[en] The exact role of biochemical markers of bone turnover in the management of metabolic bone diseases remains a topic of controversy. In this consensus paper, the Belgian Bone Club aimed to provide a state of the art on the use of these biomarkers in different clinical or physiological situations like in postmenopausal women, osteoporosis in men, in elderly patients, in patients suffering from bone metastasis, in patients with chronic renal failure, in pregnant or lactating women, in intensive care patients, and in diabetics. We also gave our considerations on the analytical issues linked to the use of these biomarkers, on potential new emerging biomarkers, and on the use of bone turnover biomarkers in the follow-up of patients treated with new drugs for osteoporosis.
Disciplines :
Laboratory medicine & medical technology
Author, co-author :
Cavalier, Etienne ; Université de Liège > Département de pharmacie > Chimie médicale
Bergmann, P.
Bruyère, Olivier ; Université de Liège > Département des sciences de la santé publique > Santé publique, Epidémiologie et Economie de la santé
DELANAYE, Pierre ; Centre Hospitalier Universitaire de Liège - CHU > Service de néphrologie
Durnez, A.
Devogelaer, J.-P.
Ferrari, S. L.
Gielen, E.
Goemaere, S.
Kaufman, J.-M.
Nzeusseu Toukap, A.
Reginster, Jean-Yves ; Université de Liège > Département des sciences de la santé publique > Santé publique, Epidémiologie et Economie de la santé
ROUSSEAU, Anne-Françoise ; Centre Hospitalier Universitaire de Liège - CHU > Service des soins intensifs généraux
Rozenberg, S.
Scheen, André ; Université de Liège > Département des sciences cliniques > Diabétologie, nutrition et maladie métaboliques
Kanis JA, McCloskey EV, Johansson H et al (2013) European guidance for the diagnosis and management of osteoporosis in postmenopausal women. Osteoporos Int 24:23–57. doi:10.1007/s00198-012-2074-y
Rizzoli R, Branco J, Brandi M et al (2014) Management of osteoporosis of the oldest old. Osteoporos Int 25:2507–2529. doi:10.1007/s00198-014-2755-9
Vasikaran S, Eastell R, Bruyère O et al (2011) Markers of bone turnover for the prediction of fracture risk and monitoring of osteoporosis treatment: a need for international reference standards. Osteoporos Int 22:391–420. doi:10.1007/s00198-010-1501-1
Bruyère O, Reginster J-Y (2014) Monitoring of osteoporosis therapy. Best Pract Res Clin Endocrinol Metab 28:835–841. doi:10.1016/j.beem.2014.07.001
Garnero P (2014) New developments in biological markers of bone metabolism in osteoporosis. Bone 66:46–55. doi:10.1016/j.bone.2014.05.016
Halleen JM, Alatalo SL, Suominen H et al (2000) Tartrate-resistant acid phosphatase as a serum marker of bone resorption. J Bone Miner Res 15:1337–1345
Garnero P, Borel O, Byrjalsen I et al (1999) The collagenolytic activity of cathepsin K is unique among mammalian proteinases. J Biol Chem 273:32347–32352. doi:10.1074/jbc.273.48.32347
Lotinun S, Kiviranta R, Matsubara T et al (2013) Osteoclast-specific cathepsin K deletion stimulates S1P-dependent bone formation. J Clin Invest 123:666–681. doi:10.1172/JCI64840
van Bezooijen RL, Roelen BAJ, Visser A et al (2004) Sclerostin is an osteocyte-expressed negative regulator of bone formation, but not a classical BMP antagonist. J Exp Med 199:805–814. doi:10.1084/jem.20031454
Papapoulos SE (2011) Targeting sclerostin as potential treatment of osteoporosis. Ann Rheum Dis 70(Suppl 1):i119–i122. doi:10.1136/ard.2010.141150
Joiner DM, Ke J, Zhong Z et al (2013) Lrp5 and Lrp 6 in development and disease. Trends Endocrinol Metab 24:31–39. doi:10.1016/j.tem.2012.10.003
