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Russell T Turner Skeletal Biology Laboratory, Center for Healthy Aging Research, Biostatistics, School of Biological and Population Health Sciences
Skeletal Biology Laboratory, Center for Healthy Aging Research, Biostatistics, School of Biological and Population Health Sciences

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Kenneth A Philbrick Skeletal Biology Laboratory, Center for Healthy Aging Research, Biostatistics, School of Biological and Population Health Sciences

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Carmen P Wong Skeletal Biology Laboratory, Center for Healthy Aging Research, Biostatistics, School of Biological and Population Health Sciences

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Dawn A Olson Skeletal Biology Laboratory, Center for Healthy Aging Research, Biostatistics, School of Biological and Population Health Sciences

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Adam J Branscum Skeletal Biology Laboratory, Center for Healthy Aging Research, Biostatistics, School of Biological and Population Health Sciences

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Urszula T Iwaniec Skeletal Biology Laboratory, Center for Healthy Aging Research, Biostatistics, School of Biological and Population Health Sciences
Skeletal Biology Laboratory, Center for Healthy Aging Research, Biostatistics, School of Biological and Population Health Sciences

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dual-energy X-ray absorptiometry (DXA), microcomputed tomography (μCT), and histomorphometry. Tibiae were removed, cleaned of soft tissue, frozen in liquid nitrogen, and stored at −80 °C for mRNA isolation and gene expression analysis. Serum chemistry

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Russell T Turner Skeletal Biology Laboratory, Center for Healthy Aging Research, Department of Neuroscience, Biostatistics, Department of Physiological Sciences, Department of Large Animal Clinical Sciences, Maine Medical Center Research Institute, School of Biological and Population Health Sciences, Oregon State University, Corvallis, Oregon 97331, USA
Skeletal Biology Laboratory, Center for Healthy Aging Research, Department of Neuroscience, Biostatistics, Department of Physiological Sciences, Department of Large Animal Clinical Sciences, Maine Medical Center Research Institute, School of Biological and Population Health Sciences, Oregon State University, Corvallis, Oregon 97331, USA

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Michael Dube Skeletal Biology Laboratory, Center for Healthy Aging Research, Department of Neuroscience, Biostatistics, Department of Physiological Sciences, Department of Large Animal Clinical Sciences, Maine Medical Center Research Institute, School of Biological and Population Health Sciences, Oregon State University, Corvallis, Oregon 97331, USA

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Adam J Branscum Skeletal Biology Laboratory, Center for Healthy Aging Research, Department of Neuroscience, Biostatistics, Department of Physiological Sciences, Department of Large Animal Clinical Sciences, Maine Medical Center Research Institute, School of Biological and Population Health Sciences, Oregon State University, Corvallis, Oregon 97331, USA

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Carmen P Wong Skeletal Biology Laboratory, Center for Healthy Aging Research, Department of Neuroscience, Biostatistics, Department of Physiological Sciences, Department of Large Animal Clinical Sciences, Maine Medical Center Research Institute, School of Biological and Population Health Sciences, Oregon State University, Corvallis, Oregon 97331, USA

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Dawn A Olson Skeletal Biology Laboratory, Center for Healthy Aging Research, Department of Neuroscience, Biostatistics, Department of Physiological Sciences, Department of Large Animal Clinical Sciences, Maine Medical Center Research Institute, School of Biological and Population Health Sciences, Oregon State University, Corvallis, Oregon 97331, USA

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Xiaoying Zhong Skeletal Biology Laboratory, Center for Healthy Aging Research, Department of Neuroscience, Biostatistics, Department of Physiological Sciences, Department of Large Animal Clinical Sciences, Maine Medical Center Research Institute, School of Biological and Population Health Sciences, Oregon State University, Corvallis, Oregon 97331, USA

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Mercedes F Kweh Skeletal Biology Laboratory, Center for Healthy Aging Research, Department of Neuroscience, Biostatistics, Department of Physiological Sciences, Department of Large Animal Clinical Sciences, Maine Medical Center Research Institute, School of Biological and Population Health Sciences, Oregon State University, Corvallis, Oregon 97331, USA

