Bisphosphonate antiresorptive drug use in a rabbit model of osteoarthritis
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AbstractFollowing anterior cruciate ligament rupture (ACLX) in the knee, rapid periarticular bone loss often occurs prior to the subchondral sclerosis of end-stage osteoarthritis (OA). In a model of knee osteoarthritis, changes were examined in subchondral periarticular bone mineral and microarchitecture (IlCT) and in the femoral insertion of the medial collateral ligament (MCL). Also assessed were whether antiresorptive therapy with a bisphosphonate (BP [risedronate]) altered those bone adaptations in the subchondral plate, at the MCL-insertion, and after ACL-reconstruction, and if BP intervention influenced ligament-complex biomechanics and OA progression. Finally, molecular expression of a bone cytokine (osteoprotegerin [OPG]) in periarticular tissues undergoing remodeling and the influence of BP therapy upon the regulation of that gene were investigated. Early alterations of periarticular bone mineral after ACLX included significant loss in subchondral trabecular bone and in bone at the MCL-insertion. Compared to normal controls, MCL-complex laxity and bone loss at the MCL-insertion were significantly greater in the ACLX cohort at 6 wk and had increased further by 14 wk after ACLX. If ACLX animals were dosed daily with risedronate bisphosphonate for 6 wk, however, MCL-complex laxity was significantly improved, and the loss of MCL insertional bone was significantly less and not significantly different from normal control animals. When animals were dosed up to 24 wk after ACLX with BP, however, the progression of OA was not altered. The transient restabilization of the joint by ACL-reconstruction, in conjunction with BP-dosing, did little to block the progression of OA. The expression of OPG was altered following loss of the ACL, and the BP risedronate countered that effect-resulting in the return of OPG expression in bone and fibrocartilaginous tissues. Such adaptive responses in connective tissues after ACLX may have been necessary for the maintenance and repair of the injured structures. The results suggested a potential therapeutic role for antiresorptive bisphosphonate therapy to inhibit adaptive remodeling early following non-fracture joint trauma. Long-term administration of the BP, however, did not appear to be beneficial, and the ultimate effect of the short-term use of the BP on osteoarthritis progression remains to be determined.
Bibliography: p. 147-159