Lower Testosterone Linked to Increased Fracture Risk in Men

Abstract & Commentary

By Mary Elina Ferris, MD, Clinical Associate Professor, University of Southern California. Dr. Ferris reports no financial relationship with this field of study.

Synopsis: Lower serum testosterone in men aged 60 and over was associated with increased fracture risk (especially hip and nonvertebral), even after adjusting for other major risk factors for fracture.

Source: Meier C, et al. Endogenous sex hormones and incident fracture risk in older men: the Dubbo Osteoporosis Epidemiology Study. Arch Intern Med. 2008;168:47-54.

An ongoing osteoporosis study in the Australian town of Dubbo is following men and women (predominately Caucasian) aged 60 and over, with baseline bone mineral density (BMD), serum samples for sex hormone-binding globulin (SBHG), estradiol (E2) and testosterone, and for fracture incidence at 2-year intervals. After almost 6 years, the authors report on a sample of 609 men, 113 of whom were found to have a total of 149 fracture incidents, or 3.4 per 100 person-years. Men with fractures were older, had lower body weight, and lower dietary calcium. Nearly 80% of the fractures occurred in men aged 70 years and older, which was 2.7-fold higher than those under age 70.

For all men, both serum testosterone and E2 decreased with age and weight, with the reverse for SHBG, which showed higher levels with age. Increased risk of fractures was significantly associated with low levels of serum testosterone but not with E2 levels, which were similar in both the fracture and non-fracture groups. Although serum E2 was positively related to BMD, there was no significant relationship between testosterone and BMD. The effect of lower testosterone on increased fracture risk in non-vertebral sites persisted independent of other risk factors including age, low BMD, smoking, prior fracture or low calcium intake. Analysis adjusting for multiple other variables, including SHBG, showed that each standard deviation decrease of serum testosterone gave an increased fracture risk of 30-40%.

Commentary

Increasing evidence points to the vital role that sex steroids play in the maintenance of bone health, and more attention is being focused on osteoporosis in men. It's now thought that fully one-third of osteoporotic fractures occur in men, making the lifetime risk for hip and vertebral fractures in men similar to that of prostate cancer.

Studies in the past gave conflicting results about the role of serum testosterone, such as the Framingham study, which linked low estradiol and testosterone levels together, but not alone, with increased fractures in men.1 Swedish studies have positively linked free testosterone with fractures,2 while a smaller Rotterdam study did not.3 However, measurement of testosterone in the past used immunoassay-based methods which are not as reliable for low levels as the current liquid chromatography tandem mass spectrometry method. Furthermore, bioavailable or "free" testosterone is dependent on how much of it is bound to sex hormone-binding globulin (SBHG). Previous values for free testosterone were often calculated using this measurement, which has its own limitations.

While the explanation for testosterone's influence on bone health is not yet understood, we do know that peak bone mass in young men is associated with higher testosterone and lower estrogens,4 which is thought to account for gender-specific differences in bone mass. It seems plausible that a decrease in testosterone with ageing would also have a role in bone health. This study suggests that serum testosterone levels are an independent risk factor for fractures, and this is a separate risk from low BMD. However, these results do not establish a causal relationship, and the study does not address whether testosterone replacement would alter fracture risk in older men.

References

1. Amin S, et al. Estradiol, testosterone, and the risk for hip fractures in elderly men from the Framingham Study. Am J Med. 2006;119:426-433.

2. Goderie-Plomp HW, et al. Endogenous sex hormones, sex hormone-binding globulin, and the risk of incident vertebral fractures in elderly men and women: the Rotterdam Study. J Clin Endocrinol Metab. 2004;89:3261-3269.

3. Mellström D, et al. Free testosterone is an independent predictor of BMD and prevalent fractures in elderly men: MrOS Sweden. J Bone Miner Res. 2006;21:529-535.

4. Lorentzon M, et al. Free testosterone is a positive, whereas free estradiol is a negative, predictor of cortical bone size in young Swedish men: the GOOD study. J Bone Miner Res. 2005;20:1334-1341.