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Higher fracture prevalence and smaller bone size in patients with hEDS/HSD—a prospective cohort study

Abstract

Summary

Increased fracture risk in patients with Ehlers-Danlos syndromes has been reported, but the reasons for it are incompletely understood. We aimed to investigate possible determinants of this increased risk and found that hEDS/HSD patients present with a cortical bone size deficit compared with control subjects, possibly related to lower mechanical loading.

Introduction

The Ehlers-Danlos syndromes (EDS) comprise a group of heritable connective tissue disorders caused by defects in the biosynthesis, secretion, and/or organization of fibrillar collagens which might impair bone strength. Our aim was to compare fracture prevalence, volumetric and areal bone mineral density (BMD), bone geometry, muscle size and the muscle-bone interaction, body composition and longitudinal changes therein between patients with hypermobile EDS (hEDS) or hypermobility spectrum disorder (HSD), and healthy control subjects.

Methods

Cross-sectional data comprised 39 female hEDS/HSD patients (age 41 ± 11 years) and 43 age-matched controls. After 8 years, 27 hEDS/HSD and 17 control subjects were re-evaluated. Tibial trabecular and cortical volumetric BMD, bone mineral content (BMC), cortical bone geometry, and lower leg muscle cross-sectional area (CSA) were measured using pQCT. Body composition, areal BMD, and BMC were determined by DXA.

Results

At baseline, patients with hEDS/HSD presented with a smaller cortical bone area, smaller cortical thickness and muscle CSA, and a higher fracture prevalence than control subjects (all p < 0.05). No differences in areal or volumetric BMD were found. Longitudinally, muscle CSA decreased in both groups and muscle density decreased in the hEDS/HSD group (p < 0.001) whereas all bone parameters remained unchanged.

Conclusion

hEDS/HSD patients have a cortical bone size deficit compared with controls, possibly contributing to their increased fracture risk. They presented with decreased muscle CSA but normal bone/muscle area ratio, suggesting that this bone size deficit is likely secondary to decreased mechanical loading. Further, there were no arguments for accelerated bone loss in hEDS/HSD subjects.

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References

  1. Syx D, De Wandele I, Symoens S, De Rycke R, Hougrand O, Voermans N et al (2019) Bi-allelic AEBP1 mutations in two patients with Ehlers–Danlos syndrome. Hum Mol Genet 00(00):1–12

    Google Scholar 

  2. Malfait F, Francomano C, Byers P, Belmont J, Berglund B, Black J et al (2017) The 2017 international classification of the Ehlers–Danlos syndromes. Am J Med Genet C Semin Med Genet 175(1):8–26

    PubMed  Article  Google Scholar 

  3. Castori M, Tinkle B, Levy H, Grahame R, Malfait F, Hakim A (2017) A framework for the classification of joint hypermobility and related conditions. Am J Med Genet C Semin Med Genet 175(1):148–157

    PubMed  Article  Google Scholar 

  4. Frost HM (1987) Bone “mass” and the “mechanostat”: a proposal. Anat Rec 219(1):1–9

    CAS  PubMed  Article  Google Scholar 

  5. Burt LA, Greene DA, Naughton GA (2017) Bone health of young male gymnasts: a systematic review. Pediatr Exerc Sci 29(4):456–464

    PubMed  Article  Google Scholar 

  6. De Paepe A, Malfait F (2012) The Ehlers-Danlos syndrome, a disorder with many faces. Clin Genet 82(1):1–11

    PubMed  Article  CAS  Google Scholar 

  7. Eller-Vainicher C, Bassotti A, Imeraj A, Cairoli E, Ulivieri FM, Cortini F et al (2016) Bone involvement in adult patients affected with Ehlers-Danlos syndrome. Osteoporos Int 27(8):2525–2531

    CAS  PubMed  Article  Google Scholar 

  8. Mazziotti G, Dordoni C, Doga M, Galderisi F, Venturini M, Calzavara-Pinton P et al (2016) High prevalence of radiological vertebral fractures in adult patients with Ehlers-Danlos syndrome. Bone 84:88–92. Available from:. https://doi.org/10.1016/j.bone.2015.12.007

