Limited-duration anabolic therapy in postmenopausal osteoporosis

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PROJECT SUMMARY One in three women and one in five men will experience an osteoporotic fracture during their lifetime. Each year over 300,000 people over the age of 65 are hospitalized for hip fractures which are associated with a 1- year mortality rate of 20-30%. 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. The most recently approved osteoporosis medication, romosozumab, has a unique mechanism of action in that it both stimulates new bone formation and inhibits bone resorption. The timing of these actions, however, differs in that its stimulation of new bone formation is transient, lasting only 1-3 months, whereas its inhibition of bone resorption is sustained. Recently, romosozumab was shown to reduce the risk of both spine and non-spine fractures more than the most widely used osteoporosis medication, alendronate. The recent FDA approval of romosozumab, however, was accompanied by a “black box” warning as studies reported a significant increased risk of major adverse cardiac events including stroke, myocardial infarction, and cardiovascular death. Because romosozumab only transiently stimulates bone formation, we hypothesize that a much shorter course of romosozumab, followed by a drug that potently but selectively inhibits bone resorption, would have similar efficacy to the standard 12-month course of romosozumab. This shorter course of romosozumab would be significantly more cost effective, more acceptable to patients (romosozumab is given as 2 injections every month) and would likely reduce the romosozumab-mediated risk of major adverse cardiac events. In this proposal, we will test our hypothesis via a single open-label proof-of-principle 12-month clinical trial in which postmenopausal women at a high risk of fracture will receive either romosozumab for 3 months followed by the antiresorptive medication, denosumab, for the 9 months or the standard 12-months treatment with romosozumab. The primary endpoint of the study is the changes in dual-energy X-ray absorptiometry-derived total hip bone mineral density from months 0-12. Changes in bone mineral density at other sites, biochemical markers of bone metabolism, high-resolution QCT-derived compartmental volumetric bone mineral density, trabecular bone microarchitecture, and cortical bone structure of the radius and tibia, as well as estimated bone strength assessed by finite element analysis will be assessed as key secondary or exploratory endpoints. The successful completion of the proposed study will define a safer, less expensive, and more rational approach to the use of a promising new osteoporosis medication. In so doing, this study has the potential to fundamentally change the way osteoporosis is treated, especially for those patients with severe and established disease.