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Iske V Larkin Skeletal Biology Laboratory, Center for Healthy Aging Research, Department of Neuroscience, Biostatistics, Department of Physiological Sciences, Department of Large Animal Clinical Sciences, Maine Medical Center Research Institute, School of Biological and Population Health Sciences, Oregon State University, Corvallis, Oregon 97331, USA

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Thomas J Wronski Skeletal Biology Laboratory, Center for Healthy Aging Research, Department of Neuroscience, Biostatistics, Department of Physiological Sciences, Department of Large Animal Clinical Sciences, Maine Medical Center Research Institute, School of Biological and Population Health Sciences, Oregon State University, Corvallis, Oregon 97331, USA

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Clifford J Rosen Skeletal Biology Laboratory, Center for Healthy Aging Research, Department of Neuroscience, Biostatistics, Department of Physiological Sciences, Department of Large Animal Clinical Sciences, Maine Medical Center Research Institute, School of Biological and Population Health Sciences, Oregon State University, Corvallis, Oregon 97331, USA

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Satya P Kalra Skeletal Biology Laboratory, Center for Healthy Aging Research, Department of Neuroscience, Biostatistics, Department of Physiological Sciences, Department of Large Animal Clinical Sciences, Maine Medical Center Research Institute, School of Biological and Population Health Sciences, Oregon State University, Corvallis, Oregon 97331, USA

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Urszula T Iwaniec Skeletal Biology Laboratory, Center for Healthy Aging Research, Department of Neuroscience, Biostatistics, Department of Physiological Sciences, Department of Large Animal Clinical Sciences, Maine Medical Center Research Institute, School of Biological and Population Health Sciences, Oregon State University, Corvallis, Oregon 97331, USA
Skeletal Biology Laboratory, Center for Healthy Aging Research, Department of Neuroscience, Biostatistics, Department of Physiological Sciences, Department of Large Animal Clinical Sciences, Maine Medical Center Research Institute, School of Biological and Population Health Sciences, Oregon State University, Corvallis, Oregon 97331, USA

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). Microcomputed tomography Microcomputed tomography (μCT) was used for nondestructive high resolution 3-dimensional evaluation of cortical and cancellous bone volume and architecture. Midshaft and distal femora and 2nd lumbar vertebrae were scanned in 70% ethanol

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Guillaume Mabilleau Groupe d'Etudes sur le Remodelage Osseux et les bioMatériaux (GEROM) – LHEA, Service Commun d'Imageries
et d'Analyses Microscopiques (SCIAM), School of Biomedical Sciences
Groupe d'Etudes sur le Remodelage Osseux et les bioMatériaux (GEROM) – LHEA, Service Commun d'Imageries
et d'Analyses Microscopiques (SCIAM), School of Biomedical Sciences

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Aleksandra Mieczkowska Groupe d'Etudes sur le Remodelage Osseux et les bioMatériaux (GEROM) – LHEA, Service Commun d'Imageries
et d'Analyses Microscopiques (SCIAM), School of Biomedical Sciences

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Nigel Irwin Groupe d'Etudes sur le Remodelage Osseux et les bioMatériaux (GEROM) – LHEA, Service Commun d'Imageries
et d'Analyses Microscopiques (SCIAM), School of Biomedical Sciences

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Peter R Flatt Groupe d'Etudes sur le Remodelage Osseux et les bioMatériaux (GEROM) – LHEA, Service Commun d'Imageries
et d'Analyses Microscopiques (SCIAM), School of Biomedical Sciences

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Daniel Chappard Groupe d'Etudes sur le Remodelage Osseux et les bioMatériaux (GEROM) – LHEA, Service Commun d'Imageries
et d'Analyses Microscopiques (SCIAM), School of Biomedical Sciences
Groupe d'Etudes sur le Remodelage Osseux et les bioMatériaux (GEROM) – LHEA, Service Commun d'Imageries
et d'Analyses Microscopiques (SCIAM), School of Biomedical Sciences

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-ray microcomputed tomography X-ray microcomputed tomography (micro-CT) analysis was performed in the proximal left femur with a Skyscan 1172 microtomograph (Bruker Micro-CT, Kontich, Belgium) equipped with an X-ray tube working at 69 kV/100 μA. The pixel size was

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H H Farman Centre for Bone and Arthritis Research at Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden

