Bisphosphonates for orthopedic applications. Studies in rat models

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

Systemic alendronate prevents resorption of necrotic bone during revascularization. A bone chamber study in rats

Abstract Background Avascular necrosis of bone (osteonecrosis) can cause structural failure and subsequent deformation, leading to joint dysfunction and pain. Structural failure is the result of resorption of necrotic bone during revascularization, before new bone has formed or consolidated enough for loadbearing. Bone resorption can be reduced by bisphosphonates. If resorption of the necrotic bone could be reduced during the revascularization phase until sufficient new bone has formed, it would appear that structural failure could be avoided. Methods To test whether resorption of necrotic bone can be prevented, structural grafts were subjected to new bone ingrowth during systemic bisphosphonate treatment in a rat model. Results In rats treated with alendronate the necrotic bone was not resorbed, whereas it was almost entirely resorbed in the controls. Conclusion Systemic alendronate treatment prevents resorption of necrotic bone during revascularization. In patients with osteonecrosis, bisphosphonates may therefore prevent collapse of the necrotic bone.</p

Bone allografts pretreated with a bisphosphonate are not resorbed

Bisphosphonates bind to bone surfaces and inactivate osteoclasts when they start to resorb the bone. Therefore, immersion of a bone graft in a bisphosphonate solution before implantation may protect it from resorption. We implanted frozen cancellous; bone allografts; into bilateral bone chambers for 6 weeks in 10 rats. One graft in each pair had been immersed in an alendronate solution (1 mg/mL) for 10 minutes, and then rinsed in saline. Controls underwent the same treatment with saline only. Results were evaluated with histomorphometry. Control grafts were almost entirely resorbed, but alendronate-treated grafts seemed intact. In the treated specimens, two thirds of the space behind the bone ingrowth frontier consisted of graft or host bone, but in the controls, only one fifth. Local graft treatment with a bisphosphonate before insertion seems to be risk-free, and may prevent mechanical graft failure due to resorption in patients

Reduction of instability-induced bone resorption using bisphosphonates: high doses are needed in rats.

Bone resorption associated with prosthetic loosening can be reduced by giving bisphosphonates since they bind to bone surfaces and inactivate osteoclasts when bisphosphonate-containing bone is resorbed. During loosening, an increase in osteoclastic activity can be triggered by mechanical instability, fluid pressure or wear particles. We used a rat model in which a titanium surface can be made to slide over a bone surface and cause instability-induced bone resorption. 111 rats were operated on with a plate implant and treated with alendronate or clodronate injections in different doses or saline controls. After 4 weeks of osseointegration, the plate was moved during 2 weeks and the findings evaluated with histomorphometry. The percentage of persisting bone-metal contact and the soft tissue area at the interface were measured to estimate bone loss. Low or intermediate doses of the bisphosphonates increased the ash weight of untraumatized bone, but did not inhibit resorption at the unstable interface. Only rats treated with the highest doses of alendronate or clodronate had more bone-metal contact than controls. Instability-induced bone resorption therefore seems to be reduced by bisphosphonates, but higher doses are needed to obtain this effect than to reduce bone resorption associated with normal remodeling of untraumatized bone

Systemic alendronate prevents resorption of necrotic bone during revascularization. A bone chamber study in rats

Background: Avascular necrosis of bone (osteonecrosis) can cause structural failure and subsequent deformation, leading to joint dysfunction and pain. Structural failure is the result of resorption of necrotic bone during revascularization, before new bone has formed or consolidated enough for loadbearing. Bone resorption can be reduced by bisphosphonates. If resorption of the necrotic bone could be reduced during the revascularization phase until sufficient new bone has formed, it would appear that structural failure could be avoided. Methods: To test whether resorption of necrotic bone can be prevented, structural grafts were subjected to new bone ingrowth during systemic bisphosphonate treatment in a rat model. Results: In rats treated with alendronate the necrotic bone was not resorbed, whereas it was almost entirely resorbed in the controls. Conclusion: Systemic alendronate treatment prevents resorption of necrotic bone during revascularization. In patients with osteonecrosis, bisphosphonates may therefore prevent collapse of the necrotic bone