{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,29]],"date-time":"2026-10-29T08:27:46Z","timestamp":1793262466463,"version":"4.5.0"},"reference-count":29,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2025,12,1]],"date-time":"2025-12-01T00:00:00Z","timestamp":1764547200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.springernature.com\/gp\/researchers\/text-and-data-mining"},{"start":{"date-parts":[[2025,12,1]],"date-time":"2025-12-01T00:00:00Z","timestamp":1764547200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.springernature.com\/gp\/researchers\/text-and-data-mining"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Calcif Tissue Int"],"DOI":"10.1007\/s00223-025-01449-8","type":"journal-article","created":{"date-parts":[[2025,12,1]],"date-time":"2025-12-01T16:10:30Z","timestamp":1764605430000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Efficacy and Safety of Oral Meclizine for Growth Promotion in Children with Achondroplasia: A Phase 2 Clinical Trial"],"prefix":"10.1007","volume":"116","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4540-1556","authenticated-orcid":false,"given":"Masaki","family":"Matsushita","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroshi","family":"Kitoh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takuo","family":"Kubota","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keita","family":"Okada","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenichi","family":"Mishima","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenta","family":"Sawamura","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Taichi","family":"Kitaoka","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Makoto","family":"Fujiwara","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuichi","family":"Kato","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuri","family":"Amano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kazuki","family":"Nishida","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shiro","family":"Imagama","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,12,1]]},"reference":[{"key":"1449_CR1","doi-asserted-by":"publisher","first-page":"335","DOI":"10.1016\/0092-8674(94)90302-6","volume":"78","author":"R Shiang","year":"1994","unstructured":"Shiang R, Thompson LM, Zhu YZ, Church DM, Fielder TJ, Bocian M, Winokur ST, Wasmuth JJ (1994) Mutations in the transmembrane domain of FGFR3 cause the most common genetic form of dwarfism, achondroplasia. Cell 78:335\u2013342","journal-title":"Cell"},{"key":"1449_CR2","doi-asserted-by":"publisher","first-page":"252","DOI":"10.1038\/371252a0","volume":"371","author":"F Rousseau","year":"1994","unstructured":"Rousseau F, Bonaventure J, Legeai-Mallet L, Pelet A, Rozet JM, Maroteaux P, Le Merrer M, Munnich A (1994) Mutations in the gene encoding fibroblast growth factor receptor-3 in achondroplasia. Nature 371:252\u2013254","journal-title":"Nature"},{"key":"1449_CR3","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1186\/s13023-018-0972-6","volume":"14","author":"RM Pauli","year":"2019","unstructured":"Pauli RM (2019) Achondroplasia: a comprehensive clinical review. Orphanet J Rare Dis 14:1","journal-title":"Orphanet J Rare Dis"},{"key":"1449_CR4","doi-asserted-by":"publisher","first-page":"181","DOI":"10.3109\/17453674.2014.899856","volume":"85","author":"SJ Kim","year":"2014","unstructured":"Kim SJ, Pierce W, Sabharwal S (2014) The etiology of short stature affects the clinical outcome of lower limb lengthening using external fixation. A systematic review of 18 trials involving 547 patients. Acta Orthop 85:181\u2013186","journal-title":"Acta Orthop"},{"key":"1449_CR5","doi-asserted-by":"publisher","first-page":"257","DOI":"10.1007\/s12306-018-0583-3","volume":"103","author":"I Ginebreda","year":"2019","unstructured":"Ginebreda