Biochemische Marker des Knochenstoffwechsels im Blickwinkel knochenrelevanter Erkrankungen

Zusammenfassung

Das knöcherne Skelett unterliegt zeitlebens einem intensiven Umbau, welcher sich unter anderem laborchemisch durch Messung von im Blut zirkulierenden Substraten des Knochenanbaus und Knochenabbaus quantifizieren lässt. Diese Substrate werden in ihrer Gesamtheit häufig unter dem Begriff „Knochenumbauparameter“ oder „biochemische Marker des Knochenumsatzes“ zusammengefasst. Sie können direkt dem Stoffwechsel knochenspezifischer Zellen entstammen, wie etwa die Alkalische Phosphatase (ALP), das Osteocalcin (OC) oder die Tartrat-resistente saure Phosphatase (TRAP), oder im Rahmen des Knochenabbaus aus der organischen Knochenmatrix freigesetzt werden, wie zum Beispiel das C-terminale oder N-terminale Telopeptid des Typ-1 Kollagens (CTX, NTX). Für eine erhebliche Anzahl unterschiedlicher Erkrankungen konnte in den vergangenen Jahren und Jahrzehnten ein Effekt auf den Knochenstoffwechsel, und somit auf die entsprechenden Knochenumbauparameter, nachgewiesen werden. Hierbei stehen Erkrankungen, welche eine Beschleunigung des Knochenumsatzes bewirken jenen gegenüber, welche zu einer Verlangsamung desselben führen. Die Messung von Knochenumbauparametern im Blut und somit die Information über das Ausmaß des Knochenumbaus können unterstützend für therapeutische Maßnahmen herangezogen werden. Die diagnostische Bedeutung oder der diagnostische Mehrwert der Knochenumbauparameter bleiben hierbei allerdings auf einige wenige Ausnahmen beschränkt.

Abstract

Bone is a living tissue characterised by a lifelong turnover process. The latter can be quantified by measurement of specific circulating substrates which reflect either bone formation or bone resorption, and thus are also referred to as biochemical markers of bone turnover, or simply bone turnover markers. They may either be secreted directly by bone cells, such as the alkaline phosphatase (ALP), osteocalcin (OC) and the tartrate-resistant acid phosphatase (TRAP), or released from bone matrix during bone degradation, such as the C-terminal and N-terminal telopeptide of type-1 collagen (CTX, NTX). In the years past, a considerable number of diseases have been identified to affect bone metabolism with the consequence of an increase or decrease of these markers. Accordingly, such diseases can be classified as either associated with high or low bone turnover. Measurement of and information about these circulating markers may support decision making when treatment is considered. However, in general their added-value remains low regarding the diagnosis of such diseases.

