Osteoporosis Genes and Prevention Strategies

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.

The good news here is that knowing where your genetic susceptibility lies can lead you to targeted, personalized solutions for osteoporosis.

Is Osteoporosis Genetic?

Osteoporosis is caused by a decrease in bone mineral density which results in a greater risk of fractures. The risk of fractures – such as breaking a hip – is the real worry with osteoporosis.

Twin studies have shown that bone mineral density (BMD) is between 50 and 80% genetic.[ref]

Your bones are constantly breaking down and reforming. When the bone cells dissolve the bone matrix, it is called resorption, and the new bone deposits are called formation.

Osteoporosis is caused by a chronic excess of bone resorption relative to the formation of new bone. This leads to bone loss and a deterioration of the architecture of the bone.

It is estimated that the causes of osteoporosis are about 62% genetic and 38% environmental.[ref] This means over half of your risk is due to your genes.  In addition to BMD, other risk factors include things like muscle strength, femoral neck geometry, nutrient deficiencies, and age at menopause. Those can be partially due to genetics but are also influenced by lifestyle choices (exercising, foods that you eat, etc.).

What lifestyle factors affect osteoporosis?

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]

Other risk factors include:[ref][ref]

  • taking oral glucocorticoids
  • alcohol intake of 3 units or more a day
  • low body mass index (less than 19)
  • low estrogen in women, low testosterone in men
  • excess thyroid hormones
  • low vitamin D and calcium intake

Osteoporosis Genotype Report:

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There are quite a few genetic variants that add a little to the risk of osteoporosis. If you have osteoporosis, it is likely that you will have multiple genetic variants that play a role in it. Not all variants are covered by 23andMe or AncestryDNA, so this is only giving you a partial picture of your osteoporosis genes.

How can you use this information? Hopefully, understanding where your genetic susceptibility lies can help you figure out ways of preventing (further) bone loss.

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.

The genetic variants below cause lower bone mineral density through increased RANKL.

Check out the natural RANKL inhibitors listed in the Lifehacks section below.

Check your genetic data for rs2277438 (23andMe v4, v5; AncestryDNA):

  • G/G: lower BMD
  • A/G: typical bone mineral density
  • A/A: typical[ref][ref]

Members: Your genotype for rs2277438 is .

Check your genetic data for rs2277439 (23andMe v5 only):

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

Members: Your genotype for rs2277439 is .

Check your genetic data for rs12585014 (23andMe v4):

  • A/A: typical
  • A/G: decreased femoral compression strength and BMD
  • G/G: decreased femoral compression strength and BMD[ref]

Members: Your genotype for rs12585014 is .

OPG gene:

The OPG gene codes for a protein that inhibits osteoclast, thus increasing bone formation.

Check your genetic data for rs3102735 (23andMe v4; AncestryDNA):

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

Members: Your genotype for rs3102735 is .

LRP5 gene:

The LRP5 gene codes for a protein involved in skeletal homeostasis. Several polymorphisms in LRP5 have been associated with lower bone mineral density. There are rare loss-of-function mutations causing severe osteoporosis and other, also rare, gain-of-function mutations that cause very dense bones.[ref]

Check your genetic data for rs3736228 (23andMe v4, v5; AncestryDNA):

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

Members: Your genotype for rs3736228 is .

SQRDL (sulfide quinone reductase-like) gene:

Sulfide quinone reductase is an enzyme that regulates the hydrogen sulfide levels in the cell. This is important in bone health because the bone marrow mesenchymal stem cells regulate their osteogenic differentiation by producing hydrogen sulfide. Researchers have created mice with low hydrogen sulfide and found that they have osteoporosis — and that giving the mice hydrogen sulfide can reverse bone loss.[ref] Notably, several other recent studies also point to hydrogen sulfide as a regulator of bone formation.[ref]

Check your genetic data for rs1044032 (23andMe v4, AncestryDNA):

  • T/T: typical
  • C/T: decreased risk of osteoporosis
  • C/C: decreased risk of osteoporosis[ref][ref]

Members: Your genotype for rs1044032 is .

VDR – Vitamin D Receptor gene:

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

Check your genetic data for rs1544410 (23andMe v4, v5; AncestryDNA):

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

Members: Your genotype for rs1544410 is .

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.[ref] The study found that for people carrying the normal genotype, there was a good correlation between vitamin D levels and osteoporosis risk. In contrast, for those carrying the less common genotype, vitamin D levels did not reflect osteoporosis risk.

Check your genetic data for rs2228570 (23andMe v4 only):

  • A/A: adequate serum vitamin D levels important in osteoporosis marker levels[ref]
  • A/G: adequate serum vitamin D levels important
  • G/G: serum vitamin D levels not correlated to osteoporosis makers. (VDR Fok-I)

Members: Your genotype for rs2228570 is .

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

ESR2 gene:

Estrogen deficiency is also a risk factor for osteoporosis. A polymorphism in the estrogen receptor 2 gene has also been associated with osteoporosis in postmenopausal women.

Check your genetic data for rs4986938 (23andMe v4, v5; AncestryDNA):

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

Members: Your genotype for rs4986938 is .

TGFB1 (transforming growth factor-beta 1) gene:

The TGFB1 gene codes for a protein that regulates cell growth, maturation, and cell death. A 2015 meta-analysis looked at the association between the TGFB1 polymorphisms and postmenopausal osteoporosis risk. The results showed an increased risk, but only for Asian women and not for Caucasian women.

Check your genetic data for rs1800470 (23andMe v4, v5): (TGFB1 T29C)

  • G/G: increased risk of osteoporosis, possibly only in Asians[ref]
  • A/G: increased risk of osteoporosis, possibly only in Asians
  • A/A: typical risk of osteoporosis

Members: Your genotype for rs1800470 is .

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 genetic data for rs1800012 (23andMe v4, v5): (Sp1)

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

Members: Your genotype for rs1800012 is .


Factors that influence osteoporosis risk that you can control include:

  • cutting back on alcohol
  • never smoking
  • get enough calcium in your diet
  • get vitamin D through supplements or sunshine

The rest of this article is for Genetic Lifehacks members only.  Consider joining today to see the rest of this article.

Natural RANKL Inhibitors

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Looking for a functional nutritionist to help you understand your genes – and who knows about osteoporosis? Check out what Jana Davis (Genetic Lifehacks PRO member) has to say about osteoporosis.

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About the Author:
Debbie Moon is the founder of Genetic Lifehacks. Fascinated by the connections between genes, diet, and health, her goal is to help you understand how to apply genetics to your diet and lifestyle decisions. Debbie has a BS in engineering and also an MSc in biological sciences from Clemson University. Debbie combines an engineering mindset with a biological systems approach to help you understand how genetic differences impact your optimal health.

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