Calcified Tissue International

, Volume 103, Issue 5, pp 512–521 | Cite as

Comparison of Bone Microarchitecture Between Adult Osteogenesis Imperfecta and Early-Onset Osteoporosis

  • Tim RolvienEmail author
  • Julian Stürznickel
  • Felix N. Schmidt
  • Sebastian Butscheidt
  • Tobias Schmidt
  • Björn Busse
  • Stefan Mundlos
  • Thorsten Schinke
  • Uwe Kornak
  • Michael Amling
  • Ralf Oheim
Original Research


Diagnosis and management of adult individuals with low bone mass and increased bone fragility before the age of 50 can be challenging. A number of these patients are diagnosed with mild osteogenesis imperfecta (OI) through detection of COL1A1 or COL1A2 mutations; however, a clinical differentiation from early-onset osteoporosis (EOOP) may be difficult. The purpose of this study was to determine the bone microstructural differences between mild OI and EOOP patients. 29 patients showed mutations in COL1A1 or COL1A2 and were classified as OI. Skeletal assessment included dual-energy X-ray absorptiometry (DXA), high-resolution peripheral quantitative computed tomography (HR-pQCT), and bone turnover serum analyses. Bone microstructure of 21/29 OI patients was assessed and compared to 23 age- and sex-matched patients clinically classified EOOP but without mutations in the known disease genes as well as to 20 healthy controls. In the OI patients, we did not observe an age-dependent decrease in DXA Z-scores. HR-pQCT revealed a significant reduction in volumetric BMD and microstructural parameters in the distal radius and tibia in both the OI and EOOP cohorts compared to the healthy controls. When comparing the bone microstructure of OI patients with the EOOP cohort, significant differences were found in terms of bone geometry in the radius, while no significant changes were detected in all other HR-pQCT parameters at the radius and tibia. Taken together, adult mild OI patients demonstrate a predominantly high bone turnover trabecular bone loss syndrome that shows minor microstructural differences compared to EOOP without mutation detection.


Osteogenesis imperfecta HR-pQCT Collagen type I Early-onset osteoporosis Gene panel sequencing 



This project has received funding from the European Community’s Seventh Framework Programme under Grant Agreement No. 602300 (SYBIL) and the German Federal Ministry of Education and Research (BMBF) within the project “Detection and Individualized Management of Early Onset Osteoporosis (DIMEOs).” Felix Schmidt acknowledges a PhD stipend of the Joachim Herz Stiftung in cooperation with the PIER initiative of the University of Hamburg and DESY Hamburg.

Compliance with Ethical Standards

Conflict of interest

Tim Rolvien, Julian Stürznickel, Felix N. Schmidt, Sebastian Butscheidt, Tobias Schmidt, Björn Busse, Stefan Mundlos, Thorsten Schinke, Uwe Kornak, Michael Amling, and Ralf Oheim declare that they have no conflict of interest.

Human and Animal Rights and Informed Consent

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Informed consent was obtained from all patients for the retrospective and anonymized database studies.

Supplementary material

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Supplementary material 1 (TIFF 1581 KB)
223_2018_447_MOESM2_ESM.docx (26 kb)
Supplementary material 2 (DOCX 25 KB)


