Osteocalcin is an important protein that is critical to the formation and maintenance of bones. It also acts as a hormone to adjust insulin and glucose levels, increase testosterone, and improve muscle strength and cognitive function. Read on to learn more about osteocalcin and its complex role in health.

What is Osteocalcin?

Definition

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4670816/

Osteocalcin is a protein hormone produced by osteoblasts, the cells that build bones. It binds calcium in the bones, working to maintain and regenerate bone tissue [1, 1, 2].

As a hormone, osteocalcin is also released into the blood, where it:

  • Increases the production of insulin by the pancreas [31]
  • Adjusts blood glucose levels [3, 1]
  • Stimulates testosterone production [1, 4]
  • Increases muscle strength [1, 5]
  • Improves brain function [1]
Osteocalcin is a protein hormone produced by the bones. It builds bones and muscles, increases insulin and testosterone, adjusts blood sugar levels, and improves brain health.

Osteocalcin Function & Health Effects

1) Builds Strong Bones

Osteocalcin is responsible for binding calcium to bone tissue, which is what gives bones their strength and flexibility. For this process to occur, osteocalcin first needs to be activated by vitamin K2 [6].

Since it increases bone strength, osteocalcin increases during periods of rapid growth, such as in children during the first year of life and during puberty [7].

Mice with low levels of osteocalcin have weaker bones that are more likely to break [1].

However, more osteocalcin is not always a sign of bone strength. Osteocalcin levels can increase as a result of a widespread bone loss. In older people, high blood levels predict lower bone density (particularly in the hip and spine) and fracture risk, including hip fractures [8, 1, 9, 10, 11, 12].

Osteocalcin helps build strong bones with the help of vitamin K2. Both high and low levels can point to bone loss and increase fracture risk.

2) Adjusts Insulin and Glucose Levels

Osteocalcin works as a hormone to control insulin and glucose (sugar) balance in the body [4].

In the pancreas, osteocalcin increases insulin production (via the GPRC6A receptor). It increases the number of beta cells that produce, store, and release insulin [13, 14].

Osteocalcin also acts on muscles and other tissues to help keep sugar levels in check. It works by increasing the production of adiponectin in fat cells (adipocytes). Adiponectin, in turn, increases the uptake of glucose into fat and muscle cells [15, 16].

Low levels of osteocalcin can impair the body’s ability to use insulin to control glucose levels [17, 18].

Osteocalcin increases insulin production and helps glucose enter muscles and other tissues, working to keep blood sugar in check.

3) Stimulates Testosterone Production

Osteocalcin is linked to reproductive health in men. From the blood, osteocalcin reaches cells in the testicles and increases the production of testosterone (through the GPRC6A receptor) [4, 19, 1, 20, 21, 4, 19].

Blood levels of osteocalcin normally rise during puberty in boys, while low levels are associated with slowed or delayed puberty. However, because osteocalcin levels can vary a lot from person to person, they are not necessarily a reliable marker of sexual development [22].

Osteocalcin supports reproductive health in men by increasing testosterone production.

4) May Improve Muscle Strength

Osteocalcin may increase the strength of skeletal (limb) muscles. It helps your muscles adapt to exercise, which is particularly important for preventing a drop in exercise capacity and muscle loss in older people [23, 24, 5, 25, 26].

Higher levels were linked to muscle strength in women over the age of 70. Plus, osteocalcin may reduce the risk of falls and bone fractures by maintaining muscle mass. Indirectly, osteocalcin helps build muscles by increasing testosterone [23, 5].

Osteocalcin increases strength, muscle mass, and exercise capacity. It may prevent muscle wasting and fractures in older people.

5) May Improve Brain Function

Osteocalcin increased the production of monoamine neurotransmitters (dopamine, noradrenaline, and serotonin) in the brains of mice. These neurotransmitters play significant roles in motivation, learning, mood, and memory [1].

In 44 people, low osteocalcin levels were linked to negative changes in the microstructure of the brain (in the caudate, hypothalamus, thalamus, putamen, and subcortical white matter) and reduced cognitive performance [27].

What’s more, osteocalcin-deficient mice have impaired learning and memory. In diabetic rats, low osteocalcin levels were associated with worse cognitive performance [28, 29].

