Proton pump inhibitors (PPIs) have been widely used since their introduction in the late 1980s because they are highly effective for acid-related conditions. However, some recent epidemiological studies have suggested a positive association between PPI therapy and the risk of osteoporotic fractures. The potential mechanisms underlying this association may be related to the physiologic effects of chronic acid suppression on calcium metabolism. First, chronic hypergastrinemia induced by PPI therapy may lead to parathyroid hyperplasia, resulting in increased loss of calcium from the bone. Second, profound gastric acid suppression may reduce the bioavailability of calcium for intestinal absorption. I will review the published evidence regarding these potential links and discuss their clinical implications.