Genetic influences on Osteoporosis

Osteoporosis is a degenerative bone disease facing many of us as we age. Affecting about 54 million people in the US currently, this is a disease that is estimated to affect 50% of women and 25% of men in their lifetime.

So while perhaps not a fun topic, this is one that everyone should spend a little time learning about.

Osteoporosis is caused by a decrease in bone mineral density which results in a greater risk of fractures. Twin studies have shown that bone mineral density is between 50 and 80% genetic. [ref] Other components of osteoporosis such as muscle strength, femoral neck geometry, and age at menopause are also affected by genetics.

Environmental factors, of course, play a role in osteoporosis as well.  Some non-genetic risk factors for osteoporosis include alcohol, smoking, age, and poor nutrition.  [ref]

Below is just a brief overview of some of the genes involved in the risk for osteoporosis. Knowing where your genetic susceptibility lies may help you to find the best way to prevent bone loss.

Genes involved in Bone Mineral Density (BMD) and Osteoporosis risk:

TNFSF11 gene: One of the newer pharmaceutical options for osteoporosis is a drug known as a RANKL inhibitor.  RANKL is the pathway for bone resorption, so blocking the resorption is thought to build stronger bones. TNFSF11 is the gene that encodes the RANKL protein. In addition to bone resorption, RANKL plays an immune system role in other tissues such as the thymus, liver, colon, and more.

Disruption of this gene in mouse models leads to severe osteoporosis as well as immune system problems.

Check your 23andMe data for rs2277438 (v.4, v.5)

Check your 23andMe data for rs2277439 (v.5)

  • G/G: associated with lower BMD
  • A/A: higher BMD[study]

Check your 23andMe data for rs12585014 (v.4)

  • A/A: normal
  • A/G: decreased femoral compression strength and BMD
  • G/G: decreased femoral compression strength and BMD [study]

Check your 23andMe data for rs2062377  (v.4, v.5)

  • A/A: normal (23andme orientation)
  • T/T: decreased BMD [study]

OPG gene: 
OPG inhibits osteoclast, thus increasing bone formation.

Check your 23andMe data for rs3102735 (v.4)

  • C/C: lower BMD
  • C/T: normal BMD
  • T/T: normal BMD [study]

LRP5 gene:
The LRP5 gene codes for a protein that is involved in skeletal homeostasis.  Several polymorphisms in LRP5 have been associated with lower bone mineral density.

Check your 23andMe results for rs3736228:

  • T/T: increased risk of osteoporosis [ref]
  • C/T:  increased risk of osteoporosis
  • C/C: normal


VDR – Vitamin D Receptor Polymorphisms

Vitamin D is important in both calcium absorption and in regulating bone cell functions.  There are several significant polymorphisms in the Vitamin D Receptor gene that have been studied for their association with osteoporosis.

Check your 23andMe results for rs1544410: (VDR Bsm-I)

  • T/T :  (known as BB in studies) increased risk of low bone mineral density, osteoporosis [ref][ref]
  • C/T:  increased risk of osteoporosis
  • C/C: (known as bb in studies) normal risk of osteoporosis

The VDR Fok-I polymorphism is also well studied.  A July 2014 study looked at the effect on osteoporosis based on Fok-I presence and serum 25(OH) D levels.  The study found:

Grouped by the VDR genotype, a significant positive correlation between the levels of serum bone-specific ALP and 25(OH)D was observed in the FF-type (p=0.005), but not in the ff-type. In addition, there was a significant positive correlation between the level of serum 25(OH)D and osteo-sono assessment index (OSI) in the FF-type (p=0.008), but not in the ff-type. These results suggest that the level of circulating 25(OH)D is an important factor when assessing the VDR Fok-I polymorphism to prevent osteoporosis.

Check your 23andMe results for rs2228570: (VDR Fok-I)

  • T/T: adequate serum vitamin D levels important in osteoporosis marker levels [ref]
  • C/T:  adequate serum vitamin D levels important
  • C/C: serum vitamin D levels not correlated to osteoporosis makers.

Other studies have shown more of a link to osteoporosis for those with multiple VDR polymorphisms. [ref]

ESR2 polymorphisms

Estrogen deficiency is also a risk factor for osteoporosis.  A polymorphism in the estrogen receptor 1 gene has also been associated with osteoporosis in postmenopausal women.

Check your 23andMe results for rs4986938:

  • T/T : lower BMD [ref]
  • C/C: normal BMD


TGF-beta 1 polymorphism

A 2015 meta-analysis looked at the association between the TGFB1 polymorphisms and postmenopausal osteoporosis risk.  It found that for two of the polymorphisms there was an increased risk, but only for Asian women and not for Caucasian women.

Check your 23andMe results for rs1800470: (TGFB1 T29C)

  • G/G: increased risk of  osteoporosis [ref]
  • A/G:  increased risk of osteoporosis
  • A/A: normal risk of osteoporosis


Collagen Type 1 Alpha 1 polymorphisms

The COL1A1 gene is involved in making collagen, which is part of the extracellular matrix of bones as well as in tendons, cartilage, skin, etc. [ref]

Check your 23andMe results for rs1800012:

  • A/A : lower BMD [ref][ref]
  • A/C: lower BMD
  • C/C: normal BMD

Here is more information on rs1800012 (also called Sp1) from a review on osteoporosis genes.  In the study, the alleles are referred to on the opposite strand than 23andMe uses, so when you read T/T, think A/A and for G/G think C/C.

COLI1A1 gene encodes for the 1 chain of collagen type I that is the principal proteic component of bone extracellular matrix, thus, this gene is an important candidate for osteoporosis risk. Several association studies have been conducted on a polymorphism in intron 1, a G/T substitution that creates a binding site for the transcription factor Sp1. The (T/T) genotype has been associated with reduced BMD [62, 63], increased age-related bone loss [64, 65], increased femoral neck angle [66], an impaired ability of osteoblast-like cells to form mineralized bone nodules in vitro and with abnormalities of bone mineralization in vivo [67] and a higher risk of fracture due to altered bone density and quality [68]. In general, association studies on this gene demonstrated a positive correlation between SS (G/G) genotype and reduced fracture risk even with lack of association with BMD values. A meta-analysis evidenced that different Sp1 alleles are associated with modest variation in BMD but with significant changes in fracture risk [69]. The T allele is associated with an abnormally increased synthesis of collagen I 1 chain generating an imbalance between the 1 and 2 chains and a reduction of bone strength and bone matrix mineralization [67].

More to read:

OrthoBullets: Bone Signaling and RANKL

National Osteoporosis Foundation



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