Osteocalcin
The bone protein that mouse studies cast as a hormone, and what measuring it in people has shown
Osteocalcin is a small protein made by bone-forming cells and the most abundant non-collagen protein in bone. Doctors measure it in blood as a marker of bone formation. Mouse studies from 2007 onward proposed that it also acts as a hormone on blood sugar, male fertility, the brain and exercise, but newer knockout mice show none of those effects, and in people the links are weak correlations. It has never been given to people as a treatment.
No established human dose Details ↓
Recommended Dosing
No established human dose
Osteocalcin has never been given to people in any study we read. Its human evidence is measurement: weak correlations with blood sugar, body fat and heart disease in meta-analyses, changes in its undercarboxylated form with vitamin K, exercise and a steroid dose, and a three-year trial in which lowering that form changed nothing in body composition.
What is it?
Osteocalcin, also called bone Gla protein, is a 49-amino-acid protein made by osteoblasts, the cells that build bone. Three of its glutamic acids are converted to gamma-carboxyglutamic acid (Gla), a change that depends on vitamin K. It is the most abundant protein in bone matrix after collagen, and knockout mice show it is needed to line up the mineral crystals along collagen fibres for normal bone strength. Some of it circulates, and serum osteocalcin is one of the routine bone formation markers. Reviews of bone turnover markers say they do not diagnose osteoporosis or predict an individual's fractures, but can show how a treatment is working.
Some of the osteocalcin in blood is undercarboxylated, missing one or more of its Gla groups. Vitamin K changes that quickly: 1,000 µg of vitamin K1 a day for two weeks cut the undercarboxylated share from 7.6% to 3.4% in 219 healthy adults, and vitamin K2 lowered it within two weeks in older women with osteoporosis. Mass spectrometry of plasma from vitamin K trials found osteocalcin circulating as more than a dozen truncated forms, each carrying anywhere from none to three Gla residues; the authors argue that claims for a hormonal role of the under-carboxylated forms need measurement at this level of detail.
In 2007 a mouse study proposed that the skeleton regulates blood sugar through osteocalcin: mice lacking it had fewer insulin-making beta cells, glucose intolerance and insulin resistance. Over the next decade the same research group reported that osteocalcin, acting mainly through the receptor GPRC6A, raises testosterone production in the testis, crosses the placenta and the blood-brain barrier to shape memory and anxiety, doubles in the blood during exercise and helps muscle use glucose and fat, and drives the acute stress response. A 2023 review by the group's lead author summarises these as the actions of a bone-derived hormone in rodents and primates. In 2020 two independent teams made new osteocalcin-deficient mice and found normal blood glucose, normal testosterone and normal male fertility, and could not explain the difference. A 2021 review argues that mouse strain, environment and receptor variants may account for the disagreement.
In people, osteocalcin has only been measured. Across 39 studies with 23,381 participants, total and undercarboxylated osteocalcin both correlated with lower fasting glucose and HbA1c, but weakly (r about -0.16). People with type 2 diabetes have lower total osteocalcin, and higher levels went with lower odds of the disease. Higher osteocalcin also went with lower body mass index and body fat across 51 studies, and lower total osteocalcin with heart and vessel disease in mostly cross-sectional data, while the composite risk of cardiovascular events did not differ by level. Exercise training raised undercarboxylated osteocalcin slightly in a meta-analysis of 22 randomised trials. Correlations like these cannot show that osteocalcin causes anything.
Two human experiments test the hormone idea more directly, and they disagree. A single 20 mg dose of prednisolone in nine healthy men lowered undercarboxylated osteocalcin by 24%, and the fall tracked the loss of insulin sensitivity. But in a three-year randomised trial in 401 older adults, vitamin K cut undercarboxylated osteocalcin by about 60% with no change in lean or fat mass. Osteocalcin itself has never been given to people, and it is not a medicine.
Mechanism of Action
Osteocalcin is made by osteoblasts and carboxylated in a vitamin K-dependent step. Its proposed hormone actions come from mouse work that newer mouse strains have not reproduced.
Bone mineral alignment
In osteocalcin-deficient mice, bone mass was normal but the mineral crystals no longer lined up with the collagen fibres, and the bone was weaker.
Vitamin K carboxylation
Three of its residues carry Gla groups whose addition depends on vitamin K; extra vitamin K lowers the undercarboxylated fraction within two weeks in people.
Proposed: glucose and insulin
Mouse studies proposed that undercarboxylated osteocalcin acts through the receptor GPRC6A to raise insulin secretion and sensitivity; two 2020 knockout strains showed normal glucose.
Proposed: testis, brain and muscle
The same research programme reported effects on testosterone synthesis, memory and anxiety, and muscle adaptation to exercise in mice.
