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DESCRIPTIONBone 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.
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 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 below summarizes the various bone-turnover markers.
There has been recent interest in the use of bone-turnover markers to evaluate age-related osteoporosis, a condition 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 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 markers have been primarily studied as an adjunct, not an alternative, to measurements of BMD to estimate the 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 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.
Bone-turnover markers have also been researched as markers of diseases associated with markedly high levels of bone turnover, such as Paget’s disease, primary hyperparathyroidism, and renal osteodystrophy.
Collagen cross-links are generally reliable markers of bone resorption because they are stable in serum and urine. Collagen cross 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-Pyr, 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 a better marker of bone formation than ALP. Serum osteocalcin is a small noncollagenous protein that is a product of osteoblasts and thus increased levels reflect bone formation. Tartrate-resistant acid phosphatase (TRAP) is produced by osteoclasts; it is thought to be active in bone matrix degradation.
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:
Other bone turnover tests:
POLICYMeasurement of bone turnover markers is considered investigational in the diagnosis and management of osteoporosis.
Measurement of bone turnover 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.
POLICY EXCEPTIONSFederal Employee Program (FEP): FEP may dictate that laboratory tests approved by the U.S. Food and Drug Administration (FDA) may not be considered investigational and thus these devices may be assessed only on the basis of their medical necessity.
POLICY GUIDELINESInvestigative service is defined as the use of any treatment procedure, facility, equipment, drug, device, or supply not yet recognized by certifying boards and/or approving or licensing agencies or published peer review criteria as standard, effective medical practice for the treatment of the condition being treated and as such therefore is not considered medically necessary.
The coverage guidelines outlined in the Medical Policy Manual should not be used in lieu of the Member's specific benefit plan language.
POLICY HISTORY1/5/2007: Policy added
3/22/2007: Reviewed and approved by the Medical Policy Advisory Committee (MPAC)
5/9/2008: Policy reviewed, no changes
12/11/2009: Policy Description revised to add additional information on bone turnover markers, their definition, and additionall indications for testing. FDA approved collagen cross-links and other bone turnover tests added. Links to related policies added. Policy Exceptions revised to add FEP verbiage.
10/21/2010: Policy title changed from "Collagen Cross Links as Markers of Bone Turnover" to "Bone Turnover Markers for the Diagnosis and Management of Osteoporosis." This terminology was changed throughout the policy. Intent of policy statement unchanged.
10/05/2011: Policy reviewed. Deleted "or other conditions associated with increased bone turnover" from the policy statement. Intent unchanged.
01/09/2013: Added "and Diseases Associated with High Bone Turnover" to the policy title. Added the following investigational policy statement: Measurement of bone turnover 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. Added 83937 to the Code Reference section as non-covered.
12/13/2013: Policy reviewed; no changes.
11/11/2014: Policy reviewed; description updated. Added "markers" to first investigational policy statement. Intent unchanged.
SOURCE(S)Blue Cross Blue Shield Association Policy # 2.04.15
CODE REFERENCEThis may not be a comprehensive list of procedure codes applicable to this policy.