title: Enzalutamide Reduces the Bone Mass in the Axial But Not the Appendicular Skeleton in Male Mice.
abstract: Testosterone is a crucial regulator of the skeleton, but the role of the androgen receptor (AR) for the maintenance of the adult male skeleton is unclear. In the present study, the role of the AR for bone metabolism and skeletal growth after sexual maturation was evaluated by means of the drug enzalutamide, which is a new AR antagonist used in the treatment of prostate cancer patients. Nine-week-old male mice were treated with 10, 30, or 100 mg/kg·d of enzalutamide for 21 days or were surgically castrated and were compared with vehicle-treated gonadal intact mice. Although orchidectomy reduced the cortical bone thickness and trabecular bone volume fraction in the appendicular skeleton, these parameters were unaffected by enzalutamide. In contrast, both enzalutamide and orchidectomy reduced the bone mass in the axial skeleton as demonstrated by a reduced lumbar spine areal bone mineral density (P < .001) and trabecular bone volume fraction in L5 vertebrae (P < .001) compared with vehicle-treated gonadal intact mice. A compression test of the L5 vertebrae revealed that the mechanical strength in the axial skeleton was significantly reduced by enzalutamide (maximal load at failure -15.3% ± 3.5%; P < .01). The effects of enzalutamide in the axial skeleton were associated with a high bone turnover. In conclusion, enzalutamide reduces the bone mass in the axial but not the appendicular skeleton in male mice after sexual maturation. We propose that the effect of testosterone on the axial skeleton in male mice is mainly mediated via the AR.
authors.affiliation: Centre for Bone and Arthritis Research (J.W., S.M.-S., A.E.B., M.K.L., K.S., S.H.W., L.G., U.I., C.O.), Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, S-413 45 Gothenburg, Sweden; Rheumatology and Bone Diseases Unit (A.E.B.), Centre for Genomic and Experimental Medicine, Medical Research Council Institute of Genetics and Molecular Medicine, Western General Hospital, University of Edinburgh, Edinburgh EH4 2XU, Scotland, United Kingdom; Centre for Comparative and Clinical Anatomy (S.H.W.), School of Veterinary Science, University of Bristol, Bristol BS28EJ, United Kingdom; Department of Anatomy and Cell Biology (A.K., J.T.), Medical Research Center, University of Oulu, FI-90014 Oulu, Finland; and The Wallenberg Laboratory for Cardiovascular and Metabolic Research (A.S.W., ÅT.), Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, SE-41345 Gothenburg, Sweden.
authors.forename: Jianyao
authors.initials: J
authors.lastname: Wu
authors.affiliation: Centre for Bone and Arthritis Research (J.W., S.M.-S., A.E.B., M.K.L., K.S., S.H.W., L.G., U.I., C.O.), Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, S-413 45 Gothenburg, Sweden; Rheumatology and Bone Diseases Unit (A.E.B.), Centre for Genomic and Experimental Medicine, Medical Research Council Institute of Genetics and Molecular Medicine, Western General Hospital, University of Edinburgh, Edinburgh EH4 2XU, Scotland, United Kingdom; Centre for Comparative and Clinical Anatomy (S.H.W.), School of Veterinary Science, University of Bristol, Bristol BS28EJ, United Kingdom; Department of Anatomy and Cell Biology (A.K., J.T.), Medical Research Center, University of Oulu, FI-90014 Oulu, Finland; and The Wallenberg Laboratory for Cardiovascular and Metabolic Research (A.S.W., ÅT.), Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, SE-41345 Gothenburg, Sweden.
