Laboratory aspects and clinical significance of bone turnover markers
Ключові слова:
diagnostics, bone metabolism, bone formation, bone resorption, biomarkers of bone tissue, biochemical markers of bone metabolismАнотація
Introduction. With an aging population, there is a marked increase in prevalence of metabolic bone diseases, especially osteoporosis. A serious complication of osteoporosis is non-traumatic bone fractures, which significantly impair quality of life and are associated with comorbid conditions and high mortality. Diseases associated with impaired bone remodeling require timely diagnosis, treatment and monitoring. The consequent public health and socioeconomic burden warrant timely diagnosis, treatment and follow-up of these disorders. Knowing the limitations of radiological techniques, biochemical markers of bone turnover measurements come handy since the changes in their levels readily reflect bone physiology. Material and methods. This paper presents a literature review concerning bone turnover biomarkers with the aim of providing comprehensive information on the applicability of these biomarkers for clinical use. A literature search was conducted in the PubMed, MedLine, Scopus and Embase databases from 1987–2019. Keywords used for search: bone turnover, bone formation, bone resorption, bone biomarkers, biochemical markers of bone turnover. We aimed to determine the clinical effectiveness, test accuracy, reliability, reproducibility and cost-effectiveness of bone turnover markers for monitoring the response to osteoporosis treatment, predicting bone loss and fracture risk, diagnostic of osteoporosis, Paget’s disease, renal osteodystrophy, and certain oncological conditions and rheumatic diseases. Results and discussion. Bone turnover markers are a series of protein or protein derivative biomarkers released during bone remodeling by osteoblasts or osteoclasts. Bone biomarkers typically analyzed in high throughput automated routine laboratories are collagen degradation products, reflecting osteoclast activity and collagenous or non-collagenous proteins produced by the osteoblasts. All these markers can be quantitated well from blood samples, serum being the preferred sample of choice. Although assays for urine examination were developed for quite a few markers, blood sampling generally detours the pre-analytic issues usually involving urine sampling. The most commonly used bone resorption and bone formation markers are discussed in this article. Biochemical markers of bone resorption are mainly different fragments of type I collagen, as well as non-collagen proteins that enter the circulation from the bone matrix resorption zone. The main biochemical indicators used in clinical practice as a criterion for bone tissue resorption are pyridinoline, deoxypyridinoline, tartrate-resistant acid phosphatase, and degradation products of type I collagen - C- and N-terminal telopeptide. All the afore mentioned markers have since been superseded by the more sensitive and specific telopeptides of type I collagen, namely the C-terminal telopeptide (CTx). As compared to the bone resorption biomarkers, there is a larger repertoire of biomarkers of bone formation, reflecting osteoblast activity, namely serum bone-specific alkaline phosphatase, osteocalcin and procollagen type I N-terminal propeptide (PINP). Although produced by the osteoblasts, osteocalcin may be defined as a bone turnover marker reflecting both bone formation and bone resorption, since it is also released from the bone matrix during bone resorption. PINP is more extensively described in literature are compared to the other bone formation biomarkers. Conclusion. Biochemical markers of bone turnover reflect bone homeostasis, i.e., the activity of osteoblasts and osteoclasts in both physiological and pathophysiological conditions. Although quite sensitive to a multitude of exogenous and endogenous pre-analytical factors, bone markers are best used in monitoring anti-osteoporosis therapy efficacy and compliance. Combination of bone mineral density measurement by dual energy x-ray absorptiometry with biochemical markers of bone turnover levels, at least one bone resorption and one bone formation marker, may potentially improve early detection of individuals at increased risk for bone loss and eventually non-traumatic bone fracture. Furthermore, they have widespread clinical utility in osteoporosis, renal osteodystrophy, certain oncological conditions and rheumatic diseases.
Посилання
Boyle WJ, Simonet WS, Lacey DL. Osteoclast differentiation and activation. // Nature. 2003.Vol.423. N 6937. P. 337-342. DOI:10.1038/nature01658
Szulc P, Bauer DC, Eastell R. Biochemical markers of bone turnover in Osteoporosis. In Primer on the metabolic bone diseases and disorders of mineral metabolism 8th edition. Ed. Rosen CJ. //American Society of Bone and Mineral Research, Washington DC, USA. 2013. pp. 297-306.
Hans D, Goertzen AL, Krieg MA, Leslie WD. Bone microarchitecture assessed by TBS predicts osteoporotic fractures independent of bone density: the Manitoba study. // J Bone Miner Res. 2011. Vol. 26. P. 2762–2769. doi: 10.1002/jbmr.499.
