Bone Turnover Markers (BTM)
Synonym/Acronym
Rationale
To assist in identifying an imbalance in bone turnover and evaluate the effectiveness of treatment for osteoporosis.
Patient Preparation
There are no food, fluid, activity, or medication restrictions unless by medical direction. As appropriate, provide the required urine collection container for NTX and specimen collection instructions.
Normal Findings
Method: Electrochemiluminescent immunoassay.
| NTx(Collagen Cross-Linked N-Telopeptide of Type I Collagen) | | 7–9 yr | | | Male | 167–578 nmol bone collagen equivalents (BCE)/mmol creatinine | | Female | 201–626 nmol bone collagen equivalents (BCE)/mmol creatinine | | 10–12 yr | | | Male | 152–505 nmol bone collagen equivalents (BCE)/mmol creatinine | | Female | 173–728 nmol bone collagen equivalents (BCE)/mmol creatinine | | 13–15 yr | | | Male | 103–776 nmol bone collagen equivalents (BCE)/mmol creatinine | | Female | 38–515 nmol bone collagen equivalents (BCE)/mmol creatinine | | 16–17 yr | | | Male | 34–313 nmol bone collagen equivalents (BCE)/mmol creatinine | | Female | 20–144 nmol bone collagen equivalents (BCE)/mmol creatinine | | Adult male | 21–83 nmol bone collagen equivalents (BCE)/mmol creatinine | | Adult female (premenopausal) | 17–94 nmol BCE/mmol creatinine | | Adult female (postmenopausal) | 26–124 nmol BCE/mmol creatinine |
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| Osteocalcin |
|---|
| Age and Sex | Conventional Units | SI Units (Conventional Units × 1) |
|---|
| 6 mo–6 yr | | | | Male | 39–121 ng/mL | 39–121 mcg/L | | Female | 44–130 ng/mL | 44–130 mcg/L | | 7–9 yr | | | | Male | 66–182 ng/mL | 66–182 mcg/L | | Female | 73–206 ng/mL | 73–206 mcg/L | | 10–12 yr | | | | Male | 85–232 ng/mL | 85–232 mcg/L | | Female | 77–262 ng/mL | 77–262 mcg/L | | 13–15 yr | | | | Male | 70–336 ng/mL | 70–336 mcg/L | | Female | 33–222 ng/mL | 33–222 mcg/L | | 16–17 yr | | | | Male | 43–237 ng/mL | 43–237 mcg/L | | Female | 24–99 ng/mL | 24–99 mcg/L | | Adult | | | | Male | 3–40 ng/mL | 3–40 mcg/L | | Female | | | | Premenopausal | 5–30 ng/mL | 5–30 mcg/L | | Postmenopausal | 9–50 ng/mL | 9–50 mcg/L |
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Study type: Urine from a random specimen collected in a clean plastic container for NTX; blood collected in a gold-, red/gray, red-, lavender [EDTA]-pink [K2EDTA], or green [sodium or lithium heparin]-top tube for osteocalcin; related body system: Musculoskeletal system.
Bone turnover markers (BTMs) provide information regarding the dynamic process of bone remodeling that occurs in various diseases affecting the bones and in the increased deterioration of bone structure observed in aging. Bone markers can be elevated under normal circumstances (e.g., fracture healing, growing children).
Markers specific to bone resorption/destruction include NTX (N-terminal telopeptide of type I collagen), C-terminal telopeptide of type I collagen (CTX), and pyridinoline cross-links.
Markers that are specific to bone formation include bone-specific alkaline phosphatase (BSAP), osteocalcin, and N-terminal propeptide of type I procollagen (PINP).
There are three types of bone tissue:
Cartilage is another type of tissue found in the nose, ears, and trachea as well as a number of other parts of the body. At birth most of the bones are made of cartilage, and as growth takes place the cartilage is gradually replaced by bone in a process called
ossification. Throughout our life span our bones continue to undergo change. Bone tissue is maintained and remodeled as needed by cells called
osteoblasts, osteoclasts, and
osteocytes.
Osteoblasts are responsible for formation of bone and
osteoclasts resorb or break down bone. Bone turnover is a balance between bone formation and bone resorption, orchestrated by a third type of bone cell called
osteocytes. Osteocytes are located in the mineral rich matrix of mature bone tissue. They are derived from osteoblasts and function to maintain the health of living bone tissue by regulating mineral homeostasis as well as communicating with other osteocytes to signal osteoblasts and osteoclasts when bone formation or resorption is required.
