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Effect of Testosterone Treatment on Volumetric Bone Density and Strength in Older Men With Low Testosterone: A Controlled Clinical Trial
Open accessAbstract
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.
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“These trials and other independent studies found that T administration in elderly men resulted in improvements in sexual function,202, 203 lean body mass,204, 205 physical function,206 strength,25, 205, 207 protein synthesis,25 cholesterol,204, 205, 208 and bone density.209”
From Hormonal and Metabolic Changes of Aging and the Influence of Lifestyle Modifications (2021) · cites this paper as [209]
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Tenuta, M., Hasenmajer, V., Gianfrilli, D., & Isidori, A. M. (2025) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/clinem/dgaf191 · Cited by 42
Assessment and clinical management of bone disease in adults with eating disorders: a review
Drabkin, A. D., Rothman, M. S., Wassenaar, E., Mascolo, M., & Mehler, P. S. (2017) · Journal of Eating Disorders · doi:10.1186/s40337-017-0172-0 · Cited by 37
“Most recently, transdermal testosterone treatment in older men with low testosterone significantly increased BMD after one year [82].”
BackgroundIcariin promotes mouse Leydig cell testosterone synthesis via the Esr1/Src/Akt/Creb/Sf-1 pathway
Sun, J., Xu, W., Zheng, S., Lv, C., Lin, J., Chen, S., Qiu, Y., Jiang, X., Draz, E. N., & Wang, S. (2022) · Toxicology and Applied Pharmacology · doi:10.1016/j.taap.2022.115969 · Cited by 37
Evidence of a Causal Effect of Estradiol on Fracture Risk in Men
Nethander, M., Vandenput, L., Eriksson, A. L., Windahl, S. H., Funck‐Brentano, T., & Ohlsson, C. (2018) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2018-00934 · Cited by 38
“The lack of any clear causal effect of T on fracture risk in the present MR analyses contrasts with findings from a number of clinical and experimental animal studies (4, 8, 13, 37).”
BackgroundResultDavid, K., Narinx, N., Antonio, L., Evenepoel, P., Claessens, F., Decallonne, B., & Vanderschueren, D. (2022) · Reviews in Endocrine and Metabolic Disorders · doi:10.1007/s11154-022-09738-5 · Cited by 37
Fode, M. M., Salonia, A., Minhas, S., Burnett, A. L. “., & Shindel, A. W. (2019) · European Urology Focus · doi:10.1016/j.euf.2019.02.021 · Cited by 36
Improving clinical outcomes through attention to sex and hormones in research
Mielke, M. M., & Miller, V. M. (2021) · Nature Reviews Endocrinology · doi:10.1038/s41574-021-00531-z · Cited by 40
Zhang, Z., Kang, D., & Li, H. (2020) · BMC Endocrine Disorders · doi:10.1186/s12902-020-0509-6 · Cited by 35
Nightingale, T. E., Moore, P. D., Harman, J., Khalil, R. E., Gill, R. S., Castillo, T. A., Adler, R. A., & Gorgey, A. S. (2017) · Journal of Spinal Cord Medicine · doi:10.1080/10790268.2017.1357917 · Cited by 37
Stephens‐Shields, A. J., Snyder, P. J., Ellenberg, S. S., Taylor, L., & Bhasin, S. (2022) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/clinem/dgac028 · Cited by 35
Self-citationEMAS position statement: Testosterone replacement therapy in older men
Kanakis, G., Pofi, R., Goulis, D. G., Isidori, A. M., Armeni, E., Erel, C. T., Fistonić, I., Hillard, T., Hirschberg, A. L., Męczekalski, B., et al. (2023) · Maturitas · doi:10.1016/j.maturitas.2023.107854 · Cited by 35
“This result confirmed the previously published bone sub-trial of the T-Trials on men with low T concentrations ( 8 nmol/L) treated for one year with T gel [87].”
ResultTestosterone deficiency and chronic kidney disease
Zitzmann, M. (2024) · Journal of Clinical & Translational Endocrinology · doi:10.1016/j.jcte.2024.100365 · Cited by 35
“These comprehensive benefits underscore the importance of TRT in addressing the multifaceted health challenges faced by hypogonadal men [2,9,21].”
