Harnessing the anabolic potential of Wnt signaling to improve bone health

About This Grant

Significance to the VA: Musculoskeletal disorders occur at a much higher in the Veteran population compared to the civilian population,(38) but there are very few approved choices for osteoanabolic therapy. Recently, the FDA approved the first bone anabolic agent outside of the PTH/PTHrP class—Evenity (Romosozumab [Romo])—to treat patients at high risk of fracture. This agent is the most potent bone-building drug available, and it works by inhibiting sclerostin. However, an increased risk of cardiovascular (CV) disease was found during several phase III clinical trials. This concern prompted the FDA to assign a “black box warning” to Romo, alerting prescribers/patients to the significant CV risks. Veterans are at significantly greater risk for CV conditions compared to the civilian patients,(11) and CV disease is the leading cause of hospitalization in the VA system.(12) Thus Romo, in its current design, is a poor choice for use as a skeletal therapy among much of the VA population. This is disappointing because Romo is a tremendous bone-builder, but the CV risks associated with its use preclude application to much of the Veteran population. Is there a way to make Romo safer in terms of CV risk factors? Innovation and Impact:. This project is innovative in that it is focused on (1) making Romosozumab more potent in the skeleton, so that much lower doses of the agent can achieve the same (or better) osteoanabolic response, while (2) minimizing/neutralizing CV side effects of sclerostin inhibition by manipulating other regulatory pathways (Dkk1 upregulation) that counter the CV deficiencies induced my sclerostin blockade. Our work revealed that the upregulation of Dkk1 (another Wnt antagonist) is directly responsible for the attenuation of the otherwise more robust bone-building effects of sclerostin inhibition. If Dkk1 upregulation is prevented during sclerostin antibody treatment, the osteoanabolic effects of Scl-Ab are remarkably greater. As a second benefit to co-treatment with Dkk1 suppressors, Dkk1 rescues CV deficiencies caused by sclerostin antibody. Dkk1 is conclusively atherogenic, and Dkk1 blockade improves CV function. While there are no current FDA- approved Dkk1 antibodies (as for sclerostin), we discovered a clinically available and potent way to suppress Dkk1 levels in bone—via statin exposure. Statins dramatically downregulate Dkk1 protein and mRNA expression, and Dkk1 itself mediates many of the main effects of statin treatment. We will harness the Dkk1- suppressing effects of statins, in combination with sclerostin antibody, to define a highly osteoanabolic therapy that requires very low doses of sclerostin antibody, while protecting CV function (Dkk1-lowering effects). This approach presents an immediately available therapy for Veterans suffering from skeletal problems. Specific Aims: Aim 1: Determine whether Dkk1 suppression via statin treatment, can serve as a co-treatment given along with sclerostin antibody, to simultaneously (subAim1.1) improve the bone-building effects of Scl- Ab while (subAim1.2) reducing cardiovascular complications of Scl-Ab. Aim 2: Determine (subAim2.1) the molecular mechanisms driving improved fracture (Fx) healing by combined Sost/Dkk1 inhibition, and (subAim2.2) whether the beneficial effects of combined Sost/Dkk1 inhibition on Fx healing can be achieved using statins to inhibit the Dkk1 arm of combined therapy. Methodology: Adult/aged mice will be used to test efficacy and optimization of statin type and duration, in concert with sclerostin neutralization, to improve bone properties. Controls for each test article will be included (via gavage or injection) and analysis of outcomes will be performed using radiographic, histologic, biomechanical, biochemical, and sequencing assays. Rigorous statistical methods will be employed. Path to translation/implementation: Both Romosozumab and many types of statins are already clinically approved, so the pathway to translation of this project is very short. We have generated significant interest in our approach/mechanism from Amgen, Inc. (producers of Romosozumab) on this project. They are supplying reagents (sclerostin antibody) for this project to help define the efficacy of our approach.