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Bone Turnover Markers for the Diagnosis and Management of Osteoporosis and Diseases Associated With High Bone Turnover

Policy Number: MP-393

Latest Review Date: January 2021

Category: Laboratory/Medicine

Policy Grade: A

POLICY:

Effective for dates of service February 1, 2020 and after:

Measurement of bone turnover markers is considered not medically necessary and investigational in the diagnosis and management of osteoporosis.

Measurement of bone turnover markers is considered not medically necessary and investigational to determine fracture risk in patients with osteoporosis or with age-related risk factors for osteoporosis.

Measurement of bone turnover markers is considered not medically necessary and investigational to determine response to therapy in patients who are being treated for osteoporosis.

Measurement of bone turnover markers is considered not medically necessary and investigational in the management of patients with conditions associated with high rates of bone turnover, including but not limited to Paget’s disease, primary hyperparathyroidism and renal osteodystrophy.


Effective for dates of service prior to February 1, 2020:

Measurement of bone turnover markers is considered not medically necessary and investigational in the diagnosis and management of osteoporosis.

Measurement of bone turnover markers is considered not medically necessary and investigational in the management of patients with conditions associated with high rates of bone turnover, including but not limited to Paget’s disease, primary hyperparathyroidism and renal osteodystrophy.


DESCRIPTION OF PROCEDURE OR SERVICE:

Bone turnover markers are biochemical markers of either bone formation or bone resorption. Commercially available tests are available to assess some of these markers in urine and/or serum by high performance liquid chromatography (HPLC) or immunoassay. Assessment of bone turnover markers is proposed to supplement bone mineral density (BMD) measurement in the diagnosis of osteoporosis and aid in treatment decisions. Bone turnover markers could also potentially be used to evaluate treatment effectiveness before changes in BMD can be observed.

Bone Turnover

After cessation of growth, bone is in a constant state of remodeling (or turnover), with initial absorption of bone by osteoclasts followed by deposition of new bone matrix by osteoblasts. This constant bone turnover is critical to the overall health of the bone, by repairing microfractures and remodeling the bony architecture in response to stress. Normally, the action of osteoblasts and osteoclasts is balanced, but bone loss occurs if the two processes become uncoupled. Bone-turnover markers can be categorized as bone-formation markers or bone-resorption markers, and can be identified in serum and/or urine. The table below summarizes the various bone-turnover markers.

Table. Bone Turnover Markers

Formation Markers

Resorption Markers

Serum osteocalcin

Serum and urinary hydroxyproline

Serum total alkaline phosphatase

Urinary total pyridinoline

Serum bone-specific alkaline phosphatase

Urinary total deoxypyridinoline

Serum procollagen I carboxyterminal propeptide

Urinary-free pyridinoline (also known as Pyrilinks)

Serum procollagen type 1 N-terminal propeptide

Urinary-free deoxypyridinoline (also known as Pyrilinks-D)

Bone sialoprotein

Serum and urinary collagen type I cross-linked N-telopeptide (also referred to as Osteomark)

 

Serum and urinary collagen type I cross-linked C-telopeptide (also referred to as CrossLaps)

 

Serum carboxyterminal telopeptide of type I collagen

 

Tartrate-resistant acid phosphatase

KEY POINTS:

The most recent literature review was updated through December 7, 2020.

Summary of Evidence

For individuals with osteoporosis or risk factors for age-related osteoporosis who receive a measurement of bone turnover markers to determine fracture risk, the evidence includes observational studies on the association between markers and osteoporosis and fracture risk and systematic reviews of those studies. Relevant outcomes are test validity and morbid events. Few studies have directly addressed whether any bone turnover markers beyond BMD measurements are independent predictors of fracture risk. Studies have suggested that bone turnover marker levels may be independently associated with osteoporosis and fracture risk in some groups, but there is insufficient evidence reporting on an association with any specific marker. Questions remain whether bone turnover markers are sufficiently sensitive to determine reliably individual treatment responses. Overall, the evidence does not suggest that any bone turnover marker is an independent predictor of fracture risk, beyond BMD. The evidence is insufficient to determine the effects of the technology in an improvement on the net health outcome.