  1. 1.
    Forlino A, Marini JC (2016) Osteogenesis imperfecta. Lancet 387:1657–1671CrossRefPubMedCentralGoogle Scholar
  2. 2.
    Sillence DO, Senn A, Danks DM (1979) Genetic heterogeneity in osteogenesis imperfecta. J Med Genet 16:101–116CrossRefPubMedCentralGoogle Scholar
  3. 3.
    Forlino A, Cabral WA, Barnes AM, Marini JC (2011) New perspectives on osteogenesis imperfecta. Nat Rev Endocrinol 7:540–557CrossRefPubMedCentralGoogle Scholar
  4. 4.
    Keupp K, Beleggia F, Kayserili H, Barnes AM, Steiner M, Semler O, Fischer B, Yigit G, Janda CY, Becker J, Breer S, Altunoglu U, Grunhagen J, Krawitz P, Hecht J, Schinke T, Makareeva E, Lausch E, Cankaya T, Caparros-Martin JA, Lapunzina P, Temtamy S, Aglan M, Zabel B, Eysel P, Koerber F, Leikin S, Garcia KC, Netzer C, Schonau E, Ruiz-Perez VL, Mundlos S, Amling M, Kornak U, Marini J, Wollnik B (2013) Mutations in WNT1 cause different forms of bone fragility. Am J Hum Genet 92:565–574CrossRefPubMedCentralGoogle Scholar
  5. 5.
    Laine CM, Joeng KS, Campeau PM, Kiviranta R, Tarkkonen K, Grover M, Lu JT, Pekkinen M, Wessman M, Heino TJ, Nieminen-Pihala V, Aronen M, Laine T, Kroger H, Cole WG, Lehesjoki AE, Nevarez L, Krakow D, Curry CJ, Cohn DH, Gibbs RA, Lee BH, Makitie O (2013) WNT1 mutations in early-onset osteoporosis and osteogenesis imperfecta. N Engl J Med 368:1809–1816CrossRefPubMedCentralGoogle Scholar
  6. 6.
    Saarinen A, Saukkonen T, Kivela T, Lahtinen U, Laine C, Somer M, Toiviainen-Salo S, Cole WG, Lehesjoki AE, Makitie O (2010) Low density lipoprotein receptor-related protein 5 (LRP5) mutations and osteoporosis, impaired glucose metabolism and hypercholesterolaemia. Clin Endocrinol 72:481–488CrossRefGoogle Scholar
  7. 7.
    van Dijk FS, Zillikens MC, Micha D, Riessland M, Marcelis CL, de Die-Smulders CE, Milbradt J, Franken AA, Harsevoort AJ, Lichtenbelt KD, Pruijs HE, Rubio-Gozalbo ME, Zwertbroek R, Moutaouakil Y, Egthuijsen J, Hammerschmidt M, Bijman R, Semeins CM, Bakker AD, Everts V, Klein-Nulend J, Campos-Obando N, Hofman A, te Meerman GJ, Verkerk AJ, Uitterlinden AG, Maugeri A, Sistermans EA, Waisfisz Q, Meijers-Heijboer H, Wirth B, Simon ME, Pals G (2013) PLS3 mutations in X-linked osteoporosis with fractures. N Engl J Med 369:1529–1536CrossRefPubMedCentralGoogle Scholar
  8. 8.
    Gatti D, Colapietro F, Fracassi E, Sartori E, Antoniazzi F, Braga V, Rossini M, Adami S (2003) The volumetric bone density and cortical thickness in adult patients affected by osteogenesis imperfecta. J Clin Densitom 6:173–177CrossRefPubMedCentralGoogle Scholar
  9. 9.
    Boutroy S, Bouxsein ML, Munoz F, Delmas PD (2005) In vivo assessment of trabecular bone microarchitecture by high-resolution peripheral quantitative computed tomography. J Clin Endocrinol Metab 90:6508–6515CrossRefPubMedCentralGoogle Scholar
  10. 10.
    Sornay-Rendu E, Boutroy S, Munoz F, Delmas PD (2007) Alterations of cortical and trabecular architecture are associated with fractures in postmenopausal women, partially independent of decreased BMD measured by DXA: the OFELY study. J Bone Miner Res 22:425–433CrossRefPubMedCentralGoogle Scholar
  11. 11.
    Folkestad L, Hald JD, Hansen S, Gram J, Langdahl B, Abrahamsen B, Brixen K (2012) Bone geometry, density, and microarchitecture in the distal radius and tibia in adults with osteogenesis imperfecta type I assessed by high-resolution pQCT. J Bone Miner Res 27:1405–1412CrossRefPubMedCentralGoogle Scholar
  12. 12.
    Kocijan R, Muschitz C, Haschka J, Hans D, Nia A, Geroldinger A, Ardelt M, Wakolbinger R, Resch H (2015) Bone structure assessed by HR-pQCT, TBS and DXL in adult patients with different types of osteogenesis imperfecta. Osteoporos Int 26:2431–2440CrossRefPubMedCentralGoogle Scholar
  13. 13.
