Medical Policy: 02.04.13
Original Effective Date: October 2007
Reviewed: February 2016
Revised: February 2016
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. 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.
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.
|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®)
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 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.
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 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.
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:
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.”
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.”
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.”.
The U.S. Preventative Services Task Force (USPSTF) 2011 recommendation on osteoporosis screening address DXA testing but do not mention bone turnover markers.
Several tests for bone turnover markers have been cleared by the U.S> Food and Drug Administration (FDA) using the 510(k) process:
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.
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