Osteocalcin Test: Low & High Levels & How to Improve

Serum Osteocalcin: Reference Range, Interpretation, Collection and Panels

Osteocalcin Test: Low & High Levels & How to Improve

Osteocalcin is a noncollagenous, 49 amino acid glutamate-rich polypeptide bone matrix protein with a molecular weight of about 5800 kDa.

Osteoblasts produce osteocalcin and incorporate it into the bone matrix.

Osteocalcin is released into the circulation from the matrix during bone resorption and, therefore, is considered a marker of bone turnover rather than a specific marker of bone formation. [1]

The production of osteocalcin is stimulated by 1,25 dihydroxy vitamin D and depends on vitamin K.

Vitamin K increases the carboxylation of osteocalcin, but it does not increase its overall rate of synthesis.

Although its function is not completely understood, osteocalcin may exist as a deposition site for hydroxyapatite crystals; it may also affect energy metabolism via the production and action of insulin.

Because different antibodies recognize different fragments, no standard currently exists for osteocalcin assays. Antibodies that recognize both the large amino-terminal mid-molecule fragment and the intact molecule appear to provide superior clinical information.

Osteocalcin levels vary widely among healthy individuals and those patients with osteoporosis, Paget disease, and chronic renal failure.

Both the large N-terminal/midregion (N-MID) fragment (amino acids 1-43) and intact osteocalcin (amino acids 1-49) and are found in blood. [5] Because of protease cleavage between amino acids 43 and 44, intact osteocalcin is unstable.

The N-MID-fragment, which results from cleavage, is considerably more stable, some assays are able to detect both intact osteocalcin and the stable N-MID-fragment. [6]

One predictor of fracture is undercarboxylated osteocalcin. Osteocalcin is rapidly cleared by the kidneys and, to a lesser extent, the liver; in circulation, the half-life of osteocalcin is about 5 minutes.

Osteocalcin increases during high bone turnover (such as with hyperparathyroidism, acromegaly, and Paget disease). It decreases with hypoparathyroidism and hypothyroidism and in patients on glucocorticoid therapy. Measurement of osteocalcin can be used to monitor therapy with antiresorptive agents.

The reference intervals for osteocalcin are about 1.1–11 ng/mL (adult male) and 0.7–6.5 ng/mL (adultfemale). [7]

The diagnosis of osteoporosis should be bone density or a clinical history that includes low-trauma fracture. Osteocalcin levels should not be used to diagnose osteoporosis. Osteocalcin is cleared by the kidneys; impaired renal function causes osteocalcin levels to increase.

Serum osteocalcin may not reflect bone formation in patients treated with 1,25 dihydroxy vitamin D. This is because osteocalcin is regulated by 1,25 dihydroxy vitamin D.

Biotin may also interfere with osteocalcin testing. Do not obtain a specimen until at least 8 hours after the last biotin administration.

Patients treated with mouse antibodies or patients who have been exposed to monoclonal mouse antibody–containing products may produce erroneous findings.

Similar to the inverse correlation found in adults between serum osteocalcin levels and body mass index (BMI), a study of overweight children by Oh et al reported serum osteocalcin levels to be negatively correlated with BMI, serum insulin levels, and the homeostasis model assessment of insulin resistance (HOMA-IR) index. A causal relationship, however, was not established. [8]

Source: https://emedicine.medscape.com/article/2093955-overview

Serum Osteocalcin as a Diagnostic Biomarker for Primary Osteoporosis in Women

Osteocalcin Test: Low & High Levels & How to Improve

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Source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4576601/

Osteocalcin Test: Low & High Levels & How to Improve

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The relationship between bone turnover markers and atherosclerosis is controversial.

The purpose of this study was to determine the association of arterial stiffness with the levels of osteocalcin and C-terminal telopeptide of type I collagen (CTx).

Design, Setting, and Participants:

This cross-sectional study included 1691 men and 1913 women who participated in the medical examination programs of a hospital from March 2008 to December 2011.

