(that is: without gastroesophageal reflux disease). A study from 2019 showed that PPI use alone and together with histamine H2-receptor antagonists was associated with an increased bone fracture hazard, which was amplified by days of use and earlier initiation of therapy. The reason is not clear, increased bone break down by osteoclasts has been suggested. Gastrointestinal Some studies have shown a correlation between use of PPIs and Clostridioides difficile infection. While the data are contradictory and controversial, the FDA had sufficient concern to include a warning about this adverse effect on the label of PPI medications. Concerns have also been raised about spontaneous bacterial peritonitis (SBP) in older people taking PPIs and in people with irritable bowel syndrome taking PPIs; both types of infections arise in these populations due to underlying conditions and it is not clear if this is a class effect of PPIs. PPIs may predispose an individual to developing small intestinal bacterial overgrowth or fungal overgrowth. In cirrhotic patients, large volume of ascites and reduced esophageal motility by varices can provoke GERD. Acidic irritation, in return, may induce the rupture of varices. Therefore, PPIs are often routinely prescribed for cirrhotic patients to treat GERD and prevent variceal bleeding. However, it has been recently shown that long term use of PPIs in patients with cirrhosis increases the risk of SBP and is associated with the development of clinical decompensation and liver-related death during long-term follow-up. There is evidence that PPI use alters the composition of the bacterial populations inhabiting the gut, the gut microbiota. Although the mechanisms by which PPIs cause these changes are yet to be determined, they may have a role in the increased risk of bacterial infections with PPI use. These infections can include Helicobacter pylori due to this species not favouring an acid environment, leading to an increased risk of ulcers and gastric cancer risk in genetically susceptible patients. PPI use in people who have received attempted H. pylori eradication may also be associated with an increased risk of gastric cancer. The validity and robustness of this finding, with the lack of causality, have led to this association being questioned. It is recommended that long-term PPIs should be used judiciously after considering individual's risk–benefit profile, particularly among those with history of H. pylori infection, and that further, well-designed, prospective studies are needed. Long-term use of PPIs is associated with the development of benign polyps