{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T11:04:22Z","timestamp":1790075062688,"version":"4.0.1"},"reference-count":36,"publisher":"Oxford University Press (OUP)","issue":"10","license":[{"start":{"date-parts":[[2024,1,27]],"date-time":"2024-01-27T00:00:00Z","timestamp":1706313600000},"content-version":"vor","delay-in-days":1152,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2022,8,17]],"date-time":"2022-08-17T00:00:00Z","timestamp":1660694400000},"content-version":"vor","delay-in-days":624,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Clementia Pharmaceuticals, Ipsen"}],"content-domain":{"domain":["asbmr.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2020,12,1]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>Fibrodysplasia ossificans progressiva (FOP) is an ultra-rare genetic disorder characterized by progressive heterotopic ossification (HO), often heralded by flare-ups, leading to reduced movement and life expectancy. This placebo-controlled, double-blind trial (NCT02190747) evaluated palovarotene, an orally bioavailable selective retinoic acid receptor gamma agonist, for prevention of HO in patients with FOP. Patients experiencing a flare-up were enrolled in two cohorts: (1) patients \u226515\u2009years were randomized 3:1 to palovarotene 10\/5\u2009mg (weeks 1\u20132\/3\u20136) or placebo; (2) patients \u22656\u2009years were randomized 3:3:2 to palovarotene 10\/5\u2009mg, palovarotene 5\/2.5\u2009mg (weeks 1\u20132\/3\u20136), or placebo. Cohort data were pooled. The primary endpoint was the proportion of responders (no\/minimal new HO at flare-up body region by plain radiograph) at week 6. Change from baseline in HO volume and new HO incidence were assessed by computed tomography (CT) at week 12. Tissue edema was assessed by magnetic resonance imaging (MRI) or ultrasound. Forty patients (aged 7\u201353\u2009years) were enrolled (placebo: n\u00a0=\u200910; palovarotene 5\/2.5\u2009mg: n\u00a0=\u20099; palovarotene 10\/5\u2009mg: n\u00a0=\u200921). Disease history was similar between groups. In the per-protocol population, the proportion of responders at week 6 by plain radiograph was 100% with palovarotene 10\/5\u2009mg; 88.9% with palovarotene 5\/2.5\u2009mg; 88.9% with placebo (Cochran-Armitage trend test: p\u00a0=\u20090.17). At week 12, the proportions were 95.0% with palovarotene 10\/5\u2009mg; 88.9% with palovarotene 5\/2.5\u2009mg; 77.8% with placebo (Cochran-Armitage trend test: p\u00a0=\u20090.15). Week 12 least-squares mean (LSmean) new HO volume, assessed by CT, was 3.8\u2009\u00d7\u2009103\u00a0mm3 with palovarotene 10\/5\u2009mg; 1.3\u2009\u00d7\u2009103\u00a0mm3 with palovarotene 5\/2.5\u2009mg; 18.0\u2009\u00d7\u2009103\u00a0mm3 with placebo (pairwise tests versus placebo: p\u00a0\u2264 0.12). Palovarotene was well-tolerated. No patients discontinued treatment or required dose reduction; one patient had dose interruption due to elevated lipase. Although these findings were not statistically significant, they support further evaluation of palovarotene for prevention of HO in FOP in larger studies. \u00a9 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).<\/jats:p>","DOI":"10.1002\/jbmr.4655","type":"journal-article","created":{"date-parts":[[2022,7,20]],"date-time":"2022-07-20T01:14:01Z","timestamp":1658279641000},"page":"1891-1902","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":48,"title":["Palovarotene for Fibrodysplasia Ossificans Progressiva (FOP): Results of a Randomized, Placebo-Controlled, Double-Blind Phase 2 Trial"],"prefix":"10.1093","volume":"37","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8533-9438","authenticated-orcid":false,"given":"Robert J.","family":"Pignolo","sequence":"first","affiliation":[{"name":"Department