Testosterone treatment in men with osteoporosis and subnormal serum testosterone levels

Testosterone treatment in men with osteoporosis and subnormal serum testosterone levels

Progressive Improvement of T-Scores in Men with Osteoporosis and Subnormal Serum Testosterone Levels upon Treatment with Testosterone over Six Years. Haider A, Meergans U, Traish A, et al. Int J Endocrinol 2014; Article ID: 496948

Testosterone treatment can have a beneficial effect on bone loss resulting from testosterone deficiency. This summary discusses the key findings from a long-term, observational, open-label, prospective, cumulative, registry study that investigated the use of parenteral testosterone undecanoate (TU) 1,000 mg/12 weeks in hypogonadal men with osteoporosis.1 Bone mineral density (BMD), expressed as a T-score in 45 men (mean age 53 ± 7 years) was measured over the six year period of TU treatment.

Key Points

  • The present study was the first to investigate the use of long-term TU 1,000 mg (up to 6 years) in hypogonadal men with osteoporosis1
  • Use of TU 1,000 mg/12 weeks was investigated in 45 men, aged between 40–68 years, with osteoporosis and subnormal testosterone levels1

    • mean age 53.07 ± 6.89 years
    • testosterone levels <12.1 nmol/L
    • mean T-scores, –3.12 ± 0.45
  • Most patients had been referred by an orthopedic clinic where serum testosterone levels were routinely monitored in patients with osteoporosis, especially in relatively young men1
  • Many of the patients in this study were subsequently diagnosed with Klinefelter’s syndrome which had previously been undiagnosed. Other underlying causes of osteoporosis in patients included in this study were other forms of primary hypogonadism, alcohol abuse and Crohn’s disease1
  • Treatment with TU 1,000 mg produced significant, progressive improvements in BMD, as measured by T-scores of the spine (L2–4) and femoral neck (Figure)1

    • T-scores increased significantly from −3.12 ± 0.45 at baseline to −1.40 ± 0.14 after 6 years (p<0.0001)
    • The increase in T-scores was progressive with significant improvements each year compared with the previous year ( p<0.0016)
    • After 2 years of TU treatment, mean T-scores for patients were −2.24 ± 0.34 and thus most patients were reclassified as having osteopenia (T-scores, −1.0 to −2.5) rather than osteoporosis (T-scores, −2.5 to −4.0). After 5 years, no patient was classified with an osteoporosis T-score.
  • TU 1,000 mg significantly improved BP, metabolic parameters and levels of an inflammatory biomarker1

    • Significant, gradual improvements were seen in systolic and diastolic BP during the study period, which were sustained over 6 years. Systolic BP decreased from 136 ± 10 mmHg at baseline to 126 ± 5 mmHg after 6 years (p<0.0001). Diastolic BP decreased from 83 ± 7 mmHg at baseline to 71 ± 4 mmHg after 6 years (p<0.0001).
    • Improvements in levels of HDL-C (+8 ± 1 mg/dL), total cholesterol (–63 ± 5 mg/dL), LDL-C (–30 ± 3 mg/dL) and triglycerides (–55 ± 5 mg/dL) were seen in the study and were sustained over 6 years (all p<0.0001)
    • Blood levels of the inflammatory biomarker C-reactive protein (CRP), were significantly decreased by a mean of 7.7 ± 1 mg/L over 6 years (p<0.0001)
  • Treatment with TU 1,000 mg produced significant, progressive improvements in the male aging symptoms and sexual function

    • Aging Male Symptom Scale scores decreased from 47 ± 10 to 18 ± 1 over 6 years (p<0.0001)
    • International Index of Erectile Function scores increased from 19.5 ± 5.1 to 28.5 ± 0.6 over 6 years (p<0.0001)

What is known

Osteoporosis in men is a condition that is often underdiagnosed and undertreated.2 Although men tend to have higher BMD than women, and hence a lower incidence of fractures, fracture related mortality and morbidity are more frequent in men, partly due to greater frailty.3 Testosterone is believed to play a significant role in the maintenance of BMD.4 Testosterone deficiency (TD) has been associated with a reduction in BMD in men and testosterone treatment has been shown to improve BMD in men with subnormal testosterone levels.5 A recent study in men <50 years with TD and experiencing infertility or sexual dysfunction, found that over one-third of these patients also had reduced BMD.6 Improvements in BMD were observed following treatment of these patients with testosterone for 2.5 years. The results of this study provide further support for the routine measurement of BMD in relatively young men with subnormal testosterone levels.

