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Clinical spectrum of rare bone fragility disorders and response to bisphosphonate treatment: a retrospective study

European Journal of Human Genetics volume 32, pages 1559–1566 (2024)Cite this article

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Abstract

Osteogenesis Imperfecta (OI) is a clinically and genetically heterogeneous group of diseases characterized by brittle bones. Though genetic mutations in COL1A1 and COL1A2 account for approximately 85–90% of OI cases, there are now more than twenty genes described, responsible for rare forms of OI. Treatment is based on the use of bisphosphonates and though it is well established that they increase lumbar spine (LS) bone mineral density (BMD), the clinical impact on fracture reduction is still debated.

In this study, we investigated the clinical characteristics of 38 patients with a bone fragility disorder that had variants in non-COL1A1/COL1A2 genes in order to study genotype-phenotype correlations, as the natural history of these rare forms is still not well known. We then studied the usefulness of bisphosphonate treatment by evaluating the effects on LS BMD, annual non-vertebral fracture rate, bone turnover markers and height. This study enabled us to better define the natural history of patients with non-COL1 pathogenic variants. Patients with CRTAP and TMEM38B variants consistently had a prenatal presentation with a short (<3rd p) and bowed femur. Importantly, this prenatal involvement does not predict the postnatal severity of the disease. Regarding treatment by bisphosphonates, all patients showed a significant increase in LS BMD while treated and this increase was dependent on the dose received. The increase in LS BMD also translated in a reduction of fracture rate during treatment. Finally, our study showed that the earlier bisphosphonates are initiated, the greater the fracture rate is reduced.

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Fig. 1: Annual ⩟LS BMD without treatment and according to treatment dose.
Fig. 2: Evolution of LS BMD (g/cm2) during treatment.
Fig. 3: Yearly fracture rates before, during and after treatment discontinuation.

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Data availability

The datasets generated and analyzed during the current study are available from the corresponding author on reasonable request.

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Funding

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Author information

Authors and Affiliations

  1. Department of Genomic Medicine for Rare Diseases, French Reference Center for Constitutional Bone Diseases, Necker-Enfants Malades Hospital, Paris, France

    Maëlle Charpié, Geneviève Baujat, Caroline Michot, Sophie Monnot & Valérie Cormier-Daire

  2. Paris Cité University, INSERM UMR 1163, Imagine institute, Paris, France

    Maëlle Charpié, Perrine Brunelle, Geneviève Baujat, Caroline Michot, Eugénie Koumakis, Zagorka Pejin, Sophie Monnot & Valérie Cormier-Daire

  3. Institute for Medical Genetics, ULR 7364, Lille University Hospital Jeanne de Flandre Hospital, Lille, Hauts-de, France

    Perrine Brunelle

  4. Department of Medical Genetics, University Hospital Centre Bordeaux, Bordeaux, Nouvelle-Aquitaine, France

    Julien Van Gils

  5. University of Bordeaux, INSERM U1211, Talence, Aquitaine, France

    Julien Van Gils

  6. Department of Clinical Genetics, Nancy Regional University Hospital Center, Nancy, Grand Est, France

    Bruno Leheup

  7. Department of Genomic Medicine for Rare Diseases, Strasbourg University Hospitals, Strasbourg, Grand Est, France

    Élise Schaefer

  8. Reference Center for Rare Bone Diseases, Rheumatology Institute, Cochin Hospital, Paris, France

    Eugénie Koumakis

  9. Department of Pediatric Orthopedic Surgery, Necker-Enfants Malades Hospital, Paris, France

    Zagorka Pejin

  10. Department of Pediatric Endocrinology, Necker-Enfants Malades Hospital, Paris, France

    Graziella Pinto

Authors
  1. Maëlle Charpié
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  2. Perrine Brunelle
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  11. Sophie Monnot
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  12. Valérie Cormier-Daire
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Contributions

MC conceived and designed the work that led to the submission, acquired data, played an important role in interpreting the results and drafted the manuscript. PB, GB, CM, JVG, BL, ES, EK, ZP, GP and SM contributed to data extraction. VCD conceived and designed the work that led to the submission, played an important role in interpreting the results. All contributing authors revised the manuscript, provided feedback and approved the final version.

Corresponding author

Correspondence to Valérie Cormier-Daire.

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The authors declare no competing interests.

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This study was approved by the CER APHP ethics committee.

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Charpié, M., Brunelle, P., Baujat, G. et al. Clinical spectrum of rare bone fragility disorders and response to bisphosphonate treatment: a retrospective study. Eur J Hum Genet 32, 1559–1566 (2024). https://doi.org/10.1038/s41431-024-01645-4

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