BackgroundJasuja, G. K., Ameli, O., Reisman, J. I., Rose, A. J., Miller, D. R., Berlowitz, D. R., & Bhasin, S. (2019) · JAMA Network Open · doi:10.1001/jamanetworkopen.2019.17141 · Cited by 28
Self-citationManagement of osteoporosis in older men
Kaufman, J. (2021) · Aging Clinical and Experimental Research · doi:10.1007/s40520-021-01845-8 · Cited by 31
“More substantial increases at the spine and significant increases at the hip were reported for volumetric BMD assessed by QCT [115].”
BackgroundMale osteoporosis-what are the causes, diagnostic challenges, and management
Björnsdóttir, S., Clarke, B. L., Mannstadt, M., & Langdahl, B. L. (2022) · Best Practice & Research Clinical Rheumatology · doi:10.1016/j.berh.2022.101766 · Cited by 28
Cunningham, G. R., Ellenberg, S. S., Bhasin, S., Matsumoto, A. M., Parsons, J. K., Preston, P. E., Cauley, J. A., Gill, T. M., Swerdloff, R. S., Wang, C., et al. (2019) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2019-00806 · Cited by 28
Self-citationAnabolic Therapy for the Treatment of Osteoporosis in Childhood
Ward, L. M., & Rauch, F. (2018) · Current Osteoporosis Reports · doi:10.1007/s11914-018-0434-z · Cited by 28
Testosterone replacement in aging men: an evidence-based patient-centric perspective
Bhasin, S. (2021) · Journal of Clinical Investigation · doi:10.1172/jci146607 · Cited by 27
Self-citationThe impact of testosterone in men’s health
Ide, H. (2023) · Endocrine Journal · doi:10.1507/endocrj.ej22-0604 · Cited by 32
Xia, K., Chen, H., Wang, J., Feng, X. G., Gao, Y., Wang, Y., Deng, R., Wu, C., Luo, P., Zhang, M., et al. (2020) · Theranostics · doi:10.7150/thno.46854 · Cited by 26
“The clinical features of TD include sexual dysfunction [5], obesity [2], muscle weakness [6, 7], osteoporosis [8, 9] and others.”
BackgroundMethodSelf-citationFui, M. N. T., Hoermann, R., Nolan, B. J., Clarke, M., Zajac, J. D., & Grossmann, M. (2018) · Scientific Reports · doi:10.1038/s41598-018-27481-3 · Cited by 26
Testosterone Treatment in Middle-Aged and Older Men with Hypogonadism
Bhasin, S., & Snyder, P. J. (2025) · New England Journal of Medicine · doi:10.1056/nejmra2404637 · Cited by 27
Self-citationGrossmann, M., Jayasena, C. N., & Anawalt, B. D. (2023) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/clinem/dgad180 · Cited by 25
Via, J. D., Daly, R. M., Owen, P. J., Mundell, N. L., Rantalainen, T., & Fraser, S. F. (2019) · Bone · doi:10.1016/j.bone.2019.06.005 · Cited by 25
Yeap, B. B., Alfonso, H. S., Chubb, S. A. P., Beilin, J., Hankey, G. J., Almeida, O. P., Golledge, J., Norman, P. E., & Flicker, L. A. (2020) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/clinem/dgaa115 · Cited by 23
Association between Serum Testosterone Levels and Body Composition among Men 20–59 Years of Age
Ye, J., Zhai, X., Yang, J., & Zhu, Z. (2021) · International Journal of Endocrinology · doi:10.1155/2021/7523996 · Cited by 24
“among older men with low testosterone levels has a positive effect on BMD and estimated bone strength [18].”
BackgroundSzulc, P. (2022) · Best Practice & Research Clinical Endocrinology & Metabolism · doi:10.1016/j.beem.2022.101624 · Cited by 26
“TRT is more efficient in men who are treatment naïve or have clearly low testosterone level prior to treatment (123-124, 131, 133-136 133-136 ).”
