Alt tag

Research news

Research news

Effect of testosterone therapy on BMD and bone strength in men with low testosterone

Bayer logo Bayer logo Bayer logo Bayer logo

Effect of testosterone therapy on BMD and bone strength in men with low testosterone

July 2018

STUDY: Snyder PJ, Kopperdahl DL, Stephens-Shields AJ, et al. Effect of Testosterone Treatment on Volumetric Bone Density and Strength in Older Men With Low Testosterone: A Controlled Clinical Trial. JAMA internal medicine. 2017;177(4):471-479.

Osteoporosis is a multifactorial disorder characterized by low bone mass and increased skeletal fragility.1 Osteoporosis and osteoporotic fractures are generally considered to mainly affect older postmenopausal women, but up to 20% of symptomatic vertebral fractures and 30% of hip fractures occur in men.2 Osteoporotic fractures in men are associated with substantial morbidity and greater excess mortality than in women.2 One of the major causes of osteoporosis in men is hypogonadism, which is found in up to 70% of elderly men with hip fractures.2,3

Low bone mineral density is a prevalent and treatable cause of osteoporosis-associated morbidity and mortality in men with hypogonadism.4 Low testosterone levels5 and bone loss6,7, with accompanying reduction in bone strength8 and increase in fractures9, is a common finding in older men. Even among men younger than 50 years who were attending an andrology/infertility clinic, 35% had bone mineral density consistent with osteopenia at the lumbar spine and/or the total hip.10 In fact, osteoporosis is a well-documented finding in men who have low testosterone levels caused by disease11 or androgen deprivation treatment12, even among younger men. This suggests that it is not age per se but rather low testosterone that contributes to the loss of bone mass and development of osteoporosis.

Here we summarise the results of the Bone Trial of the Testosterone Trials (T-Trials)13, a group of 7 coordinated trials of the effects of testosterone treatment of older men with low testosterone concentrations.14,15 The purpose of the Bone Trial was to determine whether testosterone treatment would improve bone mineral density and estimated bone strength.13

KEY POINTS

  • The Bone Trial of the TTrials series showed that testosterone treatment resulted in a significant:
    1. 6.8% increase in spine trabecular volumetric bone mineral density.
    2. 8.5% increase in estimated strength of spine trabecular bone.
      There were also increases in estimated bone strength in the other measured bone sites, but of smaller magnitude.
    3. There were also increases in volumetric bone mineral density at other locations; spine cortical bone (+2.9%), spine whole bone (4.2%), hip whole bone (+1.8%), hip trabecular bone (+1%), hip cortical bone (+1%), and DEXA measured (areal) spine bone mineral density (+1.2%).
  • The Bone Trial concluded that testosterone treatment for 1 year in older men with low testosterone significantly increases volumetric bone mineral density and estimated bone strength, more in trabecular than cortical bone and more in the spine than hip.
  • The ultimate goal for future studies is to investigate whether testosterone treatment of older men with low testosterone reduces fracture risk, as data suggest it may do.

What is known about bone mineral density, osteoporosis and testosterone

Osteoporosis is a silent disorder characterized by reduced bone mass (measured as bone mineral density) and bone strength, predisposing to increased fracture risk.1,16,17 The risk of fracture increases progressively with decreasing bone mineral density.17 Although osteoporosis is more common in women than men, up to 30–40% of all osteoporotic fractures worldwide occur in men.18 Surprisingly, the estimated residual lifetime risk of experiencing an osteoporotic fracture in men over the age of 50 is up to 27%, which is higher than the 12% lifetime risk of developing prostate cancer.19-21 With increasing longevity, the number of men aged 50 years or more at high risk of osteoporotic fracture has been projected to dramatically increase in the coming decades.22,23 Importantly, the morbidity and mortality consequences of osteoporotic fractures in men are more severe than in women24-27, and men are less likely to return to independent living than women after a hip fracture has occurred.28

 

Information box: cortical bone versus trabecular bone

Bone in human and other mammal bodies is generally classified into two types:

  1. Cortical bone, also known as compact bone.
  2. Trabecular bone, also known as cancellous or spongy bone.

These two types are classified as on the basis of porosity and microstructure. Cortical bone is dense and is found primary in the shaft of long bones and forms the outer shell around trabecular bone.

