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Browsing by Subject "Romosozumab"
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Item Combining Sclerostin and DKK1 Inhibitors to Improve Bone Properties in the Aged Skeleton(Oxford University Press, 2022-12-20) Choi, Roy; Robling, Alexander; Anatomy, Cell Biology and Physiology, School of MedicineTargeting the secreted Wnt inhibitor sclerostin has been an attractive strategy to improve skeletal health. Sclerostin antibody (romosozumab-aqqg; Evenity) was recently approved by the FDA to treat patients at increased risk of fracture. However, an increased risk of cardiovascular events was reported, resulting in issue a ‘black box warning’ requirement for romosozumab. One potential solution to lower the risk of adverse events is to reduce the medication dose. Previously, we found that dual inhibition of sclerostin and Dkk1 produced extremely potent synergistic bone anabolic effects, in both genetic and pharmacological models. While Dkk1 inhibition alone has no consistent bone-building effects, combining antibodies that target sclerostin (Scl-mAb) and Dkk1 (Dkk1-mAb) at 3:1 ratio resulted in 2-3X more bone gain as Scl-mAb alone. Further, much lower total doses of dual antibody treatment, given at optimized proportions, generated equivalent bone anabolic effects as Scl-mAb alone (at much higher doses), suggesting that a combinational strategy has obvious translational benefits. Finally, we tested whether low-dose combination therapy can maintain the same osteogenic effect as Scl-mAb in adult (6 month) and aged (20 month) mice. Outcome measures derived from radiographic, biomechanical, and histomorphometric assays revealed that a 3:1 ratio of Scl-mAb:Dkk1-mAb at 12.5mg/kg was as efficacious as 25mg/kg of Scl-mAb alone, in both age groups. Moreover, cortical porosity—a significant factor contributing to skeletal fragility in the aged skeleton—was significantly reduced by both Scl-mAb and low-dose combination treatment. In conclusion, our findings suggest that optimized low-dose combinational therapy is viable strategy for improving skeletal fragility.Item Targeting Bone Quality in Murine Models of Osteogenesis Imperfecta, Diabetes, and Chronic Kidney Disease(2024-05) Kohler, Rachel; Wallace, Joseph; Allen, Matthew; Bidwell, Joseph; Surowiec, RachelSkeletal fragility can be caused by a wide array of diseases and disorders, but the most difficult etiologies to clinically circumvent are those in which the body loses not just bone mass but the ability to create healthy bone tissue. While in conditions such as osteoporosis (the most prevalent cause of age-related skeletal fragility in which elevated resorption without compensatory elevated formation leads to bone loss), interventions can target bone remodeling pathways to protect and increase bone mass, many other diseases are characterized by genetic and metabolic crippling of the remodeling process, rendering those same mass-based interventions less effective at reducing fracture risk. Osteogenesis imperfecta (OI) is a class of genetic disorders in which gene mutations affect the formation of collagen, a crucial building block of bone tissue that makes up 90% of its organic matrix, leading to lost bone mass and quality. As the main genetic causes of OI cannot currently be directly treated, therapeutic OI treatments are needed that improve tissue-level material properties. Similarly, metabolic conditions such as diabetes, a disorder in which the body cannot properly regulate blood sugar due to loss of insulin production and/or efficacy, can have multi-organ impacts including increased risk of developing chronic kidney disease and skeletal fragility. Type 2 diabetes is especially notorious for increasing fracture risk despite maintained or even increased apparent bone mass, which is strong evidence that intrinsic bone material properties are impaired by the disease state. A possible solution to the bone quality problem may be treatments that increase bone water content, as amplifying the water content of bone can improve multi-scale material properties such as collagen fibril elasticity and whole-bone toughness. Therefore, increasing bone hydration could be a way of improving tissue-level material properties, despite being unable to eradicate the genetic or metabolic disorders that alter how collagen is produced and incorporated into the bone matrix. To that end, this dissertation presents several studies that characterize models of osteogenesis imperfecta and diabetic kidney disease in mice and investigate methods of rescuing skeletal fragility in these animals through treatments that target both bone mass and bone quality with ties to tissue hydration.