{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,3]],"date-time":"2026-03-03T06:13:32Z","timestamp":1772518412687,"version":"3.50.1"},"reference-count":34,"publisher":"Springer Science and Business Media LLC","issue":"6","license":[{"start":{"date-parts":[[2023,5,6]],"date-time":"2023-05-06T00:00:00Z","timestamp":1683331200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2023,5,6]],"date-time":"2023-05-06T00:00:00Z","timestamp":1683331200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["499533307"],"award-info":[{"award-number":["499533307"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Universit\u00e4tsklinikum Hamburg-Eppendorf (UKE)"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Calcif Tissue Int"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Hypophosphatasia (HPP) is an inborn disease that causes a rare form of osteomalacia, a mineralization disorder affecting mineralized tissues. Identification of patients at high risk for fractures or other skeletal manifestations (such as insufficiency fractures or excessive bone marrow edema) by bone densitometry and laboratory tests remains clinically challenging. Therefore, we examined two cohorts of patients with variants in the <jats:italic>ALPL<\/jats:italic> gene grouped by bone manifestations. These groups were compared by means of bone microarchitecture using high-resolution peripheral quantitative computed tomography (HR-pQCT) and simulated mechanical performance utilizing finite element analysis (FEA). Whereas the incidence of skeletal manifestations among the patients could not be determined by dual energy X-ray absorptiometry (DXA) or laboratory assessment, HR-pQCT evaluation showed a distinct pattern of HPP patients with such manifestations. Specifically, these patients had a pronounced loss of trabecular bone mineral density, increased trabecular spacing, and decreased ultimate force at the distal radius. Interestingly, the derived results indicate that the non-weight-bearing radius is superior to the weight-bearing tibia in identifying deteriorated skeletal patterns. Overall, the assessment by HR-pQCT appears to be of high clinical relevance due to the improved identification of HPP patients with an increased risk for fractures or other skeletal manifestations, especially at the distal radius.<\/jats:p>","DOI":"10.1007\/s00223-023-01082-3","type":"journal-article","created":{"date-parts":[[2023,5,6]],"date-time":"2023-05-06T03:57:38Z","timestamp":1683345458000},"page":"691-703","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Radial HR-pQCT and Finite Element Analysis in HPP Patients are Superior in Identifying Susceptibility to Fracture-Associated Skeletal Affections Compared to DXA and Laboratory Tests"],"prefix":"10.1007","volume":"112","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6586-6794","authenticated-orcid":false,"given":"Felix N.","family":"Schmidt","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Constantin","family":"Schmidt","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Julian","family":"Delsmann","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael","family":"Amling","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Florian","family":"Barvencik","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2023,5,6]]},"reference":[{"key":"1082_CR1","doi-asserted-by":"publisher","first-page":"398","DOI":"10.1007\/s00223-015-0079-1","volume":"98","author":"JL Mill\u00e1n","year":"2016","unstructured":"Mill\u00e1n JL, Whyte MP (2016) Alkaline phosphatase and hypophosphatasia. Calcif Tissue Int 98:398\u2013416. https:\/\/doi.org\/10.1007\/s00223-015-0079-1","journal-title":"Calcif Tissue Int"},{"key":"1082_CR2","doi-asserted-by":"publisher","first-page":"1977","DOI":"10.1002\/jbmr.3226","volume":"32","author":"JR Shapiro","year":"2017","unstructured":"Shapiro