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Potential adverse effects of nonsteroidal anti-inflammatory drugs (NSAIDs) on bone metabolism and fracture healing are contradictive to their wide application in post-traumatic treatment. Our objective was to investigate changes to periosteal callus formation with respect to NSAID and central analgesic drug application. Our hypothesis was that callus formation is delayed in animals treated with the non-specific NSAID diclofenac.The left tibia of forty male Wistar rats were osteotomized, stabilized with a Kirschner wire, and randomized into four groups of ten animals. Group 1 received a placebo, group 2 received the central analgesic tramadol (20 mg/kg per day) throughout the study, and groups 3 and 4 were treated with sodium diclofenac (5 mg/kg per day). Group 3 received diclofenac for seven days, followed by placebo until sacrifice (short-term), while group 4 animals received diclofenac for the full period (long-term). Animals were sacrificed 21 days after osteotomy.Under light microscopy, all osteotomies healed successfully and independently of the drug treatment. Histomorphometry revealed delayed callus maturation in long-term diclofenac treated animals, with significantly higher amounts of cartilage and less bone, particularly in the outermost region of periosteal callus. Short-term NSAID and tramadol application did not significantly alter callus differentiation.Callus maturation in vivo was impaired after long-term application of diclofenac which corresponds to the in vitro findings of a dose-dependent effect of NSAIDs on osteoblast proliferation.