{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T16:52:12Z","timestamp":1792601532641,"version":"4.5.0"},"reference-count":37,"publisher":"Oxford University Press (OUP)","issue":"10","license":[{"start":{"date-parts":[[2025,9,1]],"date-time":"2025-09-01T00:00:00Z","timestamp":1756684800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/100004807","name":"DFG","doi-asserted-by":"publisher","award":["SE2373\/1-2384170921"],"award-info":[{"award-number":["SE2373\/1-2384170921"]}],"id":[{"id":"10.13039\/100004807","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,9,3]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Osteogenesis imperfecta (OI) is a rare genetic disorder predominantly resulting from mutations in COL1A1 and COL1A2. Denosumab, a monoclonal antibody targeting RANKL, inhibits osteoclast differentiation and activation, thereby preventing bone resorption. Despite its efficacy as an anti-resorptive therapy, concerns of rebound hypercalcemia limit its clinical use. This investigation was part of the multicenter trial NCT02352753, which was terminated early due to calcium-related adverse events. We implemented a sub-study to investigate dynamics of bone resorption markers and calcium, and the precise timepoint of rebound during denosumab therapy in OI patients. About 40 participants between 2 and 16\u00a0yr received subcutaneous denosumab (1\u00a0mg\/kgBW) every 6\u00a0mo for 3\u00a0yr. Calcium supplementation was started on the day of denosumab injection. Spot urine samples were collected at weeks 2, 8, 12, 16, 18, 20, and 22 post-injection in every treatment cycle to measure urinary bone resorption markers (n-terminal telopeptide [NTX] and deoxypyridinoline [DPD]), calcium and creatinine. Calcium supplementation was ended when urinary Ca\/Creatinine ratios reached age-specific thresholds. Denosumab effectively suppressed bone resorption within the first 2 mo post-injection. However, after 8 wk, uNTX and DPD levels re-increased again, reaching baseline levels after 3 mo, followed by a mild rebound after 4 mo. Average duration of Ca supplementation was 10 wk, two patients developed mild nephrocalcinosis. In conclusion, we saw that rebound of bone resorption emerges as early as 4 mo after denosumab injection. Continuous monitoring of calcium levels and careful handling of calcium supplementation is mandatory during therapy, but Ca-related side effects can still occur.<\/jats:p>","DOI":"10.1093\/jbmrpl\/ziaf140","type":"journal-article","created":{"date-parts":[[2025,8,25]],"date-time":"2025-08-25T11:22:07Z","timestamp":1756120927000},"source":"Crossref","is-referenced-by-count":3,"title":["Urinary calcium and bone resorption markers during 3\u00a0years of denosumab treatment in pediatric osteogenesis imperfecta"],"prefix":"10.1093","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-0195-9428","authenticated-orcid":false,"given":"Stefanie","family":"Stasek","sequence":"first","affiliation":[{"name":"Department of Pediatrics, Faculty of Medicine and University Hospital Cologne, University of Cologne , 50937 Cologne ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susanna","family":"Reincke","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Faculty of Medicine and University Hospital Cologne, University of Cologne , 50937 Cologne ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9534-4102","authenticated-orcid":false,"given":"Mirko","family":"Rehberg","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Faculty of Medicine and University Hospital Cologne, University of Cologne , 50937 Cologne ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0029-7556","authenticated-orcid":false,"given":"Oliver","family":"Semler","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Faculty of Medicine and University Hospital