{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T05:42:23Z","timestamp":1790401343821,"version":"4.1.0"},"reference-count":133,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2021,1,10]],"date-time":"2021-01-10T00:00:00Z","timestamp":1610236800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Bone material strength is determined by several factors, such as bone mass, matrix composition, mineralization, architecture and shape. From a clinical perspective, bone fragility is classified as primary (i.e., genetic and rare) or secondary (i.e., acquired and common) osteoporosis. Understanding the mechanism of rare genetic bone fragility disorders not only advances medical knowledge on rare diseases, it may open doors for drug development for more common disorders (i.e., postmenopausal osteoporosis). In this review, we highlight the main disease mechanisms underlying the development of human bone fragility associated with low bone mass known to date. The pathways we focus on are type I collagen processing, WNT-signaling, TGF-\u00df signaling, the RANKL-RANK system and the osteocyte mechanosensing pathway. We demonstrate how the discovery of most of these pathways has led to targeted, pathway-specific treatments.<\/jats:p>","DOI":"10.3390\/ijms22020625","type":"journal-article","created":{"date-parts":[[2021,1,10]],"date-time":"2021-01-10T19:55:56Z","timestamp":1610308556000},"page":"625","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":77,"title":["Mechanisms of Bone Fragility: From Osteogenesis Imperfecta to Secondary Osteoporosis"],"prefix":"10.3390","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2859-7246","authenticated-orcid":false,"given":"Ahmed","family":"El-Gazzar","sequence":"first","affiliation":[{"name":"Department of Paediatrics and Adolescent Medicine, Johannes Kepler University Linz, Krankenhausstra\u00dfe 26-30, 4020 Linz, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4328-6304","authenticated-orcid":false,"given":"Wolfgang","family":"H\u00f6gler","sequence":"additional","affiliation":[{"name":"Department of Paediatrics and Adolescent Medicine, Johannes Kepler University Linz, Krankenhausstra\u00dfe 26-30, 4020 Linz, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,1,10]]},"reference":[{"key":"ref_1","first-page":"421746","article-title":"Biology of Bone Tissue: Structure, Function, and Factors That Influence Bone Cells","volume":"2015","author":"Sasso","year":"2015","journal-title":"BioMed Res. Int."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"3111","DOI":"10.1210\/jc.2017-01127","article-title":"Diagnosis and Management of Osteopetrosis: Consensus Guidelines From the Osteopetrosis Working Group","volume":"102","author":"Wu","year":"2017","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"339","DOI":"10.1016\/B978-0-12-801238-3.65426-0","article-title":"Rickets and Osteomalacia","volume":"Volume 5","author":"Uday","year":"2019","journal-title":"Encyclopedia of Endocrine Diseases"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1657","DOI":"10.1016\/S0140-6736(15)00728-X","article-title":"Osteogenesis imperfecta","volume":"387","author":"Forlino","year":"2016","journal-title":"Lancet"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"343","DOI":"10.1016\/j.ajhg.2012.06.005","article-title":"A single recurrent mutation in the 5\u2032-UTR of IFITM5 causes osteogenesis imperfecta type V","volume":"91","author":"Cho","year":"2012","journal-title":"Am. J. Hum. Genet."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"349","DOI":"10.1016\/j.ajhg.2012.06.011","article-title":"A mutation in the 5\u2032-UTR of IFITM5 creates an in-frame start codon and causes autosomal-dominant osteogenesis imperfecta type V with hyperplastic callus","volume":"91","author":"Semler","year":"2012","journal-title":"Am. J. Hum. Genet."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"362","DOI":"10.1016\/j.ajhg.2011.01.015","article-title":"Exome sequencing identifies truncating mutations in human SERPINF1 in autosomal-recessive osteogenesis imperfecta","volume":"88","author":"Becker","year":"2011","journal-title":"Am. J. Hum. Genet."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1016\/j.cell.2006.08.039","article-title":"CRTAP is required for prolyl 3-hydroxylation and mutations cause recessive osteogenesis imperfecta","volume":"127","author":"Morello","year":"2006","journal-title":"Cell"},{"key":"ref_9","first-page":"1354","article-title":"Clinical and molecular analysis in families with autosomal recessive osteogenesis imperfecta identifies mutations in five genes and suggests genotype-phenotype correlations","volume":"161A","author":"Valencia","year":"2013","journal-title":"Am. J. Med. Genet. A"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"359","DOI":"10.1038\/ng1968","article-title":"Prolyl 3-hydroxylase 1 deficiency causes a recessive metabolic bone disorder resembling lethal\/severe osteogenesis imperfecta","volume":"39","author":"Cabral","year":"2007","journal-title":"Nat. Genet."