Laboratory Section - Collagen Cross Links as Markers of Bone Turnover

IMPORTANT REMINDER

This Medical Policy has been developed through consideration of medical necessity, generally accepted standards of medical practice, and review of medical literature and government approval status.

Benefit determinations should be based in all cases on the applicable contract language. To the extent there are any conflicts between these guidelines and the contract language, the contract language will control.

The purpose of medical policy is to provide a guide to coverage. Medical Policy is not intended to dictate to providers how to practice medicine. Providers are expected to exercise their medical judgment in providing the most appropriate care.

Description

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 two processes become uncoupled. Bone turnover markers can be categorized as bone formation markers, measured in the serum, or bone resorption markers, measured in the urine. The table below summarizes the various bone turnover markers.

*For completeness, all tests that may be considered bone turnover markers are included in the above table. However, asterisked tests are not collagen cross-link tests and are thus not addressed in this policy.

Bone turnover markers have been extensively researched in diseases associated with markedly high levels of bone turnover, such as Paget's disease, primary hyperparathyroidism, glucocorticoid-induced osteoporosis or renal osteodystrophy. 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 measurement 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. 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 bone mineral density (BMD), to estimate the fracture risk and document the need for preventive or therapeutic strategies for osteoporosis.

Collagen cross links may be considered the best available markers of bone resorption. Collagen cross links bind three 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). This policy focuses on the use of collagen cross links, as identified by CPT code 82523.

Policy/Criteria

Collagen cross links as measurements of bone turnover are considered investigational in the diagnosis and management of conditions associated with increased bone turnover, including but not limited to osteoporosis, hyperparathyroidism, and renal osteodystrophy.

Scientific Background

The following clinical applications of bone turnover markers have been investigated:

1. Bone turnover markers in conjunction with measurements of bone mineral densitometry have been investigated as a technique to identify those patients at highest risk of osteoporosis-related fractures.

   Bone turnover markers may reflect fracture risk through a different mechanism than that associated with BMD. Therefore markers have been investigated as an adjunct to BMD to increase the prediction assessment for fracture risk compared to the use of BMD alone. For example, a prospective cohort study of 7,500 women over 75 years old reported the overall relative risk of hip fracture among patients with osteoporosis is 2.7, but rises to as high as 4.8 if markers of bone turnover are elevated. (2) However, it is not clear how this information may be used in the clinical management of the patient. Presumably, all patients with osteoporosis, as identified by measurement of BMD, would be considered candidates for drug therapy, typically the use of hormone replacement therapy, bisphosphonates or calcitonin. It is not clear how therapy should be adjusted according to the level of fracture risk or whether the use of bone turnover markers can predict response to therapy. For example, studies have shown that bone turnover markers are only weakly correlated to magnitude of treatment response, a finding that questions their role in treatment decisions. (3-5) Specifically, bone turnover markers were assessed as part of the postmenopausal estrogen/progestin intervention (PEPI) trial, which randomized women to receive placebo or hormone replacement therapy. (5) The changes in these turnover markers correlated poorly with treatment-related changes in BMD. Bone turnover markers were also measured in the fracture intervention trial, which randomized participants to receive either bisphosphonates or placebo. (4) Changes in bone turnover markers were measured in a subset of 390 patients. While the authors found that higher baseline levels of bone turnover markers were associated with greater increases in spine BMD (but not hip BMD), the authors concluded that association between markers and BMD may not be sufficient to predict response to bisphosphonate therapy.  In another report, 432 untreated elderly Japanese women were followed for 5 years; this observational study found that a urinary test of glycoxidative (nonenzymatic) collagen cross-links was a significant predictor (hazard ratio of 1.33) of incident vertebral fracture after adjustment for other traditional risk factors. (19) Further study of the predictive ability of this advanced glycation end product is needed. 

