The disability, mortality and costs caused by non-vertebral osteoporotic fractures are enormous. Existing osteoporosis therapies are highly effective at reducing vertebral but not non-vertebral fractures. Cortical bone is a major determinant of non-vertebral bone strength. To identify novel osteoporosis drug targets, we phenotyped cortical bone of 3 366 viable mouse strains with global knockouts of druggable genes. Cortical bone thickness was substantially elevated in Notum^−/− mice. NOTUM is a secreted WNT lipase and we observed high NOTUM expression in cortical bone and osteoblasts but not osteoclasts. Three orally active small molecules and a neutralizing antibody inhibiting NOTUM lipase activity were developed. They increased cortical bone thickness and strength at multiple skeletal sites in both gonadal intact and ovariectomized rodents by stimulating endocortical bone formation. Thus, inhibition of NOTUM activity is a potential novel anabolic therapy for strengthening cortical bone and preventing non-vertebral fractures.

非椎骨骨质疏松性骨折所造成的残疾，死亡率和费用是巨大的。现有的骨质疏松疗法在减少椎骨骨折而非非椎骨骨折方面非常有效。皮质骨是非椎骨强度的主要决定因素。为了确定新型骨质疏松症的药物靶标，我们对3 366种有活力的小鼠品系的皮质骨进行了表型分析，并将其与可药物基因的整体敲除相结合。Notum的皮质骨厚度显着增加^-/-老鼠。NOTUM是一种分泌的WNT脂肪酶，我们在皮质骨和成骨细胞中观察到了NOTUM高表达，但在破骨细胞中却没有。开发了三种口服活性小分子和一种抑制NOTUM脂肪酶活性的中和抗体。通过刺激皮质内骨的形成，它们在完整的性腺和卵巢切除的啮齿动物中增加了多个骨骼部位的皮质骨厚度和强度。因此，抑制NOTUM活性是一种潜在的新型合成代谢疗法，可用于增强皮质骨和预防非椎骨骨折。