Browsing by Subject "Sclerostin Dkk1"

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    Improving Bone Health by Optimizing the Anabolic Action of Wnt Inhibitor Multitargeting
    (Wiley, 2021-05-06) Choi, Roy B.; Bullock, Whitney A.; Hoggatt, April M.; Loots, Gabriela G.; Genetos, Damian C.; Robling, Alexander G.; Anatomy and Cell Biology, School of Medicine
    Sclerostin antibody (romosozumab) was recently approved for clinical use in the United States to treat osteoporosis. We and others have explored Wnt‐based combination therapy to disproportionately improve the anabolic effects of sclerostin inhibition, including cotreatment with sclerostin antibody (Scl‐mAb) and Dkk1 antibody (Dkk1‐mAb). To determine the optimal ratio of Scl‐mAb and Dkk1‐mAb for producing maximal anabolic action, the proportion of Scl‐mAb and Dkk1‐mAb were systematically varied while holding the total antibody dose constant. A 3:1 mixture of Scl‐mAb to Dkk1‐mAb produced two to three times as much cancellous bone mass as an equivalent dose of Scl‐mAb alone. Further, a 75% reduction in the dose of the 3:1 mixture was equally efficacious to a full dose of Scl‐mAb in the distal femur metaphysis. The Scl‐mAb/Dkk1‐mAb combination approach was highly efficacious in the cancellous bone mass, but the cortical compartment was much more subtly affected. The osteoanabolic effects of Wnt pathway targeting can be made more efficient if multiple antagonists are simultaneously targeted. © 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC. on behalf of American Society for Bone and Mineral Research.
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    Targeting Sclerostin and Dkk1 at Optimized Proportions of Low-Dose Antibody Achieves Similar Skeletal Benefits to Higher-Dose Sclerostin Targeting in the Mature Adult and Aged Skeleton
    (JKL International, 2022-12-01) Choi, Roy B.; Hoggatt, April M.; Horan, Daniel J.; Rogers, Emily Z.; Hong, Jung Min; Robling, Alexander G.; Anatomy, Cell Biology and Physiology, School of Medicine
    Age-associated low bone mass disease is a growing problem in the US. Development of osteoanabolic therapies for treating skeletal fragility has lagged behind anti-catabolic therapies, but several bone-building molecules are clinically available. We reported previously that antibody-based neutralization of the Lrp5/Lrp6 inhibitor Dkk1 has minimal effects on bone gain, but can potentiate the already potent osteoanabolic effects of sclerostin inhibition (another Lrp5/Lrp6 inhibitor highly expressed by osteocytes). In this communication, we test whether an optimized ratio of sclerostin and Dkk1 antibodies (Scl-mAb and Dkk1-mAb, respectively), administered at low doses, can maintain the same bone-building effects as higher dose Scl-mAb, in adult (6 months of age) and aged (20 months of age) wild-type mice. A 3:1 dose of Scl-mAb:Dkk1-mAb at 12.5 mg/kg was equally efficacious as 25 mg/kg of Scl-mAb in both age groups, using radiographic (DXA, µCT), biomechanical, (3-point bending tests), and histological (fluorochrome-based bone formation parameters) outcome measures. For some bone properties, including trabecular thickness and bone mineral density in the spine, and endocortical bone formation rates in the femur, the 3:1 treatment was associated with significantly improved skeletal properties compared to twice the dose of Scl-mAb. Cortical porosity in aged mice was also reduced by both Scl-mAb and low-dose 3:1 treatment. Overall, both treatments were efficacious in the mature adult (6 mo.) and aged (20 mo.) skeletons, suggesting Wnt targeting is a viable strategy for improving skeletal fragility in the very old. Further, the data suggest that low dose of combination therapy can be at least equally efficacious as higher doses of Scl-mAb monotherapy.