JR, Lewiecki EM (2017) Hypophosphatasia in adults: clinical assessment and treatment considerations. J Bone Miner Res 32:1977\u20131980. https:\/\/doi.org\/10.1002\/jbmr.3226","journal-title":"J Bone Miner Res"},{"key":"1082_CR3","doi-asserted-by":"publisher","first-page":"289","DOI":"10.1038\/s41431-020-00732-6","volume":"29","author":"E Mornet","year":"2021","unstructured":"Mornet E, Taillandier A, Domingues C et al (2021) Hypophosphatasia: a genetic-based nosology and new insights in genotype-phenotype correlation. Eur J Hum Genet 29:289\u2013299. https:\/\/doi.org\/10.1038\/s41431-020-00732-6","journal-title":"Eur J Hum Genet"},{"key":"1082_CR4","doi-asserted-by":"publisher","first-page":"822","DOI":"10.1001\/archpedi.1948.02030020840003","volume":"75","author":"JC Rathbun","year":"1948","unstructured":"Rathbun JC (1948) Hypophosphatasia; a new developmental anomaly. Am J Dis Child 75:822\u2013831. https:\/\/doi.org\/10.1001\/archpedi.1948.02030020840003","journal-title":"Am J Dis Child"},{"key":"1082_CR5","doi-asserted-by":"publisher","first-page":"444","DOI":"10.1097\/BCO.0b013e3282630851","volume":"18","author":"E Golub","year":"2007","unstructured":"Golub E, Boesze-Battaglia K (2007) The role of alkaline phosphatase in mineralization. Curr Opin Orthop 18:444\u2013448. https:\/\/doi.org\/10.1097\/BCO.0b013e3282630851","journal-title":"Curr Opin Orthop"},{"key":"1082_CR6","doi-asserted-by":"publisher","first-page":"275","DOI":"10.1055\/a-1257-7976","volume":"29","author":"L Seefried","year":"2020","unstructured":"Seefried L, Genest F, Kornak U et al (2020) Therapie der hypophosphatasie. Osteologie 29:275\u2013282. https:\/\/doi.org\/10.1055\/a-1257-7976","journal-title":"Osteologie"},{"issue":"Suppl 2","key":"1082_CR7","first-page":"380","volume":"10","author":"C Rockman-Greenberg","year":"2013","unstructured":"Rockman-Greenberg C (2013) Hypophosphatasia. Pediatr Endocrinol Rev 10(Suppl 2):380\u2013388","journal-title":"Pediatr Endocrinol Rev"},{"key":"1082_CR8","doi-asserted-by":"publisher","first-page":"377","DOI":"10.1007\/s00198-020-05612-9","volume":"32","author":"F Genest","year":"2021","unstructured":"Genest F, Clau\u00dfen L, Rak D, Seefried L (2021) Bone mineral density and fracture risk in adult patients with hypophosphatasia. Osteoporos Int 32:377\u2013385. https:\/\/doi.org\/10.1007\/s00198-020-05612-9","journal-title":"Osteoporos Int"},{"key":"1082_CR9","doi-asserted-by":"publisher","first-page":"2653","DOI":"10.1007\/s00198-017-4087-z","volume":"28","author":"T Schmidt","year":"2017","unstructured":"Schmidt T, Mussawy H, Rolvien T et al (2017) Clinical, radiographic and biochemical characteristics of adult hypophosphatasia. Osteoporos Int 28:2653\u20132662. https:\/\/doi.org\/10.1007\/s00198-017-4087-z","journal-title":"Osteoporos Int"},{"key":"1082_CR10","doi-asserted-by":"publisher","first-page":"115794","DOI":"10.1016\/j.bone.2020.115794","volume":"143","author":"J St\u00fcrznickel","year":"2021","unstructured":"St\u00fcrznickel J, Schmidt FN, von Vopelius E et al (2021) Bone healing and reactivation of remodeling under asfotase alfa therapy in adult patients with pediatric-onset hypophosphatasia. Bone 143:115794. https:\/\/doi.org\/10.1016\/j.bone.2020.115794","journal-title":"Bone"},{"key":"1082_CR11","doi-asserted-by":"publisher","first-page":"1522","DOI":"10.1016\/j.metabol.2016.07.006","volume":"65","author":"TJ Weber","year":"2016","unstructured":"Weber TJ, Sawyer EK, Moseley S et al (2016) Burden of disease in adult patients with hypophosphatasia: results from two patient-reported surveys. Metabolism 65:1522\u20131530. https:\/\/doi.org\/10.1016\/j.metabol.2016.07.006","journal-title":"Metabolism"},{"key":"1082_CR12","doi-asserted-by":"publisher","first-page":"2171","DOI":"10.1002\/jbmr.4130","volume":"35","author":"L Seefried","year":"2020","unstructured":"Seefried