Published Research
Studies of osteocalcin itself, read from their PubMed abstracts: the mouse experiments behind the hormone idea and the knockouts that questioned it, human studies that measured it, and meta-analyses of those measurements. Three key papers whose titles name the skeleton or bone markers rather than osteocalcin are listed under References.
Meta-analysis: glucose and HbA1c
Across 39 studies with 23,381 participants, total and undercarboxylated osteocalcin were both weakly and negatively correlated with fasting glucose (r -0.16 and -0.15) and HbA1c (-0.16 for both); the link with glucose was stronger in men.
Meta-analysis: type 2 diabetes
Pooling 24 papers, total osteocalcin was significantly lower in people with type 2 diabetes than in controls, and a high level was associated with lower odds of the disease (OR 0.70).
Meta-analysis: body fat
Across 51 observational studies, total and undercarboxylated osteocalcin were inversely correlated with body mass index (r -0.151 and -0.060) and with percentage body fat (about -0.18 for both).
Meta-analysis: cardiovascular disease
In 33 observational studies with 21,021 people, total osteocalcin was 2.58 ng/ml lower in those with cardiovascular conditions and inversely linked to calcification and plaque, but the risk of composite cardiovascular disease did not differ between the highest and lowest quarters (RR 0.98).
Meta-analysis: exercise training
Across 22 randomised trials in adults, exercise training raised undercarboxylated osteocalcin by 0.15 ng/ml, along with higher adiponectin and lower leptin, glucose, insulin and HOMA-IR.
Vitamin K1 in 219 healthy adults
Phylloquinone 1,000 µg a day for 2 weeks lowered the undercarboxylated share of osteocalcin from 7.6% to 3.4% in young and older men and women, and lowered serum osteocalcin, without changing other bone turnover markers.
Vitamin K2 in osteoporosis
In 20 older women with vertebral fractures, menaquinone-4 45 mg a day lowered undercarboxylated osteocalcin from 2.80 to 1.76 ng/ml within 2 weeks, with intact osteocalcin unchanged; calcium alone changed nothing.
Three years of vitamin K: no body change
In 401 older adults in a randomised trial, vitamin K reduced undercarboxylated osteocalcin by 58% in women and 61% in men over 3 years, with no difference from control in lean mass or fat mass.
The forms that circulate
Mass spectrometry of plasma from 130 people in vitamin K trials found osteocalcin in over a dozen truncated forms, each with 0 to 3 Gla residues; vitamin K raised the share with three Gla residues and did not change the truncation pattern.
A steroid dose lowered the active form
In nine healthy men, a single 20 mg prednisolone dose reduced insulin sensitivity and lowered serum undercarboxylated osteocalcin by 24%, and the fall correlated with lower insulin sensitivity before and after exercise.
Testosterone and fertility
In mice, osteocalcin promoted testosterone production through GPRC6A in parallel with luteinising hormone; in men with primary testicular failure, two carried the same variant of the receptor that kept it from the cell surface.
Brain development and memory
In mice, osteocalcin crossed the blood-brain barrier, raised monoamine neurotransmitter synthesis, and favoured learning and memory; maternal osteocalcin crossed the placenta, and giving it to pregnant knockout mothers rescued defects in their pups.
Exercise capacity
Circulating bioactive osteocalcin doubled during aerobic exercise in mice; signalling in muscle fibres was needed for adaptation, and giving osteocalcin raised exercise capacity in young mice and restored 15-month-old mice to the capacity of 3-month-olds.
Knockout mice: bone quality only
Newly made mice lacking both mouse osteocalcin genes had normal bone mass, glucose metabolism, testosterone and muscle mass, but disordered alignment of bone mineral crystals and weaker bone; the authors conclude it does not function as a hormone.
A second knockout without endocrine effects
A CRISPR-made osteocalcin-deficient mouse had no detectable serum osteocalcin, but its serum glucose and male fertility did not differ from littermates; the authors could not explain the difference from the original knockout.
The case for a bone hormone
Loss- and gain-of-function experiments in rodents and primates are summarised as showing osteocalcin acting through one of three receptors on energy metabolism, steroid synthesis and male fertility, cognition, the acute stress response and exercise capacity.
Explaining the disagreement
Reviews the osteocalcin-GPRC6A model and the newer knockouts without metabolic abnormalities, and argues that mouse strain, environmental challenges and receptor variants may explain the divergent results.
No Established Human Dose
Osteocalcin has never been given to people in any study we read. Its human evidence is measurement: weak correlations with blood sugar, body fat and heart disease in meta-analyses, changes in its undercarboxylated form with vitamin K, exercise and a steroid dose, and a three-year trial in which lowering that form changed nothing in body composition. The doses behind the hormone claims were given to mice.