In another study of 117 women between the ages of 71 and 78 years, higher osteocalcin levels improved cognitive function [30].

Osteocalcin supports brain health and enhances cognitive function by increasing key neurotransmitters. People with low levels may have learning and memory problems.

Health Risks of Low Osteocalcin

1) Insulin Resistance and Diabetes

In 98 healthy people, low osteocalcin levels were linked to the poor use of insulin by the body (insulin resistance), low production of insulin, and elevated glucose levels (high blood sugar) [31].

In a meta-analysis of 39 studies involving over 23k people, lower osteocalcin was associated with higher HbA1c (a measure of 3-month average blood glucose levels) [32].

Low osteocalcin blood levels are also associated with type 2 diabetes in men, women, and children [33, 34, 35, 36, 37, 38].

In turn, high osteocalcin was associated with better control of blood glucose levels in 128 people with type 1 diabetes. Osteocalcin also protected rat beta cells, which produce insulin, from damage caused by high glucose levels [39, 40, 41].

Daily injections of osteocalcin restored insulin sensitivity and glucose tolerance and protected from obesity and diabetes in mice on a high-fat diet [42, 43].

Sex differences may affect how osteocalcin affects insulin resistance. One study revealed that long-term osteocalcin administration actually increased insulin resistance in male mice on a high-fat diet [44].

However, some researchers dispute the existence of a causal link between osteocalcin and glucose levels. They argue that even if a link exists, it is not clear whether it is osteocalcin that affects glucose levels or the other way around [45].

Overall, more large-scale human studies are needed. Mice are far from ideal for studying osteocalcin: for example, mice have three genes for osteocalcin, while humans have just one [46, 45].

Low osteocalcin levels have been linked with diabetes and insulin resistance, but more human studies are needed to determine what is the cause and what effect.

2) Heart Disease Risk

Low levels of osteocalcin in the blood can indicate heart disease. The current evidence suggests that normal osteocalcin levels support the overall health of the heart and blood vessels. However, it’s not as simple. Many other factors–including age, sex, physical activity, and so on–play in [47, 48].

In 247 older people with heart disease, those with lower osteocalcin levels had a higher risk of future cardiovascular health problems [49].

Furthermore, lower osteocalcin levels were also associated with higher risk of heart disease in two studies with over 3.5k healthy people [50, 51].

Low osteocalcin levels may increase your risk of heart problems, whether you are healthy or already have heart disease.

3) Hardening of the Arteries (Atherosclerosis)

The relationship between osteocalcin and hardening of the arteries is complex. A meta-analysis found 26 positive, 17 negative, and 29 neutral relationships [52].

In 774 men, higher osteocalcin levels indicates less artery hardening (calcification) and lower heart disease risk [53].

Also, researchers prevented hardening of the arteries in diabetic rats by increasing osteocalcin levels [54].

However, high blood osteocalcin levels were associated with heart artery hardening in 114 men, regardless of other cardiovascular risk factors and bone density [55].

Finally, one study of over 3,000 people found that osteocalcin levels and stiffness in the arteries were related in an “inverse J-shaped curve.” This means that both low and high levels of osteocalcin can increase the risk of hardening of the arteries, although low levels increase the risk to a greater degree [56].

Both high and low osteocalcin levels increase the risk of artery hardening, though low levels are more dangerous.

4) Metabolic Syndrome

In a meta-analysis of 55 studies of 47k people, low osteocalcin blood levels were linked to a higher risk of metabolic syndrome. Similarly, in 798 older men, low levels pointed to metabolic syndrome [18, 57].

Additionally, in a study of over 2,000 people, lower osteocalcin levels were associated with higher levels of C-reactive protein (CRP), a marker of chronic inflammation in people with metabolic syndrome [58].

Finally, when obese female mice were given osteocalcin during pregnancy, their offspring were protected against metabolic disorders that are caused by maternal obesity [59].

Low osteocalcin levels are linked with metabolic syndrome and chronic inflammation.

5) Obesity

According to a meta-analysis, people with low osteocalcin levels are more likely to have a higher body mass index (BMI). Other studies in children, adolescents, and pre- and post-menopausal women support this association [60, 61, 62, 63, 64, 65].