    CAS  PubMed  Article  Google Scholar 

  9. Holick MF, Hossein-Nezhad A, Tabatabaei F (2017) Multiple fractures in infants who have Ehlers-Danlos/hypermobility syndrome and or vitamin d deficiency: a case series of 72 infants whose parents were accused of child abuse and neglect. Dermatoendocrinol 9(1):e1279768. https://doi.org/10.1080/19381980

  10. Carbone L, Tylavsky F, bush a J, Koo W, Orwoll E, Cheng S (2000) Bone density in Ehlers-Danlos syndrome. Osteoporosis Int 11:388–392

    CAS  Article  Google Scholar 

  11. Dolan AL, Arden NK, Grahame R, Spector TD (1998) Assessment of bone in Ehlers Danlos syndrome by ultrasound and densitometry. Ann Rheum Dis 57(10):630–633

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  12. Cheng S, Tylavsky FA, Orwoll ES, Rho JY, Carbone LD (1999) The role of collagen abnormalities in ultrasound and densitometry assessment: in vivo evidence. Calcif Tissue Int 64(6):470–476

    CAS  PubMed  Article  Google Scholar 

  13. Gulbahar S, Şahin E, Baydar M, Bircan Ç, Kizil R, Manisali M et al (2006) Hypermobility syndrome increases the risk for low bone mass. Clin Rheumatol 25(4):511–514

    PubMed  Article  Google Scholar 

  14. Mishra MB, Ryan P, Atkinson P, Taylor H, Bell J, Calver D et al (1996) Extra-articular features of benign joint hypermobility syndrome. Br J Rheumatol 35(9):861–866

    CAS  PubMed  Article  Google Scholar 

  15. Dolan AL, Hart DJ, Doyle DV, Grahame R, Spector TD (2003) The relationship of joint hypermobility, bone mineral density, and osteoarthritis in the general population: the Chingford study. J Rheumatol 30(4):799–803

    PubMed  Google Scholar 

  16. Rombaut L, Malfait F, De Wandele I, Taes Y, Thijs Y, De Paepe A et al (2012) Muscle mass, muscle strength, functional performance, and physical impairment in women with the hypermobility type of Ehlers-Danlos syndrome. Arthritis Care Res 64(10):1584–1592

    Article  Google Scholar 

  17. Scheper M, Rombaut L, de Vries J, De Wandele I, van der Esch M, Visser B et al (2017) The association between muscle strength and activity limitations in patients with the hypermobility type of Ehlers–Danlos syndrome: the impact of proprioception. Disabil Rehabil 39(14):1391–1397

    PubMed  Article  Google Scholar 

  18. Rombaut L, Malfait F, Cools A, De Paepe A, Calders P (2010) Musculoskeletal complaints, physical activity and health-related quality of life among patients with the Ehlers–Danlos syndrome hypermobility type. Disabil Rehabil 32(16):1339–1345

    PubMed  Article  Google Scholar 

  19. Scheper MC, Juul-Kristensen B, Rombaut L, Rameckers EAA, Verbunt J, Engelbert RHH (2016) Disability in adolescents and adults diagnosed with hypermobility related disorders: a meta-analysis. Arch Phys Med Rehabil 97(12):2174–2187

    PubMed  Article  Google Scholar 

  20. Beighton P, De Paepe A, Steinmann B, Tsipouras P, Wenstrup RJ (1998) Ehlers-Danlos syndromes: revised nosology. Am J Med Genet 77(1):31–37

    CAS  PubMed  Article  Google Scholar 

  21. Baecke JAH, Burema J, Frijters JER (1982) A short questionnaire for the measurement of habitual physical activity in epidemiological studies. Am J Clin Nutr 36(5):936–942

    CAS  PubMed  Article  Google Scholar 

  22. Bouxsein ML, Karasik D (2006) Bone geometry and skeletal fragility. Curr Osteoporos Rep 4(2):49–56

    PubMed  Article  Google Scholar 

  23. Fonseca H, Moreira-Gonçalves D, Coriolano HJA, Duarte JA (2014) Bone quality: the determinants of bone strength and fragility. Sport Med 44(1):37–53

