Osteocalcin is an important protein that is important for strong 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
Osteocalcin is a protein hormone produced by osteoblasts, the cells that build bones. Osteocalcin binds calcium in the bones, working to maintain and regenerate bone tissue [1, 2].
Studies have found that as a hormone, osteocalcin is also released into the blood, where it:
- Increases the production of insulin by the pancreas and adjusts blood glucose levels [3, 1]
- Stimulates testosterone production [1, 4]
- Increases muscle strength [1, 5]
- Improves brain function [1]
Osteocalcin Function & Health Effects
1) Builds Strong Bones
Osteocalcin is responsible for binding calcium to bones, which is what gives bones their strength and flexibility. For this process to occur, osteocalcin first needs to be activated by vitamin K2 [6].
Osteocalcin increases during periods of rapid growth, such as in children during the first year of life and during puberty [7].
Studies with mice have shown that 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 of osteocalcin predict lower bone density (particularly in the hip and spine) and fracture risk, including hip fractures [8, 1, 9, 10, 11, 12].
2) Adjusts Insulin and Glucose Levels
Osteocalcin works as a hormone to help adjust insulin and glucose (sugar) levels in the body [4].
In the pancreas, osteocalcin increases insulin production (via the GPRC6A receptor). It also increases the number of beta cells that produce, store, and release insulin [13, 14].
In addition, osteocalcin 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].
3) Stimulates Testosterone Production
Osteocalcin has been 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].
Blood levels of osteocalcin normally rise during puberty in boys. Studies have found a link between low osteocalcin levels and slowed or delayed puberty. However, because osteocalcin levels can vary a lot from person to person, they are not a reliable marker of sexual development [22].
4) May Improve Muscle Strength
Osteocalcin may increase the strength of skeletal (limb) muscles. It seems to help the muscles adapt to exercise, which is particularly important for preventing muscle loss in older people [23, 24, 5, 25, 26].
Higher levels of blood osteocalcin have been 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].
5) May Improve Brain Function
Animal studies have found that 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].
What’s more, osteocalcin-deficient mice have impaired learning and memory [27].
In diabetic rats, low osteocalcin levels were associated with worse cognitive performance [28].
In a human study of 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 [29].
In another study of 117 women between the ages of 71 and 78 years, higher osteocalcin levels were associated with better cognitive function [30].
Health Conditions Linked With Low Osteocalcin
1) Insulin Resistance and Diabetes
In a study with 98 healthy people, low osteocalcin levels were linked to poorer use of insulin by the body (insulin resistance), 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].
In fact, low osteocalcin blood levels have been 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 a study of 128 people with type 1 diabetes [39].
Animal studies found that:
- Daily injections of osteocalcin restored insulin sensitivity and glucose tolerance and protected from obesity and diabetes in mice on a high-fat diet [40, 41].
- osteocalcin protected rat beta cells, which produce insulin, from damage caused by high glucose levels [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].
2) Hardening of the Arteries (Atherosclerosis)
The relationship between osteocalcin and the hardening of the arteries is complex. A meta-analysis found 26 studies that supported positive and 17 studies that supported a negative relationship, while 29 studies found no relationships between the two [47].
In 774 men, higher osteocalcin levels were associated with less artery hardening (calcification) and lower heart disease risk [48].
Also, researchers prevented the hardening of the arteries in diabetic rats by increasing osteocalcin levels [49].
However, high blood osteocalcin levels were associated with heart artery hardening in 114 men, regardless of other cardiovascular risk factors and bone density [50].
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 may increase the risk of hardening of the arteries, although low levels likely increase the risk to a greater degree [51].
3) Heart Disease
Low levels of osteocalcin have been associated with 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 [52, 53].
In 247 seniors with heart disease, those with lower osteocalcin levels had a higher risk of future cardiovascular health problems [54].
Furthermore, lower osteocalcin levels were also associated with a higher risk of heart disease in two studies with over 3.5k healthy people [55, 56].
4) Metabolic Syndrome
Metabolic syndrome is a cluster of the following conditions that together increase a person’s risk of heart disease and diabetes:
- high blood pressure
- high blood sugar
- excess body fat around the waist
- abnormal cholesterol levels
- high triglyceride levels
In a meta-analysis of 55 studies with 47k people, low osteocalcin blood levels were associated with 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].
5) Obesity
According to a meta-analysis of 28 studies with a total of over 18.6k participants, people with low osteocalcin levels were more likely to have a higher body mass index (BMI). Studies in children, adolescents, and pre- and post-menopausal women support this association [60, 61, 62, 63, 64, 65].
6) Fatty Liver
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 [66, 67, 68, 69, 70].
Animal studies suggest that osteocalcin improves NAFLD by activating the Nrf2 protein (the master regulator of antioxidant and detox enzymes), which reduces oxidative stress [71].
Health Conditions Linked With High Osteocalcin
1) Osteoporosis
Osteocalcin blood tests can be used to monitor osteoporosis, along with scans that reveal bone mineral density [72, 73, 74]. High levels point to bone loss and predict low bone density and fracture risk in older people.
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 [72, 75, 74, 76].
Animal studies suggest that this is because of bone reabsorption – the breakdown of bone tissue that releases minerals and 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 [77].
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 [78, 79].
In another study of 134 pregnant women, gestational diabetes in the first trimester was linked with high blood osteocalcin [80].
However, pregnancy is a high-bone turnover state in which higher osteocalcin levels are expected [81]. Further studies are needed to verify a link between osteocalcin and diabetes in pregnancy.
3) Breast Density
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].
However, other preferably larger studies are needed to replicate this finding.
4) Anemia
In 939 elderly men aged 72 to 79 years, high osteocalcin levels were associated with having low numbers of red blood cells (anemia) [83].
This association may be due to poor nutrition or the presence of diseases that can both decrease red blood cell production and increase bone loss.
Limitations
Studies have found associations between osteocalcin blood levels and different health issues. However, these associations:
- May not be causal. They may be due to a third factor that affects both bones (osteocalcin production) and red blood cells (anemia), for example.
- May not be clinically relevant. Studies can find differences in levels that may be statistically significant but not clinically significant. For example, a study found that obese children have osteocalcin levels 77 ± 27 ng/ml (range of 50 – 104 ng/mL) vs. 67 ± 21 ng/ml (range of 46 – 88 ng/ml). That’s quite an overlap in ranges [61].
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. Studies suggest that once released into the blood, it may help adjust insulin and blood sugar levels, may increase testosterone, muscle mass and muscle strength, and may even improve brain function.
Low osteocalcin levels have been linked with diabetes, obesity, and heart disease. Too much osteocalcin in the blood may point to rapid bone loss in osteoporosis.
