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2014 11 20 11 Chin J Osteoporos November 2014 Vol 20 No. 11 Published online www. wanfangdate. com. cn doi 10. 3969 /j. issn. 1006-7108. 2014. 11. 001 1263 * 张萌萌 130011 R681 A 1006-7108 2014 11-1263-10 " " Bone metabolism biochemical markers calcium and phosphorus metabolism indicator Parathyroid hormone PTH Calcitonin CT D 3 vitamin D 3 VD 3 25- D 3 25- hydroxy vitamin D 3 25 OH D 3 1 25- D 3 1 25 - dihydroxy vitamin D 3 1 25- OH 2 D 3 calcium phosphorus bone resorption markers tartra-resistant acid phosphatase TRACP I Type I collagen carboxy- terminal peptide CTX I Type I collagen amino- terminal peptide NTX pyridinoline Pyr deoxy- pyridinoline D-Pyr I Urinary type I collagen carboxy- terminal peptide U-CTX I Urinary type I collagen amino- terminal peptide U-NTX 2 /Ca /Cr bone formation markers Alkaline phosphatase ALP Bone specific alkaline phosphatase BALP Osteocalcin OC Bone Glaprotein BGP I Type I procollagen carboxyl- terminal peptide PICP I Type I procollagen amino-terminal peptide PINP Osteoprotegerin OPG * Email zhmm5866@ 163. com

1264 2014 11 20 11 Chin J Osteoporos November 2014 Vol 20 No. 11 Expert consensus of clinical application of the bone metabolic and biochemical markers by Oste oporosis Committe e of Chine se Ge rontological Socie ty ZHANG Mengmeng Diagnosis and Treatment Center of Osteoporosis in Jilin Province the Fourth Hospital of Jilin University Changchun 130011 China Corresponding author ZHANG Mengmeng Email zhmm5866@ 163. com Abstract The bone metabolic and biochemical markers include calcium and phosphorus metabolic indicators bone resorption markers and bone formation markers. The bone metabolic and biochemical markers are derived from the bone cartilage soft tissue skin liver kidney small intestine blood endocrine glands etc. They are enzymes and hormones secreted by osteoblasts or osteoclasts and the metabolic products of collagen or non-collagen proteins from bone matrix. The bone metabolic and biochemical markers reflect the status of bone turnover promptly w ith high sensitivity and specificity. They have been used in osteoporosis diagnosis prediction of fracture risk curative effect observation of drug treatment and the differential diagnosis of metabolic bone disease. They have important application value in the research of the pathogenesis of osteoporosis drugs for treatment of osteoporosis and the epidemiological study. The clinical use of the bone metabolic and biochemical markers is getting popular due to the mature of the detection technology. How ever the test results vary because of different source of the specimen different methods different equipment different reagents different ages different races and different gender. So far there is no unified detection standard of bone metabolic and biochemical markers in the w orld. Therefore w e collect and summarize the biological role and clinical significance of bone metabolic and biochemical markers application technology and quality control in this paper in order to provide a readable applicable and w ell referred material to colleagues. We look forw ard to promoting the detection technology for bone metabolic and biochemical markers in clinic standardizing detection process and establishing scientific reference range through the consensus so that the bone metabolic and biochemical markers can play an important role in the standardization of osteoporosis diagnosis and treatment anti-osteoporosis drug efficacy evaluation and scientific research. 1 Bone metabolism biochemical indicators 2 1 3 4 1 ELISA CLIA ECLIA RIA 1 IRMA HPLC Table 1 Classification of bone metabolic and biochemical markers PTH CT 25- OH D 3 1 25- OH 2 D 3 Ca P TRACP CTX NTX Pyr D-Pyr U-CTX U-NTX 2h Ca /Cr ALP BALP BGP PINP PICP OPG

