Testosterone, dihydrotestosterone, bone density, and hip fracture risk among older men: The Cardiovascular Health Study

Highlights

• Dihydrotestosterone (DHT) was associated with lower hip fracture risk in elderly men.

• Testosterone (T) was not significantly associated with hip fracture risk.

• DHT and T were not significantly related to bone mineral density.

• DHT and T were similarly related to greater lean body mass.

Abstract

Background

Little is known about the relationships of dihydrotestosterone (DHT), a more potent androgen than testosterone (T), with bone mineral density (BMD) and fracture risk. Our objectives were to evaluate the relationships of T, DHT and sex hormone binding globulin (SHBG) with BMD, fracture risk, and lean body mass (LBM).

Methods

We evaluated 1128 older men free of cardiovascular disease in a prospective cohort study using data from the Cardiovascular Health Study. T and DHT were measured by liquid chromatography–tandem mass spectrometry and SHBG by fluoroimmunoassay. Our outcomes included incident hip fracture (n = 106) over a median of 10.2 years and BMD and LBM by dual-energy x-ray absorptiometry (n = 439).

Results

In Cox regression models mutually adjusted for T, SHBG, and covariates, each standard deviation increment in DHT (0.23 ng/ml) was associated with a 26% lower risk of hip fracture (adjusted hazard ratio [aHR] 0.74, 95% confidence interval (CI) 0.55–1.00, p = 0.049). Similarly, SHBG was associated with fracture in mutually adjusted models (aHR HR 1.26, 95% CI, 1.01–1.58, p = 0.045). In contrast, T (aHR, 1.16, 95% CI, 0.86–1.56, p = 0.324) was not significantly associated with fracture in mutually adjusted models. T, DHT and SHBG were not associated with BMD. T and DHT were both positively associated with LBM in individual models.

Conclusions

In older men, DHT was inversely associated with hip fracture risk and SHBG was positively associated with hip fracture risk, while T was not. Future studies should elucidate the mechanisms by which DHT affects bone health.

Introduction

Osteoporotic fractures are one of the most common causes of disability and comprise a substantial portion of medical costs worldwide [1]. The lifetime risk of hip fracture after 50 years of age is approximately 17% for Caucasian females and 6% for Caucasian males in the United States [2]. Hip fractures in particular are strongly associated with bone mineral density (BMD) and cause more disability than other types of fracture [1]. Mortality increases after both hip and non-hip fractures, and this mortality risk is even higher in men than women [3,4].

Although the pathogenesis of hip fractures is multifactorial, sex steroids are imperative for growth and maintenance of both female and male skeletons [5]. Male aging is associated with a decrease in serum sex hormones, and this decline has been shown to influence bone health [6,7], although the links between androgen levels in men and BMD and fracture risk remain an ongoing source of debate [[6], [7], [8], [9], [10], [11], [12], [13], [14], [15], [16]]. There is evidence to suggest that estradiol affects BMD and fracture risk, but the contribution of testosterone (T) remains unclear [8,17,18].

An important limitation in previous literature has been restriction of androgens tested to total or sometimes bioavailable T. Also, few studies have evaluated the effect of dihydrotestosterone (DHT), the product of 5α-reductase activity, on bone health. Accurate assessment of circulating DHT has only been possible with the advent of mass spectrometry-based DHT assays that can measure the small concentrations of DHT in blood. DHT differs from T in its higher potency and affinity and slower dissociation from the androgen receptor [19]. Although a few studies have suggested little incremental benefit to measurement of DHT in assessing fracture risk [9], we have found DHT to be more strongly associated than T in its associations with several forms of chronic disease [[20], [21], [22]].

To elucidate the relationships of total and free T and DHT, and their transport protein sex-hormone binding globulin (SHBG), with BMD and risk of hip fracture we studied men enrolled in the Cardiovascular Health Study. We hypothesized that both high SHBG and low DHT levels would be associated with increased fracture risk. We hypothesized that testosterone would not have a relationship with hip fracture risk.