Bone physiology and biochemical markers of bone turnover
- Harold N Rosen, MD
Harold N Rosen, MD
- Assistant Professor in Medicine
- Harvard Medical School
In adults, bone is constantly being remodeled, first being torn down (bone resorption) and then being rebuilt (bone formation) [1,2]. The resorption and reformation of bone is important for repair of microfractures and to allow modification of structure in response to stress and other biomechanical forces. Bone formation is normally tightly coupled to bone resorption, so that bone mass does not change. Bone diseases occur when formation and resorption are uncoupled. (See "Normal skeletal development and regulation of bone formation and resorption".)
Changes in the rate of bone turnover are an important determinant of bone disease and, therefore, measurements that correlate with the rate of turnover provide important information in assessing patients with bone disease. In the past, the best way to measure bone turnover was to perform a bone biopsy after double-labeling with tetracycline [1,3]. This technique permits measurement of the rates of bone formation and bone resorption, and the fractions of bone surface at which active resorption and formation are ongoing. However, the complexity and expense of this procedure make it unsuitable for routine clinical practice.
As an alternative, several assays are currently available that measure bone turnover markers (BTMs) (table 1). These assays measure collagen breakdown products and other molecules released from osteoclasts and osteoblasts during the process of bone resorption and formation. Although the development of better assays has improved the ability of BTMs to reflect the rate of bone turnover, biologic and laboratory variability have confounded their widespread use in clinical practice.
This topic will review bone physiology and the measurement of bone turnover markers. The clinical utility of BTMs is reviewed separately. (See "Use of biochemical markers of bone turnover in osteoporosis" and "Investigational biologic markers in the diagnosis and assessment of rheumatoid arthritis" and "Clinical features, laboratory manifestations, and diagnosis of multiple myeloma".)
The steps involved in bone formation and resorption are described briefly here and in detail separately. (See "Normal skeletal development and regulation of bone formation and resorption".)
- Baim S, Miller PD. Assessing the clinical utility of serum CTX in postmenopausal osteoporosis and its use in predicting risk of osteonecrosis of the jaw. J Bone Miner Res 2009; 24:561.
- Calvo MS, Eyre DR, Gundberg CM. Molecular basis and clinical application of biological markers of bone turnover. Endocr Rev 1996; 17:333.
- Parfitt AM, Drezner MK, Glorieux FH, et al. Bone histomorphometry: standardization of nomenclature, symbols, and units. Report of the ASBMR Histomorphometry Nomenclature Committee. J Bone Miner Res 1987; 2:595.
- Scheven BA, Visser JW, Nijweide PJ. In vitro osteoclast generation from different bone marrow fractions, including a highly enriched haematopoietic stem cell population. Nature 1986; 321:79.
- Taylor AK, Lueken SA, Libanati C, Baylink DJ. Biochemical markers of bone turnover for the clinical assessment of bone metabolism. Rheum Dis Clin North Am 1994; 20:589.
- Hanson DA, Weis MA, Bollen AM, et al. A specific immunoassay for monitoring human bone resorption: quantitation of type I collagen cross-linked N-telopeptides in urine. J Bone Miner Res 1992; 7:1251.
- Garnero P, Gineyts E, Arbault P, et al. Different effects of bisphosphonate and estrogen therapy on free and peptide-bound bone cross-links excretion. J Bone Miner Res 1995; 10:641.
- Gomez B Jr, Ardakani S, Ju J, et al. Monoclonal antibody assay for measuring bone-specific alkaline phosphatase activity in serum. Clin Chem 1995; 41:1560.
- Horgan DJ, King NL, Kurth LB, Kuypers R. Collagen crosslinks and their relationship to the thermal properties of calf tendons. Arch Biochem Biophys 1990; 281:21.
- Eyre DR, Koob TJ, Van Ness KP. Quantitation of hydroxypyridinium crosslinks in collagen by high-performance liquid chromatography. Anal Biochem 1984; 137:380.
- Robins, SP. Collagen crosslinks in metabolic bone disease. Acta Orthop Scand 1995; 66:171.
