Thyroid hormones regulate adult bone turnover. Thyrotoxicosis results in high turnover osteoporosis whilst hypothyroidism leads to low bone turnover with increased bone mass and mineralisation. T3-target tissues express thyroid hormone receptor alpha (TRα), thyroid hormone receptor beta (TRβ)or both receptors. TRα1 mediates the actions of T3 in bone and in skeletal cells TRα1 mRNA expression is 12-fold higher than TRβ1. Accordingly, adult mice lacking TRα (TRα0/0) have reduced bone turnover and increased bone mass. Dronedarone is a non-iodinated amiodarone derivative, reported to act as a TRα1 antagonist. We hypothesised, therefore, that treatment with dronedarone would increase bone mass and strength in adult mice.
To investigate this hypothesis, 9-week-old male C57Bl/6 WT mice were treated with vehicle or dronedarone 60 mg/kg per day for 17 weeks until sacrifice. Femurs and vertebrae were analysed by digital X-ray microradiography to determine bone mineral content and mid-diaphyseal cortical thickness. The bio mechanical properties of long bones were quantified by destructive three point bend testing.
Femoral bone mineral content was increased in dronedarone treated mice (Kolmogorov-Smirnov test; P<0.01, n=12) but vertebral bone mineral content was unaffected. Furthermore, a trend towards increased cortical thickness was observed in dronedarone treated animals (Students t-test; vehicle 205±10 μm, dronedarone 220±14 μm, P=0.06, n=12). Nevertheless, mechanical testing of bone strength revealed that yield load, maximum load, fracture load and stiffness did not differ in dronedarone treated mice.
These studies demonstrate treatment of adult mice with dronedarone increases bone mineral content. Further detailed and comprehensive skeletal analysis is now required to evaluate the potential of TRα1 antagonism as a novel therapeutic approach in the treatment of osteoporosis.