title: Suppression of Experimental Arthritis and Associated Bone Loss by a Tissue-Selective Estrogen Complex.
abstract: In addition to the systemic inflammation present in rheumatoid arthritis (RA), decreased estradiol levels in postmenopausal RA patients further accelerate bone loss in these patients. The tissue-selective estrogen complex (TSEC), an estrogen combined with a selective estrogen receptor modulator, is a new hormone replacement therapy option. The first approved TSEC, containing conjugated estrogens and bazedoxifene (BZA), reduces menopausal symptoms and prevents osteoporosis with an improved safety profile compared with conventional hormone replacement therapy. Previous studies have shown that estrogens strongly inhibit experimental arthritis whereas BZA is mildly suppressive. In this study the antiarthritic potential of combined BZA and estradiol is explored for the first time. Female ovariectomized DBA/1 mice were subjected to collagen-induced arthritis, an experimental postmenopausal RA model, and treated with BZA, 17β-estradiol (E2), combined BZA and E2 (BZA/E2), or vehicle. BZA/E2 suppressed arthritis severity and frequency, synovitis, and joint destruction, equally efficient as E2 alone. Unwanted estrogenic proliferative effects on the endometrium were blocked by the addition of BZA, determined by collecting uterine weights. Bone mineral density was measured by peripheral quantitative computed tomography, and all treatments protected collagen-induced arthritis mice from both trabecular and cortical bone loss. Moreover, BZA/E2, but not E2 alone, inhibited preosteoclast formation and reduced serum anticollagen type II antibodies. In conclusion, a TSEC, herein combined BZA/E2, suppresses experimental arthritis and prevents associated bone loss as efficiently as E2 alone but with minimal uterine effects, highlighting the need for clinical trials that evaluate the addition of a TSEC to conventional postmenopausal RA treatment.
authors.affiliation: Departments of Rheumatology and Inflammation Research (A.A., A.I.B., M.N.-K., A.S., L.G., H.C., U.I.) and Internal Medicine and Clinical Nutrition (C.O.), Institute of Medicine, Centre for Bone and Arthritis Research, Sahlgrenska Academy, University of Gothenburg, 405 30 Gothenburg, Sweden.
authors.forename: Annica
authors.initials: A
authors.lastname: Andersson
authors.affiliation: Departments of Rheumatology and Inflammation Research (A.A., A.I.B., M.N.-K., A.S., L.G., H.C., U.I.) and Internal Medicine and Clinical Nutrition (C.O.), Institute of Medicine, Centre for Bone and Arthritis Research, Sahlgrenska Academy, University of Gothenburg, 405 30 Gothenburg, Sweden.
authors.forename: Angelina I
authors.initials: AI
authors.lastname: Bernardi
authors.affiliation: Departments of Rheumatology and Inflammation Research (A.A., A.I.B., M.N.-K., A.S., L.G., H.C., U.I.) and Internal Medicine and Clinical Nutrition (C.O.), Institute of Medicine, Centre for Bone and Arthritis Research, Sahlgrenska Academy, University of Gothenburg, 405 30 Gothenburg, Sweden.
authors.forename: Merja
authors.initials: M
authors.lastname: Nurkkala-Karlsson
authors.affiliation: Departments of Rheumatology and Inflammation Research (A.A., A.I.B., M.N.-K., A.S., L.G., H.C., U.I.) and Internal Medicine and Clinical Nutrition (C.O.), Institute of Medicine, Centre for Bone and Arthritis Research, Sahlgrenska Academy, University of Gothenburg, 405 30 Gothenburg, Sweden.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Stubelius
authors.affiliation: Departments of Rheumatology and Inflammation Research (A.A., A.I.B., M.N.-K., A.S., L.G., H.C., U.I.) and Internal Medicine and Clinical Nutrition (C.O.), Institute of Medicine, Centre for Bone and Arthritis Research, Sahlgrenska Academy, University of Gothenburg, 405 30 Gothenburg, Sweden.
authors.forename: Louise
authors.initials: L
authors.lastname: Grahnemo
authors.affiliation: Departments of Rheumatology and Inflammation Research (A.A., A.I.B., M.N.-K., A.S., L.G., H.C., U.I.) and Internal Medicine and Clinical Nutrition (C.O.), Institute of Medicine, Centre for Bone and Arthritis Research, Sahlgrenska Academy, University of Gothenburg, 405 30 Gothenburg, Sweden.
authors.forename: Claes
authors.initials: C
authors.lastname: Ohlsson
authors.affiliation: Departments of Rheumatology and Inflammation Research (A.A., A.I.B., M.N.-K., A.S., L.G., H.C., U.I.) and Internal Medicine and Clinical Nutrition (C.O.), Institute of Medicine, Centre for Bone and Arthritis Research, Sahlgrenska Academy, University of Gothenburg, 405 30 Gothenburg, Sweden.
authors.forename: Hans
authors.initials: H
authors.lastname: Carlsten
authors.affiliation: Departments of Rheumatology and Inflammation Research (A.A., A.I.B., M.N.-K., A.S., L.G., H.C., U.I.) and Internal Medicine and Clinical Nutrition (C.O.), Institute of Medicine, Centre for Bone and Arthritis Research, Sahlgrenska Academy, University of Gothenburg, 405 30 Gothenburg, Sweden.
authors.forename: Ulrika
authors.initials: U
authors.lastname: Islander
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000000981:diagnostic imaging* / Q000276:immunology; D001172:Arthritis, Rheumatoid / Q000000981:diagnostic imaging* / Q000276:immunology; D001323:Autoantibodies / Q000187:drug effects* / Q000276:immunology; D015519:Bone Density / Q000187:drug effects*; D001851:Bone Diseases, Metabolic / Q000000981:diagnostic imaging* / Q000276:immunology; D016207:Cytokines / Q000187:drug effects* / Q000276:immunology; D004958:Estradiol / Q000494:pharmacology*; D004967:Estrogens / Q000494:pharmacology*; D005260:Female; D005269:Femur / Q000000981:diagnostic imaging / Q000187:drug effects; D007074:Immunoglobulin G / Q000187:drug effects / Q000276:immunology; D007211:Indoles / Q000494:pharmacology*; D015850:Interleukin-6 / Q000276:immunology; D051379:Mice; D010052:Ovariectomy; D011859:Radiography; D020845:Selective Estrogen Receptor Modulators / Q000494:pharmacology*; D013977:Tibia / Q000000981:diagnostic imaging / Q000187:drug effects
chemical_list: D001323:Autoantibodies; D016207:Cytokines; D004967:Estrogens; D007074:Immunoglobulin G; D007211:Indoles; D015850:Interleukin-6; D020845:Selective Estrogen Receptor Modulators; D004958:Estradiol; C447119:bazedoxifene