Long-term exposure to elevated endogenous and therapeutic glucocorticoids is associated with high risk of osteoporosis and fracture. The 11β-hydroxysteroid dehydrogenase (11β-HSD) enzymes mediate the actions of glucocorticoids in many tissues. The 11β-HSD1 enzyme converts inactive endogenous glucocorticoids such as dehydrocorticosterone and cortisone, as well as therapeutic glucocorticoids such as prednisone, to their active counterparts corticosterone, cortisol and prednisolone. In contrast, renal inactivation of glucocorticoids by the 11β-HSD2 enzyme generates a supply of inactive substrate for 11β-HSD1 in vivo. We have previously demonstrated the presence of 11β-HSD1 within bone and hypothesised that 11β-HSD1 within osteoblasts regulates the effects of exogenous glucocorticoids on bone.

Mice with transgenic deletion of 11β-HSD1 (11BKO) and their wild type (WT) littermates were treated for four weeks with the active murine glucocorticoid corticosterone (100microg/mL) or vehicle control delivered in drinking water. Upon completion, bone density and structure were analysed by microCT. Whilst serum corticosterone and body weights were increased and adrenal weights reduced in mice receiving corticosterone at four weeks, there were no significant differences between 11BKO and WT counterparts. No differences were evident in microCT parameters of bone volume to tissue volume (BV/TV), trabecular number (TN) and trabecular separation (TS) between WT and 11BKO mice given control drinking water (BV/TV: WT 8.6%+0.81 vs 11BKO 7.4%+1.3, NS; TN: WT 0.85 1/mm+0.093 vs 11BKO 0.77 1/mm+0.04, NS; TS: 669.8mm+72 vs 11BKO 706.8mm+92.8, NS). As expected, WT mice treated with corticosterone developed osteoporosis on the basis of decreased BV/TV and TN and increased TS. However, 11β-HSD1 KO animals were almost completely protected against the effects of corticosterone (BV/TV: WT 5.31%+0.84 vs 11BKO 7.51%+1.31, P<0.05; TN: WT 0.65 1/mm+0.051 vs 11BKO 0.925 1/mm+0.044, P<0.05; TS: WT 1000.2mm+72.1 vs 11BKO 809.2mm+82.6, p=0.08).

These data indicate that local reactivation of glucocorticoids within osteoblasts contributes substantially to the development of glucocorticoid-induced osteoporosis.