of Medicine, Divisions of Geriatric Medicine and Gerontology, Hospital Internal Medicine, and Endocrinology, Robert and Arlene Kogod Center on Aging Mayo Clinic Rochester MN USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Genevi\u00e8ve","family":"Baujat","sequence":"additional","affiliation":[{"name":"Departement de Genetique Institut IMAGINE and H\u00f4pital Necker-Enfants Malades Paris France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edward C.","family":"Hsiao","sequence":"additional","affiliation":[{"name":"Division of Endocrinology and Metabolism, UCSF Metabolic Bone Clinic, Institute for Human Genetics, Institute for Regeneration Medicine, and the Program for Craniofacial Biology University of California-San Francisco San Francisco CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard","family":"Keen","sequence":"additional","affiliation":[{"name":"Consultant Rheumatologist & Honorary Senior Lecturer in Metabolic Bone Disease The Royal National Orthopaedic Hospital Stanmore UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amy","family":"Wilson","sequence":"additional","affiliation":[{"name":"Ipsen Newton MA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeff","family":"Packman","sequence":"additional","affiliation":[{"name":"Ipsen Newton MA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew L.","family":"Strahs","sequence":"additional","affiliation":[{"name":"Ipsen Newton MA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Donna R.","family":"Grogan","sequence":"additional","affiliation":[{"name":"Ipsen Newton MA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frederick S.","family":"Kaplan","sequence":"additional","affiliation":[{"name":"Departments of Orthopaedic Surgery and Medicine, and The Center for Research in FOP and Related Disorders, Perelman School of Medicine University of Pennsylvania Philadelphia PA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2022,7,19]]},"reference":[{"key":"2024012714051995400_jbmr4655-bib-0001","doi-asserted-by":"crossref","first-page":"31","DOI":"10.29245\/2572-9411\/2020\/2.1196","article-title":"Epidemiology of the global fibrodysplasia ossificans progressiva (FOP) community","volume":"5","author":"Liljesthr\u00f6m","year":"2020","journal-title":"J Rare Dis Res Treat"},{"issue":"Suppl 2","key":"2024012714051995400_jbmr4655-bib-0002","first-page":"437","article-title":"Fibrodysplasia ossificans progressiva: diagnosis, management, and therapeutic horizons","volume":"10","author":"Pignolo","year":"2013","journal-title":"Pediatr Endocrinol Rev"},{"issue":"6","key":"2024012714051995400_jbmr4655-bib-0003","doi-asserted-by":"crossref","first-page":"489","DOI":"10.1007\/s11832-015-0704-6","article-title":"Quality of life of patients with fibrodysplasia ossificans progressiva","volume":"9","author":"Ortiz-Agapito","year":"2015","journal-title":"J Child Orthop"},{"issue":"1","key":"2024012714051995400_jbmr4655-bib-0004","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1302\/0301-620X.64B1.7068725","article-title":"Fibrodysplasia ossificans progressiva. The clinical features and natural history of 34 patients","volume":"64","author":"Connor","year":"1982","journal-title":"J Bone Joint Surg Br"},{"issue":"3","key":"2024012714051995400_jbmr4655-bib-0005","doi-asserted-by":"crossref","first-page":"686","DOI":"10.2106\/JBJS.I.00705","article-title":"Early mortality and cardiorespiratory failure in patients with fibrodysplasia ossificans progressiva","volume":"92","author":"Kaplan","year":"2010","journal-title":"J Bone Joint Surg Am"},{"issue":"5","key":"2024012714051995400_jbmr4655-bib-0006","doi-asserted-by":"crossref","first-page":"525","DOI":"10.1038\/ng1783","article-title":"A recurrent mutation in the BMP type I receptor