    Hald JD, Folkestad L, Harslof T, Lund AM, Duno M, Jensen JB, Neghabat S, Brixen K, Langdahl B (2016) Skeletal phenotypes in adult patients with osteogenesis imperfecta—correlations with COL1A1/COL1A2 genotype and collagen structure. Osteoporos Int 27:3331–3341CrossRefPubMedCentralGoogle Scholar
  14. 14.
    Sykes B, Ogilvie D, Wordsworth P, Wallis G, Mathew C, Beighton P, Nicholls A, Pope FM, Thompson E, Tsipouras P, Schwartz R, Jensson O, Arnason A, Børresen A-L, Heiberg A, Frey D, Steinmann B (1990) Consistent linkage of dominantly inherited osteogenesis imperfecta to the type I collagen loci: COL1A1 and COL1A2. Am J Hum Genet 46:293–307PubMedPubMedCentralGoogle Scholar
  15. 15.
    Mrosk J, Gandham SB, Shah H, Hecht J, Krüger U, Shukla A, Kornak U, Girisha KM (2018) Diagnostic strategies and genotype-phenotype correlation in a large Indian cohort of osteogenesis imperfecta. Bone 110:368–377CrossRefPubMedCentralGoogle Scholar
  16. 16.
    Rolvien T, Kornak U, Sturznickel J, Schinke T, Amling M, Mundlos S, Oheim R (2017) A novel COL1A2 C-propeptide cleavage site mutation causing high bone mass osteogenesis imperfecta with a regional distribution pattern. Osteoporos Int 29:243–246CrossRefPubMedCentralGoogle Scholar
  17. 17.
    Rolvien T, Koehne T, Kornak U, Lehmann W, Amling M, Schinke T, Oheim R (2017) A novel ANO5 mutation causing gnathodiaphyseal dysplasia with high bone turnover osteosclerosis. J Bone Miner Res 32:277–284CrossRefPubMedCentralGoogle Scholar
  18. 18.
    Zemojtel T, Kohler S, Mackenroth L, Jager M, Hecht J, Krawitz P, Graul-Neumann L, Doelken S, Ehmke N, Spielmann M, Oien NC, Schweiger MR, Kruger U, Frommer G, Fischer B, Kornak U, Flottmann R, Ardeshirdavani A, Moreau Y, Lewis SE, Haendel M, Smedley D, Horn D, Mundlos S, Robinson PN (2014) Effective diagnosis of genetic disease by computational phenotype analysis of the disease-associated genome. Sci Transl Med 6:252ra123CrossRefPubMedCentralGoogle Scholar
  19. 19.
    Milovanovic P, Adamu U, Simon MJ, Rolvien T, Djuric M, Amling M, Busse B (2015) Age- and sex-specific bone structure patterns portend bone fragility in radii and tibiae in relation to osteodensitometry: a high-resolution peripheral quantitative computed tomography study in 385 individuals. J Gerontol A 70:1269–1275CrossRefGoogle Scholar
  20. 20.
    Mussawy H, Ferrari G, Schmidt FN, Schmidt T, Rolvien T, Hischke S, Ruther W, Amling M (2017) Changes in cortical microarchitecture are independent of areal bone mineral density in patients with fragility fractures. Injury 48:2461–2465CrossRefPubMedCentralGoogle Scholar
  21. 21.
    Schmidt T, Schmidt C, Schmidt FN, Butscheidt S, Mussawy H, Hubert J, Hawellek T, Oehler N, Barvencik F, Lohse AW, Schinke T, Schramm C, Amling M, Rolvien T (2018) Disease duration and stage influence bone microstructure in patients with primary biliary cholangitis. J Bone Miner Res 33(6):1011–1019CrossRefPubMedCentralGoogle Scholar
  22. 22.
    Pollitt R, McMahon R, Nunn J, Bamford R, Afifi A, Bishop N, Dalton A (2006) Mutation analysis of COL1A1 and COL1A2 in patients diagnosed with osteogenesis imperfecta type I-IV. Hum Mutat 27:716CrossRefPubMedCentralGoogle Scholar
  23. 23.
    Spotila LD, Constantinou CD, Sereda L, Ganguly A, Riggs BL, Prockop DJ (1991) Mutation in a gene for type I procollagen (COL1A2) in a woman with postmenopausal osteoporosis: evidence for phenotypic and genotypic overlap with mild osteogenesis imperfecta. Proc Natl Acad Sci USA 88:5423–5427CrossRefPubMedCentralGoogle Scholar
  24. 24.
    Styrkarsdottir U, Thorleifsson G, Eiriksdottir B, Gudjonsson SA, Ingvarsson T, Center JR, Nguyen TV, Eisman JA, Christiansen C, Thorsteinsdottir U, Sigurdsson G, Stefansson K (2016) Two rare mutations in the COL1A2 gene associate with low bone mineral density and fractures in Iceland. J Bone Miner Res 31:173–179CrossRefPubMedCentralGoogle Scholar
