In older men, circulating levels of dihydrotestosterone (DHT) and sex hormone–binding globulin (SHBG) independently predict risk of hip fracture, but testosterone does not, according to a study involving more than 1,000 men.
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These findings could influence clinical measurement of male hormone levels and possibly intervention for low DHT, reported lead author Emily A. Rosenberg, MD, of Brigham and Women’s Hospital in Boston and colleagues.
“Male aging is associated with a decrease in serum sex hormones, and this decline has been shown to influence bone health, although the links between androgen levels in men and bone mineral density and fracture risk remain an ongoing source of debate,” the investigators wrote in Metabolism.
According to Dr. Rosenberg and colleagues, most previous studies in this area have focused on total or bioavailable testosterone; however, DHT demonstrates greater affinity with and slower dissociation from the androgen receptor, which could translate to a more significant role in bone metabolism. With the advent of mass spectrometry–based DHT assays, it is now possible to accurately measure small concentrations of DHT in blood, they added.
Their prospective, multicenter, cohort study involved 1,128 men who were 65 years or older and without history of cardiovascular disease. Beginning in 1989-1990, participants underwent a baseline examination that included standardized medical history questionnaires, physical exam, and laboratory testing. Additional participants joined the study in 1992-1993, and in 1994-1995, a subset of participants (n = 439) underwent dual-energy x-ray absorptiometry (DXA) scanning.
Hormone assays were conducted in 2010 using frozen serum samples from 1994-1995. Testosterone and DHT were measured by liquid chromatography–tandem mass spectrometry assay, while SHBG was measured by fluoroimmunoassay.
The primary outcome, incident hip fracture, was identified from medical records through 2013. Secondary outcomes included lean body mass and bone mineral density of the hip. A variety of covariates were also recorded, including age, sex, weight, alcohol consumption, smoking status, and others.
After a median follow-up of 10.2 years (interquartile range, 5.9-15.5 years), 106 cases of hip fracture occurred, which translated to an incidence rate of 0.89 per 100 person-years. Cox regression models mutually adjusted for covariates, and the other analyses showed that each standard deviation increase in DHT correlated with a 26% decreased risk of hip fracture (adjusted hazard ratio, 0.74; 95% confidence interval, 0.55-1.00; P = .049). Conversely, each standard deviation increase in SBHG was associated with a 26% increased risk of hip fracture (aHR, 1.26; 95% CI, 1.01-1.58; P = .045). In contrast with both DHT and SBHG, testosterone was not significantly associated with the primary outcome (aHR, 1.16; 95% CI, 0.86-1.56; P = .324).
Further analysis showed that testosterone, DHT, and SBHG were not significantly associated with bone mineral density of the hip. In adjusted models, testosterone and DHT were independently associated with higher lean body mass; however, in mutually adjusted models, these associations were not statistically significant, although they remained similar and positive.
“More research is needed to determine the mechanism(s) by which DHT may affect bone health and whether interventions that regulate DHT might be used to reduce risk of hip fracture,” the investigators concluded. “While our results require confirmation, there may be a role for measurement of DHT along with testosterone when the clinical scenario requires measurement of male hormone levels.”
The study was funded by the National Heart, Lung and Blood Institute and the National Institute on Aging. The investigators reported no conflicts of interest.
SOURCE: Rosenberg EA et al. Metabolism. 2020 Oct 12. doi: 10.1016/j.metabol.2020.154399.