Bone Resorption (Destruction)
The urine bone marker study is a noninvasive test to detect the presence of collagen cross-linked N-telopeptide (NTx) in urine. NTx is formed when collagenase acts on bone. Small NTx fragments are excreted in the urine after bone resorption.
Osteoporosis is often called a “silent disease” because bone loss occurs without symptoms. The formation and maintenance of bone mass is dependent on a combination of factors that include genetics, nutrition, exercise, and hormone function. Normally, the rate of bone formation is equal to the rate of bone resorption. After midlife, the rate of bone loss begins to increase. Osteoporosis is more commonly identified in women than in men. Other risk factors include thin, small-framed body structure; family history of osteoporosis; diet low in calcium; white or Asian ancestry; excessive use of alcohol; cigarette smoking; sedentary lifestyle; long-term use of corticosteroids, thyroid replacement medications, or antiepileptics; history of bulimia, anorexia nervosa, chronic liver disease, or malabsorption disorders; and postmenopausal state.
Most patients with osteopenia or osteoporosis have low, but unbalanced, bone turnover, with bone resorption dominating over bone formation. While this may result in mild elevations in bone turnover markers in these patients, the finding of significantly elevated urine NTx levels is atypical. Therefore, if levels are substantially elevated above the young adult reference range (greater than 1.5- to 2-fold) when alternative causes for elevated NTx have been excluded in a patient with osteopenia/osteoporosis, the patient must be considered at increased risk for accelerated progression of osteopenia/osteoporosis. By contrast, abnormalities in the process of bone remodeling can result in changes in skeletal mass and shape. Many diseases, in particular hyperthyroidism, all forms of hyperparathyroidism, most forms of osteomalacia and rickets (even if not associated with hyperparathyroidism), hypercalcemia of malignancy, Paget disease, multiple myeloma, and bony metastases, as well as various congenital diseases of bone formation and remodeling can result in accelerated and unbalanced bone turnover. Unbalanced bone turnover, usually without increase in bone turnover, is also found in age-related and postmenopausal osteopenia and osteoporosis. Disease-associated bone turnover abnormalities should normalize in response to effective therapeutic interventions, which can be monitored by measurement of serum and urine bone resorption and formation markers. Bone turnover markers are used to follow the progress of patients who have been diagnosed with osteoporosis and have begun treatment. A desirable response, 2 to 3 mo after therapy is initiated, is a 30% reduction in NTx and a reduction of 50% below baseline by 12 mo.
Osteoporosis is a major consequence of menopause in women owing to the decline of estrogen production. Osteoporosis is rare in premenopausal women. Estrogen replacement therapy (after menopause) is one strategy that has been commonly employed to prevent osteoporosis, although its exact protective mechanism is unknown. Results of some recently published studies indicate that there may be significant adverse effects to estrogen replacement therapy; more research is needed to understand the long-term effects (positive and negative) of this therapy. Other treatments include raloxifene (selectively modulates estrogen receptors), denosumab (increases bone density), calcitonin (interacts directly with osteoclasts), and bisphosphates to include alendronate, ibandronate, risedronate, or zoledronic acid (inhibit osteoclast-mediated bone resorption).
Bone Formation
Osteocalcin is an important bone cell matrix protein and a sensitive marker in bone metabolism. It is produced by osteoblasts during the matrix mineralization phase of bone formation and is the most abundant noncollagenous bone cell protein. Synthesis of osteocalcin is dependent on vitamin K and vitamin D. Osteocalcin levels parallel alkaline phosphatase levels. Osteocalcin levels are affected by a number of factors, including estrogen levels. Assessment of osteocalcin levels permits indirect measurement of osteoblast activity and bone formation. Osteocalcin in the bone matrix is released into the bloodstream during bone resorption and is regarded as more of a marker of bone turnover than bone formation.
Knowledge of genetics assists in identifying those who may benefit from additional education, risk assessment, and counseling. Genetics is the study and identification of genes, genetic mutations, and inheritance. Genomic studies evaluate the interaction of groups of genes. The combined activity or combined expression of groups of genes allows assumptions or predictions to be made. As an example, genomic studies measure the levels of activity in multiple genes to predict how they, along with environmental and lifestyle decisions, influence the development of reduction in bone mass, type 2 diabetes, coronary artery disease, or ischemic stroke. Further information regarding inheritance of genes can be found in the study titled “Genetic Testing.”