For individuals who are being treated for osteoporosis who receive a measurement of bone turnover markers to determine response to therapy, the evidence includes observational studies on the association between markers and osteoporosis and fracture risk and systematic reviews of those studies. Relevant outcomes are test validity and morbid events. There is a limited amount of evidence on the impact of bone turnover markers on the management of osteoporosis. Individual RCTs and a meta-analysis of these RCTs have not found that feedback on bone turnover marker results improves treatment adherence rates. No studies were identified that evaluated whether the use of bone turnover markers leads to management changes that are expected to improve outcomes. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

For individuals with conditions associated with high rates of bone turnover other than age-related osteoporosis (e.g., primary hyperparathyroidism, Paget disease, renal osteodystrophy) who receive a measurement of bone turnover markers, the evidence includes observational studies on the association between markers and disease activity and systematic reviews of those studies. Relevant outcomes are test validity and morbid events. The largest amount of evidence has been published on Paget disease; a systematic review found correlations between several bone turnover markers and disease activity prior to and/or after bisphosphonate treatment. There is a lack of evidence on how the measurement of bone turnover markers can change patient management or improve health outcomes. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

Practice Guidelines and Position Statements

The Endocrine Society

In 2019, guidelines from the Endocrine Society recommend that in postmenopausal women with a low BMD and at high-risk of fractures who are being treated for osteoporosis, monitoring should be conducted by dual-energy X-ray absorptiometry at the spine and hip every one to three years. The Society considers measuring bone turnover markers (serum CTX for antiresorptive therapy or P1NP for bone anabolic therapy) as an alternative way of monitoring for poor response or nonadherence to therapy. The society notes that there is uncertainty over what constitutes an optimal response to treatment, but some experts suggest that a meaningful change is approximately 40% when compared from before to three to six months after starting treatment.

The American Association of Clinical Endocrinologists and the American College of Endocrinology

The 2020 guidelines from the American Association of Clinical Endocrinologists and the American College of Endocrinology (AACE/ACE) gave a Grade B recommendation to consider using bone turnover markers for assessing patient compliance and therapy efficacy. AACE/ACE reviewed evidence that markers respond quickly to therapeutic intervention, and changes in markers have been associated with bone response to therapy and fracture risk reduction.

National Osteoporosis Foundation

In 2014, the National Osteoporosis Foundation published its guidelines on the prevention and treatment of osteoporosis to prevent fractures. Regarding biochemical markers of bone turnover, the guidelines stated:

“Biochemical markers of bone turnover can:

  • Aid in risk assessment and serve as an additional monitoring tool when treatment is initiated
  • Be repeated to determine if treatment is producing expected effect. "

“Biochemical markers of bone turnover may:

  • Predict rapidity of bone loss in untreated patients
  • Predict extent of fracture risk reduction when repeated after 3-6 months of treatment with FDA [Food and Drug Administration]-approved therapies
  • Predict magnitude of BMD [bone mineral density] increases with FDA-approved therapies
  • Help determine adequacy of patient compliance and persistence with osteoporosis therapy
  • Help determine duration of ‘drug holiday’ and when and if medication should be restarted (Data are quite limited to support this use, but studies are underway.)”

International Society for Clinical Densitometry

In 2011, a joint statement by the International Society for Clinical Densitometry and the International Osteoporosis Foundation on the Fracture Risk Assessment Model (FRAX) fracture risk prediction algorithms indicated that the “Evidence that bone turnover markers predict fracture risk independent of BMD is inconclusive. Therefore, bone turnover markers are not included as risk factors in FRAX.”

National Bone Health Alliance

Recommendations from the National Bone Health Alliance (2017) considered N-terminal propeptide of Type I procollagen (PINP) and C-terminal telopeptide of Type I collagen (CTX-I) as “international reference standards” for bone formation and resorption, respectively. Among the conditions associated with increased bone turnover were primary hyperparathyroidism, vitamin D deficiency, immobility, fracture, and Paget disease; the guidelines also considered diseases associated with low or disassociated bone turnover. The National Bone Health Alliance advised that caregivers control for factors such as food intake, time of sample collection, and handling procedure (i.e., CTX-I assays should be conducted in a fasting state); and that those interpreting the results of bone turnover marker tests be familiar with how uncontrollable factors (i.e., age, comorbidities, medications) may interact with a patient’s CTX-I or PINP levels.

U.S. Preventive Services Task Force Recommendations

The U.S. Preventive Services Task Force (2018) recommended screening for osteoporosis with bone measurement testing to prevent osteoporotic fractures in women 65 years and older. The Task Force recommended screening for osteoporosis with bone measurement testing to prevent osteoporotic fractures in postmenopausal women younger than 65 years who are at increased risk of osteoporosis, as determined by a formal clinical risk assessment tool. The recommendations on osteoporosis screening addressed dual-energy x-ray absorptiometry testing but did not mention bone turnover markers.