Kanis JA, Johnell O, Oden A, Johansson H, McCloskey E. FRAXTM and the assessment of fracture probability in men and women from the UK. // Osteoporosis International. 2008. Vol. 19. P. 385-397. doi: 10.1007/s00198-007-0543-5.
Devogelaer JP, Boutsen Y, Gruson D, Manicourt D. Is there a place for bone turnover markers in the assessment of osteoporosis and its treatment? // Rheum Dis Clin North Am. 2011. Vol. 37. N 3. P. 365-386. doi: 10.1016/j.rdc.2011.07.002.
Vervloet MG, Brandenburg VM; CKD-MBD working group of ERA-EDTA. Circulating markers of bone turnover. // J Nephrol. 2017. Vol.30. N5. P.663-670. doi: 10.1007/s40620-017-0408-8
Ott SM. Histomorphometric measurements of bone turnover, mineralization, and volume. // Clin J Am Soc Nephrol 2008. Vol. 3. N 3. P.151–156. doi: 10.2215/CJN. 04301206.
Wheater G, Elshahaly M, Tuck SP, Datta HK, van Laar JM. The clinical utility of bone marker measurements in osteoporosis. // J Transl Med. 2013. Vol. 11. P. 201. doi: 10.1186/1479-5876-11-201.
Halleen JM, Alatalo SL, Suominen H, Cheng S, Janckila AJ, Vaananen HK. Tartrate-resistant acid phosphatase 5b: a novel serum marker of bone resorption // J. Bone Miner. Res. 2000. Vol. 15. P. 1337–1345. DOI:10.1359/jbmr.2000.15.7.1337
Halleen JM, Karp M, Viloma S, et al. Two-site immunoassays for osteoclastic tartrate-resistant acid phosphatase based on characterisation of six monoclonal antibodies // J. Bone Miner. Res. 1999. Vol. 14. P. 464–469.
Pobel EA, Bengus LM, Dedukh NV. Bone metabolism markers with fusion of long bone fractures. // Osteoporosis and osteopathy number. 2012. Vol. 2. P. 25-32.
Eastell R, Colwell A, Hampton L, Reeve J. Biochemical markers of bone resorption compared with estimates of bone resorption from radiotracer kinetic studies in osteoporosis // J. Bone Miner. Res. 1997. Vol. 12. N 1. P.59–65.
Garnero P, Ferreras M, Karsdal MA, [et al.] The type I collagen fragments ICTP and CTX reveal distinct enzymatic pathways of bone collagen degradation. // J Bone Miner Res. 2003. Vol. 18. P. 859–67. DOI:10.1359/jbmr.2003.18.5.859
Kamel S, Brazier M, Neri V, [et al.] Multiple molecular forms of pyridinolines cross-links excreted in human urine evaluated by chromatographic and immunoassay methods. // J Bone Miner Res. 1995. Vol. 10. P. 1385–92.
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. Vol. 11. P. 1176–84.
Douglas C. Bauer, Clinical Use of Bone Turnover Markers. // JAMA. 2019.
doi:10.1001/jama.2019.9372. [Epub ahead of print].
Hlaing TT, Compston JE. Biochemical markers of bone turnover - uses and limitations. // Ann Clin Biochem. 2014. Vol. 51. N 2. P. 189-202. doi: 10.1177/0004563213515190
Greenblatt MB, Tsai JN, Wein MN. Bone Turnover Markers in the Diagnosis and Monitoring of Metabolic Bone Disease. // Clin Chem. 2017. Vol. 63. N 2. P. 464–474. doi: 10.1373/clinchem.2016.259085
Zimmermann EA, Busse B, Ritchie RO. The fracture mechanics of human bone: influence of disease and treatment. // Bonekey Rep. 2015. Vol. 4. P. 743. doi: 10.1038/bonekey.2015.112.
Vasikaran SD, Chubb SP, Ebeling PR, [et al.] Harmonised Australian reference intervals for serum PINP and CTX in adults. Clin Biochem Rev. 2014. Vol.35. N 4. P. 237–242.
Wallace JM, Erickson B, Les MC, Orr BG, Banaszak Holl M. Distribution of Type I Collagen Morphologies in Bone: Relation to Estrogen Depletion. // Bone. 2010. Vol.46. N 5. P. 1349–1354. doi: 10.1016/j.bone.2009.11.020
Сoulibaly MO, Sietsema DL, Burgers TA, Mason J, Williams BO, Jones CB. Recent advances in the use of serological bone formation markers to monitor callus development and fracture healing. // Crit Rev Eukaryot Gene Expr. 2010. Vol. 20, N 2. P. 105–127.