Schlüsselwörter

biochemische - Marker - Knochenumsatz - Erkrankungen

Key words

biochemical - markers - bone - turnover

Publication History

Received: 12 August 2023

Accepted: 10 October 2023

Article published online:
04 December 2023

• Literatur

• 1 Florencio-Silva R, Sasso GR, Sasso-Cerri E. et al. Biology of Bone Tissue: Structure, Function, and Factors That Influence Bone Cells. Biomed Res Int 2015; 2015: 421746
• 2 Schini M, Vilaca T, Gossiel F. et al. Bone Turnover Markers: Basic Biology to Clinical Applications. Endocr Rev 2023; 44: 417-73 DOI: 10.1210/endrev/bnac031.
• 3 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: 1046-53 DOI: 10.1210/jcem.77.4.8104954.
• 4 Koivula M, Risteli L, Risteli J. Measurement of aminoterminal propeptide of type I procollagen (PINP) in serum. Clin Biochem 2012; 45: 920-7 DOI: 10.1016/j.clinbiochem.2012.03.023.
• 5 Vasikaran S, Cooper C, Eastell R. et al. International Osteoporosis Foundation and International Federation of Clinical Chemistry and Laboratory Medicine position on bone marker standards in osteoporosis. Clin Chem Lab Med 2011; 49: 1271-4 DOI: 10.1515/CCLM.2011.602.
• 6 Eastell R, Delmas PD, Hodgson SF. et al. Bone formation rate in older normal women: concurrent assessment with bone histomorphometry, calcium kinetics, and biochemical markers. J Clin Endocrinol Metab 1988; 67: 741-8 DOI: 10.1210/jcem-67-4-741.
• 7 Yaziji H, Janckila AJ, Lear SC. et al. Immunohistochemical detection of tartrate-resistant acid phosphatase in non-hematopoietic human tissues. Am J Clin Pathol 1995; 104: 397-402 DOI: 10.1093/ajcp/104.4.397.
• 8 Lv Y, Wang G, Xu W. et al. Tartrate-resistant acid phosphatase 5b is a marker of osteoclast number and volume in RAW 264.7 cells treated with receptor-activated nuclear kappaB ligand. Exp Ther Med 2015; 9: 143-6 DOI: 10.3892/etm.2014.2071.
• 9 van der Spoel E, Oei N, Cachucho R. et al. The 24-hour serum profiles of bone markers in healthy older men and women. Bone 2019; 120: 61-9 DOI: 10.1016/j.bone.2018.10.002.
• 10 Redmond J, Fulford AJ, Jarjou L. et al. Diurnal Rhythms of Bone Turnover Markers in Three Ethnic Groups. J Clin Endocrinol Metab 2016; 101: 3222-30 DOI: 10.1210/jc.2016-1183.
• 11 Garnero P, Hausherr E, Chapuy MC. et al. Markers of bone resorption predict hip fracture in elderly women: the EPIDOS Prospective Study. J Bone Miner Res 1996; 11: 1531-8 DOI: 10.1002/jbmr.5650111021.
• 12 Johansson H, Oden A, Kanis JA. et al. IFCC-IOF Joint Working Group on Standardisation of Biochemical Markers of Bone Turnover. A meta-analysis of reference markers of bone turnover for prediction of fracture. Calcif Tissue Int 2014; 94: 560-7 DOI: 10.1007/s00223-014-9842-y.
• 13 Tian A, Ma J, Feng K. et al. Reference markers of bone turnover for prediction of fracture: a meta-analysis. J Orthop Surg Res 2019; 14: 68-6 DOI: 10.1186/s13018-019-1100-6.
• 14 Rogers A, Hannon RA, Eastell R. Biochemical markers as predictors of rates of bone loss after menopause. J Bone Miner Res 2000; 15: 1398-404 DOI: 10.1359/jbmr.2000.15.7.1398.
• 15 Bauer DC, Sklarin PM, Stone KL. et al. Biochemical markers of bone turnover and prediction of hip bone loss in older women: the study of osteoporotic fractures. J Bone Miner Res 1999; 14: 1404-10 DOI: 10.1359/jbmr.1999.14.8.1404.
• 16 Marques EA, Gudnason V, Lang T. et al. Association of bone turnover markers with volumetric bone loss, periosteal apposition, and fracture risk in older men and women: the AGES-Reykjavik longitudinal study. Osteoporos Int 2016; 27: 3485-94 DOI: 10.1007/s00198-016-3675-7.
• 17 Shieh A, Greendale GA, Cauley JA. et al. The Association between Fast Increase in Bone Turnover During the Menopause Transition and Subsequent Fracture. J Clin Endocrinol Metab 202 105: 1440 DOI: 10.1210/clinem/dgz281.
