Impact of Aromatase Inhibition on Bone Mineral Density and Structure: A Randomized Controlled Trial in Boys With Delayed Puberty

Treatment of boys with delayed puberty (DP) with aromatase inhibitor or low-dose testosterone (T) induces different hormonal milieus allowing assessment of the relative roles of sex steroids in bone metabolism. A prospective randomized controlled trial (NCT01797718). Peripheral quantitative computed tomography (pQCT) of the non-dominant arm and left leg was performed in 27 boys with DP. Fifteen boys were treated with letrozole (Lz) (2.5 mg/d) and twelve boys with T (1 mg/kg every 4 weeks) for 6 months. pQCT scans were performed at 0, 6, and 12 months. Circulating bone status indices were measured at 0, 3, 6, and 12 months. Between 0 and 3 months, levels of bone formation markers (P1NP, BAP) increased more in the T-group than in the Lz group (p=0.001-0.014). Accordingly, T-treated boys exhibited greater gain in bone mineral content (BMC) between 0 and 6 mo at distal site of tibia than the boys in the Lz-group (mean 18.1 mg/mm [25.4] vs. -1.8 mg/mm [SD 1.0], respectively, p=0.043). No significant between-group differences were observed in cortical or endosteal parameters. In both groups, the changes in testosterone levels during the treatment correlated positively with changes in BMC at distal radius (both p=0.041). Testosterone treatment increased bone formation markers and predicted greater BMC accrual than letrozole at metabolically active skeletal sites. These findings reinforce the anabolic role of androgens, partly mediated by estrogens, in early pubertal bone development. A short, 6-month treatment with letrozole did not appear detrimental to bone accrual based on pQCT parameters. However, these findings do not allow conclusions regarding skeletal safety of longer Lz use.