Osteoporosis - Bone Turnover Markers

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Contributor

Doyle

Kelly Doyle, PhD, DABCC, FAACC

Associate Professor of Pathology (Clinical), University of Utah

Medical Director, Special Chemistry and Endocrinology, ARUP Laboratories

Contributor

Straseski

Joely A. Straseski, PhD, MS, MT(ASCP), DABCC, FAACC

Professor of Pathology (Clinical), University of Utah

Head of Clinical Operations for Clinical Chemistry, Toxicology, and Biochemical Genetics; Medical Director, Endocrinology; Co-Director, Automated Core Laboratory, ARUP Laboratories

Osteoporosis is a skeletal disorder characterized by decreased bone strength and density that leads to an increased risk of fracture. The disorder is common and may be asymptomatic and therefore remain undiagnosed until fractures occur. Screening recommendations for osteoporosis continue to evolve. Bone mineral density testing using imaging, such as dual-energy x-ray absorptiometry (DXA), is the gold standard approach for screening and diagnosis. Laboratory testing plays a supportive role and is used in the evaluation of secondary osteoporosis and the assessment of bone turnover.

Quick Answers for Clinicians

What is the role of laboratory testing in osteoporosis?

Laboratory testing plays a supporting role in the evaluation and monitoring of osteoporosis. Although the diagnosis of osteoporosis relies on clinical and imaging factors, secondary osteoporosis can be evaluated and diagnosed using laboratory tests. Laboratory testing may also be useful in risk assessment and monitoring.

Should bone turnover markers be used for universal bone loss or fracture risk screening?

No. The applicability of bone turnover markers to predict bone loss or risk of fracture is not established in all populations.¹

Greenblatt MB, Tsai JN, Wein MN. Bone turnover markers in the diagnosis and monitoring of metabolic bone disease. Clin Chem. 2017;63(2):464-474.

Bone turnover markers may be useful in predicting bone loss in perimenopausal women, and markers of bone resorption have been correlated with fracture risk.^{1

Greenblatt MB, Tsai JN, Wein MN. Bone turnover markers in the diagnosis and monitoring of metabolic bone disease. Clin Chem. 2017;63(2):464-474.} However, these links are not sufficiently established to warrant universal screening using bone turnover markers.^{1

Greenblatt MB, Tsai JN, Wein MN. Bone turnover markers in the diagnosis and monitoring of metabolic bone disease. Clin Chem. 2017;63(2):464-474.} Bone turnover markers may be more useful to monitor responsiveness to therapy in patients diagnosed with osteoporosis.^{1

Greenblatt MB, Tsai JN, Wein MN. Bone turnover markers in the diagnosis and monitoring of metabolic bone disease. Clin Chem. 2017;63(2):464-474.}

Indications for Testing

A clinical evaluation for osteoporosis—including a history, physical exam, appropriate imaging if certain clinical features are present, and a fracture risk assessment tool when available—is recommended in postmenopausal women ≥50 years of age.²

Camacho PM, Petak SM, Binkley N, et al. American Association of Clinical Endocrinologists/American College of Endocrinology clinical practice guidelines for the diagnosis and treatment of postmenopausal osteoporosis – 2020 update. Endocr Pract. 2020;26(Suppl 1):1-46.

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LeBoff MS, Greenspan SL, Insogna KL, et al. The clinician's guide to prevention and treatment of osteoporosis [published correction appears in Osteoporos Int. 2022]. Osteoporos Int. 2022;33(10):2049-2102.} Bone mineral density testing via imaging (eg, DXA) is recommended for all women ≥65 years of age and for younger women with similar risk.^{2

Camacho PM, Petak SM, Binkley N, et al. American Association of Clinical Endocrinologists/American College of Endocrinology clinical practice guidelines for the diagnosis and treatment of postmenopausal osteoporosis – 2020 update. Endocr Pract. 2020;26(Suppl 1):1-46.

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LeBoff MS, Greenspan SL, Insogna KL, et al. The clinician's guide to prevention and treatment of osteoporosis [published correction appears in Osteoporos Int. 2022]. Osteoporos Int. 2022;33(10):2049-2102.

