SAT-033 U-Shaped Association of Plasma Testosterone, and No Association of Plasma Estradiol, with Incidence of Any Fracture and Hip Fracture in Older Men

Osteoporosis resulting in bone fractures is a major cause of morbidity in older men. Previous studies implicated reduced exposure to estradiol (E2) with increased fracture risk in men. The extent to which circulating androgens contribute to maintenance of bone health is uncertain. We examined associations of different sex hormones with incidence of any bone fracture or hip fracture in older men. We analysed 3,307 community-dwelling men aged 76.8±3.5 years, median follow-up period of 10.6 years. Medical information was collected by questionnaire. Frailty was assessed using the FRAIL scale (1). Early morning plasma testosterone (T), dihydrotestosterone (DHT) and E2 were assayed by mass spectrometry, sex hormone-binding globulin (SHBG) and luteinising hormone (LH) by immunoassay. Incidence of any fracture and hip fracture were determined via data linkage to emergency department presentations and hospital admissions. Risk of fracture according to sex hormone concentrations was analysed. Hazard ratio of fracture according to sex hormone quartiles (Q1-4) was assessed using Cox regression models adjusted for age, medical comorbidities and frailty. In 30,355 participant-years of follow-up, the incidence of any fracture was 1.1% and hip fracture 0.5% per participant per year. Incident fractures occurred in 330 men, including 144 hip fractures. Probability plots suggested non-linear relationships between hormones and risk of any fracture and hip fracture, with higher risk at lower and higher concentrations of plasma T, lower E2, higher SHBG and higher LH. In fully-adjusted models, there was a U-shaped association of plasma T with incidence of any fracture (Q1: reference group, Q2: fully-adjusted hazard ratio [HR]=0.69, 95% confidence interval [CI]=0.51-0.94, p=0.020; Q3: HR=0.59, CI=0.42-0.83, p=0.002; Q4: 0.85, CI=0.62-1.18, p=0.335). A similar U-shaped association of T was found with incidence of hip fracture (Q1: HR=1.0; Q2: HR=0.60, CI=0.37-0.93, p=0.043; Q3: HR=0.52, CI=0.31-0.88, p=0.015; Q4: HR=1.04, CI=0.65-1.68, p=0.866). DHT, E2 and LH were not associated with incidence of any fracture or hip fracture (all p>0.050). SHBG was not associated with incidence of any fracture, but was associated with hip fracture (Q4 vs Q1: HR=1.76, CI=1.05-2.96, p=0.033). In conclusion, we found a non-linear or U-shaped association of T with fracture risk, with no association of E2. Mid-range plasma T was associated with lower incidence of any fracture and hip fracture, and higher SHBG with increased risk of hip fracture. Circulating androgen rather than estrogen may be a biomarker for hormone effects on bone driving fracture risk. A randomised controlled trial of T therapy powered for the outcome of fracture may be warranted and should recruit men with baseline T in the lowest quartile of values. Reference: (1) Hyde Z, et al. J Clin Endocrinol Metab 2010; 95: 3165-3172.