Han B, Copeland M, Geiser AG, [et al.] Development of a highly sensitive, high-throughput, mass spectrometry-based assay for rat procollagen type-I N-terminal propeptide (PINP) to measure bone formation activity // J. Proteome Res. 2007. Vol.6. N 11. P. 4218–4229.
Adami S, Gatti D, Viapiana O, [et al.]. Physical activity and bone turnover markers: a cross-sectional and a longitudinal study. // Calcif. Tissue Int. 2008. Vol. 83. N 6. P. 388–392.
Watts NB, Miller PD, Kohlmeier LA, Sebba A, Chen P, Wong M, Krohn K. Vertebral fracture risk is reduced in women who lose femoral neck BMD with teriparatide treatment // J. Bone Miner Res. 2009. Vol. 24, N 6. P. 1125–1131.
Lein M, Miller K, Wirth M, [et al.] Bone turnover markers as predictive tools for skeletal complications in men with metastatic prostate cancer treated with zoledronic acid // Prostate. 2009. Vol. 69, N 6. P. 624–632.
Seibel MJ. Biochemical markers of bone turnover: part I: biochemistry and variability. // Clin Biochem Rev. 2005. Vol. 26. N 4. P. 97-122.
Price PA, Lothringer JW, Baukol SA, Hari Reddi A. Developmental appearance of the vitamin K-dependent protein of bone during calcification. Analysis of mineralizing tissues in human, calf, and rat. // J Biol Chem. 1981. Vol. 256. P. 3781–3784.
Oury F, Sumara G, Sumara O, [et al.] Endocrine regulation of male fertility by the skeleton. // Cell. 2011. Vol. 144. P. 796–809. doi: 10.1016/j.cell.2011.02.004
Oury F, Khrimian L, Denny CA, [et al.] Maternal and offspring pools of osteocalcin influence brain development and functions. // Cell. 2013. Vol. 155. P. 228–241. doi: 10.1016/j.cell.2013.08.042.
Ferron M, Wei J, Yoshizawa T, [et al.] Insulin signaling in osteoblasts integrates bone remodeling and energy metabolism. // Cell. 2010. Vol. 142. P. 296–308. doi: 10.1016/j.cell.2010.06.003
Wei J, Karsenty G. An overview of the metabolic functions of osteocalcin. // Rev Endocr Metab Disord. 2015. Vol. 16. N 2. P. 93–98. doi: 10.1007/s11154-014-9307-7
Rosenquist C, Qvist P, Bjarnason N, Christiansen C. Measurement of a more stable region of osteocalcin in serum by ELISA with two monoclonal antibodies. // Clin Chem. 1995. Vol. 41. P. 1439–1445.
Burch J, Rice S, Yang H, et al. Systematic review of the use of bone turnover markers for monitoring the response to osteoporosis treatment: the secondary prevention of fractures, and primary prevention of fractures in high-risk groups. // Health Technol Assess. 2014. Vol. 18. N 11. P. 1-180. doi:10.3310/hta18110
Magnusson P, Sharp CA, Magnusson M, [et al.] Effect of chronic renal failure on bone turnover and bone alkaline phosphatase isoforms. // Kidney Int. 2001. Vol. 60. N 1. P. 257–265. DOI:10.1046/j.1523-1755.2001.00794.x
Johnson KA, Hessle L, Vaingankar S, [et al.] Osteoblast tissue-nonspecific alkaline phosphatase antagonizes and regulates PC-1. // Am J Physiol. 2000. Vol. 279. N 4. P. 1365-1377. DOI:10.1152/ajpregu.2000.279.4.R1365
Singer FR, Eyre DR. Using biochemical markers of bone turnover in clinical practice // Cleveland Clinic Journal of Medicine. 2008. Vol. 75. N 10. P. 739–750.
Maruyama Y, Taniguchi M, Kazama JJ, [et al.] A higher serum alkaline phosphatase is associated with the incidence of hip fracture and mortality among patients receiving hemodialysis in Japan. // Nephrol Dial Transplant. 2014. Vol. 29. N 8. P. 1532–1538. doi: 10.1093/ndt/gfu055
Bhattoa HP. Laboratory aspects and clinical utility of bone turnover markers. // EJIFCC. 2018. Vol. 29. N 2. P. 117–128.
