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The TREM2 R47H variant is a known risk factor for Alzheimer's disease (AD), the most common form of dementia. To investigate whether altered TREM2 signaling could contribute to bone and skeletal muscle loss, independently of central nervous system defects, we used mice globally hemizygous for the TREM2 R47H variant (TREM2R47H\/+), which do not exhibit AD pathology, and wild-type (WT) littermate control mice. Dxa\/Piximus showed bone loss in female TREM2R47H\/+ animals between 4 and 13\u2009months of age and reduced cancellous and cortical bone (measured by micro-computed tomography [\u03bcCT]) at 13\u2009months, which stalled out by 20\u2009months of age. In addition, they exhibited decreased femoral biomechanical properties measured by three-point bending at 13\u2009months of age, but not at 4 or 20\u2009months. Male TREM2R47H\/+ animals had decreased trabecular bone geometry but increased ultimate strain and failure force at 20\u2009months of age versus WT. Only male TREM2R47H\/+ osteoclasts differentiated more ex vivo after 7\u2009days with receptor activator of nuclear factor \u03baB ligand (RANKL)\/macrophage colony-stimulating factor (M-CSF) compared to WT littermates. Yet, estrogen receptor alpha expression was higher in female and male TREM2R47H\/+ osteoclasts compared to WT mice. However, female TREM2R47H\/+ osteoclasts expressed less complement 3 (C3), an estrogen responsive element, and increased protein kinase B (Akt) activity, suggesting altered estrogen signaling in TREM2R47H\/+ cells. Despite lower bone volume\/strength in TREM2R47H\/+ mice, skeletal muscle function measured by plantar flexion and muscle contractility was increased in 13-month-old female mutant mice. Overall, these data demonstrate that an AD-associated TREM2 variant can alter bone and skeletal muscle strength in a sex-dimorphic manner independent of central neuropathology, potentially mediated through changes in osteoclastic intracellular signaling. \u00a9 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).<\/jats:p>","DOI":"10.1002\/jbmr.4572","type":"journal-article","created":{"date-parts":[[2022,5,16]],"date-time":"2022-05-16T05:41:41Z","timestamp":1652679701000},"page":"1366-1381","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["Triggering Receptor Expressed on Myeloid Cells 2 (TREM2) R47H Variant Causes Distinct Age- and Sex-Dependent Musculoskeletal Alterations in Mice"],"prefix":"10.1093","volume":"37","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7698-5342","authenticated-orcid":false,"given":"Alyson L.","family":"Essex","sequence":"first","affiliation":[{"name":"Indiana Center for Musculoskeletal Health Indianapolis IN USA"},{"name":"Roudebush Veterans Administration Medical Center Indianapolis IN USA"},{"name":"Department of Anatomy, Cell Biology & Physiology 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