Finally, the relatively weak effects of the variants discovered by GWAS do not undermine the biological relevance of the genes identified, as exemplified by the identification of genetic signals at the location of genes coding for proteins currently targeted by novel osteoporosis treatments (Supplementary Fig. 10). The novel genes identified in our study may represent new candidates to target for osteoporosis drug discovery. Most established treatments for osteoporosis currently focus on curtailing bone resorption (eg. bisphosphonates, RANKL inhibitors) while only few anabolic treatments are currently approved for the treatment of osteoporosis (i.e. recombinant truncated or altered PTH). Other anabolic compounds under Phase II development include PTHrP fragments and Wnt-signaling enhancers such as anti-Sclerostin antibodies.33 Several of the variants robustly associated with BMD map in or close to genes of proteins involved in these pharmacologic pathways, namely osteoprotegerin (TNFRSF11B), RANK (TNFRSF11A), RANKL (TNFSF11), PTHrP (PTHLH), Low-density lipoprotein receptor-related protein 5 (LRP5), Sclerostin (SOST), and Dickkopf-1 (DKK1).
