Bone Turnover Markers for Diagnosis and Management of Osteoporosis and Other Conditions

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Medical Policy: 02.04.13 
Original Effective Date: October 2007 
Reviewed: March 2015 
Revised: March 2015 

Benefit Application
Benefit determinations are based on the applicable contract language in effect at the time the services were rendered. Exclusions, limitations or exceptions may apply. Benefits may vary based on contract, and individual member benefits must be verified. Wellmark determines medical necessity only if the benefit exists and no contract exclusions are applicable. This medical policy may not apply to FEP. Benefits are determined by the Federal Employee Program.

This Medical Policy document describes the status of medical technology at the time the document was developed. Since that time, new technology may have emerged or new medical literature may have been published. This Medical Policy will be reviewed regularly and be updated as scientific and medical literature becomes available.


Bone turnover markers are biochemical markers of either bone formation or bone resorption. Commercially available tests 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) measurements 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.


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 osteoclasts and osteoblasts is balanced, but bone loss occurs if the 2 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 summarizes the various bone turnover markers.


Formation Markers

Resorption Markers

Serum osteocalcin (OC)  

Serum and urinary hydroxyproline (Hyp)  

Serum total alkaline phosphatase (ALP)  

Urinary total pyridinoline (Pyr)

Serum bone-specific alkaline phosphatase (B-ALP)

Urinary total deoxypyridinoline (d-Pyr)  

Serum procollagen I carboxyterminal propeptide (PICP)

Urinary-free pyridinoline (f-Pyr, also known as Pyrilinks®)  

Serum procollagen type 1 N-terminal propeptide (PINP)  

Urinary-free deoxypyridinoline (f-dPyr, also known as Pyrilinks-D®)  

Bone sialoprotein  

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


Serum and urinary collagen type I cross-linked C-telopeptide (CTx, also referred to as Cross Laps®)  


Serum carboxyterminal telopeptide of type I collagen (ITCP)  


Tartrate-resistant acid phosphatase (TRAP or TRACP)  


Collagen cross-links or biochemical markers are generally reliable markers of bone resorption because they are stable in serum and urine. These marker links bind 3 molecules of collagen in the bone and are released from the bone matrix after resorption, either free or bound to the N- or C- telopeptide of collagen. Collagen cross links may be detected using either HPLC (pyr and d-Pyr) or immunoassays (Pyr, d-Pry, CTx, NTx).  In addition to collagen cross-links, alkaline phosphatase (ALP) is a commonly used marker due to its ease of measurement; however, it lacks sensitivity and specificity for detecting osteoporosis since only about half of the ALP activity is derived from bone. Bone specific alkaline phosphatase (B-ALP) is better marker of bone formation than ALP. Serum osteocalcin is a small noncollagenous protein that is a produce of osteoblasts and thus increased levels reflect bone formation. Tartrate-resistance acid phosphatase (TRAP) is produced by osteroclasts; it is thought to be active in bone matrix degradation.  C-terminal telopeptide (or more formally, carboxy-terminal collagen crosslinks, and known by the acronym CTX) is a serum biomarker used to measure the rate of bone turnover has not been reliably sensitive to determine individual osteoporosis treatment responses.


There has been  interest in the use of bone turnover markers to evaluate age-related osteoporosis, a disease characterized by slow, prolonged bone loss, resulting in an increased risk of fractures at the hip, spine, or wrist. Currently, fracture risk is primarily based on measurements of bone mineral density (BMD) in conjunction with other genetic and environmental factors, such as family history of osteoporosis, history of smoking, and weight. It is thought that the level of bone turnover markers may also predict fracture risk, possibly through a different mechanism than that associated with BMD.  However, it must be emphasized that the presence of bone-turnover markers in the serum or urine is not necessarily related to bone loss. For example, even if bone turnover is high, if resorption is balanced with formation, there will be no net bone loss. Bone loss will only occur if resorption exceeds formation.  Therefore, bone-turnover makers have been primarily studied as an adjunct, not an alternative, to measurements of BMD to estimate fracture risk and document the need for preventive or therapeutic strategies for osteoporosis.  In addition, bone turnover markers might provide a more immediate assessment of treatment response and predict change in BMD (bone mineral density) in response to treatment. Treatment related changes in BMD occur very slowly. This fact, coupled with the precision of BMD technologies, suggested that clinically significant changed in BMD could not be reliable detected until at least 2 years. In contrast, changes in bone turnover markers could be anticipated after 3 months of therapy.


