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 our health.
What Is Osteocalcin?
As a hormone, osteocalcin is released from the bones into the blood, where it:
- Increases the production of insulin by the pancreas [3, 1]
- Adjusts blood glucose levels [3, 1]
- Stimulates testosterone production [1, 4]
- Improves muscle strength [1, 5]
- Improves brain function 
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 .
Because of its role in bone strength, the amount of osteocalcin increases during periods of rapid growth, notably in children during the first year of life and during puberty .
Mice with low levels of osteocalcin have weaker bones which are more likely to break .
However, more osteocalcin is not always a sign of bone strength. In older adult humans, high levels in the blood are a predictor of lower bone density (particularly in the hip and spine). High blood osteocalcin levels are also a predictor of fracture risk, including hip fractures. This is because osteocalcin levels can increase in the blood as a result of a widespread breakdown of bone tissue [8, 1, 9, 10, 11, 12].
2) Adjusts Insulin and Glucose Levels
Osteocalcin works as a hormone to control the insulin and glucose (sugar) balance in the body .
Osteocalcin also acts on muscles and other tissues to help keep glucose levels in balance. It does this 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].
3) Stimulates Testosterone Production
Osteocalcin is linked to male reproductive functions. When it acts as a hormone in the blood, osteocalcin interacts with the cells of the testicles through the GPRC6A receptor. This interaction increases the production of testosterone [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 in specific individuals .
4) May Improve Muscle Strength
Osteocalcin may affect the strength of skeletal (limb) muscles .
Osteocalcin was positively linked to muscle strength and function in women over the age of 70 and may reduce the risk of falls and bone fractures. Higher osteocalcin has also been linked to higher muscle mass and the prevention of age-related muscle loss [23, 5].
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, and memory .
In 44 human subjects, low levels of osteocalcin were linked to negative changes in the microstructure of the brain (in the caudate, hypothalamus, thalamus, putamen, and subcortical white matter). These changes can result in reduced cognitive performance, as measured by neuropsychological test battery .
A study involving 117 women between the ages of 71 and 78 found that cognitive function improved when osteocalcin levels in the blood were higher .
Osteocalcin-deficient mice have impaired learning and memory .
In diabetic rats, low levels of osteocalcin were associated with worse cognitive performance .
1) Associated with Insulin Resistance and Diabetes
In 98 healthy human subjects, low levels of osteocalcin were linked to the poor use of insulin by the body (insulin resistance), low production of insulin, and elevated glucose levels (high blood sugar) .
High osteocalcin was associated with better control of blood glucose levels (glycaemic control) in 128 people with type 1 diabetes .
However, other researchers dispute the existence of a 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 .
However, sex differences may affect how osteocalcin and insulin resistance are related because another study showed that long-term osteocalcin administration actually increased insulin resistance in male mice on a high-fat diet .
It appears that more large-scale studies are needed in order to clarify whether and what type of link exists between osteocalcin and the risk of type 2 diabetes. Part of the difficulty in clarifying this relationship may be because of differences in physiology between mice and humans: for example, mice have three genes for osteocalcin, while humans have just one [46, 36].
2) May Indicate Heart Disease Risk
Low levels of osteocalcin in the blood can indicate potential heart disease. This interaction is not yet clear because there are many varying factors (age, sex, physical activity, and so on). However, the current evidence suggests that there is a relationship between osteocalcin and the overall health of the heart and blood vessels [47, 48].
In 247 older subjects with heart disease, those with lower osteocalcin levels had a higher risk of future cardiovascular health problems .
3) Associated with Hardening of the Arteries (Atherosclerosis)
There is a complex relationship between osteocalcin and hardening of the arteries. A meta-analysis found 26 positive, 17 negative, and 29 neutral relationships .
In 774 men, higher osteocalcin levels were an indicator of lower artery hardening (calcification) and decreased heart disease risk .
Also, hardening of the arteries in diabetic rats was prevented by increasing osteocalcin levels .
However, high blood osteocalcin levels were associated with heart artery hardening in 114 men, regardless of cardiovascular risk factors and bone density .
Finally, one study of 1,691 men and 1,913 women 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 .
4) Associated with Metabolic Syndrome
In a meta-analysis of 55 studies including 46,998 participants, low levels of blood osteocalcin were linked to higher risks of metabolic syndrome .