2. Bone markers have been investigated as a technique to 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, suggests that clinically significant changes in BMD cannot be reliably detected until at least two years. In contrast, changes in bone turnover markers can be anticipated after three months of therapy. Therefore, bone turnover markers may be assessed at diagnosis to provide a baseline, followed by repeat assay at three months to determine the response to therapy. Studies have reported an inconsistent relationship between the change in bone turnover markers in response to therapy and the magnitude of subsequent change in BMD. (6) While bone turnover markers have been included in the large scale clinical trials addressing the use of hormone replacement therapy and bisphosphonates (e.g., alendronate), their role in the trials was as a validating intermediate outcome; i.e., a reduction in bone turnover markers was consistent with the anti-bone-resorptive effect of therapy. Levels of bone turnover markers were not used to guide adjustment of dosage or prompt discontinuation of therapy. In addition, changes in bone turnover markers among treated patients who nonetheless lost bone mass are not known, nor is the converse known; i.e., the likelihood of increases in BMD in those subjects who do not exhibit a change in bone turnover markers with treatment.

   Both bisphosphates and intranasal calcitonin represent new treatment options for osteoporosis. However, long-term experience with these agents is limited, and some physicians may feel uncomfortable in committing a patient to long-term therapy without prompt evidence that the intervention is working. Nonetheless, this specific role of bone turnover markers has not been formally studied in controlled trials. The limitations discussed above, i.e., the poor correlation between bone turnover markers and treatment effects, are applicable here. In addition, there is marked diurnal variation in bone turnover markers in individual patients, and results of markers measured in the urine must be correlated to the serum creatinine, all of which complicate the interpretation of serial studies. (7) Finally, validated cut-offs for response vs. non-response have not been established, although many authors define elevated levels as those that are greater than one standard deviation above the premenopausal mean.

   It has also been hypothesized that serial measurement of bone turnover markers may be used to increase compliance with therapy by demonstrating a prompt treatment response. Osteoporosis is a chronic, silent disease, and thus much like treatment of hypertension or hypercholesterolemia, long-term patient compliance may be poor, particularly if a beneficial treatment effect cannot be measured by BMD until after several years of therapy. (8)

3. Patients may be initially screened for osteoporosis using a peripheral measurement of BMD, e.g., at the heel or wrist. The use of bone turnover markers have been proposed as an alternative to a central BMD measurement, which must be used for serial measurement.

   For unknown reasons, serial BMD testing of peripheral sites does not reflect treatment response. Therefore, if a patient has been initially diagnosed with osteoporosis using a peripheral BMD measurement, some physicians may recommend an additional BMD of the more clinically relevant central sites, e.g., the hip and spine, to serve as a baseline for future serial measurements of BMD. This strategy thus requires two BMD measurements in patients with osteoporosis. In this setting bone turnover markers have been proposed as an alternative to an additional central measurement. For example, Miller and colleagues state that patients with a 50% reduction in baseline of bone turnover markers after three months of therapy may not require a central measurement to monitor therapy. (9)
   This testing strategy has never been formally examined in controlled trials. In addition, the need for serial BMD testing to monitor treatment response is controversial and is not specifically recommended by the recent practice guidelines of the National Osteoporosis Foundation. (10)

4. Bone turnover markers have also been studied in diseases associated with high bone turnover rates, such as glucocorticoid-induced osteoporosis, hyperparathyroidism or renal osteodystrophy.

   Similar to the discussion above regarding age-related osteoporosis, it is unclear how levels of collagen cross links as a marker of bone turnover might be used in the management of the patient. In 1996, the American College of Rheumatology issued practice guidelines regarding the management of glucocorticoid-induced osteoporosis. (11) Bone turnover markers were not recommended as part of the work up or management of patients. In patients with renal disease, measurement of urinary levels of collagen cross links cannot be used. (12) In patients with primary hyperparathyroidism, levels of collagen cross links have been used as a research tool to monitor bone turnover after parathyroidectomy, but again, it is unclear how these markers may be used in the management of the patient. (13)

An updated search of the MEDLINE database through September 2, 2005 did not identify any published articles that change the above conclusions. While markers of bone turnover have emerged as a useful research tool and there are several articles discussing the potential value of bone turnover markers (14-17), no outcomes studies were identified in which patient management was dictated by the results of bone turnover markers. Advocates of bone turnover markers point out that even though results of BMD testing are the single best predictor of fracture risk, determinations of bone turnover may be an independent predictor of fracture risk. However, it is unclear how that knowledge would change patient management and whether such treatment decisions would ultimately result in a reduction in the fracture risk in individual patients.

