Advertisement

Osteoporosis International

, Volume 20, Issue 6, pp 843–851 | Cite as

Bone turnover markers: understanding their value in clinical trials and clinical practice

  • R. Civitelli
  • R. Armamento-Villareal
  • N. Napoli
Review

Abstract

While bone mineral density (BMD) by dual-energy X-ray absorptiometry is the primary method of determining fracture risk, assessing bone turnover may add valuable information for the management of patients with low bone mass. Bone turnover markers (BTMs) are used in clinical trials where they can provide essential information on the biological efficacy of osteoporosis treatments. In such population-based studies, BTMs can predict fracture risk independent of BMD. When combined with BMD, they improve the fracture risk estimate above and beyond BMD alone in postmenopausal osteoporotic women. Since changes in bone turnover after the initiation of therapy with bone resorption inhibitors occur much more rapidly than changes in BMD, treatment efficacy could, in theory, be determined within weeks of using BTMs. However, such predictive value is limited by the large biological variability of these biochemical markers, even though newer automated methods have reduced their analytical variability. Consequently, widespread adoption as a means of predicting treatment efficacy in fracture prevention for individual patients cannot yet be recommended. BTMs may be useful for monitoring adherence to antiresorptive therapy and may aid in identifying patients for whom antiresorptive therapy is most appropriate. Thus, although BTMs are currently confined to clinical research applications, further improvement in assay precision may extend their diagnostic value in clinical settings.

Keywords

Bone mineral density Bone remodeling Bone turnover markers Fracture risk Osteoporosis 

Notes

Acknowledgments

Editing assistance was provided by Insight Medical Communications, which was financially supported by Roche Laboratories. Roche Laboratories did not participate in the preparation or writing of the manuscript nor did they provide direct financial support to the authors for the purpose of writing this manuscript.

Conflicts of interest

Roberto Civitelli, MD, Honoraria/Speaker Bureau: Novartis, Roche, GSK, Amgen, Research Grant Support: Eli-Lilly, Hoffman-La Roche, Stock ownership: Eli-Lilly, Wyeth, Merck, Amgen, Reina Armamento-Villareal, MD, none, Nicola Napoli, MD, none.

