Sparse dose-dependent difference in skeletal effects of short-term glucocorticoid excess in outbred Swiss mice

Abstract

Glucocorticoid-induced osteoporosis (GIO) is the most common causes of secondary osteoporosis. Several laboratory animals have been employed to model GIO, and multiple routes of administration have been utilized. Prednisolone delivered by pellets implanted subcutaneously has been suggested as a less invasive alternative to daily injections, but how the severity of GIO varies between doses and the efficacy of short-term administration are not entirely elucidated. We investigated the skeletal effects of short-term exposure to glucocorticoid (GC) excess from implantable slow-release prednisolone pellets using two different doses (2.8 and 5.4 mg/kg/d). Forty-eight female Swiss mice were randomly allocated to the following four groups: 1: Baseline, 2: Placebo pellet (PP), 3: GC 5 mg, and 4: GC 10 mg. The study lasted four weeks. The musculoskeletal effects of GC were assessed by DXA, µCT, mechanical testing, dynamic bone histomorphometry, and histological quantification of bone and muscle cells. Both doses of GC significantly reduced bone mineral density, cortical mineralizing surfaces and mineral apposition rate, trabecular osteoid-covered surfaces, and rectus femoris muscle cell cross-sectional area compared with PP. In addition, the high dose of GC significantly reduced mid-diaphyseal bone strength compared with PP. Either dose had only minor impact on trabecular microstructure, while no negative effect was found on mid-diaphyseal cortical thickness. In conclusion, prednisolone pellet-induced short-term GC excess resulted in osteopenia, reduced bone formation indices, and only few dose-dependent differences were found.