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"521","DOI":"10.1016\/j.ajhg.2009.09.001","article-title":"PPIB mutations cause severe osteogenesis imperfecta","volume":"85","author":"Nesbitt","year":"2009","journal-title":"Am. J. Hum. Genet."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"389","DOI":"10.1016\/j.ajhg.2010.01.034","article-title":"Homozygosity for a missense mutation in SERPINH1, which encodes the collagen chaperone protein HSP47, results in severe recessive osteogenesis imperfecta","volume":"86","author":"Christiansen","year":"2010","journal-title":"Am. J. Hum. Genet."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"551","DOI":"10.1016\/j.ajhg.2010.02.022","article-title":"Mutations in the gene encoding the RER protein FKBP65 cause autosomal-recessive osteogenesis imperfecta","volume":"86","author":"Alanay","year":"2010","journal-title":"Am. J. Hum. Genet."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"110","DOI":"10.1016\/j.ajhg.2010.05.016","article-title":"Identification of a frameshift mutation in Osterix in a patient with recessive osteogenesis imperfecta","volume":"87","author":"Lapunzina","year":"2010","journal-title":"Am. J. Hum. Genet."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"12941","DOI":"10.1016\/S0021-9258(18)90635-6","article-title":"Osteogenesis imperfecta: Cloning of a pro-alpha 2(I) collagen gene with a frameshift mutation","volume":"259","author":"Pihlajaniemi","year":"1984","journal-title":"J. Biol. Chem."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"630","DOI":"10.1136\/jmedgenet-2012-101142","article-title":"Study of autosomal recessive osteogenesis imperfecta in Arabia reveals a novel locus defined by TMEM38B mutation","volume":"49","author":"Shaheen","year":"2012","journal-title":"J. Med. Genet."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"565","DOI":"10.1016\/j.ajhg.2013.02.010","article-title":"Mutations in WNT1 cause different forms of bone fragility","volume":"92","author":"Keupp","year":"2013","journal-title":"Am. J. Hum. Genet."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"590","DOI":"10.1016\/j.ajhg.2013.02.009","article-title":"WNT1 mutations in families affected by moderately severe and progressive recessive osteogenesis imperfecta","volume":"92","author":"Pyott","year":"2013","journal-title":"Am. J. Hum. Genet."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"154","DOI":"10.1186\/1750-1172-8-154","article-title":"Deficiency for the ER-stress transducer OASIS causes severe recessive osteogenesis imperfecta in humans","volume":"8","author":"Symoens","year":"2013","journal-title":"Orphanet. J. Rare Dis."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"979","DOI":"10.1016\/j.ajhg.2015.04.021","article-title":"Recessive osteogenesis imperfecta caused by missense mutations in SPARC","volume":"96","author":"Fahiminiya","year":"2015","journal-title":"Am. J. Hum. Genet."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"278","DOI":"10.1136\/jmedgenet-2017-104999","article-title":"FAM46A mutations are responsible for autosomal recessive osteogenesis imperfecta","volume":"55","author":"Doyard","year":"2018","journal-title":"J. Med. Genet."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"11920","DOI":"10.1038\/ncomms11920","article-title":"MBTPS2 mutations cause defective regulated intramembrane proteolysis in X-linked osteogenesis imperfecta","volume":"7","author":"Lindert","year":"2016","journal-title":"Nat. Commun."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"836","DOI":"10.1016\/j.ajhg.2019.08.008","article-title":"Autosomal-Recessive Mutations in MESD Cause Osteogenesis Imperfecta","volume":"105","author":"Moosa","year":"2019","journal-title":"Am. J. Hum. Genet."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"432","DOI":"10.1016\/j.ajhg.2015.01.002","article-title":"Mutations in SEC24D, encoding a component of the COPII machinery, cause a syndromic form of osteogenesis imperfecta","volume":"96","author":"Garbes","year":"2015","journal-title":"Am. J. Hum. Genet."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1470","DOI":"10.1002\/jbmr.4011","article-title":"Homozygous Loss-of-Function Mutations in CCDC134 Are Responsible for a Severe Form of Osteogenesis Imperfecta","volume":"35","author":"Dubail","year":"2020","journal-title":"J. Bone Miner. Res."