  25. 25.
    Butscheidt S, Delsmann A, Rolvien T, Barvencik F, Al-Bughaili M, Mundlos S, Schinke T, Amling M, Kornak U, Oheim R (2018) Mutational analysis uncovers monogenic bone disorders in women with pregnancy-associated osteoporosis: three novel mutations in LRP5, COL1A1, and COL1A2. Osteoporos Int. CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Spotila LD, Colige A, Sereda L, Constantinou-Deltas CD, Whyte MP, Riggs BL, Shaker JL, Spector TD, Hume E, Olsen N et al (1994) Mutation analysis of coding sequences for type I procollagen in individuals with low bone density. J Bone Miner Res 9:923–932CrossRefPubMedCentralGoogle Scholar
  27. 27.
    Van Dijk FS, Nesbitt IM, Nikkels PG, Dalton A, Bongers EM, Van De Kamp JM, Hilhorst-Hofstee Y, Den Hollander NS, Lachmeijer AM, Marcelis CL (2009) CRTAP mutations in lethal and severe osteogenesis imperfecta: the importance of combining biochemical and molecular genetic analysis. Eur J Hum Genet 17:1560CrossRefPubMedCentralGoogle Scholar
  28. 28.
    Wekre LL, Eriksen EF, Falch JA (2011) Bone mass, bone markers and prevalence of fractures in adults with osteogenesis imperfecta. Arch Osteoporos 6:31–38CrossRefPubMedCentralGoogle Scholar
  29. 29.
    Paterson CR, Mole PA (1994) Bone density in osteogenesis imperfecta may well be normal. Postgrad Med J 70:104–107CrossRefPubMedCentralGoogle Scholar
  30. 30.
    Rauch F, Travers R, Parfitt AM, Glorieux FH (2000) Static and dynamic bone histomorphometry in children with osteogenesis imperfecta. Bone 26:581–589CrossRefPubMedCentralGoogle Scholar
  31. 31.
    Lisse TS, Thiele F, Fuchs H, Hans W, Przemeck GK, Abe K, Rathkolb B, Quintanilla-Martinez L, Hoelzlwimmer G, Helfrich M (2008) ER stress-mediated apoptosis in a new mouse model of osteogenesis imperfecta. PLoS Genet 4:e7CrossRefPubMedCentralGoogle Scholar
  32. 32.
    Mirigian LS, Makareeva E, Mertz EL, Omari S, Roberts-Pilgrim AM, Oestreich AK, Phillips CL, Leikin S (2016) Osteoblast malfunction caused by cell stress response to procollagen misfolding in α2 (I)-G610C mouse model of osteogenesis imperfecta. J Bone Miner Res 31:1608–1616CrossRefPubMedCentralGoogle Scholar
  33. 33.
    Glorieux FH, Devogelaer JP, Durigova M, Goemaere S, Hemsley S, Jakob F, Junker U, Ruckle J, Seefried L, Winkle PJ (2017) BPS804 anti-sclerostin antibody in adults with moderate osteogenesis imperfecta: results of a randomized phase 2a trial. J Bone Miner Res 32:1496–1504CrossRefPubMedCentralGoogle Scholar
  34. 34.
    Braga V, Gatti D, Rossini M, Colapietro F, Battaglia E, Viapiana O, Adami S (2004) Bone turnover markers in patients with osteogenesis imperfecta. Bone 34:1013–1016CrossRefPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Tim Rolvien
    • 1
    • 2
    Email author
  • Julian Stürznickel
    • 1
  • Felix N. Schmidt
    • 1
  • Sebastian Butscheidt
    • 1
  • Tobias Schmidt
    • 1
    • 2
  • Björn Busse
    • 1
  • Stefan Mundlos
    • 3
    • 4
    • 5
  • Thorsten Schinke
    • 1
  • Uwe Kornak
    • 3
    • 4
    • 5
  • Michael Amling
    • 1
  • Ralf Oheim
    • 1
  1. 1.Department of Osteology and BiomechanicsUniversity Medical Center Hamburg-EppendorfHamburgGermany
  2. 2.Department of OrthopedicsUniversity Medical Center Hamburg-EppendorfHamburgGermany
  3. 3.Institute of Medical Genetics and Human GeneticsCharité Universitätsmedizin BerlinBerlinGermany
  4. 4.Berlin-Brandenburg School for Regenerative TherapiesCharité-Universitätsmedizin BerlinBerlinGermany
  5. 5.FG Development and DiseaseMax Planck Institute for Molecular GeneticsBerlinGermany

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