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.
Osteoporosis is underdiagnosed and undertreated, and imposes a considerable economic burden on the health system.42 Effective strategies for the prevention and management of this disease are needed.42 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.32,43 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 the effect of testosterone therapy and fracture incidence, both lower areal bone mineral density and volumetric bone mineral density are associated with increased fracture incidence.44 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.35 Another study showed that testosterone therapy 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).45 The improvement in bone mineral density was directly related to the elevation in testosterone levels. In the non-treated group there was a decrease in both spine and femoral bone mineral density.45 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.46 It has been predicted that treatments that increase spine bone mineral density by 8% can reduce fracture risk by 54%.47
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.48 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, testosterone therapy for 6 years increased T-scores by +1.5 points.49 This reclassified the patients from osteoporosis to osteopenia, and reduced the calculated fracture risk by 50%.49 Another long-term study investigated hypogonadal men with aging associated low testosterone, who were treated with testosterone for up to 8 years.50 It was found that T-scores of vertebral and femoral bone mineral density increased significantly, which led to a marked decrease in the incidence of osteopenia in the spine and femoral neck.50 These two studies show that the increases in bone mineral density with long-term testosterone therapy are 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.51
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 middle-age dieting obese men mitigates the detrimental effects of caloric restriction on bone health.52 It was suggested that even during caloric restriction, testosterone treatment may lead to a temporary increase in bone formation and a sustained reduction in bone resorption.
Effect of testosterone therapy in men with osteoporotic fractures and normal testosterone levels
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).54 The subjects in this study were men aged 34-73 years, with vertebral crush fractures and back pain. 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 in the spine increased by 5% from 0.799 g/cm2 to 0.839 g/cm2,54 which could be estimated to lead to a 30% reduction in fracture risk.55 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, age was not predictive of response to treatment.54 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). A small elevation in blood thickness (hematocrit) 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.54,56 It was concluded that testosterone is a promising treatment for men with idiopathic osteoporosis.56 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, cardiovascular disease and mortality.57-60 A meta-analysis showed that lower trabecular volumetric bone 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.59 It is particularly interesting to note in the Bone Trial that the greatest improvement with testosterone therapy was seen in trabecular volumetric bone mineral density.11
Several mechanisms have been suggested to explain the relationship between low bone mineral density and cardiovascular disease.61,62 A well known risk factor for both low bone mineral density and cardiovascular disease in men is low testosterone levels.61-63 In previous editorials we have summarised research about low testosterone and risk of cardiovascular disease, as well as the beneficial effects of testosterone therapy on cardiovascular health:
Testosterone Therapy and Cardiovascular Risk - Advances and Controversies
Testosterone treatment is not associated with risk of adverse cardiovascular events – RHYME study
Low Testosterone is Associated with Elevated Cardiovascular Disease Biomarkers
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.