Brunkow ME, Gardner JC, Van Ness J et al (2001) Bone dysplasia sclerosteosis results from loss of the SOST gene product, a novel cystine knot-containing protein. Am J Hum Genet 68:577–589. doi:10.1086/318811
Ardawi M-SM, Al-Sibiany AM, Bakhsh TM et al (2012) Decreased serum sclerostin levels in patients with primary hyperparathyroidism: a cross-sectional and a longitudinal study. Osteoporos Int 23:1789–1797. doi:10.1007/s00198-011-1806-8
Garnero P, Sornay-Rendu E, Munoz F et al (2013) Association of serum sclerostin with bone mineral density, bone turnover, steroid and parathyroid hormones, and fracture risk in postmenopausal women: the OFELY study. Osteoporos Int 24:489–494. doi:10.1007/s00198-012-1978-x
Durosier C, van Lierop A, Ferrari S et al (2013) Association of circulating sclerostin with bone mineral mass, microstructure, and turnover biochemical markers in healthy elderly men and women. J Clin Endocrinol Metab 98:3873–3883. doi:10.1210/jc.2013-2113
Pelletier S, Dubourg L, Carlier MC et al (2013) The relation between renal function and serum sclerostin in adult patients with CKD. Clin J Am Soc Nephrol 8:819–823. doi:10.2215/CJN.07670712
Biver E, Chopin F, Coiffier G et al (2012) Bone turnover markers for osteoporotic status assessment? A systematic review of their diagnosis value at baseline in osteoporosis. Jt Bone Spine 79:20–25. doi:10.1016/j.jbspin.2011.05.003
Rogers A, Hannon RA, Eastell R (2000) Biochemical markers as predictors of rates of bone loss after menopause. J Bone Miner Res 15:1398–1404. doi:10.1359/jbmr.2000.15.7.1398
Garnero P, Cloos P, Sornay-Rendu E et al (2002) Type I collagen racemization and isomerization and the risk of fracture in postmenopausal women: the OFELY prospective study. J Bone Miner Res 17:826–833. doi:10.1359/jbmr.2002.17.5.826
Schousboe JT, Bauer DC, Nyman JA et al (2007) Potential for bone turnover markers to cost-effectively identify and select post-menopausal osteopenic women at high risk of fracture for bisphosphonate therapy. Osteoporos Int 18:201–210. doi:10.1007/s00198-006-0218-7
Szulc P (2012) The role of bone turnover markers in monitoring treatment in postmenopausal osteoporosis. Clin Biochem 45:907–919. doi:10.1016/j.clinbiochem.2012.01.022
Glover SJ, Eastell R, McCloskey EV et al (2009) Rapid and robust response of biochemical markers of bone formation to teriparatide therapy. Bone 45:1053–1058. doi:10.1016/j.bone.2009.07.091
Jilka RL (2007) Molecular and cellular mechanisms of the anabolic effect of intermittent PTH. Bone 40:1434–1446. doi:10.1016/j.bone.2007.03.017
Eastell R, Krege JH, Chen P et al (2006) Development of an algorithm for using PINP to monitor treatment of patients with teriparatide. Curr Med Res Opin 22:61–66. doi:10.1185/030079905X75096
Meunier PJ, Roux C et al (2004) The effects of strontium ranelate on the risk of vertebral fracture in women with postmenopausal osteoporosis. N Engl J Med 350:459–68. doi:10.1007/s00223-009-9233-y
Blumsohn A, Marin F, Nickelsen T et al (2011) Early changes in biochemical markers of bone turnover and their relationship with bone mineral density changes after 24 months of treatment with teriparatide. Osteoporos Int 22:1935–1946. doi:10.1007/s00198-010-1379-y
Delmas PD, Vrijens B, Eastell R et al (2007) Effect of monitoring bone turnover markers on persistence with risedronate treatment of postmenopausal osteoporosis. J Clin Endocrinol Metab 92:1296–1304. doi:10.1210/jc.2006-1526
Baim S, Miller PD (2009) 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 24:561–574. doi:10.1359/jbmr.090203
Goemaere S, Van Pottelbergh I, Zmierczak H et al (2001) Inverse association between bone turnover rate and bone mineral density in community-dwelling men >70 years of age: no major role of sex steroid status. Bone 29:286–291. doi:10.1016/S8756-3282(01)00503-8
