{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T16:51:02Z","timestamp":1792601462351,"version":"4.5.0"},"reference-count":45,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,5,27]],"date-time":"2025-05-27T00:00:00Z","timestamp":1748304000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81870618, 82270933"],"award-info":[{"award-number":["81870618, 82270933"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Endocrinol."],"abstract":"<jats:sec><jats:title>Purpose<\/jats:title><jats:p>Optimal dosing of denosumab in osteogenesis imperfecta (OI) remains undefined. This prospective cohort study evaluated the 12-month efficacy and safety of denosumab in OI patients, with a historical control study with alendronate.<\/jats:p><\/jats:sec><jats:sec><jats:title>Materials and methods<\/jats:title><jats:p>Eight pediatric patients (1 mg\/kg every 3 months; \u226460 mg\/dose) and ten adults (60 mg every 6 months) received denosumab. Outcomes included lumbar spine (LS) and femoral neck (FN) bone mineral density (BMD), bone turnover markers (BTMs), vertebral compression fractures (assessed via AI-assisted Genant grading [AI_OVF_SH system]), fracture incidence, height velocity and adverse events. Historical controls (n=25 alendronate-treated OI patients) were analyzed for comparative efficacy. Sensitivity analyses excluded female pediatric participants (n=4) and peri-\/post-menopausal adults (n=4) to assess hormonal confounding.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Pediatric denosumab recipients exhibited significant LS-BMD (+30.3%, <jats:italic>P<\/jats:italic>&amp;lt;0.001) and FN-BMD gains (+38.7%, <jats:italic>P<\/jats:italic>=0.001) versus baseline, whereas adults showed non-significant increases (LS: +2.6%, <jats:italic>P<\/jats:italic>=0.100; FN: +4.4%, <jats:italic>P<\/jats:italic>=0.051). Sensitivity analyses revealed attenuated BTMs suppression in adults after excluding peri-\/post-menopausal women (only ALP decreased by 27.9%, <jats:italic>P<\/jats:italic>=0.028). Rebound hypercalcemia occurred in 62.5% (5\/8) of children, peaking at 2.93 mmol\/L. Compared to alendronate, denosumab demonstrated comparable BMD improvements and fracture reduction (<jats:italic>P<\/jats:italic>&amp;gt;0.050) but superior pediatric height gain (+5.8% <jats:italic>vs<\/jats:italic>. +2.5%, <jats:italic>P<\/jats:italic>=0.004). Vertebral area loss decreased significantly with denosumab (-14.6%, <jats:italic>P<\/jats:italic>=0.029), unlike alendronate (-8.8%, <jats:italic>P<\/jats:italic>=0.296). Adverse events were more frequent with denosumab in children (hypercalcemia: 62.5% <jats:italic>vs<\/jats:italic>. 0%, <jats:italic>P<\/jats:italic>=0.002).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Denosumab demonstrates non-inferior efficacy to alendronate for BMD improvement in OI, with heightened vertebral remodeling and pediatric height gains. However, its overshoot phenomenon in children (rebound hypercalcemia) and hormone-dependent efficacy in adults necessitate risk-stratified use. Age and menopausal status considerations are critical for optimizing denosumab therapy in OI.<\/jats:p><\/jats:sec><jats:sec><jats:title>Clinical trial registration<\/jats:title><jats:p><jats:uri>https:\/\/www.chictr.org.cn\/bin\/project\/edit?pid=184231<\/jats:uri>, identifier ChiCTR2300074207.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fendo.2025.1445093","type":"journal-article","created":{"date-parts":[[2025,5,27]],"date-time":"2025-05-27T04:12:52Z","timestamp":1748319172000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":6,"title":["Denosumab in patients with osteogenesis imperfecta and a historical control study with alendronate"],"prefix":"10.3389","volume":"16","author":[{"given":"Yazhao","family":"Mei","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shiya","family":"Cai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yunyi","family":"Jiang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuan","family":"Tian","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Shen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiemei","family":"Gu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chun","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhenlin","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hao","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,5,27]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"61","DOI":"10.1210\/endrev\/bnab017","article-title":"Osteogenesis