The current R34 proposal in response to NIAMS PAR-22-205 will provide us the time and resources to complete the detailed clinical trial planning necessary to meet NIAMS and NIH standards and regulatory requirements prior to submitting a U01 application for funding. Activities included in this proposal include initiating clinical, operational and regulatory activities; developing a data safety monitoring plan; identifying and vetting clinical sites; developing and testing training materials, obtaining investigational drug; establishing data collection, management and data analysis plans; and developing a final budget; and submission of a U01 application for funding. The study being proposed will evaluate the use of denosumab and sequential zoledronic acid therapy to prevent bone loss after acute SCI. Bone loss after acute spinal cord injury (SCI) occurs rapidly and is profound in magnitude, with 50% of bone mass or more being lost in the lower extremities of non-weightbearing individuals, resulting in an elevated risk of fracture and limiting access to weight-bearing rehabilitation. Bone loss is driven primarily by increased bone resorption, and the use of bisphosphonates to prevent bone loss has slowed but not prevented significant bone loss. In contrast, an initial small clinical trial of denosumab, a more potent anti-resorptive agent, has reported efficacy in preventing DXA-determined bone loss after SCI, particularly at skeletal sites around the knee, the most common site of fracture. These data need to be replicated in a larger and more diverse SCI population with bone loss evaluated by accurate CT imaging technology and serum bone markers. And importantly, as the skeletal benefits of denosumab have been shown to be rapidly lost after its discontinuation, an additional intervention to prevent this loss of efficacy after denosumab discontinuation needs to be considered. Intravenously administered zoledronic acid has been shown to be effective in this setting, and we have recently shown in a larger clinical trial that zoledronic acid is effective in reducing bone loss at knee skeletal sites after SCI, providing further support for its use in this setting. Additionally, our data have also demonstrated a significant interaction between zoledronic acid treatment and a measure of ambulatory ability, WISCI, strongly suggesting that weight-bearing can impact skeletal outcomes after zoledronic acid treatment and be an important factor for clinical decision making regarding who should be treated. Thus, the overall goal of this study is to assess the efficacy, safety and durability of sequential treatment with denosumab and zoledronic acid to prevent and maintain bone loss after acute SCI. We will utilize the setting of a double-blind, randomized clinical trial, with initial denosumab and placebo treatment for 12 months (dosing at baseline and at 6 months) after acute SCI, followed by randomization at that point of the group receiving denosumab, stratif...