Non‐steroidal anti‐inflammatory drugs (NSAIDs) may delay bone healing. [Therefore, it is important to establish whether NSAID preparations delay bone healing and what correlations, if any, exist between different bone studies—DEXA—scanning, bone markers, roentgenology controls, and histological examination of newly formed bone]. The purpose of this prospective controlled study was to investigate whether ibuprofen affects bone mineral density, turnover biomarkers, and histomorphometric characteristics of the callus after a Colles' fracture. This study was a single‐center, triple‐blinded, randomized clinical trial. Ninety‐five patients (80 females) with displaced Colles' fracture, median age 65 (range 40–85) years were included in the study and operated on by external fixation from June 2012 through to June 2015. Eighty‐nine patients received interventional medicine and 83 completed the 1‐year follow‐up. The 7‐day ibuprofen group received 600 mg of ibuprofen three times a day (N = 29), the 3‐day ibuprofen group received ibuprofen for 3 days (N = 30) and a placebo for the following 4 days, and finally, the placebo group received a placebo for 7 days (N = 30). The primary outcome was the difference in bone mineral density between the ultra‐distal region of the injured and non‐injured radius at 3 months after surgery. The histomorphometric outcomes included the assessment of callus tissue volume and surface fractions at 6 weeks postoperatively. The biomarkers Osteocalcin and CrossLaps were measured at baseline, 1 week, 2 weeks, 6 weeks, 3 months, and 1 year. We included the results of the dropped‐out patients in the intention to treat analysis. There was no difference between treatment groups in bone mineral density, histomorphometric estimations, and changes in bone biomarkers. These findings may offer an indication of ibuprofen as a bone‐safe analgesic treatment in an acute fracture‐phase. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 38:545–554, 2020 [ABSTRACT FROM AUTHOR]