Effect of antiresorptive and anabolic bone therapy on development of osteoarthritis in a posttraumatic rat model of OA

Cedo M Bagi, Edwin Berryman, David E Zakur, Dean Wilkie, Catharine J Andresen, Cedo M Bagi, Edwin Berryman, David E Zakur, Dean Wilkie, Catharine J Andresen

Abstract

Introduction: Osteoarthritis (OA) is a leading cause of disability, but despite the high unmet clinical need and extensive research seeking dependable therapeutic interventions, no proven disease-modifying treatment for OA is currently available. Due to the close interaction and interplay between the articular cartilage and the subchondral bone plate, it has been hypothesized that antiresorptive drugs can also reduce cartilage degradation, inhibit excessive turnover of the subchondral bone plate, prevent osteophyte formation, and/or that bone anabolic drugs might also stimulate cartilage synthesis by chondrocytes and preserve cartilage integrity. The benefit of intensive zoledronate (Zol) and parathyroid hormone (PTH) therapy for bone and cartilage metabolism was evaluated in a rat model of OA.

Methods: Medial meniscectomy (MM) was used to induce OA in male Lewis rats. Therapy with Zol and human PTH was initiated immediately after surgery. A dynamic weight-bearing (DWB) system was deployed to evaluate the weight-bearing capacity of the front and hind legs. At the end of the 10-week study, the rats were euthanized and the cartilage pathology was evaluated by contrast (Hexabrix)-enhanced μCT imaging and traditional histology. Bone tissue was evaluated at the tibial metaphysis and epiphysis, including the subchondral bone. Histological techniques and dynamic histomorphometry were used to evaluate cartilage morphology and bone mineralization.

Results: The results of this study highlight the complex changes in bone metabolism in different bone compartments influenced by local factors, including inflammation, pain and mechanical loads. Surgery caused severe and extensive deterioration of the articular cartilage at the medial tibial plateau, as evidenced by contrast-enhanced μCT and histology. The study results showed the negative impact of MM surgery on the weight-bearing capacity of the operated limb, which was not corrected by treatment. Although both Zol and PTH improved subchondral bone mass and Zol reduced serum CTX-II level, both treatments failed to prevent or correct cartilage deterioration, osteophyte formation and mechanical incapacity.

Conclusions: The various methods utilized in this study showed that aggressive treatment with Zol and PTH did not have the capacity to prevent or correct the deterioration of the hyaline cartilage, thickening of the subchondral bone plate, osteophyte formation or the mechanical incapacity of the osteoarthritic knee.

Figures

Fig. 1
Fig. 1
a and b show two-dimensional micro-computed tomography (μCT) images of the proximal tibia from sham control (Sham) (a) and medial meniscectomy vehicle-treated (MM + veh) rats (b). Red line indicated the area of cancellous bone evaluation at tibial epiphysis (e) and metaphysis (m). Arrowhead points at the osteophyte. c and d show EPIC μCT images of the same tibias depicted in (a) and (b). The red arrow indicates normal articular cartilage whereas the dotted arrow indicates osteoarthritic cartilage. e and f show larger EPIC μCT images of the articular cartilage. The length of the medial tibial plateau was measured for each sample and then divided into three zones ranging from 0.8 to 1.0 mm in length. Zone 1 (Z1) was placed on the outside of the medial edge of the joint and Zone 3 (Z3) on the inside of the tibial plateau adjacent to the central collateral ligaments. Zones are delineated by dotted lines. The red arrow indicates normal articular cartilage whereas the dotted arrow indicates osteoarthritic cartilage
Fig. 2
Fig. 2
Changes in the body weight (a) and weight-bearing activity of the front feet (b), rear left leg (c) and on the operated rear right leg (d). The weight-bearing load on the front feet in all three groups of medial meniscectomy (MM) rats was greater at the 5-week time point compared to the sham control (Sham) rats. The load on the rear right leg was diminished in all three groups of MM rats at both week 5 and week 10. *p < 0.05 relative to Sham rats
Fig. 3
Fig. 3
Two-dimensional micro-computed tomography (μCT) images of the proximal tibia from rats assign to study group 3A to 3D. Arrows indicate cancellous bone at the tibial metaphysis. Graph underneath depicts trabecular bone volume (a), trabecular number (b) and trabecular thickness (c) parameter obtained by μCT at proximal tibial metaphysis of the operated right leg. ap < 0.05 relative to sham control (Sham) rats; *p < 0.05 or **p < 0.01 relative to medial meniscectomy vehicle-treated (MM + veh) rats
Fig. 4
Fig. 4
Two-dimensional micro-computed tomography (μCT) images of the medial tibial epiphysis from rats assign to study group 4A to 4D. Pink lines indicate area of the cancellous bone assessment. Arrowheads indicate osteophytes; arrows indicate accumulation of subchondral bone. Graph underneath depicts trabecular bone volume (a), trabecular number (b) and trabecular thickness (c) parameter obtained by μCT at proximal tibial metaphysis of the operated right leg. ap < 0.05 relative to sham control (Sham) rats; *p < 0.05 relative to medial meniscectomy vehicle-treated (MM + veh) rats
Fig. 5
Fig. 5
Top row shows EPIC micro-computed tomography (μCT) images of the articular cartilage covering the medial tibial plateau from rats assign to study group 5A to 5D. Arrows indicate cartilage defects present in all three groups of operated rats. Second row depicts large cartilage defects extending over the lateral half of Zone 1 and medial half of Zone 2, as indicated by arrows in three-dimensional μCT color thickness (“heat”) map of the articular cartilage at the medial tibial plateau
Fig. 6
Fig. 6
Polarized light picture of the proximal tibial epiphysis stained with hematoxylin and eosin (H&E) from rats assign to study group 6A to 6D. All three groups of medial meniscectomy (MM) rats had thicker subchondral bone plate (sbp), particularly the rats treated with zoledronate (Zol). Additionally, the calcified cartilage layer seemed to be better preserved in the Zol-treated group. The arrowhead indicates defects of the articular cartilage, and the green arrowhead indicates osteophytes
Fig. 7
Fig. 7
The grading of osteoarthritis (OA) lesions using damage score (a), significant cartilage degeneration width (b), osteophyte size (c), cartilage thickness (d), and cartilage matrix loss width (e). **Significantly different from sham control group (Sham) at p < 0.01
Fig. 8
Fig. 8
Ultraviolet (UV) images of the medial tibial epiphysis. There is little bone formation in the epiphysis of the sham control (Sham) (a) rat and more intensive bone formation and buildup of the subchondral bone and osteophyte formation (arrow) in the epiphysis of the medial meniscectomy vehicle-treated (MM + veh) rat (b). Intensive formation of subchondral bone plate and osteophyte formation is seen in the MM + zoledronic acid (Zol)- (c) and MM + parathyroid hormone (PTH)-treated rats (d); however, more intensive labeling with both alizarin red and osteocalcin is evident in the PTH-treated rats. The arrowheads indicate osteophyte formation; e – epiphysis; m – metaphysis; gp – growth plate

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