{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,24]],"date-time":"2026-07-24T19:22:41Z","timestamp":1784920961628,"version":"3.55.0"},"reference-count":54,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2023,11,27]],"date-time":"2023-11-27T00:00:00Z","timestamp":1701043200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Children"],"abstract":"<jats:p>The present study aimed to evaluate the burden and management of fragility fractures in subjects with Rett syndrome. We searched all relevant medical literature from 1 January 1986 to 30 June 2023 for studies under the search term \u201cRett syndrome and fracture\u201d. The fracture frequency ranges from a minimum of 13.9% to a maximum of 36.1%. The majority of such fractures occur in lower limb bones and are associated with low bone mineral density. Anticonvulsant use, joint contractures, immobilization, low physical activity, poor nutrition, the genotype, and lower calcium and vitamin D intakes all significantly impair skeletal maturation and bone mass accrual in Rett syndrome patients, making them more susceptible to fragility fractures. This review summarizes the knowledge on risk factors for fragility fracture in patients with Rett syndrome and suggests a possible diagnostic and therapeutic care pathway for improving low bone mineral density and reducing the risk of fragility fractures. The optimization of physical activity, along with adequate nutrition and the intake of calcium and vitamin D supplements, should be recommended. In addition, subjects with Rett syndrome and a history of fracture should consider using bisphosphonates.<\/jats:p>","DOI":"10.3390\/children10121861","type":"journal-article","created":{"date-parts":[[2023,11,27]],"date-time":"2023-11-27T07:56:10Z","timestamp":1701071770000},"page":"1861","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Bone Fracture in Rett Syndrome: Mechanisms and Prevention Strategies"],"prefix":"10.3390","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4163-7289","authenticated-orcid":false,"given":"Carla","family":"Caffarelli","sequence":"first","affiliation":[{"name":"Department of Medicine, Surgery and Neuroscience, University of Siena, 53100 Siena, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonella","family":"Al Refaie","sequence":"additional","affiliation":[{"name":"Department of Medicine, Surgery and Neuroscience, University of Siena, 53100 Siena, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caterina","family":"Mondillo","sequence":"additional","affiliation":[{"name":"Department of Medicine, Surgery and Neuroscience, University of Siena, 53100 Siena, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michela","family":"De Vita","sequence":"additional","affiliation":[{"name":"Department of Medicine, Surgery and Neuroscience, University of Siena, 53100 Siena, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leonardo","family":"Baldassini","sequence":"additional","affiliation":[{"name":"Department of Medicine, Surgery and Neuroscience, University of Siena, 53100 Siena, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8792-0947","authenticated-orcid":false,"given":"Giuseppe","family":"Valacchi","sequence":"additional","affiliation":[{"name":"Department of Biomedical and Specialist Surgical Sciences, University of Ferrara, 44121 Ferrara, Italy"},{"name":"Animal Science Department, Plants for Human Health Institute, North Carolina Research Campus, North Carolina State University, Kannapolis, NC 27695, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefano","family":"Gonnelli","sequence":"additional","affiliation":[{"name":"Department of Medicine, Surgery and Neuroscience, University of Siena, 53100 Siena, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,11,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"422","DOI":"10.1016\/j.neuron.2007.10.001","article-title":"The story of Rett syndrome: From clinic to neurobiology","volume":"56","author":"Chahrour","year":"2007","journal-title":"Neuron"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1002\/mrdd.10020","article-title":"Clinical manifestations and stages of Rett syndrome","volume":"8","author":"Hagberg","year":"2002","journal-title":"Ment. Retard. Dev. Disabil. Res. Rev."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1313","DOI":"10.1212\/01.wnl.0000291011.54508.aa","article-title":"Specific mutations in methyl-CpGbinding protein 2 confer different severity in Rett syndrome","volume":"15","author":"Neul","year":"2008","journal-title":"Neurology"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"944","DOI":"10.1002\/ana.22124","article-title":"RettSearch Consortium Rett syndrome: Revised diagnostic criteria and nomenclature","volume":"68","author":"Neul","year":"2010","journal-title":"Ann. Neurol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"248","DOI":"10.1007\/s00223-014-9888-x","article-title":"A comparative study of dual-X-ray absorptiometry and quantitative ultrasonography for the evaluating bone status in subjects with Rett syndrome","volume":"95","author":"Caffarelli","year":"2014","journal-title":"Calcif. Tissue Int."