Medical Policy: 02.04.13 
Original Effective Date: October 2007 
Reviewed: February 2016 
Revised: February 2016 


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.


Description:

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.  Also, bone turnover markers have been considered in the management of conditions associated with high bone turnover including but not limited to Paget's disease, primary hyperparathyroidism and renal osteodystrophy.

 

Background Information on Bone Turnover Markers

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 MarkersResorption 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)  

 

 

Diagnosis and Management of Osteoporosis 

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 changes in BMD could not be reliably detected until at least 2 years. In contrast, changes in bone turnover markers could be anticipated after 3 months of therapy.

 

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.

 

Summary
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.

 

Management of Other Conditions Associated with High Rates of Bone Turnover
There is little published literature on the use of bone turnover markers in the management of conditions associated with high rates of bone turnover, such a Paget disease, primary hyperparathyroidism, and renal osteodystrophy. Many of the available studies were published 10 or more years ago.

 

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.

  

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 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.”.

 

U.S. Preventative Services Task Force
The U.S. Preventative Services Task Force (USPSTF) 2011 recommendation on osteoporosis screening address DXA testing but do not mention bone turnover markers. 


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


Policy:

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

 

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 marker 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.

 

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 phosphatase, alkaline; isoenzymes (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 womenExternal Site 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.
  • UpToDateExternal Site Use of Biochemical Markers of Bone Turnover in Osteoporosis. Harold N. Rosen, M.D. , Topic last updated March 20, 2014.
  • ECRI InstituteExternal Site Hotline Response. Biochemical Markers of Bone Turnover in Age Related Osteoporosis. January 2013.
  • National Guideline ClearinghouseExternal Site 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.
  • American Association for Clinical ChemistryExternal Site (AACC). Bone Turnover Markers. July 2013.
  • International Society for Clinical DensitometryExternal Site and International Osteoporosis Foundation, Interpretation and Use of FRAX in Clinical Practice.
  • U.S. Preventative Service Task ForceExternal Site (USPSTF) Osteoporosis Screening, January 2011.
  • Watts N, Bilezikian J, et. al. American Association of Clinical Endocrinologists (AACE) Medical Guidelines for Clinical Practice for the Diagnosis and Treatment of Postmenopausal Osteoporosis, Endocrine Practice Vol 16 (Suppl 3) November/December 2010
  • Bolland M, Cundy T. Paget’s Disease of Bone. J Clin Pathol. 2013;66(11):924-927. Available on MedscapeExternal Site 
  • Wheater G, Elshahaly M, et. al. The clinical utility of bone marker measurements in osteoporosisExternal Site Journal of Translational Medicine 2013. 11:201.
  • 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
  • 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. Jun 2012;36(6):1320-1326
  • Al Nofal AA, Altayar O, BenKhadra K, et. al. Bone turnover markers in Paget’s disease of the bone: A systemic review and meta-analysis. Osteoporos Int. July 2015;26(7):1875-1891
  • Unnanuntana A, Gladnick B, Donnelly E, et. al. Current Concepts Review The Assessment of Fracture Risk, J Bone Joint Surg Am 2010;92:743-53
  • National Osteoporosis FoundationExternal Site 2014 Clinician’s Guide to Prevention and Treatment of Osteoporosis, Released April 1, 2014.
  • International Osteoporosis Foundation (IOF) and the International Federation of Clinical Chemistry and Laboratory Medicine (IFCC), 2011 Position Statement by a joint IOF-IFCC Bone Marker Standards Work Group.
  • CMSExternal Site National Coverage Determinations. 190.19 Collagen Crosslinks, Any Method..
  • UpToDateExternal Site Screening for Osteoporosis. Michael Kleerekoper, M.D., Topic last updated September 22, 2015.
  • UpToDateExternal Site Primary Hyperparathyroidism: Diagnosis, Differential Diagnosis and Evaluation. Ghada El-Haji Fuleihan, M.D., MPH, Shonni J. Silverberg, M.D., Topic last updated September 30, 2015.
  • UpToDateExternal Site Evaluation and Management of  Aromatase Inhibitor Induced Bone Loss. Charles L. Shapiro, M.D., Shubham Pant, M.D., Topic last updated March 13, 2014.
  • UpToDateExternal Site Treatment of Paget Disease of Bone. Margaret Seton, M.D., Topic last updated January 4, 2016.
  • UpToDateExternal Site Antiepileptic Drugs and Bone Disease. Alison M Pack, M.D., Elizabeth Shane, M.D., Topic last updated December 9, 2013.
  • UpToDateExternal Site Bone Biopsy and the Diagnosis of Renal Osteodystrophy. L Darryl Quarles, M.D., Topic last updated December 21, 2015.
  • Chubb SA, Byrnes E, Manning L, et. al. Reference intervals for bone turnover markers and their association with incident hip fractures in older men: The health in men study, J Clin Endocrinol Metab 2015 Jan;100(1):90-9
  • Michelsen J, Wallashofski H, Friedrich N, et. al. Reference intervals for serum concentrations of three bone turnover markers for men and women, Bone 2013 Dec:57(2):399-404
  • Lehmann G, Ott U, Kaemmerer D, et. al. Bone histomorphometry and biochemical markers of bone turnover in patients with chronic kidney disease stages 3-5, Clin Nephrol 2008 Oct:70(4):296-305

Policy History:

  • February 2016 - Annual Review, Policy Revised
  • March 2015 - Annual Review, Policy Revised
  • April 2014 - Annual Review, Policy Revised
  • May 2013 - Annual Review, Policy Revised
  • May 2012 - Annual Review, Policy Renewed
  • August 2011 - Annual Review, Policy Revised

Wellmark medical policies address the complex issue of technology assessment of new and emerging treatments, devices, drugs, etc.   They are developed to assist in administering plan benefits and constitute neither offers of coverage nor medical advice. Wellmark medical policies contain only a partial, general description of plan or program benefits and do not constitute a contract. Wellmark does not provide health care services and, therefore, cannot guarantee any results or outcomes. Participating providers are independent contractors in private practice and are neither employees nor agents of Wellmark or its affiliates. Treating providers are solely responsible for medical advice and treatment of members. Our medical policies may be updated and therefore are subject to change without notice.

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