Trabecular bone is porous and is found at the ends of long bones like the legs (femur) and also in the pelvic bones, ribs, skull, and the vertebrae in spine.

 

Trabecular bone

 

Between 3-11% of men over the age of 50 in the United States have osteoporosis and 31-53% have osteopenia.29 An important risk factor for fractures in men is testosterone deficiency.2,3 Even among men younger than 50 years, those with testosterone levels of 12.1 nmol/L (350 ng/dL) or below had a significantly increased risk for osteopenia (OR 3.79, p <0.001) and osteoporosis (OR 7.64, p <0.001).10

The international Mr Osteoporosis study showed that both low total testosterone and bioavailable testosterone, but not estradiol or SHBG, are associated with increased falls.30 This confirms the results from the Osteoporotic Fractures in Men Study, which demonstrated that fall risk was higher in men with total testosterone below 9.3 nmol/L vs. above 20.5 nmol/L (<268 ng/dL vs. >590 ng/dL) and bioavailable testosterone below 1.75 ng/dL vs. above 2.51 ng/dL.31 Remarkably, the effect of testosterone level was independent of poorer physical performance, suggesting that the effect of testosterone on fall risk may be mediated by other androgen effects.31

Bone mineral density is a strong predictor of fractures in older men and may serve as a useful clinical tool in the evaluation of osteoporosis and fracture risk.32 Most prospective studies show that low testosterone is significantly associated with reduced bone mineral density and increased risk of osteoporotic fractures.33-35 For example, after a follow-up period of up to 13 years, low testosterone was associated with an almost 2-fold increased risk of hip fractures, even after adjustment for major risk factors for fractures (age, weight or bone mineral density, fracture history, smoking status, calcium intake, and SHBG).33 This study concluded that in community-dwelling men older than 60 years, testosterone levels are independently associated with the risk of osteoporotic fracture and its measurement may provide additional clinical information for the assessment of fracture risk in elderly men.33

In men who are severely hypogonadal, testosterone treatment improves bone mineral density36-38, trabecular bone structure39, and mechanical bone properties.40 Some prior studies of the effect of testosterone treatment on bone in older men have been inconclusive.41-44 The explanation for this is likely inadequate testosterone treatment44, and/or differences in baseline levels of testosterone41 and baseline bone mineral density.45

What this study adds

The Bone Trial was rigorously designed to find out the effects of testosterone therapy on bone mineral density and estimated bone strength.13 211 men 65 years or older with testosterone levels of 9.5 nmol/L (275 ng/dL) or less were randomized to receive treatment with either testosterone or placebo for 12 months. Spine and hip volumetric bone mineral density (expressed as cm3) and areal bone mineral density (expressed as cm2) was determined by quantitative computed tomography (qCT) and dual energy x-ray absorptiometry (DEXA), respectively. Bone strength was estimated by finite element analysis of qCT data. Effect was reported as the mean difference in change from baseline between testosterone and placebo arms.

Testosterone treatment resulted in significantly greater increases than placebo in spine trabecular volumetric bone mineral density (7.5% vs 0.8%; treatment effect, 6.8%) and estimated strength of spine trabecular bone (10.8% vs 2.4%; treatment effect, 8.5%), figure 1 and 2. The estimated strength increases were greater in trabecular than cortical bone and greater in the spine than hip. There were also increases in volumetric bone mineral density at other locations; spine cortical bone (+2.9%), spine whole bone (4.2%), hip whole bone (+1.8%), hip trabecular bone (+1%), hip cortical bone (+1%), and DEXA measured (areal) spine bone mineral density (+1.2%).

 

igure 1: Effect of testosterone therapy for 1 year on volumetric bone mineral density.

Figure 1: Effect of testosterone therapy for 1 year on volumetric bone mineral density.

Figure 2: Effect of testosterone therapy for 1 year on estimated bone strength.

Figure 2: Effect of testosterone therapy for 1 year on estimated bone strength.

It was concluded that testosterone treatment for 1 year in older men with low testosterone significantly increases volumetric bone mineral density and estimated bone strength, more in trabecular than cortical bone and more in the spine than hip. These results should give impetus to a larger and longer trial to determine whether testosterone treatment of older men with low testosterone reduces fracture risk.