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U.S. Preventive Services Task Force, Curry SJ, Krist AH, et al. Screening for osteoporosis to prevent fractures: U.S. Preventive Services Task Force Recommendation Statement. JAMA. 2018;319(24):2521-2531.} The Endocrine Society recommends an evaluation with bone mineral density testing in all men ≥70 years of age and for men between the ages of 50 and 69 years who are at increased risk,^{4

U.S. Preventive Services Task Force, Curry SJ, Krist AH, et al. Screening for osteoporosis to prevent fractures: U.S. Preventive Services Task Force Recommendation Statement. JAMA. 2018;319(24):2521-2531.

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Watts NB, Adler RA, Bilezikian JP, et al. Osteoporosis in men: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2012;97(6):1802-1822.} although the U.S. Preventive Services Task Force finds insufficient evidence to address screening in men.^{4

U.S. Preventive Services Task Force, Curry SJ, Krist AH, et al. Screening for osteoporosis to prevent fractures: U.S. Preventive Services Task Force Recommendation Statement. JAMA. 2018;319(24):2521-2531.} Follow-up laboratory testing may be appropriate in individuals diagnosed with osteoporosis.

Laboratory Testing

Testing for Causes of Secondary Osteoporosis

Many conditions are associated with bone loss and secondary osteoporosis. Laboratory testing should be considered to look for underlying causes in all individuals diagnosed with osteoporosis.²

Laboratory Evaluation in Individuals With Osteoporosis
Population	Recommended Laboratory Testing
All individuals with osteoporosis	25(OH)D CBC Liver function tests Parathyroid hormone Serum metabolic panel: Albumin Alkaline phosphatase Calcium Creatinine with eGFR Magnesium Phosphate
Individuals with normal vitamin D concentrations and calcium intake (either initially or achieved via supplementation)	24-hour urine with: Calcium Creatinine Sodium
Individuals with suspected hyperthyroidism Individuals taking thyroid hormone	Serum TSH
Men with osteoporosis	Total testosterone
Individuals with suggestive clinical features	Homocysteine Prolactin Serum ferritin Serum iron Serum protein electrophoresis Tissue transglutaminase antibodies Tryptase Urine histamine Urine protein electrophoresis Urine or salivary free cortisol
25(OH)D, 25-hydroxyvitamin D; eGFR, estimated glomerular filtration rate; TSH, thyroid-stimulating hormone Sources: Sources: Camacho, 2020² Camacho PM, Petak SM, Binkley N, et al. American Association of Clinical Endocrinologists/American College of Endocrinology clinical practice guidelines for the diagnosis and treatment of postmenopausal osteoporosis – 2020 update. Endocr Pract. 2020;26(Suppl 1):1-46. ; LeBoff, 2022^{3 LeBoff MS, Greenspan SL, Insogna KL, et al. The clinician's guide to prevention and treatment of osteoporosis [published correction appears in Osteoporos Int. 2022]. Osteoporos Int. 2022;33(10):2049-2102.}; Watts, 2012^{5 Watts NB, Adler RA, Bilezikian JP, et al. Osteoporosis in men: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2012;97(6):1802-1822.}

Testing for the following conditions, among others, may also be considered depending on the results of the clinical evaluation and initial tests²

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LeBoff MS, Greenspan SL, Insogna KL, et al. The clinician's guide to prevention and treatment of osteoporosis [published correction appears in Osteoporos Int. 2022]. Osteoporos Int. 2022;33(10):2049-2102.

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Watts NB, Adler RA, Bilezikian JP, et al. Osteoporosis in men: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2012;97(6):1802-1822.}:

Genetic testing may be appropriate in individuals with features suggestive of a metabolic bone disorder.²

Bone Turnover Markers

Bone turnover marker testing may be useful to predict bone loss, assess fracture risk, provide a reference for analytes in clinical studies, and investigate the effects of therapy.¹

Greenblatt MB, Tsai JN, Wein MN. Bone turnover markers in the diagnosis and monitoring of metabolic bone disease. Clin Chem. 2017;63(2):464-474.

