Osteocalcin: Definition, Function, Composition, Test, Values ​​and Interpretation

We are talking about a protein produced by osteoblasts during bone formation.

Bone is known for its established role as a connective tissue that provides support and protection for vital organs and mobility to the body.

These functions are exercised by the three main types of skeletal cells: osteoblasts, osteoclasts, and osteocytes.

Osteoblasts, which originate from skeletal stem cells, are responsible for the synthesis and secretion of type I collagen to synthesize and maintain the extracellular matrix and can control osteoclast differentiation.

In addition to this thoroughly studied role, a new line of research has emerged in recent years, suggesting that osteoblasts secrete factors that possess hormonal function and, therefore, can control other organs.

Based on this, numerous studies have proposed that bone is an essential endocrine organ that controls a range of physiological processes, such as energy metabolism, adipogenesis, neuronal development, muscle growth, and male fertility.

One of the key players in bone endocrinology is osteocalcin or bone γ-carboxyglutamic acid protein; a factor expressed and secreted only by osteoblasts.


After protein synthesis, the mature peptide first undergoes several splicing events. It then is γ-carboxylated at three residues, resulting in a peptide with a high affinity for bone and extracellular matrix.

However, due to the low pH within the osteoclast reabsorption compartments, osteocalcin is decarboxylated again, reducing its affinity for bone and triggering the release of non-carboxylated osteocalcin into the circulation.

Initially, osteocalcin was assumed to act on the mineralization of the extracellular matrix and was used as a serum marker for osteoblastic bone formation.

However, in the late 1990s, depletion of osteocalcin was found to have minor effects on bone density and mineralization in mice.

Since then, significant efforts have been made to determine the proper function of this protein.

Osteocalcin function

So far, various roles of osteocalcin have been revealed, and current reports suggest that the non-carboxylated form of osteocalcin controls physiological pathways endocrine.

Osteocalcin’s currently known essential functions are its role in glucose metabolism and adaptation to exercise, neuronal development, and male fertility. There is a very recent hypothesis linking osteocalcin to tumorigenesis.

Insulin secretion

In mammals, glucose metabolism is the primary source of energy generation. It could not be explained why a hormone secreted by the skeleton would be involved in this metabolic pathway for a long time.

However, taking a closer look at ongoing processes in the bone, such as bone formation during childhood, repair of fractures after injury, or constant remodeling of the skeleton in adults, clearly indicates that the bone requires a significant amount of energy to carry out its functions.

An investigation demonstrated that secreted non-carboxylated osteocalcin induces insulin production in pancreatic islets and adiponectin expression in adipocytes.

Other research provided further confirmation of this mechanism and proposed that insulin receptor clearance in osteoblasts mimics the observed phenotypes of osteocalcin clearance.

These findings support the idea of ​​a bone-pancreas endocrine circuit where insulin signaling induces osteocalcin expression in osteoblasts, further stimulating insulin secretion from pancreatic islet cells.

Importantly, confirming the role of osteocalcin during glucose metabolism in humans may have direct therapeutic implications for patients with type 2 diabetes mellitus.

Overall, the role of osteocalcin in glucose metabolism is not yet fully supported by human studies due to the difficulties mentioned above.

Brain development and cognitive function

In addition to the well-studied role of osteocalcin in energy homeostasis, it has also been found to regulate proper brain development and function.

Osteocalcin has been described to regulate the synthesis of neurotransmitters in the brain, such as dopamine, serotonin, or norepinephrine.

Osteocalcin can rescue memory loss, and impaired neuronal development has sparked interest in the medical field.

Because Western society is aging disproportionately and increasing numbers of people suffer from cognitive decline, osteocalcin may be a promising novel therapeutic agent to alleviate these symptoms.

Male fertility and cancer prevention

Since sex hormones are known to be important regulators of bone strength during various stages of life, such as adolescence or menopause, it seems likely that osteocalcin may also function in a feedback loop in this metabolic process.