Commentary

Osteoporosis is underdiagnosed and undertreated, and imposes a considerable economic burden on the health system.46 Effective strategies for the prevention and management of this disease are needed.46 The Bone Trial presented here shows unequivocally that testosterone therapy for 1 year significantly increases volumetric bone mineral density and estimated bone strength, especially in the spine and trabecular bone. This is remarkable considering that the full effect of testosterone on bone mineral density takes at least 24 months, and probably even longer to achieve.36,47 Thus, had the study continued for a longer time-period, even greater improvements would likely have been seen. While to date there are no studies on testosterone therapy and fracture incidence, both lower areal bone mineral density and volumetric bone mineral density are associated with increased fracture incidence.48 Hence, the increase in volumetric bone mineral density and to a lesser degree areal bone mineral density the Bone Trial suggests that testosterone therapy may reduce fracture risk.

Comparison with previous studies

Several previous longer-term studies have investigated the effect of testosterone therapy on bone mineral density. Testosterone treatment for 24 months significantly increased bone mineral density in the spine and total hip by 7.4% (from 0.93 to 1.00 cm2) and 3.8% (from 0.96 to 0.99 cm2), respectively.39 Another study showed that treating hypogonadal men with testosterone undecanoate for 36 months significantly increased spine bone mineral density by 18% (from 0.891 to 1.053 cm2) and femoral bone mineral density by 17% (from 0.847 to 0.989 cm2).49 The improvement in bone mineral density was directly related to the elevation in testosterone levels. No relationship between improvement in bone mineral density and serum estradiol levels was found. In the control group there was a decrease in both spine and femoral bone mineral density.49 Notably, the increase in spine and femur bone mineral density with testosterone therapy for 36 months is larger than that seen with medications specifically approved to treat osteoporosis, which increase spine and hip bone mineral density by only 4% to 13.5% and 2% to 6.5%, respectively.50 It has been predicted that treatments that increase spine bone mineral density by 8% would reduce fracture risk by 54%.51

The longest-term studies to date reported effects of testosterone therapy on T-scores. The T-score is defined as the difference between a patient’s bone mineral density and that of a young normal population.52 Minus values indicate that bone mineral density is below average, and plus values indicate that bone mineral density is above average.

In a study population of hypogonadal patients with various diseases - including Klinefelter’s syndrome, Crohn’s disease, alcohol abuse, Hodgkin’s lymphoma, kidney transplant, and undescended testis – who were all diagnosed with osteoporosis at baseline, treatment with testosterone undecanoate for 6 years increased T-scores by +1.5 points.53 This reclassified the patients from osteoporosis to osteopenia, and reduced the calculated fracture risk by 50%.53 Another long-term study investigated hypogonadal men with aging associated low testosterone, who were treated with testosterone undecanoate for up to 8 years.54 It was found that T-scores of vertebral and femoral bone mineral density increased significantly from 0.06 and 0.55 at baseline to 0.85 and 0.31, respectively. At baseline, 18 men were diagnosed with osteopenia and 1 with osteoporosis in the lumbar spine and 35 with osteopenia and 1 with osteoporosis of the femoral neck. At the end of the 8-year study period, there was a marked decrease in the incidence of osteopenia in the lumbar spine and femoral neck (4 and 14, respectively). No osteoporosis was reported at either of these sites.54 These two studies show that the increases in bone mineral density with long-term testosterone therapy are clinically meaningful and that benefits are seen in all hypogonadal men, regardless of whether low testosterone is caused by disease or associated with aging. The Bone Trial of the TTrials is the largest randomized clinical trial showing that testosterone therapy confers significant bone benefits in men with low testosterone associated with aging, and refutes previous ideas that testosterone therapy should be limited to hypogonadism caused by rare diseases.55

It should be pointed out that estrogen modulators, such as clomiphene citrate, and aromatase inhibitors – which are sometimes prescribed off label to increase testosterone levels in men with low testosterone who are concerned about fertility - decrease bone mineral density.10

