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Simultaneous pharmacologic inhibition of the Wnt antagonists sclerostin and Dkk1 can be optimized to create potentiated effects in the cancellous bone compartment. We looked for other candidates that might be co-inhibited along with sclerostin to potentiate the effects in the cortical compartment. Sostdc1 (Wise), like sclerostin and Dkk1, also binds and inhibits Lrp5\/6 coreceptors to impair canonical Wnt signaling, but Sostdc1 has greater effects in the cortical bone. To test this concept, we deleted Sostdc1 and Sost from mice and measured the skeletal effects in cortical and cancellous compartments individually. Sost deletion alone produced high bone mass in all compartments, whereas Sostdc1 deletion alone had no measurable effects on either envelope. Mice with codeletion of Sostdc1 and Sost had high bone mass and increased cortical properties (bone mass, formation rates, mechanical properties), but only among males. Combined administration of sclerostin antibody and Sostdc1 antibody in wild-type female mice produced potentiation of cortical bone gain despite no effect of Sostdc1 antibody alone. In conclusion, Sostdc1 inhibition\/deletion can work in concert with sclerostin deficiency to improve cortical bone properties. \u00a9 2023 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.4798","type":"journal-article","created":{"date-parts":[[2023,3,9]],"date-time":"2023-03-09T03:36:02Z","timestamp":1678332962000},"page":"765-774","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Sostdc1 Suppression in the Absence of Sclerostin Potentiates Anabolic Action of Cortical Bone in Mice"],"prefix":"10.1093","volume":"38","author":[{"given":"Roy B.","family":"Choi","sequence":"first","affiliation":[{"name":"Department of Anatomy, Cell Biology & Physiology Indiana University School of Medicine Indianapolis Indiana USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"April M.","family":"Hoggatt","sequence":"additional","affiliation":[{"name":"Department of Anatomy, Cell Biology & Physiology Indiana University School of Medicine Indianapolis Indiana USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel J.","family":"Horan","sequence":"additional","affiliation":[{"name":"Department of Anatomy, Cell Biology & Physiology Indiana University School of Medicine Indianapolis Indiana USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emily Z.","family":"Rogers","sequence":"additional","affiliation":[{"name":"Department of Anatomy, Cell Biology & Physiology Indiana University School of Medicine Indianapolis Indiana USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabriela G.","family":"Loots","sequence":"additional","affiliation":[{"name":"Department of Orthopaedic Surgery School of Medicine, UC Davis Health Sacramento California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3989-4780","authenticated-orcid":false,"given":"Alexander G.","family":"Robling","sequence":"additional","affiliation":[{"name":"Indiana Center for Musculoskeletal Health Indianapolis Indiana USA"},{"name":"Department of Biomedical Engineering Indiana University\u2013Purdue University at Indianapolis Indianapolis Indiana USA"},{"name":"Richard L. 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