,^{2

Camacho PM, Petak SM, Binkley N, et al. American Association of Clinical Endocrinologists/American College of Endocrinology clinical practice guidelines for the diagnosis and treatment of postmenopausal osteoporosis – 2020 update. Endocr Pract. 2020;26(Suppl 1):1-46.

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LeBoff MS, Greenspan SL, Insogna KL, et al. The clinician's guide to prevention and treatment of osteoporosis [published correction appears in Osteoporos Int. 2022]. Osteoporos Int. 2022;33(10):2049-2102.} Specific guidance regarding the application of these tests has not been established in most cases.

Bone turnover marker tests may be costly, and reference ranges may not be well established.²

The same assay (same laboratory and methodology) should be used for longitudinal comparisons.^{3

LeBoff MS, Greenspan SL, Insogna KL, et al. The clinician's guide to prevention and treatment of osteoporosis [published correction appears in Osteoporos Int. 2022]. Osteoporos Int. 2022;33(10):2049-2102.

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Watts NB, Adler RA, Bilezikian JP, et al. Osteoporosis in men: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2012;97(6):1802-1822.

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Eastell R, Rosen CJ, Black DM, et al. Pharmacological management of osteoporosis in postmenopausal women: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2019;104(5):1595-1622.} Fasting samples should be taken in the morning because bone turnover marker concentrations vary over the course of the day, and serial measurements should be taken at the same time of day.^{2

Camacho PM, Petak SM, Binkley N, et al. American Association of Clinical Endocrinologists/American College of Endocrinology clinical practice guidelines for the diagnosis and treatment of postmenopausal osteoporosis – 2020 update. Endocr Pract. 2020;26(Suppl 1):1-46.

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LeBoff MS, Greenspan SL, Insogna KL, et al. The clinician's guide to prevention and treatment of osteoporosis [published correction appears in Osteoporos Int. 2022]. Osteoporos Int. 2022;33(10):2049-2102.

,}^{5

Watts NB, Adler RA, Bilezikian JP, et al. Osteoporosis in men: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2012;97(6):1802-1822.

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Eastell R, Rosen CJ, Black DM, et al. Pharmacological management of osteoporosis in postmenopausal women: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2019;104(5):1595-1622.} The concentrations of some markers (eg, procollagen type 1 N-propeptide [PINP]) may be affected by renal insufficiency because many markers are renally cleared; alternative markers (eg, bone-specific alkaline phosphatase) may be useful if renal insufficiency is present.^{2

Camacho PM, Petak SM, Binkley N, et al. American Association of Clinical Endocrinologists/American College of Endocrinology clinical practice guidelines for the diagnosis and treatment of postmenopausal osteoporosis – 2020 update. Endocr Pract. 2020;26(Suppl 1):1-46.}

Bone Turnover Markers Useful in Osteoporosis
Bone Resorption Markers
Marker	Use
Serum CTX	Preferred marker of bone resorption Use to monitor antiresorptive treatments Reference analyte for bone turnover in clinical studies
Serum or urine NTX	Alternative marker of bone resorption Use to monitor antiresorptive treatments
Urine deoxypyridinoline	Alternative marker
Bone Formation Markers
Marker	Use
Serum PINP	Preferred marker of bone formation Use to monitor anabolic treatment Reference analyte for bone turnover in clinical studies
Bone-specific alkaline phosphatase	Preferred marker if renal insufficiency is present Use to monitor anabolic treatment
Osteocalcin	Alternative marker
CTX, C-terminal telopeptide of type-1 collagen; NTX, N-telopeptide of type I collagen Sources: Greenblatt, 2017¹ Greenblatt MB, Tsai JN, Wein MN. Bone turnover markers in the diagnosis and monitoring of metabolic bone disease. Clin Chem. 2017;63(2):464-474. ; Camacho, 2020^{2 Camacho PM, Petak SM, Binkley N, et al. American Association of Clinical Endocrinologists/American College of Endocrinology clinical practice guidelines for the diagnosis and treatment of postmenopausal osteoporosis – 2020 update. Endocr Pract. 2020;26(Suppl 1):1-46.}; LeBoff, 2022^{3 LeBoff MS, Greenspan SL, Insogna KL, et al. The clinician's guide to prevention and treatment of osteoporosis [published correction appears in Osteoporos Int. 2022]. Osteoporos Int. 2022;33(10):2049-2102.}; Watts, 2012^{5 Watts NB, Adler RA, Bilezikian JP, et al. Osteoporosis in men: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2012;97(6):1802-1822.}; Eastell, 2019^{6 Eastell R, Rosen CJ, Black DM, et al. Pharmacological management of osteoporosis in postmenopausal women: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2019;104(5):1595-1622.}