Effect of testosterone therapy on bone in dieting obese men

Considering that diet-induced weight loss leads to a reduction in bone mineral density, it is notable that testosterone therapy in dieting obese men mitigates the detrimental effects of caloric restriction on bone health.56 Middle-age obese hypogonadal men were randomly allocated to receive 1000 mg testosterone undecanoate or placebo injections at weeks 0 and 6 and every 10 weeks thereafter throughout the 56-week study. During weeks 1 to 8 all subjects followed a very low calorie diet (VLCD) providing 640 calories per day and two cups of low-starch vegetables. During weeks 9-10, subjects weaned their VLED and ordinary foods were gradually reintroduced. After 10 weeks, subjects had completely ceased the VLED and were instructed to follow an energy-restricted diet providing 1350 calories per day, aimed at preventing weight regain, for the remaining 46 study weeks. Subjects were advised to perform at least 30 minutes of moderate-intensity exercise each day.

Interestingly, compared to placebo, the bone formation marker P1NP (procollagen type I N propeptide, s-PINP) was higher in testosterone-treated men at the end of the VLED phase, but lower by study end. In contrast, the bone resorption marker CTx (C-terminal telopeptide of type I collagen) was markedly reduced throughout the 56-week study period. This suggests that even during caloric restriction, testosterone treatment may lead to a temporary increase in bone formation and a sustained reduction in bone resorption. Bone turnover markers predict fracture risk, and treatment-induced changes in specific markers account for a substantial proportion of fracture risk reduction.57 Therefore, the effect of testosterone therapy on bone turnover markers, along with bone mineral density, merits further study.

Effect of testosterone therapy in eugonadal men with osteoporotic fractures

Most studies on the effects of testosterone therapy on bone mineral density have been conducted in men with low testosterone. However, one notable study showed that testosterone therapy also significantly increases bone mineral density in men with idiopathic vertebral fractures (i.e. fractures not associated with hypogonadism-related low bone mineral density).58 The subjects in this study were men aged 34-73 years, with vertebral crush fractures and back pain, in whom secondary causes of osteoporosis had been excluded. Their mean baseline testosterone level was 19.4 nmol/L (560 ng/dL), which is typically not considered low. Testosterone therapy for 6 months elevated testosterone to 29 nmol/L (836 ng/dL). bone mineral density at the lumbar spine increased by 5% from 0.799 g/cm2 to 0.839 g/cm2,58 which could be estimated to lead to a 30% reduction in fracture risk.59 In contrast, there were no significant changes in bone mineral density at the femoral neck, trochanter, and total hip, likely due to the relatively short treatment duration of only 6 months. Interestingly, neither age nor baseline gonadotrophin levels were predictive of response to treatment.58 The increase in spine bone mineral density was accompanied by significant favorable reductions in diastolic blood pressure (-4.7 mmHg), serum triglyceride (-0.405 mmol/L), and total cholesterol (-0.27 mmol/L). There was only a minor reduction in HDL cholesterol (-0.087 mmol/L). A small elevation in plasma viscosity was seen at 3 months which then plateaued and stayed within normal range. There was no change in glucose levels, serum electrolytes, hepatic or renal function.58,60 It was concluded that testosterone is a promising treatment for men with idiopathic osteoporosis.60 This study is particularly interesting because it shows significant bone mineral density benefit in men who do not have low testosterone and who therefore would not receive testosterone treatment in general routine clinical practice. The potential benefits of testosterone therapy on bone health – regardless of baseline testosterone status – merits further study.

Association of bone mineral density with Atherosclerosis, cardiovascular disease and mortality

Atherosclerosis and osteoporosis have traditionally been viewed as separate pathological conditions, however accumulating data show interesting associations between bone mineral density, atherosclerosis, CVD and mortality.61-64 A meta-analysis showed that lower trabecular vbone mineral density at baseline was found to predict long-term mortality after adjusting for demographics, hip size, health behaviors, chronic conditions, and history of bone fractures.63 It is particularly interesting to note in the Bone Trial that the greatest improvement with testosterone therapy was seen in trabecular vbone mineral density.13

Several mechanisms have been suggested to explain the relationship between low bone mineral density and cardiovascular disease.65,66 Two well known risk factors common to both low bone mineral density and cardiovascular disease in men are low testosterone and low estrogen levels.65-67 In previous editorials we have summarised the research about low testosterone and risk of cardiovascular disease, as well as the beneficial effects of testosterone therapy on cardiovascular health:

Long-Term Testosterone Therapy Improves Cardiometabolic Function and Reduces Risk of Cardiovascular Disease: Real-Life Results

Benefits of Testosterone Therapy in Men with Testosterone Deficiency

Testosterone Therapy and Cardiovascular Risk - Advances and Controversies

Low Testosterone is Associated with Elevated Cardiovascular Disease Biomarkers

Testosterone levels, testosterone therapy and all-cause mortality in men with type 2 diabetes

Survival and cardiovascular events in men treated with testosterone

Testosterone Therapy and Mortality in Older Men

Effects of testosterone treatment in older men

Effects of Testosterone Administration for 3 Years on Subclinical Atherosclerosis Progression in Older Men

Effective testosterone treatment reduces incidence of atrial fibrillation

Conclusion

The Bone Trial unequivocally shows significant benefits of testosterone therapy on bone mineral density and estimates bone strength in older men with aging related low testosterone. This study adds to the evidence base showing that testosterone has significant osteoanabolic effects, which supports the use of testosterone therapy in men with low bone mineral density. Data from other studies suggest that men with low bone mineral density may benefit even if their baseline testosterone level is higher than what is normally considered low testosterone.

Recommendations

Long term therapy with Nebido®

Long term therapy with Nebido®
Resources

Resources

Related topics

Hypogonadism Therapy Product Information

References

  • Rosen CJ. The Epidemiology and Pathogenesis of Osteoporosis. In: De Groot LJ, Chrousos G, Dungan K, et al., eds. Endotext. South Dartmouth (MA)2000. Return to content
  • Tuck SP, Francis RM. Testosterone, bone and osteoporosis. Front Horm Res. 2009;37:123-132. Return to content
  • Jackson JA, Riggs MW, Spiekerman AM. Testosterone deficiency as a risk factor for hip fractures in men: a case-control study. Am J Med Sci. 1992;304(1):4-8. Return to content
  • Gaffney CD, Pagano MJ, Kuker AP, Stember DS, Stahl PJ. Osteoporosis and Low Bone Mineral Density in Men with Testosterone Deficiency Syndrome. Sex Med Rev. 2015;3(4):298-315. Return to content
  • Harman SM, Metter EJ, Tobin JD, Pearson J, Blackman MR. Longitudinal effects of aging on serum total and free testosterone levels in healthy men. Baltimore Longitudinal Study of Aging. J Clin Endocrinol Metab. 2001;86(2):724-731. Return to content
  • Orwoll ES, Oviatt SK, McClung MR, Deftos LJ, Sexton G. The rate of bone mineral loss in normal men and the effects of calcium and cholecalciferol supplementation. Ann Intern Med. 1990;112(1):29-34. Return to content
  • Riggs BL, Melton LJ, Robb RA, et al. A population-based assessment of rates of bone loss at multiple skeletal sites: evidence for substantial trabecular bone loss in young adult women and men. J Bone Miner Res. 2008;23(2):205-214. Return to content
  • Samelson EJ, Christiansen BA, Demissie S, et al. QCT measures of bone strength at the thoracic and lumbar spine: the Framingham Study. J Bone Miner Res. 2012;27(3):654-663. Return to content
  • Moayyeri A, Kaptoge S, Luben RN, et al. Estimation of absolute fracture risk among middle-aged and older men and women: the EPIC-Norfolk population cohort study. Eur J Epidemiol. 2009;24(5):259-266. Return to content
  • Kacker R, Conners W, Zade J, Morgentaler A. Bone mineral density and response to treatment in men younger than 50 years with testosterone deficiency and sexual dysfunction or infertility. J Urol. 2014;191(4):1072-1076. Return to content
  • Finkelstein JS, Klibanski A, Neer RM, Greenspan SL, Rosenthal DI, Crowley WF, Jr. Osteoporosis in men with idiopathic hypogonadotropic hypogonadism. Ann Intern Med. 1987;106(3):354−361. Return to content
