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Osteoporosis, Laboratory Support of Risk Assessment and Management

Osteoporosis, Laboratory Support of Risk Assessment and Management

Clinical Focus

Osteoporosis

Laboratory Support of Risk Assessment, Diagnosis, and Management

  

Contents:

Clinical Background - Table 1 - Table 2 - Table 3 - Figure

Individuals Suitable for Testing

Test Availability

Test Selection

Test Interpretation  - Table 4

Summary

Ordering Information

References
 

Clinical Background [return to contents]

Millions of people in the US are affected by osteoporosis and the number is expected to rise as the population ages. Postmenopausal women are most often affected. Also at risk are elderly males and individuals with calcium or vitamin D deficiency, hypogonadism, hyperparathyroidism, hyperthyroidism, Paget disease, malignancy, gastrointestinal disease, and connective tissue disease, as well as those who smoke, abuse alcohol, or take certain medications. Afflicted individuals are at significantly increased risk for bone fracture (wrist, spine, proximal femur, humerus) leading to chronic pain, disability, and even death. Treatment options include vitamin D and calcium supplementation, bisphosphonates (eg, alendronate, risedronate), calcitonin, hormone replacement therapy (HRT), parathyroid hormone (PTH, amino acids 1-34) and raloxifene, a selective estrogen receptor modulator (SERM).

Osteoporosis is a preventable disorder. Since patients are asymptomatic in the early stages, current guidelines recommend evaluating fracture risk in postmenopausal women and in men once they reach
50 years of age.1 The World Health Organization (WHO) has developed the FRAX® tool, which is available online, to assess the 10-year fracture risk in these individuals.2 Factors used in the tool are listed in
Table 1.

Table 1. Factors Included in the FRAX Risk Assessment Tool2

Patient Demographics Medical History Lifestyle Factors
Age

Height (cm)a

Race

Sex

Weight (kg)a

Femoral neck BMDb

Glucocorticoid use

Parent hip fracture

Previous fracture

Rheumatoid arthritis history

Secondary osteoporosis history

Alcohol use

Smoking

 

a Used to calculate body mass index (BMI).

b Risk can be calculated with or without bone mineral density measurements.

Bone mineral density (BMD), which is the basis of osteoporosis diagnosis, is recommended for women 65 years of age and men 70 years. When indicated by their risk profile, BMD is recommended for postmenopausal women and for men between 50 and 70 years old. Furthermore, BMD is recommended for patients who have suffered a fracture,1 and it should be accompanied by a thorough evaluation for secondary osteoporosis in the young, as secondary causes account for 64% of all osteoporosis in young men and women.3 Additionally, secondary causes account for 20% of osteoporosis in postmenopausal women.3 The National Osteoporosis Foundation (NOF) recommends consideration of secondary causes in all postmenopausal women and in men 50 years of age.1

Screening for secondary causes begins with a history and physical examination followed by routine laboratory testing (chemistry profile; CBC; serum TSH; and 24-hour urine calcium, sodium, and creatinine). Individuals suspected of or at higher risk for vitamin D deficiency (eg, those with persistent, nonspecific musculoskeletal pain; pregnant or lactating women; the elderly; dark-skinned individuals; housebound individuals; those with malabsorptive syndromes; those treated with anticonvulsants; etc.) should also have their 25-hydroxyvitamin D concentration determined. If abnormal results are obtained, further evaluation is recommended. The causes of secondary osteoporosis are listed in the NOF guidelines1 and testing for the most common of these is listed in Table 2.