imperfecta: mechanisms and signaling pathways connecting classical and rare OI types","volume":"43","author":"Jovanovic","year":"2022","journal-title":"Endocr Rev"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(15)00728-X","article-title":"Osteogenesis imperfecta","volume":"387","author":"Forlino","year":"2016","journal-title":"Lancet"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1210\/clinem\/dgad035","article-title":"Approach to the Patient: Pharmacological therapies for fracture risk reduction in adults with osteogenesis imperfecta","volume":"108","author":"Liu","year":"2023","journal-title":"J Clin Endocrinol Metab"},{"key":"B4","doi-asserted-by":"publisher","first-page":"CD005088","DOI":"10.1002\/14651858.CD005088.pub4","article-title":"Bisphosphonate therapy for osteogenesis imperfecta","volume":"10","author":"Dwan","year":"2016","journal-title":"Cochrane Database Syst Rev"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa044459","article-title":"Denosumab in postmenopausal women with low bone mineral density","volume":"354","author":"McClung","year":"2006","journal-title":"N Engl J Med"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1038\/nrd3705","article-title":"Bench to bedside: elucidation of the OPG-RANK-RANKL pathway and the development of denosumab","volume":"11","author":"Lacey","year":"2012","journal-title":"Nat Rev Drug Discov"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1359\/jbmr.0809010","article-title":"Comparison of the effect of denosumab and alendronate on BMD and biochemical markers of bone turnover in postmenopausal women with low bone mass: a randomized, blinded, phase 3 trial","volume":"24","author":"Brown","year":"2009","journal-title":"J Bone Miner Res"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1016\/S2213-8587(17)30138-9","article-title":"10 years of denosumab treatment in postmenopausal women with osteoporosis: results from the phase 3 randomised FREEDOM trial and open-label extension","volume":"5","author":"Bone","year":"2017","journal-title":"Lancet Diabetes Endocrinol"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1111\/apa.2018.107.issue-3","article-title":"Systematic review of the effect of denosumab on children with osteogenesis imperfecta showed inconsistent findings","volume":"107","author":"Li","year":"2018","journal-title":"Acta Paediatr"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.3390\/jcm10010152","article-title":"Denosumab discontinuation and the rebound phenomenon: A narrative review","volume":"10","author":"Anastasilakis","year":"2021","journal-title":"J Clin Med"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2014-3072","article-title":"Effect of denosumab on the growing skeleton in osteogenesis imperfecta","volume":"99","author":"Hoyer-Kuhn","year":"2014","journal-title":"J Clin Endocrinol Metab"},{"key":"B12","first-page":"24","article-title":"Safety and efficacy of denosumab in children with osteogenesis imperfect\u2013a first prospective trial","volume":"16","author":"Hoyer-Kuhn","year":"2016","journal-title":"J Musculoskelet Neuronal Interact"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.3390\/jcm7120479","article-title":"Efficacy and safety of denosumab therapy for osteogenesis imperfecta patients with osteoporosis-case series","volume":"109","author":"Kobayashi","year":"2018","journal-title":"J Clin Med"},{"key":"B14","doi-asserted-by":"publisher","first-page":"219","DOI":"10.1186\/s13023-019-1197-z","article-title":"Individualized treatment with denosumab in children with osteogenesis imperfecta - follow up of a trial cohort","volume":"14","author":"Hoyer-Kuhn","year":"2019","journal-title":"Orphanet J Rare Dis"},{"key":"B15","first-page":"76","article-title":"Hypercalcemia and hypercalciuria during denosumab treatment in children with osteogenesis imperfecta type VI","volume":"18","author":"Trejo","year":"2018","journal-title":"J Musculoskelet Neuronal Interact"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1210\/clinem\/dgae012","article-title":"Efficacy and safety of denosumab versus zoledronic acid in OI adults: A prospective, open-label, randomized study","volume":"109","author":"Lin","year":"2024","journal-title":"J