Clinical and Laboratory Standards Institute (CLSI; formerly NCCLS). Urinalysis and Collection, Transportation, and Preservation of Urine Specimens; Approved Guideline – Second Edition. 2001. Vol. 21. N. 19. Document GP-16A2.
More C, Bhattoa HP, Bettembuk P, Balogh A. The effects of pregnancy and lactation on hormonal status and biochemical markers of bone turnover. // Eur J Obstet Gynecol Reprod Biol. 2003. Vol. 106. N 2. P. 209-213.
Veitch SW, Findlay SC, Hamer AJ, [et al.] Changes in bone mass and bone turnover following tibial shaft fracture. // Osteoporos Int. 2006. Vol. 17. P. 364–372 DOI:10.1007/s00198-005-2025-y
Brown JE, Sim S. Evolving role of bone biomarkers in castration-resistant prostate cancer. // Neoplasia. 2010. Vol. 12. P. 685–696.
Seibel MJ. Clinical use of markers of bone turnover in metastatic bone disease. // Nat Clin Pract Oncol. 2005. Vol. 2. P. 504–517. DOI:10.1038/ncponc0320
Malmgren L, McGuigan F, Christensson A, Akesson KE. Reduced kidney function is associated with BMD, bone loss and markers of mineral homeostasis in older women: a 10-year longitudinal study. // Osteoporos Int. 2017. Vol. 28. N 12. P. 3463-3473. doi: 10.1007/s00198-017-4221-y
Zittermann A, Schwarz I, Scheld K, [et al.] Physiologic fluctuations of serum estradiol levels influence biochemical markers of bone resorption in young women. J Clin Endocrinol Metab. 2000. Vol. 85. N 1. P. 95-101. DOI:10.1210/jcem.85.1.6250
Woitge HW, Scheidt-Nave C, Kissling C, [et al.] Seasonal variation of biochemical indexes of bone turnover: results of a population-based study. // J Clin Endocrinol Metab. 1998. Vol. 83. N 1. P. 68-75.
Gombos Császár G, Bajsz V, Sió E, [et al.] The direct effect of specific training and walking on bone metabolic markers in young adults with peak bone mass. // Acta Physiol Hung. 2014. Vol. 101. P. 205–215. doi: 10.1556/APhysiol.101.2014.001.
Lombardi G, Lanteri P, Colombini A, Banfi G. Blood biochemical markers of bone turnover: pre-analytical and technical aspects of sample collection and handling. // Clin Chem Lab Med. 2012. Vol. 50. N 5. P. 771-789. doi: 10.1515/cclm-2011-0614.
Hannon R, Eastell R. Preanalytical variability of biochemical markers of bone turnover. // Osteoporos Int. 2000. Vol. 11. N 6. P. 30–44.
Glover SJ, Garnero P, Naylor K, Rogers A, Eastell R. Establishing a reference range for bone turnover markers in young, healthy women. // Bone. 2008. Vol. 42. P. 623–630. doi: 10.1016/j.bone.2007.12.218
Kunishige M, Kijima Y, Sakai T, [et al.] Transient enhancement of oxidant stress and collagen turnover in patients with acute worsening of congestive heart failure. // Circ J. 2007. Vol. 71. P. 1893–1897.
Vasikaran S, Eastell R, Bruyere O, [et al.] IOF-IFCC Bone Marker Standards Working Group. Markers of bone turnover for the prediction of fracture risk and monitoring of osteoporosis treatment: a need for international reference standards. // Osteoporos Int. 2011. Vol. 22. N 2. P. 391-420. doi:10.1007/s00198-010-1501-1
Schafer AL, Vittinghoff E, Ramachandran R, Mahmoudi N, Bauer DC. Laboratory reproducibility of biochemical markers of bone turnover in clinical practice. // Osteoporos Int. 2010. Vol. 21. N 3. P. 439-445. doi:10.1007/s00198-009-0974-2
Garnero P, Sornay-Rendu E, Chapuy MC, [et al.] Increased bone turnover in late postmenopausal women is a major determinant of osteoporosis. // J Bone Miner Res. 1996. Vol.11. P. 337–349.