In addition, bone turnover makers have been researched in diseases associated with markedly high levels of bone turnover, such as Paget’s disease, primary hyperparathyroidism and renal osterodystrophy. However, there is insufficient evidence that measurement of bone turnover markers improves patient management or health outcomes in patients with conditions associated with high bone turnover.


Bone turnover makers or biochemical makers are predictive of the rate of bone loss and, in some studies, risk of fracture. However, there is not role for bone turnover markers in selecting candidates for bone density testing or for osteoporosis therapy. The decision to measure bone density should be based upon age and the presence of clinical risk factors for fracture. Similarly, the decision to treat patients should be based upon fracture risk assessment using bone mineral density (BMD) and clinical risk factors.


The use of bone turnover markers or biochemical markers for managing osteoporosis is not a central component of most osteoporosis guidelines. When bone turnover makers or biochemical markers are addressed, guideline committees typically recommend against their routine use, due to limitations of measuring and interpreting bone turnover markers in individual patients. Most committees agree that potential role of bone turnover makers in monitoring osteoporosis therapy to identify non-responders. However, prospective trials to define the most optimal approach for incorporating markers into management strategies are needed.


The literature suggests that bone turnover marker levels may be independently associated with osteoporosis and fracture risk in some groups, but there is insufficient evidence reporting an association for any specific marker. Questions remain about whether bone turnover markers are sufficiently sensitive to reliably determine individual treatment responses. In addition, there is insufficient evidence from controlled studies that bone turnover maker measurement improves adherence to treatment, impacts management decisions, and/or improves health outcomes such as reducing fracture rates. Thus, the use of bone turnover markers for the diagnosis and management of osteoporosis is considered investigational.


There is insufficient evidence that measurement of bone turnover markers improves patient management or health outcomes in patients with conditions associated with high bone turnover including Paget disease, primary hyperparathyroidism, and renal osteodystrophy. Thus, bone turnover marker testing for these conditions is considered investigational.


Practice Guidelines and Position Statements


National Osteoporosis Foundation
In 2014, the National Osteoporosis Foundation updated their guideline for prevention and treatment of osteoporosis. Regarding biochemical markers of bone turnover, the guideline states:


Biochemical markers of bone turnover may:

  • Predict risk of fracture independently of bone density.
  • Predict extent of fracture risk reduction when repeated after 3-6 months of treatment with FDA-approved therapies.
  • Predict magnitude of BMD increases with FDA-approved therapies.
  • Predict rapidity of bone loss.
  • 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).

The North American Menopause Society

In 2010, the North American Menopause Society issued an updated position statement on the management of osteoporosis in postmenopausal women. The statement included the recommendation, “the routine use of biochemical markers of bone turnover in clinical practice is not generally recommended.”


Internationl Osteoporosis Foundation (IOF) and the International Federation of Clinical Chemistry and Laboratory Medicine (IFCC)
In 2011, the International Osteoporosis Foundation (IOF) and the International Federation of Clinical Chemistry and Laboratory Medicine (IFCC) published a position statement by a joint IOF-IFCC Bone Marker Standards Working Group. The aim of the group was to evaluated evidence on using bone turnover markers for fracture risk assessment and monitoring of treatment. The group’s overall conclusion was, “In summary, the available studies relating to bone turnover marker changes to fracture risk reduction with osteoporosis treatments are promising. Further studies are needed that take care of sample handling, ensure that bone turnover markers are measured in all available patients, and use the appropriate statistical methods, including an assessment of whether the final bone turnover marker level is a guide to facture risk.”


International Society for Clinical Densitometry and the International Osteoporosis Foundation (IOF)
In 2011, the Joint Official Positions Development Conference of the International Society for Clinical Densitometry and the IOF on the FRAX fracture risk prediction algorithms published the following statement “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.” 

Regulatory Status
Several tests for bone turnover markers have been cleared by the U.S> Food and Drug Administration (FDA) using the 510(k) process:


Collagen cross-links tests:
Pyrilinks test (Metra Biosystems, Santa Clara, CA) measures collagen type 1 cross-link, pyridium.


Osteomark test (Ostex International, Seattle, WA) measures cross-linked N-telopeptides of type 1 collagen (NTx).


Serum Crosslaps One-step ELISA test measures hydroxyproline.


Other bone turnover tests:
Ostase (Beckman Coulter) measures bone-specific alkaline phosphatase (B-ALP).


