High gastrin levels may help explain the association between several conditions and osteoporosis, such as pernicious anaemia, 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 and, therefore, be a suitable preventive measure for osteoporosis. We conducted a randomised, double-blind, placebo-controlled clinical trial to assess the efficacy, safety, and tolerability of an oral GRA (netazepide) 100 mg administered daily for 90 days in postmenopausal women. Our primary endpoint was the change in the bone turnover marker (BTM) plasma CTX (automated immunoassay analyser) 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 bone turnover marker 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 years and BMD T- scores for the spine and total hip of -0.96 and -0.09, respectively. We found that gastrin increased by 90% in response to GRA as early as 7 days (p-value for treatment 0.0008), and group I pepsinogens decreased by 15% as early as 7 days (p-value 0.0002). There was no significant change in plasma CTX. A high percentage of women (81/99) completed the study, and the GRA was well tolerated. GRA 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 a preliminary exploration of a novel hypothesis and larger studies might be needed.
Keywords: CLINICAL TRIALS; DXA < ANALYSIS/QUANTITATION OF BONE; MENOPAUSE; Osteoporosis < DISEASES AND DISORDERS OF/RELATED TO BONE; Other < THERAPEUTICS.
Some health conditions, like pernicious anaemia and long-term use of acid-reducing medications have been linked to weaker bones and a higher risk of osteoporosis. A commonality of these conditions is a low acid state of the stomach and high levels of a gastric hormone called gastrin. This chemical messenger is a regulator of stomach acid secretion and levels. Our pre-clinical studies suggested that blocking the effect of gastrin in animal models simulating osteoporosis was effective in maintaining bone integrity. This study in humans addressed whether blocking gastrin’s effects could help protect bone health. We tested whether a medicine called netazepide (a gastrin antagonist) could help protect bones in older women. In this carefully controlled trial, participants took the medicine daily for 90 days. The treatment worked as expected in the stomach: it raised gastrin levels and lowered certain digestive markers. But when it came to bones, the results were unanticipated. There was no change in a key sign of bone breakdown (called CTX), suggesting that blocking gastrin failed to prevent osteoporosis. So, while the medicine affected stomach hormones, it didn’t show promise as a way to protect bone health. This may also reflect the short duration the agent was administered for or may mean that other agents associated with low acid states may be responsible.
© The Author(s) 2025. Published by Oxford University Press on behalf of the American Society for Bone and Mineral Research.