Table 2. First-line Tests Available for Diagnosis of Secondary Osteoporosis

Disorder Tests

Lifestyle-related Disorders

Alcohol abuse

Low dietary calcium

Vitamin D insufficiency

Chemistry profile, CBC

Serum and urine calcium

25-hydroxyvitamin D [25(OH)D]

Genetic Disorders

Cystic fibrosis

Gaucher disease

Glycogen storage disease

Homocystinuria

Hemochromatosis

Hypophosphatasia

Porphyria

Riley-Day syndrome

Idiopathic hypercalciuria

Sweat test

Gaucher disease mutation analysis

Glucose-6-phosphate dehydrogenase

Homocystine

Ferritin, iron and iron binding capacity (transferrin saturation)

Alkaline phosphatase

Porphyrins, delta aminolevulinic acid, porphobilinogen

Familial dysautonomia mutation analysis

Urine calcium, sodium, and creatinine

Endocrine Disorders

Adrenal insufficiency

Cushing syndrome

Diabetes mellitus

Hyperparathyroidism

Hyperprolactinemia

Klinefelter syndrome

Panhypopituitarism

Premature ovarian failure

Thyrotoxicosis

Turner syndrome

ACTH, cortisol

Free cortisol (urine or saliva)

Glucose

Parathyroid hormone (PTH) and calcium

Prolactin

FSH, LH, testosterone, chromosome analysis

FSH, LH, testosterone, estrogen

FSH, LH

TSH, free T4, free T3

FSH, LH, testosterone, dihydrotestosterone (DHT), chromosome analysis

Gastrointestinal Disorders

Celiac disease

Inflammatory bowel disease

Primary biliary cirrhosis

tTG IgA, EMA IgA, immunoglobulin A (IgA) level

pANCA and ASCA

Alkaline phosphatase, GGT, mitochondrial antibody (AMA)

Hematologic Disorders

Hemophilia

Leukemia, lymphoma

Multiple myeloma

Sickle cell

Systemic mastocytosis

Thalassemia

Activated partial thromboplastin time (aPTT), factor VIII, factor IX

CBC

CBC, calcium, serum protein electrophoresis

CBC, sickle cell prep

CBC

CBC

Rheumatic/Autoimmune Disorders

Lupus, rheumatoid arthritis

Ankylosing spondylitis

Antinuclear antibody (ANA)

Sedimentation rate (ESR) or C-reactive protein (CRP)

CBC, complete blood count; ACTH, adrenocorticotropic hormone; FSH, follicle stimulating hormone; LH, luteinizing hormone; TSH, thyroid stimulating hormone; tTG, tissue transglutaminase antibody; EMA, endomysial antibody; pANCA, perinuclear anti-neutrophil cytoplasmic antibody; ASCA, anti-Saccharomyces cerevisiae antibody; GGT, gamma-glutamyl transpeptidase.

Bone turnover markers (formation and resorption) are helpful in predicting the rate of postmenopausal bone loss4,5 and in assessing the risk for bone fracture.6-8 When assessing risk, the combined use of BMD and bone turnover markers is more effective than use of either risk factor alone (Figure). Baseline levels (ie, pretreatment levels) of some markers may predict those who will benefit most from selected therapy and/or may predict the amplitude of response. For example, Chestnut et al found that the odds of BMD gain from HRT increased by a factor of 5.0 for every 30 nmol BCE/mmol creatinine increase in baseline urine NTx level.9 Either bone formation or bone resorption markers may be used for therapeutic monitoring. After 3 to 6 months of antiresorptive therapy, bone markers predict BMD response and changes in fracture risk.8-12 Thus, they provide a more real-time assessment of therapeutic response than BMD measurements (ie, 3 to 6 months vs 1 to 2 years for BMD).9,13 Since evidence of therapeutic response is rapidly available, bone markers may assist in rapid optimization of drug dosage and in encouraging patient compliance.

Figure. Risk for bone fracture based on BMD and bone turnover markers.

Various guidelines address the use of bone turnover markers (Table 3). Multiple factors that contribute to variability in measurement must be considered when using them, however. These factors include patient age, gender, and menopausal status; diurnal variation; food intake; certain medications; and lack of assay standardization. Variability can be minimized by 1) use of age-, gender-, and menopausal-specific reference ranges; 2) collection of samples at the same time of day to minimize diurnal variation when monitoring therapy; 3) overnight fasting to minimize dietary effects; 4) use of a washout period for any drugs that affect bone or calcium metabolism prior to sample collection for baseline measurements; and 5) use of the same method and laboratory to circumvent assay standardization issues.