N-MID Osteocalcin One-step ELISA (Osteometer Bio Tech) measures osteocalcin (OC)


Prior Approval: 


Not applicable



Measurement of serum or urine bone turnover markers (collagen cross-links/biochemical markers) is considered investigational in the diagnosis and management of osteoporosis.


Measurement of serum or urine bone turnover markers (collagen cross-links/biochemical markers) is considered 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. 

There is insufficient evidence that measurement of bone turnover markers improves patient management or health outcomes in patients with conditions associated with high bone turnover including but not limited to Paget’s disease, primary hyperparathyroidism, and renal osteodystrophy. Thus, bone turnover marker testing for these other conditions is considered investigational.


Procedure Codes and Billing Guidelines: 

  • To report provider services, use appropriate CPT* codes, Modifiers, Alpha Numeric (HCPCS level 2) codes, Revenue codes, and/or diagnosis codes.
  • 82523 collagen cross links, any method
  • 83937 osteocalcin (bone g1a protein)
  • 84080 (bone specific alkaline phosphatase isoenzymes) as being used for Ostase test


Selected References: 

  • National Osteoporosis Foundation. Physician's guide to prevention and treatment of osteoporosis. April 2003.
  • Stepan JJ.  Clinical utility of bone markers in the evaluation and follow-up of osteoporotic patients: why are the markers poorly accepted by clinicians?  J Endocrinol Invest. 2003 May;26(5):458-63.
  • Meunier PJ, Roux C, et al. The effects of strontium ranelate on the risk of vertebral fracture in women with postmenopausal osteoporosis.  N Engl J Med. 2004 Jan 29;350(5):459-68.
  • Paschalis EP, Glass EV,et al.  Bone mineral and collagen quality in iliac crest biopsies of patients given teriparatide: new results from the fracture prevention trial.  J Clin Endocrinol Metab. 2005 Aug;90(8):4644-9.
  • Bauer DC, Garnero P, et al.  Pretreatment levels of bone turnover and the antifracture efficacy of alendronate: the fracture intervention trial.  J Bone Miner Res. 2006 Feb;21(2):292-9.
  • Black DM, Schwartz AV,et al.   Effects of continuing or stopping alendronate after 5 years of treatment: the Fracture Intervention Trial Long-term Extension (FLEX): a randomized trial. JAMA. 2006 Dec 27;296(24):2927-38.
  •  Deane A, Constancio L, et al. The impact of vitamin D status on changes in bone mineral density during treatment with bisphosphonates and after discontinuation following long-term use in post-menopausal osteoporosis.  BMC Musculoskelet Disord. 2007 Jan 10;8:3.
  • 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.
  • 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.
  • Management of osteoporosis in postmenopausal women: 2010 position statement of the North American Menopause Society. Last accessed August 2011.
  • Funck-Brentano T, Biver E, Chopin F, Bouvard B, et al. Clinical utility of serum bone turnover markers in postmenopausal osteoporosis therapy monitoring: a systematic review. Semin Arthritis Rheum. 2011 Oct; 41(2):157-69.
  • Biver E, Chopin F, Coiffier G, Brentano TF, et al. Bone turnover markers for osteoporotic status assessment? A systematic review of their diagnosis value at baseline in osteoporosis. Joint Bone Spine. 2012 Jan;79(1):20-5.
  • UpToDate. Use of Biochemical Markers of Bone Turnover in Osteoporosis. Harold N. Rosen, M.D. , Topic last updated March 20, 2014.
  • ECRI Institute. Hotline Response. Biochemical Markers of Bone Turnover in Age Related Osteoporosis. January 2013.
  • National Guideline Clearinghouse. American College of Obstetricians and Gynecologists (ACOG), practice bulletin; no 129, Osteoporosis and Osteoporotic Fractures.
  • Sonsoles Botella, Patricia Restituto, et. al. Traditional and Novel Bone Remodeling Markers in Premenopausal and Postmenopausal Women, Journal of Clinical Endocrinology & Metabolism September 3, 2013. Also available at
  • AACC. Bone Turnover Markers. Also available at
  • International Society for Clinical Densitometry and International Osteoporosis Foundation, Interpretation and Use of FRAX in Clinical Practice. Also available at www.ISCD


Policy History: 



Date                                        Reason                              Action

August 2011                           Annual review                   Policy revised

May 2012                               Annual review                   Policy renewed

May 2013                               Annual review                   Policy revised

April 2014                               Annual review                   Policy revised

March 2015                            Annual review                   Policy revised


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*Current Procedural Terminology © 2012 American Medical Association. All Rights Reserved.

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