BlueCross BlueShield of Tennessee Medical Policy Manual

Bone Turnover Markers for Diagnosis and Management of Osteoporosis and Other Diseases Associated with High 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. Constant bone turnover is critical to the overall health of the bone. Normally, the action of osteoblasts and osteoclasts is balanced, but bone loss occurs if the two processes become discordant.

Bone-turnover markers can be categorized as bone-formation markers or bone-resorption 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)  

There has been recent 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 based primarily 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. Bone-turnover markers have been primarily studied as an adjunct, not an alternative, to measurements of bone mineral density (BMD) to estimate the fracture risk and document the need for preventive or therapeutic strategies for osteoporosis.

Bone-turnover markers have also been researched in other diseases associated with markedly high levels of bone turnover, such as Paget's disease, primary hyperparathyroidism, glucocorticoid-induced osteoporosis, or renal osteodystrophy.

Several tests for bone turnover markers have been cleared for marketing by the U.S. Food and Drug Administration.  Examples include: Pyrilinks®, Osteomark®, Serum CrossLaps®, Ostase®, and N-MID Osteocalcin One-Step.




Available studies have not shown that the measurement of bone markers is useful in treatment management decisions, effective in improving compliance, nor reliable in predicting clinical end points.


Al Nofal, A., Altayar, O., BenKhadra, K., Qasim Agha, O., Asi, N., Nabhan, M., et al. (2015). Bone turnover markers in Paget’s disease of the bone: a systematic review and meta-analysis. Osteoporosis International, 26 (7), 1875-1891. Abstract retrieved September 21, 2017 from PubMed database.

Albeshri, S., Alblaihess, A., Niazy, A.A., Ramalingham, S., Sundar, C., & Alghamdi, H.S. (2018). Biomarkers as independent predictors of bone regeneration around biomaterials: a systematic review of literature. Journal of Contemporary Dental Practice, 19 (5), 605-618. Abstract retrieved August 23, 2018 from PubMed database.

American Association of Clinical Endocrinologists and American College of Endocrinology. (2016). Clinical practice guidelines for the diagnosis and treatment of postmenopausal osteoporosis - 2016. Retrieved October 17, 2016 from

BlueCross BlueShield Association. Evidence Positioning System. (1:2019). Bone turnover markers for the diagnosis and management of osteoporosis and diseases associated with high bone turnover (2.04.15). Retrieved June 27, 2019 from (21 articles and/or guidelines reviewed)

Burch, J., Rice, S., Yang, H., Neilson, A., Stirk, L., Francis, R., et al. (2014). 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 Technology Assessment, 18 (11), 1-180. Abstract retrieved September 21, 2017 from PubMed database.

Centers for Medicare & Medicaid Services. NCD for collagen crosslinks, any method (190.19). Retrieved October 14, 2016 from

Deveza, L. A., Kraus, V. B., Collins, J. E., Guermazi, A., Roemer, F. W., Bowes, M., et al. (2016). The association between biochemical markers of bone turnover and bone changes on imaging – data from the Osteoarthritis Initiative. Arthritis Care Research Impact Factor, Epub ahead of print October 9, 2016. Abstract retrieved October 17, 2016 from PubMed database.

National Osteoporosis Foundation. (2014). Clinician’s guide to prevention and treatment of osteoporosis. Retrieved October 17, 2016 from




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