ACVR1 causes inherited and sporadic fibrodysplasia ossificans progressiva","volume":"38","author":"Shore","year":"2006","journal-title":"Nat Genet"},{"issue":"2","key":"2024012714051995400_jbmr4655-bib-0007","doi-asserted-by":"crossref","first-page":"386","DOI":"10.1016\/j.bone.2013.09.002","article-title":"The phenotype and genotype of fibrodysplasia ossificans progressiva in China: a report of 72 cases","volume":"57","author":"Zhang","year":"2013","journal-title":"Bone"},{"issue":"5","key":"2024012714051995400_jbmr4655-bib-0008","doi-asserted-by":"crossref","first-page":"705","DOI":"10.1517\/14712598.7.5.705","article-title":"A new era for fibrodysplasia ossificans progressiva: a druggable target for the second skeleton","volume":"7","author":"Kaplan","year":"2007","journal-title":"Expert Opin Biol Ther"},{"key":"2024012714051995400_jbmr4655-bib-0009","first-page":"1","article-title":"The medical management of fibrodysplasia ossificans progressiva: current treatment considerations","volume":"1","author":"Kaplan","year":"2019","journal-title":"Proceedings of the International Clinical Council (ICC) on Fibrodysplasia Ossificans Progressiva (FOP)"},{"issue":"2","key":"2024012714051995400_jbmr4655-bib-0010","doi-asserted-by":"crossref","first-page":"220","DOI":"10.2106\/00004623-199302000-00009","article-title":"The histopathology of fibrodysplasia ossificans progressiva. An endochondral process","volume":"75","author":"Kaplan","year":"1993","journal-title":"J Bone Joint Surg Am"},{"issue":"2","key":"2024012714051995400_jbmr4655-bib-0011","doi-asserted-by":"crossref","first-page":"469","DOI":"10.1016\/0014-4827(80)90517-0","article-title":"Vitamin A inhibits chondrogenesis but not myogenesis","volume":"129","author":"Pacifici","year":"1980","journal-title":"Exp Cell Res"},{"issue":"4","key":"2024012714051995400_jbmr4655-bib-0012","doi-asserted-by":"crossref","first-page":"454","DOI":"10.1038\/nm.2334","article-title":"Potent inhibition of heterotopic ossification by nuclear retinoic acid receptor-gamma agonists","volume":"17","author":"Shimono","year":"2011","journal-title":"Nat Med"},{"issue":"1","key":"2024012714051995400_jbmr4655-bib-0013","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1083\/jcb.200112029","article-title":"Requirement for RAR-mediated gene repression in skeletal progenitor differentiation","volume":"158","author":"Weston","year":"2002","journal-title":"J Cell Biol"},{"issue":"11","key":"2024012714051995400_jbmr4655-bib-0014","first-page":"1243","article-title":"Palovarotene, a novel retinoic acid receptor gamma agonist for the treatment of emphysema","volume":"10","author":"Hind","year":"2009","journal-title":"Curr Opin Investig Drugs"},{"issue":"9","key":"2024012714051995400_jbmr4655-bib-0015","doi-asserted-by":"crossref","first-page":"1666","DOI":"10.1002\/jbmr.2820","article-title":"Palovarotene inhibits heterotopic ossification and maintains limb mobility and growth in mice with the human ACVR1(R206H) fibrodysplasia ossificans progressiva (FOP) mutation","volume":"31","author":"Chakkalakal","year":"2016","journal-title":"J Bone Miner Res"},{"key":"2024012714051995400_jbmr4655-bib-0016","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1016\/j.bone.2017.09.016","article-title":"Cartilage-derived retinoic acid-sensitive protein (CD-RAP): a stage-specific biomarker of heterotopic endochondral ossification (HEO) in fibrodysplasia ossificans progressiva (FOP)","volume":"109","author":"Lindborg","year":"2018","journal-title":"Bone"},{"issue":"3","key":"2024012714051995400_jbmr4655-bib-0017","doi-asserted-by":"crossref","first-page":"650","DOI":"10.1002\/jbmr.2728","article-title":"The natural history of flare-ups in fibrodysplasia ossificans progressiva (FOP): a comprehensive