Background and Objectives: Individuals classified as having very high fracture risk remain vulnerable to imminent fractures even when treated with antiresorptive therapies. This meta-analysis evaluated whether initiating treatment with anabolic agents, including teriparatide, abaloparatide, and romosozumab, provides superior fracture protection in this high-risk population. Materials and Methods: A systematic review and meta-analysis of randomized controlled trials was conducted following PRISMA standards. Eligible studies included adults at very high fracture risk, defined by recent or multiple fragility fractures or markedly low bone mineral density, who received anabolic therapy as initial treatment compared with placebo or antiresorptive agents. Outcomes of interest were new vertebral, non-vertebral, hip, and clinical fractures. Effect estimates were pooled using random-effects models. Results: Six randomized trials encompassing 17,872 participants were analyzed. Initiation with anabolic therapy was associated with a marked reduction in incident vertebral fractures. The labeled pooled summary estimate for vertebral fractures was 0.43 (95% confidence interval 0.34–0.54). Significant risk reductions were also observed for clinical fractures (hazard ratio 0.62, 95% confidence interval 0.51–0.75), non-vertebral fractures (pooled effect estimate 0.71, 95% confidence interval 0.59–0.85), and hip fractures (risk ratio 0.65, 95% confidence interval 0.45–0.96). Exploratory subgroup analyses suggested greater vertebral fracture protection versus placebo and persistent benefit versus active antiresorptive comparators. Sequential therapy using an anabolic agent followed by an antiresorptive reduced spinal fracture risk by approximately half. Considerable heterogeneity was noted for vertebral fracture outcomes. Conclusions: Starting osteoporosis treatment with anabolic agents results in faster and more-pronounced fracture risk reduction across all major fracture categories in patients at very high fracture risk. These findings support a shift toward anabolic-first treatment sequencing in this particularly vulnerable group.