While the original National Osteoporosis Foundation guidelines for the treatment of osteoporosis did not comment on the use of biochemical markers, a report subtitled, "A Report from the Ad Hoc Committee on Bone Turnover Markers of the National Osteoporosis Foundation" was subsequently published. (6) This report pointed out that there have been few studies that have been specifically designed to examine the use of markers in the care of individual patients with osteoporosis, ranging from elderly women to younger post-menopausal women. This review offered the following conclusions regarding the potential applications of bone turnover markers:

• Combining Biochemical Markers and BMD to Predict Fractures

  "…although the combination of bone turnover markers and BMD is appealing from a theoretical standpoint, currently there are few published data that have appropriately analyzed such combinations. Until additional studies are published and verified, the routine use of combinations of markers and BMD for the prediction of fracture is not justified."

• Biochemical Markers for the Prediction of Fractures in Individuals

  "…there are encouraging data to suggest that elevated markers of bone resorption in older women are associated with an increased risk of hip and non-spine fractures. If additional studies confirm that resorption markers provide information about fracture risk, clinicians might consider measurement of markers in older women when BMD measurements are not available... clinicians will need further guidance regarding treatment thresholds to judge whether modest information about fracture risk provided by markers is clinically useful."

• Ability of Baseline Markers to Predict BMD Changes

  Among untreated patients, the published data do not support the ability of bone markers to predict the magnitude of changes in axial BMD from baseline. Among treated patients, none of the reported studies show a strong relationship between baseline marker and magnitude of change in BMD in response to alendronate or hormone replacement therapy.

• Ability of Change in Marker to Predict Change in BMD in Response to Treatment

  Published data are inconsistent regarding the ability of change in a bone marker to predict magnitude of change in BMD from baseline in postmenopausal women treated with either alendronate or hormone replacement therapy. Interpretation of change in marker levels in individuals is complicated by large within-person variability.

The review concluded by stating, "Markers have potential in the clinical management of the patient with osteoporosis, but, based on presently available information, recommendations for or against the use of current markers in this regard is not warranted."

Updated guidelines from the National Osteoporosis Foundation (2008) stated that osteoporosis (defined by BMD at the hip or spine of less than or equal to 2.5 standard deviations below the young normal mean reference population) “is an intermediate outcome for fractures and is a risk factor for fracture, just as hypertension is for stroke. The majority of fractures, however, occur in patients with low bone mass rather than osteoporosis.” (25) This indicates a need to better assess bone strength using non-invasive technologies. The guidelines also indicated that although biochemical markers of bone turnover may be predictive of greater mean BMD responses when evaluating large groups of patients in clinical trials, the “precision error” of the specific biochemical marker, along with daily and seasonal variability in bone turnover, must be taken into account when evaluating individuals. Thus, “because of the high degree of biological and analytical variability in measurement of biochemical markers, changes in individuals must be large in order to be clinically meaningful.”

An updated search of the literature through December 2008 did not return any clinical studies that would result in a change in the policy criteria. Biochemical markers of bone turnover continue to be used primarily to test the efficacy of new pharmaceutical agents. No new studies were identified to indicate that the results from markers of bone turnover alter clinical decision making and no definitive guidelines have been developed. (19-24)    One study has shown that for alendronate the efficacy of preventing nonspine fractures is greater for those with high pretreatment procollagen type 1 N-terminal propeptide (PINP). (18) The authors indicated that this result needs confirmation in additional studies.  Similar findings have been noted for the impact on bone mineral density during treatment.

In summary, current literature indicates that alternative measures of bone strength have the potential to assess individual responses to treatment or identify individuals at high risk of future fracture, thereby potentially altering clinical management. However, current methods for measuring collagen cross links are not sufficiently sensitive (the least significant change) to reliably determine individual treatment responses, and other types of assays appear to be at an early stage of development. Current methods of assessing bone turnover have not been shown to improve health outcomes.