authors.forename: Sofia
authors.initials: S
authors.lastname: Movérare-Skrtic
authors.affiliation: Centre for Bone and Arthritis Research (J.W., S.M.-S., A.E.B., M.K.L., K.S., S.H.W., L.G., U.I., C.O.), Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, S-413 45 Gothenburg, Sweden; Rheumatology and Bone Diseases Unit (A.E.B.), Centre for Genomic and Experimental Medicine, Medical Research Council Institute of Genetics and Molecular Medicine, Western General Hospital, University of Edinburgh, Edinburgh EH4 2XU, Scotland, United Kingdom; Centre for Comparative and Clinical Anatomy (S.H.W.), School of Veterinary Science, University of Bristol, Bristol BS28EJ, United Kingdom; Department of Anatomy and Cell Biology (A.K., J.T.), Medical Research Center, University of Oulu, FI-90014 Oulu, Finland; and The Wallenberg Laboratory for Cardiovascular and Metabolic Research (A.S.W., ÅT.), Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, SE-41345 Gothenburg, Sweden.
authors.forename: Anna E
authors.initials: AE
authors.lastname: Börjesson
authors.affiliation: Centre for Bone and Arthritis Research (J.W., S.M.-S., A.E.B., M.K.L., K.S., S.H.W., L.G., U.I., C.O.), Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, S-413 45 Gothenburg, Sweden; Rheumatology and Bone Diseases Unit (A.E.B.), Centre for Genomic and Experimental Medicine, Medical Research Council Institute of Genetics and Molecular Medicine, Western General Hospital, University of Edinburgh, Edinburgh EH4 2XU, Scotland, United Kingdom; Centre for Comparative and Clinical Anatomy (S.H.W.), School of Veterinary Science, University of Bristol, Bristol BS28EJ, United Kingdom; Department of Anatomy and Cell Biology (A.K., J.T.), Medical Research Center, University of Oulu, FI-90014 Oulu, Finland; and The Wallenberg Laboratory for Cardiovascular and Metabolic Research (A.S.W., ÅT.), Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, SE-41345 Gothenburg, Sweden.
authors.forename: Marie K
authors.initials: MK
authors.lastname: Lagerquist
authors.affiliation: Centre for Bone and Arthritis Research (J.W., S.M.-S., A.E.B., M.K.L., K.S., S.H.W., L.G., U.I., C.O.), Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, S-413 45 Gothenburg, Sweden; Rheumatology and Bone Diseases Unit (A.E.B.), Centre for Genomic and Experimental Medicine, Medical Research Council Institute of Genetics and Molecular Medicine, Western General Hospital, University of Edinburgh, Edinburgh EH4 2XU, Scotland, United Kingdom; Centre for Comparative and Clinical Anatomy (S.H.W.), School of Veterinary Science, University of Bristol, Bristol BS28EJ, United Kingdom; Department of Anatomy and Cell Biology (A.K., J.T.), Medical Research Center, University of Oulu, FI-90014 Oulu, Finland; and The Wallenberg Laboratory for Cardiovascular and Metabolic Research (A.S.W., ÅT.), Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, SE-41345 Gothenburg, Sweden.
authors.forename: Klara
authors.initials: K
authors.lastname: Sjögren
authors.affiliation: Centre for Bone and Arthritis Research (J.W., S.M.-S., A.E.B., M.K.L., K.S., S.H.W., L.G., U.I., C.O.), Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, S-413 45 Gothenburg, Sweden; Rheumatology and Bone Diseases Unit (A.E.B.), Centre for Genomic and Experimental Medicine, Medical Research Council Institute of Genetics and Molecular Medicine, Western General Hospital, University of Edinburgh, Edinburgh EH4 2XU, Scotland, United Kingdom; Centre for Comparative and Clinical Anatomy (S.H.W.), School of Veterinary Science, University of Bristol, Bristol BS28EJ, United Kingdom; Department of Anatomy and Cell Biology (A.K., J.T.), Medical Research Center, University of Oulu, FI-90014 Oulu, Finland; and The Wallenberg Laboratory for Cardiovascular and Metabolic Research (A.S.W., ÅT.), Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, SE-41345 Gothenburg, Sweden.