• 18 Lips P. Vitamin D deficiency and secondary hyperparathyroidism in the elderly: consequences for bone loss and fractures and therapeutic implications. Endocr Rev 2001; 22: 477-501 DOI: 10.1210/edrv.22.4.0437.
• 19 Demiaux B, Arlot ME, Chapuy MC. et al. Serum osteocalcin is increased in patients with osteomalacia: correlations with biochemical and histomorphometric findings. J Clin Endocrinol Metab 1992; 74: 1146-51 DOI: 10.1210/jcem.74.5.1569162.
• 20 McKenna MJ, Martin-Grace J, Crowley R. et al. Congenital hypophosphataemia in adults: determinants of bone turnover markers and amelioration of renal phosphate wasting following total parathyroidectomy. J Bone Miner Metab 2019; 37: 685-93 DOI: 10.1007/s00774-018-0957-5.
• 21 Kilbane MT, Crowley R, Heffernan E. et al. High bone turnover and hyperparathyroidism after surgery for tumor-induced osteomalacia: A case series. Bone Rep 2021; 15: 101142 DOI: 10.1016/j.bonr.2021.101142.
• 22 Insogna KL, Briot K, Imel EA. et al. A Randomized, Double-Blind, Placebo-Controlled, Phase 3 Trial Evaluating the Efficacy of Burosumab, an Anti-FGF23 Antibody, in Adults With X-Linked Hypophosphatemia: Week 24 Primary Analysis. J Bone Miner Res 2018; 33: 1383-93 DOI: 10.1002/jbmr.3475.
• 23 Minisola S, Fukumoto S, Xia W. et al. Tumor-induced Osteomalacia: A Comprehensive Review. Endocr Rev 2023; 44: 323-53 DOI: 10.1210/endrev/bnac026.
• 24 Maeda K, Yoshida K, Nishizawa T. et al Inflammation and Bone Metabolism in Rheumatoid Arthritis: Molecular Mechanisms of Joint Destruction and Pharmacological Treatments. Int J Mol Sci 2022; 23: 2871 DOI: 10.3390/ijms23052871. 10.3390/ijms23052871
• 25 Danks L, Komatsu N, Guerrini MM. et al. RANKL expressed on synovial fibroblasts is primarily responsible for bone erosions during joint inflammation. Ann Rheum Dis 2016; 75: 1187-95 DOI: 10.1136/annrheumdis-2014-207137.
• 26 Thudium CS, Nielsen SH, Sardar S. et al. Bone phenotypes in rheumatology – there is more to bone than just bone. BMC Musculoskelet Disord 2020; 21: 789-2 DOI: 10.1186/s12891-020-03804-2.
• 27 Al-Awadhi A, Olusi S, Al-Zaid N. et al. Serum concentrations of interleukin 6, osteocalcin, intact parathyroid hormone, and markers of bone resorption in patients with rheumatoid arthritis. J Rheumatol 1999; 26: 1250-6
• 28 Bilezikian JP, Cusano NE, Khan AA. et al. Primary hyperparathyroidism. Nat Rev Dis Primers 2016; 2: 16033 DOI: 10.1038/nrdp.2016.33.
• 29 Bilezikian JP, Khan AA, Clarke BL. The Fifth International Workshop on the Evaluation and Management of Primary Hyperparathyroidism. J Bone Miner Res 2022; 37: 2290-2 DOI: 10.1002/jbmr.4670.
• 30 Abate EG, Clarke BL. Review of Hypoparathyroidism. Front Endocrinol (Lausanne) 2017; 7: 172 DOI: 10.3389/fendo.2016.00172.
• 31 Gennari L, Rendina D, Falchetti A. et al. Paget's Disease of Bone. Calcif Tissue Int 2019; 104: 483-500 DOI: 10.1007/s00223-019-00522-3.
• 32 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; 26: 1875-91 DOI: 10.1007/s00198-015-3095-0.
• 33 Shankar S, Hosking DJ. Biochemical assessment of Paget's disease of bone. J Bone Miner Res 2006; 21: 22 DOI: 10.1359/jbmr.06s204.
• 34 Boyce AM, Collins MT. Fibrous Dysplasia/McCune-Albright Syndrome: A Rare, Mosaic Disease of Galpha s Activation. Endocr Rev 2020; 41: 345-70 DOI: 10.1210/endrev/bnz011.
• 35 Jreige M, Hall N, Becce F. A novel approach for fibrous dysplasia assessment using combined planar and quantitative SPECT/CT analysis of Tc-99m-diphosphonate bone scan in correlation with biological bone turnover markers of disease activity. Front Med (Lausanne) 2022; 9: 1050854 DOI: 10.3389/fmed.2022.1050854.