Table 3. Recommendations for Use of Bone Turnover Markers in Management of Osteoporosis

Organization Yeara Guideline
American Association of Clinical Endocrinologists14 2010

Precise role in osteoporosis not established but may be useful for assessing fracture risk in the elderly; assess adherence, absorption, and therapeutic response to antiresorptive therapy (eg, estrogen, bisphosphonates, and estrogen agonists/antagonists such as raloxifene); and predict rapid bone loss as evidenced by rapid bone turnover

Assist in evaluating patients with osteoporosis suspected of having a secondary cause of bone loss

National Osteoporosis Foundation1

2010

Assess fracture risk, predict bone loss, predict reduction in fracture risk following 3 to 6 months of antiresorptive therapy, predict BMD response to antiresorptive and anabolic therapies

North American Menopause Society15

2010

Value in routine clinical practice not established; routine use not generally recommended

a Year guideline published.

Individuals Suitable for Testing [return to contents]

  • Individuals being evaluated for secondary osteoporosis

  • Individuals with decreased BMD and/or adult bone fracture

  • Individuals who are about to begin therapy

  • Individuals who are currently receiving therapy

Test Availability [return to contents]

Secondary Osteoporosis

The list of secondary causes of osteoporosis is long; thus, a large number of laboratory tests are available. As mentioned previously, the primary screening tests include a chemistry profile; CBC; serum TSH and 25-hydroxyvitamin D; and 24-hour urine measurements of calcium, sodium, and creatinine in at-risk individuals. Additional tests are listed in Table 2.

Bone Formation Markers

  • Osteocalcin: This electrochemiluminescence assay (ECLIA) measures the serum level of the N-mid fragment of osteocalcin (amino acids 1-43) and of the intact osteocalcin molecule (amino acids 1-49).

  • Alkaline Phosphatase, Bone Specific (BSAP): This immunochemiluminescence assay (ICMA) measures the level of the bone-specific isoenzyme of alkaline phosphatase in serum. Crossreactivity with other alkaline phosphatase isoenzymes is 15% for liver, 5% for intestinal, and <1% for placental alkaline phosphatase.16 BSAP provides a general index of bone formation and a specific index of total osteoblast activity.

Bone Resorption Markers

  • C-telopeptide (CTx): This electrochemiluminescence assay (ECLIA) measures the level of collagen type I C-telopeptide in serum.

  • N-telopeptide (NTx): This enhanced ICMA measures the level of type I collagen cross-linked aminoterminal peptide in urine.

  • Tartrate Resistant Acid Phosphatase (TRAP): This enzymatic method measures the serum level of acid phosphatase that is resistant to tartrate inhibition. TRAP includes acid phosphatase from bone and other sources such as alveolar and monocyte-derived macrophages, placenta, spleen, and erythrocytes.

  • Hydroxyproline: This colorimetric method measures the urinary level of total, free, or total and free hydroxyproline.

Test Selection [return to contents]

Secondary Osteoporosis

Tests that can be used to screen for or rule out secondary osteoporosis are listed in Table 2. For example, abnormalities in FSH, LH, estrogen, and testosterone can establish sex hormone deficiency as a secondary cause of osteoporosis. Calcium and vitamin D concentrations can point to a host of nutritional and absorption disorders. An abnormal CBC can suggest benign or malignant hematologic disorders, and an ESR or CRP can be used to screen for inflammatory disorders. TSH can be used to screen for thyrotoxicosis and PTH for parathyroid disorders, while a chemistry profile and CBC can be used to screen for alcohol abuse and other disorders.