2014 11 20 11 Chin J Osteoporos November 2014 Vol 20 No. 11 1265 CT 2 2. 1 calcium and phosphorus metabolism indicator Table 2 2 Classification of calcium and phosphorus metabolic indicators parathyroid hormone PTH calcitonin CT D 3 vitamin D 3 VD 3 calcium Ca phosphorus P 2. 1. 1 Parathyroid hormone PTH D 3 1 25 - dihydroxy vitamin D 3 1 25-84 OH 2 D 3 D VDR 1 25- OH 2 D 3 PTH 6 PTH Ca 2 + OC D OC 7 IGF-1 PTH PTH 2 PTH 25- OH D 3 21 D 3 PTH 1 25- OH 2 D 3 3 25- OH D 3 D 3 2. 1. 2 Calcitonin CT D parafollicular cells C 32 PTH PTH Ⅰ 4 2. 1. 4 Serum Calcium 99% 1% PTH CT CT 2. 1. 3 D 3 vitamin D 3 VD 3 25- hydroxy vitamin D 3 25 OH D 3 1 25 - dihydroxy vitamin D 3 1 25- OH 2 D 3 D 3 VD 3 5 VD 3 25-25 -hydroxy vitamin D 3 25 OH D 3 1a 1 25-1 25- OH 2 D 3 4 ~ 6 CT 50% D 3

1266 2014 11 20 11 Chin J Osteoporos November 2014 Vol 20 No. 11 3 Table 3 The normal reference values of calcium and ph phosphorus metabolic indicators D PTH 15 ~ 65 pg /ml ECLIA 3 2. 1. 5 Serum phosphorus 2. 2 bone resorption markers 2. 2. 1 tartra-resistant acid Na 2 HPO 4 NaH 2 PO 4 CaHPO 4 MgHPO 4 phosphatase TRACP 6 2 HPO - 4 / Gaucher H 2 PO - 4 TRACP OC TRACP 19 P13. 2 ~ 13. 3 30 ~ 40kD TRACP 85% ~ 95% D CT 0. 00 ~ 6. 40 pg /ml 0. 00 ~ 9. 52 pg /ml ECLIA ECLIA 25- OH D 3 10 ~ 30 ng /ml ECLIA Ca 2. 15 ~ 2. 55 mmol /L P 0. 87 ~ 1. 45 mmol /L PTH. Parathyroid hormone CT. Calcitonin 25- OH D 3. 25 - dihy droxyvitamin D 3 25 D 3 Ca. calciump. phosphoruseclia. Table 4 4 Classification of bone resorption markers Tartrate resistant acid phosphatase TRACP I Type I collagen carboxy-terminal peptide CTX I Type I collagen amino-terminal peptide NTX Urinary pyridinoline Pyr Urinary deoxypyridinoline D-Pyr I Urinary type I collagen carboxy-terminal peptide U-CTX I Urinary type I collagen amino-terminal peptide U-NTX 2 / Ca /Cr TRACP TRACP-5b 8 TRACP-5b 4 2. 2. 2 I Type I collagen Paget s carboxy-terminal peptide CTX I

2014 11 20 11 Chin J Osteoporos November 2014 Vol 20 No. 11 1267 90% I CTX NTX α2 Ⅰ 3 α2 Ⅰ MMP CTX-MMP CTX α2 Ⅰ 8 α-ctx β- CTX CTX- Ⅰ NTX MMP Pyr D- Pyr 3 C 1 Ⅰ C α1 Ⅰ 13 1 Ⅰ C α1 Ⅰ α2 NTX 14 Ⅰ α-ctx β- CTX 2. 2. 4 pyridinoline Pyr CrossLaps CTX 1000Da deoxypyridinoline D-Pyr Pyr 3- CTX CTX Hydroxylysyl pyridinoline HP D-Pyr Paget s Lysyl pyridinoline HP CTX 9-11 429. 37 413. 34 Pyr D-Pyr I Pyr D- 12 Pyr NTX CTX 2. 2. 3 I Type I collagen aminoterminal peptide NTX NTX Pyr Pyr D-Pyr Ⅰ D-Pyr Ⅰ D-Pyr NTX 3-2 N- 1 1 Pyr D-Pyr Pyr D-Pyr NTX 40% 60% NTX /Cr BMD Pyr D-Pyr 4 1 Table 5 5 The normal reference values of bone resorption makers Pyr D-Pyr CTX NTX TRACP-5b 19. 5 ~ 25. 1 nmol /mmol Cr HPLC /ELISA 1. 8 ~ 15. 5 nmol /mmol Cr HPLC /ELISA 3. 9 ~ 4. 9nmol /mmol Cr 0. 29 ± 0. 14 μg /L 0. 56 ± 0. 23 μg /L 0. 30 ± 0. 14 μg /L 5 ~ 65nmol BCE /mmol Cr 3 ~ 63nmol BCE /mmol Cr 6. 2 ~ 19nmol BCE 5. 4 ~ 24. 2nmol /L BCE /L 0. 5 ~ 3. 8U /L 0. 5 ~ 4. 8U /L 0. 5 ~ 3. 8U /L Crosslaps ELISA /RIA ELISA /RIA ELISA /RIA Osteomark TM Osteomark TM ELISA /RIA ELISA /RIA /RIA Pyr. D-Pyr. CTX. I NTX. I TRACP-5b. HPLC. ELISA. RIA.

