Bisphosphonates for orthopedic applications. Studies in rat models

University dissertation from Department of Orthopaedics (Lund)

Abstract: Prosthetic loosening, bone graft resorption and osteonecrosis are examples of problems in orthopedic surgery caused by or augmented by bone resorption. Bone resorption is caused by osteoclasts. Osteoclasts can be inactivated with biphosphonates, a drug in clinical use against osteoporosis and osteolytic tumors. The bone resorption-reducing ability of bisphosphonates was analyzed in rat models. An implant with a moveable disk in contact with cortical bone was used to stimulate bone resorption induced by movement. Oscillating fluid pressure have also been suggested to cause bone resorption around joint implants. We used a plate implant where a soft tissue membrane adjacent to cortical bone was compressed intermittently, creating increased hydrostatic pressure that cause bone resorption. In these two models bone resorption was reduced, but the required dose was high. Since bisphosphonates have high affinity for bone mineral, topical administration is feasible. Using the fluid pressure plate, we exposed a bone surface for bisphosphonates for one minute after which we rinsed with saline. Bone resorption was reduced compared to controls. Bone graft resorption is a complication to revision arthroplasties and tumor surgery. We tested topical bisphosphonate treatment of structural allografts using a rat chamber model. The grafts were soaked in bisphosphonates or saline and subjected to host bone ingrowth. Control grafts were almost entirely resorbed, but bisphosphonate treated grafts appeared intact. The collapse of bone associated with osteonecrosis is caused by bone resorption following revascularisation. We tested structural allografts in rat chambers. During host bone ingrowth, vascularisation and subsequent bone resorption ocurred during systemic treatment with bisphosphonates or saline. The grafts from treated rats were less resorbed. In conclusion, bisphosphonates can reduce bone resorption induced by movement or fluid pressure in rats, although high doses were needed compared to doses used against osteoporosis. Topical treatment appears to be advantageous and could be administered prior to cementing an implant, and could also be used to prevent resorption of a structural bone graft. Systemic bisphosphonate treatment could be used to reduce bone resorption during the revascularisation phase following osteonecrosis. If bone resorption and thereby collapse of a joint segment could be prevented, joint destruction caused by osteonecrosis could perhaps be avoided.

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