Glucocorticoid excess (endogenous or exogenous) inhibits bone formation, leading to bone loss and fracture. Patients with a disorder characterized by excess cortisol production and those receiving long-term glucocorticoid therapy should be monitored using: 1) osteocalcin levels to assess the degree of bone formation inhibition, or 2) BMD measurements.

Bone Formation and Resorption Markers

BSAP and osteocalcin are the most effective markers of bone formation17 and are particularly useful for monitoring bone formation therapies. They can be utilized to monitor patients on antiresorptive therapies as well. Osteocalcin and BSAP levels are generally concordant in osteoporosis. Contraindications include renal disease (osteocalcin) and hepatic disease (BSAP).

NTx (Osteomark®) and CTx (CrossLaps®) are the preferred markers of bone resorption. These markers are more specific to bone than other bone turnover markers.

Studies indicate that baseline levels of NTx are useful for predicting BMD response to HRT, and serial measurements reflect response to HRT and bisphosphonates (alendronate).18,19 The magnitude of NTx change during and following therapy provides an advantage when monitoring short-term responses.20,21

Studies have shown that baseline CTx levels are useful for assessing fracture risk in postmenopausal women and indicating response to HRT and bisphosphonate therapy as early as 3 months after initiation of therapy.22-24 Such response predicted an increase in BMD23 or a reduced fracture risk.24

The newer resorption markers detailed above are more reliable than TRAP and urinary hydroxyproline. TRAP is adversely affected by enzyme inhibitors in serum, has limited stability and analytical sensitivity, and lacks specificity for bone. The assays for urinary hydroxyproline are tedious, and levels are affected by diet and crossreaction with the C1q fraction of complement. Hydroxyproline is useful only when careful patient preparation and sample collection guidelines are followed.

Test Interpretation [return to contents]

Secondary Osteoporosis

Primary screening test results for some of the disorders causing secondary osteoporosis are listed below.

Alcoholism

Alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl transferase (GGT), bilirubin, and alkaline phosphatase may be increased in alcoholism. Since ALT is less sensitive to alcoholism than is AST, an increased AST:ALT ratio is likely. Uric acid and the mean corpuscular volume (MCV) may also be increased.

Gastrointestinal Disorders

Celiac disease may manifest with anemia associated with decreased iron or folic acid; increased ESR or CRP; decreased calcium, vitamin D, albumin, sodium, and potassium; and increased alkaline phosphatase.

Inflammatory bowel disease may manifest with anemia (decreased hemoglobin), increased platelet and white blood cell (WBC) counts, and increased ESR or CRP. The severity of anemia and the magnitude of increased ESR correlate with severity of the disease.

Primary biliary cirrhosis is initially detected by a 2-fold or greater elevation in the alkaline phosphatase concentration; GGT is also elevated. In the initial stages, bilirubin is normal and ALT and AST are minimally increased. Levels of these analytes increase as the disease progresses.

Hypo- and Hypercalcemia

Low calcium levels are consistent with low dietary intake, inadequate gastrointestinal absorption such as occurs in celiac disease, and vitamin D deficiency. Elevated calcium levels are consistent with hyperparathyroidism (PTH also increased), leukemia, lymphoma, multiple myeloma, thyrotoxicosis, and idiopathic hypercalciuria.

Leukemia and Lymphoma

The CBC with differential may reveal an increased WBC count (except in hairy cell leukemia), decreased red blood cell (RBC) count, decreased platelet count, decreased hemoglobin, and immature WBCs.

Multiple Myeloma

Plasma cell proliferation leads to bone resorption, leading to increased blood calcium levels. Serum creatinine, urea nitrogen, and uric acid levels may also be elevated, but alkaline phosphatase is usually normal. The CBC with differential is likely to indicate normochromic, normocytic anemia; some patients have megaloblastic anemia. The ESR will be elevated and serum and/or urine protein electrophoresis will usually show abnormal monoclonal proteins known as “M-spikes.” However, a bone marrow evaluation is required for diagnosis.

