Locally Delivered Bisphosphonate for Enhancement of Bone Formation and Implant Fixation

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IntroductionBone growth into porous materials has proven to be a very effective method for attaching prosthetic implants to the osseous skeleton1-3. However, there remains a need to develop modalities that can accelerate and/or increase biologic fixation. The more rapidly that bone forms and the greater the amount of bone that forms about and/or within an implant, the faster the implant becomes mechanically secured against the disruptive forces of load bearing and the sooner patients can safely return to their activities of daily living. In situations in which the condition of the bone stock or the healing process is compromised (e.g., when the patient is elderly or has osteoporosis) or the initial stability of the implant is more tenuous or crucial (e.g., during posttraumatic, revision, or minimally invasive procedures), the construct would clearly benefit from enhanced mechanical support.Bisphosphonates reduce bone catabolism by interfering with cell metabolism and causing osteoclast apoptosis; the resulting net gain in bone formation explains their widespread use in treating osteoporosis. There is also the possibility that some bisphosphonates have a catabolic effect by direct action on osteoblasts, although the information is variable4-6. There is growing evidence that bisphosphonate compounds can be utilized to modify the peri-implant bone response in favor of enhanced bone formation and implant fixation. This has been shown in numerous clinical and basic research studies involving the oral, systemic, and local delivery of bisphosphonates7-26. Local delivery is a sensible approach because it reduces the amount of drug used and preferentially targets the site of interest, thereby avoiding systemic exposure. Previous studies in rats and dogs have shown that direct elution of zoledronic acid from implants increased net local bone formation, but the results have been limited primarily to twelve weeks or less and the dose response is not yet fully characterized14,19,20.We hypothesized that the extent of peri-implant net bone gain is dose dependent and that the bone gain persists over the long term. The purpose of this study was to quantify the effect of local delivery of different doses of zoledronic acid on bone growth within and about porous tantalum implants one year after surgery.Materials and MethodsImplants that measured 9 mm in diameter and 90 mm in length (Fig. 1) were manufactured for use in a canine femoral intramedullary model. The implants were made of porous tantalum (Trabecular Metal; Zimmer, Warsaw, Indiana), a metallic biomaterial that is approximately 80% porous, with a mean pore size of about 450 μm27,28. The implants were plasma-spray-coated with a 10 to 15-μm layer of hydroxyapatite, the composition of which was 98% pure, 99% dense, and 64% crystalline and had a calcium-to-phosphate ratio of 1.67. As previously described, the hydroxyapatite served to partially immobilize the zoledronic acid through its chemical affinity for calcium phosphate14,19. After use of this delivery system, Tanzer et al.14 and Roberts et al.29 described a biphasic zoledronic acid elution profile consisting of an initial burst release within a few hours followed by a much slower, protracted, and progressive release over many weeks.Zoledronic acid was utilized because it is a third-generation compound that is considered to be the most potent aminobisphosphonate, as much as 1000 times more potent than pamidronate30. Commercially pure zoledronic acid (Novartis Pharmaceuticals, Basel, Switzerland) was dissolved in distilled water, after which a 1-mL aliquot containing either 0.05 mg or 0.20 mg of zoledronic acid was systematically and evenly applied to implants with use of a micropipette.

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