Darelid A, Nilsson M, Kindblom JM et al (2015) Bone turnover markers predict bone mass development in young adult men: a five-year longitudinal study. J Clin Endocrinol Metab 100:1460–1468. doi:10.1210/jc.2014-3947
Dennison E, Eastell R, Fall CH et al (1999) Determinants of bone loss in elderly men and women: a prospective population-based study. Osteoporos Int 10:384–391
Stoch SA, Parker RA, Chen L et al (2001) Bone loss in men with prostate cancer treated with gonadotropin-releasing hormone agonists. J Clin Endocrinol Metab 86:2787–2791. doi:10.1210/jcem.86.6.7558
Szulc P, Montella A, Delmas PD (2008) High bone turnover is associated with accelerated bone loss but not with increased fracture risk in men aged 50 and over: the prospective MINOS study. Ann Rheum Dis 67:1249–1255. doi:10.1136/ard.2007.077941
Bauer DC, Garnero P, Harrison SL et al (2009) Biochemical markers of bone turnover, hip bone loss, and fracture in older men: the MrOS study. J Bone Miner Res 24:2032–2038. doi:10.1359/JBMR.090526
Meier C, Nguyen TV, Center JR et al (2005) Bone resorption and osteoporotic fractures in elderly men: the dubbo osteoporosis epidemiology study. J Bone Miner Res 20:579–587. doi:10.1359/JBMR.041207
Luukinen H, Käkönen SM, Pettersson K et al (2000) Strong prediction of fractures among older adults by the ratio of carboxylated to total serum osteocalcin. J Bone Miner Res 15:2473–2478. doi:10.1359/jbmr.2000.15.12.2473
Kaufman J-M, Lapauw B, Goemaere S (2014) Current and future treatments of osteoporosis in men. Best Pract Res Clin Endocrinol Metab 28:871–884. doi:10.1016/j.beem.2014.09.002
Orwoll E, Teglbjærg CS, Langdahl BL et al (2012) A randomized, placebo-controlled study of the effects of denosumab for the treatment of men with low bone mineral density. J Clin Endocrinol Metab 97:3161–9. doi:10.1210/jc.2012-1569
Smith M, Egerdie B, Toriz NH et al (2009) Denosumab in men receiving androgen-deprivation therapy for prostate cancer. N Engl J Med 361:745–755. doi:10.1056/NEJMoa1404595
Orwoll ES, Scheele WH, Paul S et al (2003) The effect of teriparatide [human parathyroid hormone (1-34)] therapy on bone density in men with osteoporosis. J Bone Miner Res 18:9–17. doi:10.1359/jbmr.2003.18.1.9
Farahmand P, Marin F, Hawkins F et al (2013) Early changes in biochemical markers of bone formation during teriparatide therapy correlate with improvements in vertebral strength in men with glucocorticoid-induced osteoporosis. Osteoporos Int 24:2971–2981. doi:10.1007/s00198-013-2379-5
Seibel MJ (2005) Biochemical markers of bone turnover: part I: biochemistry and variability. Clin Biochem Rev 26:97–122
Naylor K, Eastell R (2012) Bone turnover markers: use in osteoporosis. Nat Rev Rheumatol 8:379–389. doi:10.1038/nrrheum.2012.86
Ivaska KK, Lenora J, Gerdhem P et al (2008) Serial assessment of serum bone metabolism markers identifies women with the highest rate of bone loss and osteoporosis risk. J Clin Endocrinol Metab 93:2622–2632. doi:10.1210/jc.2007-1508
Khosla S, Melton LJ, Atkinson EJ et al (1998) Relationship of serum sex steroid levels and bone turnover markers with bone mineral density in men and women: a key role for bioavailable estrogen. J Clin Endocrinol Metab 83:2266–2274. doi:10.1210/jc.83.7.2266
Garnero P, Sornay-Rendu E, Duboeuf F, Delmas PD (1999) Markers of bone turnover predict postmenopausal forearm bone loss over 4 years: the OFELY study. J Bone Miner Res 14:1614–1621. doi:10.1359/jbmr.1999.14.9.1614