Other Hematologic Disorders

A CBC with differential may reveal decreased RBC count, decreased hemoglobin, and sickle cells in those with sickle cell anemia. Anemia, decreased WBC count, decreased platelets, and a decreased percentage of lymphocytes are consistent with systemic mastocytosis. Some patients may have increased WBC count and/or increased percentage of eosinophils, basophils, monocytes, or platelets. A low hemoglobin, hematocrit, and MCV along with anisocytosis, poikilocytosis, target cells, and microcytic, hypochromic, nucleated RBCs are consistent with thalassemia.

Sex Hormone Deficiency

Klinefelter and Turner syndromes are chromosomal disorders that are associated with an increased risk of osteoporosis. Diagnosis is established using karyotyping. FSH, LH, and testosterone levels vary in Klinefelter syndrome according to the age of the patient.25 FSH, LH, and estradiol levels also vary by age in patients with Turner syndrome.26 Low blood levels of FSH, LH, estrogen, and testosterone are consistent with panhypopituitarism, which may lead to secondary osteoporosis. An elevation in FSH and LH levels and decreased estradiol levels in a young woman is consistent with premature ovarian failure.

Thyrotoxicosis

Thyroid hormone excess leads to increased bone resorption. A low TSH level, along with high free T4 and free T3 levels, suggests thyrotoxicosis. Alkaline phosphatase and serum calcium levels may be elevated.

Vitamin D Insufficiency/Deficiency

Low levels of vitamin D (25-hydroxy) are consistent with inadequate sun exposure, low dietary intake, and inadequate gastrointestinal absorption such as occurs in celiac disease.

Bone Formation and Resorption Markers

In adults, elevated levels of bone turnover markers (both formation and resorption markers) may be associated with increased bone loss, decreased BMD, and increased risk for bone fractures. The higher the rate of bone turnover, the greater the rate of bone loss, particularly at or soon after menopause. Independent of BMD, elevated levels may predict future decreases in BMD and an increased risk for fractures.10,25 Excessive rates of bone turnover are associated with primary osteoporosis as well as secondarily with hyperthyroidism, glucocorticoid excess, hyperparathyroidism, clinical use of gonadotropin-releasing hormone (Gn-RH) agonists or antagonists, or deficient skeletal growth and maturation.

During or post therapy, a 30% to 60% decrease in bone turnover levels (into the premenopausal range) is indicative of therapeutic response (Table 4). Levels of bone resorption markers decrease within 1 to 3 months of therapy, whereas bone formation marker values decrease later (within 3 to 9 months).9,13 Such decreases predict an increase in BMD over 2 years.13 The absence of decreasing levels post therapy may be due to patient noncompliance, inadequate dosage, or an ineffective therapeutic agent.

Table 4. Bone Marker Response to Alendronate Therapy13

Bone Marker

Mean Decrease (%)

Correlation (r) with BMD Increase

P

Osteocalcin
BSAP
NTx
-38
-38
-65

-0.63
-0.67
-0.53

0.0001
0.0001
0.0001

BMD, bone mineral density; BSAP, bone-specific alkaline phosphatase; NTx, collagen cross-linked N-telopeptide.

CTx response to HRT: mean decrease = -43%; correlation (r) with BMD increase = -0.534, P = 0.01.23
In side-by-side studies, the magnitude of decrease in CTx is similar to that of NTx.24

Levels of bone turnover markers are affected by marker specificity for bone collagen and metabolic clearance (liver uptake, renal excretion, etc.), and thus are of unequal sensitivity and specificity. Estimates of net excess of bone resorption over bone formation may be misleading; however, either bone formation or bone resorption markers will reflect the overall rate of bone turnover. Bone marker levels are also affected by the timing of sample collection due to diurnal variation (early morning peak and afternoon nadir). Intra-individual biological variations range from a low of 20% in NTx to a high of 53% in hydroxyproline.28 Interpretation is highly dependent on the specific marker and method of analysis used.