Arterial stiffness was estimated by brachial-ankle pulse wave velocity (baPWV). Osteocalcin and CTx were assayed by chemiluminescence immunoassay. Bone mineral density was measured by dual-energy X-ray absorptiometry.

The mean baPWV was elevated at both ends of the osteocalcin quintiles in both men and women. However, the adjusted mean was higher in the lowest quintile of osteocalcin than in the other quintiles in men and women.

Before adjustment, negative and positive relationships of baPWV with the levels of osteocalcin and CTx were observed in men (β = −0.123 and −0.078 for osteocalcin and CTx, respectively) and women (β = 0.151 and 0.193), respectively.

After adjustment for age and metabolic parameters, osteocalcin was negatively related with baPWV at lower osteocalcin levels (Q1–Q2) in both sexes (in the fully adjusted model, β = −0.090 for men and −0.053 for women).

No significant relationship was observed at higher values. The osteocalcin level was fit for a quadratic model for baPWV showing an inverse J-shape.

The level of serum osteocalcin showed an inverse J-shaped relationship with arterial stiffness in both men and women. However, the association between the CTx level and arterial stiffness was not significant.

Osteoporosis and atherosclerosis are degenerative disorders related to aging in bone and blood vessels, respectively, and frequently coexist with each other.

However, some evidence suggests that the degenerative change in bone is associated with atherosclerosis independent of age (1–6).

It is expected that bone-derived materials such as bone turnover markers play a role in atherosclerotic change (7).

A few studies reported that higher levels of C-terminal telopeptide of type I collagen (CTx) were associated with atherosclerosis (8, 9).

In a prospective study, men with low bone mineral density (BMD) or high bone resorption rates were at increased risk of myocardial infarction (MI) and stroke (2).

In this study, bone formation markers such as osteocalcin, bone-specific alkaline phosphatase, and N-terminal propeptide of type I procollagen (P1NP) did not influence the risk of cardiovascular events.

Various studies have investigated the relationship between osteocalcin and atherosclerosis. Although some of the studies reported a positive association between osteocalcin and atherosclerosis (10, 11), others showed a negative relationship (12–17).

These studies analyzed a linear relationship. Meanwhile, a prospective cohort study showed a U-shaped relationship between the baseline osteocalcin level and cardiovascular mortality in elderly men (18).

Thus, the relationship between osteocalcin and atherosclerosis may not necessarily be linear.

Carotid-femoral pulse wave velocity (cfPWV) is considered the gold standard measurement for arterial stiffness (19). Compared with cfPWV, brachial-ankle pulse wave velocity (baPWV) exhibits a similar extent of associations with cardiovascular disease risk factors and clinical events (20).

The baPWV recently became a popular technique for screening vascular damages in a large population due to its simple and noninvasive measuring method (21). Similar to previous studies, we hypothesized that serum osteocalcin or CTx is associated with subclinical atherosclerosis estimated by baPWV.

To assess whether the relationship is linear or nonlinear, we evaluated the association of the level of serum osteocalcin and CTx with baPWV in a large population in Korea.

Study design and participants

The participants in our cross-sectional study were recruited from adults who visited the hospital for health check-ups from March 2008 to December 2011. All participants voluntarily took part in our study without any reward. Informed consent was obtained from all subjects.

The subjects were excluded if they were receiving hormone therapy or osteoporosis treatment to reduce external influence on bone metabolism.

In addition, we excluded patients taking vitamin K metabolism–related drugs such as warfarin, as well as those with other metabolic bone diseases. We also excluded those with acute disease, abnormal liver or kidney function, and a history of stroke, angina, MI, or cancer.

A total of 1691 men and 1913 women were enrolled in our study. This study was approved by the institutional review board of CHA Hospital in Korea.

Measurements

We collected information on the subjects' medical history and lifestyle habits using a self-report questionnaire. Smoking history was categorized into nonsmokers, ex-smokers, and current smokers.