Szulc P (2011) Biochemical bone turnover markers and osteoporosis in older men: where are we? J Osteoporos. doi:10.4061/2011/704015
Johansson H, Odén A, Kanis JA et al (2014) A meta-analysis of reference markers of bone turnover for prediction of fracture. Calcif Tissue Int 94:560–567. doi:10.1007/s00223-014-9842-y
Gielen E, O’Neill T, Pye S et al (2015) Bone turnover markers predict hip bone loss in elderly European men: results of the European Male Ageing Study (EMAS). Osteoporos Int 26:617–627. doi:10.1007/s00198-014-2884-1
Devogelaer J-P (2006) Glucocorticoid-induced osteoporosis: mechanisms and therapeutic approach. Rheum Dis Clin North Am 32:733–757. doi:10.1016/j.rdc.2006.09.001
Weinstein RS, Jilka RL, Michael Parfitt A, Manolagas SC (1998) Inhibition of osteoblastogenesis and promotion of apoptosis of osteoblasts end osteocytes by glucocorticoids potential mechanisms of their deleterious effects on bone. J Clin Invest 102:274–282. doi:10.1172/JCI2799
Paglia F, Dionisi S, De Geronimo S et al (2001) Biomarkers of bone turnover after a short period of steroid therapy in elderly men. Clin Chem 47:1314–6
Szappanos Á, Toke J, Lippai D et al (2010) Bone turnover in patients with endogenous Cushing’s syndrome before and after successful treatment. Osteoporos Int 21:637–645. doi:10.1007/s00198-009-0978-y
Kaji H, Kuroki Y, Murakawa Y et al (2010) Effect of alendronate on bone metabolic indices and bone mineral density in patients treated with high-dose glucocorticoid: a prospective study. Osteoporos Int 21:1565–1571. doi:10.1007/s00198-009-1110-z
von Tirpitz C, Epp S, Klaus J et al (2003) Effect of systemic glucocorticoid therapy on bone metabolism and the osteoprotegerin system in patients with active Crohn’s disease. Eur J Gastroenterol Hepatol 15:1165–1170. doi:10.1097/01.meg.0000085485.12407.82
Fahrleitner A, Prenner G, Leb G et al (2003) Serum osteoprotegerin is a major determinant of bone density development and prevalent vertebral fracture status following cardiac transplantation. Bone 32:96–106. doi:10.1016/S8756-3282(02)00926-2
Devogelaer JP, Sambrook P, Reid DM et al (2013) Effect on bone turnover markers of once-yearly intravenous infusion of zoledronic acid versus daily oral risedronate in patients treated with glucocorticoids. Rheumatology (Oxford) 52:1058–1069. doi:10.1093/rheumatology/kes410
Saag KG, Zanchetta JR, Devogelaer JP et al (2009) Effects of teriparatide versus alendronate for treating glucocorticoid-induced osteoporosis: thirty-six-month results of a randomized, double-blind, controlled trial. Arthritis Rheum 60:3346–3355. doi:10.1002/art.24879
Coleman R, Body JJ, Aapro M et al (2014) Bone health in cancer patients: ESMO Clinical Practice Guidelines. Ann Oncol 25:1–14. doi:10.1093/annonc/mdu103
Ferreira A, Alho I, Casimiro S, Costa L (2015) Bone remodeling markers and bone metastases: from cancer research to clinical implications. Bonekey Rep 4:668. doi:10.1038/bonekey.2015.35
Coleman R, Costa L, Saad F et al (2011) Consensus on the utility of bone markers in the malignant bone disease setting. Crit Rev Oncol Hematol 80:411–432. doi:10.1016/j.critrevonc.2011.02.005
Costa L, Demers LM, Gouveia-Oliveira A et al (2002) Prospective evaluation of the peptide-bound collagen type I cross-links N-telopeptide and C-telopeptide in predicting bone metastases status. J Clin Oncol 20:850–856. doi:10.1200/JCO.20.3.850
Som A, Tu S-M, Liu J et al (2012) Response in bone turnover markers during therapy predicts overall survival in patients with metastatic prostate cancer: analysis of three clinical trials. Br J Cancer 107:1547–53. doi:10.1038/bjc.2012.436