1268 2014 11 20 11 Chin J Osteoporos November 2014 Vol 20 No. 11 Pyr D-Pyr D-Pyr BMD 15 D-Pyr Pyr D-Pyr Pyr D-Pyr 17 Pyr D-Pyr Pyr D-Pyr Pyr D-Pyr SLE Pyr D-Pyr Paget s Pyr D-Pyr 12 Pyr D-Pyr 5 Pyr D-Pyr 292 4-10 Pyr D-Pyr 16 Table 6 6 Classification of bone formation markers Alkaline phosphatase ALP Bone specific alkaline phosphatase BALP Osteocalcin bone Glaprotein OC BGP I Type I procollagen carboxyl-terminal peptide PICP I Type I procollagen amino-terminal peptide PINP Osteoprotegerin OPG 2. 3 bone formation markers 2. 3. 1 Alkaline phosphatase ALP Bone specific alkaline phosphatase BALP 49 OC BALP OC OC γ 4 OC OC OC BALP OC ALP BALP OC Paget s OC 4 18 BALP OC OC 2. 3. 2 Osteocalcin OC Bone Glaprotein BGP γ- bone Glaprotein BGP

2014 11 20 11 Chin J Osteoporos November 2014 Vol 20 No. 11 1269 OC OPG OC 19 OC BMD OPG 2. 3. 3 I Type I procollagen carboxyl-terminal peptide PICP I RA OPG Type I procollagen amino-terminal peptide PINP 90% I I OPG OC OPG / RANKL I α OPG N C OPG PINP PICP PICP PINP OPG OPG 20 PICP 10000 6 ~ 8 min PINP OPG OPG I OPG OPG P1NP OPG 29 OPG OP PINP 21 2. 3. 4 Osteoprotegerin OPG ostoeprotegerin OPG Simonet tumor necrosis factor TNF 22 7 OPG OPG 289 4-7 23-26 3. 1 OPG 401 I OPG / κb RANK / Ⅱ I OP RANK RANKL II OPG 8q23-24 Southern OP OPG 1 27 kb 270 367 192 225 1765 bp 5 27 OPG 401 N 21 OPG 30 osteoclast OC 28 AS PICP 4 3 PICP PINP OP

1270 2014 11 20 11 Chin J Osteoporos November 2014 Vol 20 No. 11 Table 7 7 The normal reference values of bone formation makers BALP OC PICP PINP OPG 3. 8 ~ 22. 6 μg /L 3. 7 ~ 20. 9 μg /L 1. 0 ~ 36 μg /L 1. 0 ~ 35 μg /L 50 ~ 170 μg /L 38 ~ 202 μg /L 31. 7 ~ 70. 7 ng /ml 21 ~ 78 ng /ml /IRMA /EIA IRMA /RIA /ELISA RIA /ELISA RIA /ELISA 2. 42 ± 0. 26 ng /L ELISA BALP. Bone alkaline phosphatase OC. Osteocalcin PICP. Type I procollagen carboxyl-terminal peptide I PINP. Type I procollagen amino terminal peptide I OPG. Osteoprotegerin IRMA. immunoradiometric assay EIA. enzyme immunoassay 3. 2 3. 4 1 3 33 31 BMD 3. 3 PINP CTX < 25% BMD PINP CTX 32 Table 8 8 Application of bone metabolic and biochemical markers in the type diagnosis and differential diagnosis of osteoporosis OP BALP TRACP E 2 IL-1 PINP PICP 25 OH D 3 OP 25 OH D 3 1 25- OH 2 D 3 T TGF-β PINP OP GH E 2 T PICP CTX-1 PTH 1 25- OH 2 D 3 25 OH D 3 OP PTH 25 OH D 3 IGF-1 E 2 BALP PICP CTX-1 Table 9 9 The monitoring indicators and time recommendation in the osteoporosis treatment E 2 CTX-1 BALP 3 6 IL-1 BALP PINP PICP BGP TRACP CTX-1 Ca 1 2 6 CT PTH Ca P 1 3 1 25 OH 2 D 3 Ca PTH 1 2 D 3 PTH CT Ca P 25 OH D 3 1 2