I, Campillo-Recio D, C\u00e1rdenas C, Tapiolas J, Rovira P, Isart A (2019) Surgical technique and outcomes for bilateral humeral lengthening for achondroplasia: 26-year experience. Musculoskelet Surg 103:257\u2013262","journal-title":"Musculoskelet Surg"},{"key":"1449_CR6","doi-asserted-by":"publisher","first-page":"419","DOI":"10.1007\/s00264-017-3632-x","volume":"42","author":"M Shadi","year":"2018","unstructured":"Shadi M, Musielak B, Koczewski P, Janusz P (2018) Humeral lengthening in patients with achondroplasia and in patients with post-septic shortening: comparison of procedure efficiency and safety. Int Orthop 42:419\u2013426","journal-title":"Int Orthop"},{"key":"1449_CR7","doi-asserted-by":"publisher","DOI":"10.3390\/children8070540","author":"D Paley","year":"2021","unstructured":"Paley D (2021) Extensive limb lengthening for achondroplasia and hypochondroplasia. Children (Basel). https:\/\/doi.org\/10.3390\/children8070540","journal-title":"Children (Basel)"},{"key":"1449_CR8","doi-asserted-by":"publisher","first-page":"1269","DOI":"10.1302\/0301-620X.96B9.33840","volume":"96-B","author":"H Kitoh","year":"2014","unstructured":"Kitoh H, Mishima K, Matsushita M, Nishida Y, Ishiguro N (2014) Early and late fracture following extensive limb lengthening in patients with achondroplasia and hypochondroplasia. Bone Joint J 96-B:1269\u20131273","journal-title":"Bone Joint J"},{"key":"1449_CR9","doi-asserted-by":"publisher","first-page":"268","DOI":"10.1177\/2192568221994786","volume":"13","author":"K Shafi","year":"2023","unstructured":"Shafi K, Lovecchio F, Sava M, Steinhaus M, Samuel A, Carter E, Lebl D, Farmer J, Raggio C (2023) Complications and revisions after spine surgery in patients with skeletal dysplasia: have we improved? Glob Spine J 13:268\u2013275","journal-title":"Glob Spine J"},{"key":"1449_CR10","doi-asserted-by":"publisher","first-page":"227","DOI":"10.1093\/hmg\/ddn339","volume":"18","author":"T Matsushita","year":"2009","unstructured":"Matsushita T, Wilcox WR, Chan YY, Kawanami A, Bukulmez H, Balmes G, Krejci P, Mekikian PB, Otani K, Yamaura I, Warman ML, Givol D, Murakami S (2009) FGFR3 promotes synchondrosis closure and fusion of ossification centers through the MAPK pathway. Hum Mol Genet 18:227\u2013240","journal-title":"Hum Mol Genet"},{"key":"1449_CR11","doi-asserted-by":"publisher","first-page":"873","DOI":"10.1007\/s00431-017-2923-y","volume":"176","author":"D Harada","year":"2017","unstructured":"Harada D, Namba N, Hanioka Y, Ueyama K, Sakamoto N, Nakano Y, Izui M, Nagamatsu Y, Kashiwagi H, Yamamuro M, Ishiura Y, Ogitani A, Seino Y (2017) Final adult height in long-term growth hormone-treated achondroplasia patients. Eur J Pediatr 176:873\u2013879","journal-title":"Eur J Pediatr"},{"issue":"1","key":"1449_CR12","doi-asserted-by":"publisher","first-page":"25","DOI":"10.1056\/NEJMoa1813446","volume":"381","author":"R Savarirayan","year":"2019","unstructured":"Savarirayan R, Irving M, Bacino CA, Bostwick B, Charrow J, Cormier-Daire V, Le Quan Sang KH, Dickson P, Harmatz P, Phillips J, Owen N, Cherukuri A, Jayaram K, Jeha GS, Larimore K, Chan ML, Huntsman Labed A, Day J, Hoover-Fong J (2019) C-type natriuretic peptide analogue therapy in children with achondroplasia. N Engl J Med 381(1):25\u201335. https:\/\/doi.org\/10.1056\/NEJMoa1813446","journal-title":"N Engl J Med"},{"key":"1449_CR13","doi-asserted-by":"publisher","first-page":"684","DOI":"10.1016\/S0140-6736(20)31541-5","volume":"396","author":"R Savarirayan","year":"2020","unstructured":"Savarirayan R, Tofts L, Irving M, Wilcox W, Bacino CA, Hoover-Fong J, Ullot Font R, Harmatz P, Rutsch F, Bober MB, Polgreen LE, Ginebreda I, Mohnike K, Charrow J, Hoernschemeyer D, Ozono K, Alanay Y, Arundel P, Kagami S, Yasui N, White KK, Saal HM, Leiva-Gea A, Luna-Gonz\u00e1lez