β-Adrenergic blockade and leptin replacement effectively mitigate disuse bone loss

Abstract

Our objective was to test effects of β-adrenergic blockade on hindlimb unloading (HU)-induced bone loss and serum leptin and to compare these responses with those observed with leptin replacement. Adult male rats were randomized into six groups (n = 10 each): HU rats treated with vehicle (VEHHU), leptin analog (LEPHU), or β-blocker (BBHU) during a 28-day HU and cage activity controls (CC) treated with the same three agents and pair-fed to HU rats. On days 0 and 28, pQCT scans of proximal tibia and serum collections for leptin assays were performed, and histomorphometric measures of proximal tibia cancellous bone were assessed. The 20% decrease in cancellous vBMD observed in the VEHHU group was halved in BBHU rats and LEPHU rats. Bone formation rate (BFR) in BBHU rats, but not in LEPHU rats, was preserved. The 3-fold increase in resorption surface with HU was abolished by BB and LEP treatments. The decrease in serum leptin after a 28-day HU was attenuated in BBHU and LEPHU rats and was predictive of the decrease in BFR with HU. Blocking sympathetic adrenergic signaling by peripheral administration of a β-blocker during HU mitigates disuse-induced decreases in cancellous bone mass through stimulation of osteoblastic activity and suppression of osteoclastic activity. A direct effect of β-adrenergic blockade on bone cells during HU may be enhanced by an indirect effect mitigating reductions in circulating leptin, possibly through disinhibition of leptin release from adipocytes.