L, Dahir K, Petryk A et al (2020) Burden of Illness in adults with hypophosphatasia: data from the global hypophosphatasia patient registry. J Bone Miner Res 35:2171\u20132178. https:\/\/doi.org\/10.1002\/jbmr.4130","journal-title":"J Bone Miner Res"},{"key":"1082_CR13","doi-asserted-by":"publisher","first-page":"21","DOI":"10.1016\/j.bone.2013.01.024","volume":"54","author":"KE Berkseth","year":"2013","unstructured":"Berkseth KE, Tebben PJ, Drake MT et al (2013) Clinical spectrum of hypophosphatasia diagnosed in adults. Bone 54:21\u201327. https:\/\/doi.org\/10.1016\/j.bone.2013.01.024","journal-title":"Bone"},{"key":"1082_CR14","doi-asserted-by":"publisher","first-page":"233","DOI":"10.1038\/nrendo.2016.14","volume":"12","author":"MP Whyte","year":"2016","unstructured":"Whyte MP (2016) Hypophosphatasia\u2014Aetiology, nosology, pathogenesis, diagnosis and treatment. Nat Rev Endocrinol 12:233\u2013246. https:\/\/doi.org\/10.1038\/nrendo.2016.14","journal-title":"Nat Rev Endocrinol"},{"key":"1082_CR15","doi-asserted-by":"publisher","first-page":"203","DOI":"10.4103\/2230-8210.109659","volume":"17","author":"MK Garg","year":"2013","unstructured":"Garg MK, Kharb S (2013) Dual energy X-ray absorptiometry: pitfalls in measurement and interpretation of bone mineral density. Indian J Endocrinol Metab 17:203\u2013210. https:\/\/doi.org\/10.4103\/2230-8210.109659","journal-title":"Indian J Endocrinol Metab"},{"key":"1082_CR16","doi-asserted-by":"publisher","first-page":"231","DOI":"10.1016\/j.bone.2019.02.025","volume":"122","author":"MP Whyte","year":"2019","unstructured":"Whyte MP, McAlister WH, Mumm S, Bierhals AJ (2019) No vascular calcification on cardiac computed tomography spanning asfotase alfa treatment for an elderly woman with hypophosphatasia. Bone 122:231\u2013236. https:\/\/doi.org\/10.1016\/j.bone.2019.02.025","journal-title":"Bone"},{"key":"1082_CR17","doi-asserted-by":"publisher","first-page":"392","DOI":"10.1359\/jbmr.071108","volume":"23","author":"S Boutroy","year":"2008","unstructured":"Boutroy S, Van Rietbergen B, Sornay-Rendu E et al (2008) Finite element analysis based on in vivo HR-pQCT images of the distal radius is associated with wrist fracture in postmenopausal women. J Bone Miner Res 23:392\u2013399. https:\/\/doi.org\/10.1359\/jbmr.071108","journal-title":"J Bone Miner Res"},{"key":"1082_CR18","doi-asserted-by":"publisher","first-page":"1607","DOI":"10.1007\/s00198-020-05438-5","volume":"31","author":"DE Whittier","year":"2020","unstructured":"Whittier DE, Boyd SK, Burghardt AJ et al (2020) Guidelines for the assessment of bone density and microarchitecture in vivo using high-resolution peripheral quantitative computed tomography. Osteoporos Int 31:1607\u20131627. https:\/\/doi.org\/10.1007\/s00198-020-05438-5","journal-title":"Osteoporos Int"},{"key":"1082_CR19","doi-asserted-by":"publisher","first-page":"405","DOI":"10.1038\/gim.2015.30","volume":"17","author":"S Richards","year":"2015","unstructured":"Richards S, Aziz N, Bale S et al (2015) Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med 17:405\u2013424. https:\/\/doi.org\/10.1038\/gim.2015.30","journal-title":"Genet Med"},{"key":"1082_CR20","doi-asserted-by":"publisher","first-page":"453","DOI":"10.1016\/j.jocd.2019.07.001","volume":"22","author":"CR Shuhart","year":"2019","unstructured":"Shuhart CR, Yeap SS, Anderson PA et al (2019) Executive summary of the 2019 ISCD position development conference on monitoring treatment, DXA cross-calibration and least significant change, spinal cord injury, peri-prosthetic and orthopedic bone health, transgender medicine, and pediatrics. J Clin Densitom 22:453\u2013471. https:\/\/doi.org\/10.1016\/j.jocd.2019.07.001","journal-title":"J Clin Densitom"},{"key":"1082_CR21","doi-asserted-by":"publisher","first-page":"1291","DOI":"10.1016\/j.bone.2011.03.755","volume":"48","author":"M