{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,7]],"date-time":"2026-01-07T14:40:18Z","timestamp":1767796818768,"version":"3.49.0"},"reference-count":11,"publisher":"BMJ","issue":"12","license":[{"start":{"date-parts":[[2025,12,5]],"date-time":"2025-12-05T00:00:00Z","timestamp":1764892800000},"content-version":"unspecified","delay-in-days":4,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"name":"European Union\u2019s Horizon Europe Research & Innovation programme.","award":["101057442"],"award-info":[{"award-number":["101057442"]}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["BMJ Open"],"accepted":{"date-parts":[[2025,10,31]]},"published-print":{"date-parts":[[2025,12]]},"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>Osteogenesis imperfecta (OI) is the most common inherited cause of bone fragility (approximately 1 in 16 000). People with OI suffer bone fragility causing fractures, pain and deformity; sarcopenia causing fatigue and poor endurance; aortic root dilatation and hearing loss. No drug currently has market authorisation to treat OI in Europe. Current standard-of-care is multidisciplinary, with pharmacological interventions\u2014primarily bisphosphonates\u2014directed at increasing bone mass; however, such interventions are of equivocal efficacy. The structural damage that can accumulate as a result of repeated fractures over time may not be reversible. The lack of a treatment with clearly defined efficacy in terms of reducing fracture frequency or the sarcopenia, that is increasingly recognised in this condition, leads to the consideration of alternatives based on what is known about the molecular pathophysiology of the condition. For reasons that are currently unclear, transforming growth factor beta (TGF\u03b2) pathway signalling is increased in OI, and both studies in mouse models and more recently also in humans suggest that reducing TGF\u03b2 pathway signalling could be of benefit in OI. This demonstrator project tests the hypothesis that losartan, an antihypertensive agent known to reduce circulating TGF\u03b2, will reduce bone turnover and bone loss and have a positive effect on muscle function and quality of life in adults and older adolescents with OI.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods and analysis<\/jats:title>\n                    <jats:p>This is a phase 2\/pilot, open-label, dose-escalating study. This study aims to identify the effective dose for losartan in this population to inform the design of a pivotal phase III study. The study aims to recruit 30 adolescents and adults aged 16 years and above with OI across secondary care study sites in the UK and Italy. Participants will be recruited from the patient populations attending for treatment of OI at the participating hospital sites or referred by clinicians at the Participant Identification Centres (PIC sites). Participants will be randomised to one of three \u2018final doses\u2019\u201425, 50 or 75\u2009mg losartan once daily. All participants will start on 25\u2009mg once daily. Those assigned to higher \u2018final doses\u2019 will increase in 25\u2009mg once daily increments on day 8 and day 15 following safety assessments. The primary outcome measures are to establish the effective dose of losartan in OI patients, based on maximal reduction in the bone resorption marker carboxy-terminal crosslink of type I collagen telopeptide (CTX) over the 24-week period of the study.<\/jats:p>\n                    <jats:p>Secondary outcome measures are to determine the changes in proxy efficacy outcomes for bone (turnover, mass, architecture and strength) using blood tests, high-resolution peripheral quantitative CT (HRpQCT), dual-energy X-ray absorptiometry (DXA) and muscle (strength) using the \u2018Timed Up and Go\u2019 test. In addition, the changes in quality of life, including pain and fatigue, will be evaluated by using a disease-specific tool (OI-QOL) and a validated generic tool (EQ-5D-5L-VAS).