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K L Gustafsson Centre for Bone and Arthritis Research at Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden

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P Henning Centre for Bone and Arthritis Research at Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden

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L Grahnemo Centre for Bone and Arthritis Research at Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden

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V Lionikaite Centre for Bone and Arthritis Research at Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden

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S Movérare-Skrtic Centre for Bone and Arthritis Research at Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden

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J Wu Centre for Bone and Arthritis Research at Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden

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H Ryberg Centre for Bone and Arthritis Research at Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
Clinical Chemistry, Sahlgrenska University Hospital, Gothenburg, Sweden

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A Koskela Unit of Cancer Research and Translational Medicine, MRC Oulu and Department of Anatomy and Cell Biology, University of Oulu, Oulu, Finland

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J Tuukkanen Unit of Cancer Research and Translational Medicine, MRC Oulu and Department of Anatomy and Cell Biology, University of Oulu, Oulu, Finland

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E R Levin Division of Endocrinology, Departments of Medicine and Biochemistry, University of California, Irvine, California, USA
The Long Beach VA Medical Center, Long Beach, California, USA

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C Ohlsson Centre for Bone and Arthritis Research at Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden

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M K Lagerquist Centre for Bone and Arthritis Research at Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden

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-resolution microcomputed tomography (μCT) High-resolution microcomputed tomography (μCT) analyses were performed on the tibiae and lumbar vertebrae L 5 using an 1172 model μCT (Bruker MicroCT, Aartselaar, Belgium) as previously described ( Moverare-Skrtic et al. 2014

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Russell T Turner Skeletal Biology Laboratory, School of Biological and Population Health Sciences, Oregon State University, Corvallis, Oregon, USA
Center for Healthy Aging Research, Oregon State University, Corvallis, Oregon, USA

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Kenneth A Philbrick Skeletal Biology Laboratory, School of Biological and Population Health Sciences, Oregon State University, Corvallis, Oregon, USA

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Amida F Kuah Skeletal Biology Laboratory, School of Biological and Population Health Sciences, Oregon State University, Corvallis, Oregon, USA

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Adam J Branscum Biostatistics Program, School of Biological and Population Health Sciences, Oregon State University, Corvallis, Oregon, USA

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Urszula T Iwaniec Skeletal Biology Laboratory, School of Biological and Population Health Sciences, Oregon State University, Corvallis, Oregon, USA
Center for Healthy Aging Research, Oregon State University, Corvallis, Oregon, USA

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vertebrae were removed, fixed for 24h in 10% buffered formalin and stored in 70% ethanol for dual energy absorptiometry (DXA), microcomputed tomography (µCT) and histomorphometric analyses. The experimental protocol was approved by the Institutional Animal

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M J Devlin Department of Anthropology, University of Michigan, Ann Arbor, Michigan, USA

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D J Brooks Center for Advanced Orthopedic Studies, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA

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C Conlon Center for Advanced Orthopedic Studies, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA

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M van Vliet Center for Advanced Orthopedic Studies, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA

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L Louis Center for Advanced Orthopedic Studies, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA

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C J Rosen Maine Medical Center Research Institute, Scarborough, Maine, USA

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M L Bouxsein Center for Advanced Orthopedic Studies, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA
Harvard Medical School, Boston, Massachusetts, USA

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right tibia was fixed in 10% neutral buffered formalin at 4°C overnight and stored in PBS for osmium tetroxide staining ( Scheller et al . 2014 ). Trabecular and cortical bone morphology by microcomputed tomography Bone microarchitecture of the

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Chandrika D Mahalingam Division of Endocrinology, Department of Orthopedic Surgery, Department of Urology and Pathology, Departments of Craniofacial Biology and Microbiology and Immunology, Barbara Ann Karmanos Cancer Institute, Cardiovascular Research Institute, Department of Internal Medicine, Wayne State University School of Medicine, Detroit, Michigan 48201, USA

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Tanuka Datta Division of Endocrinology, Department of Orthopedic Surgery, Department of Urology and Pathology, Departments of Craniofacial Biology and Microbiology and Immunology, Barbara Ann Karmanos Cancer Institute, Cardiovascular Research Institute, Department of Internal Medicine, Wayne State University School of Medicine, Detroit, Michigan 48201, USA

