{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,30]],"date-time":"2026-03-30T14:55:39Z","timestamp":1774882539431,"version":"3.50.1"},"reference-count":27,"publisher":"Oxford University Press (OUP)","issue":"4","license":[{"start":{"date-parts":[[2025,11,8]],"date-time":"2025-11-08T00:00:00Z","timestamp":1762560000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Clifton Life Biosciences LLC"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,3,30]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>High gastrin levels may help to explain the association between several conditions and osteoporosis, such as pernicious anemia, the use of proton pump inhibitors, and atrophic gastritis. This study aimed to determine whether administering a gastrin receptor antagonist (GRA) to older women would lower their bone turnover markers (BTM) and, therefore, be a suitable preventive measure for osteoporosis. We conducted a randomized, double-blind, placebo-controlled clinical trial to assess the efficacy, safety, and tolerability of an oral GRA (netazepide) 100\u00a0mg administered daily for 90\u00a0d in postmenopausal women. Our primary endpoint was the change in the BTM plasma CTX (automated immunoassay analyzer) at days 0, 7, 28, 56, and 90. We also measured other BTMs, and gastrin and group I pepsinogens (ELISA assays). We studied the effect of the drug on the log-transformed baseline scaled ratio for BTM and gastric markers using mixed-model ANOVA for the fixed effects of treatment, time, and the treatment-by-time interaction, with the baseline value included as a covariate. We studied 99 women, with a mean age of 60\u00a0yr and bone mineral density (BMD) T-scores for the spine and total hip (TH) of \u22120.96 and \u22120.09, respectively. We found that gastrin increased by 90% in response to GRA as early as 7\u00a0d (p-value for treatment: .0008), and group I pepsinogens decreased by 15% as early as 7\u00a0d (p-value: .0002). There was no significant change in plasma CTX. A high percentage of women (81\/99) completed the study, and the GRA was well tolerated. Gastrin receptor antagonist had the expected effects on the gastric markers with an increase in gastrin and a decrease in group I pepsinogens. However, the absence of any change in the bone resorption marker plasma CTX was a bit surprising. Based on this study, it appears that short-term gastrin receptor antagonism is unlikely to be a successful strategy in the prevention of osteoporosis. However, this is a preliminary exploration of a novel hypothesis and larger studies might be needed.<\/jats:p>","DOI":"10.1093\/jbmr\/zjaf165","type":"journal-article","created":{"date-parts":[[2025,11,7]],"date-time":"2025-11-07T13:05:20Z","timestamp":1762520720000},"page":"387-395","source":"Crossref","is-referenced-by-count":0,"title":["Randomized controlled trial of an oral gastrin receptor antagonist for the treatment of postmenopausal osteoporosis"],"prefix":"10.1093","volume":"41","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2204-2095","authenticated-orcid":false,"given":"Marian","family":"Schini","sequence":"first","affiliation":[{"name":"University of Sheffield , Sheffield S10 2TN ,","place":["United Kingdom"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fatma","family":"Gossiel","sequence":"additional","affiliation":[{"name":"University of Sheffield , Sheffield S10 2TN ,","place":["United Kingdom"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1030-0723","authenticated-orcid":false,"given":"Margaret A","family":"Paggiosi","sequence":"additional","affiliation":[{"name":"University of Sheffield , Sheffield S10 2TN ,","place":["United Kingdom"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sara L","family":"Hilditch","sequence":"additional","affiliation":[{"name":"University of Sheffield , Sheffield S10 2TN ,","place":["United Kingdom"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stuart","family":"More","sequence":"additional","affiliation":[{"name":"University of Cape Town , Cape Town 7700 ,","place":["South Africa"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Irvin","family":"Modlin","sequence":"additional","affiliation":[{"name":"Keewaydin Consulting Inc , 650 Park Ave, New York,","place":["USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0323-3366","authenticated-orcid":false,"given":"Richard","family":"Eastell","sequence":"additional","affiliation":[{"name":"University of Sheffield , Sheffield S10 2TN ,","place":["United Kingdom"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2025,11,8]]},"reference":[{"issue":"5","key":"2026033010071203200_ref1","doi-asserted-by":"publisher","first-page":"1595","DOI":"10.1210\/jc.2019-00221","article-title":"Pharmacological Management of Osteoporosis in postmenopausal women: an Endocrine Society Clinical Practice