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The disease presents a broad spectrum of clinical manifestations primarily determined by the degree of residual TNAP activity. Adults with HPP of moderate clinical severity may present with spontaneous femoral fractures that are like the atypical femoral fractures (AFF) of long-term bisphosphonates users. In this review, we will focus on the paradox that while HPP can cause biopsy-proven osteomalacia (pathologically impaired bone mineralisation), the spontaneous femoral fractures that characterise adult HPP do not exhibit typical osteomalacia features. Instead, they resemble the femoral fractures that occur in other diseases such as osteopetrosis where bone becomes excessively dense, brittle and highly mineralised due to osteoclast dysfunction.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Summary<\/jats:title>\n                    <jats:p>This review examines the key aspects of the pathophysiology of femoral fractures in adults with HPP, offering new insights into the role of anatomical, molecular and biochemical bone abnormalities that characterise the disease. Further investigations of HPP patients with femoral fracture are needed to examine the nanoscale crystal structure of the bone and to study abnormalities in fracture healing and bone resorption.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1007\/s11914-025-00929-y","type":"journal-article","created":{"date-parts":[[2025,9,4]],"date-time":"2025-09-04T04:34:08Z","timestamp":1756960448000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Pathophysiology of Femoral Fractures in Hypophosphatasia"],"prefix":"10.1007","volume":"23","author":[{"given":"Fabiana G.A.","family":"Tabegna","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark","family":"Garton","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simona","family":"D\u2019Amore","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Linda","family":"Skingle","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Scott","family":"Dillon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melinda J.","family":"Duer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gavin P.R.","family":"Clunie","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4546-7352","authenticated-orcid":false,"given":"Kenneth E. 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