Glucocorticoid-induced loss of cortical bone is exacerbated during cold-exposure in male mice

Introduction:

Despite their desired immunosuppressive properties, glucocorticoids (GCs) are associated with multiple adverse effects severely limiting their clinical use. Patients receiving continuous GC therapy frequently suffer from a reduced bone mass and a high propensity for spinal fractures, rendering glucocorticoid-induced osteoporosis (GIO) the most common form of secondary osteoporosis. The sympathetic nervous system has been shown to be a potent regulator of bone metabolism. Here we examine a possible interaction between the sympathetic nervous system and GC exposure as a potential underlying reason for GCs site-specific effects throughout the skeleton.

Methods:

To modulate the outflow of the sympathetic nervous system 8-month-old C57BL/6NRj male mice were housed at either 29 °C (thermoneutrality), 22 °C (room/ambient temperature) or 13 °C (cold), while simultaneously receiving corticosterone or placebo via the drinking water for a total duration of 6 weeks. After sacrifice, bone quality was examined via micro-CT, static and dynamic histomorphometry as well as serum markers of bone turnover.

Results:

GC exposure did not alter trabecular bone structure in the vertebra or the femur across experimental groups regardless of thermal condition. However, following 6 weeks of GC treatment at thermoneutrality, mice showed a loss in cortical bone, reflected by a significant decrease in femoral cortical thickness (-11% vs. placebo; p < 0.01). GC exposure at thermoneutrality decreased the cortical osteoblast perimeter (Ob.Pm.) (-40% vs. placebo; p < 0.01) and serum levels of PINP (-58% vs. placebo; p < 0.01), a marker for bone formation. Conversely, indicators of bone resorption such as osteoclast surface/bone surface (Oc.S./B.S.) (+49% vs. placebo; p < 0.01) as well as serum levels of TRAP5b (+53% vs. placebo; p < 0.01) were increased by GC treatment at thermoneutrality. Treating mice with GCs at room temperature resulted in similar levels of femoral cortical bone loss and concomitant cellular changes as GC treatment at thermoneutrality. After 6 weeks of GC exposure at cold temperature femoral cortical bone loss was exacerbated compared to higher temperatures (-17% vs. placebo at cold temperature; p < 0.01). Interestingly, the increased loss of cortical bone in the cold environment was correlated with a GC-induced increase in Oc.S/B.S. (+67% vs. placebo; p < 0.01) above and beyond what was observed at ambient temperature and thermoneutrality.

Discussion:

These results suggest that the deleterious skeletal effects of GCs are exacerbated during cold exposure; potentially indicating a significant interplay between local GC action and the activation of the sympathetic nervous system following cold exposure.