References

  1. 1.
    World Health Organization (1994) Assessment of fracture risk and its application to screening for postmenopausal osteoporosis. Report of a WHO Study Group.. World Health Organ Tech Rep Ser 843:1–129Google Scholar
  2. 2.
    ACOG practice bulletin (2004) Clinical management guidelines for obstetrician-gynecologists. Obstet Gynecol 103:203–216 (Number 50, January 2003)Google Scholar
  3. 3.
    Kanis JA (2002) Diagnosis of osteoporosis and assessment of fracture risk. Lancet 359:1929–1936PubMedCrossRefGoogle Scholar
  4. 4.
    Burr DB (2003) Introduction—bone turnover and fracture risk. J Musculoskelet Neuronal Interact 3:408–409PubMedGoogle Scholar
  5. 5.
    Siris ES, Chen YT, Abbott TA et al (2004) Bone mineral density thresholds for pharmacological intervention to prevent fractures. Arch Intern Med 164:1108–1112PubMedCrossRefGoogle Scholar
  6. 6.
    Kanis JA, Johnell O, Oden A et al (2008) FRAX and the assessment of fracture probability in men and women from the UK. Osteoporos Int 19:385–397PubMedCrossRefGoogle Scholar
  7. 7.
    Garnero P, Sornay-Rendu E, Chapuy MC et al (1996) Increased bone turnover in late postmenopausal women is a major determinant of osteoporosis. J Bone Miner Res 11:337–349PubMedGoogle Scholar
  8. 8.
    Riggs BL, Melton LJ 3rd (2002) Bone turnover matters: the raloxifene treatment paradox of dramatic decreases in vertebral fractures without commensurate increases in bone density. J Bone Miner Res 17:11–14PubMedCrossRefGoogle Scholar
  9. 9.
    Heaney RP (2003) Remodeling and skeletal fragility. Osteoporos Int 14(suppl 5):S12–S15Google Scholar
  10. 10.
    Cummings SR, Karpf DB, Harris F et al (2002) Improvement in spine bone density and reduction in risk of vertebral fractures during treatment with antiresorptive drugs. Am J Med 112:281–289PubMedCrossRefGoogle Scholar
  11. 11.
    Claudon A, Vergnaud P, Valverde C et al (2008) New automated multiplex assay for bone turnover markers in osteoporosis. Clin Chem 54:1554–1563PubMedCrossRefGoogle Scholar
  12. 12.
    Garnero P, Vergnaud P, Hoyle N (2008) Evaluation of a fully automated serum assay for total N-terminal propeptide of type I collagen in postmenopausal osteoporosis. Clin Chem 54:188–196PubMedCrossRefGoogle Scholar
  13. 13.
    Schmidt-Gayk H, Spanuth E, Kötting J et al (2004) Performance evaluation of automated assays for beta-CrossLaps, N-MID-Osteocalcin and intact parathyroid hormone (BIOROSE Multicenter Study). Clin Chem Lab Med 42:90–95PubMedCrossRefGoogle Scholar
  14. 14.
    Cremers S, Garnero P (2006) Biochemical markers of bone turnover in the clinical development of drugs for osteoporosis and metastatic bone disease: potential uses and pitfalls. Drugs 66:2031–2058PubMedCrossRefGoogle Scholar
  15. 15.
    Abe Y, Ishikawa H, Fukao A (2008) Higher efficacy of urinary bone resorption marker measurements in assessing response to treatment for osteoporosis in postmenopausal women. Tohoku J Exp Med 214:51–59PubMedCrossRefGoogle Scholar
  16. 16.
    Clemens JD, Herrick MV, Singer FR et al (1997) Evidence that serum NTx (collagen-type I N-telopeptides) can act as an immunochemical marker of bone resorption. Clin Chem 43:2058–2063PubMedGoogle Scholar
  17. 17.
    Hanson DA, Weis MA, Bollen AM et al (1992) A specific immunoassay for monitoring human bone resorption: quantitation of type I collagen cross-linked N-telopeptides in urine. J Bone Miner Res 7:1251–1258PubMedGoogle Scholar
  18. 18.
    Risteli J, Risteli L (1999) Products of bone collagen metabolism. In: Seibel M, Robins S, Bilezikian J (eds) Dynamics of bone and cartilage metabolism. Academic, San Diego, California, pp 275–288Google Scholar
  19. 19.
    Risteli J, Elomaa I, Niemi S et al (1993) Radioimmunoassay for the pyridinoline cross-linked carboxy-terminal telopeptide of type I collagen: a new serum marker of bone collagen degradation. Clin Chem 39:635–640PubMedGoogle Scholar
  20. 20.
