Effect of testosterone therapy on BMD and bone strength in men with low testosterone
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
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:
- Cortical bone, also known as compact bone.
- 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.
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%).
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.
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
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.