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Effects of long-term long-acting testosterone undecanoate on bone mineral density in men with late-onset hypogonadism and metabolic syndrome

Effects of long-acting testosterone undecanoate on bone mineral density in middle-aged men with late-onset hypogonadism and metabolic syndrome: results from a 36 months controlled study. Aversa A, Bruzziches R, Francomano D, et al. Aging Male 2011;15(2):96-102.

This Research News article reviews an open-access article available in full from informa healthcare.

This study evaluated the long-term effects of testosterone replacement therapy (TRT) on the bone mineral density (BMD) of obese patients with metabolic syndrome (MetS) and/or type 2 diabetes mellitus (T2DM) and late-onset hypogonadism. Sixty Caucasian men aged 45–65 (mean 57) years with low serum testosterone (>11 nmol/L [320 ng/dL]) or calculated free testosterone >74 pg/mL (255 pmol/L) were enrolled. Treatment consisted of intramuscular testosterone undecanoate 4 times/year for 36 months (20 men). Twenty age-matched hypogonadal men with MetS in whom TRT was contraindicated were used as controls.

The remaining 20 men in the TRT group did not complete the study (and were not included in the analysis) because of mild and transient erythrocytosis (4 patients), increased prostate-specific antigen levels (1), personal reasons (6) or dropped out before completing the 36 months of observation (9).1 At baseline, mean lumbar BMD was 0.891±0.097 g/cm2, femoral BMD was 0.847±0.117 g/cm2, lumbar T-score was –1.6±0.9 and femoral neck T-score was 0.9±0.8, indicating that patients had mild osteopenia.

Key Points1

  • Bone mineral density (BMD) improved significantly (by approximately 5% per year) in men treated with testosterone undecanoate for 36 months, but there was no improvement in BMD in the untreated control group (Figure 1)
  • At 36 months:
    • Lumbar BMD was 1.053±0.145 g/cm2 in the testosterone replacement therapy (TRT) group versus 0.866±0.109 g/cm2 in controls (p<0.002 vs testosterone undecanoate)
    • Femoral BMD was 0.989±0.109 g/cm2 versus 0.823±0.126 g/cm2 in controls (p<0.003 vs testosterone undecanoate)
  • There was a direct correlation between change in total testosterone levels and change in BMD at the lumbar site (r2 = 0.66, p<0.0001) and femoral site (r2 = 0.52, p<0.0001)
  • There was a significant reduction in high-sensitivity C-reactive protein (hs-CRP) levels in the TRT, but not the control, group after 12, 24 and 36 months
  • No relationship between improvement in BMD and estradiol levels was observed
  • Body mass index (BMI) did not change in either group during the study
  • Adherence to study treatment was 50%
  • No serious testosterone undecanoate-related adverse events were reported.

What is known

Osteoporosis, characterized by increased risk of spontaneous and traumatic fractures due to reduced bone strength, is an underestimated, underdiagnosed and undertreated condition in men.2,3 Men with late-onset hypogonadism or those receiving androgen deprivation therapy for prostate cancer are at particular increased risk of osteoporosis.1,4 Studies have shown a positive association between BMD and endogenous androgen levels in the aging male population.5 It has been postulated that testosterone plays an important role in the maintenance of male bone health, in large part through the aromatization of testosterone to estradiol.6


The MetS, a cluster of risk factors for cardiovascular disease, characterized by abdominal obesity, insulin resistance, impaired glucose tolerance, dyslipidaemia and hypertension,7,8 is associated with low testosterone levels.9,10 Furthermore, an association between severe obesity and decreased BMD has also been demonstrated.11 However, data from interventional studies to investigate the effects of TRT on BMD in men with MetS and late-onset hypogonadism are limited and contradictory. Therefore this study aimed to determine whether TRT with a long-acting formulation of testosterone undecanoate could induce modifications in BMD in men affected by MetS and/or T2DM and late-onset hypogonadism.

What this study adds

This study shows for the first time the long-term effects of TRT with testosterone undecanoate on BMD in a small patient population of middle-aged men with MetS and/or T2DM and late-onset hypogonadism. Testosterone undecanoate was associated with a significant increase in vertebral and femoral BMD. While there was correlation between vertebral and femoral BMD and serum testosterone levels achieved, circulating estradiol levels did not appear to play a crucial role in improving BMD.1 Improvements in bone architecture were apparent after 12 months of testosterone undecanoate treatment, and progressively increased throughout the 36-month trial.

The authors speculated that the data support the hypothesis that testosterone may exert a specific action on the osteoblast through direct activation of the androgen receptor. Furthermore, the observed reduction in the inflammatory marker, hs-CRP, suggests that testosterone-mediated reduction in inflammation may be an additional mechanism for a beneficial effect on bone, in parallel with the suggested effect of estrogen in women.12 Additional and larger studies are warranted to further clarify the specific mechanisms underlying the actions of testosterone on BMD.

Figure 1: Improvement in bone mineral during 36 month of testosterone undecanoate therapy


1. Aversa A, Bruzziches R, Francomano D, et al. Effects of long-acting testosterone undecanoate on bone mineral density in middle-aged men with late-onset hypogonadism and metabolic syndrome: results from a 36 months controlled study. Aging Male 2011;15(2):96-102.
2. Kiebzak GM, Beinart GA, Perser K, et al. Undertreatment of osteoporosis in men with hip fracture. Arch Intern Med 2002;162(19):2217-2222.
3. Liu H, Paige NM, Goldzweig CL, et al. Screening for osteoporosis in men: a systematic review for an American College of Physicians guideline. Ann Intern Med 2008;148(9):685-701.
4. Hamilton EJ, Ghasem-Zadeh A, Gianatti E, et al. Structural decay of bone microarchitecture in men with prostate cancer treated with androgen deprivation therapy. J Clin Endocrinol Metab 2010;95(12):E456-463.
5. Rucker D, Ezzat S, Diamandi A, et al. IGF-I and testosterone levels as predictors of bone mineral density in healthy, community-dwelling men. Clin Endocrinol (Oxf) 2004;60(4):491-499.
6. Amory JK, Watts NB, Easley KA, et al. Exogenous testosterone or testosterone with finasteride increases bone mineral density in older men with low serum testosterone. J Clin Endocrinol Metab 2004;89(2):503-510.
7. Alberti KG, Eckel RH, Grundy SM, et al. Harmonizing the metabolic syndrome: a joint interim statement of the International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; and International Association for the Study of Obesity. Circulation 2009;120(16):1640-1645.
8. Corona G, Rastrelli G, Vignozzi L, et al. Testosterone, cardiovascular disease and the metabolic syndrome. Best Pract Res Clin Endocrinol Metab 2011;25(2):337-353.
9. Corona G, Monami M, Rastrelli G, et al. Testosterone and metabolic syndrome: a meta-analysis study. J Sex Med 2011;8(1):272-283.
10. Corona G, Rastrelli G, Morelli A, et al. Hypogonadism and metabolic syndrome. J Endocrinol Invest 2011;34(7):557-567.
11. Greco EA, Fornari R, Rossi F, et al. Is obesity protective for osteoporosis? Evaluation of bone mineral density in individuals with high body mass index. Int J Clin Pract 2010;64(6):817-820.
12. Pacifici R. The immune system and bone. Arch Biochem Biophys 2010;503(1):41-53.

The original article is recommended for additional detail and supporting references for the statements summarised in this Research News article, which are too numerous to cite in full.

Last updated: 2018