Bone Formation Markers

Osteocalcin is the major non-collagenous matrix protein of bone. Serum levels are increased in primary and secondary hyperparathyroidism, secondary osteosarcoma, healing bone fractures, hyperthyroidism, Paget disease, acromegaly, impaired renal glomerular function and renal failure, and in response to coumarin anticoagulants, slow-release sodium fluoride, phenytoin and 1,25-dihydroxyvitamin D. Osteocalcin is also increased in elderly men (>60 years) and postmenopausal women. Levels in Mexican-Americans are generally increased relative to non-Hispanic Caucasians.27

Osteocalcin decreases in response to successful osteoporosis therapy. It is decreased in hypoparathyroidism, hypothyroidism, Cushing syndrome, and sometimes in multiple myeloma and malignant hypercalcemia. Decreased levels may also be attributed to hemolysis, lipidemia, and excessive freezing and thawing of the sample. There is a 10% to 30% difference between the peak and nadir levels.

Bone specific alkaline phosphatase (BSAP) replaces the previously used, less sensitive and less specific total alkaline phosphatase test. It is produced by osteoblasts during bone formation and is increased in osteoporosis as well as in hyperthyroidism, osteomalacia, Paget disease, primary hyperparathyroidism, and other metabolic bone diseases. BSAP is increased by 77% in women within 10 years of menopause.30 Decreased levels are observed in response to osteoporosis therapy.

Bone Resorption Markers

C-telopeptide (CTx): Increased CTx results indicate an increased rate of bone resorption. Increased levels are associated with osteoporosis, osteopenia, celiac disease, Paget disease, primary hyperthyroidism, rheumatoid arthritis, and non-adult onset growth hormone deficiency. A decreased level following HRT or bisphosphonate therapy suggests favorable response and may predict an increase in BMD or a decrease in fracture risk.23,24

A CTx result within the premenopausal reference range does not rule out osteoporosis nor the need for therapy.

N-telopeptide (NTx): Increased NTx results indicate an increased rate of bone resorption. Increased urinary levels predict a rapid decrease in BMD; the greater the NTx elevation, the greater the decrease in BMD.31 Increased NTx may also be observed in osteopenia, osteoporosis, celiac disease, Paget disease, primary hyperparathyroidism, acromegaly, rheumatoid arthritis, growth hormone deficiency (non-adult onset), and malignant metastases to bone. Early postmenopausal women (<3 years postmenopausal) with urinary baseline NTx levels 67 nmol/mmol experience the greatest benefit from hormone replacement therapy (HRT).9 A 30% decline in urinary N-telopeptide concentration following 6 months of HRT or alendronate is indicative of a positive therapeutic response in postmenopausal women.9 Eighty-eight percent of women with such a decline were shown to have maintained or increased their BMD at 1 year.9 Similar declines in NTx and similar correlation with BMD was observed post alendronate therapy.11

An NTx result within the premenopausal reference range does not rule out osteoporosis nor the need for therapy.

Tartrate Resistant Acid Phosphatase (TRAP) results are not specific to bone; erythrocytic acid phosphatase released during in vitro clotting may falsely increase values as well as other non-bone sources. Levels are increased in osteoporosis, osteomalacia, Paget disease, primary hyperparathyroidism, metastatic cancer, advanced renal failure, and growing children.

