength in Older Men With Low Testosterone: A Controlled Clinical Trial

Abstract

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.

Trial registration: clinicaltrials.gov Identifier: NCT00799617.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Snyder reports grants from the National Institute on Aging (NIA), National Institutes of Health (NIH), grants and nonfinancial support from AbbVie (formerly Solvay and Abbott Laboratories), during the conduct of the study; personal fees from Watson Laboratories, outside the submitted work. Dr Kopperdahl is an employee of and has equity interest in O.N. Diagnostics. Dr Stephens-Shields reports grants from NIA and NIH, grants and other from AbbVie (formerly Solvay & Abbott Lab), during the conduct of the study. Dr Ellenberg reports grants from NIH and AbbVie, Inc, during the conduct of the study; grants from AbbVie, Inc, outside the submitted work. Dr Ensrud reports grants from NIA, during the conduct of the study. Dr Lewis reports grants from NIH and AbbVie, during the conduct of the study. Dr Schwartz reports grants from NIH, during the conduct of the study; personal fees from Amgen, Janssen Pharmaceutical, and Merck, and personal fees and nonfinancial support from Chugai Pharmaceutical, outside the submitted work. Dr Lee is an employee of and has equity interest in O.N. Diagnostics. Dr Bhasin reports grants from NIA, during the conduct of the study; grants and personal fees from Abbvie, Lilly, and Regeneron, and grants from Transition Therapeutics, outside the submitted work. In addition, Dr Bhasin has a patent free testosterone calculator pending and has equity interest in FPT, LLC. Dr Cunningham reports personal fees from AbbVie, Apricus, Besins, Clarus Therapeutics, Endo Pharma, Ferring, Lilly, Pfizer, and Repros Therapeutics, outside the submitted work. Dr Matsumoto reports personal fees from AbbVie, Endo, Lilly, Lipocine, and Clarus, outside the submitted work. Dr Swerdloff reports grants from the Bone Trial of the Testosterone Trials during the conduct of the study; grants and other from Clarus and Antares and grants from Lipesene, outside the submitted work. Dr Basaria reports other from Eli Lilly and Takeda Pharmaceuticals, outside the submitted work. Dr Diem reports grants from NIA, during the conduct of the study. Dr Wang reports grants from Besins Health International, other from Abbvie, during the conduct of the study; grants from Clarus Therapeutics, outside the submitted work. Dr Keaveny reports grants from NIA and NIH, grants and other from AbbVie (formerly Solvay & Abbott Lab), during the conduct of the study.

Figures

Figure 1. Screening and Retention of Participants

Figure 2. Median Serum Concentrations of Total Testosterone, Free Testosterone, and Estradiol From Months 0 to 12 in Men Treated With Testosterone or Placebo

The P values indicate the significance of the difference in serum concentrations in men in the testosterone arm compared with men in the placebo arm. The shaded areas represent the normal ranges for healthy young men. Error bars indicate interquartile ranges. SI conversion factors: To convert testosterone to nanomoles per liter, multiply by 0.0347; to convert free testosterone to picomoles per liter, multiply by 3.47; to convert estradiol to picomoles per liter, multiply by 3.67.

Figure 3. Effects of Testosterone or Placebo Treatment for 12 Months on Volumetric Bone Mineral Density and Estimated Bone Strength of Trabecular, Peripheral, and Whole Bone of the Spine and Hip, as Assessed by Quantitative Computed Tomography

Bars indicate means, and error bars, standard deviations. The P values indicate the significance of the difference in change in percent volumetric bone mineral density or estimated strength from baseline to 12 months for men in the testosterone arm compared with the placebo arm.