Active osteocalcin signaling could indicate bone strength and health, which can contribute to fertility along with many other fitness markers in the body. This would favor healthy and robust individuals to generate offspring from an evolutionary perspective.

Osteocalcin in optimal adaptation to exercise

Since osteocalcin has been reported to regulate glucose metabolism, which provides muscle energy during exercise, it may be involved in communication between these two tissues.

This suggests that osteocalcin and its receptor may be a promising target for combating the age-related decline in muscle strength or alleviating muscle disease.

Considering that this role of osteocalcin has been reported only very recently, further clinical studies are needed to draw definitive conclusions on possible therapeutic applications in bone-muscle communication.


Osteocalcin, the most significant non-collagenous protein in the bone matrix, represents approximately 1% of the total protein in human bone.

It is a 49 amino acid protein with a molecular weight of approximately 5800 daltons.

Osteocalcin contains up to 3 gamma-carboxyglutamic acid residues due to vitamin K-dependent post-translational enzymatic carboxylation.

Its production is dependent on vitamin K and is stimulated by 1,25 dihydroxy vitamin D.

Osteocalcin is produced by osteoblasts and is widely accepted as a marker of bone osteoblastic activity.

Osteocalcin, incorporated into the bone matrix, is released into the circulation from the matrix during bone resorption and is therefore considered a marker of bone turnover rather than a specific marker of bone formation.

Osteocalcin levels are increased in metabolic bone diseases with increased bone or osteoid formation, including osteoporosis, osteomalacia, rickets, hyperparathyroidism, renal osteodystrophy, thyrotoxicosis, and in people with fractures, acromegaly, and bone metastases.

By measurements of osteocalcin, it is possible to monitor therapy with antiresorptive agents (bisphosphonates or hormone replacement therapy) in, for example, patients with osteoporosis or hypercalcemia.

Decreased osteocalcin is also seen in some disorders (such as hypoparathyroidism, hypothyroidism, and growth hormone deficiency).

Osteocalcin test

The osteocalcin test is used to:

  • Monitoring and evaluation of the effectiveness of antiresorptive therapy in patients treated for osteopenia, osteoporosis, Paget’s disease, or other disorders in which osteocalcin levels are elevated.
  • As an adjunct to diagnosing medical conditions associated with increased bone turnover, including Paget’s disease, cancer accompanied by bone metastases, primary hyperparathyroidism, and renal osteodystrophy.

Immunochemical and chromatographic studies have shown considerable heterogeneity in circulating osteocalcin concentrations in normal individuals and patients with osteoporosis, chronic renal failure, and Paget’s disease.

Both intact osteocalcin (amino acids 1-49) and the large N-terminal / middle region fragment (N-MID) (amino acids 1-43) are present in the blood.

Reference values

  • Under 18 years: not established.
  • Over 18 years: 9-42 ng / mL.


Elevated levels of osteocalcin indicate an increase in bone turnover.

In patients taking antiresorptive agents (bisphosphonates or hormone replacement therapy), a 20% decrease in baseline osteocalcin level (i.e., before initiation of treatment) after 3 to 6 months of treatment suggests an effective response to treatment.

Patients with conditions such as hyperparathyroidism, which can be cured, should regain osteocalcin levels within the reference range within 3 to 6 months after complete healing.


Twelve hours before this blood test, do not take multivitamins or dietary supplements that contain biotin or vitamin B7, which are commonly found in hair, skin, and nail supplements and multivitamins.

Measurements of bone turnover markers are not helpful for the diagnosis of osteoporosis; The diagnosis of osteoporosis should be made based on bone density or a history of low trauma fracture.

The kidneys eliminate Osteocalcin. Therefore elevations can be observed in patients with renal failure without an increased bone turnover.

Serum osteocalcin may not reflect bone formation in patients treated with the hormone 1,25 dihydroxyvitamin D or those with abnormalities in this hormone since osteocalcin is regulated by 1,25 dihydroxy vitamin D.

In rare cases, interference can occur due to extremely high titers of antibodies to ruthenium or streptavidin.