  • Wadhwa VK, Weston R, Mistry R, Parr NJ. Long-term changes in bone mineral density and predicted fracture risk in patients receiving androgen-deprivation therapy for prostate cancer, with stratification of treatment based on presenting values. BJU Int. 2009;104(6):800-805. Return to content
  • Snyder PJ, Kopperdahl DL, Stephens-Shields AJ, et al. Effect of Testosterone Treatment on Volumetric Bone Density and Strength in Older Men With Low Testosterone: A Controlled Clinical Trial. JAMA internal medicine. 2017;177(4):471-479. Return to content
  • Snyder PJ, Ellenberg SS, Cunningham GR, et al. The Testosterone Trials: Seven coordinated trials of testosterone treatment in elderly men. Clin Trials. 2014;11(3):362-375. Return to content
  • Snyder PJ, Bhasin S, Cunningham GR, et al. Effects of Testosterone Treatment in Older Men. N Engl J Med. 2016;374(7):611-624. Return to content
  • Watts NB, Adler RA, Bilezikian JP, et al. Osteoporosis in men: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2012;97(6):1802-1822. Return to content
  • Compston J, Cooper A, Cooper C, et al. UK clinical guideline for the prevention and treatment of osteoporosis. Archives of osteoporosis. 2017;12(1):43. Return to content
  • Johnell O, Kanis JA. An estimate of the worldwide prevalence and disability associated with osteoporotic fractures. Osteoporos Int. 2006;17(12):1726-1733. Return to content
  • Merrill RM, Weed DL, Feuer EJ. The lifetime risk of developing prostate cancer in white and black men. Cancer Epidemiol Biomarkers Prev. 1997;6(10):763-768. Return to content
  • Nguyen ND, Ahlborg HG, Center JR, Eisman JA, Nguyen TV. Residual lifetime risk of fractures in women and men. J Bone Miner Res. 2007;22(6):781-788. Return to content
  • Cooley H, Jones G. A population-based study of fracture incidence in southern Tasmania: lifetime fracture risk and evidence for geographic variations within the same country. Osteoporos Int. 2001;12(2):124−130. Return to content
  • Oden A, McCloskey EV, Kanis JA, Harvey NC, Johansson H. Burden of high fracture probability worldwide: secular increases 2010-2040. Osteoporos Int. 2015;26(9):2243- 2248. Return to content
  • Gullberg B, Johnell O, Kanis JA. World-wide projections for hip fracture. Osteoporos Int. 1997;7(5):407-413. Return to content
  • Center JR, Nguyen TV, Schneider D, Sambrook PN, Eisman JA. Mortality after all major types of osteoporotic fracture in men and women: an observational study. Lancet. 1999;353(9156):878−882. Return to content
  • Haentjens P, Magaziner J, Colon-Emeric CS, et al. Meta-analysis: excess mortality after hip fracture among older women and men. Ann Intern Med. 2010;152(6):380-390. Return to content
  • Bliuc D, Nguyen ND, Milch VE, Nguyen TV, Eisman JA, Center JR. Mortality risk associated with low-trauma osteoporotic fracture and subsequent fracture in men and women. JAMA. 2009;301(5):513-521. Return to content
  • Olszynski WP, Shawn Davison K, Adachi JD, et al. Osteoporosis in men: epidemiology, diagnosis, prevention, and treatment. Clin Ther. 2004;26(1):15-28. Return to content
  • Schurch MA, Rizzoli R, Mermillod B, Vasey H, Michel JP, Bonjour JP. A prospective study on socioeconomic aspects of fracture of the proximal femur. J Bone Miner Res. 1996;11(12):1935−1942. Return to content
  • Wright NC, Looker AC, Saag KG, et al. The recent prevalence of osteoporosis and low bone mass in the United States based on bone mineral density at the femoral neck or lumbar spine. J Bone Miner Res. 2014;29(11):2520- 2526. Return to content
  • Vandenput L, Mellstrom D, Laughlin GA, et al. Low Testosterone, but Not Estradiol, Is Associated With Incident Falls in Older Men: The International MrOS Study. J Bone Miner Res. 2017;32(6):1174-1181. Return to content
  • Orwoll E, Lambert LC, Marshall LM, et al. Endogenous testosterone levels, physical performance, and fall risk in older men. Arch Intern Med. 2006;166(19):2124- 2131. Return to content