Monitoring

Bone Turnover Markers for Monitoring

Although osteoporosis is generally monitored using imaging to assess bone mineral density, this testing is not recommended during the initial years of therapy.¹

Greenblatt MB, Tsai JN, Wein MN. Bone turnover markers in the diagnosis and monitoring of metabolic bone disease. Clin Chem. 2017;63(2):464-474.

,^{6

Eastell R, Rosen CJ, Black DM, et al. Pharmacological management of osteoporosis in postmenopausal women: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2019;104(5):1595-1622.} Bone turnover marker testing may be considered before the initiation of treatment and then after 3-6 months of therapy, as the concentrations of bone turnover markers usually change the most within the first year of therapy (before the results of imaging tests would be expected to change) and stabilize thereafter.^{5

Watts NB, Adler RA, Bilezikian JP, et al. Osteoporosis in men: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2012;97(6):1802-1822.

,}^{6

Eastell R, Rosen CJ, Black DM, et al. Pharmacological management of osteoporosis in postmenopausal women: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2019;104(5):1595-1622.}

Although there is not a specific standard for optimal bone turnover marker concentrations, and although concentrations may vary depending on the specific treatment, an early decrease (in the first 1-6 months) in bone resorption markers or an increase in bone formation markers suggests good therapeutic response and that fracture risk may be reduced.²

,^{3

LeBoff MS, Greenspan SL, Insogna KL, et al. The clinician's guide to prevention and treatment of osteoporosis [published correction appears in Osteoporos Int. 2022]. Osteoporos Int. 2022;33(10):2049-2102.

,}^{5

Watts NB, Adler RA, Bilezikian JP, et al. Osteoporosis in men: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2012;97(6):1802-1822.

,}^{6

Eastell R, Rosen CJ, Black DM, et al. Pharmacological management of osteoporosis in postmenopausal women: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2019;104(5):1595-1622.} Unexpected results, such as a lack of change in bone turnover markers despite treatment, or high bone resorption markers in an individual taking antiresorptive medication, warrant further investigation because they may suggest issues with medication (eg, poor absorption, poor adherence to the treatment regimen), secondary osteoporosis, or a recent fracture.^{2

Camacho PM, Petak SM, Binkley N, et al. American Association of Clinical Endocrinologists/American College of Endocrinology clinical practice guidelines for the diagnosis and treatment of postmenopausal osteoporosis – 2020 update. Endocr Pract. 2020;26(Suppl 1):1-46.

,}^{5

Watts NB, Adler RA, Bilezikian JP, et al. Osteoporosis in men: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2012;97(6):1802-1822.

,}^{6

Eastell R, Rosen CJ, Black DM, et al. Pharmacological management of osteoporosis in postmenopausal women: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2019;104(5):1595-1622.}

Other Monitoring Tests

Laboratory testing may be useful to assess for secondary osteoporosis in individuals with significant decreases in bone mineral density despite treatment.²

25(OH)D testing may be considered to evaluate for adequate vitamin D concentrations following supplementation in individuals with osteoporosis.²

The Bone Health and Osteoporosis Foundation (BHOF) recommends serum 24(OH)D monitoring in all postmenopausal women and men ≥50 years of age.^{3

LeBoff MS, Greenspan SL, Insogna KL, et al. The clinician's guide to prevention and treatment of osteoporosis [published correction appears in Osteoporos Int. 2022]. Osteoporos Int. 2022;33(10):2049-2102.}