Johansson H, Odn A, Kanis JA, [et al.] IFCC-IOF JointWorking Group on Standardisation of Biochemical Markers of Bone Turnover. Ameta-analysis of reference markers of bone turnover for prediction of fracture. // Calcif Tissue Int. 2014. Vol. 94. N 5. P. 560-567. doi:10.1007/s00223-014-9842-y
Burch J, Rice S, Yang H, [et al.] Systematic review of the use of bone turnover markers for monitoring the response to osteoporosis treatment: the secondary prevention of fractures, and primary prevention of fractures in high-risk groups. // Health Technol Assess. 2014. Vol.18. P. 1–180. doi: 10.3310/hta18110
Eastell R, Szulc P. Use of bone turnover markers in postmenopausal osteoporosis. // Lancet Diabetes Endocrinol. 2017. Vol. 5. N 11. P. 908-923. doi:10.1016/S2213-8587(17)30184-5
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. Vol. 21. N 2. P. 292–299. DOI:10.1359/JBMR.051018
Black DM, Delmas PD, Eastell R, [et al.] Once-yearly zoledronic acid for treatment of postmenopausal osteoporosis. // N Engl J Med. 2007. Vol. 356. P. 1809–1822.
Cummings SR, San MJ, McClung MR, [et al.] Denosumab for prevention of fractures in postmenopausal women with osteoporosis. // N Engl J Med. 2009. Vol. 361. P. 756–765. doi: 10.1056/NEJMoa0809493.
Glover SJ, Eastell R, McCloskey EV, [et al.] Rapid and robust response of biochemical markers of bone formation to teriparatide therapy. // Bone. 2009. Vol. 45. N 6. P. 1053–1058. doi: 10.1016/j.bone.2009.07.091.
Clowes JA, Peel NF, Eastell R. The impact of monitoring on adherence and persistence with antiresorptive treatment for postmenopausal osteoporosis: a randomized controlled trial. // J Clin Endocrinol Metab. 2004. Vol. 89. N 3. P. 1117–1123. DOI: 10.1210/jc.2003-030501
Delmas PD, Vrijens B, Eastell R, [et al.] Effect of monitoring bone turnover markers on persistence with risedronate treatment of postmenopausal osteoporosis. // J Clin Endocrinol Metab. 2007. Vol. 92. N 4. P. 1296–1304. DOI:10.1210/jc.2006-1526
Sarkar S, Reginster J-Y, Crans GG, [et al.] Relationship between changes in biochemical markers of bone turnover and BMD to predict vertebral fracture risk. // J Bone Miner Res. 2004. Vol. 19. N 3. P. 394–40. DOI:10.1359/JBMR.0301243
Jacques RM, Boonen S, Cosman F, [et al.] Relationship of changes in total hip bone mineral density to vertebral and nonvertebral fracture risk in women with postmenopausal osteoporosis treated with once-yearly zoledronic acid 5 mg: the HORIZON-Pivotal Fracture Trial (PFT). // J Bone Miner Res. 2012. Vol. 27. N 8. P. 1627–1634. doi: 10.1002/jbmr.1644.
Garrett G, Sardiwal S, Lamb EJ, Goldsmith DJA. PTH–a particularly tricky hormone: why measure it at all in kidney patients? // Clin J Am Soc Nephrol. 2013. Vol. 8. N 2. P. 299–312. doi: 10.2215/CJN.09580911
Coleman R, Costa L, Saad F, [et al.] Consensus on the utility of bone markers in the malignant bone disease setting. // Crit Rev Oncol Hematol. 2011. Vol. 80. N 3. P. 411–432. doi: 10.1016/j.critrevonc.2011.02.005
Confavreux CB, Borel O, Lee F, [et al.] Osteoid osteoma is an osteocalcinoma affecting glucose metabolism. // Osteoporos Int. 2012. Vol. 23. N 5. P. 1645–1650. doi: 10.1007/s00198-011-1684-0
Wang J, Pei F, Tu C, Zhang H, Qiu X. Serum bone turnover markers in patients with primary bone tumors. // Oncology. 2007. Vol. 72. N 5-6. P. 338–342. doi: 10.1159/000113063
Barnes TC, Daroszewska A, Fraser WD, Bucknall RC. Bone turnover in untreated polymyalgia rheumatica. // Rheumatology. 2004. Vol. 43. N 4. P. 486–490. DOI:10.1093/rheumatology/keh072
Krabben A, Knevel R, Huizinga TWJ, [et al.] Serum pyridinoline levels and prediction of severity of joint destruction in rheumatoid arthritis. // J Rheumatol. 2013. Vol. 40. N 8. P. 1303–1306. doi: 10.3899/jrheum.121392.
Al Nofal AA, Altayar O, BenKhadra K, [et al.] Bone turnover markers in Paget’s disease of the bone: a systematic review and meta-analysis. // Osteoporos Int. 2015. Vol. 26. N 7. P. 1875–1891. doi: 10.1007/s00198-015-3095-0
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