title: Propranolol Attenuates Risperidone-Induced Trabecular Bone Loss in Female Mice.
abstract: Atypical antipsychotic (AA) drugs cause significant metabolic side effects, and clinical data are emerging that demonstrate increased fracture risk and bone loss after treatment with the AA, risperidone (RIS). The pharmacology underlying the adverse effects on bone is unknown. However, RIS action in the central nervous system could be responsible because the sympathetic nervous system (SNS) is known to uncouple bone remodeling. RIS treatment in mice significantly lowered trabecular bone volume fraction (bone volume/total volume), owing to increased osteoclast-mediated erosion and reduced osteoblast-mediated bone formation. Daytime energy expenditure was also increased and was temporally associated with the plasma concentration of RIS. Even a single dose of RIS transiently elevated expression of brown adipose tissue markers of SNS activity and thermogenesis, Pgc1a and Ucp1. Rankl, an osteoclast recruitment factor regulated by the SNS, was also increased 1 hour after a single dose of RIS. Thus, we inferred that bone loss from RIS was regulated, at least in part, by the SNS. To test this, we administered RIS or vehicle to mice that were also receiving the nonselective β-blocker propranolol. Strikingly, RIS did not cause any changes in trabecular bone volume/total volume, erosion, or formation while propranolol was present. Furthermore, β2-adrenergic receptor null (Adrb2(-/-)) mice were also protected from RIS-induced bone loss. This is the first report to demonstrate SNS-mediated bone loss from any AA. Because AA medications are widely prescribed, especially to young adults, clinical studies are needed to assess whether β-blockers will prevent bone loss in this vulnerable population.
authors: Center for Clinical and Translational Research (K.J.M., V.E.D., D.O., C.J.R.), Maine Medical Center Research Institute, Scarborough, Maine 04074; Department of Pharmaceutical Sciences (D.B., K.L.H.), College of Pharmacy, University of New England, Portland, Maine 04005; and Department of Oral Medicine (K.N., R.B.), Infection and Immunity, Harvard School of Dental Medicine, Harvard University, Boston, Massachusetts 02115.
authors: Katherine J
authors: KJ
authors: Motyl
authors: Center for Clinical and Translational Research (K.J.M., V.E.D., D.O., C.J.R.), Maine Medical Center Research Institute, Scarborough, Maine 04074; Department of Pharmaceutical Sciences (D.B., K.L.H.), College of Pharmacy, University of New England, Portland, Maine 04005; and Department of Oral Medicine (K.N., R.B.), Infection and Immunity, Harvard School of Dental Medicine, Harvard University, Boston, Massachusetts 02115.
authors: Victoria E
authors: VE
authors: DeMambro
authors: Center for Clinical and Translational Research (K.J.M., V.E.D., D.O., C.J.R.), Maine Medical Center Research Institute, Scarborough, Maine 04074; Department of Pharmaceutical Sciences (D.B., K.L.H.), College of Pharmacy, University of New England, Portland, Maine 04005; and Department of Oral Medicine (K.N., R.B.), Infection and Immunity, Harvard School of Dental Medicine, Harvard University, Boston, Massachusetts 02115.
authors: Deborah
authors: D
authors: Barlow
authors: Center for Clinical and Translational Research (K.J.M., V.E.D., D.O., C.J.R.), Maine Medical Center Research Institute, Scarborough, Maine 04074; Department of Pharmaceutical Sciences (D.B., K.L.H.), College of Pharmacy, University of New England, Portland, Maine 04005; and Department of Oral Medicine (K.N., R.B.), Infection and Immunity, Harvard School of Dental Medicine, Harvard University, Boston, Massachusetts 02115.
authors: David
authors: D
authors: Olshan
authors: Center for Clinical and Translational Research (K.J.M., V.E.D., D.O., C.J.R.), Maine Medical Center Research Institute, Scarborough, Maine 04074; Department of Pharmaceutical Sciences (D.B., K.L.H.), College of Pharmacy, University of New England, Portland, Maine 04005; and Department of Oral Medicine (K.N., R.B.), Infection and Immunity, Harvard School of Dental Medicine, Harvard University, Boston, Massachusetts 02115.
authors: Kenichi
authors: K
authors: Nagano
authors: Center for Clinical and Translational Research (K.J.M., V.E.D., D.O., C.J.R.), Maine Medical Center Research Institute, Scarborough, Maine 04074; Department of Pharmaceutical Sciences (D.B., K.L.H.), College of Pharmacy, University of New England, Portland, Maine 04005; and Department of Oral Medicine (K.N., R.B.), Infection and Immunity, Harvard School of Dental Medicine, Harvard University, Boston, Massachusetts 02115.
authors: Roland
authors: R
authors: Baron
authors: Center for Clinical and Translational Research (K.J.M., V.E.D., D.O., C.J.R.), Maine Medical Center Research Institute, Scarborough, Maine 04074; Department of Pharmaceutical Sciences (D.B., K.L.H.), College of Pharmacy, University of New England, Portland, Maine 04005; and Department of Oral Medicine (K.N., R.B.), Infection and Immunity, Harvard School of Dental Medicine, Harvard University, Boston, Massachusetts 02115.
authors: Clifford J
authors: CJ
authors: Rosen
authors: Center for Clinical and Translational Research (K.J.M., V.E.D., D.O., C.J.R.), Maine Medical Center Research Institute, Scarborough, Maine 04074; Department of Pharmaceutical Sciences (D.B., K.L.H.), College of Pharmacy, University of New England, Portland, Maine 04005; and Department of Oral Medicine (K.N., R.B.), Infection and Immunity, Harvard School of Dental Medicine, Harvard University, Boston, Massachusetts 02115.
authors: Karen L
authors: KL
authors: Houseknecht
mesh_terms: D002001:Adipose Tissue, Brown / Q000187:drug effects / Q000378:metabolism; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology*; D000818:Animals; D014150:Antipsychotic Agents / Q000009:adverse effects*; D001851:Bone Diseases, Metabolic / Q000139:chemically induced*; D016723:Bone Remodeling / Q000187:drug effects*; D001842:Bone and Bones / Q000187:drug effects* / Q000378:metabolism; D004734:Energy Metabolism / Q000187:drug effects; D005260:Female; D007473:Ion Channels / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D024101:Mitochondrial Proteins / Q000187:drug effects / Q000378:metabolism; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D011433:Propranolol / Q000494:pharmacology*; D053245:RANK Ligand / Q000187:drug effects / Q000378:metabolism; D018343:Receptors, Adrenergic, beta-2 / Q000235:genetics; D018967:Risperidone / Q000009:adverse effects*; D013564:Sympathetic Nervous System / Q000187:drug effects* / Q000378:metabolism; D022722:Thermogenesis; D014157:Transcription Factors / Q000187:drug effects / Q000378:metabolism; D000071256:Uncoupling Protein 1
chemical_list: D000319:Adrenergic beta-Antagonists; D014150:Antipsychotic Agents; D007473:Ion Channels; D024101:Mitochondrial Proteins; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D053245:RANK Ligand; D018343:Receptors, Adrenergic, beta-2; C505689:Tnfsf11 protein, mouse; D014157:Transcription Factors; C000604372:Ucp1 protein, mouse; D000071256:Uncoupling Protein 1; D011433:Propranolol; D018967:Risperidone