{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,18]],"date-time":"2026-07-18T17:01:25Z","timestamp":1784394085893,"version":"3.55.0"},"reference-count":31,"publisher":"Oxford University Press (OUP)","issue":"7","license":[{"start":{"date-parts":[[2016,2,4]],"date-time":"2016-02-04T00:00:00Z","timestamp":1454544000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"name":"NJB"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2016,7,1]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n               <jats:sec>\n                  <jats:title>\u2003<\/jats:title>\n                  <jats:p>Long-term bisphosphonate (BP) therapy in adults with osteoporosis is associated with atypical femoral fractures, caused by increased material bone density and prolonged suppression of bone remodeling which may reduce fracture toughness. In children with osteogenesis imperfecta (OI), long-term intravenous BP therapy improves bone structure and mass without further increasing the already hypermineralized bone matrix, and is generally regarded as safe. Here we report a teenage girl with OI type IV, who was started on cyclical intravenous pamidronate therapy at age 6 years because of recurrent fractures. Transiliac bone biopsy revealed classical structural features of OI but unusually low bone resorption surfaces. She made substantial improvements in functional ability, bone mass, and fracture rate. However, after 5 years of pamidronate therapy she started to develop recurrent, bilateral, nontraumatic, and proximal femur fractures, which satisfied the case definition for atypical femur fractures. Some fractures were preceded by periosteal reactions and prodromal pain. Pamidronate was discontinued after 7 years of therapy, following which she sustained two further nontraumatic femur fractures, and continued to show delayed tibial osteotomy healing. Despite rodding surgery, and very much in contrast to her affected, untreated, and normally mobile mother, she remains wheelchair-dependent. The case of this girl raises questions about the long-term safety of BP therapy in some children, in particular about the risk of oversuppressed bone remodeling with the potential for microcrack accumulation, delayed healing, and increased stiffness. The principal concern is whether there is point at which benefit from BP therapy could turn into harm, where fracture risk increases again. This case should stimulate debate whether current adult atypical femoral fracture guidance should apply to children, and whether low-frequency, low-dose cyclical, intermittent, or oral treatment maintenance regimens should be considered on a case-by-case basis. \u00a9 2016 American Society for Bone and Mineral Research.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1002\/jbmr.2805","type":"journal-article","created":{"date-parts":[[2016,2,4]],"date-time":"2016-02-04T17:59:43Z","timestamp":1454608783000},"page":"1449-1454","source":"Crossref","is-referenced-by-count":38,"title":["Recurrent Proximal Femur Fractures in a Teenager With Osteogenesis Imperfecta on Continuous Bisphosphonate Therapy: Are We Overtreating?"],"prefix":"10.1093","volume":"31","author":[{"given":"Rashida F","family":"Vasanwala","sequence":"first","affiliation":[{"name":"Department of Endocrinology and DiabetesKK Women's and Children's HospitalSingapore"},{"name":"Department of Endocrinology and DiabetesBirmingham Children's HospitalBirminghamUK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anish","family":"Sanghrajka","sequence":"additional","affiliation":[{"name":"Department of OrthopaedicsNorfolk and Norwich University HospitalNorwichUK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicholas J","family":"Bishop","sequence":"additional","affiliation":[{"name":"Department of Human MetabolismSheffield Children's HospitalSheffieldUK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wolfgang","family":"H\u00f6gler","sequence":"additional","affiliation":[{"name":"Institute of Metabolism and Systems ResearchUniversity of BirminghamBirminghamUK"},{"name":"Department of Endocrinology and DiabetesBirmingham Children's HospitalBirminghamUK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2016,2,4]]},"reference":[{"key":"2024021014180613600_jbmr2805-bib-0001","first-page":"2","article-title":"Osteogenesis imperfecta","author":"Forlino","year":"2015","journal-title":"Lancet. Forthcoming. Epub"},{"key":"2024021014180613600_jbmr2805-bib-0002","doi-asserted-by":"crossref","first-page":"1377","DOI":"10.1016\/S0140-6736(04)16051-0","article-title":"Osteogenesis imperfecta","volume":"363","author":"Rauch","year":"2004","journal-title":"Lancet"},{"key":"2024021014180613600_jbmr2805-bib-0003","doi-asserted-by":"crossref","first-page":"616","DOI":"10.1016\/j.bone.2006.02.071","article-title":"Pamidronate does not adversely affect bone intrinsic material properties in children with osteogenesis