The most common gastrointestinal tract AEs were constipation, gastric discomfort,

and diarrhea. Among serious AEs, more patients in minodronate group reported infections/infestations and cardiac disorders. Infections included two pneumonia patients in both minodronate and placebo groups, and all the other infections were reported in only one patient in either group. Cardiac disorders included three patients in minodronate and two patients in placebo group with ischemic heart diseases, and one patient each with cardiac insufficiency and sinus arrhythmia in minodronate group. None of them reported atrial fibrillation. The proportion of subjects who discontinued the study due to AEs was also Smoothened antagonist similar between the two groups. Complaints related to digestive system were the most common AEs associated with withdrawal from the study (Table 3). Table 3 Summary of adverse events   Minodoronate, n (%) Placebo, n (%) No. of patients 354 342 Any AE 334 (94.4) 327 AT9283 (95.6)  Gastrointestinal AE 173 (48.9) 155 (45.3)  “Drug-related” AEa 57 (16.1) 54 (15.8)  Serious AEb 49 (13.8) 65 (19.0)   Injury, poisoning and procedural complications 10 (2.8) 13 (3.8)   Musculoskeletal and connective tissue disorders 8 (2.3) 9 (2.6)   Gastrointestinal disorders 7 (2.0) 9 (2.6)   Nervous system disorders 4 (1.1) 10 (2.9)   Infections and infestations 7 (2.0) 3 (0.9)   Eye disorders 1 (0.3) 8 (2.3)   Respiratory,

thoracic and mediastinal disorders 3 (0.8) 5 (1.5)   Cardiac disorders 5 (1.4) 2 (0.6)   Neoplasms benign, malignant and unspecified 2 (0.6) 4 (1.2) Discontinued due to AE 55 (15.5) 47 (13.7)  Discontinued due to gastrointestinal AE 17 (4.8) 13 (3.8)  Discontinued due to “drug-related” AE 17 (4.8)

14 (4.1) Data are number of patients AE adverse event aAEs reported as drug-related by the investigators are listed as “drug-related” bSerious AEs with more than two patients in either treatment group are listed Discussion The present study demonstrated that daily oral administration of 1 mg minodronate for 24 months reduced the risk of new vertebral fractures by 59% compared with that in the placebo group. The effect Protein kinase N1 of minodronate on vertebral fracture was observed within 12 months, and there was also a significant decrease in height loss at 12 months. The overall safety profile including gastrointestinal safety was similar between the two groups. In the present study, a large number of vertebral fractures occurred during the first 6 months in both groups (20 and 27 in minodronate and placebo groups, respectively). In our previous study, to compare the effect of minodronate on lumbar BMD and bone markers with that of alendronate (Hagino et al., submitted for publication), bone resorption markers were suppressed within 1 month, and lumbar BMD was significantly increased after 3 months of minodronate treatment.