Collagen Cross Links as Markers of Bone Turnover
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 that are measured in the serum or bone-resorption markers that are measured in the urine.
There are several types of markers that fall into two categories, each depending on the indices of the bone turnover process it is attempting to measure, as indicated below. Collagen cross links are markers of bone resorption. They bind 3 molecules of collagen in the bone and are released from the bone matrix after resorption. They may be detected using Pyr and dPyr or immunoassays (Pyr, D-Pyr, CTx, NTx).
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 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. 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.
POLICY
The use of collagen cross links as markers of bone turnover in the treatment of osteoporosis is considered investigational.
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ADDITIONAL INFORMATION
Available studies have not shown that the measurement of bone markers is effective in improving compliance nor in predicting clinical end points sufficiently well in individual patients. It is not known whether early changes in markers can predict the long-term changes in bone density with therapy.
SOURCES
Bergmann, P., Body, J. J., Boonen, S., Boutsenm Y., Devogelaer, J. P., Goemaere, S., et al. (2009). 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. International Journal of Clinical Practice, 63 (1), 19-26.
BlueCross BlueShield Association. Medical Policy Reference Manual. (9:2009). Bone turnover markers for diagnosis and management of osteoporosis (2.04.15). Retrieved March 19, 2010 from BlueWeb. (14 articles and/or guidelines reviewed)
Carrasco, R., Lovell, D. J., Giannini, E. H., Henderson, C. J., Huang, B., Kramer, S., et al. (2008). Biochemical markers of bone turnover associated with calcium supplementation in children with juvenile rheumatoid arthritis: Results of a double-blind, placebo-controlled intervention trial. Arthritis and Rheumatism, 58 (12), 3932-3940. (Level 1 Evidence - Independent study)
Complete Guide to Medicare Coverage Issues [Computer software]. (2009, November). Collagen crosslinks, any method (NCD 190.19, p. 2-118, 2-119, 2-120). The Ingenix Complete Guide to Medicare Coverage Issues.
Garnero, P. (2008). Biomarkers for osteoporosis management: utility in diagnosis, fracture risk prediction and therapy monitoring. Molecular Diagnosis & Therapy, 12 (3), 157-170.
Greenspan, S. L., Resnick, N. M., & Parker, R. A. (2005). Early changes in biochemical markers of bone turnover are associated with long-term changes in bone mineral density in elderly women on Alendronate, hormone replacement therapy, or combination therapy: A three-year, double-blind, placebo-controlled, randomized clinical trial. The Journal of Clinical Endocrinology & Metabolism. 90 (5), 2762-2767. (Level 1 Evidence - Industry sponsored)
Hodgson, S. F., Watts, N. B., Bilezilian, J. P., Clarke, B. L., Gray, T. K., Harris, D. W., et al. (2003). American Association of Clinical Endocrinologists medical guidelines for clinical practice for the prevention and treatment of postmenopausal osteoporosis: 2001 edition, with selected updates for 2003. Endocrine Practice, 9 (6), 544-564.
Ivaska, K. K., Lenora, J., Gerdhem, P., Akesson, K., Vaananen, H. K., & Obrant, K. J. (2008). Serial assessment of serum bone metabolism markers identifies women with the highest rate of bone loss and osteoporosis risk. The Journal of Clinical Endocrinology and Metabolism, 93 (7), 2622-2632. (Level 2 Evidence - Industry sponsored)
Kraenzlin, M. E., Kraenzlin, C. A., Meier, C., Giunta, C., & Steinmann, B. (2008). Automated HPLC assay for urinary collagen cross-links: Effect of age, menopause, and metabolic bone diseases. Clinical Chemistry, 54 (9), 1546-1553. (Level 3 Evidence - Independent study)
Leder, B. Z., Araujo, A. B., Travison, T. G., & McKinlay, J. B. (2007). Racial and ethic differences in bone turnover markers in men. The Journal of Clinical Endocrinology and Metabolism, 92 (9), 3453-3457. (Level 2 Evidence - Independent study)
National Guideline Clearinghouse. (2006, February). Management of osteoporosis in postmenopausal women: 2006 position statement of The North American Menopause Society. Retrieved March 22, 2010 from http://www.guidelines.gov.
National Guideline Clearinghouse. (2008, November). Osteoporosis/fractures prevention clinical practice guidelines. Retrieved March 22, 2010 from http://www.guidelines.gov.
National Guideline Clearinghouse. (2008, September). Diagnosis and treatment of osteoporosis. Retrieved March 22, 2010 from http://www.guidelines.gov.
National Osteoporosis Foundation. (2010, January). Clinician’s guide to prevention and treatment of osteoporosis. Retrieved March 22, 2010 from http://www.nof.org/professionals/pdfs/NOF_ClinicianGuide2009_v7.pdf.
Reiter, A. L., Volk, A., Vollmar, J., Fromm, B., & Gerner, H. J. (2007). Changes of basic bone turnover parameters in short-term and long-term patients with spinal cord injury. European Spine Journal, 16 (6), 771-776. (Level 3 Evidence - Independent study)
Schousboe, J. T., Bauer, D. C., Nyman, J. A., Kane, R. L., Melton, L. J., & Ensrud, K. E. (2007). Potential for bone turnover markers to cost-effectively identify and select post-menopausal osteopenic women at high risk of fracture for bisphosphonate therapy. Osteoporosis International, 18 (2), 201-210.
Seibel, M. J. (2006). Biochemical markers of bone turnover part II: Clinical applications in the management of osteoporosis. The Clinical Biochemist. Reviews/Australian Association of Clinical Biochemists, 27 (3), 123-138.
ORIGINAL EFFECTIVE DATE: 1/13/2007
MOST RECENT REVIEW DATE: 4/8/2010
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