Drinking was categorized into current drinkers or nondrinkers. Exercise was categorized into routine (moderate to strenuous intensity, 3 times a week or more frequently) and nonroutine.

Menopause was defined as natural cessation of menstruation for longer than 12 months or cessation by hysterectomy.

Height and weight were measured in a standing position without shoes and were recorded to the first decimal point in centimeters and kilograms, respectively.

Body mass index (BMI) was calculated as the weight in kilograms divided by the square of the height in meters. Waist circumference was measured midway between the lower rib margin and the iliac crest in a standing position.

Blood pressure (BP) was measured after resting for 10 minutes in a sitting position using an automatic sphygmomanometer.

Blood sampling

Fasting blood samples were drawn from the antecubital area in the morning. Serum samples were stored at 4°C and analyzed within a day of sampling. All serum analyses were performed on a daily basis.

Glucose, creatinine, and lipid profiles were tested using an automatic analyzer (Hitachi 7600). Glomerular filtration rate (GFR) was estimated using the Modification of Diet in Renal Disease method (22).

Serum osteocalcin was measured by electrogenerated chemiluminescence using an Elecsys N-MID osteocalcin kit (Roche Diagnostics) with intra- and interassay coefficients of variation of 1.2 to 4.0% and 1.7 to 6.5%, respectively.

Serum CTx was measured by chemiluminescence immunoassay using an Elecsys β-CrossLaps kit (Roche Diagnostics). The intra- and interassay coefficients of variation were 1.2 to 4.7% and 1.5 to 5.7%, respectively.

Arterial stiffness

The baPWV was measured using the Colin VP-1000 Plus system (Omron). Patients were examined in a supine position, with a volume plethysmographic sensor in cuffs on both the brachia and ankles.

After 15 minutes of rest, the subject's volume pulse form was recorded, and the time intervals between the wave front of the arm and that of the ankles were calculated.

The distance between the arm and sampling points was calculated automatically.

BMD

BMD was measured in the lumbar spine (L1–L4), the total hip, and the femur neck using dual-energy X-ray absorptiometry (Hologic Discovery-W; Hologic).

Statistical analysis

All analyses were performed by sex. For descriptive analysis, the results are expressed as mean ± SD, median (interquartile range), or number (proportion). Pearson correlation analyses were used to investigate the linear relationship of the levels of osteocalcin and CTx with age and metabolic parameters.

The participants were separated into quintiles according to the levels of osteocalcin and CTx, respectively. The mean baPWV was compared among the subjects with the lowest quintile and those with the other quintiles using t tests.

The adjusted mean was estimated using analysis of covariance (ANCOVA) with controls for the variables of age, BMI, systolic BP, glucose, total cholesterol, GFR, smoking, drinking, exercise, menopause, history of hypertension and diabetes, and total hip BMD.

To assess the linear relationship of baPWV with the levels of osteocalcin and CTx, linear regression analyses were performed. To control the influence of the risk factors for cardiovascular disease (CVD) on baPWV, the regression models included potential confounders. First, crude models (model 1) were set as univariate models including only osteocalcin or CTx.

Model 2 additionally included the variables of age, BMI, and systolic BP. Next, model 3 included the additional variables of glucose (logarithmically transformed), total cholesterol, GFR, smoking, drinking, exercise, menopause (women only), history of hypertension and diabetes, and total hip BMD.

To confirm the elevation of baPWV at both ends of the distribution for the level of osteocalcin and CTx, the regression models were recreated in 2 subgroups (quintile [Q] 1–Q2 and Q4–Q5). Finally, to assess the nonlinear relationship, a quadratic term for osteocalcin or CTx was included in a regression model combining men and women together.

All analyses were conducted using SPSS 21.0 statistical analysis software (IBM). P < .05 was considered statistically significant.

