Osteoporosis is characterized by low bone mineral density and structural deterioration of bone tissue, leading to an increased risk of fractures. It is the most common metabolic bone disorder worldwide, affecting one in three women and one in eight men over the age of 50. In the past 15 years, a large number of genes have been reported as being associated with osteoporosis. However, only in the past 4 years we have witnessed an accelerated pace in identifying and validating osteoporosis susceptibility loci. This increase in pace is mostly due to large-scale association studies, meta-analyses, and genome-wide association studies of both single nucleotide polymorphisms and copy number variations. A comprehensive review of these developments revealed that, to date, at least 15 genes (VDR, ESR1, ESR2, LRP5, LRP4, SOST, GRP177, OPG, RANK, RANKL, COLIA1, SPP1, ITGA1, SP7, and SOX6) can be reasonably assigned as confirmed osteoporosis susceptibility genes, whereas, another >30 genes are promising candidate genes. Notably, confirmed and promising genes are clustered in three biological pathways, the estrogen endocrine pathway, the Wnt/beta-catenin signaling pathway, and the RANKL/RANK/OPG pathway. New biological pathways will certainly emerge when more osteoporosis genes are identified and validated. These genetic findings may provide new routes toward improved therapeutic and preventive interventions of this complex disease.

Osteoporosis is the most common metabolic bone disorder worldwide. At least 15 genes (e.g., ESR1, LRP5, SOST, OPG, RANK and RANKL) have been confirmed as osteoporosis susceptibility genes, and another 30 have been highlighted as promising susceptibility genes. Notably, these genes are clustered in three biological pathways: the estrogen endocrine pathway, the Wnt/β-catenin signaling pathway and the RANK/RANKL/osteoprotegerin (OPG) pathway. In this article, using data pertaining to these three biological pathways as examples, we illustrate possible principles of personalized therapy for osteoporosis. In particular, we propose to use inhibitors (e.g., denosumab) of the RANK/RANKL/OPG signaling pathway to circumvent resistance to estrogen-replacement therapy: a novel idea resulting from the consideration of a mechanistic link between the estrogen endocrine pathway and the RANK/RANKL/OPG signaling pathway. In addition, we call for more attention to be focused on rare variants of major effects in future studies.

Osteoporosis is characterised by comprised bone strength predisposing to an increased risk of fracture. It is a complex trait that is influenced by many genetic variants and their interactions with environmental factors. In the past four to five years, we have witnessed an accelerated pace in identifying and validating osteoporosis susceptibility loci, which was largely attributable to the use of genome‐wide association studies (GWAS). At least 15 genes (i.e. VDR , ESR1 , ESR2 , LRP5 , LRP4 , SOST , GRP177 , OPG , RANK , RANKL , COLIA1 , SPP1 , ITGA1 , SP7 and SOX6 ) may be reasonably assigned as confirmed osteoporosis genes; and new osteoporosis‐associated genes are being increasingly reported. Notably, confirmed and promising osteoporosis genes are clustered in three biological pathways, the estrogen endocrine pathway, the Wnt/β‐catenin signalling pathway and the RANKL / RANK / OPG pathway. The ultimate promise of osteoporosis genetics is not only to better understand the disease process, but more importantly, to lead better therapeutic and preventive interventions. Key Concepts: Osteoporosis is characterised by low bone mineral density (BMD) and structural deterioration of bone tissue, leading to an increased risk of fractures that occur mostly at the hip, spine and wrist. Osteoporosis is the most common metabolic bone disorder worldwide. The burden of osteoporosis on the healthcare system is extremely large. Osteoporosis is a complex trait that is influenced by many genetic variants and their interactions with environmental factors. An accelerated pace in identifying and validating osteoporosis susceptibility loci has been observed in the past four to five years, which was largely attributable to the use of genome‐wide association studies (GWAS). At least 15 genes (i.e. VDR , ESR1 , ESR2 , LRP5 , LRP4 , SOST , GRP177 , OPG , RANK , RANKL , COLIA1 , SPP1 , ITGA1 , SP7 and SOX6 ) have recently been assigned as confirmed osteoporosis genes. The currently reported osteoporosis‐associated genes are clustered in three biological pathways, the estrogen endocrine pathway, the Wnt/β‐catenin signalling pathway and the RANKL/RANK/OPG pathway. Some newly found genes may be classified into the aforementioned three biological pathways once a clearer picture of their functional roles is developed. New biological pathways may also emerge once more if association and functional data are available. Both common and rare genetic variants are likely to contribute to osteoporosis. The advances in the genetics of osteoporosis hold promise for personalised medicine.