F, Mochizuki H, Basel D, Porco DM, Jayaram K, Fisheleva E, Huntsman-Labed A, Day J (2020) Once-daily, subcutaneous vosoritide therapy in children with achondroplasia: a randomised, double-blind, phase 3, placebo-controlled, multicentre trial. Lancet 396:684\u2013692","journal-title":"Lancet"},{"key":"1449_CR14","doi-asserted-by":"publisher","first-page":"865","DOI":"10.1056\/NEJMoa2411790","volume":"392","author":"R Savarirayan","year":"2025","unstructured":"Savarirayan R, De Bergua JM, Arundel P, Salles JP, Saraff V, Delgado B, Leiva-Gea A, McDevitt H, Nicolino M, Rossi M, Salcedo M, Cormier-Daire V, Skae M, Kannu P, Phillips J, Saal H, Harmatz P, Candler T, Hill D, Muslimova E, Weng R, Bai Y, Raj S, Hoover-Fong J, Irving M, Rogoff D (2025) Oral infigratinib therapy in children with achondroplasia. N Engl J Med 392:865\u2013874","journal-title":"N Engl J Med"},{"key":"1449_CR15","doi-asserted-by":"publisher","first-page":"e81569","DOI":"10.1371\/journal.pone.0081569","volume":"8","author":"M Matsushita","year":"2013","unstructured":"Matsushita M, Kitoh H, Ohkawara B, Mishima K, Kaneko H, Ito M, Masuda A, Ishiguro N, Ohno K (2013) Meclozine facilitates proliferation and differentiation of chondrocytes by attenuating abnormally activated FGFR3 signaling in achondroplasia. PLoS ONE 8:e81569","journal-title":"PLoS ONE"},{"key":"1449_CR16","doi-asserted-by":"publisher","first-page":"694018","DOI":"10.3389\/fcell.2021.694018","volume":"9","author":"G Takemoto","year":"2021","unstructured":"Takemoto G, Matsushita M, Okamoto T, Ito T, Matsuura Y, Takashima C, Chen-Yoshikawa TF, Ebi H, Imagama S, Kitoh H, Ohno K, Hosono Y (2021) Meclozine attenuates the MARK pathway in mammalian chondrocytes and ameliorates FGF2-induced bone hyperossification in larval zebrafish. Front Cell Dev Biol 9:694018","journal-title":"Front Cell Dev Biol"},{"key":"1449_CR17","doi-asserted-by":"publisher","first-page":"7371","DOI":"10.1038\/s41598-017-07044-8","volume":"7","author":"M Matsushita","year":"2017","unstructured":"Matsushita M, Esaki R, Mishima K, Ishiguro N, Ohno K, Kitoh H (2017) Clinical dosage of meclozine promotes longitudinal bone growth, bone volume, and trabecular bone quality in transgenic mice with achondroplasia. Sci Rep 7:7371","journal-title":"Sci Rep"},{"key":"1449_CR18","doi-asserted-by":"publisher","first-page":"ziae018","DOI":"10.1093\/jbmrpl\/ziae018","volume":"8","author":"H Funahashi","year":"2024","unstructured":"Funahashi H, Matsushita M, Esaki R, Mishima K, Ohkawara B, Kamiya Y, Takegami Y, Ohno K, Kitoh H, Imagama S (2024) Long-term oral meclozine administration improves survival rate and spinal canal stenosis during postnatal growth in a mouse model of achondroplasia in both sexes. JBMR Plus 8:ziae018","journal-title":"JBMR Plus"},{"key":"1449_CR19","doi-asserted-by":"publisher","first-page":"e0229639","DOI":"10.1371\/journal.pone.0229639","volume":"15","author":"H Kitoh","year":"2020","unstructured":"Kitoh H, Matsushita M, Mishima K, Nagata T, Kamiya Y, Ueda K, Kuwatsuka Y, Morikawa H, Nakai Y, Ishiguro N (2020) Pharmacokinetics and safety after once and twice a day doses of meclizine hydrochloride administered to children with achondroplasia. PLoS ONE 15:e0229639","journal-title":"PLoS ONE"},{"key":"1449_CR20","doi-asserted-by":"publisher","first-page":"e0283425","DOI":"10.1371\/journal.pone.0283425","volume":"18","author":"M Matsushita","year":"2023","unstructured":"Matsushita M, Kitoh H, Mishima K, Kamiya Y, Kato D, Takemoto G, Sawamura K, Ueno S, Yasuhiro N, Nishida K, Imagama S (2023) Phase 1b study on the repurposing of meclizine hydrochloride for children with achondroplasia. PLoS ONE 18:e0283425","journal-title":"PLoS ONE"},{"key":"1449_CR21","doi-asserted-by":"publisher","first-page":"71","DOI":"10.1297\/cpe.25.71","volume":"25","author":"T