- Eyre DR, Dickson IR, Van Ness K. Collagen cross-linking in human bone and articular cartilage. Age-related changes in the content of mature hydroxypyridinium residues. Biochem J 1988; 252:495.
- Christgau S, Rosenquist C, Alexandersen P, et al. Clinical evaluation of the Serum CrossLaps One Step ELISA, a new assay measuring the serum concentration of bone-derived degradation products of type I collagen C-telopeptides. Clin Chem 1998; 44:2290.
- Szulc P, Delmas PD. Biochemical markers of bone turnover in osteoporosis. In: Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism, Rosen CJ (Ed), ASBMR, 2008. p.174.
- Garnero P, Delmas PD. Assessment of the serum levels of bone alkaline phosphatase with a new immunoradiometric assay in patients with metabolic bone disease. J Clin Endocrinol Metab 1993; 77:1046.
- Hill CS, Wolfert RL. The preparation of monoclonal antibodies which react preferentially with human bone alkaline phosphatase and not liver alkaline phosphatase. Clin Chim Acta 1990; 186:315.
- Hannon R, Blumsohn A, Naylor K, Eastell R. Response of biochemical markers of bone turnover to hormone replacement therapy: impact of biological variability. J Bone Miner Res 1998; 13:1124.
- Eyre D. New biomarkers of bone resorption. J Clin Endocrinol Metab 1992; 74:470A.
- Rosen HN, Dresner-Pollak R, Moses AC, et al. Specificity of urinary excretion of cross-linked N-telopeptides of type I collagen as a marker of bone turnover. Calcif Tissue Int 1994; 54:26.
- Fink E, Cormier C, Steinmetz P, et al. Differences in the capacity of several biochemical bone markers to assess high bone turnover in early menopause and response to alendronate therapy. Osteoporos Int 2000; 11:295.
- Eastell R, Mallinak N, Weiss S, et al. Biological variability of serum and urinary N-telopeptides of type I collagen in postmenopausal women. J Bone Miner Res 2000; 15:594.
- Risteli J, Elomaa I, Niemi S, et al. Radioimmunoassay for the pyridinoline cross-linked carboxy-terminal telopeptide of type I collagen: a new serum marker of bone collagen degradation. Clin Chem 1993; 39:635.
- Garnero P, Gineyts E, Riou JP, Delmas PD. Assessment of bone resorption with a new marker of collagen degradation in patients with metabolic bone disease. J Clin Endocrinol Metab 1994; 79:780.
- Rosenquist C, Fledelius C, Christgau S, et al. Serum CrossLaps One Step ELISA. First application of monoclonal antibodies for measurement in serum of bone-related degradation products from C-terminal telopeptides of type I collagen. Clin Chem 1998; 44:2281.
- Glover SJ, Gall M, Schoenborn-Kellenberger O, et al. Establishing a reference interval for bone turnover markers in 637 healthy, young, premenopausal women from the United Kingdom, France, Belgium, and the United States. J Bone Miner Res 2009; 24:389.
- Melkko J, Kauppila S, Niemi S, et al. Immunoassay for intact amino-terminal propeptide of human type I procollagen. Clin Chem 1996; 42:947.
- Halleen JM, Alatalo SL, Suominen H, et al. Tartrate-resistant acid phosphatase 5b: a novel serum marker of bone resorption. J Bone Miner Res 2000; 15:1337.
- Scariano JK, Garry PJ, Montoya GD, et al. Critical differences in the serial measurement of three biochemical markers of bone turnover in the sera of pre- and postmenopausal women. Clin Biochem 2001; 34:639.
- Seibel MJ, Lang M, Geilenkeuser WJ. Interlaboratory variation of biochemical markers of bone turnover. Clin Chem 2001; 47:1443.
- de Papp AE, Bone HG, Caulfield MP, et al. A cross-sectional study of bone turnover markers in healthy premenopausal women. Bone 2007; 40:1222.
- Pagani F, Francucci CM, Moro L. Markers of bone turnover: biochemical and clinical perspectives. J Endocrinol Invest 2005; 28:8.