Abildgaard N, Brixen K, Eriksen EF et al (2004) Sequential analysis of biochemical markers of bone resorption and bone densitometry in multiple myeloma. Haematologica 89:567–577
Coleman RE, Major P, Lipton A et al (2005) Predictive value of bone resorption and formation markers in cancer patients with bone metastases receiving the bisphosphonate zoledronic acid. J Clin Oncol 23:4925–4935. doi:10.1200/JCO.2005.06.091
Body J-J (2012) Denosumab for the management of bone disease in patients with solid tumors. Expert Rev Anticancer Ther 12:307–322. doi:10.1586/era.11.204
Brown JE, Cook RJ, Major P et al (2005) Bone turnover markers as predictors of skeletal complications in prostate cancer, lung cancer, and other solid tumors. J Natl Cancer Inst 97:59–69. doi:10.1093/jnci/dji002
Delanaye P, Souberbielle J-CC, Lafage-Proust MH et al (2014) Can we use circulating biomarkers to monitor bone turnover in CKD haemodialysis patients? Hypotheses and facts. Nephrol Dial Transplant 29:997–1004. doi:10.1093/ndt/gft275
Torres PU, Bover J, Mazzaferro S et al (2014) When, how, and why a bone biopsy should be performed in patients with chronic kidney disease. Semin Nephrol 34:612–625. doi:10.1016/j.semnephrol.2014.09.004
Kidney Disease: Improving Global Outcomes (KDIGO) CKD-MBD Work Group (2009) KDIGO clinical practice guideline for the diagnosis, evaluation, prevention, and treatment of chronic kidney disease-mineral and bone disorder (CKD-MBD). Kidney Int. doi:10.1038/ki.2009.188
Cavalier E, Delanaye P, Vranken L et al (2011) Interpretation of serum PTH concentrations with different kits in dialysis patients according to the KDIGO guidelines: importance of the reference (normal) values. Nephrol Dial Transplant 27:1950–6. doi:10.1093/ndt/gfr535
Chu P, Chao TY, Lin YF et al (2003) Correlation between histomorphometric parameters of bone resorption and serum type 5b tartrate-resistant acid phosphatase in uremic patients on maintenance hemodialysis. Am J Kidney Dis 41:1052–1059. doi:10.1016/S0272-6386(03)00203-8
Moorthi RN, Moe SM (2014) Recent advances in the noninvasive diagnosis of renal osteodystrophy. Kidney Int 84:886–894. doi:10.1038/ki.2013.254.Recent
Malluche HH, Davenport DL, Cantor T, Monier-Faugere M-C (2014) Bone mineral density and serum biochemical predictors of bone loss in patients with CKD on dialysis. Clin J Am Soc Nephrol 9:1254–1262. doi:10.2215/CJN.09470913
Sanz-Salvador L, Garcia-Perez MA, Tarin JJ, Cano A (2014) ENDOCRINOLOGY IN PREGNANCY: bone metabolic changes during pregnancy: a period of vulnerability to osteoporosis and fracture. Eur J Endocrinol 172:R53–R65. doi:10.1530/EJE-14-0424
Honjo S, Mizunuma H (2001) Changes in biochemical parameters of bone turnover and bone mineral density in post-pregnancy osteoporosis. Am J Obstet Gynecol 185:246–247. doi:10.1067/mob.2001.113910
Orford N, Cattigan C, Brennan SL et al (2014) The association between critical illness and changes in bone turnover in adults: a systematic review. Osteoporos Int 25:2335–2346. doi:10.1007/s00198-014-2734-1
Rousseau A-F, Damas P, Janssens M et al (2014) Critical care and vitamin D status assessment: what about immunoassays and calculated free 25OH-D? Clin Chim Acta 437:43–47. doi:10.1016/j.cca.2014.07.007
Orford NR, Saunders K, Merriman E et al (2011) Skeletal morbidity among survivors of critical illness. Crit Care Med 39:1295–1300. doi:10.1097/CCM.0b013e318211ff3d
Klein GL, Xie Y, Bonewald LF (2014) Preliminary evidence of early bone resorption in a sheep model of acute burn injury: an observational study. J Bone Miner Metab 32:136–141. doi:10.1007/s00774-013-0483-4
Klein GL et al (1993) Bone disease in burn patients. J Bone Miner Res 8:337–345