What this rests on: PMID 26089135, PMID 32945990, PMID 31397589, PMID 26372899, PMID 32803318, PMID 11101481, PMID 27604070, PMID 25855755, PMID 30138543.
Educational information, not medical advice. The doses on this page come from approved labels, published studies and, where no study exists, amounts reported by users. None is a recommendation for you. An unapproved compound has no established safe or effective human dose, and products sold for “research use only” are not made or tested for people. Talk to a doctor before acting on anything on this site, including before you start, stop or change any medicine or dose. Full medical disclaimer.
What a Buyer Needs to Know
What is sold, how it is mixed, stored and taken, and what is known about its safety, quality and legal status. Each part names its source. Where we have none, it says unknown.
What is sold
Unknown: we hold no label and no published test that says what forms or vial sizes Osteocalcin is sold in. A vial's own label is a seller's claim, not a source.
Mixing a vial: a worked example
Unknown: no human dose of Osteocalcin has been established (see No Established Human Dose below), so there is no amount to work out. The reconstitution calculator does the arithmetic for any vial, water and dose.
Storage before and after mixing
Unknown: no label or published stability study on file says how to store Osteocalcin, before or after mixing. The mixing guide sets out the general rules, with their sources: keep a mixed vial in the fridge, and use it promptly, as the bacteriostatic water label says of any drug dissolved in it. The 28 days often quoted is the limit for an opened multiple-dose vial from a manufacturer, an outer limit set for sterility, not a time a mixed solution has been shown to keep. Nobody has published how long Osteocalcin stays intact once mixed.
How it is taken
Unknown: with no established human dose, there is no established way of taking Osteocalcin. What the human studies gave and how is set out under No Established Human Dose.
What to expect, and when
Unknown: no cited half-life and no label or trial duration on this page says how long Osteocalcin lasts or how long it was given. Results reported in the studies are under Published Research.
Side effects, and when to stop or get help
From the Side Effects section: No human safety data: every administration in the studies read was in animals; Vitamin K, which changes its carboxylation, is a separate substance with its own safety profile. Full list and cautions ↓
When to stop or get help: unknown; no label or trial on file sets rules for stopping Osteocalcin. Treat a severe or unexpected reaction as a reason to stop and see a doctor.
Source: the Side Effects section below (“Osteocalcin has not been given to people, so there are no human side-effect data”).
Interactions
Unknown: a PubMed search for human interaction studies of Osteocalcin (reviewed 2026-10-28) found none. Unknown is not the same as safe to combine.
Every peptide's record, with its source: the interaction matrix.
Checking what you bought
Unknown: no published independent test of Osteocalcin products is in our lab-results database yet, so how products sold under this name measure up is not known.
To read a certificate of analysis, paste it into the COA decoder. Trust & Verification explains what independent testing can and cannot show.
Legal status
US: Research Chemical (Not a medicine anywhere in the sources read). Sport: Prohibited (S0 catch-all).
Country by country ↓ · Regulatory tracker
Source: this entry's approval status and the WADA Prohibited List, as in Legal Status below.
Side Effects & Contraindications
Reported Side Effects
Osteocalcin has not been given to people, so there are no human side-effect data.
Contraindications & Cautions
Not a medicine.
Legal Status
Osteocalcin is measured in laboratories; it is not a drug.
Frequently Asked Questions
?What is osteocalcin?
A 49-amino-acid protein made by bone-forming cells, carrying three Gla groups whose addition depends on vitamin K. Some of it circulates in blood, where it is measured as a bone formation marker.
?Is osteocalcin a hormone?
Mouse studies say it acts on blood sugar, testosterone, the brain and exercise. Two 2020 knockout mouse strains showed none of those effects, and in people only weak correlations have been found, so it is unsettled.
?What is undercarboxylated osteocalcin?
Osteocalcin missing one or more of its Gla groups. Vitamin K supplements lower it within two weeks; in a three-year trial, cutting it by about 60% did not change muscle or fat mass.
?Can you take osteocalcin?
It has never been given to people in any study we found, and it is not an approved medicine.
References
- [review] Liu DM, et al. "Association between osteocalcin and glucose metabolism: a meta-analysis." Osteoporos Int, 2015;26(12):2823-33. PMID: 26089135.
- [review] Liu C, et al. "Association between Serum Total Osteocalcin Level and Type 2 Diabetes Mellitus: A Systematic Review and Meta-Analysis." Horm Metab Res, 2015;47(11):813-9. PMID: 26372899.
- [review] Liu X, et al. "Osteocalcin and measures of adiposity: a systematic review and meta-analysis of observational studies." Arch Osteoporos, 2020;15(1):145. PMID: 32945990.