- Hannon R, Eastell R. Preanalytical variability of biochemical markers of bone turnover. Osteoporos Int 2000; 11 Suppl 6:S30.
- Hassager C, Risteli J, Risteli L, et al. Diurnal variation in serum markers of type I collagen synthesis and degradation in healthy premenopausal women. J Bone Miner Res 1992; 7:1307.
- Schlemmer A, Hassager C, Jensen SB, Christiansen C. Marked diurnal variation in urinary excretion of pyridinium cross-links in premenopausal women. J Clin Endocrinol Metab 1992; 74:476.
- Christgau S. Circadian variation in serum CrossLaps concentration is reduced in fasting individuals. Clin Chem 2000; 46:431.
- Bollen AM, Martin MD, Leroux BG, Eyre DR. Circadian variation in urinary excretion of bone collagen cross-links. J Bone Miner Res 1995; 10:1885.
- Glover SJ, Garnero P, Naylor K, et al. Establishing a reference range for bone turnover markers in young, healthy women. Bone 2008; 42:623.
- Adami S, Bianchi G, Brandi ML, et al. Determinants of bone turnover markers in healthy premenopausal women. Calcif Tissue Int 2008; 82:341.
- Gorai I, Taguchi Y, Chaki O, et al. Serum soluble interleukin-6 receptor and biochemical markers of bone metabolism show significant variations during the menstrual cycle. J Clin Endocrinol Metab 1998; 83:326.
- Garnero P, Sornay-Rendu E, Delmas PD. Decreased bone turnover in oral contraceptive users. Bone 1995; 16:499.
- Henriksen DB, Alexandersen P, Bjarnason NH, et al. Role of gastrointestinal hormones in postprandial reduction of bone resorption. J Bone Miner Res 2003; 18:2180.
- Woitge HW, Friedmann B, Suttner S, et al. Changes in bone turnover induced by aerobic and anaerobic exercise in young males. J Bone Miner Res 1998; 13:1797.
- Ivaska KK, Gerdhem P, Akesson K, et al. Effect of fracture on bone turnover markers: a longitudinal study comparing marker levels before and after injury in 113 elderly women. J Bone Miner Res 2007; 22:1155.
- Stoffel K, Engler H, Kuster M, Riesen W. Changes in biochemical markers after lower limb fractures. Clin Chem 2007; 53:131.
- Garnero P, Grimaux M, Seguin P, Delmas PD. Characterization of immunoreactive forms of human osteocalcin generated in vivo and in vitro. J Bone Miner Res 1994; 9:255.
- Uebelhart D, Schlemmer A, Johansen JS, et al. Effect of menopause and hormone replacement therapy on the urinary excretion of pyridinium cross-links. J Clin Endocrinol Metab 1991; 72:367.
- Weaver CM, Peacock M, Martin BR, et al. Quantification of biochemical markers of bone turnover by kinetic measures of bone formation and resorption in young healthy females. J Bone Miner Res 1997; 12:1714.
- Benker G, Breuer N, Windeck R, Reinwein D. Calcium metabolism in thyroid disease. J Endocrinol Invest 1988; 11:61.
- Delmas PD, Schlemmer A, Gineyts E, et al. Urinary excretion of pyridinoline crosslinks correlates with bone turnover measured on iliac crest biopsy in patients with vertebral osteoporosis. J Bone Miner Res 1991; 6:639.
- Eriksen EF, Charles P, Melsen F, et al. Serum markers of type I collagen formation and degradation in metabolic bone disease: correlation with bone histomorphometry. J Bone Miner Res 1993; 8:127.
- Parfitt AM, Simon LS, Villanueva AR, Krane SM. Procollagen type I carboxy-terminal extension peptide in serum as a marker of collagen biosynthesis in bone. Correlation with Iliac bone formation rates and comparison with total alkaline phosphatase. J Bone Miner Res 1987; 2:427.
- Cheung CK, Panesar NS, Haines C, et al. Immunoassay of a tartrate-resistant acid phosphatase in serum. Clin Chem 1995; 41:679.