    Garnero P, Borel O, Delmas PD (2001) Evaluation of a fully automated serum assay for C-terminal cross-linking telopeptide of type I collagen in osteoporosis. Clin Chem 47:694–702PubMedGoogle Scholar
  21. 21.
    Fledelius C, Johnsen AH, Cloos PA et al (1997) Characterization of urinary degradation products derived from type I collagen. Identification of a beta-isomerized Asp-Gly sequence within the C-terminal telopeptide (alpha1) region. J Biol Chem 272:9755–9763PubMedCrossRefGoogle Scholar
  22. 22.
    Garnero P, Gineyts E, Schaffer AV et al (1998) Measurement of urinary excretion of nonisomerized and beta-isomerized forms of type I collagen breakdown products to monitor the effects of the bisphosphonate zoledronate in Paget’s disease. Arthritis Rheum 41:354–360PubMedCrossRefGoogle Scholar
  23. 23.
    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 17:826–833PubMedCrossRefGoogle Scholar
  24. 24.
    Srivastava AK, Vliet EL, Lewiecki EM et al (2005) Clinical use of serum and urine bone markers in the management of osteoporosis. Curr Med Res Opin 21:1015–1026PubMedCrossRefGoogle Scholar
  25. 25.
    Gunja-Smith Z, Boucek RJ (1981) Collagen cross-linking compounds in human urine. Biochem J 197:759–762PubMedGoogle Scholar
  26. 26.
    Seibel MJ (2005) Biochemical markers of bone turnover: part I: biochemistry and variability. Clin Biochem Rev 26:97–122PubMedGoogle Scholar
  27. 27.
    Kraenzlin ME, Kraenzlin CA, Meier C et al (2008) Automated HPLC assay for urinary collagen cross-links: effect of age, menopause, and metabolic bone diseases. Clin Chem 54:1546–1553PubMedCrossRefGoogle Scholar
  28. 28.
    Halleen JM, Alatalo SL, Janckila AJ et al (2001) Serum tartrate-resistant acid phosphatase 5b is a specific and sensitive marker of bone resorption. Clin Chem 47:597–600PubMedGoogle Scholar
  29. 29.
    Hannon R, Blumsohn A, Naylor K et al (1998) Response of biochemical markers of bone turnover to hormone replacement therapy: impact of biological variability. J Bone Miner Res 13:1124–1133PubMedCrossRefGoogle Scholar
  30. 30.
    Prestwood KM, Pilbeam CC, Burleson JA et al (1994) The short-term effects of conjugated estrogen on bone turnover in older women. J Clin Endocrinol Metab 79:366–371PubMedCrossRefGoogle Scholar
  31. 31.
    Eyre D (1992) New biomarkers of bone resorption. J Clin Endocrinol Metab 74:470A–470CPubMedCrossRefGoogle Scholar
  32. 32.
    Delmas PD (1990) Biochemical markers of bone turnover for the clinical assessment of metabolic bone disease. Endocrinol Metab Clin North Am 19:1–18PubMedGoogle Scholar
  33. 33.
    Moro L, Pozzi Mucelli RS et al (1988) Urinary beta-1-galactosyl-0-hydroxylysine (GH) as a marker of collagen turnover of bone. Calcif Tissue Int 42:87–90PubMedCrossRefGoogle Scholar
  34. 34.
    Price PA (1987) Vitamin K-dependent proteins. In: Cohn DV (ed) Calcium regulation and bone metabolism basic and clinical aspects. Amsterdam, Elsevier Science, The Netherlands, pp 419–425Google Scholar
  35. 35.
    Dickson IR (1993) Bone. In: Royce PM, Steinmann B (eds) Connective tissue and its heritable disorders. Wiley-Liss, New York, pp 249–285Google Scholar
  36. 36.
    Price PA (1985) Vitamin K-dependent formation of bone Gla protein (osteocalcin) and its function. Vitam Horm 42:65–108PubMedCrossRefGoogle Scholar
  37. 37.
    Riggs BL, Tsai KS, Mann KG (1986) Effect of acute increases in bone matrix degradation on circulating levels of bone-Gla protein. J Bone Miner Res 1:539–542PubMedGoogle Scholar
  38. 38.
    Garnero P, Grimaux M, Seguin P et al (1994) Characterization of immunoreactive forms of human osteocalcin generated in vivo and in vitro. J Bone Miner Res 9:255–264PubMedGoogle Scholar
  39. 39.
    Taylor AK, Linkhart S, Mohan S et al (1990) Multiple osteocalcin fragments in human urine and serum as detected by a midmolecule osteocalcin radioimmunoassay. J Clin Endocrinol Metab 7:467–472CrossRefGoogle Scholar
  40. 40.
    Low MG (1987) Biochemistry of the glycosyl–phosphatidylinositol membrane protein anchors. Biochem J 244:1–13PubMedGoogle Scholar
  41. 41.