global assessment","volume":"31","author":"Pignolo","year":"2016","journal-title":"J Bone Miner Res"},{"issue":"3","key":"2024012714051995400_jbmr4655-bib-0018","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1016\/j.acra.2016.10.010","article-title":"Analog method for radiographic assessment of heterotopic bone in fibrodysplasia ossificans progressiva","volume":"24","author":"Rajapakse","year":"2017","journal-title":"Acad Radiol"},{"issue":"2","key":"2024012714051995400_jbmr4655-bib-0019","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1016\/S0304-3959(01)00314-1","article-title":"The faces pain scale-revised: toward a common metric in pediatric pain measurement","volume":"93","author":"Hicks","year":"2001","journal-title":"Pain"},{"issue":"3","key":"2024012714051995400_jbmr4655-bib-0020","doi-asserted-by":"crossref","first-page":"A165","DOI":"10.1016\/j.jval.2015.03.954","article-title":"Patient-reported physical function outcome measure for adults with fibrodysplasia ossificans progressiva: intelligent test design based on PROMIS item banks","volume":"18","author":"Mattera","year":"2015","journal-title":"Value Health"},{"key":"2024012714051995400_jbmr4655-bib-0021","author":"Pignolo","year":"2020"},{"issue":"1","key":"2024012714051995400_jbmr4655-bib-0022","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1186\/s13023-019-1068-7","article-title":"Natural history of fibrodysplasia ossificans progressiva: cross-sectional analysis of annotated baseline phenotypes","volume":"14","author":"Pignolo","year":"2019","journal-title":"Orphanet J Rare Dis"},{"issue":"4","key":"2024012714051995400_jbmr4655-bib-0023","doi-asserted-by":"crossref","first-page":"1221","DOI":"10.1007\/s11136-013-0581-8","article-title":"Development of the PROMIS((R)) pediatric global health (PGH-7) measure","volume":"23","author":"Forrest","year":"2014","journal-title":"Qual Life Res"},{"issue":"7","key":"2024012714051995400_jbmr4655-bib-0024","doi-asserted-by":"crossref","first-page":"873","DOI":"10.1007\/s11136-009-9496-9","article-title":"Development of physical and mental health summary scores from the Patient-Reported Outcomes Measurement Information System (PROMIS) global items","volume":"18","author":"Hays","year":"2009","journal-title":"Qual Life Res"},{"issue":"12","key":"2024012714051995400_jbmr4655-bib-0025","doi-asserted-by":"crossref","first-page":"1266","DOI":"10.1176\/appi.ajp.2011.10111704","article-title":"The Columbia-Suicide Severity Rating Scale: initial validity and internal consistency findings from three multisite studies with adolescents and adults","volume":"168","author":"Posner","year":"2011","journal-title":"Am J Psychiatry"},{"issue":"1","key":"2024012714051995400_jbmr4655-bib-0026","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1213\/XAA.0000000000000037","article-title":"General anesthesia treatment of propriospinal myoclonus in a patient with fibrodysplasia ossificans progressiva","volume":"3","author":"Char","year":"2014","journal-title":"A A Case Rep"},{"key":"2024012714051995400_jbmr4655-bib-0027","doi-asserted-by":"crossref","first-page":"115116","DOI":"10.1016\/j.bone.2019.115116","article-title":"Skeletal malformations and developmental arthropathy in individuals who have fibrodysplasia ossificans progressiva","volume":"130","author":"Towler","year":"2020","journal-title":"Bone"},{"key":"2024012714051995400_jbmr4655-bib-0028","author":"ClinicalTrials.gov","year":"2014"},{"key":"2024012714051995400_jbmr4655-bib-0029","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1016\/j.bone.2017.04.015","article-title":"A cumulative analogue joint involvement scale (CAJIS) for fibrodysplasia ossificans progressiva (FOP)","volume":"101","author":"Kaplan","year":"2017","journal-title":"Bone"},{"issue":"5","key":"2024012714051995400_jbmr4655-bib-0030","first-page":"484","article-title":"Adverse effects of isotretinoin therapy","volume":"33","author":"Bruno","year":"1984","journal-title":"Cutis"},{"issue":"3 Pt 2","key":"2024012714051995400_jbmr4655-bib-0031","doi-asserted-by":"crossref","first-page":"S7","DOI":"10.1016\/S0190-9622(99)70359-2","article-title":"Acitretin in psoriasis: an overview of adverse effects","volume":"41","author":"Katz","year":"1999","journal-title":"J Am Acad Dermatol"},{"issue":"4","key":"2024012714051995400_jbmr4655-bib-0032","doi-asserted-by":"crossref","first-page":"280","DOI":"10.2165\/00002018-199309040-00006","article-title":"Adverse reactions to oral retinoids. An update","volume":"9","author":"Mills","year":"1993","journal-title":"Drug Saf"},{"issue":"1","key":"2024012714051995400_jbmr4655-bib-0033","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1186\/s13023-020-01465-x","article-title":"Patients with ACVR1R206H mutations have an increased prevalence of cardiac conduction abnormalities on electrocardiogram in a natural history study of fibrodysplasia ossificans progressiva","volume":"15","author":"Kou","year":"2020","journal-title":"Orphanet J Rare Dis"},{"key":"2024012714051995400_jbmr4655-bib-0034","author":"Pignolo"},{"issue":"6","key":"2024012714051995400_jbmr4655-bib-0035","doi-asserted-by":"crossref","first-page":"1199","DOI":"10.1111\/bcp.13777","article-title":"Special considerations for clinical trials in fibrodysplasia ossificans progressiva (FOP)","volume":"85","author":"Hsiao","year":"2019","journal-title":"Br J Clin Pharmacol"},{"key":"2024012714051995400_jbmr4655-bib-0036","author":"ClinicalTrials.gov","year":"2017"}],"container-title":["Journal of Bone and Mineral Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/jbmr.4655","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/jbmr.4655","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/academic.oup.com\/jbmr\/article-pdf\/37\/10\/1891\/55454906\/jbmr4655.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jbmr\/article-pdf\/37\/10\/1891\/55454906\/jbmr4655.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,3,13]],"date-time":"2024-03-13T10:45:39Z","timestamp":1710326739000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jbmr\/article\/37\/10\/1891-1902\/7512337"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,12,1]]},"references-count":36,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2022,7,19]]},"published-print":{"date-parts":[[2020,12,1]]}},"URL":"https:\/\/doi.org\/10.1002\/jbmr.4655","relation":{"has-review":[{"id-type":"doi","id":"10.1002\/JBMR.4655\/v2\/decision1","asserted-by":"object"},{"id-type":"doi","id":"10.1002\/JBMR.4655\/v2\/response1","asserted-by":"object"},{"id-type":"doi","id":"10.1002\/JBMR.4655\/v3\/decision1","asserted-by":"object"},{"id-type":"doi","id":"10.1002\/JBMR.4655\/v3\/response1","asserted-by":"object"},{"id-type":"doi","id":"10.1002\/JBMR.4655\/v1\/review1","asserted-by":"object"},{"id-type":"doi","id":"10.1002\/JBMR.4655\/v1\/decision1","asserted-by":"object"},{"id-type":"doi","id":"10.1002\/JBMR.4655\/v1\/review2","asserted-by":"object"},{"id-type":"doi","id":"10.1002\/JBMR.4655\/v2\/review1","asserted-by":"object"},{"id-type":"doi","id":"10.1002\/JBMR.4655\/v2\/review2","asserted-by":"object"}]},"ISSN":["0884-0431","1523-4681"],"issn-type":[{"value":"0884-0431","type":"print"},{"value":"1523-4681","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2020,12,1]]},"published":{"date-parts":[[2020,12,1]]},"assertion":[{"value":"2021-12-19","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2022-07-16","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2022-08-17","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}