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Li, L., Zhao, D., Zheng, W., Wang, O., Jiang, Y., Xia, W., Xing, X., and Li, M. (2019). A novel missense mutation in P4HB causes mild osteogenesis imperfecta. Biosci. Rep., 39.","DOI":"10.1042\/BSR20182118"},{"key":"ref_27","first-page":"115","article-title":"Phenotypic and molecular characterization of Bruck syndrome (osteogenesis imperfecta with contractures of the large joints) caused by a recessive mutation in PLOD2","volume":"131","author":"Alanay","year":"2004","journal-title":"Am. J. Med. Genet. A"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"8953217","DOI":"10.1155\/2018\/8953217","article-title":"Clinical, Genetics, and Bioinformatic Characterization of Mutations Affecting an Essential Region of PLS3 in Patients with BMND18","volume":"2018","author":"Chen","year":"2018","journal-title":"Int. J. Endocrinol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"989","DOI":"10.1016\/j.ajhg.2020.09.009","article-title":"Interaction between KDELR2 and HSP47 as a Key Determinant in Osteogenesis Imperfecta Caused by Bi-allelic Variants in KDELR2","volume":"107","author":"Semler","year":"2020","journal-title":"Am. J. Hum. Genet."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1136\/jmg.16.2.101","article-title":"Genetic heterogeneity in osteogenesis imperfecta","volume":"16","author":"Sillence","year":"1979","journal-title":"J. Med. Genet."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"943","DOI":"10.1002\/ajmg.a.33909","article-title":"Nosology and classification of genetic skeletal disorders: 2010 revision","volume":"155A","author":"Warman","year":"2011","journal-title":"Am. J. Med. Genet. A"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1111\/cge.13846","article-title":"The Evolution of the Nosology of Osteogenesis Imperfecta","volume":"99","author":"Manogari","year":"2021","journal-title":"Clin. Genet."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"17052","DOI":"10.1038\/nrdp.2017.52","article-title":"Osteogenesis imperfecta","volume":"3","author":"Marini","year":"2017","journal-title":"Nat. Rev. Dis Primers"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1001","DOI":"10.1007\/s00198-019-05264-4","article-title":"No longer a historical ailment: Two cases of childhood scurvy with recommendations for bone health providers","volume":"31","author":"Alten","year":"2020","journal-title":"Osteoporos Int."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Pozzer, D., Invernizzi, R.W., Blaauw, B., Cantoni, O., and Zito, E. (2020). Ascorbic Acid Route to the Endoplasmic Reticulum: Function and Role in Disease. Antioxid Redox Signal.","DOI":"10.1089\/ars.2019.7912"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"2019","DOI":"10.1210\/jc.2016-3766","article-title":"Phenotypic Spectrum in Osteogenesis Imperfecta Due to Mutations in TMEM38B: Unraveling a Complex Cellular Defect","volume":"102","author":"Webb","year":"2017","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"E6036","DOI":"10.1073\/pnas.1609571113","article-title":"Intracellular mechanisms of molecular recognition and sorting for transport of large extracellular matrix molecules","volume":"113","author":"Ishikawa","year":"2016","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"399","DOI":"10.1016\/S0945-053X(98)90013-0","article-title":"Procollagen N-proteinase and procollagen C-proteinase. Two unusual metalloproteinases that are essential for procollagen processing probably have important roles in development and cell signaling","volume":"16","author":"Prockop","year":"1998","journal-title":"Matrix Biol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"929","DOI":"10.1146\/annurev.biochem.77.032207.120833","article-title":"Collagen structure and stability","volume":"78","author":"Shoulders","year":"2009","journal-title":"Annu. Rev. Biochem."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"18273","DOI":"10.1073\/pnas.0808452105","article-title":"Structural basis of sequence-specific collagen recognition by SPARC","volume":"105","author":"Hohenester","year":"2008","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_41","first-page":"CD005088","article-title":"Bisphosphonate therapy for osteogenesis imperfecta","volume":"10","author":"Dwan","year":"2016","journal-title":"Cochrane Database Syst. Rev."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"924","DOI":"10.3389\/fendo.2019.00924","article-title":"Management of Osteogenesis Imperfecta","volume":"10","author":"Ralston","year":"2019","journal-title":"Front. Endocrinol."},{"key":"ref_43","unstructured":"Feingold, K.R., Anawalt, B., Boyce, A., Chrousos, G., de Herder, W.W., Dungan, K., Grossman, A., Hershman, J.M., Hofland, H.J., and Kaltsas, G. (2020). Osteogenesis Imperfecta. Endotext, MDText.xom, Inc."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1007\/s11914-020-00594-3","article-title":"Stem Cell Therapy as a Treatment for Osteogenesis Imperfecta","volume":"18","author":"Gotherstrom","year":"2020","journal-title":"Curr. Osteoporos Rep."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1038\/nm.3074","article-title":"WNT signaling in bone homeostasis and disease: From human mutations to treatments","volume":"19","author":"Baron","year":"2013","journal-title":"Nat. Med."