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Ethics and dissemination<\/jats:title>\n                    <jats:p>In the UK, the study protocol and amendments have been approved by the London Bridge Research Ethics Committee (REC reference: 23\/LO\/015) and by the Medicines and Healthcare products Regulatory Agency (MHRA). In Italy, the study protocol and amendments have been approved by the Italian and European ethics and regulatory authorities (Clinical Trials Information System European Union (CTIS EU) portal according to EU Regulation 536\/2014). Final version of study protocol: Version 3.2, 05.03.2025. Final results will be disseminated in peer-reviewed journals through local OI, orthopaedic and other relevant clinical networks and at national and international meetings. Sheffield Children\u2019s National Health Service Foundation Trust (UK) and Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Istituto Ortopedico Rizzoli (Italy) are the joint study sponsors.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Trial registration number<\/jats:title>\n                    <jats:p>\n                      ISRCTN (\n                      <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"isrctn\" xlink:href=\"ISRCTN13317811\">ISRCTN13317811<\/jats:ext-link>\n                      ).\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1136\/bmjopen-2025-107243","type":"journal-article","created":{"date-parts":[[2025,12,8]],"date-time":"2025-12-08T06:30:24Z","timestamp":1765175424000},"page":"e107243","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":0,"title":["Matrix-directed therapy losartan to identify the effect on the bone resorption marker carboxy-terminal crosslink of type I collagen telopeptide (CTX) in older adolescents and adults with osteogenesis imperfecta recruited from secondary care sites: the \u2018MOI-A\u2019 study; a randomised, phase 2\/pilot, dose-escalating trial"],"prefix":"10.1136","volume":"15","clinical-trial-number":[{"clinical-trial-number":"isrctn13317811","registry":"10.18810\/isrctn"}],"author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0332-6933","authenticated-orcid":false,"given":"Mahboobeh","family":"Haji Sadeghi","sequence":"first","affiliation":[{"name":"Hull Health Trials Unit, University of Hull, Hull, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1538-3521","authenticated-orcid":false,"given":"Judith","family":"Cohen","sequence":"additional","affiliation":[{"name":"Hull Health Trials Unit, University of Hull, Hull, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bronwen","family":"Williams","sequence":"additional","affiliation":[{"name":"Hull Health Trials Unit, University of Hull, Hull, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Amy","family":"Wilkinson","sequence":"additional","affiliation":[{"name":"Hull Health Trials Unit, University of Hull, Hull, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sarah","family":"Sumpter","sequence":"additional","affiliation":[{"name":"Hull Health Trials Unit, University of Hull, Hull, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-7950-5178","authenticated-orcid":false,"given":"Laura","family":"Simms","sequence":"additional","affiliation":[{"name":"Hull Health Trials Unit, University of Hull, Hull, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3627-7218","authenticated-orcid":false,"given":"Chao","family":"Huang","sequence":"additional","affiliation":[{"name":"Hull Health Trials Unit, University of Hull, Hull, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Keith","family":"Pugh","sequence":"additional","affiliation":[{"name":"Sheffield Children\u2019s NHS Foundation Trust, Sheffield, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-4819-9114","authenticated-orcid":false,"given":"Charlotte","family":"Heath","sequence":"additional","affiliation":[{"name":"Sheffield Children\u2019s NHS Foundation Trust, Sheffield, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Luca","family":"Sangiorgi","sequence":"additional","affiliation":[{"name":"IRCCS Istituto Ortopedico Rizzoli, Bologna, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-4284-8618","authenticated-orcid":false,"given":"Francesca","family":"Gurioli","sequence":"additional","affiliation":[{"name":"IRCCS Istituto Ortopedico Rizzoli, Bologna, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5907-7470","authenticated-orcid":false,"given":"Maria","family":"Gnoli","sequence":"additional","affiliation":[{"name":"IRCCS