    Harris H (1990) The human alkaline phosphatases: what we know and what we don’t know. Clin Chim Acta 186:133–150PubMedCrossRefGoogle Scholar
  42. 42.
    Green S, Anstiss CL, Fishman WH (1971) Automated differential isoenzyme analysis. II. The fractionation of serum alkaline phosphatases into “liver”, “intestinal” and “other” components. Enzymologia 41:9–26PubMedGoogle Scholar
  43. 43.
    Farley JR, Chesnut CH 3rd, Baylink DJ (1981) Improved method for quantitative determination in serum of alkaline phosphatase of skeletal origin. Clin Chem 27:2002–2007PubMedGoogle Scholar
  44. 44.
    Liu SH, Yang RS, al-Shaikh R et al (1995) Collagen in tendon, ligament, and bone healing. A current review. Clin Orthop Relat Res 318:265–278PubMedGoogle Scholar
  45. 45.
    Woo SLY, An KN, Arnoczky SP et al (1994) Anatomy, biology and biomechanics of tendon, ligament and meniscus. In: Simon SR (ed) Orthopaedic basic science. American Academy of Orthopaedic Surgeons, Chicago, pp 45–88Google Scholar
  46. 46.
    Smedsrod B, Melkko J, Risteli L et al (1990) Circulating C-terminal propeptide of type I procollagen is cleared mainly via the mannose receptor in liver endothelial cells. Biochem J 271:345–350PubMedGoogle Scholar
  47. 47.
    Lüftner D, Jozereau D, Schildhauer S et al (2005) PINP as serum marker of metastatic spread to the bone in breast cancer patients. Anticancer Res 25:1491–1499PubMedGoogle Scholar
  48. 48.
    Toivonen J, Tähtelä R, Laitinen K et al (1998) Markers of bone turnover in patients with differentiated thyroid cancer with and following withdrawal of thyroxine suppressive therapy. Eur J Endocrinol 138:667–673PubMedCrossRefGoogle Scholar
  49. 49.
    Crofton PM, Wade JC, Taylor MR et al (1997) Serum concentrations of carboxyl-terminal propeptide of type I procollagen, amino-terminal propeptide of type III procollagen, cross-linked carboxyl-terminal telopeptide of type I collagen, and their interrelationships in schoolchildren. Clin Chem 43:1577–1581PubMedGoogle Scholar
  50. 50.
    Garnero P, Sornay-Rendu E, Claustrat B et al (2000) Biochemical markers of bone turnover, endogenous hormones and the risk of fractures in postmenopausal women: the OFELY Study. J Bone Miner Res 15:1526–1536PubMedCrossRefGoogle Scholar
  51. 51.
    Garnero P, Hausherr E, Chapuy MC et al (1996) Markers of bone resorption predict hip fracture in elderly women: the EPIDOS Prospective Study. J Bone Miner Res 11:1531–1538PubMedCrossRefGoogle Scholar
  52. 52.
    van Daele PL, Seibel MJ, Burger H et al (1996) Case-control analysis of bone resorption markers, disability, and hip fracture risk: the Rotterdam Study. BMJ 312:482–483PubMedGoogle Scholar
  53. 53.
    Ross PD, Kress BC, Parson RE et al (2000) Serum bone alkaline phosphatase and calcaneus bone density predict fractures: a prospective study. Osteoporos Int 11:76–82PubMedCrossRefGoogle Scholar
  54. 54.
    Bauer DC, Sklarin PM, Stone KL et al (1999) Biochemical markers of bone turnover and prediction of hip bone loss in older women: the study of osteoporotic fractures. J Bone Miner Res 14:1404–1410PubMedCrossRefGoogle Scholar
  55. 55.
    Eastell R, Barton I, Hannon RA et al (2003) Relationship of early changes in bone resorption to the reduction in fracture risk with risedronate. J Bone Miner Res 18:1051–1056PubMedCrossRefGoogle Scholar
  56. 56.
    Eastell R, Hannon RA, Garnero P et al (2007) Relationship of early changes in bone resorption to the reduction in fracture risk with risedronate: review of statistical analysis. J Bone Miner Res 22:1656–1660PubMedCrossRefGoogle Scholar
  57. 57.
    Reginster JY, Adami S, Lakatos P et al (2006) Efficacy and tolerability of once-monthly oral ibandronate in postmenopausal osteoporosis: 2-year results from the MOBILE Study. Ann Rheum Dis 65:654–661PubMedCrossRefGoogle Scholar
  58. 58.
    Recker R, Stakkestad JA, Chesnut CH 3rd et al (2004) Insufficiently dosed intravenous ibandronate injections are associated with suboptimal antifracture efficacy in postmenopausal osteoporosis. Bone 34:890–899PubMedCrossRefGoogle Scholar