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Rashmi V Patil Division of Endocrinology, Department of Orthopedic Surgery, Department of Urology and Pathology, Departments of Craniofacial Biology and Microbiology and Immunology, Barbara Ann Karmanos Cancer Institute, Cardiovascular Research Institute, Department of Internal Medicine, Wayne State University School of Medicine, Detroit, Michigan 48201, USA

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Jaclynn Kreider Division of Endocrinology, Department of Orthopedic Surgery, Department of Urology and Pathology, Departments of Craniofacial Biology and Microbiology and Immunology, Barbara Ann Karmanos Cancer Institute, Cardiovascular Research Institute, Department of Internal Medicine, Wayne State University School of Medicine, Detroit, Michigan 48201, USA

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R Daniel Bonfil Division of Endocrinology, Department of Orthopedic Surgery, Department of Urology and Pathology, Departments of Craniofacial Biology and Microbiology and Immunology, Barbara Ann Karmanos Cancer Institute, Cardiovascular Research Institute, Department of Internal Medicine, Wayne State University School of Medicine, Detroit, Michigan 48201, USA
Division of Endocrinology, Department of Orthopedic Surgery, Department of Urology and Pathology, Departments of Craniofacial Biology and Microbiology and Immunology, Barbara Ann Karmanos Cancer Institute, Cardiovascular Research Institute, Department of Internal Medicine, Wayne State University School of Medicine, Detroit, Michigan 48201, USA

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Keith L Kirkwood Division of Endocrinology, Department of Orthopedic Surgery, Department of Urology and Pathology, Departments of Craniofacial Biology and Microbiology and Immunology, Barbara Ann Karmanos Cancer Institute, Cardiovascular Research Institute, Department of Internal Medicine, Wayne State University School of Medicine, Detroit, Michigan 48201, USA

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Steven A Goldstein Division of Endocrinology, Department of Orthopedic Surgery, Department of Urology and Pathology, Departments of Craniofacial Biology and Microbiology and Immunology, Barbara Ann Karmanos Cancer Institute, Cardiovascular Research Institute, Department of Internal Medicine, Wayne State University School of Medicine, Detroit, Michigan 48201, USA

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Abdul B Abou-Samra Division of Endocrinology, Department of Orthopedic Surgery, Department of Urology and Pathology, Departments of Craniofacial Biology and Microbiology and Immunology, Barbara Ann Karmanos Cancer Institute, Cardiovascular Research Institute, Department of Internal Medicine, Wayne State University School of Medicine, Detroit, Michigan 48201, USA

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Nabanita S Datta Division of Endocrinology, Department of Orthopedic Surgery, Department of Urology and Pathology, Departments of Craniofacial Biology and Microbiology and Immunology, Barbara Ann Karmanos Cancer Institute, Cardiovascular Research Institute, Department of Internal Medicine, Wayne State University School of Medicine, Detroit, Michigan 48201, USA
Division of Endocrinology, Department of Orthopedic Surgery, Department of Urology and Pathology, Departments of Craniofacial Biology and Microbiology and Immunology, Barbara Ann Karmanos Cancer Institute, Cardiovascular Research Institute, Department of Internal Medicine, Wayne State University School of Medicine, Detroit, Michigan 48201, USA
Division of Endocrinology, Department of Orthopedic Surgery, Department of Urology and Pathology, Departments of Craniofacial Biology and Microbiology and Immunology, Barbara Ann Karmanos Cancer Institute, Cardiovascular Research Institute, Department of Internal Medicine, Wayne State University School of Medicine, Detroit, Michigan 48201, USA

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the last injection, and bone tissues were collected. Skeletal phenotyping, and microcomputed tomography analysis Femora and tibiae were dissected free of soft tissue, fixed in 10% neutral buffered formalin for 48 h, and analyzed by microcomputed

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M J Devlin Beth Israel Deaconess Medical Center, Harvard Medical School, Hospital for Sick Children, The University of Toronto, Kinderklinik UK‐Essen, The University of Duisburg‐Essen, Department of Anthropology, University of Michigan, Boston, Massachusetts, USA
Beth Israel Deaconess Medical Center, Harvard Medical School, Hospital for Sick Children, The University of Toronto, Kinderklinik UK‐Essen, The University of Duisburg‐Essen, Department of Anthropology, University of Michigan, Boston, Massachusetts, USA