KEY WORDS:

Bone Turnover Markers, Collagen Cross links, Osteoporosis

APPROVED BY GOVERNING BODIES:

Several tests for bone turnover markers have been cleared for marketing by the U.S. Food and Drug Administration (FDA) through the 510(k) process. Examples are listed in the table below.

Table. FDA-Cleared Tests for Bone Turnover Markers

Test

Manufacturer

Year

Indication

Pyrilinks®

Metra Biosystems

1995

Collagen Type 1 cross-link, pyridinium

Osteomark®

Ostex International

1996

Cross-linked N-telopeptides of Type 1 collagen

Serum CrossLaps® ELISA

Immunodiagnostic Systems

1999

Hydroxyproline

Ostase®

Beckman Coulter

2000

Bone-specific alkaline phosphatase

N-MID Osteocalcin One-Step ELISA

Osteometer Bio Tech

2001

Osteocalcin

ELISA: enzyme-linked immunosorbent assay; FDA: Food and Drug Administration

BENEFIT APPLICATION:

Coverage is subject to member’s specific benefits.  Group specific policy will supersede this policy when applicable.

ITS: Home Policy provisions apply

FEP:  Special benefit consideration may apply.  Refer to member’s benefit plan.  FEP does not consider investigational if FDA approved and will be reviewed for medical necessity.

CURRENT CODING:

CPT Codes:

82523

Collagen cross-links, any method

83937

Osteocalcin (bone g1a protein)

84080

Phosphatase, alkaline, isoenzymes

REFERENCES:

  1. Abe Y, Ishikawa H, Fukao A. Higher efficacy of urinary bone resorption marker measurements in assessing response to treatment for osteoporosis in postmenopausal women. Tohoku J Exp Med 2008; 214(1):51-9.
  2. Al Nofal AA, Altayar O, BenKhadra K, et al. Bone turnover markers in Paget's disease of the bone: A Systematic review and meta-analysis. Osteoporos Int. Jul 2015; 26(7):1875-1891.
  3. Alvarez L, Guanabens N, Peris P et al. Usefulness of biochemical markers of bone turnover in assessing response to the treatment of Paget's disease. Bone 2001; 29(5):447-52.
  4. Bauer DC, Black DM, Ott SM et al. Biochemical markers predict spine but not hip BMD response to bisphosphonates: the Fracture Intervention Trial (FIT). J Bone Miner Res 1997; 12(suppl 1):S150.
  5. Bauer DC, Garnero P, Harrison SL et al. Biochemical markers of bone turnover, hip bone loss and fracture in older men: the MrOS Study. J Bone Mineral Res 2009; 24(12):2032-8.
  6. Bauer DC, Garnero P, Hochberg MC et al. Pretreatment levels of bone turnover and the antifracture efficacy of alendronate: the fracture intervention trial. J Bone Miner Res 2006; 21(2):292-9.
  7. Baxter I, Rogers A, Eastell R et al. Evaluation of urinary N-telopeptide of type I collagen measurements in the management of osteoporosis in clinical practice. Osteoporos Int 2013; 24(3):941-7.
  8. Bergmann P, Body JJ, Boonen S et al. Evidence-based guidelines for the use of biochemical markers of bone turnover in the selection and monitoring of bisphosphonate treatment in osteoporosis: a consensus document of the Belgian Bone Club. Int J Clin Pract 2008; 63(1):19-26.
  9. Biver E, Chopin F, Coiffier G et al.  Bone turnover markers for osteoporotic status assessment?  A systematic review of their diagnosis value at baseline in osteoporosis.  Joint Bone Spine 2012; 79(1):20-5.
  10. Blumsohn A, Eastell R. The performance and utility of biochemical markers of bone turnover: do we know enough to use them in clinical practice? Ann Clin Biochem 1997; 34(pt 5):449-59.
  11. Bone HG, Downs RW, Tucci JR et al. Dose-response relationships for alendronate treatment in osteoporotic elderly women. J Clin Endocrine Metab 1997; 82(1):265-74.
  12. Burch J, Rice S, Yang H, et al. Systematic review of the use of bone turnover markers for monitoring the response to osteoporosis treatment: the secondary prevention of fractures, and primary prevention of fractures in high-risk groups. Health Technol Assess. Feb 2014; 18(11):1-180.
  13. 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. May 2020; 26(Suppl 1): 1-46.
  14. Chopin F, Biver E, Funch-Brentato T et al.  Prognostic interest of bone turnover markers in the management of postmenopausal osteoporosis.  Joint Bone Spine 2012; 79(1):26-31.
  15. Cosman F, de Beur SJ, LeBoff MS, et al. Clinician's guide to prevention and treatment of osteoporosis. Osteoporos Int. Oct 2014; 25(10):2359-2381.
  16. 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. May 01 2019; 104(5): 1595-1622.
  17. Federal Register, November 23, 2001. Vol. 66, No. 226. Rules and Regulations.
  18. Funck-Brentano T, Biver E, Chopin F et al. Clinical utility of serum bone turnover markers in postmenopausal osteoporosis therapy monitoring: a systematic review. Semin Arthritis Rheum 2011; 41(2):157-69.
  19. 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(10):1531-8.
  20. Gutierrez-Buey G, Restituto P, Botella S, et al. Trabecular bone score and bone remodelling markers identify perimenopausal women at high risk of bone loss. Clin Endocrinol (Oxf). Sep 2019; 91(3): 391-399.
  21. Johansson H, Oden A, Kanis JA, et al. A meta-analysis of reference markers of bone turnover for prediction of fracture. Calcif Tissue Int. May 2014; 94(5):560-567.
  22. Looker AC, Bauer DC, Chestnut CH et al. Clinical use of biochemical markers of bone remodeling: current status and future directions. Osteoporosis Int 2000; 11(6):467-80.
  23. Management of osteoporosis in postmenopausal women: 2010 position statement of the North American Menopause Society. Available online at: www.guideline.gov.
  24. Marcus R, Holloway L, Wells B. Turnover markers only weakly predict bone response to estrogen: the Postmenopausal Estrogen/Progestin Interventions Trial (PEPI). J Bone Miner Res 1997; 12(suppl 1):S103.
  25. McCloskey EV, Vasikaran S, Cooper C. Official Positions for FRAX(R) clinical regarding biochemical markers from Joint Official Positions Development Conference of the International Society for Clinical Densitometry and International Osteoporosis Foundation on FRAX(R). J Clin Densitom 2011; 14(3):220-2.
  26. National Osteoporosis Foundation. 2013 Clinician's guide to prevention and treatment of osteoporosis. Available online at: www.nof.org/professionals/clinical-guidelines. Last accessed September, 2013.
  27. National Osteoporosis Foundation. 2014 Clinician's guide to prevention and treatment of osteoporosis. nof.org/files/nof/public/content/file/2610/upload/895.pdf.
  28. North American Menopause Society. Management of osteoporosis in postmenopausal women: 2010 position statement of the North American Menopause Society. Menopause 2010; 17(1):25-54; quiz 55-6.
  29. Reid IR, Davidson JS, Wattie D et al. Comparative responses of bone turnover markers to bisphosphonate therapy in Paget's disease of bone. Bone 2004; 35(1):224-30.
  30. Rianon N, Alex G, Callender G et al. Preoperative serum osteocalcin may predict postoperative elevated parathyroid hormone in patients with primary hyperparathyroidism. World J Surg 2012; 36(6):1320-6.
  31. Roux C, Giradeau B, Rouanet S et al.  Monitoring of bone turnover markers does not improve persistence with ibandronate treatment.  Joint Bone Spine 2012; 79(4):389-92.
  32. Shieh A, Greendale GA, Cauley JA, et al. Urinary N-Telopeptide as Predictor of Onset of Menopause-Related Bone Loss in Pre- and Perimenopausal Women. JBMR Plus. Apr 2019; 3(4): e10116.
  33. Shiraki M, Itabashi A. Short-term menatetrenone therapy increases gamma-carboxylation of osteocalcin with a moderate increase of bone turnover in postmenopausal osteoporosis: a randomized prospective study. J Bone Miner Metab 2009; 27(3):333-40.
  34. Shiraki M, Kuroda T, Tanaka S et al. Nonenzymatic collagen cross-links induced by glycoxidation (pentosidine) predicts vertebral fractures. J Bone Miner Metab 2008; 26(1):93-100.
  35. Silverman SL, Nasser K, Nattrass S et al. Impact of bone turnover markers and/or educational information on persistence to oral bisphosphonate therapy: a community setting-based trial. Osteoporos Int 2012; 23(3):1069-74.
  36. Szulc P, Naylor K, Hoyle NR, et al. Use of CTX-I and PINP as bone turnover markers: National Bone Health Alliance recommendations to standardize sample handling and patient preparation to reduce pre-analytical variability. Osteoporos Int. Jun 19 2017.
  37. Tamaki J, Iki M, Kadowaki E et al. Biochemical markers for bone turnover predict risk of vertebral fractures in postmenopausal women over 10 years: the Japanese Population-based Osteoporosis (JPOS) Cohort Study. Osteoporos Int 2013; 24(3):887-97.
  38. U.S. Preventive Services Task Force (USPSTF). Osteoporosis to Prevent Fractures: Screening. June 2018 https://www.uspreventiveservicestaskforce.org/Page/ Document/UpdateSummaryFinal/osteoporosis-screening1 Accessed November 17, 2019.
  39. U.S. Preventive Services Task Force (USPSTF). Osteoporosis to Prevent Fractures: Screening. June 2018 https://www.uspreventiveservicestaskforce.org/uspstf/recommendation/osteoporosis-screening#fullrecommendationstart Accessed December 8, 2020.
  40. Vasikaran S, Cooper C, Eastell R et al.  International Osteoporosis Foundation and Internationals Federation of Clinical Chemistry and Laboratory Medicine Position on bone marker standards in osteoporosis.  Clin Chem L Med 2011; 49(8):1271-4.
  41. Woitge HW, Oberwittler H, Heichel S et al. Short- and long-term effects of ibandronate treatment on bone turnover in Paget disease of bone. Clin Chem 2000; 46(5):684-90.
  42. Zhang T, Liu P, Zhang Y, et al. Combining information from multiple bone turnover markers as diagnostic indices for osteoporosis using support vector machines. Biomarkers. Mar 2019; 24(2): 120-126.