Istituto Ortopedico Rizzoli, Bologna, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4777-341X","authenticated-orcid":false,"given":"Alice","family":"Moroni","sequence":"additional","affiliation":[{"name":"IRCCS Istituto Ortopedico Rizzoli, Bologna, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Martina Piccinni","family":"Leopardi","sequence":"additional","affiliation":[{"name":"IRCCS Istituto Ortopedico Rizzoli, Bologna, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Clara","family":"Del Coco","sequence":"additional","affiliation":[{"name":"IRCCS Istituto Ortopedico Rizzoli, Bologna, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7263-8546","authenticated-orcid":false,"given":"Nick","family":"Bishop","sequence":"additional","affiliation":[{"name":"Sheffield Children\u2019s NHS Foundation Trust, Sheffield, UK"},{"name":"The University of Sheffield, Sheffield, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"239","published-online":{"date-parts":[[2025,12,7]]},"reference":[{"key":"2026010703460536000_15.12.e107243.1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(13)61091-0"},{"key":"2026010703460536000_15.12.e107243.2","doi-asserted-by":"crossref","first-page":"929","DOI":"10.1002\/jbmr.2410","article-title":"Bisphosphonates for the prevention of fractures in osteogenesis imperfecta: meta-analysis of placebo-controlled trials","volume":"30","author":"Hald","year":"2015","journal-title":"J Bone Miner Res"},{"key":"2026010703460536000_15.12.e107243.3","doi-asserted-by":"publisher","DOI":"10.1038\/nm.3544"},{"key":"2026010703460536000_15.12.e107243.4","doi-asserted-by":"crossref","DOI":"10.1038\/s41598-022-06063-4","article-title":"Characterization and functional analysis of the adipose tissue-derived stromal vascular fraction of pediatric patients with osteogenesis imperfecta","volume":"12","author":"Tauer","year":"2022","journal-title":"Sci Rep"},{"key":"2026010703460536000_15.12.e107243.5","doi-asserted-by":"crossref","DOI":"10.1172\/JCI152571","article-title":"Targeting TGF-\u03b2 for treatment of osteogenesis imperfecta","volume":"132","author":"Song","year":"2022","journal-title":"J Clin Invest"},{"key":"2026010703460536000_15.12.e107243.6","doi-asserted-by":"crossref","DOI":"10.1016\/j.bonr.2024.101795","article-title":"Losartan alters osteoblast differentiation and increases bone mass through inhibition of TGFB signalling in vitro and in an OIM mouse model","volume":"22","author":"Morita","year":"2024","journal-title":"Bone Rep"},{"key":"2026010703460536000_15.12.e107243.7","doi-asserted-by":"publisher","DOI":"10.1038\/nm1536"},{"key":"2026010703460536000_15.12.e107243.8","doi-asserted-by":"publisher","DOI":"10.1046\/j.1523-1755.1999.00597.x"},{"key":"2026010703460536000_15.12.e107243.9","doi-asserted-by":"publisher","DOI":"10.4103\/0976-0105.177703"},{"key":"2026010703460536000_15.12.e107243.10","doi-asserted-by":"crossref","unstructured":"Savas U , Wei S , Hsu MH , et al . 20-Hydroxyeicosatetraenoic Acid (HETE)-dependent Hypertension in Human Cytochrome P450 (CYP) 4A11 Transgenic Mice: NORMALIZATION OF BLOOD PRESSURE BY SODIUM RESTRICTION, HYDROCHLOROTHIAZIDE, OR BLOCKADE OF THE TYPE 1 ANGIOTENSIN II RECEPTOR. J Biol Chem 2016;16904\u201319. doi:10.1074\/jbc.M116.732297","DOI":"10.1074\/jbc.M116.732297"},{"key":"2026010703460536000_15.12.e107243.11","doi-asserted-by":"publisher","DOI":"10.1002\/sim.6052"}],"container-title":["BMJ Open"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1136\/bmjopen-2025-107243","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,7]],"date-time":"2026-01-07T11:47:00Z","timestamp":1767786420000},"score":1,"resource":{"primary":{"URL":"https:\/\/bmjopen.bmj.com\/lookup\/doi\/10.1136\/bmjopen-2025-107243"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,12]]},"references-count":11,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2025,12,7]]},"published-print":{"date-parts":[[2025,12]]}},"alternative-id":["10.1136\/bmjopen-2025-107243"],"URL":"https:\/\/doi.org\/10.1136\/bmjopen-2025-107243","relation":{},"ISSN":["2044-6055","2044-6055"],"issn-type":[{"value":"2044-6055","type":"print"},{"value":"2044-6055","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,12]]}}}