Isojima","year":"2016","unstructured":"Isojima T, Kato N, Ito Y, Kanzaki S, Murata M (2016) Growth standard charts for Japanese children with mean and standard deviation (SD) values based on the year 2000 national survey. Clin Pediatr Endocrinol 25:71\u201376","journal-title":"Clin Pediatr Endocrinol"},{"key":"1449_CR22","doi-asserted-by":"publisher","first-page":"1226","DOI":"10.1002\/ajmg.a.38150","volume":"173","author":"J Hoover-Fong","year":"2017","unstructured":"Hoover-Fong J, McGready J, Schulze K, Alade AY, Scott CI (2017) A height-for-age growth reference for children with achondroplasia: expanded applications and comparison with original reference data. Am J Med Genet A 173:1226\u20131230","journal-title":"Am J Med Genet A"},{"key":"1449_CR23","doi-asserted-by":"publisher","first-page":"3160","DOI":"10.1210\/jc.2011-1111","volume":"96","author":"BS Zemel","year":"2011","unstructured":"Zemel BS, Kalkwarf HJ, Gilsanz V, Lappe JM, Oberfield S, Shepherd JA, Frederick MM, Huang X, Lu M, Mahboubi S, Hangartner T, Winer KK (2011) Revised reference curves for bone mineral content and areal bone mineral density according to age and sex for black and non-black children: results of the bone mineral density in childhood study. J Clin Endocrinol Metab 96:3160\u20133169","journal-title":"J Clin Endocrinol Metab"},{"key":"1449_CR24","doi-asserted-by":"publisher","first-page":"e70051","DOI":"10.1002\/ajhb.70051","volume":"37","author":"Y Hirano","year":"2025","unstructured":"Hirano Y, Inokuchi M, Narumi S, Hasegawa T (2025) Reference values of arm span and arm span to height ratio of Japanese population in childhood and adolescence: comparison with Dutch and Turkish population. Am J Hum Biol 37:e70051","journal-title":"Am J Hum Biol"},{"key":"1449_CR25","doi-asserted-by":"publisher","first-page":"593","DOI":"10.1007\/s00228-016-2012-6","volume":"72","author":"K Heitmann","year":"2016","unstructured":"Heitmann K, Solheimsnes A, Havnen GC, Nordeng H, Holst L (2016) Treatment of nausea and vomiting during pregnancy -a cross-sectional study among 712 Norwegian women. Eur J Clin Pharmacol 72:593\u2013604","journal-title":"Eur J Clin Pharmacol"},{"key":"1449_CR26","doi-asserted-by":"publisher","first-page":"30","DOI":"10.1080\/02813432.2019.1569424","volume":"37","author":"GC Havnen","year":"2019","unstructured":"Havnen GC, Truong MB, Do MH, Heitmann K, Holst L, Nordeng H (2019) Women\u2019s perspectives on the management and consequences of hyperemesis gravidarum - a descriptive interview study. Scand J Prim Health Care 37:30\u201340","journal-title":"Scand J Prim Health Care"},{"key":"1449_CR27","doi-asserted-by":"publisher","first-page":"553","DOI":"10.1016\/0002-9378(65)90515-6","volume":"93","author":"J Yerushalmy","year":"1965","unstructured":"Yerushalmy J, Milkovich L (1965) Evaluation of the teratogenic effect of meclizine in man. Am J Obstet Gynecol 93:553\u2013562","journal-title":"Am J Obstet Gynecol"},{"key":"1449_CR28","doi-asserted-by":"publisher","first-page":"899","DOI":"10.1007\/s00228-005-0055-1","volume":"61","author":"C Asker","year":"2005","unstructured":"Asker C, Norstedt Wikner B, Kallen B (2005) Use of antiemetic drugs during pregnancy in Sweden. Eur J Clin Pharmacol 61:899\u2013906","journal-title":"Eur J Clin Pharmacol"},{"key":"1449_CR29","doi-asserted-by":"publisher","first-page":"359","DOI":"10.1097\/00004703-198812000-00008","volume":"9","author":"JE Fagan","year":"1988","unstructured":"Fagan JE, Kaplan BJ, Raymond JE, Edgington ES (1988) The failure of antimotion sickness medication to improve reading in developmental dyslexia: results of a randomized trial. J Dev Behav Pediatr 9:359\u2013366","journal-title":"J Dev Behav Pediatr"}],"updated-by":[{"DOI":"10.1007\/s00223-026-01528-4","type":"correction","label":"Correction","source":"publisher","updated":{"date-parts":[[2026,5,13]],"date-time":"2026-05-13T00:00:00Z","timestamp":1778630400000}}],"container-title":["Calcified Tissue International"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00223-025-01449-8.