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Pecorelli, A., Cordone, V., Schiavone, M.L., Caffarelli, C., Cervellati, C., Cerbone, G., Gonnelli, S., Hayek, J., and Valacchi, G. (2021). Altered Bone Status in Rett Syndrome. Life, 11.","DOI":"10.3390\/life11060521"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"540","DOI":"10.1542\/peds.2007-1641","article-title":"Early determinants of fractures in Rett syndrome","volume":"121","author":"Downs","year":"2008","journal-title":"Pediatrics"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"359","DOI":"10.1203\/PDR.0b013e31820bc6d3","article-title":"Patients with Rett syndrome sustain low-energy fractures","volume":"69","author":"Roende","year":"2011","journal-title":"Pediatr. Res."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"486","DOI":"10.1016\/j.bone.2007.07.008","article-title":"Osteoporosis in children and adolescents","volume":"41","author":"Bianchi","year":"2007","journal-title":"Bone"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"102","DOI":"10.1159\/000103007","article-title":"Risk factors for fractures in normally active children and adolescents","volume":"51","author":"Goulding","year":"2007","journal-title":"Med. Sport. Sci."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"557","DOI":"10.1097\/01241398-198909010-00010","article-title":"Orthopedic aspects of Rett syndrome: A multicenter review","volume":"9","author":"Loder","year":"1989","journal-title":"J. Pediatr. Orthop."},{"key":"ref_12","first-page":"323","article-title":"A population-based approach to the investigation of osteopenia in Rett syndrome","volume":"41","author":"Leonard","year":"1999","journal-title":"Dev. Med. Child. Neurol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1619","DOI":"10.1100\/tsw.2006.266","article-title":"Osteoporosis in Rett syndrome: A study on normal values","volume":"15","author":"Zysman","year":"2006","journal-title":"Sci. World J."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"435","DOI":"10.1203\/PDR.0b013e318180ebcd","article-title":"Bone mineral content and bone mineral density are lower in older than in younger females with Rett syndrome","volume":"64","author":"Motil","year":"2008","journal-title":"Pediatr. Res."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"737","DOI":"10.1016\/j.bone.2007.12.003","article-title":"Bone ultrasonography at phalanxes in patients with Rett syndrome: A 3-year longitudinal study","volume":"42","author":"Gonnelli","year":"2008","journal-title":"Bone"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"444","DOI":"10.1136\/adc.2008.148932","article-title":"Valproate and risk of fracture in Rett syndrome","volume":"95","author":"Leonard","year":"2010","journal-title":"Arch. Dis. Child."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1203\/PDR.0b013e31820b937d","article-title":"Bone mineral content and density in Rett syndrome and their contributing factors","volume":"69","author":"Jefferson","year":"2011","journal-title":"Pediatr. Res."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"2280","DOI":"10.1002\/jbmr.423","article-title":"DXA-measurements in Rett syndrome reveal small bones with low bone mass","volume":"26","author":"Roende","year":"2011","journal-title":"J. Bone. Miner. Res."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"292","DOI":"10.1097\/MPG.0b013e31824b6159","article-title":"Gastrointestinal and nutritional problems occur frequently throughout life in girls and women with Rett syndrome","volume":"55","author":"Motil","year":"2012","journal-title":"J. Pediatr. Gastroenterol. Nutr."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"E1972","DOI":"10.1210\/jc.2013-2627","article-title":"Vitamin D deficiency in Serbian patients with Rett syndrome","volume":"98","author":"Sarajlija","year":"2013","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"167","DOI":"10.3233\/PRM-140286","article-title":"The effect of low magnitude mechanical stimulation (LMMS) on bone density in patients with Rett syndrome: A pilot and feasibility study","volume":"7","author":"Afzal","year":"2014","journal-title":"J. Pediatr. Rehabil. Med."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1016\/j.bone.2015.01.023","article-title":"Longitudinal bone mineral content and density in Rett syndrome and their contributing factors","volume":"74","author":"Jefferson","year":"2015","journal-title":"Bone"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"232","DOI":"10.1111\/cch.12392","article-title":"A qualitative investigation of recovery after femoral fracture in Rett syndrome","volume":"43","author":"Horne","year":"2017","journal-title":"Child. Care. Health. Dev."