A Systematic Review of Basic Science and Animal Studies on the Use of Doxycycline to Reduce the Risk of Posttraumatic Osteoarthritis After Anterior Cruciate Ligament Rupture/Transection

Abstract

Background: Posttraumatic osteoarthritis (PTOA) after injury to the anterior cruciate ligament (ACL) is common. Purpose: To perform a systematic review of basic science and animal studies to determine the effect of doxycycline treatment on the prevention of PTOA after ACL rupture/transection. Study Design: Systematic review. Methods: A systematic review was performed by searching the PubMed, Cochrane Library, and Embase databases to identify basic science and animal studies evaluating the effect of doxycycline treatment on the prevention of PTOA of the knee joint after ACL/cranial cruciate ligament (CCL) injury. The search phrase used was “doxycycline cruciate ligament.” Inclusion criteria were basic science and animal studies evaluating the effect of oral administration of doxycycline in ACL/CCL-deficient animals with or without a control group. Results: Seven studies met inclusion criteria and were included in this systematic review. Five studies were performed in dogs, 1 in rabbits, and 1 in mice. Overall, the effects of doxycycline treatment on the prevention of PTOA after ACL/CCL rupture/transection were mixed. In dogs, no significant effects of doxycycline treatment were found in terms of matrix metalloproteinase (MMP) activity, while a mouse study found significantly lower MMP-13 expression on the tibia in doxycycline-treated animals, suggesting that doxycycline may protect against proteoglycan loss and decrease osteoarthritis progression. Cartilage nitric oxide concentrations were lower in doxycycline-treated dogs compared with untreated dogs, suggesting decreased cartilage degradation among doxycycline-treated dogs, although there were no significant effects on cartilage stromelysin levels with no significant effects in terms of physiological remodeling or catabolism of cartilage. Bone formation or resorption was not found to be affected by doxycycline treatment. One study demonstrated a substantial beneficial effect of doxycycline on gross morphology of the medial femoral condyle. Doxycycline was found to conserve bone strain energy density and appeared to limit subchondral bone loss in 1 study. Conclusion: Based on the limited available animal studies, doxycycline appears to demonstrate some benefits in the prevention of PTOA after ACL/CCL rupture/transection. Additional studies are needed to further characterize the potential benefits, side effects, dosage, and duration of this treatment after ACL injury in human patients.