Hydroxyproline is a modified amino acid that is present in all collagen. Urinary levels are increased significantly in Paget disease and to a lesser degree in primary and secondary hyperparathyroidism. It is also increased in osteoporosis, hypo- and hyperthyroidism, burns, psoriasis, acromegaly, inborn errors of metabolism, hydroxyprolinemia, familial aminoglycinuria, and possibly lymphomas, mammary carcinoma, and bone metastatic prostate carcinoma. Substantial increases may also occur in inflammatory conditions due to crossreactivity with complement factor C1q. Diets high in gelatin may cause falsely elevated results. Hydroxyproline is poorly correlated with bone resorption assessed by calcium kinetics and with histomorphometry. Decreased levels, however, virtually exclude increased bone turnover.32

Summary [return to contents]

Osteoporosis is a preventable disorder and patient management is moving toward a scenario in which postmenopausal women and elderly men will be evaluated for osteoporosis and fracture risk.1,14,15 BMD evaluation should be offered to at-risk individuals as well as elderly women (65 years of age) and men (70 years of age)1  Counseling regarding life-style changes and possible preventive therapy including HRT, bisphosphonates, or recombinant parathyroid hormone is encouraged. Although BMD remains the primary tool for diagnosis and monitoring, bone turnover markers are useful for assessing fracture risk, predicting bone loss, and monitoring antiresorptive therapy.1,14

References [return to contents]

  1. National Osteoporosis Foundation. Clinician’s Guide to Prevention and Treatment of Osteoporosis. Washington, DC: National Osteoporosis Foundation; 2010.

  2. World Health Organization Fracture Risk Assessment Tool (FRAX®). http://www.shef.ac.uk/FRAX. Accessed September 20, 2012.

  3. Harper KD, Weber TJ. Secondary osteoporosis. Endocrinol Metab Clin North Am. 1998;27:325-348.

  4. Christiansen C, Riis BJ, Rodbro P. Prediction of rapid bone loss in postmenopausal women. Lancet. 1987;1:1105-1108.

  5. Hansen M, Overgaard K, Riis B, et al. Role of peak bone mass and bone loss in postmenopausal osteoporosis: 12-year study. BMJ. 1991;303:961-964.

  6. Garnero P, Hausherr E, Chapuy MC, et al. Markers of bone resorption predict hip fracture in elderly women: the EPIDOS prospective study. J Bone Miner Res. 1996;11:1531-1538.

  7. Riis BJ, Hansen MA, Jensen AM, et al. Low bone mass and fast rate of bone loss at menopause: equal risk factors for future fracture: a 15-year follow-up study. Bone. 1996;19:9-12.

  8. Hochberg MC, Greenspan S, Wasnich RD, et al. Changes in bone density and turnover explain the reductions in incidence of nonvertebral fractures that occur during treatment with antiresorptive agents. J Clin Endocrinol Metab. 2002;87:1586-1592.

  9. Chestnut CH III, Bell NH, Clark GS, et al, Hormone replacement therapy in postmenopausal women: Urinary N-telopeptide of type I collagen monitors therapeutic effect and predicts response of bone mineral density. Am J Med. 1997;102:29-37.

  10. Riggs BL, Melton LJ III, O’Fallon WM. Drug therapy for vertebral fractures in osteoporosis: Evidence that decreases in bone turnover and increases in bone mass both determine antifracture efficacy. Bone. 1996;18(Suppl):197S-201S

  11. Greenspan SL, Parker RA, Ferguson L, et al. Early changes in biochemical markers of bone turnover predict the long-term response to alendronate therapy in representative elderly women: a randomized clinical trial. J Bone Miner Res. 1998;13:1431-1438.

  12. Bjarnason NH, Sarkar S, Duong T, et al. Six and twelve month changes in bone turnover are related to reduction in vertebral fracture risk during 3 years of raloxifene treatment in postmenopausal osteoporosis. Osteoporos Int. 2001;12:922-930.

  13. Garnero P, Shih WJ, Gineyts E, et al. Comparison of new biochemical markers of bone turnover in late postmenopausal osteoporotic women in response to alendronate treatment. J Clin Endocrinol Metab. 1994;79:1693-1700.

  14. Watts NB, Bilezikian JP, Camacho PM, et al; AACE Osteoporosis Task Force. American Association of Clinical Endocrinologists medical guidelines for clinical practice for the diagnosis and treatment of postmenopausal osteoporosis. Endocr Pract. 2010;16(Suppl 3):1-37.