Guideline","volume":"104","author":"Eastell","year":"2019","journal-title":"J Clin Endocr Metab"},{"key":"2026033010071203200_ref2","volume-title":"Achlorhydria","author":"Fatima","year":"2024"},{"issue":"3","key":"2026033010071203200_ref3","doi-asserted-by":"publisher","DOI":"10.1093\/ageing\/afaf047","article-title":"Common occurrence of atrophic gastritis in an ageing non-hospitalised population: an autopsy study","volume":"54","author":"Karhunen","year":"2025","journal-title":"Age Ageing"},{"issue":"4","key":"2026033010071203200_ref4","doi-asserted-by":"crossref","first-page":"1330","DOI":"10.1053\/j.gastro.2009.12.007","article-title":"Hip fracture risk in patients with a diagnosis of pernicious anemia","volume":"138","author":"Merriman","year":"2010","journal-title":"Gastroenterology"},{"issue":"5","key":"2026033010071203200_ref5","doi-asserted-by":"publisher","first-page":"573","DOI":"10.1002\/jbmr.5650070514","article-title":"Risk of fractures in patients with pernicious anemia","volume":"7","author":"Goerss","year":"1992","journal-title":"J Bone Miner Res"},{"issue":"6","key":"2026033010071203200_ref6","doi-asserted-by":"publisher","first-page":"681","DOI":"10.1042\/cs0820681","article-title":"Pernicious anaemia as a risk factor for osteoporosis","volume":"82","author":"Eastell","year":"1992","journal-title":"Clin Sci (Lond)"},{"issue":"13","key":"2026033010071203200_ref7","doi-asserted-by":"crossref","first-page":"1729","DOI":"10.1001\/jama.290.13.1729","article-title":"Effects of estrogen plus progestin on risk of fracture and bone mineral density: the Women's Health Initiative randomized trial","volume":"290","author":"Cauley","year":"2003","journal-title":"JAMA"},{"issue":"1","key":"2026033010071203200_ref8","doi-asserted-by":"publisher","first-page":"152","DOI":"10.1359\/JBMR.041018","article-title":"Low plasma vitamin B12 is associated with lower BMD: the Framingham osteoporosis study","volume":"20","author":"Tucker","year":"2005","journal-title":"J Bone Miner Res"},{"issue":"18","key":"2026033010071203200_ref9","doi-asserted-by":"publisher","first-page":"10733","DOI":"10.3390\/ijms231810733","article-title":"Proton pump inhibitors and bone health: an update narrative review","volume":"23","author":"Lespessailles","year":"2022","journal-title":"Int J Mol Sci"},{"issue":"3","key":"2026033010071203200_ref10","doi-asserted-by":"publisher","first-page":"211","DOI":"10.7326\/0003-4819-120-3-199402010-00006","article-title":"Omeprazole therapy causes malabsorption of cyanocobalamin (vitamin B12)","volume":"120","author":"Marcuard","year":"1994","journal-title":"Ann Intern Med"},{"issue":"7","key":"2026033010071203200_ref11","doi-asserted-by":"publisher","first-page":"778","DOI":"10.1016\/j.amjmed.2005.02.007","article-title":"Effects of proton pump inhibitors on calcium carbonate absorption in women: a randomized crossover trial","volume":"118","author":"O'Connell","year":"2005","journal-title":"Am J Med"},{"issue":"9","key":"2026033010071203200_ref12","doi-asserted-by":"publisher","first-page":"1159","DOI":"10.1007\/s00228-023-03534-z","article-title":"Proton pump inhibitor use: systematic review of global trends and practices","volume":"79","author":"Shanika","year":"2023","journal-title":"Eur J Clin Pharmacol"},{"issue":"1","key":"2026033010071203200_ref13","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1002\/PHAR.1007","article-title":"Fracture risk and bone mineral density reduction associated with proton pump inhibitors","volume":"32","author":"Lau","year":"2012","journal-title":"Pharmacotherapy"},{"issue":"9","key":"2026033010071203200_ref14","doi-asserted-by":"publisher","first-page":"1571","DOI":"10.3390\/ijerph16091571","article-title":"Proton pump inhibitors and fracture risk: a review of current evidence and mechanisms involved","volume":"16","author":"Thong","year":"2019","journal-title":"Int J Environ Res Public Health"},{"issue":"1","key":"2026033010071203200_ref15","doi-asserted-by":"publisher","first-page":"113","DOI":"10.1046\/j.1365-2036.1997.110281000.x","article-title":"YF476 is a new potent and selective gastrin\/cholecystokinin-B receptor antagonist in vitro and in vivo","volume":"11","author":"Takinami","year":"1997","journal-title":"Aliment Pharmacol Ther"},{"issue":"10","key":"2026033010071203200_ref16","doi-asserted-by":"publisher","first-page":"e76462","DOI":"10.1371\/journal.pone.0076462","article-title":"Netazepide, a gastrin receptor antagonist, normalises tumour biomarkers and causes regression of type 1 gastric neuroendocrine tumours in a nonrandomised trial of patients with chronic atrophic gastritis","volume":"8","author":"Moore","year":"2013","journal-title":"PLoS One"},{"issue":"11-12","key":"2026033010071203200_ref17","doi-asserted-by":"publisher","first-page":"1067","DOI":"10.1111\/apt.12090","article-title":"Treatment of gastric carcinoids