The aim of osteoporosis therapy is to reduce the increased fracture risk associated with osteoporosis-related bone fragility. Prevention of fragility fracture relies on balanced nutrition, weight-bearing and balance-improving physical exercises, and pharmacological therapies. Among the latter, the antiresorptive drugs are the most widely used. Bone formation stimulators (anabolics) are second line-therapy with reversible effects once discontinued. For patients at very high risk or imminent risk of fracture, the question arises of whether combining drugs with different modes of action, or using sequential regimens with these agents, could achieve early, higher-magnitude antifracture efficacy than is obtained with usual antiresorptives, and sustained antifracture efficacy. As regards combination therapies, until we have clear evidence that using drugs together provides greater fracture risk reduction than monotherapy, these therapies are not recommended. Anabolic treatments like teriparatide, the amino-terminal fragment of parathyroid hormone, abaloparatide, an analog of parathyroid hormone related protein, and romosozumab, the monoclonal antibody against sclerostin, decrease vertebral and non-vertebral fracture risk and are more efficacious in fracture risk reduction than antiresorptives, as shown in head-to-head trials. However, an anabolic agent should be followed by an antiresorptive drug to maintain and even further increase its antifracture efficacy, which is otherwise rapidly reversible. Because of their early, high-magnitude and sustained antifracture efficacy, such sequential regimens should become the standard of care for patients at very high or imminent risk of fracture.