authors.forename: Sara H
authors.initials: SH
authors.lastname: Windahl
authors.affiliation: Centre for Bone and Arthritis Research (J.W., S.M.-S., A.E.B., M.K.L., K.S., S.H.W., L.G., U.I., C.O.), Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, S-413 45 Gothenburg, Sweden; Rheumatology and Bone Diseases Unit (A.E.B.), Centre for Genomic and Experimental Medicine, Medical Research Council Institute of Genetics and Molecular Medicine, Western General Hospital, University of Edinburgh, Edinburgh EH4 2XU, Scotland, United Kingdom; Centre for Comparative and Clinical Anatomy (S.H.W.), School of Veterinary Science, University of Bristol, Bristol BS28EJ, United Kingdom; Department of Anatomy and Cell Biology (A.K., J.T.), Medical Research Center, University of Oulu, FI-90014 Oulu, Finland; and The Wallenberg Laboratory for Cardiovascular and Metabolic Research (A.S.W., ÅT.), Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, SE-41345 Gothenburg, Sweden.
authors.forename: Antti
authors.initials: A
authors.lastname: Koskela
authors.affiliation: Centre for Bone and Arthritis Research (J.W., S.M.-S., A.E.B., M.K.L., K.S., S.H.W., L.G., U.I., C.O.), Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, S-413 45 Gothenburg, Sweden; Rheumatology and Bone Diseases Unit (A.E.B.), Centre for Genomic and Experimental Medicine, Medical Research Council Institute of Genetics and Molecular Medicine, Western General Hospital, University of Edinburgh, Edinburgh EH4 2XU, Scotland, United Kingdom; Centre for Comparative and Clinical Anatomy (S.H.W.), School of Veterinary Science, University of Bristol, Bristol BS28EJ, United Kingdom; Department of Anatomy and Cell Biology (A.K., J.T.), Medical Research Center, University of Oulu, FI-90014 Oulu, Finland; and The Wallenberg Laboratory for Cardiovascular and Metabolic Research (A.S.W., ÅT.), Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, SE-41345 Gothenburg, Sweden.
authors.forename: Louise
authors.initials: L
authors.lastname: Grahnemo
authors.affiliation: Centre for Bone and Arthritis Research (J.W., S.M.-S., A.E.B., M.K.L., K.S., S.H.W., L.G., U.I., C.O.), Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, S-413 45 Gothenburg, Sweden; Rheumatology and Bone Diseases Unit (A.E.B.), Centre for Genomic and Experimental Medicine, Medical Research Council Institute of Genetics and Molecular Medicine, Western General Hospital, University of Edinburgh, Edinburgh EH4 2XU, Scotland, United Kingdom; Centre for Comparative and Clinical Anatomy (S.H.W.), School of Veterinary Science, University of Bristol, Bristol BS28EJ, United Kingdom; Department of Anatomy and Cell Biology (A.K., J.T.), Medical Research Center, University of Oulu, FI-90014 Oulu, Finland; and The Wallenberg Laboratory for Cardiovascular and Metabolic Research (A.S.W., ÅT.), Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, SE-41345 Gothenburg, Sweden.
authors.forename: Ulrika
authors.initials: U
authors.lastname: Islander
authors.affiliation: Centre for Bone and Arthritis Research (J.W., S.M.-S., A.E.B., M.K.L., K.S., S.H.W., L.G., U.I., C.O.), Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, S-413 45 Gothenburg, Sweden; Rheumatology and Bone Diseases Unit (A.E.B.), Centre for Genomic and Experimental Medicine, Medical Research Council Institute of Genetics and Molecular Medicine, Western General Hospital, University of Edinburgh, Edinburgh EH4 2XU, Scotland, United Kingdom; Centre for Comparative and Clinical Anatomy (S.H.W.), School of Veterinary Science, University of Bristol, Bristol BS28EJ, United Kingdom; Department of Anatomy and Cell Biology (A.K., J.T.), Medical Research Center, University of Oulu, FI-90014 Oulu, Finland; and The Wallenberg Laboratory for Cardiovascular and Metabolic Research (A.S.W., ÅT.), Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, SE-41345 Gothenburg, Sweden.
