Improvement of the bony incorporation of a soft-tissue graft after ACL reconstruction by local administration of Osteoprotegerin between the bone and tendon graft. Fifteen New Zealand White rabbits underwent unilateral anterior cruciate ligament (ACL) reconstruction using an autologous semitendinosis tendon graft. We compared the effect of three OPG doses (5 microg, 50 microg, or 100 microg) at the tendon-bone interface to the controls (OPG carrier) and ACL reconstruction only. Specimens were analyzed at 3 weeks using radiology, histology and histomorphometry to investigate the effect of OPG on the bony incorporation of the tendon graft. Animals treated with OPG 100 microg had a significant (p = 0.007) increase in newly-formed bone around the graft compared to the control group (0.16 +/- 0.01 mm(2); 0.06 +/- 0.02 mm(2)). No significant differences were found between the controls and the other groups (tendon graft only, OPG 5 microg, and 50 microg) (p > 0.05). Bone mineral density, measured in image-pixel brightness (IPB; reference range: 0-255), along the edge of the bone tunnel was greater in the OPG 100 microg group (169.5 +/- 5.9 IPB) compared to the control group (150.3 +/- 4.3 IPB) but this was not statistically significant (p = 0.083). There was a significant decrease in the number of osteoclasts per high-power microscopic fields (HPF) lining the bone tunnel in the OPG 100 microg group compared to the control group (4.4 +/- 2.5 cells/HPF; 6.4 +/- 1.8 cells/HPF) (p = 0.022). No significant differences were found between the control group and the other groups in osteoclast numbers (p > 0.05). Since tendon-bone healing requires new bone formation and bone ingrowth around a tendon graft, OPG may improve biologic graft fixation. A potential implication could be earlier return to function or better conditions in revision surgery.