This study aimed to determine whether locally applied anti-resorptive agents acetazolamide or zoledronic acid would improve mechanical stability in implant osseointegration when applied as a solution within the medullary canal. Thirty-three rats received titanium-implants bilaterally in their intramedullary femoral canals. Prior to implantation, animals received 0.1 ml saline, 1 mM acetazolamide solution, or 0.7 mM zoledronic acid solution directly into the medullary cavity. The control group only received saline within the medullary canal while the treatment groups only received the respective treatment to which they were randomized. Animals were allowed to heal 4 weeks, at which time they were euthanized and femurs isolated for mechanical and radiographic evaluation. Push-out force to failure increased 152% in the zoledronic acid group relative to the control. There was no significant difference in push-out force with acetazolamide relative to control. Also, zoledronic acid increased metaphyseal bone volume fraction 46% and increased metaphyseal bone-implant contact 58% relative to the control. Recent research exploring local injection of medications to improve implant osseointegration and minimize systemic-effects has failed to quantitatively evaluate implant fixation strength on non-hydroxyapatite coated implants or implants without previous bone compaction. This study demonstrated that a simple injection of zoledronic acid into the medullary canal, rather than coatings or commercial gels, can increase fixation strength of an uncoated titanium-implant. Our findings indicate simple injection of zoledronic acid in saline solution has the potential for improving fixation of uncemented joint implants. Clinical Significance: Intramedullary injection of local bisphosphonate solutions could be implemented to improve osseointegration in cementless arthroplasty. © 2018 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:3294-3298, 2018.