Increased In
NTX
Conditions that reflect increased bone resorption/destruction are associated with increased levels of N-telopeptide in the urine.
- Chronic immobilization
- Chronic treatment with anticonvulsants, corticosteroids, gonadotropin releasing hormone agonists, heparin, or thyroid hormone
- Conditions that include hypercortisolism, hyperparathyroidism, hyperthyroidism, and hypogonadism
- Gastrointestinal disease (related to inadequate dietary intake or absorption of minerals required for bone formation and maintenance)
- Growth disorders (acromegaly, growth hormone deficiency, osteogenesis imperfecta)
- Hyperparathyroidism (related to imbalance in calcium and phosphorus that affects the rate of bone resorption)
- Multiple myeloma and metastatic tumors
- Osteomalacia (related to defective bone mineralization)
- Osteoporosis
- Paget disease
- Postmenopausal women (related to estrogen deficiency)
- Recent fracture
- Renal insufficiency (related to excessive loss through renal dysfunction)
- Rheumatoid arthritis and other connective tissue diseases (related to inadequate diet due to loss of appetite)
- Substance use disorder (alcohol) (related to inadequate nutrition)
Osteocalcin levels are increased in normal phases of bone growth. Levels are also increased in metabolic bone diseases that accompany abnormal bone formation and those in which osteocalcin is released from bone matrix into circulation as the result of bone destruction.
- Acromegaly
- Adolescents undergoing a growth spurt (levels in the blood increase as the rate of bone formation increases)
- Bone fractures
- Bone metastases
- Chronic kidney disease (related to accumulation in circulation due to decreased renal excretion)
- Hyperthyroidism (primary and secondary) (related to increased bone turnover)
- Metastatic skeletal disease (levels in the blood increase as bone destruction releases it into circulation)
- Osteomalacia
- Paget disease (levels in the blood increase as bone destruction releases it into circulation)
- Renal osteodystrophy(related to bone degeneration secondary to hyperparathyroidism of chronic kidney disease)
- Rickets
- Some patients with osteoporosis (levels in the blood increase as bone destruction releases it into circulation)
Decreased In
NTX
- Effective therapy for osteoporosis
Osteocalcin
- Growth hormone deficiency (bone mineralization is stimulated by growth hormone)
- Pregnancy (increased demand by developing fetus results in an increase in maternal bone resorption)
- Primary biliary cholangitis (related to increased bone loss)
Potential Nursing Problems: Assessment & Nursing Diagnosis
| Problems | Signs and Symptoms |
|---|
| Body image (related to kyphosis secondary to vertebral fractures; altered sense of self related to necessary use of assistive devices) | Focus on notable physical changes in posture and height, lingering focus on physical loss and impacted personal changes, altered body structure and function, social withdrawal | | Fall risk (related to altered mobility associated with loss of bone mass; history of falls; assistive device use; inadequate balance) | Postural instability; jerky movement; uncoordinated movement; slow, unsteady movement; impaired gait | | Self-care (deficit—related to loss of bone mass and physical deformity, pain, and limited range of motion) | Difficulty fastening clothing, difficulty performing personal hygiene, inability to maintain appropriate appearance, difficulty with independent mobility |
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Before the Study: Planning and Implementation
Teaching the Patient What to Expect
- Discuss how this test can assist in evaluating for bone disease, diagnosing osteoporosis, and evaluating therapy effectiveness.
- Explain that a blood sample is needed for osteocalcin.
- Explain that a urine sample is needed for the NTX test.
- Instruct the patient to collect a second-void morning specimen as follows: (1) void and then drink a glass of water; (2) wait 30 min and then try to void again.
- Information regarding urine specimen collection is presented with other general guidelines in Appendix A: Patient Preparation and Specimen Collection.
Potential Nursing Actions
- Include on the collection container’s label the specimen collection type (e.g., clean catch, catheter), date and time of collection, and any medications that may interfere with test results.
After the Study: Implementation & Evaluation Potential Nursing Actions
Treatment Considerations
General
- Explain that the test may need to be repeated to evaluate disease progression and therapy effectiveness.
- Discuss the symptoms of osteoporosis: ongoing loss of height, back and trunk pain, bent stooped posture, dorsal spine dowagers hump, fragile bones with common fractures of the wrist, hip, or vertebra.
Body Image
- Assess the patient’s perception of self-image.
- Assess the patient’s perception on their ability to perform self-care.
- Assess and acknowledge the patients emotional response to changed physical appearance (kyphosis) and self-care abilities.