imperfecta","volume":"39","author":"Weber","year":"2006","journal-title":"Bone"},{"key":"2024021014180613600_jbmr2805-bib-0004","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1007\/s11914-014-0225-0","article-title":"Osteogenesis imperfecta: diagnosis and treatment","volume":"12","author":"Biggin","year":"2014","journal-title":"Curr Osteoporos Rep"},{"key":"2024021014180613600_jbmr2805-bib-0005","doi-asserted-by":"crossref","first-page":"1470","DOI":"10.1002\/ajmg.a.36545","article-title":"Osteogenesis imperfecta: clinical diagnosis, nomenclature and severity assessment","volume":"164A","author":"Van Dijk","year":"2014","journal-title":"Am J Med Genet A"},{"key":"2024021014180613600_jbmr2805-bib-0006","doi-asserted-by":"crossref","first-page":"1424","DOI":"10.1016\/S0140-6736(13)61091-0","article-title":"Risedronate in children with osteogenesis imperfecta: a randomised, double-blind, placebo-controlled trial","volume":"382","author":"Bishop","year":"2013","journal-title":"Lancet"},{"key":"2024021014180613600_jbmr2805-bib-0007","doi-asserted-by":"crossref","first-page":"947","DOI":"10.1056\/NEJM199810013391402","article-title":"Cyclic administration of pamidronate in children with severe osteogenesis imperfecta","volume":"339","author":"Glorieux","year":"1998","journal-title":"N Engl J Med"},{"key":"2024021014180613600_jbmr2805-bib-0008","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1016\/S8756-3282(01)00485-9","article-title":"Alendronate increases degree and uniformity of mineralization in cancellous bone and decreases the porosity in cortical bone of osteoporotic women","volume":"29","author":"Roschger","year":"2001","journal-title":"Bone"},{"key":"2024021014180613600_jbmr2805-bib-0009","doi-asserted-by":"crossref","first-page":"687","DOI":"10.1016\/S8756-3282(00)00376-8","article-title":"Alendronate increases bone strength by increasing the mean degree of mineralization of bone tissue in osteoporotic women","author":"Boivin","year":"2000","journal-title":"Bone"},{"key":"2024021014180613600_jbmr2805-bib-0010","doi-asserted-by":"crossref","first-page":"1293","DOI":"10.1172\/JCI0215952","article-title":"The effects of intravenous pamidronate on the bone tissue of children and adolescents with osteogenesis imperfecta","volume":"110","author":"Rauch","year":"2002","journal-title":"J Clin Invest"},{"key":"2024021014180613600_jbmr2805-bib-0011","doi-asserted-by":"crossref","first-page":"1299","DOI":"10.1007\/s00198-009-0899-9","article-title":"Bone microdamage: a clinical perspective","volume":"20","author":"Chapurlat","year":"2009","journal-title":"Osteoporos Int"},{"key":"2024021014180613600_jbmr2805-bib-0012","doi-asserted-by":"crossref","first-page":"457","DOI":"10.1056\/NEJMoa023110","article-title":"Bisphosphonate-induced osteopetrosis","volume":"349","author":"Whyte","year":"2003","journal-title":"N Engl J Med"},{"key":"2024021014180613600_jbmr2805-bib-0013","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1002\/jbmr.1998","article-title":"Atypical subtrochanteric and diaphyseal femoral fractures: second report of a task force of the American Society for Bone and Mineral Research","volume":"29","author":"Shane","year":"2014","journal-title":"J Bone Miner Res"},{"key":"2024021014180613600_jbmr2805-bib-0014","doi-asserted-by":"crossref","first-page":"539","DOI":"10.1016\/j.bone.2003.11.019","article-title":"Intravenous pamidronate treatment in children with moderate to severe osteogenesis imperfecta: assessment of indices of dual-energy X-ray absorptiometry and bone metabolic markers during the first year of therapy","volume":"34","author":"Arikoski","year":"2004","journal-title":"Bone"},{"key":"2024021014180613600_jbmr2805-bib-0015","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1016\/S0169-6009(08)80094-3","article-title":"Development of bone mass and bone density of the spine and femoral neck\u2014a prospective study of 65 children and adolescents","volume":"23","author":"Kroger","year":"1993","journal-title":"Bone Miner"},{"key":"2024021014180613600_jbmr2805-bib-0016","doi-asserted-by":"crossref","first-page":"184","DOI":"10.1097\/01241398-199103000-00008","article-title":"Fractures in early childhood: osteogenesis imperfecta or child abuse","volume":"11","author":"Dent","year":"1991","journal-title":"J Pediatr Orthop"},{"key":"2024021014180613600_jbmr2805-bib-0017","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1007\/s11832-011-0380-0","article-title":"Changing pattern of femoral fractures in osteogenesis imperfecta with prolonged use of bisphosphonates","volume":"6","author":"Nicolaou","year":"2012","journal-title":"J Child Orthop"},{"key":"2024021014180613600_jbmr2805-bib-0018","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1007\/s11154-010-9153-1","article-title":"Cellular mechanisms of bone remodeling","volume":"11","author":"Eriksen","year":"2010","journal-title":"Rev Endocr Metab Disord"},{"key":"2024021014180613600_jbmr2805-bib-0019","doi-asserted-by":"crossref","first-page":"1362","DOI":"10.1002\/jbmr.2486","article-title":"Osteotomy