The initial evidence came from the identification of loss-of-function (LOF) and gain-of-function (GOF) mutations in the human LRP5 gene (low-density-lipoprotein receptor-related protein 5; a co-receptor of the Wnt/βcatenin pathway) as responsible for the Osteoporosis-Pseudoglioma Syndrome and for the hereditary High Bone Mass trait, respectively3, 4. This evidence concerns the gene LRP5 and osteoporosis.