Cologne, University of Cologne , 50937 Cologne ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5297-3662","authenticated-orcid":false,"given":"Heike","family":"Hoyer-Kuhn","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Faculty of Medicine and University Hospital Cologne, University of Cologne , 50937 Cologne ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2025,9,1]]},"reference":[{"issue":"10028","key":"2025091916230915000_ref1","doi-asserted-by":"publisher","first-page":"1657","DOI":"10.1016\/S0140-6736(15)00728-X","article-title":"Osteogenesis imperfecta","volume":"387","author":"Forlino","year":"2016","journal-title":"Lancet"},{"issue":"6","key":"2025091916230915000_ref2","doi-asserted-by":"publisher","first-page":"891","DOI":"10.1007\/s00223-024-01266-5","article-title":"Update on the genetics of osteogenesis imperfecta","volume":"115","author":"Jovanovic","year":"2024","journal-title":"Calcif Tissue Int"},{"issue":"1","key":"2025091916230915000_ref3","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1038\/nrdp.2017.52","article-title":"Osteogenesis imperfecta","volume":"3","author":"Marini","year":"2017","journal-title":"Nat Rev Dis Primers"},{"issue":"3","key":"2025091916230915000_ref4","doi-asserted-by":"publisher","first-page":"573","DOI":"10.1542\/peds.111.3.573","article-title":"Intravenous bisphosphonate therapy in children with osteogenesis imperfecta","volume":"111","author":"Falk","year":"2003","journal-title":"Pediatrics"},{"issue":"1","key":"2025091916230915000_ref5","doi-asserted-by":"publisher","first-page":"26","DOI":"10.1159\/000381713","article-title":"Efficacy and safety of bisphosphonate therapy in children with osteogenesis imperfecta: a systematic review","volume":"84","author":"Rijks","year":"2015","journal-title":"Horm Res Paediatr"},{"issue":"6","key":"2025091916230915000_ref6","doi-asserted-by":"publisher","first-page":"e0197984","DOI":"10.1371\/journal.pone.0197984","article-title":"Pharmacokinetics, pharmacodynamics, safety, and tolerability of single-dose denosumab in healthy Chinese volunteers: a randomized, single-blind, placebo-controlled study","volume":"13","author":"Chen","year":"2018","journal-title":"PLoS One"},{"issue":"2","key":"2025091916230915000_ref7","doi-asserted-by":"publisher","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"},{"issue":"10","key":"2025091916230915000_ref8","doi-asserted-by":"publisher","first-page":"1075","DOI":"10.1056\/NEJMc062792","article-title":"Prolonged bisphosphonate release after treatment in children","volume":"356","author":"Papapoulos","year":"2007","journal-title":"N Engl J Med"},{"issue":"8","key":"2025091916230915000_ref9","doi-asserted-by":"publisher","first-page":"756","DOI":"10.1056\/NEJMoa0809493","article-title":"Denosumab for prevention of fractures in postmenopausal women with osteoporosis","volume":"361","author":"Cummings","year":"2009","journal-title":"N Engl J Med"},{"issue":"7","key":"2025091916230915000_ref10","doi-asserted-by":"publisher","first-page":"1462","DOI":"10.1002\/jbmr.1603","article-title":"Denosumab treatment for fibrous dysplasia","volume":"27","author":"Boyce","year":"2012","journal-title":"J Bone Miner Res"},{"issue":"8","key":"2025091916230915000_ref11","doi-asserted-by":"publisher","first-page":"745","DOI":"10.1056\/NEJMoa0809003","article-title":"Denosumab in men receiving androgen-deprivation therapy for prostate cancer","volume":"361","author":"Smith","year":"2009","journal-title":"N Engl J Med"},{"issue":"9","key":"2025091916230915000_ref12","doi-asserted-by":"publisher","first-page":"2290","DOI":"10.3390\/cancers14092290","article-title":"Denosumab in Giant cell tumor of bone: multidisciplinary medical management based on pathophysiological mechanisms and real-world evidence","volume":"14","author":"Borkowska","year":"2022","journal-title":"Cancers (Basel)"},{"issue":"6","key":"2025091916230915000_ref13","doi-asserted-by":"publisher","first-page":"1181","DOI":"10.1016\/j.otsr.2019.04.028","article-title":"Denosumab for treating aneurysmal bone cysts in children","volume":"105","author":"Raux","year":"2019","journal-title":"Orthop Traumatol Surg Res"},{"issue":"8","key":"2025091916230915000_ref14","doi-asserted-by":"publisher","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"},{"issue":"4","key":"2025091916230915000_ref15","doi-asserted-by":"publisher","first-page":"519","DOI":"10.1111\/scd.12588","article-title":"Successful denosumab treatment for central giant cell granuloma in a 9-year-old child","volume":"41","author":"Mariz","year":"2021","journal-title":"Spec Care Dentist"},{"issue":"3","key":"2025091916230915000_ref16","doi-asserted-by":"publisher","first-page":"638","DOI":"10.1016\/j.bone.2006.10.010","article-title":"Osteogenesis imperfecta type VI in childhood and adolescence: effects of cyclical intravenous pamidronate treatment","volume":"40","author":"Land","year":"2007","journal-title":"Bone"},{"issue":"1","key":"2025091916230915000_ref17","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"},{"issue":"1","key":"2025091916230915000_ref18","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"},{"issue":"1","key":"2025091916230915000_ref19","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 \u2013 follow up of a trial cohort","volume":"14","author":"Hoyer-Kuhn","year":"2019","journal-title":"Orphanet J Rare Dis"},{"issue":"7","key":"2025091916230915000_ref20","doi-asserted-by":"publisher","first-page":"1827","DOI":"10.1210\/clinem\/dgad732","article-title":"Safety and efficacy of denosumab in children with osteogenesis imperfecta\u2014the first prospective comparative study","volume":"109","author":"Liu","year":"2024","journal-title":"J Clin Endocrinol Metab"},{"issue":"1","key":"2025091916230915000_ref21","first-page":"24","article-title":"Safety and efficacy of denosumab in children with osteogenesis imperfect--a first prospective trial","volume":"16","author":"Hoyer-Kuhn","year":"2016","journal-title":"J Musculoskelet Neuronal Interact"},{"key":"2025091916230915000_ref22","article-title":"Safety, & pharmacokinetics of denosumab in children with OI. Identifier: NCT02352753","author":"Multicenter, Single-arm Study to Evaluate Efficacy"},{"issue":"2","key":"2025091916230915000_ref23","doi-asserted-by":"publisher","first-page":"190","DOI":"10.1002\/jbmr.3337","article-title":"Vertebral fractures after discontinuation of denosumab: a post hoc analysis of the randomized placebo-controlled FREEDOM trial and its extension","volume":"33","author":"Cummings","year":"2018","journal-title":"J Bone Miner Res"},{"key":"2025091916230915000_ref24","doi-asserted-by":"publisher","first-page":"100267","DOI":"10.1016\/j.bonr.2020.100267","article-title":"Rebound-associated vertebral fractures may occur in sequential time points following denosumab discontinuation: need for prompt treatment re-initiation","volume":"12","author":"Anastasilakis","year":"2020","journal-title":"Bone Rep"},{"key":"2025091916230915000_ref25","doi-asserted-by":"publisher","first-page":"101148","DOI":"10.1016\/j.bonr.2021.101148","article-title":"Hypercalcemia following discontinuation of denosumab therapy: a systematic review","volume":"15","author":"Horiuchi","year":"2021","journal-title":"Bone Rep"},{"issue":"2","key":"2025091916230915000_ref26","doi-asserted-by":"publisher","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"},{"issue":"3","key":"2025091916230915000_ref27","first-page":"476","article-title":"Marked diurnal variation in urinary excretion of pyridinium cross-links in premenopausal women","volume":"74","author":"Schlemmer","year":"1992","journal-title":"J Clin Endocrinol