type 1 with the gastrin receptor antagonist netazepide (YF476) results in regression of tumours and normalisation of serum chromogranin A","volume":"36","author":"Fossmark","year":"2012","journal-title":"Aliment Pharmacol Ther"},{"issue":"2","key":"2026033010071203200_ref18","doi-asserted-by":"publisher","first-page":"129","DOI":"10.1007\/s00228-016-2150-x","article-title":"Randomised trial of the effect of a gastrin\/CCK2 receptor antagonist on esomeprazole-induced hypergastrinaemia: evidence against rebound hyperacidity","volume":"73","author":"Boyce","year":"2017","journal-title":"Eur J Clin Pharmacol"},{"issue":"3","key":"2026033010071203200_ref19","doi-asserted-by":"publisher","first-page":"466","DOI":"10.1111\/bcp.13146","article-title":"Netazepide, a gastrin\/cholecystokinin-2 receptor antagonist, can eradicate gastric neuroendocrine tumours in patients with autoimmune chronic atrophic gastritis","volume":"83","author":"Boyce","year":"2017","journal-title":"Br J Clin Pharmacol"},{"issue":"2","key":"2026033010071203200_ref20","doi-asserted-by":"publisher","first-page":"251","DOI":"10.1530\/JOE-16-0017","article-title":"Skeletal effects of a gastrin receptor antagonist in H+\/K+ATPase beta subunit KO mice","volume":"230","author":"Aasar\u00f8d","year":"2016","journal-title":"J Endocrinol"},{"issue":"1","key":"2026033010071203200_ref21","doi-asserted-by":"publisher","first-page":"141","DOI":"10.1002\/jcb.23337","article-title":"Decreased bone mineral density and reduced bone quality in H+\/K+ATPase beta-subunit deficient mice","volume":"113","author":"Fossmark","year":"2012","journal-title":"J Cell Biochem"},{"issue":"7","key":"2026033010071203200_ref22","doi-asserted-by":"crossref","first-page":"637","DOI":"10.1001\/jama.282.7.637","article-title":"Reduction of vertebral fracture risk in postmenopausal women with osteoporosis treated with raloxifene: results from a 3-year randomized clinical trial. Multiple outcomes of raloxifene evaluation (MORE) investigators","volume":"282","author":"Ettinger","year":"1999","journal-title":"JAMA"},{"issue":"8","key":"2026033010071203200_ref23","doi-asserted-by":"publisher","first-page":"2585","DOI":"10.1007\/s00198-016-3573-z","article-title":"Response of bone turnover markers to raloxifene treatment in postmenopausal women with osteopenia","volume":"27","author":"Naylor","year":"2016","journal-title":"Osteoporos Int"},{"issue":"6","key":"2026033010071203200_ref24","doi-asserted-by":"crossref","first-page":"1044","DOI":"10.1016\/j.bone.2009.07.089","article-title":"A randomised, double-blinded, placebo-controlled, trial to determine the individual response in bone turnover markers to lasofoxifene therapy","volume":"45","author":"Rogers","year":"2009","journal-title":"Bone"},{"issue":"5","key":"2026033010071203200_ref25","doi-asserted-by":"publisher","first-page":"680","DOI":"10.1111\/bcp.12095","article-title":"Effect of repeated doses of netazepide, a gastrin receptor antagonist, omeprazole and placebo on 24\u2009h gastric acidity and gastrin in healthy subjects","volume":"76","author":"Boyce","year":"2013","journal-title":"Br J Clin Pharmacol"},{"issue":"5","key":"2026033010071203200_ref26","doi-asserted-by":"publisher","first-page":"744","DOI":"10.1111\/bcp.12534","article-title":"Effect of netazepide, a gastrin\/CCK2 receptor antagonist, on gastric acid secretion and rabeprazole-induced hypergastrinaemia in healthy subjects","volume":"79","author":"Boyce","year":"2015","journal-title":"Br J Clin Pharmacol"},{"issue":"3","key":"2026033010071203200_ref27","doi-asserted-by":"crossref","first-page":"417","DOI":"10.1210\/endrev\/bnac031","article-title":"Bone turnover markers: basic biology to clinical applications","volume":"44","author":"Schini","year":"2023","journal-title":"Endocr Rev"}],"container-title":["Journal of Bone and Mineral Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/jbmr\/advance-article-pdf\/doi\/10.1093\/jbmr\/zjaf165\/65246204\/zjaf165.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jbmr\/article-pdf\/41\/4\/387\/65246204\/zjaf165.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jbmr\/article-pdf\/41\/4\/387\/65246204\/zjaf165.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,30]],"date-time":"2026-03-30T14:07:18Z","timestamp":1774879638000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jbmr\/article\/41\/4\/387\/8317146"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,11,8]]},"references-count":27,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2025,11,8]]},"published-print":{"date-parts":[[2026,3,30]]}},"URL":"https:\/\/doi.org\/10.1093\/jbmr\/zjaf165","relation":{},"ISSN":["0884-0431","1523-4681"],"issn-type":[{"value":"0884-0431","type":"print"},{"value":"1523-4681","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2026,4]]},"published":{"date-parts":[[2025,11,8]]}}}