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The mechanism is unclear, but it has been speculated that by neutralising gastric acid, they may reduce intestinal calcium absorption, causing secondary hyperparathyroidism and bone loss. Here we investigated that hypothesis that the skeletal effects of PPI might be mediated by inhibitory effects on the bone-specific phosphatase PHOSPHO1. We found that the all PPIs tested inhibited the activity of PHOSPHO1 with IC50 ranging between 0.73\u00a0\u00b5M for esomeprazole to 19.27\u00a0\u00b5M for pantoprazole. In contrast, these PPIs did not inhibit TNAP activity. We also found that mineralisation of bone matrix in primary osteoblast cultures was inhibited by several PPIs in a concentration dependent manner. In contrast, the histamine-2 receptor antagonists (H2RA) nizatidine, famotidine, cimetidine and ranitidine had no inhibitory effects on PHOSPHO1 activity. Our experiments show for the first time that PPIs inhibit PHOSPHO1 activity and matrix mineralisation in vitro revealing a potential mechanism by which these widely used drugs are associated with the risk of fractures.<\/jats:p>","DOI":"10.1007\/s00223-021-00882-9","type":"journal-article","created":{"date-parts":[[2021,7,2]],"date-time":"2021-07-02T05:03:03Z","timestamp":1625202183000},"page":"696-705","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Proton Pump Inhibitors Inhibit PHOSPHO1 Activity and Matrix Mineralisation In Vitro"],"prefix":"10.1007","volume":"109","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8492-9778","authenticated-orcid":false,"given":"Katherine A.","family":"Staines","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katherine","family":"Myers","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kirsty","family":"Little","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stuart H.","family":"Ralston","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Colin","family":"Farquharson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,7,2]]},"reference":[{"key":"882_CR1","doi-asserted-by":"publisher","first-page":"1019","DOI":"10.1002\/pds.1969","volume":"19","author":"S Hollingworth","year":"2010","unstructured":"Hollingworth S, Duncan EL, Martin JH (2010) Marked increase in proton pump inhibitors use in Australia. 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