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Non-steroidal anti-inflammatory drug (NSAID) is well known to significantly delay fracture healing. Results from in vitro studies implicate an impairment of osteoblast proliferation due to NSAIDs during the initial stages of healing. We studied whether diclofenac, a non-selective NSAID, also impairs appearance of osteoblasts in vivo during the early phase of healing (at 10 days). Two defects (Ø 1.1 mm) were drilled within distal femurs of 20 male Wistar rats. Ten rats received diclofenac continuously; the other obtained a placebo until sacrificing at 10 days. Osteoblast proliferation was assessed by cell counting using light microscopy, and bone mineral density (BMD) was measured using pQCT. Osteoblast counts from the centre of bone defect were significantly reduced in the diclofenac group (median 73.5 ± 8.4 cells/grid) compared to animals fed with placebo (median 171.5 ± 13.9 cells/grid). BMD within the defect showed a significant reduction after diclofenac administration (median 111.5 ± 9.3 mg/cm³) compared to the placebo group (median 177 ± 45.4 mg/cm³). The reduced appearance of osteoblasts in vivo implicates an inhibiting effect of diclofenac on osteoblasts at a very early level of bone healing. The inhibition of proliferation and migration of osteoblasts, or differentiation from progenitor cells, is implicated in the delay of fracture healing after NSAID application. [ABSTRACT FROM AUTHOR]

Introduction. Nonsteroidal antirheumatics (NSAR; NSAID) are often used in patients with fractured bones for analgetic reasons. This animal experiment was performed to determine the influence of NSAR on the process of fracture healing. As an alternative, tramadol, the centrally acting analgetic without peripheral effects, was included in this experiment. Materials and methods. Wistar rats were operated on by a transverse osteotomy of the proximal tibia of the left leg. The fracture was stabilized by intramedullary nailing (healing period 21 days). All drugs were applied orally twice a day. The animals were divided into four groups with 10 rats each: Group 1 was treated with placebo (P), group 2 with tramadol (T; 20 mg/kg body weight/day), group 3 with diclofenac sodium (DS; 5 mg/kg bw/day) for 7 days followed by 14 days of placebo, group 4 with diclofenac sodium (DL; 5 mg/kgbw/day) over 21 days. On day 21 the rats were killed, and each leg was examined by X-ray, then the tibia was examined by CT scan, three-point bending, and histology. Results. The results of CT and three-point bending showed that rats treated by diclofenac presented with delayed fracture healing compared with those treated by placebo or tramadol. Bone density in CT was highest in group 1 (mean 611.4±50.1 mg/ml), followed by group 2 (mean 542.5±29.5 mg/ml). Groups 3 (mean 411±34.0 mg/ml; p=0.006) and 4 (mean 395.2±15.4 mg/ml; p=0.009) were significantly lower. The stability of the bones, as measured by the breaking force (Fmax), was highest in group 1 (mean 45.8±19.0 N), followed by group 2 (mean 39.0±7.9 N; NS); group 3 (mean 20.6±7.8 N; p=0.01) was significantly lower than the placebo animals, followed by group 4 (mean 26.5±8.3 N; p=0.03). Similar results were shown for bending stiffness: group 1 (mean 1404.6±611.4 Nmm/mm), group 2 (mean 1033.2±232.1 Nmm/mm; NS), group 3 (mean 564.2±457 Nmm/mm; p=0.045), and group 4 (mean 494.8±340.2 Nmm/mm; p=0.028). There were no significant differences between groups 1 and 2 and between groups 3 and 4, respectively. Diclofenac serum levels on day 21 in rats with long-term diclofenac application (mean 301.4±83.3 ng/ml) were comparable to those in humans. Conclusion. Oral application of diclofenac significantly delayed fracture healing in rats. This effect might be comparable to other NSAR and fracture healing in humans. [ABSTRACT FROM AUTHOR]