Peri-tunnel bone loss after anterior cruciate ligament (ACL) reconstruction is commonly observed, both clinically and experimentally. We aimed to study the effect and mechanisms of different doses of alendronate in the reduction of peritunnel bone loss and promotion of graft-bone tunnel healing in ACL reconstruction. Eighty-four ACL-reconstructed rats were divided into 4 groups. Alendronate at different dosages, or saline, were injected subcutaneously weekly, for 2 or 6 weeks post-reconstruction, for vivaCT (computed tomography) imaging, biomechanical tests, histology and immunohistochemistry. Alendronate significantly increased bone mass and density of tissue inside bone tunnels except at the epiphyseal region of tibial tunnel. The femoral tunnel diameter decreased significantly in the mid-dose and highdose alendronate groups compared to that in the saline group at week 6. Alendronate significantly increased the peri-tunnel bone mass and density along all tunnel regions at week 6. Better graft-bone tunnel integration and intra-tunnel graft integrity were observed in the alendronate groups. The ultimate load was significantly higher in the mid-dose and high-dose alendronate groups at week 2, but not at week 6. There was a reduction in matrix metalloprotein (MMP)1, MMP13 and CD68-positive cells at the peri-tunnel region and graft-bone interface in the alendronate-treated group compared to the saline group. Alendronate reduced peritunnel bone resorption, increased mineralised tissue inside bone tunnel as well as histologically and biomechanically promoted graft-bone tunnel healing, probably by reducing the expression of MMP1, MMP13 and CD68-positive cells. Alendronate might be used for reducing peri-tunnel bone loss and promoting graft-bone tunnel healing at early stage post-ACL reconstruction.

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Continued systemic administration of alendronate was reported to reduce peri-tunnel bone resorption and promoted graftbone tunnel healing at the early stage post-anterior cruciate ligament (ACL) reconstruction. However, systemic increase in bone mineral density (BMD) in the contralateral intact knee was observed. We tested if single local administration of alendronate into the bone tunnel during ACL reconstruction could achieve similar benefits yet without the systemic effect on bone. Seventy-two rats with unilateral ACL reconstruction were divided into three groups: saline, low-dose (6 mg/kg) and mid-dose (60 mg/kg) alendronate. For local administration, alendronate was applied to the bone tunnels for 2 min before graft insertion and repair. At weeks 2 and 6, the reconstructed complex was harvested for high-resolution computed tomography (vivaCT) imaging followed by biomechanical test or histology. Our results showed that local administration of low-dose alendronate showed comparable benefits on the reduction of peritunnel bone loss, enhancement of bone tunnel mineralization, tunnel graft integrity, graft osteointegration and mechanical strength of the reconstructed complex at early stage post-reconstruction, yet with minimal systemic effect on mineralized tissue at the contralateral intact knee. A single local administration of alendronate at the low-dose therefore might be used to promote early tunnel graft healing post-reconstruction. ß 2013 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res31:1897Res31: -1906Res31: , 2013 Keywords: anterior cruciate ligament reconstruction; tendon graft to bone tunnel healing; bisphosphonate; alendronate; peri-tunnel bone loss Peri-tunnel bone loss was commonly observed after anterior cruciate ligament (ACL) reconstruction both clinically 1-6 and in animal model. 7-11 Theoretically, local bone loss around the knee region after ACL reconstruction could have a negative impact on graft to bone tunnel healing. The tunnel surface might become less stable for graft osteointegration. The decrease in peri-tunnel bone mineral density (BMD) might also undermine the support of the graft-bone tunnel complex and lead to bone fracture due to the reduction in bone strength as well as complicate revision surgery. The production of inflammatory cytokines associated with bone resorption might also negatively impact graft osteointegration and graft integrity. Prevention of local bone loss therefore might promote tendon graft to bone tunnel healing. We have reported that continued systemic administration of alendronate reduced peri-tunnel bone resorption and promoted graft to bone tunnel healing at early stage post-ACL reconstruction.12 However, we observed systemic increase in BMD in the contralateral intact knee, particularly at the tibial metaphysis. While we did not observe any negative effect of this increase and the administration of alendronate is only for limited time post-reconstruction, we hypothesized that single local administration of alendro...

There was time-dependent loss of peri-tunnel bone early post-reconstruction, with the greatest loss occurring at the tibial metaphysis. This was consistent with high expression of MMP1, MMP13 and CD68+ cells at the graft-bone tunnel interface and the peri-tunnel region. The significant loss of peri-tunnel bone, though not critically affecting early tunnel healing, suggested the need to protect the knee joint early post-reconstruction.