Protective effect of zoledronic acid on articular cartilage and subchondral bone of rabbits with experimental knee osteoarthritis

Abstract

Subchondral bone reabsorption and remodeling are responsible for the initiation and progression of osteoarthritis (OA). Zoledronic acid (ZOL), a third-generation bisphosphonate (BIS), is an inhibitor of bone reabsorption. However, the intervention effect of ZOL on OA has not been fully characterized and remains to be directly demonstrated in animal experiments. The present study examined the microscopic and macroscopic changes in the anterior cruciate ligament transection (ACLT) model of OA in rabbits and evaluated the effects of ZOL on cartilage degeneration and subchondral bone loss. A total of 32 New Zealand white rabbits were randomly divided into four groups: High-, medium- and low-dose ZOL groups, which received an intravenous injection of 250, 50 and 10 µg/kg ZOL, respectively, after modeling, as well as an untreated group. The bone mineral density (BMD) of the knee joint was evaluated by dual-energy X-ray absorptiometry scanning immediately after modeling and at 4 and 8 weeks. At week 8, quantitative measurement of cartilage was performed by a specialized magnetic resonance imaging (MRI) technique, including three-dimensional fat-suppressed spoil gradient-recalled sequence and T2 mapping. The rabbits were sacrificed by air embolism after anesthesia and both knee joints were harvested and evaluated by general and histological observation. Toluidine blue and hematoxylin and eosin staining were used to assess histological changes in the articular cartilage. Quantitative analysis of cartilage histopathology was performed according to the Mankin scoring system. The BMD of ACLT joints dropped after modeling, which was effectively suppressed by ZOL at the high and medium dose but not the low dose. MRI scans demonstrated that in the untreated group, articular cartilages on ACLT knees were thinner than those on normal knees. The high dose of ZOL preserved the cartilage tissue thickness more efficiently than the medium and low doses. Observation of specimens and pathological slices revealed that the articular cartilage degeneration in the high-dose ZOL group was lightest, while that in the medium- and low-dose ZOL group was moderate, and the untreated group exhibited the most severe defect. The untreated group had the highest Mankin score, whereas the high-dose ZOL group had the lowest score. In conclusion, ZOL increased the subchondral bone density, improved the microstructure and reduced the degeneration of articular cartilage in OA according to morphological as well as quantitative observation. ZOL exerted significant chondroprotective effects in a dose-dependent manner. A favorable chondroprotective effect was induced at the dose of 250 µg/kg. ZOL may represent a novel promising drug to complement the treatment of OA.

Bisphosphonates as disease-modifying drugs in osteoarthritis preclinical studies: a systematic review from 2000 to 2020

“…Preclinical studies included healthy animals of both sexes and were performed in rabbits (9 out of 26; 34.6%) and rats (9 out of 26; 34.6%), followed by mice (3 out of 26; 11.5%), guinea pigs (2 out of 26, 7.8%), and dogs (3 out of 26; 11.5%). In this review, in the majority of the studies that included dog and rabbit models, OA was surgically induced by anterior cruciate ligament transection (ACLT) and/or medial meniscectomy (MMT) [ 20 – 27 , 43 – 45 ]. Only one study in rabbits used intraarticular injection of chymopapain for chemically-induced OA [ 28 ].…”

“…The most common type was alendronate, studied in 11 articles: two in rabbits [ 23 , 24 ], five in rats [ 31 – 33 , 35 , 37 ], three in mice [ 38 – 40 ], and one in guinea pigs [ 42 ]. It was followed by zoledronic acid with 7 articles: three in rabbits [ 20 , 21 , 28 ], three in rats [ 29 , 30 , 36 ], and one in dogs [ 43 ], and risedronate with 6 studies: four in rabbits [ 22 , 25 – 27 ], one in rats [ 35 ], and one in guinea pigs [ 41 ]. Two studies in dogs evaluated the effect of tiludronate [ 44 , 45 ], and only one study in rats focused on the effect of pamidronate [ 34 ].…”

“… + x x ? Panahafir et al [ 33 ] + x x + x Shirai et al, 2011 [ 23 ] + + x – + Zhang et al [ 24 ] + + x x + Sniekers et al [ 40 ] + + x x x Jones et al [ 35 ] + + x + x Ding et al [ 42 ] – + x x x Hayami et al [ 37 ] + + x + + Zoledronic acid ( n = 7) She et al [ 20 ] + + x x x Cinar et al [ 29 ] + x + x – Bagi et al [ 30 ] – + x – + Lampropoulou et al [ 21 ] + x x x x Dearmin et al, 2014 [ 43 ] + x x …”

No Effect of Long-Term Risedronate Use on Cartilage and Subchondral Bone in an Experimental Rabbit Model of Osteoarthritis

“…In this regard, antiresorptive agents have been proposed as potential disease-modifying OA drugs. It is believed that bisphosphonates could modulate the subchondral bone remodeling and consequently inducing changes in the OA progression, reducing the cartilage degeneration ( 3 , 10 , 13 , 18 – 20 , 49 ). In previous preclinical studies, risedronate has shown a reduction in the cartilage pathology ( 50 ) and changes in cancellous bone microarchitecture leading to improved mechanical properties ( 17 , 23 , 24 ).…”

“…Currently, there is an increasing interest in their application in OA (7,15,16). Treatment with BPs seems to induce a decrease in the severity of OA scores, showing less cartilage pathology and bone changes in experimental animal models such as rats (3,10,17,18), and rabbits (13,19,20). But it is still controversial whether these are effective in stopping the disease progression, because in some osteoarthritis preclinical research using guinea pigs (21), rats (14), and dogs (22), it was reported that the administration of BPs showed no effect on preventing the articular cartilage damage or even worsened the cartilage conditions in spite of greater subchondral bone quality.…”