Clin Endocrinol Metab"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1210\/clinem\/dgad732","article-title":"Safety and efficacy of denosumab in children with osteogenesis imperfecta-the first prospective comparative study","volume":"109","author":"Liu","year":"2024","journal-title":"J Clin Endocrinol Metab"},{"key":"B18","doi-asserted-by":"publisher","first-page":"e59569","DOI":"10.1371\/journal.pone.0059569","article-title":"Construction of a new growth references for China based on urban Chinese children: comparison with the WHO growth standards","volume":"8","author":"Zong","year":"2013","journal-title":"PloS One"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1038\/aps.2010.91","article-title":"Polymorphisms in the HOXD4 gene are not associated with peak bone mineral density in Chinese nuclear families","volume":"31","author":"Zhang","year":"2010","journal-title":"Acta Pharmacol Sin"},{"key":"B20","doi-asserted-by":"publisher","first-page":"e82098","DOI":"10.1371\/journal.pone.0082098","article-title":"Bone mineral density of the spine in 11,898 Chinese infants and young children: a cross-sectional study","volume":"8","author":"Xu","year":"2013","journal-title":"PloS One"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1016\/j.bone.2010.12.013","article-title":"Normative data and percentile curves for Dual Energy X-ray Absorptiometry in healthy Indian girls and boys aged 5\u201317 years","volume":"48","author":"Khadilkar","year":"2011","journal-title":"Bone"},{"key":"B22","doi-asserted-by":"publisher","first-page":"497","DOI":"10.1007\/s00198-013-2418-2","article-title":"Reference values of bone mineral density and prevalence of osteoporosis in Chinese adults","volume":"25","author":"Zhang","year":"2014","journal-title":"Osteoporos Int"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1002\/jbmr.v38.9","article-title":"Using artificial intelligence to diagnose osteoporotic vertebral fractures on plain radiographs","volume":"38","author":"Shen","year":"2023","journal-title":"J Bone Miner Res"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1016\/j.bone.2016.02.018","article-title":"Scoliosis in osteogenesis imperfecta caused by COL1A1\/COL1A2 mutations - genotype-phenotype correlations and effect of bisphosphonate treatment","volume":"86","author":"Sato","year":"2016","journal-title":"Bone"},{"key":"B25","doi-asserted-by":"publisher","first-page":"115879","DOI":"10.1016\/j.bone.2021.115879","article-title":"Reference intervals in Danish children and adolescents for bone turnover markers carboxy-terminal cross-linked telopeptide of type I collagen (\u03b2-CTX), pro-collagen type I N-terminal propeptide (PINP), osteocalcin (OC) and bone-specific alkaline phosphatase (bone ALP)","volume":"146","author":"Diemar","year":"2021","journal-title":"Bone"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1016\/j.bone.2019.01.021","article-title":"Clinical and genetic analysis in a large Chinese cohort of patients with X-linked hypophosphatemia","volume":"121","author":"Zhang","year":"2019","journal-title":"Bone"},{"key":"B27","article-title":"First use of the RANKL antibody denosumab in osteogenesis imperfecta type VI","volume":"12","author":"Semler","year":"2012","journal-title":"J Musculoskelet Neuronal Interact"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1620\/tjem.242.115","article-title":"Efficacy of denosumab for osteoporosis in three female patients with osteogenesis imperfecta","volume":"242","author":"Uehara","year":"2017","journal-title":"Tohoku J Exp Med"},{"key":"B29","doi-asserted-by":"publisher","first-page":"145","DOI":"10.1186\/s13023-014-0145-1","article-title":"Two years\u2019 experience with denosumab for children with osteogenesis imperfecta type VI","volume":"9","author":"Hoyer-Kuhn","year":"2014","journal-title":"Orphanet J Rare Dis"},{"key":"B30","article-title":"Bone metabolism in children and adolescents: main characteristics of the determinants of peak bone mass","volume":"10","author":"Stagi","year":"2013","journal-title":"Clin cases Miner Bone Metab"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1007\/s00223-016-0110-1","article-title":"Osteogenesis imperfecta type VI in individuals from northern Canada","volume":"98","author":"Ward","year":"2016","journal-title":"Calcif Tissue