{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,6]],"date-time":"2026-09-06T04:44:00Z","timestamp":1788669840555,"version":"build-2803163510"},"reference-count":17,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2025,2,28]],"date-time":"2025-02-28T00:00:00Z","timestamp":1740700800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Medicina in-silico nella diagnosi, prognosi e trattamento dei disordini muscoloscheletrici TI-RAMS","award":["RCR-2022-23682299"],"award-info":[{"award-number":["RCR-2022-23682299"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Factor VIII (FVIII) is involved in several molecular pathways and biological processes; indeed, it has a role in the coagulative cascade, cardiovascular disease, hypertension, brain and renal function, cancer incidence and spread, macrophage polarization, and angiogenesis. Hemophilic patients usually present an increase in fracture risk, bone resorption, and an excess of osteoporosis as compared to healthy individuals. Several studies have tried to clarify their etiology but unfortunately it is still unclear. This review focuses on the role of FVIII in bone biology by summarizing all the knowledge present in the literature. We carried out a systematic review of the available literature following the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). Several studies demonstrated that FVIII is involved in different molecular pathways interfering with bone physiology; it exerts interesting effects on OPG\/RANK\/RANKL pathways and thrombin\/PAR1 pathways. These data confirm a relationship between FVIII and bone metabolism; however, there are still many aspects to be clarified. This review highlights the role of the coagulation factor FVIII in bone metabolism, suggesting new hypotheses for future studies both in vitro and in vivo to better understand the important pleiotropic role of FVIII and hopefully to develop new therapeutic agents for skeletal diseases.<\/jats:p>","DOI":"10.3390\/ijms26052172","type":"journal-article","created":{"date-parts":[[2025,2,28]],"date-time":"2025-02-28T04:28:18Z","timestamp":1740716898000},"page":"2172","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Bone and Hemophilia: The Role of Factor VIII\u2014Systematic Review"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0009-0005-2078-0272","authenticated-orcid":false,"given":"Micaela","family":"Berni","sequence":"first","affiliation":[{"name":"Department of Clinical, Surgical, Diagnostic and Pediatric Sciences, University of Pavia, 27100 Pavia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6385-1182","authenticated-orcid":false,"given":"Antonella","family":"Forlino","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine, Biochemistry Unit, University of Pavia, 27100 Pavia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7545-7337","authenticated-orcid":false,"given":"Laura","family":"Caliogna","sequence":"additional","affiliation":[{"name":"Orthopedics and Traumatology Clinic, IRCCS Policlinico San Matteo Foundation, 27100 Pavia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liliana","family":"De Felice","sequence":"additional","affiliation":[{"name":"Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, IRCCS Policlinico di Milano, Ospedale Maggiore Fondation, 20122 Milano, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8059-3819","authenticated-orcid":false,"given":"Matteo Nicola Dario","family":"Di Minno","sequence":"additional","affiliation":[{"name":"Department of Translational Medical Sciences, Federico II University, 80131 Napoli, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4447-1480","authenticated-orcid":false,"given":"Eugenio","family":"Jannelli","sequence":"additional","affiliation":[{"name":"Department of Clinical, Surgical, Diagnostic and Pediatric Sciences, University of Pavia, 27100 Pavia, Italy"},{"name":"Orthopedics and Traumatology Clinic, IRCCS Policlinico San Matteo Foundation, 27100 Pavia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mario","family":"Mosconi","sequence":"additional","affiliation":[{"name":"Department of Clinical, Surgical, Diagnostic and Pediatric Sciences, University of Pavia, 27100 Pavia, Italy"},{"name":"Orthopedics and Traumatology Clinic, IRCCS Policlinico San Matteo Foundation, 27100 Pavia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesca","family":"Tonelli","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine, Biochemistry Unit, University of Pavia, 27100 Pavia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-5879-6795","authenticated-orcid":false,"given":"Camilla","family":"Torriani","sequence":"additional","affiliation":[{"name":"Department of Public Health, Experimental and Forensic Medicine, University of Pavia, 27100 Pavia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1919-5130","authenticated-orcid":false,"given":"Gianluigi","family":"Pasta","sequence":"additional","affiliation":[{"name":"Orthopedics and Traumatology Clinic, IRCCS Policlinico San Matteo Foundation, 27100 Pavia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,2,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1016\/j.blre.2018.05.002","article-title":"Increased Bone Resorption in Hemophilia","volume":"33","author":"Valentino","year":"2019","journal-title":"Blood Rev."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"31704","DOI":"10.1074\/jbc.M109.030312","article-title":"Factor VIII-von Willebrand Factor Complex Inhibits Osteoclastogenesis and Controls Cell Survival","volume":"284","author":"Duplomb","year":"2009","journal-title":"J. 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