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Currently, Wnt-targeted therapeutic agents that prevent soluble antagonists of the Wnt signaling pathway, sclerostin (SOST) and dickkopf-1 (DKK1), have been shown to prevent bone loss and improve bone strength in preclinical models of MM. In this study, we show increasing Wnt signaling via a novel anti\u2013low-density lipoprotein receptor-related protein 6 (LRP6) antibody, which potentiates Wnt1-class ligand signaling through binding the Wnt receptor LRP6, prevented the development of myeloma-induced bone loss primarily through preventing bone resorption. When combined with an agent targeting the soluble Wnt antagonist DKK1, we showed more robust improvements in bone structure than anti-LRP6 treatment alone. Micro\u2013computed tomography (\u03bcCT) analysis demonstrated substantial increases in trabecular bone volume in na\u00efve mice given the anti-LRP6\/DKK1 combination treatment strategy compared to control agents. Mice injected with 5TGM1eGFP murine myeloma cells had significant reductions in trabecular bone volume compared to na\u00efve controls. The anti-LRP6\/DKK1 combination strategy significantly improved bone volume in 5TGM1-bearing mice by 111%, which was also superior to anti-LRP6 single treatment; with similar bone structural changes observed within L4 lumbar vertebrae. Consequently, this combination strategy significantly improved resistance to fracture in lumbar vertebrae in 5TGM1-bearing mice compared to their controls, providing greater protection against fracture compared to anti-LRP6 antibody alone. Interestingly, these improvements in bone volume were primarily due to reduced bone resorption, with significant reductions in osteoclast numbers and osteoclast surface per bone surface demonstrated in 5TGM1-bearing mice treated with the anti-LRP6\/DKK1 combination strategy. Importantly, Wnt stimulation with either single or combined Wnt-targeted agents did not exacerbate tumor activity. This work provides a novel approach of targeting both membrane-bound and soluble Wnt pathway components to provide superior skeletal outcomes in patients with multiple myeloma and other bone destructive cancers. \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.4809","type":"journal-article","created":{"date-parts":[[2023,3,29]],"date-time":"2023-03-29T06:11:45Z","timestamp":1680070305000},"page":"814-828","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":27,"title":["Multi-Targeting DKK1 and LRP6 Prevents Bone Loss and Improves Fracture Resistance in Multiple Myeloma"],"prefix":"10.1093","volume":"38","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9374-3599","authenticated-orcid":false,"given":"Marija K.","family":"Simic","sequence":"first","affiliation":[{"name":"St Vincent's Clinical Campus, School of Clinical Medicine University of New South Wales Kensington NSW Australia"},{"name":"Skeletal Diseases Program Garvan Institute of Medical Research Darlinghurst NSW 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Research Darlinghurst NSW Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olga","family":"Charlat","sequence":"additional","affiliation":[{"name":"Novartis Institutes for Biomedical Research Cambridge MA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7102-2413","authenticated-orcid":false,"given":"Peter I.","family":"Croucher","sequence":"additional","affiliation":[{"name":"St Vincent's Clinical Campus, School of Clinical Medicine University of New South Wales Kensington NSW Australia"},{"name":"Skeletal Diseases Program Garvan Institute of Medical Research Darlinghurst NSW Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3928-2506","authenticated-orcid":false,"given":"Michelle M.","family":"McDonald","sequence":"additional","affiliation":[{"name":"School of Medical Science, Faculty of Medicine and Health The University of Sydney Sydney NSW 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