• 36 Fenn JS, Lorde N, Ward J. et al. Hypophosphatasia. J Clin Pathol 2021; 74: 635-40 DOI: 10.1136/jclinpath-2021-207426.
• 37 Desborough R, Nicklin P, Gossiel F. et al. Clinical and biochemical characteristics of adults with hypophosphatasia attending a metabolic bone clinic. Bone 2021; 144: 115795 DOI: 10.1016/j.bone.2020.115795.
• 38 Shah VN, Shah CS, Snell-Bergeon JK. Type 1 diabetes and risk of fracture: meta-analysis and review of the literature. Diabet Med 2015; 32: 1134-42 DOI: 10.1111/dme.12734.
• 39 Hough FS, Pierroz DD, Cooper C. et al. IOF CSA Bone and Diabetes Working Group. MECHANISMS IN ENDOCRINOLOGY: Mechanisms and evaluation of bone fragility in type 1 diabetes mellitus. Eur J Endocrinol 2016; 174: 127 DOI: 10.1530/EJE-15-0820.
• 40 Hygum K, Starup-Linde J. et al. MECHANISMS IN ENDOCRINOLOGY: Diabetes mellitus, a state of low bone turnover – a systematic review and meta-analysis. Eur J Endocrinol 2017; 176: R137-57 DOI: 10.1530/EJE-16-0652.
• 41 Delitala AP, Scuteri A, Doria C. Thyroid Hormone Diseases and Osteoporosis. J Clin Med 2020; 9: 1034 DOI: 10.3390/jcm9041034. 10.3390/jcm9041034
• 42 Isaia GC, Roggia C, Gola D. et al. Bone turnover in hyperthyroidism before and after thyrostatic management. J Endocrinol Invest 2000; 23: 727-31 DOI: 10.1007/BF03345061.
• 43 El Hadidy EHM, Ghonaim M. et al. Impact of severity, duration, and etiology of hyperthyroidism on bone turnover markers and bone mineral density in men. BMC Endocr Disord 2011; 11: 15 DOI: 10.1186/1472-6823-11-15.
• 44 Bjerkreim BA, Hammerstad SS, Eriksen EF. Bone Turnover in Relation to Thyroid-Stimulating Hormone in Hypothyroid Patients on Thyroid Hormone Substitution Therapy. J Thyroid Res 2022; 2022: 8950546 DOI: 10.1155/2022/8950546.
• 45 Lakatos P, Foldes J, Horvath C. et al. Serum interleukin-6 and bone metabolism in patients with thyroid function disorders. J Clin Endocrinol Metab 1997; 82: 78-81 DOI: 10.1210/jcem.82.1.3641.
• 46 Williams GR, Bassett JHD. Thyroid diseases and bone health. J Endocrinol Invest 2018; 41: 99-109 DOI: 10.1007/s40618-017-0753-4.
• 47 Siru R, Alfonso H, Chubb SAP. et al. Subclinical thyroid dysfunction and circulating thyroid hormones are not associated with bone turnover markers or incident hip fracture in older men. Clin Endocrinol (Oxf) 2018; 89: 93-9 DOI: 10.1111/cen.13615.
• 48 Zuo C, Yin D, Fan H. et al. Study on diagnostic value of P1NP and beta-CTX in bone metastasis of patients with breast cancer and the correlation between them. Eur Rev Med Pharmacol Sci 2019; 23: 5277-84 DOI: 10.26355/eurrev_201906_18194.
• 49 Lumachi F, Basso SMM, Camozzi V. et al. Bone turnover markers in women with early stage breast cancer who developed bone metastases. A prospective study with multivariate logistic regression analysis of accuracy. Clin Chim Acta 2016; 460: 227-30 DOI: 10.1016/j.cca.2016.07.005.
• 50 Koopmans N, de Jong IJ, Breeuwsma AJ. et al Serum bone turnover markers (PINP and ICTP) for the early detection of bone metastases in patients with prostate cancer: a longitudinal approach. J Urol 2007; 178: 849-53 discussion 853; quiz 1129 DOI: 10.1016/j.juro.2007.05.029.
• 51 Ott SM. Histomorphometric measurements of bone turnover, mineralization, and volume. Clin J Am Soc Nephrol 2008; 3: 151 DOI: 10.2215/CJN.04301206.
• 52 CKD-MBD working group of ERA-EDTA. Vervloet MG, Brandenburg VM. Circulating markers of bone turnover. J Nephrol 2017; 30: 663-70 DOI: 10.1007/s40620-017-0408-8.
• 53 Sprague SM, Bellorin-Font E, Jorgetti V. et al. Diagnostic Accuracy of Bone Turnover Markers and Bone Histology in Patients With CKD Treated by Dialysis. Am J Kidney Dis 2016; 67: 559-66 DOI: 10.1053/j.ajkd.2015.06.023.