title: Implant-delivered Alendronate Causes a Dose-dependent Response on Net Bone Formation Around Porous Titanium Implants in Canines.
abstract: BACKGROUND
  Bony fixation of cementless orthopaedic implants is not always achieved, particularly in challenging scenarios such as revision surgery, trauma, and tumor reconstruction. An adjunct therapy for improving porous implant fixation could improve the reliability and durability of these reconstructive procedures.
  
  
  OBJECTIVE
  In this study, we asked whether there is a positive and dose-dependent effect of the local release of the bisphosphonate alendronate from (1) alendronate/hydroxyapatite (HA) porous-coated titanium implants compared with bare metal porous controls; and (2) alendronate/HA on porous-coated titanium implants compared with HA-coated porous controls with respect to extent of bone ingrowth, bone apposition, and periimplant bone formation in a canine model?
  
  
  METHODS
  Three-dimensional printed porous-coated cylindrical implants coated with three different doses (0.02, 0.06, and 0.18 mg/cm(2)) of alendronate were inserted bilaterally in the intramedullary canal of the proximal femora of 15 adult mongrel dogs (age range, 3-9 years; mean, 5 years) weighing between 36 kg and 60 kg (mean, 43 kg). In each dog, an implant coated with HA and one of three different doses of alendronate was inserted on one side while the contralateral femur had a bare metal porous control implant and an identical control implant with a coating of HA. The dose effect of locally released alendronate on the extent of bone ingrowth, bone apposition, and periimplant bone was assessed by backscattered electron microscopy of three pairs of cross-sections taken from each implant at 12 weeks after surgery. A linear mixed model was used to perform the statistical analyses to account for the correlation in the data resulting from the multiple measures performed on each dog.
  
  
  RESULTS
  Compared with paired bare metal controls, periimplant bone increased by 92% (p = 0.007), and 114% (p < 0.001) in the femora with the alendronate implants with a dose of 0.06 mg/cm(2), or 0.18 mg/cm(2), respectively. At a dose of 0.02 mg/cm(2), there was no difference (46% change; p = 0.184, with the numbers available). The comparison of the alendronate-dosed implants with their HA-coated controls showed that the intermediate dose of 0.06 mg/cm(2) alendronate had the greatest effect on net bone formation. Bone apposition was enhanced with the 0.06-mg/cm(2) alendronate femoral implants (82%; p = 0.008), although there was no change in bone ingrowth (37% change; p = 0.902, with the numbers available). When compared with the HA-coated control implants, the greatest effect of the alendronate-dosed implants was the increased amount of periimplant bone at the intermediate dose of 0.06-mg/cm(2) (108%, p = 0.009). There was no effect of the low (0.02-mg/cm(2)) and high (0.18-mg/cm(2)) alendronate-dosed implants (4%, and 6%, respectively; p = 0.321, p = 0.502). Overall, all three alendronate-dosed implants revealed little to no effect on bone ingrowth compared with the HA-coated control implants.
  
  
  CONCLUSIONS
  The local release of alendronate from a three-dimensional printed porous-coated implant from the three doses studied showed an overall improvement in bone apposition and periimplant bone at the intermediate dose compared with bare metal or with HA-coated controls, although the effect was more pronounced compared with bare metal. Long-term studies to show the effects of localized alendronate delivery and mechanical fixation would be the next step for future studies.
  
  
  CONCLUSIONS
  Local release of alendronate from a three-dimensional printed porous-coated implant may improve the reliability of cementless fixation of currently available porous-coated bare metal implants.
authors.affiliation: Jo Miller Orthopaedic Research Laboratory, Montreal General Hospital, Montreal, QC, Canada. jennyann.pura@mail.mcgill.ca.|Montreal General Hospital, 1650 Cedar Avenue, Room C9-136, Montreal, QC, H3G1A4, Canada. jennyann.pura@mail.mcgill.ca.
authors.forename: Jenny Ann
authors.identifier: http://orcid.org/0000-0001-6506-9218
authors.initials: JA
authors.lastname: Pura
authors.affiliation: Jo Miller Orthopaedic Research Laboratory, Montreal General Hospital, Montreal, QC, Canada.|Division of Orthopaedic Surgery, Department of Surgery, McGill University, Montreal, QC, Canada.
authors.forename: J Dennis
authors.initials: JD
authors.lastname: Bobyn
authors.affiliation: Jo Miller Orthopaedic Research Laboratory, Montreal General Hospital, Montreal, QC, Canada.|Division of Orthopaedic Surgery, Department of Surgery, McGill University, Montreal, QC, Canada.
authors.forename: Michael
authors.initials: M
authors.lastname: Tanzer
mesh_terms: D019386:Alendronate / Q000008:administration & dosage*; D000818:Animals; D050071:Bone Density Conservation Agents / Q000008:administration & dosage*; D000069343:Bone-Implant Interface / Q000000981:diagnostic imaging / Q000601:surgery; D020099:Coated Materials, Biocompatible; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D005260:Female; D005269:Femur / Q000000981:diagnostic imaging / Q000187:drug effects* / Q000601:surgery*; D006882:Hydroxyapatites / Q000737:chemistry*; D008297:Male; D023421:Models, Animal; D016348:Osseointegration / Q000187:drug effects*; D010012:Osteogenesis / Q000187:drug effects*; D016062:Porosity; D011474:Prosthesis Design; D019919:Prosthesis Implantation / Q000295:instrumentation*; D011859:Radiography; D013499:Surface Properties; D014025:Titanium / Q000737:chemistry*
chemical_list: D050071:Bone Density Conservation Agents; D020099:Coated Materials, Biocompatible; D006882:Hydroxyapatites; C098170:hydroxyapatite-titanium alloy; D014025:Titanium; D019386:Alendronate
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