SAT-799 - Romosozumab Improves Systemic Metabolism Despite Impaired Osteoanabolic Capacity in High Fat Diet Fed Mice

Sclerostin is an osteocyte-secreted protein that acts locally to suppress new bone formation and systemically to enhance the accumulation of adipose tissue mass. Neutralization of sclerostin increases bone mineral density and reduces fracture risk; therefore, we questioned whether the monoclonal neutralizing antibody romosozumab could improve bone and metabolic indices in a mouse diet-induced obesity model. Male C57Bl/6 mice were randomly assigned to either a high fat diet (HFD, 60% kcal from fat) or a control, low fat diet (LFD, 10% kcal from fat), and treated with weekly injections of romosozumab or saline either from the initiation of the experimental diet or after a 4-week lead-in period, allowing the high fat diet to induce weight gain and metabolic dysfunction. Consistent with our previous work using a preclinical sclerostin antibody, romosozumab treatment at the start of LFD or HFD feeding induced substantial increases in bone mineral density and trabecular bone volume in mice on both diets. Intriguingly, 4 weeks of HFD feeding before the start of romosozumab treatment strongly suppressed the osteoanabolic activity of sclerostin neutralization. While romosozumab increased BMD relative to saline controls in mice fed either diet, the endpoint BMD in HFD fed, romosozumab treated mice was significantly lower than in LFD fed, romosozumab treated mice, and was closer to the BMD of LFD fed, saline treated mice. Similarly, microCT analysis and biomechanical testing of the femur demonstrated that the increase in trabecular bone volume, ultimate moment, and bending rigidity induced by romosozumab was reduced in HFD mice versus LFD mice. The dampened skeletal response in HFD mice could be attributed to a compensatory upregulation of Wnt signaling antagonist Dkk-1 in bone tissue, without a corresponding change in the circulating levels. HFD fed, romosozumab treated mice had preserved metabolic benefits, possibly due to the tissue-specific increase in Dkk-1. When compared to saline treated mice, tissue histology indicated that romosozumab reduced white adipose tissue inflammation and suppressed hepatic lipid accumulation. Additionally, HFD fed, romosozumab treated mice exhibited lower serum insulin, triglycerides, non-esterified fatty acids, and cholesterol relative to saline treated mice. When taken together, these data indicate that metabolic status impacts efficacy of romosozumab for improving bone mass and strength, although pharmacologic sclerostin inhibition improves metabolic outcomes.

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