Similarly, in 798 older men, low blood osteocalcin levels were an indicator of metabolic syndrome .
Additionally, in a study of over 2,000 people, lower levels of osteocalcin were associated with higher levels of C-reactive protein (CRP), leading to higher levels of chronic inflammation in those with metabolic syndrome .
Finally, when obese female mice were given osteocalcin during pregnancy, their offspring were protected against metabolic disorders that are caused by maternal obesity .
5) Associated with Obesity
According to a meta-analysis, low levels of blood osteocalcin are associated with higher body mass index (BMI) in humans .
6) Associated with Fatty Liver (NAFLD)
Osteocalcin blood tests can help predict the severity of fatty liver disease (NAFLD).
A study of 120 children in the age range of 7 to 13 years old (60 NAFLD patients and 60 controls) found that low osteocalcin blood levels provided a good prediction for the severity of NAFLD .
1) May Indicate Osteoporosis
Studies have found that high blood osteocalcin levels are an indicator of bone loss and, in older people, a predictor of reduced bone density and a higher risk of fractures.
Animal studies suggest that this is because the re-absorption of bone (the breakdown of bone tissue and the resulting transfer of minerals to the blood) releases osteocalcin from the bones into the blood .
Vitamin K, vitamin D, and calcium supplements reduced the level of osteocalcin in the blood and increased bone density in a study of 78 postmenopausal women .
2) Associated with Diabetes in Pregnancy
A study in 130 pregnant women showed a link between high blood osteocalcin levels and the risk of increased insulin resistance during pregnancy, which can lead to a condition called gestational diabetes (a temporary form of diabetes associated with pregnancy and childbirth) .
Osteocalcin levels in the blood were higher throughout pregnancy in 48 women with gestational diabetes, compared to 48 controls .
Another study of 134 pregnant showed that in the first trimester, gestational diabetes pregnancies tended to show increased levels of osteocalcin in the blood .
3) Associated with Increased 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. This was identified through a study of 239 premenopausal and postmenopausal women aged between 40 and 60 .
4) May Indicate Anemia
Osteocalcin levels may affect the formation of red blood cells (the oxygen-carrying cells in the blood). In 939 elderly men aged 72 to 79 years, high blood osteocalcin levels were associated with having low numbers of red blood cells (anemia). However, the mechanism through which osteocalcin would be linked to the formation of red blood cells is not yet known .
Factors That Decrease Osteocalcin
Smoking lowers osteocalcin levels by interfering with the genes that produce osteocalcin. This can lead to difficulties with bone healing, and can loosen teeth and dental implants by weakening bone tissue in the mouth and jaw (alveolar bone) .
However, glucocorticoids may also reduce osteocalcin in the bones, which may increase the risk of osteoporosis in people who take glucocorticoids regularly .
Reducing the dosage of glucocorticoids in 208 patients with rheumatoid arthritis led to improvements in osteocalcin levels and bone metabolism .
3) Iron Deficiency
There may be a link between iron deficiency and low osteocalcin.
In rats, iron deficiency led to reduced osteocalcin, lower bone mineral density, and reduced bone strength .
Factors That Increase Osteocalcin
1) Vitamin K
Vitamin K is necessary to activate osteocalcin in the body. A lack of vitamin K results in a lack of osteocalcin protein in the bones. Vitamin K deficiency is also associated with low bone mineral density and increased risk of fractures [91, 92].
A placebo-controlled study of 40 healthy young men showed that vitamin K supplements increased osteocalcin levels after just 4 weeks. This improved the body’s use of insulin (by reducing insulin resistance) and the maintenance of healthy glucose levels. These results were consistent with other clinical studies involving the use of vitamin K supplements by young males as well as older women and men [93, 94, 95].
An analysis of blood samples from 896 persons suggested that most people do not receive enough vitamin K from their diet. However, vitamin K can be taken as a supplement, to ensure that the body produces enough osteocalcin. The best type of vitamin K to take for this is vitamin K2, particularly the MK-7 type .
However, persons who are taking some types of blood-thinning medication (anticoagulants), such as warfarin, must be careful. There is a significant risk that some of these medications will become less effective if vitamin K2 in MK-7 form is taken as well, and so this combination is not advised .