Results

The baseline characteristics of the participants are presented in Table 1. The median age was 51 years in both men and women. Among 1913 female subjects, 56% were postmenopausal. The median baPWV was 1.38 and 1.30 m/s in men and women, respectively. The median levels of osteocalcin and CTx were 15.48 and 0.46 ng/mL in men and 16.29 and 0.43 ng/mL in women, respectively.

General Characteristics of Subjects

. Men (n = 1691) . Women (n = 1913) . P . 
Age, y 51.3 ± 9.8 50.8 ± 9.8 .138 
Smoking 

Source: https://academic.oup.com/jcem/article/101/1/96/2806594

A meta-analysis of serum osteocalcin level in postmenopausal osteoporotic women compared to controls

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Osteocalcin Test: Low & High Levels & How to Improve

Osteocalcin Test: Low & High Levels & How to Improve

Osteocalcin is a protein that helps build and maintain bones. Read on to learn more about the osteocalcin test, normal levels, what low and high osteocalcin levels mean, and what you can do to improve your bone health.

Osteocalcin Test

The osteocalcin test measures the amount of osteocalcin in your blood.

Osteocalcin is a protein hormone produced in the bones. It binds calcium and helps build and heal bones. Osteocalcin may also help adjust insulin production and blood sugar levels, stimulate testosterone production, and improve muscle strength and brain health [1, 2, 3, 4, 5].

Why Doctors Order It

Osteocalcin blood levels reflect the rate of bone turnover. Therefore, the osteocalcin test is useful for monitoring disorders that affect bone health, such as osteoporosis, primary and secondary hyperparathyroidism, cancer with bone metastasis, and Paget’s disease [6].

Your doctor can use this test to help diagnose Paget’s disease, cancer accompanied by bone metastases, primary hyperparathyroidism, and renal osteodystrophy. However, this test can’t be used to diagnose osteoporosis.

Your doctor may also order the osteocalcin test to monitor how well bone-building therapy is working.

Procedure

You shouldn’t take supplements containing biotin or vitamin B7 at least 12 hours before the test. Otherwise, you don’t need to prepare for the test in any special way.

Normal Range

The levels of osteocalcin in your serum (the liquid part of the blood) are usually reported in ng/mL (nanograms per milliliter).

The normal range is around 8 – 32 ng/mL. Levels can vary slightly between labs, due to differences in equipment, chemicals, and methods used.

Some labs give a different range for men, pre- and post-menopausal women.

Causes:

Low osteocalcin levels usually indicate lower bone turnover.

Causes shown below are commonly associated with low osteocalcin levels. Work with your doctor or another health care professional to get an accurate diagnosis. Your doctor will interpret your value, taking into account your medical history, symptoms, and other test results.

Osteocalcin can be decreased by:

  • Underactive thyroid (Hypothyroidism) [7]
  • Underactive parathyroid gland (Hypoparathyroidism) [8]
  • Growth hormone deficiency [9, 10]
  • Liver disease [11]
  • Smoking [12]
  • Some drugs, such as glucocorticoids and drugs that slow the progression of bone loss (i.e., antiresorptive agents such as bisphosphonates or hormone-replacement therapy [HRT]) [13, 14]

Increasing Osteocalcin and Improving Bone Health

If your osteocalcin is low, the most important thing is to work with your doctor to find out what’s causing your low osteocalcin and to treat any underlying conditions.

Discuss the additional lifestyle changes listed below with your doctor. None of these strategies should ever be done in place of what your doctor recommends or prescribes!

1) Weight Loss

Lose weight if you are overweight. Obesity has been associated with lower osteocalcin levels [15].

In a study of 107 older, frail adults, osteocalcin blood levels increased on a calorie restriction diet [16].

In a study of 49 obese men, osteocalcin blood levels increased after weight loss [15].

However, in a study of 71 postmenopausal women, there was no link between weight loss and osteocalcin [17].

