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Mice Lacking β-Adrenergic Receptors Have Increased Bone Mass but Are Not Protected from Deleterious Skeletal Effects of Ovariectomy

Orthopedic Biomechanics Laboratory (M.L.B., M.J.D., V.G.), Beth Israel Deaconess Medical Center and Harvard Medical School, and Endocrine Division (H.D.), Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215; and Service of Bone Diseases (D.D.P., S.L.F.), Department of Rehabilitation and Geriatrics, Geneva University Hospital, 1211 Geneva 14, Switzerland

Address all correspondence and requests for reprints to: Mary L. Bouxsein, Ph.D., Orthopedic Biomechanics Laboratory, RN115, Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Boston, Massachusetts 02215. E-mail: mbouxsei{at}bidmc.harvard.edu.

Activation of β2-adrenergic receptors inhibits osteoblastic bone formation and enhances osteoclastic bone resorption. Whether β-blockers inhibit ovariectomy-induced bone loss and decrease fracture risk remains controversial. To further explore the role of β-adrenergic signaling in skeletal acquisition and response to estrogen deficiency, we evaluated mice lacking the three known β-adrenergic receptors (β-less). Body weight, percent fat, and bone mineral density were significantly higher in male β-less than wild-type (WT) mice, more so with increasing age. Consistent with their greater fat mass, serum leptin was significantly higher in β-less than WT mice. Mid-femoral cross-sectional area and cortical thickness were significantly higher in adult β-less than WT mice, as were femoral biomechanical properties (+28 to +49%, P < 0.01). Young male β-less had higher vertebral (1.3-fold) and distal femoral (3.5-fold) trabecular bone volume than WT (P < 0.001 for both) and lower osteoclast surface. With aging, these differences lessened, with histological evidence of increased osteoclast surface and decreased bone formation rate at the distal femur in β-less vs. WT mice. Serum tartrate-resistance alkaline phosphatase-5B was elevated in β-less compared with WT mice from 8–16 wk of age (P < 0.01). Ovariectomy inhibited bone mass gain and decreased trabecular bone volume/total volume similarly in β-less and WT mice. Altogether, these data indicate that absence of β-adrenergic signaling results in obesity and increased cortical bone mass in males but does not prevent deleterious effects of estrogen deficiency on trabecular bone microarchitecture. Our findings also suggest direct positive effects of weight and/or leptin on bone turnover and cortical bone structure, independent of adrenergic signaling.

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