Int"},{"key":"B32","doi-asserted-by":"publisher","first-page":"398","DOI":"10.1111\/j.1442-200X.2010.03086.x","article-title":"Urinary N-telopeptides of type I collagen in healthy children","volume":"52","author":"Sato","year":"2010","journal-title":"Pediatr Int"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1002\/jbmr.2920","article-title":"Fracture rates and fracture sites in patients with osteogenesis imperfecta: A nationwide register-based cohort study","volume":"32","author":"Folkestad","year":"2017","journal-title":"J Bone Miner Res"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1007\/s11914-017-0380-1","article-title":"Denosumab: an emerging therapy in pediatric bone disorders","volume":"15","author":"Boyce","year":"2017","journal-title":"Curr Osteoporos Rep"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1007\/s00198-021-06002-5","article-title":"Denosumab for the treatment of primary pediatric osteoporosis","volume":"32","author":"Anastasilakis","year":"2021","journal-title":"Osteoporos Int"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1007\/s00198-020-05676-7","article-title":"Hypercalcemia upon denosumab withdrawal in primary hyperparathyroidism: a case report and literature review","volume":"31","author":"Camponovo","year":"2020","journal-title":"Osteoporos Int"},{"key":"B37","unstructured":"Denosumab 60mg (Prolia): should not be used in patients under 18 years due to the risk of serious hypercalcaemia 2022"},{"key":"B38","doi-asserted-by":"publisher","first-page":"e68","DOI":"10.3346\/jkms.2022.37.e68","article-title":"Comparison of denosumab and zoledronic acid in postmenopausal women with osteoporosis: bone mineral density (BMD) and trabecular bone score (TBS)","volume":"37","author":"Kang","year":"2022","journal-title":"J Korean Med Sci"},{"key":"B39","doi-asserted-by":"publisher","first-page":"194","DOI":"10.1186\/s13018-018-0865-3","article-title":"Denosumab compared to bisphosphonates to treat postmenopausal osteoporosis: a meta-analysis","volume":"13","author":"Wu","year":"2018","journal-title":"J Orthop Surg Res"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1007\/s00198-016-3607-6","article-title":"Denosumab compared to other treatments to prevent or treat osteoporosis in individuals at risk of fracture: a systematic review and meta-analysis","volume":"27","author":"Beaudoin","year":"2016","journal-title":"Osteoporos Int"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2013-3081","article-title":"Effects of denosumab treatment and discontinuation on human growth plates","volume":"99","author":"Wang","year":"2014","journal-title":"J Clin Endocrinol Metab"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1016\/j.bone.2006.04.004","article-title":"Vertebral morphometry in children and adolescents with osteogenesis imperfecta: effect of intravenous pamidronate treatment","volume":"39","author":"Land","year":"2006","journal-title":"Bone"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1159\/000331128","article-title":"Reshaping of vertebrae during treatment with neridronate or pamidronate in children with osteogenesis imperfecta","volume":"76","author":"Semler","year":"2011","journal-title":"Horm Res Paediatr"},{"key":"B44","doi-asserted-by":"publisher","first-page":"279","DOI":"10.1210\/edrv.23.3.0465","article-title":"Sex steroids and the construction and conservation of the adult skeleton","volume":"23","author":"Riggs","year":"2002","journal-title":"Endocr Rev"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.2147\/DDDT.S270829","article-title":"A review on the role of denosumab in fracture prevention","volume":"14","author":"Pang","year":"2020","journal-title":"Drug Des Devel Ther"}],"container-title":["Frontiers in Endocrinology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fendo.2025.1445093\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,5,27]],"date-time":"2025-05-27T04:12:56Z","timestamp":1748319176000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fendo.2025.1445093\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,5,27]]},"references-count":45,"alternative-id":["10.3389\/fendo.2025.1445093"],"URL":"https:\/\/doi.org\/10.3389\/fendo.2025.1445093","relation":{},"ISSN":["1664-2392"],"issn-type":[{"value":"1664-2392","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,5,27]]},"article-number":"1445093"}}