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s00223-025-01449-8","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00223-025-01449-8.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,13]],"date-time":"2026-05-13T05:44:15Z","timestamp":1778651055000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s00223-025-01449-8"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,12,1]]},"references-count":29,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2025,12]]}},"alternative-id":["1449"],"URL":"https:\/\/doi.org\/10.1007\/s00223-025-01449-8","relation":{},"ISSN":["1432-0827"],"issn-type":[{"value":"1432-0827","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,12,1]]},"assertion":[{"value":"28 July 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"1 November 2025","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"1 December 2025","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"14 May 2026","order":5,"name":"change_date","label":"Change Date","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"Update","order":6,"name":"change_type","label":"Change Type","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"Figures 1and 2 have been corrected","order":7,"name":"change_details","label":"Change Details","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"13 May 2026","order":8,"name":"change_date","label":"Change Date","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"Correction","order":9,"name":"change_type","label":"Change Type","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"A Correction to this paper has been published:","order":10,"name":"change_details","label":"Change Details","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"https:\/\/doi.org\/10.1007\/s00223-026-01528-4","URL":"https:\/\/doi.org\/10.1007\/s00223-026-01528-4","order":11,"name":"change_details","label":"Change Details","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"Matsushita M reports lecture fees, brochure production, and travel expenses from BioMarin; Kitoh H reports lecture fees, brochure production and travel expenses from BioMarin, and lecture fees and travel expenses from Kyowa Kirin; Kubota T reports fees for research grants from BioMarin and Kyowa Kirin, consulting fees from Kyowa Kirin and Teijin Pharma, lecture fees from BioMarin, Kyowa Kirin, and Novo Nordisk, and Travel expenses from BioMarin and Kyowa Kirin; Okada K reports lecture fees and brochure production from BioMarin, lecture fees from Alexion Pharmaceuticals, and travel expenses from BioMarin; Kitaoka T reports lecture fees and travel expenses from BioBarin. Mishima K, Sawamura K, Fujiwara M, Kato Y, Amano Y, Nishida K, and Imagama S declare that they have no conflict of interest.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}},{"value":"The Institutional Review Boards of Nagoya University Hospital, Aichi Children\u2019s Health and Medical Center, the University of Osaka Hospital, and the University of Tokyo Hospital have approved the study protocol and all subsequent amendments. This study has been registered with the Japan Registry of Clinical Trials (ID: jRCT2041230001) (\n                      \n                      ).","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethical Approval"}},{"value":"No animals were involved in the study. Legal guardians provided written informed consent for all participants. Participants aged\u2009>\u20096\u00a0years old signed an assent form prior to study initiation.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Human and Animal Rights and Informed Consent"}}],"article-number":"143"}}