  • Cawthon PM, Shahnazari M, Orwoll ES, Lane NE. Osteoporosis in men: findings from the Osteoporotic Fractures in Men Study (MrOS). Ther Adv Musculoskelet Dis. 2016;8(1):15-27. Return to content
  • Meier C, Nguyen TV, Handelsman DJ, et al. Endogenous sex hormones and incident fracture risk in older men: the Dubbo Osteoporosis Epidemiology Study. Arch Intern Med. 2008;168(1):47−54. Return to content
  • Kuchuk NO, van Schoor NM, Pluijm SM, Smit JH, de Ronde W, Lips P. The association of sex hormone levels with quantitative ultrasound, bone mineral density, bone turnover and osteoporotic fractures in older men and women. Clin Endocrinol (Oxf). 2007;67(2):295-303. Return to content
  • Cauley JA, Ewing SK, Taylor BC, et al. Sex steroid hormones in older men: longitudinal associations with 4.5-year change in hip bone mineral density--the osteoporotic fractures in men study. J Clin Endocrinol Metab. 2010;95(9):4314- 4323. Return to content
  • Snyder PJ, Peachey H, Berlin JA, et al. Effects of testosterone replacement in hypogonadal men. J Clin Endocrinol Metab. 2000;85(8):2670- 2677. Return to content
  • Katznelson L, Finkelstein JS, Schoenfeld DA, Rosenthal DI, Anderson EJ, Klibanski A. Increase in bone density and lean body mass during testosterone administration in men with acquired hypogonadism. J Clin Endocrinol Metab. 1996;81(12):4358- 4365. Return to content
  • Behre HM, Kliesch S, Leifke E, Link TM, Nieschlag E. Long-term effect of testosterone therapy on bone mineral density in hypogonadal men. J Clin Endocrinol Metab. 1997;82(8):2386- 2390. Return to content
  • Benito M, Vasilic B, Wehrli FW, et al. Effect of testosterone replacement on trabecular architecture in hypogonadal men. J Bone Miner Res. 2005;20(10):1785-1791. Return to content
  • Al Mukaddam M, Rajapakse CS, Bhagat YA, et al. Effects of testosterone and growth hormone on the structural and mechanical properties of bone by micro-MRI in the distal tibia of men with hypopituitarism. J Clin Endocrinol Metab. 2014;99(4):1236-1244. Return to content
  • Snyder PJ, Peachey H, Hannoush P, et al. Effect of testosterone treatment on bone mineral density in men over 65 years of age. J Clin Endocrinol Metab. 1999;84(6):1966-1972. Return to content
  • Kenny AM, Prestwood KM, Gruman CA, Marcello KM, Raisz LG. Effects of transdermal testosterone on bone and muscle in older men with low bioavailable testosterone levels. J Gerontol A Biol Sci Med Sci. 2001;56(5):M266-272. Return to content
  • 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. Return to content
  • Nair KS, Rizza RA, O'Brien P, et al. DHEA in elderly women and DHEA or testosterone in elderly men. N Engl J Med. 2006;355(16):1647-1659. Return to content
  • Wang C, Cunningham G, Dobs A, et al. Long-term testosterone gel (AndroGel) treatment maintains beneficial effects on sexual function and mood, lean and fat mass, and bone mineral density in hypogonadal men. J Clin Endocrinol Metab. 2004;89(5):2085-2098. Return to content
  • Haussler B, Gothe H, Gol D, Glaeske G, Pientka L, Felsenberg D. Epidemiology, treatment and costs of osteoporosis in Germany--the BoneEVA Study. Osteoporos Int. 2007;18(1):77-84. Return to content
  • Saad F, Aversa A, Isidori AM, Zafalon L, Zitzmann M, Gooren L. Onset of effects of testosterone treatment and time span until maximum effects are achieved. Eur J Endocrinol. 2011;165(5):675-685. Return to content
  • Chalhoub D, Orwoll ES, Cawthon PM, et al. Areal and volumetric bone mineral density and risk of multiple types of fracture in older men. Bone. 2016;92:100-106. Return to content
  • 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. Return to content
  • Choksi P, Jepsen KJ, Clines GA. The challenges of diagnosing osteoporosis and the limitations of currently available tools. Clin Diabetes Endocrinol. 2018;4:12. Return to content
  • Wasnich RD, Miller PD. Antifracture efficacy of antiresorptive agents are related to changes in bone density. J Clin Endocrinol Metab. 2000;85(1):231-236. Return to content
