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Skeletal phenotypes in adult patients with osteogenesis imperfecta—correlations with COL1A1/COL1A2 genotype and collagen structure

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Abstract

Summary

Osteogenesis imperfecta (OI) is characterized by a high fracture rate and great heterogeneity. This cross-sectional study presents skeletal investigations and protein analyses in 85 adult OI patients. We find significant differences in bone mass, architecture, and fracture rate that correlate well with the underlying biochemical and molecular abnormalities.

Introduction

OI is a hereditary disease characterized by compromised connective tissue predominantly caused by mutations in collagen type 1 (COL-1) encoding genes. Widespread symptoms reflect the ubiquity of COL-1 throughout the body. The purpose of this study was to improve our understanding of clinical manifestations by investigating anthropometry and skeletal phenotypes (DXA, HRpQCT) in an adult OI population and compare the findings to underlying COL-1 genotype and structure.

Methods

The study comprised 85 OI patients aged 45 (19–78) years, Sillence type I (n = 58), III (n = 12), and IV (n = 15). All patients underwent DXA, HRpQCT, spine X-ray, biochemical testing, and anthropometry. COL1A1 and COL1A2 were sequenced and 68 OI causing mutations identified (46 in COL1A1, 22 in COL1A2). Analysis of COL-1 structure (quantitative/qualitative defect) by SDS-PAGE was performed in a subset (n = 67).

Results

A qualitative collagen defect predisposed to a more severe phenotype with reduced aBMD, more fractures, and affected anthropometry compared to patients with a quantitative COL-1 defect (p < 0.05). HRpQCT revealed significant differences between patients with OI type I and IV. Patients with type I had lower vBMD (p < 0.005), thinner cortexes (p < 0.001), and reduced trabecular number (p < 0.005) compared to patients with type IV indicating that HRpQCT may distinguish type I from type IV better than DXA.

Conclusion

The defective collagen in patients with OI has pronounced effects on the skeleton. The classical OI types based on the clinical classification show profound differences in bone mass and architecture and the differences correlate well with the underlying biochemical and molecular collagen abnormalities.

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Acknowledgments

We thank Osteoporoseforeningen, A.P. Møllers Fond for almene Formaal, Karen Elise Jensens Fond, and Toyotafonden for financial support for the HRpQCT scanner, and Clinical Institute, AUH and Grosserer L.F.Foghts Fond for supporting the collagen analyses.

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Authors and Affiliations

  1. Department of Endocrinology and Metabolism, Aarhus University Hospital, Tage Hansensgade 2, Aarhus C, Denmark

    J. D. Hald, T. Harsløf & B. Langdahl

  2. Department of Endocrinology, Odense University Hospital, Odense, Denmark

    L. Folkestad & K. Brixen

  3. Institute of Clinical Research, University of Southern Denmark, Odense, Denmark

    L. Folkestad

  4. Department of Endocrinology, Hospital of Southwest Denmark, Esbjerg, Denmark

    L. Folkestad

  5. Centre for Inherited Metabolic Diseases, Department of Clinical Genetics, Rigshospitalet, Copenhagen, Denmark

    A. M. Lund & M. Duno

  6. Department of Endocrinology, Hvidovre Hospital, Hvidovre, Denmark

    J. B. Jensen

  7. Department of Radiology, Aarhus University Hospital, Aarhus, Denmark

    S. Neghabat

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  1. J. D. Hald
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  2. L. Folkestad
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  3. T. Harsløf
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  4. A. M. Lund
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  7. S. Neghabat
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  8. K. Brixen
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  9. B. Langdahl
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Corresponding author

Correspondence to J. D. Hald.

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Conflicts of interests

Authors JDH and TH received speaker fee from Amgen. LF received speaker fee from Genzymes. JEBJ received board membership and speaker fee from Amgen, Eli Lilly, and MSD. BL received advisory boards and speaker fee from Amgen, Eli Lilly, Merck, and UCB, and received research support from Eli Lilly, Novo Nordisk, and Orkla. All the other authors declare that they have no conflicts of interest.

Grant supporters

Grants were by the Clinical Institute of Health, AUH, Denmark; Central Region of Denmark; Osteoporoseforeningen, Denmark; Grosserer L.F. Foghts Fond; A.P. Møller og Hustru Chastine Mc-Kinney Møllers Fond til almene Formaal; Karen Elise Jensens Fond; Toyota-Fonden.

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Hald, J.D., Folkestad, L., Harsløf, T. et al. Skeletal phenotypes in adult patients with osteogenesis imperfecta—correlations with COL1A1/COL1A2 genotype and collagen structure. Osteoporos Int 27, 3331–3341 (2016). https://doi.org/10.1007/s00198-016-3653-0

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  • DOI: https://doi.org/10.1007/s00198-016-3653-0

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