healing in children with osteogenesis imperfecta receiving bisphosphonate treatment","volume":"30","author":"Anam","year":"2015","journal-title":"J Bone Miner Res"},{"key":"2024021014180613600_jbmr2805-bib-0020","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1530\/EC-14-0120","article-title":"Association between alendronate and atypical femur fractures: a meta-analysis","volume":"4","author":"Liu","year":"2015","journal-title":"Endocr Connect"},{"key":"2024021014180613600_jbmr2805-bib-0021","doi-asserted-by":"crossref","first-page":"1191","DOI":"10.1359\/JBMR.040303","article-title":"Sclerotic metaphyseal lines in a child treated with pamidronate: histomorphometric analysis","volume":"19","author":"Rauch","year":"2004","journal-title":"J Bone Miner Res"},{"key":"2024021014180613600_jbmr2805-bib-0022","first-page":"82","article-title":"A direct role of collagen glycation in bone fracture","volume":"50","author":"Poundarik","year":"2015","journal-title":"J Mech Behav Biomed Mater"},{"key":"2024021014180613600_jbmr2805-bib-0023","doi-asserted-by":"crossref","first-page":"423","DOI":"10.1056\/NEJMp038103","article-title":"Do bisphosphonates make children's bones better or brittle","volume":"349","author":"Marini","year":"2003","journal-title":"N Engl J Med"},{"key":"2024021014180613600_jbmr2805-bib-0024","doi-asserted-by":"crossref","first-page":"1698","DOI":"10.1359\/jbmr.080511","article-title":"Bisphosphonate-induced osteopetrosis: novel bone modeling defects, metaphyseal osteopenia, and osteosclerosis fractures after drug exposure ceases","volume":"23","author":"Whyte","year":"2008","journal-title":"J Bone Miner Res"},{"key":"2024021014180613600_jbmr2805-bib-0025","doi-asserted-by":"crossref","first-page":"565","DOI":"10.1007\/s00223-013-9799-2","article-title":"Hyperosteoidosis and hypermineralization in the same bone: bone tissue analyses in a boy with a homozygous BMP1 mutation","volume":"93","author":"Hoyer-Kuhn","year":"2013","journal-title":"Calcif Tissue Int"},{"key":"2024021014180613600_jbmr2805-bib-0026","doi-asserted-by":"crossref","first-page":"598","DOI":"10.1002\/humu.21475","article-title":"COL1 C-propeptide cleavage site mutations cause high bone mass osteogenesis imperfecta","volume":"32","author":"Lindahl","year":"2011","journal-title":"Hum Mutat"},{"key":"2024021014180613600_jbmr2805-bib-0027","doi-asserted-by":"crossref","first-page":"2245","DOI":"10.1002\/jbmr.413","article-title":"Relationship between vitamin D status and bone mineralization, mass, and metabolism in children with osteogenesis imperfecta: histomorphometric study","volume":"26","author":"Edouard","year":"2011","journal-title":"J Bone Miner Res"},{"key":"2024021014180613600_jbmr2805-bib-0028","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1111\/nyas.12551","article-title":"Questioning the association between bisphosphonates and atypical femoral fractures","volume":"1335","author":"Pazianas","year":"2015","journal-title":"Ann N Y Acad Sci"},{"key":"2024021014180613600_jbmr2805-bib-0029","doi-asserted-by":"crossref","first-page":"1848","DOI":"10.1056\/NEJMc0910389","article-title":"Atypical femoral fractures and bisphosphonate use","volume":"362","author":"Girgis","year":"2010","journal-title":"N Engl J Med"},{"key":"2024021014180613600_jbmr2805-bib-0030","doi-asserted-by":"crossref","first-page":"1353","DOI":"10.1007\/s00198-008-0805-x","article-title":"Association of low-energy femoral fractures with prolonged bisphosphonate use: a case control study","volume":"20","author":"Lenart","year":"2009","journal-title":"Osteoporos Int"},{"key":"2024021014180613600_jbmr2805-bib-0031","doi-asserted-by":"crossref","first-page":"1294","DOI":"10.1210\/jc.2004-0952","article-title":"Severely suppressed bone turnover: a potential complication of alendronate therapy","volume":"90","author":"Odvina","year":"2005","journal-title":"J Clin Endocrinol Metab"}],"container-title":["Journal of Bone and Mineral Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fjbmr.2805","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/academic.oup.com\/jbmr\/article-pdf\/31\/7\/1449\/56648657\/jbmr2805.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jbmr\/article-pdf\/31\/7\/1449\/56648657\/jbmr2805.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,3,13]],"date-time":"2024-03-13T14:55:54Z","timestamp":1710341754000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jbmr\/article\/31\/7\/1449-1454\/7605057"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2016,2,4]]},"references-count":31,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2016,2,4]]},"published-print":{"date-parts":[[2016,7,1]]}},"URL":"https:\/\/doi.org\/10.1002\/jbmr.2805","relation":{},"ISSN":["0884-0431","1523-4681"],"issn-type":[{"value":"0884-0431","type":"print"},{"value":"1523-4681","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2016,7,1]]},"published":{"date-parts":[[2016,2,4]]}}}