POLICY HISTORY:

Medical Policy Group, February 2011, (2)

Medical Policy Administration Committee, February 2011

Available for comment February 24 through April 11, 2011

Medical Policy Panel, September 2011

Medical Policy Group, September 2011 (2): Key points, References updated

Medical Policy Panel, October 2012

Medical Policy Group, January 2013 (2): 2012 Update to policy statement – added investigational in the management of patients with conditions associated with high rates of bone turnover, including but not limited to Paget’s disease, primary hyperparathyroidism and renal osteodystrophy; Key Points and References also updated.

Medical Policy Administration Committee, February 2013

Available for comment February 21 through April 7, 2013

Medical Policy Panel, October 2013

Medical Policy Group, October 2013 (1): Update to Key Points and References; no change to policy statement

Medical Policy Panel, September 2014

Medical Policy Group, September 2014 (1): Update to Key Points and References; no change to policy statement

Medical Policy Panel, December 2016

Medical Policy Group, December 2016 (3): 2016 Updates to Title & Key Points; no new References to add; no change to policy statement

Medical Policy Panel, December 2017

Medical Policy Group, January 2018 (3): 2018 Updates to Description, Key Points & References; no change in policy statement.

Medical Policy Panel, December 2018

Medical Policy Group, January 2019 (9): 2019 Updates to Description, Key Points & References. No change to policy statement.

Medical Policy Panel, January 2020

Medical Policy Group, January 2020 (9): 2020 Updates to Description, Key Points, References. Investigational statements added to policy section related to determining fracture risk in osteoporosis/age related risk factors for osteoporosis and response to therapy in patients with osteoporosis. No change to policy statement intent.

Medical Policy Administration Committee, February 2020.

Medical Policy Panel, January 2021

Medical Policy Group, January 2021 (9): 2021 Updates to Description, Key Points, References. No change to policy statement.


This medical policy is not an authorization, certification, explanation of benefits, or a contract. Eligibility and benefits are determined on a case-by-case basis according to the terms of the member’s plan in effect as of the date services are rendered. All medical policies are based on (i) research of current medical literature and (ii) review of common medical practices in the treatment and diagnosis of disease as of the date hereof. Physicians and other providers are solely responsible for all aspects of medical care and treatment, including the type, quality, and levels of care and treatment.

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As a general rule, benefits are payable under health plans only in cases of medical necessity and only if services or supplies are not investigational, provided the customer group contracts have such coverage.

The following Association Technology Evaluation Criteria must be met for a service/supply to be considered for coverage:

  1. The technology must have final approval from the appropriate government regulatory bodies;
  2. The scientific evidence must permit conclusions concerning the effect of the technology on health outcomes;
  3. The technology must improve the net health outcome;
  4. The technology must be as beneficial as any established alternatives;
  5. The improvement must be attainable outside the investigational setting.

Medical Necessity means that health care services (e.g., procedures, treatments, supplies, devices, equipment, facilities or drugs) that a physician, exercising prudent clinical judgment, would provide to a patient for the purpose of preventing, evaluating, diagnosing or treating an illness, injury or disease or its symptoms, and that are:

  1. In accordance with generally accepted standards of medical practice; and
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