2014 11 20 11 Chin J Osteoporos November 2014 Vol 20 No. 11 1271 4 34 cell formation J 35 36 37 38 TRACP PINP PICP OC BALP Pyr D-Pyr NTX CTX Cr / mmol Cr EDTA -20 OC TRACP 1 Zhang Mengmeng. Bone metabolism indexes in bone remodeling J. Chinese Journal of Osteoporosis 2013 19 8 866-873.. J. 2013 19 8 866-873. 2 Lee SK Lorenzo JA. Parathyroid hormone stimulates TRANCE and inhibits esteopmtegerin messenger ribonucleic acid expresion in mutine bone marrow cultures correlation with osteoelast-like. Endocrinology 1999 140 3552-3561. 3 Kidney Disease Improving Global Outcomes CKDMBDWG. KDIGO clinical practice guideline for the diagnosis evaluation prevention and treatment of Chronic Kidney Disease-Mineral and Bone Disorder CKD-MBD. Kidney international. Supplement 2009 113 S1-130. 4 Liu Zhonghou. The diagnosis of osteoporosis M. Chinese modern literature and Art Publishing House 2011 452-465 520-523.. M. 2011 452-465 520-523. 5 Vesper H. Cosman F. Endres DB et al. Application of biochemical markers of bone turnover in the assessment and monitoring of bone diseases approved guidelines. 2008 NCCLS document C48-A. ISBN 1-56238-539-9. 6 Kim CJ. Vitamin D dependent rickets Type I J. Korean J Pediatr 2011 54 2 51-54. 7 Liu Zhonghou. Bone mineral and clinical M. Beijing China Science and Technology Press 2006 722-723.. M. 2006 722-723. 8 Naknsato YR Janckila AJ Halleen JM et al. Clinical Significance of immunoasays for type-5 tartrate-resistant acid phosphatase J. Clin Chem. 1999 45 12 2150-2157. 9 Shiga T Tsuji Y Fujioka M et al. Risk factors for hip fracture in Japanese elderly women with osteoporosis applicability of biochemical markers in bone turnover J. Geriatr Gerontol Int 2009 9 1 69-74. 10 Bauer DC Garnero P Harrison SL et al. Biochemical markers of bone turnover hip bone loss and fracture in older men the MrOS study J. J Bone Miner Res 2009 24 12 2032-8. 11 Donescu OS BattieMc Videman T et al. Anthropometrics and Biochemical markers in men. J Clin Densitom 2005 8 222-227. 12 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 18 859-867. 13 Jung K Lein M Stephan C et al. Comparison of 10 serum bone turnover markers in prostste carcinoma patients with metastatic spread diagnostic and prognostics implications J. Int J Cancer 2004 111 783-791. 14 Abildgaard N Brixen K Kristensen JE et al. Comparison of five biochemical markers of bone resorption in multiple myeloma elevated pre-treatment levels of S-ICTP and U-NTX are predictive for early progression of the bone disease during standard chemotherapy J. Br J Haematol 2003 120 235-242.