- Ohishi T, Takahashi M, Kushida K, et al. Quantitative analyses of urinary pyridinoline and deoxypyridinoline excretion in patients with hyperthyroidism. Endocr Res 1992; 18:281.
- Seibel MJ, Gartenberg F, Silverberg SJ, et al. Urinary hydroxypyridinium cross-links of collagen in primary hyperparathyroidism. J Clin Endocrinol Metab 1992; 74:481.
- De la Piedra C, Díaz Martín MA, Díaz Diego EM, et al. Serum concentrations of carboxyterminal cross-linked telopeptide of type I collagen (ICTP), serum tartrate resistant acid phosphatase, and serum levels of intact parathyroid hormone in parathyroid hyperfunction. Scand J Clin Lab Invest 1994; 54:11.
- Hassager C, Colwell A, Assiri AM, et al. Effect of menopause and hormone replacement therapy on urinary excretion of pyridinium cross-links: a longitudinal and cross-sectional study. Clin Endocrinol (Oxf) 1992; 37:45.
- Bonde M, Qvist P, Fledelius C, et al. Applications of an enzyme immunoassay for a new marker of bone resorption (CrossLaps): follow-up on hormone replacement therapy and osteoporosis risk assessment. J Clin Endocrinol Metab 1995; 80:864.
- Randall AG, Kent GN, Garcia-Webb P, et al. Comparison of biochemical markers of bone turnover in Paget disease treated with pamidronate and a proposed model for the relationships between measurements of the different forms of pyridinoline cross-links. J Bone Miner Res 1996; 11:1176.
- Blumsohn A, Naylor KE, Assiri AM, Eastell R. Different responses of biochemical markers of bone resorption to bisphosphonate therapy in Paget disease. Clin Chem 1995; 41:1592.
- Alvarez L, Guañabens N, Peris P, et al. Discriminative value of biochemical markers of bone turnover in assessing the activity of Paget's disease. J Bone Miner Res 1995; 10:458.
- Nakayama K, Fukumoto S, Takeda S, et al. Differences in bone and vitamin D metabolism between primary hyperparathyroidism and malignancy-associated hypercalcemia. J Clin Endocrinol Metab 1996; 81:607.
- Abildgaard N, Nielsen JL, Heickendorff L. Connective tissue components in serum in multiple myeloma: analyses of propeptides of type I and type III procollagens, type I collagen telopeptide, and hyaluronan. Am J Hematol 1994; 46:173.
- Elomaa I, Virkkunen P, Risteli L, Risteli J. Serum concentration of the cross-linked carboxyterminal telopeptide of type I collagen (ICTP) is a useful prognostic indicator in multiple myeloma. Br J Cancer 1992; 66:337.
- Demers LM, Costa L, Chinchilli VM, et al. Biochemical markers of bone turnover in patients with metastatic bone disease. Clin Chem 1995; 41:1489.
- Body JJ, Delmas PD. Urinary pyridinium cross-links as markers of bone resorption in tumor-associated hypercalcemia. J Clin Endocrinol Metab 1992; 74:471.
- Cooper EH, Whelan P, Purves D. Bone alkaline phosphatase and prostate-specific antigen in the monitoring of prostate cancer. Prostate 1994; 25:236.
- Alvarez L, RicOs C, Peris P, et al. Components of biological variation of biochemical markers of bone turnover in Paget's bone disease. Bone 2000; 26:571.
- Alvarez L, Guañabens N, Peris P, et al. Usefulness of biochemical markers of bone turnover in assessing response to the treatment of Paget's disease. Bone 2001; 29:447.
- Greenspan SL, Resnick NM, Parker RA. 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. J Clin Endocrinol Metab 2005; 90:2762.
- BONE REMODELING
- Bone resorption
- Bone formation
- MARKERS OF BONE TURNOVER
- Assay variability
- Biologic variability
- Practical aspects of measurement
- VALIDATION OF MARKERS OF BONE TURNOVER
- Correlation of markers with histomorphometry and calcium kinetics
- Elevation of markers in conditions characterized by increased bone turnover
- Decline in markers after antiresorptive therapy
- SUMMARY AND RECOMMENDATIONS