- Note the presence of social withdrawal due to physical changes.
Self-Care
- Facilitate management of self-care deficit.
- Reinforce self-care techniques as taught by occupational therapy.
- Ensure the patient has adequate time to perform self-care, and encourage use of assistive devices to maintain independence.
- Ask if there is any interference with lifestyle activities.
- Collaborate with the health-care team to provide opportunities to learn new ways to perform self-care and maintain independence.
Safety Considerations
Fall, Risk
- Closely observe and assess gait and ability to move.
- Evaluate the immediate environment for barriers to clear and easy movement.
- Discuss fall precautions and assess home environment for fall risk.
- Evaluate medications for contributory cause related to recent falls.
- Encourage physical therapy to facilitate moderate exercise.
- Discuss how low, comfortable walking shoes can promote safe ambulation and decrease fall risk.
- Encourage participation in a physical therapy program designed to strengthen muscles and improve coordination.
Nutritional Considerations
NTX
- Increased NTx levels may be associated with osteoporosis. Nutritional therapy may be indicated for patients identified as being at high risk for developing osteoporosis. Educate the patient about the National Osteoporosis Foundation’s guidelines regarding a regular regimen of weight-bearing exercises, limited alcohol intake, avoidance of tobacco products, and adequate dietary intake of vitamin D and calcium.
- Dietary calcium can be obtained from animal or plant sources. Almonds (milk, nuts), beet greens, broccoli, cheese, clams, kale, legumes, milk and milk products, oysters, rhubarb, salmon (canned), sardines (canned), spinach, tofu, yogurt, and calcium-fortified foods such as orange juice are high in calcium.
- Milk and milk products also contain vitamin D and lactose, which assist calcium absorption.
- Facilitate discussion of culturally congruent sample menus that focus on ways to include both calcium and vitamin D in the diet.
Osteocalcin Levels
- Increased osteocalcin levels may be associated with skeletal disease.
- Nutritional therapy is indicated for those at high risk for developing osteoporosis.
- Educate the patient regarding the National Osteoporosis Foundation’s guidelines (www.nof.org), which include a regular regimen of weight-bearing exercises, limited alcohol intake, avoidance of tobacco products, and adequate dietary intake of vitamin D and calcium.
Abnormal Calcium Values
- Patients with abnormal calcium values should be informed that daily intake of calcium is important even though body stores in the bones can be called on to supplement circulating levels.
- Dietary calcium can be obtained from animal or plant sources: milk and milk products, sardines, clams, oysters, salmon, rhubarb, spinach, beet greens, broccoli, kale, tofu, legumes, and fortified orange juice are high in calcium. Milk and milk products also contain vitamin D and lactose, which assist calcium absorption. Cooked vegetables provide more absorbable calcium than raw vegetables.
- Explain that there are substances that can inhibit calcium absorption by irreversibly binding to some of the calcium, making it unavailable for absorption. Examples include oxalates, which naturally occur in some vegetables (e.g., beet greens, collards, leeks, okra, parsley, quinoa, spinach, Swiss chard) and are found in tea; phytic acid, found in some cereals (e.g., wheat bran, wheat germ); phosphoric acid, found in dark cola; and insoluble dietary fiber (in excessive amounts).
- Excessive protein intake can negatively affect calcium absorption, especially when combined with foods high in phosphorus and in the presence of a reduced dietary calcium intake.
Vitamin D Deficiency
- Discuss that the main dietary sources of vitamin D are fortified dairy foods and cod liver oil, and that vitamin D is also synthesized by the body, in the skin, and is activated by sunlight.
Vitamin K Deficiency
- Explain that the main dietary sources of vitamin K are broccoli, cabbage, cauliflower, kale, spinach, leaf lettuce, watercress, parsley, and other raw green leafy vegetables, pork, liver, soybeans, mayonnaise, and vegetable oils.
Clinical Judgement
- Consider ways to encourage self-care to facilitate independence.
Follow-Up and Desired Outcomes
- Acknowledges contact information provided for the National Osteoporosis Foundation (www.nof.org) or American College of Rheumatology (www.rheumatology.org).
- Acknowledges contact information provided for the U.S. Department of Agriculture’s resource for nutrition (www.choosemyplate.gov).
- Agrees to modify diet to incorporate calcium and vitamin D rich foods.
- Acknowledges the importance of adhering to fall prevention strategies to decrease injury risk.
- Seeks counseling to discuss strategies to meet emotional challenges associated with body image changes.