Background/Purpose:

The most common cause of total joint replacement revision surgeries is loosening of the implant due to loss of bone around the prosthesis. Wear particles shed from the prosthesis plays a critical role by increasing local inflammation and osteoclast number and activity, ultimately causing osteolysis. We have previously reported that an A_2A adenosine receptor selective agonist (CGS21680, CGS) prevents osteolysis in wear particle-induced osteolysis model in mice. Frequent administration requirements and potential toxicity make it a less than optimal treatment for inflammatory osteolysis. We therefore generated and tested a novel alendronate-CGS conjugate (MRS7216) that specifically localizes to bone targeting the agonist to the site of tissue injury and thereby diminishing the frequency of administration and curtailing systemic side effects.

Methods:

The conjugate was synthesized from CGS by sequential activation of the carboxylic acid moiety and reacting with the appropriate amino acid under basic conditions. A PEG₆ linker was incorporated to alendronic acid by direct coupling. Osteolysis in 6–8-week-old C57BL/6J mice was induced by surgical implantation of 3mg of ultrahigh-molecular-weight-polyethylene particles over the calvaria. Mice received a weekly 10mg/kg intraperitoneal dose of MRS7216 conjugate, starting at the time of surgery. Other groups of mice were treated with equivalent weekly doses of alendronate-PEG₆ (AlenP) or saline respectively. An additional control group underwent sham surgery. After 2 weeks, animals were sacrificed and microCT and histology analyses were performed. The studies were approved by the Institutional Animal Care and Use Committee of NYU School of Medicine.

Results:

Receptor binding studies demonstrate that the K_i for CGS, 7216 conjugates and the control AlenP molecules were 21.5 nM, 69.2 nM and >10,000 nM respectively, indicating that MRS7216 efficiently binds the A_2A adenosine receptor. MicroCT studies showed that mice treated with weekly doses of 7216 had a significant reduction in bone damage of 40% (p=0.04) compared to saline treated mice. In contrast, AlenP molecules did not prevent bone erosion. Histological analysis of TRAP stained samples showed a significant decrease of osteoclast number/high-power field (HPF) of 55% (p=0.03) in AlenP treated mice compared to the saline treated group. The osteoclast depletion was more dramatic in MRS7216 treated group with an 81% reduction of osteoclasts number/HPF (p= 0.002). Additionally alkaline phosphatase staining in MRS7216 treated group, showed a significant increase in osteoblast number/HPF compared to saline (55%, p=0.01) and to AlenP group (45%, p=0.03).

Conclusion:

Alendronate-CGS conjugates represent a novel therapeutic approach to prevent osteolysis and prosthetic failure in patients with prosthetic joints.

« Back to 2018 ACR/ARHP Annual Meeting

ACR Meeting Abstracts - https://acrabstracts.org/abstract/alendronate-cgs21680-conjugates-prevent-bone-erosion-in-a-murine-osteolysis-model/