Metab"},{"issue":"3","key":"2025091916230915000_ref28","doi-asserted-by":"publisher","first-page":"730","DOI":"10.1210\/jcem.79.3.8077353","article-title":"The effect of calcium supplementation on the circadian rhythm of bone resorption","volume":"79","author":"Blumsohn","year":"1994","journal-title":"J Clin Endocrinol Metab"},{"issue":"3","key":"2025091916230915000_ref29","doi-asserted-by":"publisher","first-page":"403","DOI":"10.1007\/s00467-008-1073-x","article-title":"Diagnostic examination of the child with urolithiasis or nephrocalcinosis","volume":"25","author":"Hoppe","year":"2010","journal-title":"Pediatr Nephrol"},{"issue":"6","key":"2025091916230915000_ref30","doi-asserted-by":"publisher","first-page":"561","DOI":"10.1016\/j.clinbiochem.2005.11.015","article-title":"Pediatric reference intervals for bone markers","volume":"39","author":"Yang","year":"2006","journal-title":"Clin Biochem"},{"key":"2025091916230915000_ref31","doi-asserted-by":"publisher","DOI":"10.1055\/b-003-106490","volume-title":"Ultraschalldiagnostik in P\u00e4diatrie Und Kinderchirurgie","author":"Deeg","year":"2014"},{"issue":"2","key":"2025091916230915000_ref32","doi-asserted-by":"publisher","first-page":"394","DOI":"10.1210\/jc.2010-1805","article-title":"Effect of denosumab on bone mineral density and biochemical markers of bone turnover: six-year results of a phase 2 clinical trial","volume":"96","author":"Miller","year":"2011","journal-title":"J Clin Endocrinol Metab"},{"issue":"6","key":"2025091916230915000_ref33","doi-asserted-by":"publisher","first-page":"505","DOI":"10.1007\/s11914-022-00756-5","article-title":"Osteoclast recycling and the rebound phenomenon following denosumab discontinuation","volume":"20","author":"Kim","year":"2022","journal-title":"Curr Osteoporos Rep"},{"issue":"7","key":"2025091916230915000_ref34","doi-asserted-by":"publisher","first-page":"1873","DOI":"10.1210\/clinem\/dgae012","article-title":"Efficacy and safety of denosumab vs zoledronic acid in OI adults: a prospective, open-label, randomized study","volume":"109","author":"Lin","year":"2024","journal-title":"J Clin Endocrinol Metab"},{"issue":"3","key":"2025091916230915000_ref35","first-page":"183","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"},{"issue":"1","key":"2025091916230915000_ref36","doi-asserted-by":"publisher","first-page":"121","DOI":"10.1146\/annurev-pathol-011110-130203","article-title":"Disorders of bone remodeling","volume":"6","author":"Feng","year":"2011","journal-title":"Ann Rev Pathol"},{"issue":"5","key":"2025091916230915000_ref37","doi-asserted-by":"publisher","first-page":"457","DOI":"10.1056\/NEJMoa023110","article-title":"Bisphosphonate-induced osteopetrosis","volume":"349","author":"Whyte","year":"2003","journal-title":"N Engl J Med"}],"container-title":["JBMR Plus"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/jbmrplus\/advance-article-pdf\/doi\/10.1093\/jbmrpl\/ziaf140\/64170470\/ziaf140.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jbmrplus\/article-pdf\/9\/10\/ziaf140\/64170470\/ziaf140.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jbmrplus\/article-pdf\/9\/10\/ziaf140\/64170470\/ziaf140.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,9,19]],"date-time":"2025-09-19T20:23:16Z","timestamp":1758313396000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jbmrplus\/article\/doi\/10.1093\/jbmrpl\/ziaf140\/8245067"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,9,1]]},"references-count":37,"journal-issue":{"issue":"10","published-print":{"date-parts":[[2025,9,3]]}},"URL":"https:\/\/doi.org\/10.1093\/jbmrpl\/ziaf140","relation":{},"ISSN":["2473-4039"],"issn-type":[{"value":"2473-4039","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2025,10]]},"published":{"date-parts":[[2025,9,1]]},"article-number":"ziaf140"}}