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"68","DOI":"10.4161\/org.4.2.5851","article-title":"Wnt signal transduction pathways","volume":"4","author":"Komiya","year":"2008","journal-title":"Organogenesis"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1809","DOI":"10.1056\/NEJMoa1215458","article-title":"WNT1 mutations in early-onset osteoporosis and osteogenesis imperfecta","volume":"368","author":"Laine","year":"2013","journal-title":"N. Engl. J. Med."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1016\/j.gene.2004.06.044","article-title":"Wnt signaling in osteoblasts and bone diseases","volume":"341","author":"Westendorf","year":"2004","journal-title":"Gene"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"985","DOI":"10.1016\/j.cell.2017.05.016","article-title":"Wnt\/beta-Catenin Signaling, Disease, and Emerging Therapeutic Modalities","volume":"169","author":"Nusse","year":"2017","journal-title":"Cell"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"303","DOI":"10.1007\/s11914-017-0388-6","article-title":"Recent Discoveries in Monogenic Disorders of Childhood Bone Fragility","volume":"15","author":"Makitie","year":"2017","journal-title":"Curr. Osteoporos Rep."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"2678","DOI":"10.1172\/JCI92617","article-title":"Osteocyte-specific WNT1 regulates osteoblast function during bone homeostasis","volume":"127","author":"Joeng","year":"2017","journal-title":"J. Clin. Investig."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"969","DOI":"10.1016\/0092-8674(91)90369-A","article-title":"Swaying is a mutant allele of the proto-oncogene Wnt-1","volume":"67","author":"Thomas","year":"1991","journal-title":"Cell"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"4035","DOI":"10.1093\/hmg\/ddu117","article-title":"The swaying mouse as a model of osteogenesis imperfecta caused by WNT1 mutations","volume":"23","author":"Joeng","year":"2014","journal-title":"Hum. Mol. Genet."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"739","DOI":"10.1016\/j.devcel.2005.03.016","article-title":"Wnt\/beta-catenin signaling in mesenchymal progenitors controls osteoblast and chondrocyte differentiation during vertebrate skeletogenesis","volume":"8","author":"Day","year":"2005","journal-title":"Dev. Cell"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"3071","DOI":"10.1128\/MCB.01428-09","article-title":"Osteocyte Wnt\/beta-catenin signaling is required for normal bone homeostasis","volume":"30","author":"Kramer","year":"2010","journal-title":"Mol. Cell Biol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"513","DOI":"10.1016\/S0092-8674(01)00571-2","article-title":"LDL receptor-related protein 5 (LRP5) affects bone accrual and eye development","volume":"107","author":"Gong","year":"2001","journal-title":"Cell"},{"key":"ref_57","doi-asserted-by":"crossref","unstructured":"Korvala, J., Juppner, H., Makitie, O., Sochett, E., Schnabel, D., Mora, S., Bartels, C.F., Warman, M.L., Deraska, D., and Cole, W.G. (2012). Mutations in LRP5 cause primary osteoporosis without features of OI by reducing Wnt signaling activity. BMC Med. Genet., 13.","DOI":"10.1186\/1471-2350-13-26"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"1513","DOI":"10.1056\/NEJMoa013444","article-title":"High bone density due to a mutation in LDL-receptor-related protein 5","volume":"346","author":"Boyden","year":"2002","journal-title":"N. Engl. J. Med."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"3261","DOI":"10.1007\/s10067-020-04948-1","article-title":"Efficacy and safety of Romosozumab in treatment for low bone mineral density: A systematic review and meta-analysis","volume":"39","author":"Kaveh","year":"2020","journal-title":"Clin. Rheumatol."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"319","DOI":"10.1016\/j.cytogfr.2005.02.005","article-title":"SOST\/sclerostin, an osteocyte-derived negative regulator of bone formation","volume":"16","author":"Papapoulos","year":"2005","journal-title":"Cytokine Growth Factor Rev."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"537","DOI":"10.1093\/hmg\/10.5.537","article-title":"Increased bone density in sclerosteosis is due to the deficiency of a novel secreted protein (SOST)","volume":"10","author":"Balemans","year":"2001","journal-title":"Hum. Mol. Genet."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1016\/j.bone.2016.10.007","article-title":"Role and mechanism of action of sclerostin in bone","volume":"96","author":"Sato","year":"2017","journal-title":"Bone"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"471","DOI":"10.1007\/s40265-019-01072-6","article-title":"Romosozumab: First Global Approval","volume":"79","author":"Markham","year":"2019","journal-title":"Drugs"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1177\/1759720X17726744","article-title":"Sclerostin antibodies in osteoporosis: Latest evidence and therapeutic potential","volume":"9","author":"McClung","year":"2017","journal-title":"Ther. Adv. Musculoskelet Dis."