Finally, in 178 obese persons, high osteocalcin levels were associated with reduced body fat. However, osteocalcin levels actually decreased after weight loss [18].

If you’re overweight, even it doesn’t affect your osteocalcin levels, weight loss will improve your overall health, including your bone health [19].

2) Quitting Smoking

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) [20].

Smoking can also decrease osteocalcin levels in saliva, which has been associated with chronic gum inflammation (periodontitis) [21, 22].

3) Exercise

Osteocalcin levels are higher in people who are more physically active [23].

A link between physical activity and higher osteocalcin levels has been found in a study of 54 adolescents [24].

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) [25].

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 [26].

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 [27].

In a study of 39 obese but otherwise healthy young men, those who followed an 8-week program of exercise with four sessions per week had increased osteocalcin and leptin levels [28].

4) 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 [29, 30].

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 [31, 32, 33].

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 [34].

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 K is taken as well [34]. Always consult with your doctor before using any supplements!

5) Vitamin D

Vitamin D directly stimulates osteocalcin production [35].

In a clinical trial 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 [35].

Check your vitamin D levels. If they are low, you may benefit from getting more sun or taking vitamin D supplements. Discuss vitamin D supplements with your doctor.

6) Zinc

Dietary zinc intake increased osteocalcin in a study of 66 people with type 1 diabetes [36].

Zinc supplements increased osteocalcin levels in 22 shorter-than-average children. However, this has not been linked to more growth (height and weight) [37].

7) Decreasing Glucocorticoids

Glucocorticoids are steroid hormones that inhibit inflammation. They are frequently used to treat asthma and rheumatoid arthritis [38, 39].

However, glucocorticoids may also reduce osteocalcin in the bones, which may increase the risk of osteoporosis in people who take glucocorticoids regularly [40].

A study found that reducing the dosage of glucocorticoids in 208 patients with rheumatoid arthritis led to improvements in osteocalcin levels and bone metabolism [40].

Discuss your medications, their dosage, and possible alternatives with your doctor.

Causes

High osteocalcin levels indicate higher bone turnover.

Causes shown below are commonly associated with high osteocalcin levels. Work with your doctor or another health care professional to get an accurate diagnosis. Your doctor will interpret your value, taking into account your medical history, symptoms, and other test results.

These can increase osteocalcin levels can be caused by:

  • Periods of rapid growth (puberty) [6]
  • Intense physical exercise [27]
  • Bone fractures [41]
  • Osteoporosis [42]
  • Softening of bones (osteomalacia) [43]
  • Vitamin D deficiency [44]
  • Overactive parathyroid gland (hyperparathyroidism) [45]
  • Overactive thyroid gland (hyperthyroidism) [46]
  • Paget disease (a bone remodeling disease) [47]
  • Chronic kidney disease (renal osteodystrophy) [48]
  • Bone cancer and other cancers that metastasize to the bone [49]
  • Excess growth hormone (acromegaly) [50]

Decreasing Osteocalcin

If your osteocalcin is high, the most important thing is to work with your doctor to find out what’s causing your high osteocalcin and to treat any underlying conditions.

Your doctor may suggest vitamin D supplements if you’re deficient [44].

Genetics

Skip this part if you are not interested in genetics and haven’t sequenced your DNA.

Two SNPs in the Osteocalcin Gene, BGLAP, have been associated with osteocalcin levels.

rs1800247

The ‘T’ variant of this gene has been associated with higher osteocalcin levels, while the ‘C’ variant is linked to lower osteocalcin levels [51, 52].

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 [52].

However, in another study with 302 athletes, no relationship was observed between this variant and bone quality. This genetic variant may only be relevant in older people [53].

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 osteocalcin improves insulin sensitivity and energy metabolism [54].

More studies are needed to confirm these associations.

rs1543294

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 [51].

Further Reading

  • What Is Osteocalcin? Definition, Function & Health Effects

Source: https://selfhacked.com/blog/osteocalcin-test/

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