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

Bagi CM, Berryman E, Zakur DE, Wilkie D, Andresen CJ - Arthritis Res. Ther. (2015)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Global Science and Technology, Pfizer Global Research and Development, Pfizer Inc., 100 Eastern Point Road, Groton, CT, 06340, USA. cedo.bagi@pfizer.com.

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.

No MeSH data available.


Related in: MedlinePlus

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
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Fig6: 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

Mentions: Histological evaluation of the articular cartilage revealed classic images of cartilage degradation caused by the MM surgery, including a thinning to complete absence of the cartilage due to chondrocyte death or atrophy, cartilage fibrillation and the presence of osteophytes. In the control rats, the articular cartilage at the medial tibial plateau grew progressively thicker from the most medial (Z1) to the most lateral part (Z3), as revealed in histological sections and scoring (Fig. 6a; 7d). As a result of mechanical imbalance caused by the MM surgery, articular cartilage at the most medial half of Z1 next to the osteophytes was thickening, whereas the most lateral half of Z1 became very thin. The cartilage was very thin and in some cases completely missing in Z2 in the MM + veh rats, whereas the cartilage thickness in Z3 was comparable between the Sham and MM rats (Fig. 6b; 7a-d). Treatment with Zol and PTH did not have significant effects on the thickness of the articular cartilage or on the formation and size of the osteophytes (Fig. 6c and d; 7a-d).Fig. 6


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

Bagi CM, Berryman E, Zakur DE, Wilkie D, Andresen CJ - Arthritis Res. Ther. (2015)

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
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4635572&req=5

Fig6: 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
Mentions: Histological evaluation of the articular cartilage revealed classic images of cartilage degradation caused by the MM surgery, including a thinning to complete absence of the cartilage due to chondrocyte death or atrophy, cartilage fibrillation and the presence of osteophytes. In the control rats, the articular cartilage at the medial tibial plateau grew progressively thicker from the most medial (Z1) to the most lateral part (Z3), as revealed in histological sections and scoring (Fig. 6a; 7d). As a result of mechanical imbalance caused by the MM surgery, articular cartilage at the most medial half of Z1 next to the osteophytes was thickening, whereas the most lateral half of Z1 became very thin. The cartilage was very thin and in some cases completely missing in Z2 in the MM + veh rats, whereas the cartilage thickness in Z3 was comparable between the Sham and MM rats (Fig. 6b; 7a-d). Treatment with Zol and PTH did not have significant effects on the thickness of the articular cartilage or on the formation and size of the osteophytes (Fig. 6c and d; 7a-d).Fig. 6

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Global Science and Technology, Pfizer Global Research and Development, Pfizer Inc., 100 Eastern Point Road, Groton, CT, 06340, USA. cedo.bagi@pfizer.com.

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.

No MeSH data available.


Related in: MedlinePlus