Osteoporosis affects over 20 million Americans leading to 2 million fragility fractures and 300,000 hip fractures every year. Among older adults with hip fracture, there is 5- to 8-fold increased risk of death during the first 3 months post-fracture, and mortality 1-year post-fracture is approximately 25%. Current osteoporosis therapies reduce vertebral fracture risk in high-risk patients but their ability to reduce the risk of non-vertebral fractures and hip fractures, specifically, is modest. Osteoporosis therapies fall into two classes: 1) antiresorptive agents that inhibit bone breakdown and 2) anabolic agents that stimulate new bone formation. Anabolic osteoporosis drugs (which include parathyroid hormone analogs such as teriparatide and the sclerostin inhibitor, romosozumab) are among the most efficacious medications available but do have limitations. Teriparatide, for example, not only stimulates bone formation but bone resorption as well, resulting in increasing porosity of cortical bone. Additionally, the anabolic effects of teriparatide wane after 6-12 months of treatment. Conversely, romosozumab has a unique mechanism of action in that it both stimulates new bone formation and inhibits bone resorption. While its inhibition of bone resorption is sustained, however, its stimulation of bone formation is even more transient than teriparatide’s, lasting only 1-3 months. Developing a therapeutic regimen that stimulates bone formation in a sustained and durable fashion, while also limiting bone resorption would represent a major advance in osteoporosis management and greatly improve patient outcomes. Animal studies have suggested that combining parathyroid hormone analogs with sclerostin inhibition results in greater gains in bone mass than with either drug alone, but this approach has not yet been systematically assessed in patients with osteoporosis. Thus, the aim of this study is to comparatively assess the therapeutic potential of combined anabolic therapy versus the current standard-of-care single-drug approach in postmenopausal women at high risk of fragility fracture. Specifically, in this proposal, we will test the hypothesis that in postmenopausal women with osteoporosis, combined treatment with teriparatide and romosozumab will improve skeletal parameters more than a standard treatment course of 12 months of romosozumab alone. The successful completion of this study and confirmation of our hypothesis has the potential to fundamentally shift the way established osteoporosis is treated and introduce a new concept in osteoporosis management.