Summary of the clinical practice manual for late‐onset hypogonadism
Ide, H., Akehi, Y., Fukuhara, S., Ohira, S., Ogawa, S., Kataoka, T., Kumagai, H., Kobayashi, K., Komiya, A., Shigehara, K., et al. (2023) · International Journal of Urology · doi:10.1111/iju.15160 · Cited by 28
Circadian Rhythm: Biological Functions, Diseases, and Therapeutic Targets
Zha, K., Mi, B., Xiong, Y., Wu, S., Li, L., Zhang, S., Lu, X., Mak, H. C., Huang, J., Panayi, A. C., et al. (2025) · MedComm · doi:10.1002/mco2.70435 · Cited by 27
Testosterone Therapy Effects on Bone Mass and Turnover in Hypogonadal Men with Type 2 Diabetes
Colleluori, G., Aguirre, L. E., Napoli, N., Qualls, C., Villareal, D. T., & Armamento‐Villareal, R. (2021) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/clinem/dgab181 · Cited by 22
Research advances in crosstalk between muscle and bone in osteosarcopenia (Review)
Yu, C., Du, Y., Peng, Z. Y., Ma, C., Fang, J., Ma, L., Chen, F., Zhang, C., Geng, R., Zhang, Y., et al. (2023) · Experimental and Therapeutic Medicine · doi:10.3892/etm.2023.11888 · Cited by 24
Metadata
- Authors
- Snyder, P. J., Kopperdahl, D. L., Stephens-Shields, A. J., Ellenberg, S. S., Cauley, J. A., Ensrud, K. E., Lewis, C. E., Barrett-Connor, E., Schwartz, A. V., Lee, D. C., Bhasin, S., Cunningham, G. R., Gill, T. M., Matsumoto, A. M., Swerdloff, R. S., Basaria, S., Diem, S. J., Wang, C., Hou, X., Cifelli, D., Dougar, D., Zeldow, B., Bauer, D. C., & Keaveny, T. M.
- Affiliations
- University of Pennsylvania (US)
- O.N. Diagnostics (United States) (US)
- Department of Biostatistics and Epidemiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia
- University of Pittsburgh (US)
- University of Minnesota (US)
- University of Alabama at Birmingham (US)
- University of California San Diego (US)
- University of California, San Francisco (US)
- Brigham and Women's Hospital (US)
- Baylor College of Medicine (US)
- Yale University (US)
- University of Washington (US)
- University of California, Los Angeles (US)
- University of California, Berkeley (US)
- Corresponding author
- Snyder, Peter J.
- ORCID
- Snyder, Peter J.
- Kopperdahl, David L.
- Ellenberg, Susan S.
- Cauley, Jane A.
- Ensrud, Kristine E.
- Lewis, Cora E.
- Barrett-Connor, Elizabeth
- Schwartz, Ann V.
- Lee, David C.
- Bhasin, Shalender
- Cunningham, Glenn R.
- Gill, Thomas M.
- Matsumoto, Alvin M.
- Swerdloff, Ronald S.
- Basaria, Shehzad
- Diem, Susan J.
- Wang, Christina
- Hou, Xiaoling
- Zeldow, Bret
- Bauer, Douglas C.
- Keaveny, Tony M.
- Venue
- JAMA Internal Medicine
- Publisher
- American Medical Association (AMA)
- Published
- 2017-04-01
- Volume
- 177
- Issue
- 4
- Pages
- 471
- ISSN
- 2168-6106 (ISSN-L)
- PMC
- PMC5433755
- OpenAlex
- W2591696989
- Cited by
- 363
- References
- 47
- Citations by year
- 2026: 37 · 2025: 47 · 2024: 37 · 2023: 37 · 2022: 41 · 2021: 44 · 2020: 30 · 2019: 34 · 2018: 32 · 2017: 22
- FWCI
- 25.39
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- JAMA Internal Medicine (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- National Institutes of Health (5p60dk079626-05, UL1TR000142, 5p30ag031679-15, UL1TR001863)
- National Institute on Aging (U01AG030644, R01AG037679, K07AG043587, P30-AG031679, P30AG021342)
- National Institute of Diabetes and Digestive and Kidney Diseases (P60-DK-079626, P30DK079626)
- National Center for Advancing Translational Sciences
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Hormonal and reproductive studies
- Health Sciences › Medicine › Orthopedics and Sports Medicine › Bone health and osteoporosis research
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Menopause: Health Impacts and Treatments
- Keywords
- testosterone replacement therapy, androgen deficiency, hypogonadism, older men, volumetric bone mineral density, bone strength, trabecular bone, hip bone, spine bone, testosterone gel, finite element analysis, fracture risk, bone mineral density, hormone replacement therapy, osteoporosis prevention
- MeSH terms
- Aged, Androgens, Double-Blind Method, Drug Administration Routes, Hip Fractures, Humans, Lumbar Vertebrae, Male, Testosterone, Tomography, X-Ray Computed, Absorptiometry, Photon, Bone Density, Spinal Fractures, Treatment Outcome, Drug Monitoring
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