- [review] Seidu S, et al. "Association of circulating osteocalcin with cardiovascular disease and intermediate cardiovascular phenotypes: systematic review and meta-analysis." Scand Cardiovasc J, 2019;53(6):286-295. PMID: 31397589.
- [review] Mohammad Rahimi GR, et al. "The effect of exercise training on osteocalcin, adipocytokines, and insulin resistance: a systematic review and meta-analysis of randomized controlled trials." Osteoporos Int, 2021;32(2):213-224. PMID: 32803318.
- [clinical-trial] Binkley NC, et al. "Vitamin K supplementation reduces serum concentrations of under-gamma-carboxylated osteocalcin in healthy young and elderly adults." Am J Clin Nutr, 2000;72(6):1523-8. PMID: 11101481.
- [clinical-trial] Miki T, et al. "Vitamin K(2) (menaquinone 4) reduces serum undercarboxylated osteocalcin level as early as 2 weeks in elderly women with established osteoporosis." J Bone Miner Metab, 2003;21(3):161-5. PMID: 12720050.
- [clinical-trial] Shea MK, et al. "Reducing Undercarboxylated Osteocalcin With Vitamin K Supplementation Does Not Promote Lean Tissue Loss or Fat Gain Over 3 Years in Older Women and Men: A Randomized Controlled Trial." J Bone Miner Res, 2017;32(2):243-249. PMID: 27604070.
- [clinical-trial] Rehder DS, et al. "Gamma-carboxylation and fragmentation of osteocalcin in human serum defined by mass spectrometry." Mol Cell Proteomics, 2015;14(6):1546-55. PMID: 25855755.
- [clinical-trial] Parker L, et al. "Glucocorticoid-Induced Insulin Resistance in Men Is Associated With Suppressed Undercarboxylated Osteocalcin." J Bone Miner Res, 2019;34(1):49-58. PMID: 30138543.
- [pubmed] Oury F, et al. "Osteocalcin regulates murine and human fertility through a pancreas-bone-testis axis." J Clin Invest, 2013;123(6):2421-33. PMID: 23728177.
- [pubmed] Oury F, et al. "Maternal and offspring pools of osteocalcin influence brain development and functions." Cell, 2013;155(1):228-41. PMID: 24074871.
- [pubmed] Mera P, et al. "Osteocalcin Signaling in Myofibers Is Necessary and Sufficient for Optimum Adaptation to Exercise." Cell Metab, 2016;23(6):1078-1092. PMID: 27304508.
- [pubmed] Moriishi T, et al. "Osteocalcin is necessary for the alignment of apatite crystallites, but not glucose metabolism, testosterone synthesis, or muscle mass." PLoS Genet, 2020;16(5):e1008586. PMID: 32463816.
- [pubmed] Diegel CR, et al. "An osteocalcin-deficient mouse strain without endocrine abnormalities." PLoS Genet, 2020;16(5):e1008361. PMID: 32463812.
- [review] Karsenty G. "Osteocalcin: A Multifaceted Bone-Derived Hormone." Annu Rev Nutr, 2023;43:55-71. PMID: 37603430.
- [review] Pi M, et al. "Explaining Divergent Observations Regarding Osteocalcin/GPRC6A Endocrine Signaling." Endocrinology, 2021;162(4). PMID: 33474566.
- [pubmed] Lee NK, et al. "Endocrine regulation of energy metabolism by the skeleton." Cell, 2007;130(3):456-69. PMID: 17693256.
- [pubmed] Berger JM, et al. "Mediation of the Acute Stress Response by the Skeleton." Cell Metab, 2019;30(5):890-902.e8. PMID: 31523009.
- [review] Brown JP, et al. "Current use of bone turnover markers in the management of osteoporosis." Clin Biochem, 2022;109-110:1-10. PMID: 36096182.
- [other] UniProt P02818: OSTCN_HUMAN, osteocalcin; chain 52-100, with 4-carboxyglutamate at 68 (partial), 72 and 75 and a disulfide bond 74-80. Read October 28, 2026. https://www.uniprot.org/uniprotkb/P02818/entry
Sources & Citations
Studies were read from their PubMed abstracts on October 28, 2026; the sequence and modifications are from UniProt P02818. Osteocalcin has no label. Searches on October 28, 2026 found no osteocalcin medicine in Drugs@FDA or the EMA list (0 records each), and the one ClinicalTrials.gov record was a zinc study that measured it.
Medical Disclaimer: This content is for educational and informational purposes only. It is not medical advice, and nothing here is an instruction to obtain or use any compound. Talk to a licensed clinician about your own situation.