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Lambert, A.-S., Rothenbuhler, A., Charles, P., Brailly-Tabard, S., Trabado, S., C\u00e9lestin, E., Durand, E., Fontaine, I., Miladi, L., and Wicart, P. (2017). Lower incidence of fracture after IV bisphosphonates in girls with Rett syndrome and severe bone fragility. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0186941"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"355","DOI":"10.1007\/s00223-018-0505-2","article-title":"Annual Injection of Zoledronic Acid Improves Bone Status in Children with Cerebral Palsy and Rett Syndrome","volume":"104","author":"Wiedemann","year":"2019","journal-title":"Calcif. Tissue. Int."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"639","DOI":"10.1038\/s41390-018-0111-z","article-title":"Bone status in relation to ambulatory performance in girls with Rett syndrome: A 10-year longitudinal study","volume":"85","author":"Caffarelli","year":"2019","journal-title":"Pediatr. Res."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Caffarelli, C., Gonnelli, S., Pitinca, M.D.T., Camarri, S., Al Refaie, A., Hayek, J., and Nuti, R. (2020). Methyl-CpG-Binding Protein 2 (MECP2) Mutation Type Is Associated with Bone Disease Severity in Rett Syndrome. BMC Med. Genet., 21.","DOI":"10.1186\/s12881-020-0960-2"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"374","DOI":"10.1016\/j.jocd.2020.10.011","article-title":"A Comparison of Lumbar Spine and Lateral Distal Femur Bone Density in Girls with Rett Syndrome","volume":"24","author":"Gripp","year":"2021","journal-title":"J. Clin. Densitom."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"S69","DOI":"10.1016\/j.braindev.2005.03.018","article-title":"Clinical profile of a male with Rett syndrome","volume":"27","author":"Budden","year":"2005","journal-title":"Brain. Dev."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"96","DOI":"10.1016\/j.jcfm.2005.08.013","article-title":"Forensic issues and possible mechanisms of sudden death in Rett syndrome","volume":"13","author":"Byard","year":"2006","journal-title":"J. Clin. Forensic Med."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"3059","DOI":"10.1007\/s00198-013-2423-5","article-title":"Osteoporosis in Rett syndrome: A case study presenting a novel management intervention for severe osteoporosis","volume":"24","author":"Lotan","year":"2013","journal-title":"Osteoporos. Int."},{"key":"ref_32","first-page":"253","article-title":"Teriparatide in the treatment of recurrent fractures in a Rett patient","volume":"12","author":"Caffarelli","year":"2015","journal-title":"Clin. Cases Min. Bone Metab."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"2873","DOI":"10.1007\/s00198-016-3586-7","article-title":"Bone microarchitecture in Rett syndrome and treatment with teriparatide: A case report","volume":"27","author":"Zanchetta","year":"2016","journal-title":"Osteoporos. Int."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1016\/j.jclinane.2016.01.017","article-title":"Rett syndrome: A concern for the anesthesiologists","volume":"31","author":"Som","year":"2016","journal-title":"J. Clin. Anesth."},{"key":"ref_35","first-page":"73","article-title":"The mechanostat: A proposed pathogenic mechanism of osteoporoses and the bone mass effects of mechanical and non-mechanical agents","volume":"2","author":"Frost","year":"1987","journal-title":"Bone Mineral"},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Tsaknakis, K., Kreuzer, J.H., Metzger, F.L., J\u00e4ckle, K., L\u00fcders, K.A., Braunschweig, L., Lorenz, H.M., and Hell, A.K. (2022). Reduced Volumetric Bone Mineral Density of the Spine in Adolescent Rett Girls with Scoliosis. Children, 9.","DOI":"10.3390\/children9121902"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1097\/BPO.0b013e3180317403","article-title":"Fractures in patients with cerebral palsy","volume":"27","author":"Presedo","year":"2007","journal-title":"J. Pediatr. Orthop."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1016\/j.bone.2015.01.024","article-title":"Osteoblast function and bone histomorphometry in a murine model of Rett syndrome","volume":"76","author":"Blue","year":"2015","journal-title":"Bone"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"346","DOI":"10.1016\/j.bone.2009.04.251","article-title":"Mecp2 deficiency decreases bone formation and reduces bone volume in a rodent model of Rett syndrome","volume":"45","author":"Zayzafoon","year":"2009","journal-title":"Bone"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"386","DOI":"10.1097\/MPG.0000000000000440","article-title":"Low bone mineral mass is associated with decreased bone formation and diet in girls with Rett syndrome","volume":"593","author":"Motil","year":"2014","journal-title":"J. Pediatr. Gastroenterol. Nutr."