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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 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.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.

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

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
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Fig2: 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

Mentions: During the 10 weeks of the study, the weight gain was similar in all four experimental groups; however, the MM rats showed a different pattern of weight distribution compared to the sham controls. The rats tended to shift their weight forward to their front legs gradually as they became heavier with age (Fig. 2). In all of the MM rats, the shift toward the front legs occurred earlier and was clearly visible at the 5-week time point; therefore, the weight-bearing load on the front feet in the MM rats was approximately 20 % greater than in the sham controls (Fig. 2). During the second half of the study, the sham control rats increased the weight bearing on the front feet by 34 %, whereas weight bearing in the MM rats did not change. The load placed on the rear right leg steadily increased in the sham control rats as they gained weight during the course of the study, but the MM rats did not change their load-bearing activity on the operated limb despite the gain in body weight being similar between the Sham and MM groups. The weight-bearing loads placed on the left hind leg were also increased in MM rats treated with Zol and PTH (Fig. 2).Fig. 2


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)

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
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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

Fig2: 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
Mentions: During the 10 weeks of the study, the weight gain was similar in all four experimental groups; however, the MM rats showed a different pattern of weight distribution compared to the sham controls. The rats tended to shift their weight forward to their front legs gradually as they became heavier with age (Fig. 2). In all of the MM rats, the shift toward the front legs occurred earlier and was clearly visible at the 5-week time point; therefore, the weight-bearing load on the front feet in the MM rats was approximately 20 % greater than in the sham controls (Fig. 2). During the second half of the study, the sham control rats increased the weight bearing on the front feet by 34 %, whereas weight bearing in the MM rats did not change. The load placed on the rear right leg steadily increased in the sham control rats as they gained weight during the course of the study, but the MM rats did not change their load-bearing activity on the operated limb despite the gain in body weight being similar between the Sham and MM groups. The weight-bearing loads placed on the left hind leg were also increased in MM rats treated with Zol and PTH (Fig. 2).Fig. 2

Bottom Line: 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.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.

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