Prior studies have indicated an excess risk of gastroduodenal ulcers and esophagus perforations with the use of bisphosphonates. However, little is known about the contribution of comorbid conditions and concomitant drug use on this risk. We studied the risk of esophagus and gastric events in patients on a wide range of drugs against osteoporosis both before and after initiation of these drugs. We studied a nationwide register-based cohort from Denmark with all users of drugs against osteoporosis between 1996 and 2006 (n = 103,562) as cases and three age- and sex-matched controls from the general population (n = 310,683). In a crude analysis, most drugs were already associated with an increased risk of esophagitis, esophageal ulcerations, or esophageal perforations or gastroduodenal ulcers before initiation of the drugs. Upon adjustment, this excess risk disappeared for most drugs except parathyroid hormone and its analogues, etidronate and clodronate. Only for etidronate, alendronate, and raloxifene were sufficient data present for events after initiation of the drugs, and for these, an increased risk was present for all events except gastroduodenal ulcers with raloxifene. Several drugs against osteoporosis are associated with an increased risk of esophagitis, esophageal ulcers, esophageal perforation, and gastroduodenal ulcers. However, the increase was already present before initiation of the drug for several types of drugs against osteoporosis. This points at an effect of the underlying condition being treated or comorbid conditions and drugs being provided in patients with osteoporosis, such as nonsteroidal anti-inflammatory drugs and corticosteroids.