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C Grasemann Beth Israel Deaconess Medical Center, Harvard Medical School, Hospital for Sick Children, The University of Toronto, Kinderklinik UK‐Essen, The University of Duisburg‐Essen, Department of Anthropology, University of Michigan, Boston, Massachusetts, USA
Beth Israel Deaconess Medical Center, Harvard Medical School, Hospital for Sick Children, The University of Toronto, Kinderklinik UK‐Essen, The University of Duisburg‐Essen, Department of Anthropology, University of Michigan, Boston, Massachusetts, USA

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A M Cloutier Beth Israel Deaconess Medical Center, Harvard Medical School, Hospital for Sick Children, The University of Toronto, Kinderklinik UK‐Essen, The University of Duisburg‐Essen, Department of Anthropology, University of Michigan, Boston, Massachusetts, USA

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L Louis Beth Israel Deaconess Medical Center, Harvard Medical School, Hospital for Sick Children, The University of Toronto, Kinderklinik UK‐Essen, The University of Duisburg‐Essen, Department of Anthropology, University of Michigan, Boston, Massachusetts, USA

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C Alm Beth Israel Deaconess Medical Center, Harvard Medical School, Hospital for Sick Children, The University of Toronto, Kinderklinik UK‐Essen, The University of Duisburg‐Essen, Department of Anthropology, University of Michigan, Boston, Massachusetts, USA

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M R Palmert Beth Israel Deaconess Medical Center, Harvard Medical School, Hospital for Sick Children, The University of Toronto, Kinderklinik UK‐Essen, The University of Duisburg‐Essen, Department of Anthropology, University of Michigan, Boston, Massachusetts, USA

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M L Bouxsein Beth Israel Deaconess Medical Center, Harvard Medical School, Hospital for Sick Children, The University of Toronto, Kinderklinik UK‐Essen, The University of Duisburg‐Essen, Department of Anthropology, University of Michigan, Boston, Massachusetts, USA
Beth Israel Deaconess Medical Center, Harvard Medical School, Hospital for Sick Children, The University of Toronto, Kinderklinik UK‐Essen, The University of Duisburg‐Essen, Department of Anthropology, University of Michigan, Boston, Massachusetts, USA

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by microcomputed tomography Assessment of bone morphology and microarchitecture was performed with high-resolution microcomputed tomography (μCT40, Scanco Medical, Brüttisellen, Switzerland) of the distal femoral metaphysis and L5 vertebral body, as

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Rosa Chung
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Bruce K Foster School of Pharmacy and Medical Sciences, Department of Orthopaedic Surgery, Sansom Institute for Health Research, University of South Australia, City East Campus, GPO Box 2471, Adelaide, South Australia 5001, Australia

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Cory J Xian
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24 h at 4 °C and then wrapped in saline-soaked gauze and frozen at −80 °C until use for microcomputed tomography (microCT) analysis (see below). Following microCT scans, bones were immediately decalcified for 14 days in Immunocal solution (Decal

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Saranyapin Potikanond Department of Pharmacology, Neurophysiology Unit, Center of Calcium and Bone Research (COCAB), Department of Physiology, Cardiac Electrophysiology Unit, Center of Excellence in Cardiac Electrophysiology Research, Department of Oral Biology and Diagnostic Sciences, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
Department of Pharmacology, Neurophysiology Unit, Center of Calcium and Bone Research (COCAB), Department of Physiology, Cardiac Electrophysiology Unit, Center of Excellence in Cardiac Electrophysiology Research, Department of Oral Biology and Diagnostic Sciences, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand

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Pinyada Rattanachote Department of Pharmacology, Neurophysiology Unit, Center of Calcium and Bone Research (COCAB), Department of Physiology, Cardiac Electrophysiology Unit, Center of Excellence in Cardiac Electrophysiology Research, Department of Oral Biology and Diagnostic Sciences, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand

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Hiranya Pintana Department of Pharmacology, Neurophysiology Unit, Center of Calcium and Bone Research (COCAB), Department of Physiology, Cardiac Electrophysiology Unit, Center of Excellence in Cardiac Electrophysiology Research, Department of Oral Biology and Diagnostic Sciences, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand

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Panan Suntornsaratoon Department of Pharmacology, Neurophysiology Unit, Center of Calcium and Bone Research (COCAB), Department of Physiology, Cardiac Electrophysiology Unit, Center of Excellence in Cardiac Electrophysiology Research, Department of Oral Biology and Diagnostic Sciences, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
Department of Pharmacology, Neurophysiology Unit, Center of Calcium and Bone Research (COCAB), Department of Physiology, Cardiac Electrophysiology Unit, Center of Excellence in Cardiac Electrophysiology Research, Department of Oral Biology and Diagnostic Sciences, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand

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Narattaphol Charoenphandhu Department of Pharmacology, Neurophysiology Unit, Center of Calcium and Bone Research (COCAB), Department of Physiology, Cardiac Electrophysiology Unit, Center of Excellence in Cardiac Electrophysiology Research, Department of Oral Biology and Diagnostic Sciences, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
Department of Pharmacology, Neurophysiology Unit, Center of Calcium and Bone Research (COCAB), Department of Physiology, Cardiac Electrophysiology Unit, Center of Excellence in Cardiac Electrophysiology Research, Department of Oral Biology and Diagnostic Sciences, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand

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Nipon Chattipakorn Department of Pharmacology, Neurophysiology Unit, Center of Calcium and Bone Research (COCAB), Department of Physiology, Cardiac Electrophysiology Unit, Center of Excellence in Cardiac Electrophysiology Research, Department of Oral Biology and Diagnostic Sciences, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
Department of Pharmacology, Neurophysiology Unit, Center of Calcium and Bone Research (COCAB), Department of Physiology, Cardiac Electrophysiology Unit, Center of Excellence in Cardiac Electrophysiology Research, Department of Oral Biology and Diagnostic Sciences, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
Department of Pharmacology, Neurophysiology Unit, Center of Calcium and Bone Research (COCAB), Department of Physiology, Cardiac Electrophysiology Unit, Center of Excellence in Cardiac Electrophysiology Research, Department of Oral Biology and Diagnostic Sciences, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand

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Siriporn Chattipakorn Department of Pharmacology, Neurophysiology Unit, Center of Calcium and Bone Research (COCAB), Department of Physiology, Cardiac Electrophysiology Unit, Center of Excellence in Cardiac Electrophysiology Research, Department of Oral Biology and Diagnostic Sciences, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
Department of Pharmacology, Neurophysiology Unit, Center of Calcium and Bone Research (COCAB), Department of Physiology, Cardiac Electrophysiology Unit, Center of Excellence in Cardiac Electrophysiology Research, Department of Oral Biology and Diagnostic Sciences, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand

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The present study aimed to test the hypothesis that testosterone deprivation impairs osteoblastic insulin signaling, decreases osteoblast survival, reduces bone density, and that obesity aggravates those deleterious effects in testosterone-deprived rats. Twenty four male Wistar rats underwent either a bilateral orchiectomy (O, n=12) or a sham operation (S, n=12). Then the rats in each group were further divided into two subgroups fed with either a normal diet (ND) or a high-fat diet (HF) for 12 weeks. At the end of the protocol, blood samples were collected to determine metabolic parameters and osteocalcin ratios. The tibiae were collected to determine bone mass using microcomputed tomography and for osteoblast isolation. The results showed that rats fed with HF (sham-operated HF-fed rats (HFS) and ORX HF-fed rats (HFO)) developed peripheral insulin resistance and had decreased trabecular bone density. In ND-fed rats, only the ORX ND-fed rats (NDO) group had decreased trabecular bone density. In addition, osteoblastic insulin resistance, as indicated by a decrease in tyrosine phosphorylation of the insulin receptor and Akt, were observed in all groups except the sham-operated ND-fed rats (NDS) rats. Those groups, again with the exception of the NDS rats, also had decreased osteoblastic survival. No differences in the levels of osteoblastic insulin resistance and osteoblastic survival were found among the NDO, HFS, and HFO groups. These findings suggest that either testosterone deprivation or obesity alone can impair osteoblastic insulin signaling and decrease osteoblastic survival leading to the development of osteoporosis. However, obesity does not aggravate those deleterious effects in the bone of testosterone-deprived rats.

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