  59. 59.
    Bauer DC, Garnero P, Hochberg MC, for the Fracture Intervention Research Group et al (2006) Pretreatment levels of bone turnover and the antifracture efficacy of alendronate: the fracture intervention trial. J Bone Miner Res 21:292–299PubMedCrossRefGoogle Scholar
  60. 60.
    Black DM, Delmas PD, Eastell R et al (2007) Once-yearly zoledronic acid for treatment of postmenopausal osteoporosis. N Engl J Med 356:1809–1822PubMedCrossRefGoogle Scholar
  61. 61.
    Weinstein RS, Parfitt AM, Marcus R et al (2003) Effects of raloxifene, hormone replacement therapy, and placebo on bone turnover in postmenopausal women. Osteoporos Int 14:814–822PubMedCrossRefGoogle Scholar
  62. 62.
    Bone HG, Bolognese MA, Yuen CK et al (2008) Effects of denosumab on bone mineral density and bone turnover in postmenopausal women. J Clin Endocrinol Metab 93:2149–2157PubMedCrossRefGoogle Scholar
  63. 63.
    Anastasilakis AD, Goulis DG, Polyzos SA, et al (2009) No difference between strontium ranelate and calcium/vitamin D on bone turnover markers in women with established osteoporosis previously treated with teriparatide: a randomized controlled trial. Clin Endocrinol (Oxf). doi: 10.1111/j.1365-2265.2008.03342.x
  64. 64.
    Hochberg MC, Greenspan S, Wasnich RD et al (2002) Changes in bone density and turnover explain the reductions in incidence of nonvertebral fractures that occur during treatment with antiresorptive agents. J Clin Endocrinol Metab 87:1586–1592PubMedCrossRefGoogle Scholar
  65. 65.
    Raisz L, Smith JA, Trahiotis M et al (2000) Short-term risedronate treatment in postmenopausal women: effects on biochemical markers of bone turnover. Osteoporos Int 11:615–620PubMedCrossRefGoogle Scholar
  66. 66.
    Braga de Castro Machado A, Hannon R, Eastell R (1999) Monitoring alendronate therapy for osteoporosis. J Bone Miner Res 14:602–608PubMedCrossRefGoogle Scholar
  67. 67.
    Aoshima H, Kushida K, Takahashi M et al (1998) Circadian variation of urinary type I collagen crosslinked C-telopeptide and free and peptide-bound forms of pyridinium crosslinks. Bone 22:73–78PubMedCrossRefGoogle Scholar
  68. 68.
    Borderie D, Roux C, Toussaint B et al (2001) Variability in urinary excretion of bone resorption markers: limitations of a single determination in clinical practice. Clin Biochem 34:571–577PubMedCrossRefGoogle Scholar
  69. 69.
    Ju HS, Leung S, Brown B et al (1997) Comparison of analytical performance and biological variability of three bone resorption assays. Clin Chem 43:1570–1576PubMedGoogle Scholar
  70. 70.
    Gluer C (1999) Monitoring skeletal changes by radiologic techniques. J Bone Miner Res 14:1952–1962PubMedCrossRefGoogle Scholar
  71. 71.
    Shepherd JA, Morgan SL, Lu Y (2008) Comparing BMD results between two similar DXA systems using the generalized least significant changes. J Clin Densitom 11:237–242PubMedCrossRefGoogle Scholar
  72. 72.
    Bauer DC, Garnero P, Bilezikian JP et al (2006) Short-term changes in bone turnover markers and bone mineral density response to parathyroid hormone in postmenopausal women with osteoporosis. J Clin Endocrinol Metab 91:1370–1375PubMedCrossRefGoogle Scholar
  73. 73.
    Raehl CL, Bond CA, Woods TJ et al (2006) Screening tests for intended medication adherence among the elderly. Ann Pharmacother 40:888–893PubMedCrossRefGoogle Scholar
  74. 74.
    McHorney CA, Schousboe JT, Cline RR et al (2007) The impact of osteoporosis medication beliefs and side-effect experiences on non-adherence to oral bisphosphonates.. Curr Med Res Opin 23:3137–3152 (Erratum in: Curr Med Res Opin. 2008;24:707)PubMedCrossRefGoogle Scholar
  75. 75.
    Caro JJ, Ishak KJ, Huybrechts KF et al (2004) The impact of compliance with osteoporosis therapy on fracture rates in actual practice. Osteoporos Int 15:1003–1008PubMedCrossRefGoogle Scholar
  76. 76.
    Cramer JA, Amonkar MM, Hebborn A et al (2005) Compliance and persistence with bisphosphonate dosing regimens among women with postmenopausal osteoporosis. Curr Med Res Opin 21:1453–1460PubMedCrossRefGoogle Scholar