  15. North American Menopause Society. Management of osteoporosis in postmenopausal women: 2010 position statement of The North American Menopause Society. Menopause. 2010;17:23-24.

  16. Access® Ostase® [package insert]. Fullerton, CA: Beckman Coulter; 2007.

  17. Garnero P, Delmas PD. Osteoporosis. Endocrinol Metab Clin North Am. 1997;26:913-936.

  18. Campodarve I, Ulrich U, Bell N, et al. Urinary N-telopeptide of type I collagen monitors bone resorption and may predict change in bone mass of the spine in response to hormone replacement therapy. Bone Miner Res. 1995;10(Suppl 1):S182.

  19. Marshall LA, Cain DF, Dmowski WB, et al. Urinary N-telopeptides to monitor bone resorption while on GnRH agonist therapy. Obstet Gyn. 1996;87:350-354.

  20. Garnero P, Gineyts E, Arbault P, et al. Different effects of bisphosphonate and estrogen therapy on free and peptide-bound bone cross-links excretion. J Bone Miner Res. 1995;10:641-649.

  21. Braga de Castro Machado A, Hannon R, Eastell R. Monitoring alendronate therapy for osteoporosis. J Bone Miner Res. 1999;14:602-608.

  22. Garnero P, Sornay-Rendu E, Claustrat B, et al. Biochemical markers of bone turnover, endogenous hormones and the risk of fractures in postmenopausal women: the OFELY study. J Bone Miner Res. 2000;15:1526-1536.

  23. Okabe R, Inaba M, Nakatsuka K, et al. Significance of serum CrossLaps as a predictor of changes in bone mineral density during estrogen replacement therapy; comparison with serum carboxyterminal telopeptide of type I collagen and urinary deoxypyridinoline. J Bone Miner Metab. 2004;22:127-131.

  24. Eastell R, Barton I, Hannon RA, et al. Relationship of early changes in bone resorption to the reduction in fracture risk with risedronate. J Bone Miner Res. 2003;18:1051-1056.

  25. Wikstrom AM, Dunkel L. Testicular function in Klinefelter syndrome. Horm Res. 2008:69:317-326.

  26. Hagen CP, Main KM, Kjaergaard S, et al. FSH, LH, inhibin B and estradiol levels in Turner syndrome depend on age and karyotype: longitudinal study of 70 Turner girls with or without spontaneous puberty. Hum Reprod. 2010;25:3134-3141.

  27. Melton LJ, Khosla S, Atkinson EJ, et al. Relationship of bone turnover to bone density and fractures. J Bone Miner Res. 1997;12:1083-1091.

  28. Gertz BJ, Shao P, Hanson DA, et al. Monitoring bone resorption in early postmenopausal women by an immunoassay for cross-linked collagen peptides in urine. J Bone Miner Res. 1994;9:135-142.

  29. Villa ML, Marcus R, Ramirez Delay R, et al. Factors contributing to skeletal health of postmenopausal Mexican-American women. J Bone Miner Res. 1995;10:1233-1242.

  30. Garnero P, Delmas PD. Assessment of the serum levels of bone alkaline phosphatase with a new immunoradiometric assay in patients with metabolic bone disease. J Clin Endocrinol Metab. 1993;77:1046-1053.

  31. Schneider DL, Barrett-Connor EL. Urinary N-telopeptide levels discriminate normal, osteopenic and osteoporotic bone mineral density. Arch Intern Med. 1997;157:1241-1245.

  32. Kleerekoper M, Avioli LV. Evaluation and treatment of postmenopausal osteoporosis. In: Favus MJ, ed. Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism. 2nd ed. New York, NY: Raven Press; 1993:223-229.

Content reviewed 12/2012

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* The tests listed by specialist are a select group of tests offered. For a complete list of Quest Diagnostics tests, please refer to our Directory of Services.