Terzi R, Güven M (2015) Bone mineral density after burn injury and its relation to the characteristics of scar tissue. J Burn Care Res 1–5. doi: 10.1097/BCR.0000000000000241
Klein L, Herndon DN, Craig BL (1995) Long-term reduction in bone mass after severe burn injury in children. J Pediatr 126:252–6
Nierman DM, Mechanick JI (2000) Biochemical response to treatment of bone hyperresorption in chronically critically ill patients. Chest 118:761–766. doi:10.1378/chest.118.3.761
Klein GL, Wimalawansa SJ, Kulkarni G et al (2005) The efficacy of acute administration of pamidronate on the conservation of bone mass following severe burn injury in children: a double-blind, randomized, controlled study. Osteoporos Int 16:631–635. doi:10.1007/s00198-004-1731-1
Przkora R, Herndon DN, Sherrard DJ et al (2007) Pamidronate preserves bone mass for at least 2 years following acute administration for pediatric burn injury. Bone 41:297–302. doi:10.1016/j.bone.2007.04.195
Porro LJ et al (2012) Five-year outcomes after oxandrolone administration in severely burned children: a randomized clinical trial of safety and efficacy. J Am Coll Surg 214:489–504. doi:10.1016/j.biotechadv.2011.08.021.Secreted
Przkora R, Herndon DN, Suman OE et al (2006) Beneficial effects of extended growth hormone treatment after hospital discharge in pediatric burn patients. Ann Surg 243:796–801. doi:10.1097/01.sla.0000219676.69331.fd, discussion 801–803
Khan TS, Fraser L-A (2015) Type 1 diabetes and osteoporosis: from molecular pathways to bone phenotype. J Osteoporos 2015:1–8. doi:10.1155/2015/174186
Dede AD, Tournis S, Dontas I, Trovas G (2014) Type 2 diabetes mellitus and fracture risk. Metabolism 63:1480–1490. doi:10.1016/j.metabol.2014.09.002
Gilbert MP, Pratley RE (2015) The impact of diabetes and diabetes medications on bone health. Endocr Rev 36:194–213. doi:10.1210/er.2012-1042
Farr JN, Khosla S (2016) Determinants of bone strength and quality in diabetes mellitus in humans. Bone 82:28–34. doi:10.1016/j.bone.2015.07.027
Ferrari S (2014) Future directions for new medical entities in osteoporosis. Best Pract Res Clin Endocrinol Metab 28:859–870. doi:10.1016/j.beem.2014.08.002
Bone HG, McClung MR, Roux C et al (2009) Odanacatib, a cathepsin-K inhibitor for osteoporosis: a two-year study in postmenopausal women with low bone density. J Bone Miner Res 25:937–947. doi:10.1359/jbmr.091035
Borel O, Gineyts E, Bertholon C, Garnero P (2012) Cathepsin K preferentially solubilizes matured bone matrix. Calcif Tissue Int 91:32–39. doi:10.1007/s00223-012-9604-7
Pennypacker BL, Chen CM, Zheng H et al (2014) Inhibition of cathepsin K increases modeling-based bone formation, and improves cortical dimension and strength in adult ovariectomized monkeys. J Bone Miner Res 29:1847–1858. doi:10.1002/jbmr.2211
McClung MR, Grauer A, Boonen S et al (2014) Romosozumab in postmenopausal women with low bone mineral density. N Engl J Med 370:412–20. doi:10.1056/NEJMoa1305224
Ominsky MS, Niu QT, Li C et al (2014) Tissue-level mechanisms responsible for the increase in bone formation and bone volume by sclerostin antibody. J Bone Miner Res 29:1424–1430. doi:10.1002/jbmr.2152
Nioi P, Taylor S, Hu R et al (2015) Transcriptional profiling of laser capture microdissected subpopulations of the osteoblast lineage provides insight into the early response to sclerostin antibody in rats. J Bone Miner Res 30:1457–1467. doi:10.1002/jbmr.2482
Leder BZ, O’Dea LSL, Zanchetta JR et al (2015) Effects of abaloparatide, a human parathyroid hormone-related peptide analog, on bone mineral density in postmenopausal women with osteoporosis. J Clin Endocrinol Metab 100:697–706. doi:10.1210/jc.2014-3718
