Proton pump inhibitors (PPIs) are commonly used to treat acid-related diseases. At present, the mechanisms by which long-term use of PPIs induces bone fracture remain unclear. One possible mechanism is that PPIs can induce acid inhibition, impair intestinal calcium absorption, promote parathyroid hormone (PTH) secretion, and increase bone absorption. Long-term use of high-dose PPIs appears to be associated with an increased risk of hip or vertebral fractures in patients at high risk for bone fractures. Therefore, PPIs should be used for appropriate indications but not at higher doses or for longer durations than necessary to achieve desired outcomes.