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

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

doi:10.1186/s13075-015-0829-5

Abstract

IntroductionOsteoarthritis (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.MethodsMedial 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.ResultsThe 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.ConclusionsThe 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.

Highlights

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
Proposals to use antiresorptive bone therapy to treat OA is largely based on the premise that this therapy will reduce cartilage degradation, inhibit excessive turnover of the subchondral bone plate and prevent bone loss in the limb affected by OA [6, 12]
Serum biomarkers of bone and cartilage metabolism After 5 weeks of dosing the MM rats showed higher C-terminal telopeptide of type II collagen (CTX-II) (p < 0.05) values compared to sham controls

Summary

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. Proposals to use antiresorptive bone therapy to treat OA is largely based on the premise that this therapy will reduce cartilage degradation, inhibit excessive turnover of the subchondral bone plate and prevent bone loss in the limb affected by OA [6, 12]. Sharing of a mesenchymal cell lineage by osteoblasts and chondrocytes suggests that treatment with PTH might stimulate cartilage synthesis by chondrocytes and protect against cartilage degradation [23,24,25,26,27] This implies that perhaps immediate and aggressive treatment with PTH will be more beneficial to prevent cartilage degeneration and initiate the healing in patients with posttraumatic OA (PTOA). The data suggest that aggressive preemptive antiresorptive therapy might be more effective in inhibiting cartilage degradation and excessive turnover of the subchondral bone in posttraumatic states [15, 28, 29]. It should be noted that the majority of preclinical studies utilize intermittent dosing with PTH based on bone-efficacy data [30], even though the work done by Kudo and colleagues showed similar efficacy on cartilage repair with continuous and intermittent administration of PTH [26]

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