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"e10174","DOI":"10.1002\/jbm4.10174","article-title":"Osteogenesis Imperfecta: New Perspectives From Clinical and Translational Research","volume":"3","author":"Tauer","year":"2019","journal-title":"JBMR Plus"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"3420","DOI":"10.3892\/mmr.2017.6390","article-title":"Sclerostin is a possible candidate marker of arterial stiffness: Results from a cohort study in Catania","volume":"15","author":"Gaudio","year":"2017","journal-title":"Mol. Med. Rep."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"554","DOI":"10.1007\/s00223-019-00532-1","article-title":"Camurati-Engelmann Disease","volume":"104","author":"Boudin","year":"2019","journal-title":"Calcif. Tissue Int."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"524","DOI":"10.1002\/humu.22977","article-title":"Marfan Syndrome and Related Disorders: 25 Years of Gene Discovery","volume":"37","author":"Verstraeten","year":"2016","journal-title":"Hum. Mutat."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"1910","DOI":"10.1002\/ajmg.a.36029","article-title":"Increased fracture risk and low bone mineral density in patients with loeys-dietz syndrome","volume":"161A","author":"Tan","year":"2013","journal-title":"Am. J. Med. Genet. A"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"670","DOI":"10.1038\/nm.3544","article-title":"Excessive transforming growth factor-beta signaling is a common mechanism in osteogenesis imperfecta","volume":"20","author":"Grafe","year":"2014","journal-title":"Nat. Med."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1002\/jbmr.3617","article-title":"Effect of Anti-TGF-beta Treatment in a Mouse Model of Severe Osteogenesis Imperfecta","volume":"34","author":"Tauer","year":"2019","journal-title":"J. Bone Miner. Res."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"772","DOI":"10.1007\/s00774-020-01132-y","article-title":"Role of the renin-angiotensin-aldosterone system in bone metabolism","volume":"38","author":"Mo","year":"2020","journal-title":"J. Bone Miner. Metab."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"3978","DOI":"10.1210\/jc.2014-2025","article-title":"Elimination of pain and improvement of exercise capacity in Camurati-Engelmann disease with losartan","volume":"99","author":"Ayyavoo","year":"2014","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"1283","DOI":"10.3389\/fonc.2020.01283","article-title":"Targeting the RANKL\/RANK\/OPG Axis for Cancer Therapy","volume":"10","author":"Ming","year":"2020","journal-title":"Front. Oncol."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1016\/j.abb.2008.03.018","article-title":"Functions of RANKL\/RANK\/OPG in bone modeling and remodeling","volume":"473","author":"Boyce","year":"2008","journal-title":"Arch. Biochem. Biophys."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1056\/NEJMoa013096","article-title":"Osteoprotegerin deficiency and juvenile Paget\u2019s disease","volume":"347","author":"Whyte","year":"2002","journal-title":"N. Engl. J. Med."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1016\/j.metabol.2017.10.007","article-title":"Juvenile Paget disease","volume":"80","author":"Polyzos","year":"2018","journal-title":"Metabolism"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"210","DOI":"10.1210\/jc.2016-2905","article-title":"Loss of Functional Osteoprotegerin: More Than a Skeletal Problem","volume":"102","author":"Grasemann","year":"2017","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_79","first-page":"81","article-title":"Familial hyperphosphatasemia with ateliosis and hypermetabolism of growing membranous bone; review of the clinical, radiographic and chemical features","volume":"33","author":"Caffey","year":"1972","journal-title":"Bull. Hosp. Joint Dis."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"132","DOI":"10.1002\/jbmr.5650110118","article-title":"Juvenile Paget disease: Life-long features of a mildly affected young woman","volume":"11","author":"Golob","year":"1996","journal-title":"J. Bone Miner. Res."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1038\/71667","article-title":"Mutations in TNFRSF11A, affecting the signal peptide of RANK, cause familial expansile osteolysis","volume":"24","author":"Hughes","year":"2000","journal-title":"Nat. Genet."