References

1. BlueCross BlueShield Association Medical Policy Reference Manual, Policy No. 2.04.15
2. Garnero P, Hausher E, Chapuy MC et al. Bone resorption markers predict hip fracture risk in women. The EPIDOS prospective study. J Bone Min Res 1996;11:1531-38
3. Bone H, Downs RW, Tucci JR et al. Dose-response relationships for bisphosphonates treatment in osteoporotic elderly women. J Clin Endocrinol Metab 1997:82:265-74
4. Bauer DC, Black DM, Ott SM et al. Biochemical markers predict spine but not hip BMD response to bisphosphonates: The Fracture Intervention Trial (FIT). J Bone Miner Res 1997;12 (suppl 1):S150
5. Marcus R, Holloway L, Wells B. Turnover markers only weakly predict bone response to estrogen: The Postmenopausal Estrogen/Progestin Interventions Trial (PEPI). J Bone Miner Res 1997;12(suppl 1):S103
6. Looker AC, Bauer DC, Chestnut CH et al. Clinical use of biochemical markers of bone remodeling. Current status and future directions. Osteoporos Int 2000;11(6):467-80
7. Blumsohn A, Eastell R. The performance and utility of biochemical markers of bone turnover: do we know enough to use them in clinical practice? Ann Clin Biochem 1997;34:449-59
8. Salamone LM, Pressman AR, Seeley DG, Cauley JA. Estrogen replacement therapy. Arch Intern Med 1996;156:1293-97
9. Miller PD, Bonnick SL, Johnston CC et al. The challenges of peripheral bone density measurements: Which patients need additional central density skeletal measurements? J Clin Densitometry 1998;1:211-17
10. National Osteoporosis Foundation. Physician's Guide to Diagnosis and Management of Osteoporosis. Bell Meade, NJ. Excerpta Medica 1998
11. American College of Rheumatology Task Force on Osteoporosis Guidelines. Recommendations for the prevention and treatment of glucocorticoid-induced osteoporosis. Arthritis Rheum 1996; 39:1791-1801
12. de Vernejoul M. Markers of bone remodeling in metabolic bone disease. Drugs Aging 1998;12 (suppl 1):9-14
13. Tanaka Y, Funahashi H, Imai T. Parathyroid function and bone metabolic markers in primary and secondary hyperparathyroidism. Semin Surg Oncol 1997;13:125-33
14. Lindsay R. Clinical utility of biochemical markers. Osteoporosis Int 1999(Suppl 2):S29-S32
15. Miller PD, Zapalowski C, Kulak CAM, Bilezikian JP. Bone densitometry: The best way to detect osteoporosis and to monitor therapy. J Clin Metab Endocrinol 1999;84:1867-71
16. Miller PD, Baran DT, Bilezikian JP et al. Practical application of biochemical markers of bone turnover.   Consensus of an expert panel. J Clin Densitometry 1999;2:323-42
17. Delmas PD, Eastell R, Garnero P et al. The use of biochemical markers of bone turnover in osteoporosis. Osteoporosis Int 2000(suppl 6):S2-S17
18. Bauer DC, Garnero P, Hochberg MC et al. Pretreatment levels of bone turnover and the antifracture efficacy of alendronate: the fracture intervention trial. J Bone Miner Res 2006;21:292-9
19. Shiraki M, Kuroda T, Tanaka S et al. Nonenzymatic collagen cross-links induced by glycoxidation (pentosidine) predicts vertebral fractures. J Bone Miner Metab 2008; 26(1):93-100
20. Välimäki MJ, Farrerons-Minguella J, Halse J et al. Effects of risedronate 5 mg/d on bone mineral density and bone turnover markers in late-postmenopausal women with osteopenia: a multinational, 24-month, randomized, double-blind, placebo-controlled, parallel-group, phase III trial. Clin Ther 2007; 29(9):1937-49
21. Abe Y, Ishikawa H, Fukao A. Higher efficacy of urinary bone resorption marker measurements in assessing response to treatment for osteoporosis in postmenopausal women. Tohoku J Exp Med 2008; 214(1):51-9
22. Camacho PM, Lopez NA. Use of biochemical markers of bone turnover in the management of postmenopausal osteoporosis. Clin Chem Lab Med. 2008;46(10):1345-57
23. Vasikaran SD. Utility of biochemical markers of bone turnover and bone mineral density in management of osteoporosis. Crit Rev Clin Lab Sci. 2008;45(2):221-58
24. Majima T, Shimatsu A, Satoh N, et al. Three-month changes in bone turnover markers and bone mineral density response to raloxifene in Japanese postmenopausal women with osteoporosis. J Bone Miner Metab. 2008;26(2):178-84
25. National Osteoporosis Foundation. Clinician's guide to prevention and treatment of osteoporosis. Accessible at: http://www.nof.org/professionals/NOF_Clinicians_Guide.pdf (verified 12/4/08)

Cross References

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