  • Faulkner KG. The tale of the T-score: review and perspective. Osteoporos Int. 2005;16(4):347-352. Return to content
  • 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. International journal of endocrinology. 2014;2014:496948. Return to content
  • Permpongkosol S, Khupulsup K, Leelaphiwat S, Pavavattananusorn S, Thongpradit S, Petchthong T. Effects of 8-Year Treatment of Long-Acting Testosterone Undecanoate on Metabolic Parameters, Urinary Symptoms, Bone Mineral Density, and Sexual Function in Men With Late-Onset Hypogonadism. The journal of sexual medicine. 2016;13(8):1199-1211. Return to content
  • Nguyen CP, Hirsch MS, Moeny D, Kaul S, Mohamoud M, Joffe HV. Testosterone and "Age-Related Hypogonadism"--FDA Concerns. N Engl J Med. 2015;373(8):689-691. Return to content
  • Soltani S, Hunter GR, Kazemi A, Shab-Bidar S. The effects of weight loss approaches on bone mineral density in adults: a systematic review and meta-analysis of randomized controlled trials. Osteoporos Int. 2016;27(9):2655- 2671. Return to content
  • Vasikaran S, Eastell R, Bruyere O, et al. Markers of bone turnover for the prediction of fracture risk and monitoring of osteoporosis treatment: a need for international reference standards. Osteoporos Int. 2011;22(2):391-420. Return to content
  • Anderson FH, Francis RM, Faulkner K. Androgen supplementation in eugonadal men with osteoporosis-effects of 6 months of treatment on bone mineral density and cardiovascular risk factors. Bone. 1996;18(2):171-177. Return to content
  • Black DM, Cummings SR, Genant HK, Nevitt MC, Palermo L, Browner W. Axial and appendicular bone density predict fractures in older women. J Bone Miner Res. 1992;7(6):633-638. Return to content
  • Anderson FH, Francis RM, Peaston RT, Wastell HJ. Androgen supplementation in eugonadal men with osteoporosis: effects of six months treatment on markers of bone formation and resorption. J Bone Miner Res. 1997;12(3):472-478. Return to content
  • Ye C, Xu M, Wang S, et al. Decreased Bone Mineral Density Is an Independent Predictor for the Development of Atherosclerosis: A Systematic Review and Meta-Analysis. PloS one. 2016;11(5):e0154740. Return to content
  • Veronese N, Stubbs B, Crepaldi G, et al. Relationship Between Low Bone Mineral Density and Fractures With Incident Cardiovascular Disease: A Systematic Review and Meta-Analysis. J Bone Miner Res. 2017;32(5):1126-1135. Return to content
  • Marques EA, Elbejjani M, Gudnason V, et al. Proximal Femur Volumetric Bone Mineral Density and Mortality: 13 Years of Follow-Up of the AGES-Reykjavik Study. J Bone Miner Res. 2017;32(6):1237-1242. Return to content
  • Qu X, Huang X, Jin F, et al. Bone mineral density and all-cause, cardiovascular and stroke mortality: a meta-analysis of prospective cohort studies. Int J Cardiol. 2013;166(2):385-393. Return to content
  • Isidori AM, Giannetta E, Pozza C, Bonifacio V, Isidori A. Androgens, cardiovascular disease and osteoporosis. J Endocrinol Invest. 2005;28(10 Suppl):73-79. Return to content
  • Lampropoulos CE, Papaioannou I, DCruz DP. Osteoporosis--a risk factor for cardiovascular disease? Nature reviews Rheumatology. 2012;8(10):587-598. Return to content
  • Yeap BB. Testosterone and its metabolites: differential associations with cardiovascular and cerebrovascular events in men. Asian journal of andrology. 2018;20(2):109-114. Return to content

Copyright © 2021, Bayer AG

This website contains information on Nebido® (testosterone undecanoate) which is based on the Summary of Product Characteristics (SPC) as approved by the European Commission.

 

This website is intended to provide information to an international audience outside Austria, France, Germany, Hungary, Ireland, the Middle East, the Philippines, Thailand, the UK, and the USA.

Page last modified 01/04/2021

PP-NEB-ALL-0222-1 April 2021

  • PP-NEB-ALL-0222-1 April 2021

BayerBayer