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"551","DOI":"10.1038\/pr.2013.252","article-title":"Low bone turnover phenotype in Rett syndrome: Results of biochemical bone marker analysis","volume":"75","author":"Roende","year":"2014","journal-title":"Pediatr. Res."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1111\/j.1469-8749.2009.03402.x","article-title":"Chronic antiepileptic monotherapy, bone metabolism, and body composition in non-institutionalized children","volume":"52","author":"Rauchenzauner","year":"2010","journal-title":"Dev. Med. Child. Neurol."},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Jefferson, A., Leonard, H., Siafarikas, A., Woodhead, H., Fyfe, S., Ward, L.M., Munns, C., Motil, K., Tarquinio, D., and Shapiro, J.R. (2016). Clinical Guidelines for Management of Bone Health in Rett Syndrome Based on Expert Consensus and Available Evidence. PLoS ONE, 5.","DOI":"10.1371\/journal.pone.0146824"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"e000717","DOI":"10.1136\/bmjpo-2020-000717","article-title":"Consensus guidelines on managing Rett syndrome across the lifespan","volume":"13","author":"Fu","year":"2020","journal-title":"BMJ Paediatr. Open"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1016\/j.jocd.2014.01.003","article-title":"Dual-energy X-ray absorptiometry interpretation and reporting in children and adolescents: The revised 2013 ISCD Pediatric Official Positions","volume":"17","author":"Crabtree","year":"2014","journal-title":"J. Clin. Densitom."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"567","DOI":"10.1016\/j.jocd.2019.07.002","article-title":"The Utility of DXA Assessment at the Forearm, Proximal Femur, and Lateral Distal Femur, and Vertebral Fracture Assessment in the Pediatric Population: 2019 ISCD Official Position","volume":"22","author":"Weber","year":"2019","journal-title":"J. Clin. Densitom."},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Al Refaie, A., Baldassini, L., Mondillo, C., Giglio, E., De Vita, M., Pitinca, M.D.T., Gonnelli, S., and Caffarelli, C. (2023). Radiofrequency Echographic Multi Spectrometry (R.E.M.S.): New Frontiers for Ultrasound Use in the Assessment of Bone Status\u2014A Current Picture. Diagnostics, 9.","DOI":"10.3390\/jimaging9100210"},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Caffarelli, C., Al Refaie, A., Mondillo, C., Versienti, A., Baldassini, L., De Vita, M., Pitinca, M.D.T., and Gonnelli, S. (2023). Radiofrequency Echographic Multispectrometry (REMS): A New Option in the Assessment Bone Status in Adults with Osteogenesis Imperfecta. J. Imaging, 9.","DOI":"10.3390\/jimaging9100210"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"218","DOI":"10.1007\/s00223-022-00964-2","article-title":"Bone Turnover Markers in Children: From Laboratory Challenges to Clinical Interpretation","volume":"112","author":"Ladang","year":"2023","journal-title":"Calcif. Tissue. Int."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"P23","DOI":"10.1530\/EJE-18-0736","article-title":"Current vitamin D status in European and Middle East countries and strategies to prevent vitamin D deficiency: A position statement of the European Calcified Tissue Society","volume":"180","author":"Lips","year":"2019","journal-title":"Eur. J. Endocrinol."},{"key":"ref_51","first-page":"CD005324","article-title":"Bisphosphonate therapy for children and adolescents with secondary osteoporosis","volume":"4","author":"Ward","year":"2007","journal-title":"Cochrane Database Syst. Rev."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"144","DOI":"10.1016\/j.bone.2017.07.004","article-title":"Treatment with neridronate in children and adolescents with osteogenesis imperfecta: Data from open-label, not controlled, three-year Italian study","volume":"103","author":"Idolazzi","year":"2017","journal-title":"Bone"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"578","DOI":"10.1016\/j.bone.2012.05.003","article-title":"Black bear parathyroid hormone has greater anabolic effects on trabecular bone in dystrophin-deficient mice than in a wild type mice","volume":"51","author":"Gray","year":"2012","journal-title":"Bone"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"52","DOI":"10.5606\/ehc.2018.58165","article-title":"Basic principles of fracture treatment in children","volume":"29","year":"2018","journal-title":"Eklem Hastalik Cerrahisi"}],"container-title":["Children"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2227-9067\/10\/12\/1861\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T21:31:25Z","timestamp":1760131885000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2227-9067\/10\/12\/1861"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,11,27]]},"references-count":54,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2023,12]]}},"alternative-id":["children10121861"],"URL":"https:\/\/doi.org\/10.3390\/children10121861","relation":{},"ISSN":["2227-9067"],"issn-type":[{"value":"2227-9067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,11,27]]}}}