Effects of a bisphosphonate on bone histomorphometry and dynamics in the canine cruciate deficiency model of osteoarthritis

Objective. To examine the effect of the bisphosphonate NE-10035 on bone his tomorphometry and bone dynamics in dogs after transection of the anterior c ruciate ligament (ACL), and to determine, in a place bo controlled trial, w hether treatment modified the severity of pathologic changes of osteoarthri tis (OA) in the unstable joint. Methods. Ten adult male mongrel dogs underwent ipsilateral ACL transection. Five dogs then received daily subcutaneous injections of NE-10035 on 5 day s per week for 12 weeks beginning the day after surgery. The other 5 dogs s erved as concurrent OA controls and received subcutaneous injections of sal ine on the same schedule. At sacrifice, 12 weeks after ACL transection, the articular cartilage and synovium of both knees of each dog were evaluated grossly and histologically and the water content and uronic acid concentrat ion of the articular cartilage was determined. Fifteen days before sacrific e, each dog was injected with the fluorochrome label calcein. The injection regimen was repeated 10 days after the initial date. At sacrifice, static and dynamic variables of bone formation were assessed and bone resorption w as quantified. Results. In the OA knee of the control group, bone formation and resorption were markedly increased. NE-10035 markedly reduced both formation and reso rption of cancellous subchondral bone, but had no effect on osteophyte form ation or pathologic changes of OA in the articular cartilage, which were mi ld in both treatment groups, Water content of the OA cartilage was increase d by about 8% in both treatment groups. However, among the controls. the me an uronic acid concentration of the OA cartilage was increased by about 30% in comparison with values for the contralateral knee, while in the NE-1003 5 treatment group the mean uronic acid concentration of OA knee cartilage w as about 15% lower in the active treatment group than in cartilage from the contralateral knee (p = 0.003 for the difference in OA knee uronic acid co ncentration between the 2 treatment groups, relative to that in the contral ateral knee). Conclusion. The antiresorptive agent employed in this study effectively red uced turnover of subchondral bone in the OA joint, consistent with the coup ling of bone formation to bone resorption at that site. Nonetheless, over t he 12 week period of the study it had no effect on osteophyte formation, in which bone formation occurs via enchondral ossification and is not linked to bone resorption, and, despite the clear inhibition of bone turnover in t he OA knee of the active treatment group, did not affect the severity of ca rtilage changes of OA. it should be noted, however, that although treatment with this antiresorptive agent did not affect the level of chondropathy, t he cartilage changes in both treatment groups were relatively mild and the sample size relatively small. Additional studies with a larger number of an imals and a longer period of observation (to increase the severity of patho logy) are warranted to determine whether the inhibition of bone turnover an d the decrease in proteoglycan concentration that resulted from therapy wil l affect articular cartilage degeneration in the OA joint.