What this study adds

This is the first long-term (6-year follow-up) study in men with osteoporosis treated with 1,000 mg TU and demonstrates that TU significantly improves T-scores associated with BMD in men with osteoporosis and TD.1 These results complement findings from several studies that have reported beneficial effects of testosterone treatment on BMD in hypogonadal men.7-13 Despite a number of conditions being responsible for patients’ TD (including Klinefelter’s syndrome, other forms of primary hypogonadism, alcohol abuse and Crohn’s disease), they all saw progressive increases in T-scores, with osteoporosis improving to a classification of osteopenia (Figure).1 Many of the patients included in this study were found to have Klinefelter’s syndrome, a condition which had previously remained undiagnosed. These findings support routine testing for TD in men with osteoporosis to enable effective treatment with testosterone in men with subnormal testosterone levels.

A number of other pathologies including metabolic effects, inflammation and erectile dysfunction have also been associated with chronic TD.14,15 In the current study, significant improvements in lipid profiles over the 6 year period were also observed following TU treatment, including statistically significant increases in HDL-C and statistically significant decreases in LDL-C, total cholesterol and triglycerides.1 Blood levels of an inflammatory biomarker, CRP, were also significantly decreased. In addition, significant and progressive improvements in male aging symptoms and erectile function were also observed.

Whilst the findings of this study merit further exploration, there are some limitations to be noted. This was a long-term, open-label, observational, and uncontrolled study which was not primarily designed to monitor the effects of normalizing serum testosterone on BMD in hypogonadal men with osteoporosis. Biomarkers of bone remodeling were not measured as there was not expected to be such a large number of patients with osteoporosis identified as having TD. As such, longitudinal, placebo-controlled, randomized trials are warranted to understand the role of TU treatment in hypogonadal men with osteoporosis.

Figure: Mean change (±SD) in T-scores from baseline following testosterone treatment

References

1. Haider A, Meergans U, Traish A, et al. Progressive Improvement of T-Scores in Men with Osteoporosis and Subnormal Serum Testosterone Levels upon Treatment with Testosterone over Six Years. Int J Endocrinol 2014; Article ID: 496948.
2. Laurent M, Gielen E, Claessens F, et al. Osteoporosis in older men: recent advances in pathophysiology and treatment. Best practice & research Clinical endocrinology & metabolism 2013;27(4):527-539.
3. Kannegaard PN, van der Mark S, Eiken P, et al. Excess mortality in men compared with women following a hip fracture. National analysis of comedications, comorbidity and survival. Age and ageing 2010;39(2):203-209.
4. Fink HA, Ewing SK, Ensrud KE, et al. Association of testosterone and estradiol deficiency with osteoporosis and rapid bone loss in older men. The Journal of clinical endocrinology and metabolism 2006;91(10):3908-3915.
5. Tuck SP, Francis RM. Testosterone, bone and osteoporosis. Frontiers of hormone research 2009;37:123-132.
6. Kacker R, Conners W, Zade J, et al. Bone mineral density and response to treatment in men younger than 50 years with testosterone deficiency and sexual dysfunction or infertility. The Journal of urology 2014;191(4):1072-1076.
7. 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. The aging male : the official journal of the International Society for the Study of the Aging Male 2012;15(2):96-102.
8. Jo DG, Lee HS, Joo YM, et al. Effect of testosterone replacement therapy on bone mineral density in patients with Klinefelter syndrome. Yonsei medical journal 2013;54(6):1331-1335.
9. Katznelson L, Finkelstein JS, Schoenfeld DA, et al. Increase in bone density and lean body mass during testosterone administration in men with acquired hypogonadism. The Journal of clinical endocrinology and metabolism 1996;81(12):4358-4365.
10. Rodriguez-Tolra J, Torremade J, di Gregorio S, et al. Effects of testosterone treatment on bone mineral density in men with testosterone deficiency syndrome. Andrology 2013;1(4):570-575.
11. Snyder PJ, Peachey H, Hannoush P, et al. Effect of testosterone treatment on bone mineral density in men over 65 years of age. The Journal of clinical endocrinology and metabolism 1999;84(6):1966-1972.
12. Wang C, Swerdloff RS, Iranmanesh A, et al. Effects of transdermal testosterone gel on bone turnover markers and bone mineral density in hypogonadal men. Clinical endocrinology 2001;54(6):739-750.
13. Amory JK, Watts NB, Easley KA. Exogenous testosterone or testosterone with finasteride increases bone mineral density in older men with low serum testosterone,. The Journal of Clinical Endocrinology & Metabolism 2004;89(2):503–510.
14. Corona G, Vignozzi L, Sforza A, et al. Risks and benefits of late onset hypogonadism treatment: an expert opinion. The World Journal of Men’s Health 2013;31(2):103–125.
15. Corona G, and M. Maggi. Diagnosis and treatment of late-onset hypogonadism: systematic review and metaanalysis of TRT outcomes. Best Practice & Research Clinical Endocrinology & Metabolism 2013;27(4):557–579.

Last updated: 2018
G.MKT.GM.MH.01.2018.0500