Osteocalcin levels are higher in people who are more physically active .
A link between more physical activity and higher osteocalcin levels has been found in 54 adolescents .
One hour of exercise, 3 times per week for 12 weeks, increased osteocalcin levels and bone mineral density in 29 women with osteoporosis (with an age range of 71 to 78) .
A study of 11 middle-aged men found that osteocalcin levels increased and remained at higher levels for several hours after a brief period of high-intensity exercise (4 sets of 4 minutes of cycling at nearly peak performance levels). This was also linked to increased insulin sensitivity .
There is also evidence that longer periods of less intense exercise can increase osteocalcin levels. A study involving 31 middle-aged subjects found a significant increase in osteocalcin levels after cycling for an hour, 3 to 4 days per week .
3) Diet/Calorie Restriction
In a study of 107 older, frail adults, osteocalcin blood levels increased on a calorie restriction diet .
However, in a study of 71 postmenopausal women, there was no link between weight loss and osteocalcin .
Finally, in 178 obese persons, high osteocalcin levels were associated with reduced body fat. However, osteocalcin levels actually decreased after weight loss .
4) Vitamin D
Vitamin D directly stimulates osteocalcin production .
In a DB-RCT of 76 obese but otherwise healthy menopausal women between the ages of 51 and 63, vitamin D supplements in combination with a calorie-restricted diet increased osteocalcin and improved insulin sensitivity, compared to diet alone .
Zinc supplements increased osteocalcin levels in 22 shorter-than-average children. However, this has not been linked to more growth (height and weight) .
Manganese supplements have been shown to increase osteocalcin levels, bone mineral density, and bone formation in rats .
7) Olive Oil
A 12-month DB-RCT of postmenopausal women with decreased bone mass (but without a diagnosis of osteoporosis) showed that an olive tree extract increased blood osteocalcin levels, leading to increased bone density in the spine .
8) Omega-3 Fatty Acids
Omega-3 fatty acid supplements increased osteocalcin levels in rats. This may be beneficial to bones, but that link has not been demonstrated and so further studies are required .
9) Ellagic Acid
Ellagic acid is found in many fruits and vegetables such as pecans, walnuts, pomegranates, raspberries, strawberries, and cranberries. It f1unctions as an antioxidant, preventing cell damage .
Ellagic acid increased osteocalcin in rats after tooth extraction .
10) Milk Thistle
Silymarin increased osteocalcin, bone healing, and bone density in mice with bone fractures .
A 24-month DB-RCT suggests that icariin may help prevent bone loss in postmenopausal women. Icariin maintained osteocalcin levels and prevented bone tissue loss .
12) Insulin Therapy/Low Glucose
Type 1 diabetes can cause changes in the skeleton, especially when glucose levels are poorly controlled. Several studies have found that insulin therapy increases osteocalcin levels, leading to improved bone structure and flexibility in type 1 diabetes [118, 119].
Alendronate (Fosamax, Binosto) is a drug used to treat osteoporosis and Paget disease.
The use of alendronate in low doses is associated with increased osteocalcin and improved bone repair .
In a study of older women with rheumatoid arthritis, long-term treatment with teriparatide (48 weeks) increased osteocalcin levels .
Since people with rheumatoid arthritis have a higher risk of osteoporosis, pre-treatment with teriparatide may be beneficial .
Ibutamoren is a substance that increases growth hormone levels.
Elderly adults who received ibutamoren had increased osteocalcin levels, showing that this treatment has a positive effect on improving bone health in the elderly .
The Osteocalcin Gene (BGLAP)
In 5,561 older people, the ‘T’ variant of rs1800247 was associated with higher osteocalcin levels in women. In men, those with the ‘T’ variant had a higher risk of bone fractures .
However, in another study with 302 athletes, no relationship was observed between this variant and bone quality. This may suggest that the above-mentioned links become more significant with age .
In another study of 5,647 people, those with the ‘C’ variant had a lower risk of high blood pressure (hypertension). This may be because of the relationship between osteocalcin, insulin sensitivity, and energy metabolism .
This variant is found close to the osteocalcin gene and may influence its production. In 998 women, the rs1543294 variant was associated with higher osteoporosis-related fracture risk .
Irregular Osteocalcin Levels?
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