Influence of diclofenac (group of nonsteroidal anti-inflammatory drugs) on fracture healing.
BACKGROUND
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.


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 ( F(max)), 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.


CONCLUSIONS
Oral application of diclofenac significantly delayed fracture healing in rats. This effect might be comparable to other NSAR and fracture healing in humans.
Beck
A
A
Department of Trauma, Hand and Reconstructive Surgery, University Hospital, Steinhoevelstrasse 9, 89075 Ulm, Germany. alexander.beck@medizin.uni-ulm.de
Krischak
G
G
Sorg
T
T
Augat
P
P
Farker
K
K
Merkel
U
U
Kinzl
L
L
Claes
L
L
D000701:Analgesics, Opioid / Q000627:therapeutic use; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use*; D001696:Biomechanical Phenomena; D004008:Diclofenac / Q000627:therapeutic use*; D017102:Fracture Healing / Q000187:drug effects*; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D013978:Tibial Fractures / Q000188:drug therapy / Q000503:physiopathology; D014147:Tramadol / Q000627:therapeutic use
D000701:Analgesics, Opioid; D000894:Anti-Inflammatory Agents, Non-Steroidal; D004008:Diclofenac; D014147:Tramadol