    Article  Google Scholar 

  24. Szulc P (2006) Bone density, geometry, and fracture in elderly men. Curr Osteoporos Rep 4(2):57–63

    PubMed  Article  Google Scholar 

  25. Ohlsson C, Sundh D, Wallerek A, Nilsson M, Karlsson M, Johansson H, Mellström D, Lorentzon M (2017) Cortical bone area predicts incident fractures independently of areal bone mineral density in older men. J Clin Endocrinol Metab 102(2):516–524

    PubMed  Google Scholar 

  26. Voermans NC, Van Alfen N, Pillen S, Lammens M, Schalkwijk J, Zwarts MJ et al (2009) Neuromuscular involvement in various types of Ehlers-Danlos syndrome. Ann Neurol 65(6):687–697

    PubMed  Article  Google Scholar 

  27. Rombaut L, Malfait F, De Wandele I, Mahieu N, Thijs Y, Segers P et al (2012) Muscle-tendon tissue properties in the hypermobility type of Ehlers-Danlos syndrome. Arthritis Care Res (Hoboken) 64(5):766–772

    Article  Google Scholar 

  28. Rombaut L, Malfait F, De Wandele I, Thijs Y, Palmans T, De Paepe A et al (2011) Balance, gait, falls, and fear of falling in women with the hypermobility type of ehlers-danlos syndrome. Arthritis Care Res 63(10):1432–1439

    Article  Google Scholar 

  29. Rombaut L, Malfait F, De Wandele I, Cools A, Thijs Y, De Paepe A et al (2011) Medication, surgery, and physiotherapy among patients with the hypermobility type of Ehlers-Danlos syndrome. Arch Phys Med Rehabil 92(7):1106–1112

    PubMed  Article  Google Scholar 

  30. Keer R, Simmonds J (2011) Joint protection and physical rehabilitation of the adult with hypermobility syndrome. Curr Opin Rheumatol 23(2):131–136

    PubMed  Article  Google Scholar 

  31. Zhao R, Zhang M, Zhang Q (2017) The effectiveness of combined exercise interventions for preventing postmenopausal bone loss: a systematic review and meta-analysis. J Orthop Sport Phys Ther 47(4):241–251

    Article  Google Scholar 

  32. James MMS, Carroll S (2010) Effects of different impact exercise modalities on bone mineral density in premenopausal women: a meta-analysis. J Bone Miner Metab 28(3):251–267

    Article  Google Scholar 

  33. Xu J, Lombardi G, Jiao W, Banfi G (2016) Effects of exercise on bone status in female subjects, from young girls to postmenopausal women: an overview of systematic reviews and meta-analyses. Sport Med 46(8):1165–1182

    Article  Google Scholar 

  34. Anliker E, Toigo M (2012) Functional assessment of the muscle-bone unit in the lower leg. J Musculoskelet Neuronal Interact 12(2):46–55

    CAS  PubMed  Google Scholar 

  35. Frost HM (2003) Bone’s Mechanostat: a 2003 update. Anat Rec A Discov Mol Cell Evol Biol 275(2):1081–1101

    PubMed  Article  Google Scholar 

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Acknowledgments

We thank the patients and controls subjects for their contribution to the study. Prof. Dr. Fransiska Malfait is a senior clinical research fellow of the Research Foundation Flanders (FWO), Belgium. Finally, we would like to thank Roel Vandecappelle and Jolien Delahaye for their technical assistance.

Funding

This work was supported by a Methusalem Grant from Ghent University to Anne De Paepe (BOFMET2015000401).

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Correspondence to T. Banica.

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All participants gave written informed consent to participate in the study, which was approved by the Ethical Review Board of the Ghent University Hospital and conducted according to the principles of the Declaration of Helsinki.

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Banica, T., Coussens, M., Verroken, C. et al. Higher fracture prevalence and smaller bone size in patients with hEDS/HSD—a prospective cohort study. Osteoporos Int 31, 849–856 (2020). https://doi.org/10.1007/s00198-019-05269-z

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  • DOI: https://doi.org/10.1007/s00198-019-05269-z

Keywords

  • Ehlers-Danlos syndrome
  • Bone size
  • Body composition
  • DXA
  • pQCT