Sode","year":"2011","unstructured":"Sode M, Burghardt AJ, Pialat J-B et al (2011) Quantitative characterization of subject motion in HR-pQCT images of the distal radius and tibia. Bone 48:1291\u20131297. https:\/\/doi.org\/10.1016\/j.bone.2011.03.755","journal-title":"Bone"},{"key":"1082_CR22","doi-asserted-by":"publisher","first-page":"111","DOI":"10.1016\/j.bone.2011.10.003","volume":"50","author":"JB Pialat","year":"2012","unstructured":"Pialat JB, Burghardt AJ, Sode M et al (2012) Visual grading of motion induced image degradation in high resolution peripheral computed tomography: impact of image quality on measures of bone density and micro-architecture. Bone 50:111\u2013118. https:\/\/doi.org\/10.1016\/j.bone.2011.10.003","journal-title":"Bone"},{"key":"1082_CR23","doi-asserted-by":"publisher","first-page":"2041","DOI":"10.1002\/jbmr.2873","volume":"31","author":"LA Burt","year":"2016","unstructured":"Burt LA, Liang Z, Sajobi TT et al (2016) Sex- and site-specific normative data curves for HR-pQCT. J Bone Miner Res 31:2041\u20132047. https:\/\/doi.org\/10.1002\/jbmr.2873","journal-title":"J Bone Miner Res"},{"key":"1082_CR24","doi-asserted-by":"publisher","first-page":"743","DOI":"10.2106\/JBJS.I.00919","volume":"92","author":"A Unnanuntana","year":"2010","unstructured":"Unnanuntana A, Gladnick BP, Donnelly E, Lane JM (2010) The assessment of fracture risk. J Bone Joint Surg Am 92:743\u2013753. https:\/\/doi.org\/10.2106\/JBJS.I.00919","journal-title":"J Bone Joint Surg Am"},{"key":"1082_CR25","doi-asserted-by":"publisher","first-page":"E954","DOI":"10.1210\/jc.2012-4133","volume":"98","author":"M Cheung","year":"2013","unstructured":"Cheung M, Roschger P, Klaushofer K et al (2013) Cortical and trabecular bone density in X-linked hypophosphatemic rickets. J Clin Endocrinol Metab 98:E954-961. https:\/\/doi.org\/10.1210\/jc.2012-4133","journal-title":"J Clin Endocrinol Metab"},{"key":"1082_CR26","doi-asserted-by":"publisher","first-page":"329","DOI":"10.1097\/00005792-197909000-00001","volume":"58","author":"MP Whyte","year":"1979","unstructured":"Whyte MP, Teitelbaum SL, Murphy WA et al (1979) Adult hypophosphatasia. Clinical, laboratory, and genetic investigation of a large kindred with review of the literature. Medicine (Baltimore) 58:329\u2013347","journal-title":"Medicine (Baltimore)"},{"key":"1082_CR27","doi-asserted-by":"publisher","first-page":"965","DOI":"10.1002\/jbmr.297","volume":"26","author":"N Vilayphiou","year":"2011","unstructured":"Vilayphiou N, Boutroy S, Szulc P et al (2011) Finite element analysis performed on radius and tibia HR-pQCT images and fragility fractures at all sites in men. J Bone Miner Res 26:965\u2013973. https:\/\/doi.org\/10.1002\/jbmr.297","journal-title":"J Bone Miner Res"},{"key":"1082_CR28","doi-asserted-by":"publisher","first-page":"425","DOI":"10.1359\/jbmr.061206","volume":"22","author":"E Sornay-Rendu","year":"2007","unstructured":"Sornay-Rendu E, Boutroy S, Munoz F, Delmas PD (2007) Alterations of cortical and trabecular architecture are associated with fractures in postmenopausal women, partially independent of decreased BMD measured by DXA: the OFELY Study. J Bone Miner Res 22:425\u2013433. https:\/\/doi.org\/10.1359\/jbmr.061206","journal-title":"J Bone Miner Res"},{"key":"1082_CR29","doi-asserted-by":"publisher","first-page":"1254","DOI":"10.1136\/bmj.312.7041.1254","volume":"312","author":"D Marshall","year":"1996","unstructured":"Marshall D, Johnell O, Wedel H (1996) Meta-analysis of how well measures of bone mineral density predict occurrence of osteoporotic fractures. BMJ 312:1254\u20131259","journal-title":"BMJ"},{"key":"1082_CR30","doi-asserted-by":"publisher","first-page":"1225","DOI":"10.1007\/s00198-011-1656-4","volume":"23","author":"A Moustafa","year":"2012","unstructured":"Moustafa