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"703","DOI":"10.1210\/jc.2013-3762","article-title":"Denosumab treatment for juvenile Paget's disease: Results from two adult patients with osteoprotegerin deficiency (\u201cBalkan\u201d mutation in the TNFRSF11B gene)","volume":"99","author":"Polyzos","year":"2014","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"3121","DOI":"10.1210\/jc.2013-1143","article-title":"Effects of RANK-ligand antibody (denosumab) treatment on bone turnover markers in a girl with juvenile Paget\u2019s disease","volume":"98","author":"Grasemann","year":"2013","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"1073274820934822","DOI":"10.1177\/1073274820934822","article-title":"Denosumab for Effective Tumor Size Reduction in Patients With Giant Cell Tumors of the Bone: A Systematic Review and Meta-Analysis","volume":"27","author":"Yayan","year":"2020","journal-title":"Cancer Control."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"596","DOI":"10.1210\/jc.2017-02025","article-title":"Osteonecrosis of the Jaw and Rebound Hypercalcemia in Young People Treated With Denosumab for Giant Cell Tumor of Bone","volume":"103","author":"Uday","year":"2018","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"1085","DOI":"10.1517\/13543780903048929","article-title":"RANKL inhibition for the management of patients with benign metabolic bone disorders","volume":"18","author":"Anastasilakis","year":"2009","journal-title":"Expert. Opin. Investig. Drugs"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"115048","DOI":"10.1016\/j.bone.2019.115048","article-title":"Off-label uses of denosumab in metabolic bone diseases","volume":"129","author":"Polyzos","year":"2019","journal-title":"Bone"},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"306","DOI":"10.1038\/nm1716","article-title":"Notch signaling maintains bone marrow mesenchymal progenitors by suppressing osteoblast differentiation","volume":"14","author":"Hilton","year":"2008","journal-title":"Nat. Med."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"6402","DOI":"10.1128\/MCB.00299-08","article-title":"The association of Notch2 and NF-kappaB accelerates RANKL-induced osteoclastogenesis","volume":"28","author":"Fukushima","year":"2008","journal-title":"Mol. Cell Biol."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"303","DOI":"10.1038\/ng.779","article-title":"Mutations in NOTCH2 cause Hajdu-Cheney syndrome, a disorder of severe and progressive bone loss","volume":"43","author":"Simpson","year":"2011","journal-title":"Nat. Genet."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"3415","DOI":"10.1242\/dev.126.15.3415","article-title":"Mutation in ankyrin repeats of the mouse Notch2 gene induces early embryonic lethality","volume":"126","author":"Hamada","year":"1999","journal-title":"Development"},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1016\/j.metabol.2017.08.002","article-title":"Clinical and experimental aspects of notch receptor signaling: Hajdu-Cheney syndrome and related disorders","volume":"80","author":"Canalis","year":"2018","journal-title":"Metabolism"},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"518","DOI":"10.1002\/ajmg.a.35772","article-title":"Clinical consequences in truncating mutations in exon 34 of NOTCH2: Report of six patients with Hajdu-Cheney syndrome and a patient with serpentine fibula polycystic kidney syndrome","volume":"161A","author":"Narumi","year":"2013","journal-title":"Am. J. Med. Genet. A"},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1097\/MCD.0000000000000034","article-title":"Hajdu-Cheney syndrome: Phenotypical progression with de-novo NOTCH2 mutation","volume":"23","author":"Descartes","year":"2014","journal-title":"Clin. Dysmorphol."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"306","DOI":"10.1038\/ng.778","article-title":"Truncating mutations in the last exon of NOTCH2 cause a rare skeletal disorder with osteoporosis","volume":"43","author":"Isidor","year":"2011","journal-title":"Nat. Genet."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"4163","DOI":"10.1210\/jc.2017-01102","article-title":"Bone Structural Characteristics and Response to Bisphosphonate Treatment in Children With Hajdu-Cheney Syndrome","volume":"102","author":"Sakka","year":"2017","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"791","DOI":"10.1016\/j.jpeds.2005.07.014","article-title":"Bone measurements by peripheral quantitative computed tomography (pQCT) in children with cerebral palsy","volume":"147","author":"Binkley","year":"2005","journal-title":"J. Pediatr."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1016\/S1090-3801(02)00071-X","article-title":"Disuse and deconditioning in chronic low back pain: Concepts and hypotheses on contributing mechanisms","volume":"7","author":"Verbunt","year":"2003","journal-title":"Eur. J. Pain."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"144","DOI":"10.1016\/j.bone.2015.02.016","article-title":"Quantifying the osteocyte network in the human skeleton","volume":"75","author":"Buenzli","year":"2015","journal-title":"Bone"},{"key":"ref_100","doi-asserted-by":"crossref","unstructured":"Bonewald, L.F. (2018). Osteocytes. Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism, American Society for Bone and Mineral Research. [9th ed.].","DOI":"10.1002\/9781119266594.ch5"},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"858","DOI":"10.1096\/fj.05-4966.com","article-title":"Bone cell responses to high-frequency vibration stress: Does the nucleus oscillate within the cytoplasm?","volume":"20","author":"Bacabac","year":"2006","journal-title":"FASEB J."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"505","DOI":"10.1002\/ar.a.20050","article-title":"Ultrastructure of the osteocyte process and its pericellular matrix","volume":"278","author":"You","year":"2004","journal-title":"Anat. Rec. A Discov. Mol. Cell. Evol. Biol."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"C633","DOI":"10.1152\/ajpcell.00278.2004","article-title":"Mechanical stimulation prevents osteocyte apoptosis: Requirement of integrins, Src kinases, and ERKs","volume":"289","author":"Plotkin","year":"2005","journal-title":"Am. J. Physiol. Cell. Physiol."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"605","DOI":"10.1359\/jbmr.060107","article-title":"Osteocyte apoptosis is induced by weightlessness in mice and precedes osteoclast recruitment and bone loss","volume":"21","author":"Aguirre","year":"2006","journal-title":"J. Bone Miner. Res."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"1163","DOI":"10.1016\/j.bbrc.2004.06.056","article-title":"Shear stress inhibits while disuse promotes osteocyte apoptosis","volume":"320","author":"Bakker","year":"2004","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"658","DOI":"10.1210\/er.2012-1026","article-title":"The osteocyte: An endocrine cell \u2026 and more","volume":"34","author":"Dallas","year":"2013","journal-title":"Endocr. Rev."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"127S","DOI":"10.1016\/S8756-3282(98)00010-6","article-title":"Microgravity and bone cell mechanosensitivity","volume":"22","author":"Burger","year":"1998","journal-title":"Bone"},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"2248","DOI":"10.1210\/jc.2010-0067","article-title":"Increased sclerostin serum levels associated with bone formation and resorption markers in patients with immobilization-induced bone loss","volume":"95","author":"Gaudio","year":"2010","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1007\/s11914-019-00507-z","article-title":"Pro-inflammatory Cytokines and Osteocytes","volume":"17","author":"Zhou","year":"2019","journal-title":"Curr. Osteoporos Rep."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"e11918","DOI":"10.1097\/MD.0000000000011918","article-title":"Whole-body vibration training and bone health in postmenopausal women: A systematic review and meta-analysis","volume":"97","author":"Alcaraz","year":"2018","journal-title":"Medicine"},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"405","DOI":"10.3389\/fendo.2020.00405","article-title":"The Osteocyte as the New Discovery of Therapeutic Options in Rare Bone Diseases","volume":"11","author":"Pathak","year":"2020","journal-title":"Front. Endocrinol."},{"key":"ref_112","first-page":"570","article-title":"The polymorphism of the C3b\/C4b receptor in the normal population and in patients with systemic lupus erythematosus","volume":"68","author":"Holers","year":"1987","journal-title":"Clin. Exp. Immunol."},{"key":"ref_113","first-page":"1427","article-title":"Nitric oxide signaling in mechanical adaptation of bone","volume":"25","author":"Bakker","year":"2014","journal-title":"Osteoporos Int."},{"key":"ref_114","first-page":"E171","article-title":"Signal transduction pathways involved in fluid flow-induced PGE2 production by cultured osteocytes","volume":"276","author":"Ajubi","year":"1999","journal-title":"Am. J. Physiol."},{"key":"ref_115","first-page":"E318","article-title":"Increased insulin-like growth factor I mRNA expression in rat osteocytes in response to mechanical stimulation","volume":"268","author":"Lean","year":"1995","journal-title":"Am. J. Physiol."},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"872","DOI":"10.1016\/j.bone.2010.08.007","article-title":"Activation of beta-catenin signaling in MLO-Y4 osteocytic cells versus 2T3 osteoblastic cells by fluid flow shear stress and PGE2: Implications for the study of mechanosensation in bone","volume":"47","author":"Kamel","year":"2010","journal-title":"Bone"},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"62","DOI":"10.1006\/bbrc.1996.1131","article-title":"Pulsating fluid flow increases prostaglandin production by cultured chicken osteocytes\u2014A cytoskeleton-dependent process","volume":"225","author":"Ajubi","year":"1996","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"1345","DOI":"10.1002\/jbmr.5650061212","article-title":"Loading-related increases in prostaglandin production in cores of adult canine cancellous bone in vitro: A role for prostacyclin in adaptive bone remodeling?","volume":"6","author":"Rawlinson","year":"1991","journal-title":"J. Bone Miner. Res."