In one study of 132 people, obesity was linked to low osteocalcin levels, which may have contributed to insulin resistance and chronic inflammation [66].

People with low osteocalcin levels are more likely to be obese and have inflammation.

6) Fatty Liver

Osteocalcin blood tests can help predict the severity of fatty liver disease (NAFLD).

In a study of 120 children aged 7 to 13 years old (60 NAFLD patients and 60 controls), low osteocalcin blood levels predicted the severity of NAFLD. Low levels were also an indicator of NAFLD in 4 studies that included almost 9k adults [67, 68, 69, 70, 71].

Animal studies suggest that osteocalcin improves NAFLD by activating the Nrf2 protein (the master regulator of antioxidant and detox enzymes), which reduces oxidative stress [72].

Osteocalcin may help the body detox and clear free radicals. Low levels have been linked with fatty liver disease.

Health Risks of High Osteocalcin

1) Osteoporosis

Higher levels of osteocalcin in the blood were linked to lower bone mineral density (low skeletal mass) and osteoporosis in 4 studies with a total of 417 postmenopausal women [73, 74, 75, 76].

Osteocalcin blood tests can be used to diagnose and monitor osteoporosis, along with scans that reveal bone mineral density [73, 77, 75].

High levels point to bone loss and predict low bone density and fracture risk in older people.

Animal studies suggest that this is because bone re-absorption–the breakdown of bone tissue that releases minerals–frees osteocalcin from the bones, raising its blood levels [8].

Vitamin K, vitamin D, and calcium supplements reduced osteocalcin levels and increased bone density in a study of 78 postmenopausal women [78].

Bone breakdown frees osteocalcin into the blood. High levels point to osteoporosis, low bone density, and increased fracture risk.

2) Diabetes in Pregnancy

From 130 pregnant women, those with high blood osteocalcin levels were more likely to experience insulin resistance during pregnancy, which can lead to a condition called gestational diabetes. Osteocalcin levels were higher throughout pregnancy in 48 women with gestational diabetes, compared to 48 healthy pregnant women [79, 80].

In another study of 134 pregnant women, gestational diabetes in the first trimester was linked with high blood osteocalcin [81].

High osteocalcin levels may increase the risk of diabetes during pregnancy.

3) Increased Breast Cancer Risk

Obese, postmenopausal women with high blood osteocalcin levels are more likely to have higher breast density, a significant risk factor for developing breast cancer. A study of 239 premenopausal and postmenopausal women aged between 40 and 60 identified this link [82].

4) Anemia

Osteocalcin levels may affect the formation of red blood cells, which carry oxygen. In 939 elderly men aged 72 to 79 years, high levels were associated with having low numbers of red blood cells (anemia). However, how osteocalcin affects the formation of red blood cells is not yet known [83].

Women with high osteocalcin levels may be at an increased risk of breast cancer, while older men are more likely to get anemia.

What Now?

Read the next post in this series:

Irregular Osteocalcin Levels?

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Takeaway

Osteocalcin is a protein produced by the bones. It helps lock calcium into bones, increasing their strength and healing.

Osteocalcin also works as a hormone. Released into the blood, it increases muscle mass and exercise capacity. Plus, it helps the pancreas produce insulin, maintains normal blood sugar levels, and enhances cognition.

Low osteocalcin levels have been linked with numerous health problems–from diabetes to obesity to bone fractures to heart disease to chronic inflammation.

However, abnormally high levels are not good either. Too much osteocalcin in the blood may point to rapid bone loss and increase your risk of breast cancer, anemia, and diabetes in pregnancy.

About the Author

Biljana Novkovic - PHD (ECOLOGICAL GENETICS) - Writer at Selfhacked

Dr. Biljana Novkovic, PhD

PhD (Ecological Genetics)

Biljana received her PhD from Hokkaido University.

Before joining SelfHacked, she was a research scientist with extensive field and laboratory experience. She spent 4 years reviewing the scientific literature on supplements, lab tests and other areas of health sciences. She is passionate about releasing the most accurate science & health information available on topics, and she's meticulous when writing and reviewing articles to make sure the science is sound. She believes that SelfHacked has the best science that is also layperson-friendly on the web.

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