A, Sugiyama T, Prasad J et al (2012) Mechanical loading-related changes in osteocyte sclerostin expression in mice are more closely associated with the subsequent osteogenic response than the peak strains engendered. Osteoporos Int 23:1225\u20131234. https:\/\/doi.org\/10.1007\/s00198-011-1656-4","journal-title":"Osteoporos Int"},{"key":"1082_CR31","doi-asserted-by":"publisher","first-page":"139","DOI":"10.1002\/(SICI)1097-0185(199602)244:2<139::AID-AR1>3.0.CO;2-X","volume":"244","author":"HM Frost","year":"1996","unstructured":"Frost HM (1996) Perspectives: a proposed general model of the \u201cmechanostat\u201d (suggestions from a new skeletal-biologic paradigm). Anat Rec 244:139\u2013147. https:\/\/doi.org\/10.1002\/(SICI)1097-0185(199602)244:2%3c139::AID-AR1%3e3.0.CO;2-X","journal-title":"Anat Rec"},{"key":"1082_CR32","doi-asserted-by":"publisher","first-page":"34","DOI":"10.1016\/S2213-8587(18)30308-5","volume":"7","author":"EJ Samelson","year":"2019","unstructured":"Samelson EJ, Broe KE, Xu H et al (2019) Cortical and trabecular bone microarchitecture as an independent predictor of incident fracture risk in older women and men in the Bone Microarchitecture International Consortium (BoMIC): a prospective study. Lancet Diabetes Endocrinol 7:34\u201343. https:\/\/doi.org\/10.1016\/S2213-8587(18)30308-5","journal-title":"Lancet Diabetes Endocrinol"},{"key":"1082_CR33","doi-asserted-by":"publisher","first-page":"446","DOI":"10.1002\/jbmr.3901","volume":"35","author":"N Mikolajewicz","year":"2020","unstructured":"Mikolajewicz N, Bishop N, Burghardt AJ et al (2020) HR-pQCT measures of bone microarchitecture predict fracture: systematic review and meta-analysis. J Bone Miner Res 35:446\u2013459. https:\/\/doi.org\/10.1002\/jbmr.3901","journal-title":"J Bone Miner Res"},{"key":"1082_CR34","doi-asserted-by":"publisher","first-page":"589","DOI":"10.1002\/jbmr.3347","volume":"33","author":"LA Burt","year":"2018","unstructured":"Burt LA, Manske SL, Hanley DA, Boyd SK (2018) Lower bone density, impaired microarchitecture, and strength predict future fragility fracture in postmenopausal women: 5-year follow-up of the calgary CaMos cohort. J Bone Miner Res 33:589\u2013597. https:\/\/doi.org\/10.1002\/jbmr.3347","journal-title":"J Bone Miner Res"}],"container-title":["Calcified Tissue International"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00223-023-01082-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s00223-023-01082-3\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00223-023-01082-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,5,19]],"date-time":"2023-05-19T16:03:27Z","timestamp":1684512207000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s00223-023-01082-3"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,5,6]]},"references-count":34,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2023,6]]}},"alternative-id":["1082"],"URL":"https:\/\/doi.org\/10.1007\/s00223-023-01082-3","relation":{},"ISSN":["1432-0827"],"issn-type":[{"value":"1432-0827","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,5,6]]},"assertion":[{"value":"29 January 2023","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"5 April 2023","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"6 May 2023","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"Felix N. Schmidt, Constantin Schmidt, Julian Delsmann and Michael Amling declare that they have no conflicts of interest. Florian Barvencik recieved research funds and speakers fee from Alexion Pharmaceuticals (Boston, United Stated of America).","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}},{"value":"This retrospective study was performed in accordance with the local ethical guidelines and the Declaration of Helsinki.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Human and Animal Rights and Informed Consent"}}]}}