Dose effects of butoxamine, a selective β2-adrenoceptor antagonist, on bone metabolism in spontaneously hypertensive rat

Abstract

Recent studies have shown that osteoblasts and osteoclasts express β2-adrenoceptor, and increased sympathetic nervous activity causes bone loss via an increase in osteoclastic bone resorption and a decrease in osteoblastic bone formation. We previously demonstrated that non-selective β-adrenoceptor antagonist propranolol at low doses (0.1 and 1mg/kg), but not at a higher dose (10mg/kg), prevented a decrease in bone mass and an increase in bone fragility in spontaneously hypertensive rat (SHR), an animal model of osteoporosis with hyperactivity of the sympathetic nervous system, without affecting blood pressure. In the present study, the dose effects of butoxamine, a selective β2-adrenoceptor antagonist, on bone metabolism were examined in SHR by analysis of microcomputed tomography, bone histomorphometry, biomechanical testing and plasma biochemistry. Treatment of SHR with butoxamine at 0.1, 1 and 10mg/kg (per os) for 12 weeks increased bone mass indices and biomechanical parameters of strength and toughness of the lumbar vertebrae, suggesting antiosteoporotic activity. Butoxamine dose-dependently decreased osteoclast number and surface per bone surface with decreases in plasma tartrate-resistant acid phosphatase-5b level, a biochemical index of osteoclastic activity. On the other hand, histomorphometry indices of bone formation and plasma osteocalcin concentration reflecting osteoblastic activity were increased in SHR treated with butoxamine at 0.1 and 1mg/kg, but not at 10mg/kg. These results suggest that β-adrenoceptor antagonists at a low dose may improve osteoporosis with hyperactivity of the sympathetic nervous system via β2-adrenoceptor blocking action, while they may have a somewhat inhibitory effect on osteoblastic activity at a high dose.