Osteoporosis: Genetics

Abstract

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.

Keywords: BMD; bone mineral density; complex disease; genome‐wide association study (GWAS); osteoporosis susceptibility gene; osteoporotic fracture risk; the estrogen endocrine pathway; RANKL/RANK/OPG pathway; Wnt/β‐catenin signalling pathway

Figure 1.

Schematic representation of the Wnt/β‐catenin signalling pathway. Signalling is initiated by the binding of Wnt to a Frizzled receptor as well as a low‐density lipoprotein receptor‐related protein co‐receptor (e.g. LRP5) but is inhibited by sclerostin (SOST) to LRP5 binding.

Figure 2.

Schematic representation of the RANK/RANKL/OPG signalling pathway. Signalling is initiated by the binding of RANKL to RANK. The binding of OPG to RANKL prevents RANKL to RANK binding, thereby protecting the skeleton from excessive bone resorption.

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Li, Wen‐Feng, Hou, Shu‐Xun, Férec, Claude, and Chen, Jian‐Min(Apr 2011) Osteoporosis: Genetics. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0022925]