  77. 77.
    Solomon DH, Avorn J, Katz JN et al (2005) Compliance with osteoporosis medications. Arch Intern Med 165:2414–2419PubMedCrossRefGoogle Scholar
  78. 78.
    Cooper A, Drake J, Brankin E (2006) Treatment persistence with once monthly ibandronate and patient support vs once-weekly alendronate: results from the PERSIST Study. Int J Clin Pract 60:896–905PubMedCrossRefGoogle Scholar
  79. 79.
    Seibel MJ (2006) Biochemical markers of bone turnover part II: clinical applications in the management of osteoporosis. Clin Biochem Rev 27:123–138PubMedGoogle Scholar
  80. 80.
    Russell RG, Rogers MJ (1999) Bisphosphonates: from the laboratory to the clinic and back again. Bone 25:97–106PubMedCrossRefGoogle Scholar
  81. 81.
    Clowes JA, Peel NF, Eastell R (2004) The impact of monitoring on adherence and persistence with antiresorptive treatment for postmenopausal osteoporosis: a randomized controlled trial. J Clin Endocrinol Metab 89:1117–1123PubMedCrossRefGoogle Scholar
  82. 82.
    Delmas PD, Vrijens B, Roux C et al (2003) A reinforcement message based on bone turnover markers response influences long-term persistence with risedronate in osteoporosis: the IMPACT Study. J Bone Miner Res 18(suppl 2):S374Google Scholar
  83. 83.
    Civitelli R, Gonnelli S, Zacchei F et al (1988) Bone turnover in postmenopausal osteoporosis. Effect of calcitonin treatment. J Clin Invest 82:1268–1274PubMedCrossRefGoogle Scholar
  84. 84.
    Chesnut CH III, Bell NH, Clark GS et al (1997) Hormone replacement therapy in postmenopausal women: urinary N-telopeptide of type I collagen monitors therapeutic effect and predicts response of bone mineral density. Am J Med 102:29–37PubMedCrossRefGoogle Scholar
  85. 85.
    Uebelhart D, Schlemmer A, Johansen JS et al (1991) Effect of menopause and hormone replacement therapy on the urinary excretion of pyridinium cross-links. J Clin Endocrinol Metab 72:367–373PubMedCrossRefGoogle Scholar
  86. 86.
    Ettinger B, Black DM, Mitlak BH et al (1999) Reduction of vertebral fracture risk in postmenopausal women with osteoporosis treated with raloxifene: results from a 3-year randomized clinical trial. Multiple Outcomes of Raloxifene Evaluation (MORE) Investigators. JAMA 282:637–645PubMedCrossRefGoogle Scholar
  87. 87.
    Harris ST, Watts NB, Genant HK et al (1999) Effects of risedronate treatment on vertebral and nonvertebral fractures in women with postmenopausal osteoporosis: a randomized controlled trial. Vertebral Efficacy With Risedronate Therapy (VERT) Study Group. JAMA 282:1344–1352PubMedCrossRefGoogle Scholar
  88. 88.
    Schaffler MB, Choi K, Milgrom C (1995) Aging and matrix microdamage accumulation in human compact bone. Bone 17:521–525PubMedCrossRefGoogle Scholar
  89. 89.
    Mashiba T, Hirano T, Turner CH et al (2000) Suppressed bone turnover by bisphosphonates increases microdamage accumulation and reduces some biomechanical properties in dog rib. J Bone Miner Res 15:613–620PubMedCrossRefGoogle Scholar
  90. 90.
    Bouxsein ML (2003) Bone quality: where do we go from here? Osteoporos Int 14(suppl 5):118–127CrossRefGoogle Scholar
  91. 91.
    Visekruna M, Wilson D, McKiernan FE (2008) Severely suppressed bone turnover and atypical skeletal fragility. J Clin Endocrinol Metab 93:2948–2952PubMedCrossRefGoogle Scholar
  92. 92.
    Neviaser AS, Lane JM, Lenart BA et al (2008) Low-energy femoral shaft fractures associated with alendronate use. J Orthop Trauma 22:346–350PubMedCrossRefGoogle Scholar

Copyright information

© International Osteoporosis Foundation and National Osteoporosis Foundation 2009

Authors and Affiliations

  • R. Civitelli
    • 1
  • R. Armamento-Villareal
    • 1
  • N. Napoli
    • 1
    • 2
  1. 1.Division of Bone and Mineral Diseases, Department of Internal MedicineWashington University School of MedicineSt. LouisUSA
  2. 2.Campus Bio-Medico di RomaRomeItaly

Personalised recommendations