1272 2014 11 20 11 Chin J Osteoporos November 2014 Vol 20 No. 11 15 Lenora J Ivaska KK Obrant et al. Prediction of bone loss using Biochemical markers of bone turnover J. Ostoprosis Int 2007 18 9 1297-1305 16 Corso A Arcaini L Mangiacavalli S et al. Biochemical markers of bone disease in asymptomatic early stage multiple myeloma J. Haematologica 2001 86 4 394-8. 17 SEBEL MJ GARTENBERG F SILVERBERG SJ et al. Urinary hydroxypyridinium cross-link of collagen in primary Acta Reumatol Port 2011 36 3 209-218. hyperparathyoidism J. J Clin Endocrinol Metab 1992 74 481-486. 29 Stern A Laughlin GA Bergstrom J ET AL. The sex-specific association of serum osteoprotegerin and receptor activator of 18 Liu Zhenhua. The progress of laboratory diagnosis of bone nuclear factor kappab legend with bone mineal density in order metabolism J. Clinical medicine 2011 8 4 463-466. adults the Rancho Bermardo study J. Eur J Endocrinol.. J. 2007 156 5 555-562. 2011 8 4 463-466. 19 Zhang Mengmeng ZhangYanhui Mao Weixian et al. Correlation between BMD and TRACP CTX-1 BALP BGP calcium and phosphorus metabolism indicator in 1084 female J. 31 Miller PD. Chinese Journal of Osteoporosis 2013 19 9 902-906.. 1084 TRACP CTX-1 BALP BGP BMD J. 103-110.. 2013 19 9 902-906. 20 Zhu Hanmin. Advances in bone metabolism laboratory diagnosis J. Shanghai Journal of Medical Laboratory 2000 15 5 277-278.. J. J 2000 15 5 277-278. 21 Hern ández MV Guanabens N Alvarez L et al. Immunocytochemical evidence on the effects of glucocorticoids on typeⅠcoids on type Ⅰcollagen synthesis in human osteoblastic cells J. Calcif Tissue Int 2004 74 284-293. 22 Krieger I Odrowaz-syoniewska G Osteoprotegerin J. Ortop Trauma-tol Rehabil 2004 6 1 123-129. 1141-1147. 23 Xu Ling. Osteoporosis M. Shanghai Shanghai Science and Technology Press 2011 252-253.. M. 2011 252-253. 24 Udagawa N Takahashi N Yasuda H etal. Osteoproteger in produced by osteoblasts is an important regulator in osteoclast development and function J. Endocrinology 2000 141 9 3478-3484. 25 Xiao En Meng Ping. The roles of bone metabolic biochemical markers in patients with osteoporosis An update J. Chinese Journal of Osteoporosis 2008 14 3 212-216.. J. 2008 14 3 212-216. 26 Zhou Jian Chen Keming Wang Jiaqi et al. Research progress on bone metaboliam-related factors J. Chinese Journal of Osteoporosis 2012 18 2 175-178.. J. 2012 18 2 175-178. 27 Xiaohai Long. Expression purification and functional studies of osteoclast formation suppress factor OPG. Hang Zhou Zhejiang University doctoral dissertation 2005.. OPG. 2005. 28 Silva I Branco JC. Rank /Rankl /opg literature review J. 30 Bonnick SL Shulman L. Monitoring osteoporosis therapy bone mineral density bone turnover markers or both J. Am J Med 2006 119 4 Suppl 1 S25-31. Bone density and markers of bone turnover in predicting fracture risk and how changes in these measures predict fracture risk reduction J. Curr Osteoporos Rep 2005 3 3 32 Yu Jing Yu Xuefeng. Markers of bone metabolism and bone mineral density s in the application of osteoporosi J. Clinical Internal Medicine 2009 26 3 155-157... 2009 26 3 155-157. 33 Civitelli R Armamento-Villareal R Napoli N. Bone turnover markers understanding their value in clinical trials and clinical practice J. Osteoporos Int 2009 20 6 843-851. 34 Eastell R Garnero P Audebert C et al. Reference intervals of bone turnover markers in healthy premenopausal women results from a cross-sectional European study J. Bone. 2012 11 5 35 Garnero P Sornay-Rendu E Claustrat B et al. Biochemical markers of bone turnover endogenous hormones and the risk of fractures in postmenopausal women the OFELY study J. J Bone Miner Res. 2000 11 1526-1536. 36 Henry Y M Eastell R. Ethnic and gender differences in bone mineral density and bone turnover in young adults Effect of bone size J. Osteoporosis Int 2000 11 6 512-517. 37 Chinese sanitary industry standard Guide of bone metabolism markers in clinical application. 2011-12-14. 2011-12-14. 38 Vasikaran S Eastell R Bruyère O et al. Markers of bone turnover for the prediction of fracture risk and monitoring of osteoporosis treatment a need for international reference standards J. Osteoporos Int 2011 22 2 391-420. 2014-09-01