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Alkaline phosphatase (ALP) enzyme therapy prevented poor bone mineralization and poor mechanical properties in mouse models of NF1 skeletal dysplasia; but transition to clinical trials is hampered by the lack of a technique that (i) identifies NF1 patients at risk of tibia bowing and fracture making them eligible for trial enrollment and (ii) monitors treatment effects on matrix characteristics related to bone strength. Therefore, we assessed the ability of matrix-sensitive techniques to provide characteristics that differentiate between cortical bone from mice characterized by postnatal loss of Nf1 in Osx-creTet-Off;Nf1flox\/flox osteoprogenitors (cKO) and from wild-type (WT) mice. Following euthanasia at two time points of bone disease progression, femur and tibia were harvested from both genotypes (n\u2009\u2265\u20098\/age\/sex\/genotype). A reduction in the mid-diaphysis ultimate force during three-point bending at 20\u2009weeks confirmed deleterious changes in bone induced by Nf1 deficiency, regardless of sex. Pooling females and males, low bound water (BW), and low cortical volumetric bone mineral density (Ct.vBMD) were the most accurate outcomes in distinguishing cKO from WT femurs with accuracy improving with age. Ct.vBMD and the average unloading slope (Avg-US) from cyclic reference point indentation tests were the most sensitive in differentiating WT from cKO tibias. Mineral-to-matrix ratio and carbonate substitution from Raman spectroscopy were not good classifiers. However, when combined with Ct.vBMD and BW (femur), they helped predict bending strength. Nf1 deficiency in osteoprogenitors negatively affected bone microstructure and matrix quality with deficits in properties becoming more pronounced with duration of Nf1 deficiency. Clinically measurable without ionizing radiation, BW and Avg-US are sensitive to deleterious changes in bone matrix in a preclinical model of NF1 bone dysplasia and require further clinical investigation as potential indicators of an onset of bone weakness in children with NF1. \u00a9 2022 American Society for Bone and Mineral Research (ASBMR).<\/jats:p>","DOI":"10.1002\/jbmr.4633","type":"journal-article","created":{"date-parts":[[2022,6,12]],"date-time":"2022-06-12T06:09:55Z","timestamp":1655014195000},"page":"1603-1621","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Identifying Bone Matrix Impairments in a Mouse Model of Neurofibromatosis Type 1 (NF1) by Clinically Translatable Techniques"],"prefix":"10.1093","volume":"37","author":[{"given":"Rafay","family":"Ahmed","sequence":"first","affiliation":[{"name":"Center for Bone Biology Vanderbilt University Medical Center Nashville TN USA"},{"name":"Department of Orthopaedic Surgery Vanderbilt University Medical Center Nashville TN USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sasidhar","family":"Uppuganti","sequence":"additional","affiliation":[{"name":"Center for Bone Biology Vanderbilt University Medical Center Nashville TN USA"},{"name":"Department of Orthopaedic Surgery Vanderbilt University Medical Center Nashville TN USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shrey","family":"Derasari","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering Vanderbilt University Nashville TN USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joshua","family":"Meyer","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering Vanderbilt University Nashville TN USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacquelyn S.","family":"Pennings","sequence":"additional","affiliation":[{"name":"Center for Musculoskeletal Research Vanderbilt University Medical Center Nashville TN USA"},{"name":"Department of Orthopaedic Surgery Vanderbilt University Medical Center Nashville TN USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2972-5633","authenticated-orcid":false,"given":"Florent","family":"Elefteriou","sequence":"additional","affiliation":[{"name":"Department of Orthopaedic Surgery Baylor College of Medicine Houston TX USA"},{"name":"Department of Molecular and Human Genetics Baylor College of Medicine Houston TX USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7403-7605","authenticated-orcid":false,"given":"Jeffry S.","family":"Nyman","sequence":"additional","affiliation":[{"name":"Department of Veterans Affairs Tennessee Valley Healthcare System Nashville TN USA"},{"name":"Center for Musculoskeletal Research Vanderbilt University Medical Center Nashville TN USA"},{"name":"Department of Biomedical Engineering Vanderbilt University Nashville TN USA"},{"name":"Center for Bone Biology Vanderbilt University Medical Center Nashville TN USA"},{"name":"Department of Orthopaedic Surgery Vanderbilt University Medical Center Nashville TN USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2022,6,12]]},"reference":[{"issue":"1627","key":"2024012802581458300_jbmr4633-bib-0001","doi-asserted-by":"crossref","first-page":"1617","DOI":"10.1056\/NEJM198112313052704","article-title":"Von Recklinghausen neurofibromatosis","volume":"305","author":"Riccardi","year":"1981","journal-title":"N Engl J Med"},{"issue":"1","key":"2024012802581458300_jbmr4633-bib-0002","doi-asserted-by":"crossref","first-page":"17004","DOI":"10.1038\/nrdp.2017.4","article-title":"Neurofibromatosis type 1","volume":"3","author":"Gutmann","year":"2017","journal-title":"Nat Rev Dis Primers"},{"key":"2024012802581458300_jbmr4633-bib-0003","doi-asserted-by":"crossref","first-page":"116060","DOI":"10.1016\/j.bone.2021.116060","article-title":"RASopathies: the musculoskeletal consequences and their etiology and pathogenesis","volume":"152","author":"Fowlkes","year":"2021","journal-title":"Bone"},{"issue":"11","key":"2024012802581458300_jbmr4633-bib-0004","doi-asserted-by":"crossref","first-page":"704","DOI":"10.1136\/jmg.26.11.704","article-title":"A genetic study of von Recklinghausen neurofibromatosis in south east Wales. 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