},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"2657","DOI":"10.1002\/jbmr.168","article-title":"Mechanical induction of PGE2 in osteocytes blocks glucocorticoid-induced apoptosis through both the beta-catenin and PKA pathways","volume":"25","author":"Kitase","year":"2010","journal-title":"J. Bone Miner. Res."},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"507","DOI":"10.3389\/fcell.2020.00507","article-title":"Osteoclast Signal Transduction During Bone Metastasis Formation","volume":"8","author":"Gyori","year":"2020","journal-title":"Front. Cell Dev. Biol."},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1016\/S0092-8674(00)81569-X","article-title":"Osteoprotegerin ligand is a cytokine that regulates osteoclast differentiation and activation","volume":"93","author":"Lacey","year":"1998","journal-title":"Cell"},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"1421","DOI":"10.1002\/jbmr.3142","article-title":"PTHrP(12\u201348) Modulates the Bone Marrow Microenvironment and Suppresses Human Osteoclast Differentiation and Lifespan","volume":"32","author":"Kamalakar","year":"2017","journal-title":"J. Bone Miner. Res."},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"2053","DOI":"10.1359\/JBMR.050706","article-title":"Self-assembled RANK induces osteoclastogenesis ligand-independently","volume":"20","author":"Kanazawa","year":"2005","journal-title":"J. Bone Miner. Res."},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"1329","DOI":"10.1210\/endo.139.3.5837","article-title":"Identity of osteoclastogenesis inhibitory factor (OCIF) and osteoprotegerin (OPG): A mechanism by which OPG\/OCIF inhibits osteoclastogenesis in vitro","volume":"139","author":"Yasuda","year":"1998","journal-title":"Endocrinology"},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"763","DOI":"10.1359\/jbmr.1998.13.5.763","article-title":"A unitary model for involutional osteoporosis: Estrogen deficiency causes both type I and type II osteoporosis in postmenopausal women and contributes to bone loss in aging men","volume":"13","author":"Riggs","year":"1998","journal-title":"J. Bone Miner. Res."},{"key":"ref_126","doi-asserted-by":"crossref","first-page":"539","DOI":"10.1038\/nm.4076","article-title":"LGR4 is a receptor for RANKL and negatively regulates osteoclast differentiation and bone resorption","volume":"22","author":"Luo","year":"2016","journal-title":"Nat. Med."},{"key":"ref_127","doi-asserted-by":"crossref","first-page":"893","DOI":"10.1126\/science.3616618","article-title":"A parathyroid hormone-related protein implicated in malignant hypercalcemia: Cloning and expression","volume":"237","author":"Suva","year":"1987","journal-title":"Science"},{"key":"ref_128","first-page":"1298","article-title":"Variations in glucocorticoid induced osteoporosis prevention in a managed care cohort","volume":"28","author":"Mudano","year":"2001","journal-title":"J. Rheumatol."},{"key":"ref_129","doi-asserted-by":"crossref","first-page":"294","DOI":"10.1002\/acr.21796","article-title":"Prevalence of oral glucocorticoid usage in the United States: A general population perspective","volume":"65","author":"Overman","year":"2013","journal-title":"Arthritis Care Res."},{"key":"ref_130","doi-asserted-by":"crossref","first-page":"1975","DOI":"10.1007\/s00296-018-4106-1","article-title":"Denosumab in the treatment of glucocorticoid-induced osteoporosis","volume":"38","year":"2018","journal-title":"Rheumatol. Int."},{"key":"ref_131","doi-asserted-by":"crossref","first-page":"612","DOI":"10.3899\/jrheum.170054","article-title":"Glucocorticoids Are Associated with an Increased Risk for Vertebral Fracture in Patients with Rheumatoid Arthritis","volume":"45","author":"Kim","year":"2018","journal-title":"J. Rheumatol."},{"key":"ref_132","doi-asserted-by":"crossref","first-page":"388","DOI":"10.1097\/BOR.0000000000000608","article-title":"Glucocorticoid-induced osteoporosis update","volume":"31","author":"Adami","year":"2019","journal-title":"Curr. Opin. Rheumatol."},{"key":"ref_133","doi-asserted-by":"crossref","first-page":"1759720X19876468","DOI":"10.1177\/1759720X19876468","article-title":"Glucocorticoid-induced osteoporosis: From clinical trials to clinical practice","volume":"11","author":"Adami","year":"2019","journal-title":"Ther. Adv. Musculoskelet Dis."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/2\/625\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T05:09:20Z","timestamp":1760159360000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/2\/625"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,1,10]]},"references-count":133,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2021,1]]}},"alternative-id":["ijms22020625"],"URL":"https:\/\/doi.org\/10.3390\/ijms22020625","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,1,10]]}}}