authors.forename: Anna S
authors.initials: AS
authors.lastname: Wilhelmson
authors.affiliation: Centre for Bone and Arthritis Research (J.W., S.M.-S., A.E.B., M.K.L., K.S., S.H.W., L.G., U.I., C.O.), Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, S-413 45 Gothenburg, Sweden; Rheumatology and Bone Diseases Unit (A.E.B.), Centre for Genomic and Experimental Medicine, Medical Research Council Institute of Genetics and Molecular Medicine, Western General Hospital, University of Edinburgh, Edinburgh EH4 2XU, Scotland, United Kingdom; Centre for Comparative and Clinical Anatomy (S.H.W.), School of Veterinary Science, University of Bristol, Bristol BS28EJ, United Kingdom; Department of Anatomy and Cell Biology (A.K., J.T.), Medical Research Center, University of Oulu, FI-90014 Oulu, Finland; and The Wallenberg Laboratory for Cardiovascular and Metabolic Research (A.S.W., ÅT.), Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, SE-41345 Gothenburg, Sweden.
authors.forename: Åsa
authors.initials: Å
authors.lastname: Tivesten
authors.affiliation: Centre for Bone and Arthritis Research (J.W., S.M.-S., A.E.B., M.K.L., K.S., S.H.W., L.G., U.I., C.O.), Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, S-413 45 Gothenburg, Sweden; Rheumatology and Bone Diseases Unit (A.E.B.), Centre for Genomic and Experimental Medicine, Medical Research Council Institute of Genetics and Molecular Medicine, Western General Hospital, University of Edinburgh, Edinburgh EH4 2XU, Scotland, United Kingdom; Centre for Comparative and Clinical Anatomy (S.H.W.), School of Veterinary Science, University of Bristol, Bristol BS28EJ, United Kingdom; Department of Anatomy and Cell Biology (A.K., J.T.), Medical Research Center, University of Oulu, FI-90014 Oulu, Finland; and The Wallenberg Laboratory for Cardiovascular and Metabolic Research (A.S.W., ÅT.), Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, SE-41345 Gothenburg, Sweden.
authors.forename: Juha
authors.initials: J
authors.lastname: Tuukkanen
authors.affiliation: Centre for Bone and Arthritis Research (J.W., S.M.-S., A.E.B., M.K.L., K.S., S.H.W., L.G., U.I., C.O.), Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, S-413 45 Gothenburg, Sweden; Rheumatology and Bone Diseases Unit (A.E.B.), Centre for Genomic and Experimental Medicine, Medical Research Council Institute of Genetics and Molecular Medicine, Western General Hospital, University of Edinburgh, Edinburgh EH4 2XU, Scotland, United Kingdom; Centre for Comparative and Clinical Anatomy (S.H.W.), School of Veterinary Science, University of Bristol, Bristol BS28EJ, United Kingdom; Department of Anatomy and Cell Biology (A.K., J.T.), Medical Research Center, University of Oulu, FI-90014 Oulu, Finland; and The Wallenberg Laboratory for Cardiovascular and Metabolic Research (A.S.W., ÅT.), Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, SE-41345 Gothenburg, Sweden.
authors.forename: Claes
authors.initials: C
authors.lastname: Ohlsson
mesh_terms: D015502:Absorptiometry, Photon; D059002:Androgen Receptor Antagonists / Q000494:pharmacology*; D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology*; D001549:Benzamides; D015519:Bone Density / Q000187:drug effects*; D016723:Bone Remodeling / Q000187:drug effects*; D005269:Femur / Q000000981:diagnostic imaging / Q000187:drug effects*; D008159:Lumbar Vertebrae / Q000000981:diagnostic imaging / Q000187:drug effects*; D008297:Male; D051379:Mice; D009570:Nitriles; D009919:Orchiectomy; D009929:Organ Size / Q000187:drug effects; D010669:Phenylthiohydantoin / Q000031:analogs & derivatives* / Q000494:pharmacology; D013131:Spine / Q000000981:diagnostic imaging / Q000187:drug effects; D013977:Tibia / Q000000981:diagnostic imaging / Q000187:drug effects*; D055114:X-Ray Microtomography
chemical_list: D059002:Androgen Receptor Antagonists; D018931:Antineoplastic Agents, Hormonal; D001549:Benzamides; D009570:Nitriles; D010669:Phenylthiohydantoin; C540278:enzalutamide