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Review article: Biomedical intelligence

Vol. 146 No. 2526 (2016)

Osteogenesis imperfecta: from diagnosis and multidisciplinary treatment to future perspectives

  • Aline Bregou Bourgeois
  • Bérengère Aubry-Rozier
  • Luisa Bonafé
  • Lee Laurent-Applegate
  • Dominique P Pioletti
  • Pierre-Yves Zambelli
Cite this as:
Swiss Med Wkly. 2016;146:w14322


Osteogenesis imperfecta is an inherited connective tissue disorder with wide phenotypic and molecular heterogeneity. A common issue associated with the molecular abnormality is a disturbance in bone matrix synthesis and homeostasis inducing bone fragility. In very early life, this can lead to multiple fractures and progressive bone deformities, including long bone bowing and scoliosis. Multidisciplinary management improves quality of life for patients with osteogenesis imperfecta. It consists of physical therapy, medical treatment and orthopaedic surgery as necessary. Medical treatment consists of bone-remodelling drug therapy. Bisphosphonates are widely used in the treatment of moderate to severe osteogenesis imperfecta, from infancy to adulthood. Other more recent drug therapies include teriparatide and denosumab. All these therapies target the symptoms and have effects on the mechanical properties of bone due to modification of bone remodelling, therefore influencing skeletal outcome and orthopaedic surgery. Innovative therapies, such as progenitor and mesenchymal stem cell transplantation, targeting the specific altered pathway rather than the symptoms, are in the process of development.


  1. Sillence DO, Senn A, Danks D. Genetic heterogeneity in osteogenesis imperfecta. J Med Genet. 1979;16(2):101–16.
  2. Chu ML, Williams CJ, Pepe G, Hirsch JL, Prockop DJ, Ramirez F. Internal deletion in a collagen gene in a perinatal lethal form of osteogenesis imperfecta. Nature. 1983;304(5921):78–80.
  3. Rauch F, Glorieux FH. Osteogenesis imperfecta. Lancet. 2004;363(9418):1377–85.
  4. Barnes AM, Chang W, Morello R, Cabral WA, Weis M, Eyre DR, et al. Deficiency of cartilage-associated protein in recessive lethal osteogenesis imperfecta. N Engl J Med. 2006;355(26):2757–64.
  5. Forlino A, Marini JC. Osteogenesis imperfecta. Lancet. 2016;387(10028):1657–71.
  6. Bonafe L, Cormier-Daire V, Hall C, Lachman R, Mortier G, Mundlos S, et al. Nosology and classification of genetic skeletal disorders: 2015 revision. Am J Med Genet A. 2015;167A(12):2869–92
  7. Van Dijk FS, Sillence DO. Osteogenesis imperfecta: clinical diagnosis, nomenclature and severity assessment. Am J Med Genet A. 2014;164A(6):1470–81.
  8. Marini JC, Forlino A, Cabral WA, Barnes AM, San Antonio JD, Milgrom S, et al. Consortium for osteogenesis imperfecta mutations in the helical domain of type I collagen: regions rich in lethal mutations align with collagen binding sites for integrins and proteoglycans. Hum Mutat. 2007;28(3):209–21.
  9. Warman ML, Cormier-Daire V, Hall C, Krakow D, Lachman R, LeMerrer M, et al. Nosology and classification of genetic skeletal disorders: 2010 revision. Am J Med Genet A. 2011;155A(5):943–68.
  10. Bishop N, Adami S, Ahmed SF, Antón J, Arundel P, Burren CP, et al. Risedronate in children with osteogenesis imperfecta: a randomised, double-blind, placebo-controlled trial. Lancet. 2013;382(9902):1424–32
  11. Vetter U, Pontz B, Zauner E, Brenner RE, Spranger J. Osteogenesis imperfecta: a clinical study of the first ten years of life. Calcif Tissue Int. 1992;50(1):36–41.
  12. Zeitlin L, Rauch F, Plotkin H, Glorieux FH. Height and weight development during four years of therapy with cyclical intravenous pamidronate in children and adolescents with osteogenesis imperfecta types I, III, and IV. Pediatrics. 2003;111(5 Pt 1):1030–6.
  13. Calder AD. Radiology of Osteogenesis Imperfecta, Rickets and Other Bony Fragility States. Endocr Dev. 2015;28:56–71.
  14. Forlino A, Cabral WA, Barnes AM, Marini JC. New perspectives on osteogenesis imperfecta. Nat Rev Endocrinol. 2011;7(9):540–57.
  15. Ashournia H, Johansen FT, Folkestad L, Diederichsen AC, Brixen K. Heart disease in patients with osteogenesis imperfecta – A systematic review. Int J Cardiol. 2015;196:149–57.
  16. Renaud A, Aucourt J, Weill J, Bigot J, Dieux A, Devisme L, et al. Radiographic features of osteogenesis imperfecta. Insights Imaging. 2013;4(4):417–29.
  17. Montpetit K, Palomo T, Glorieux FH, Fassier F, Rauch F. Multidisciplinary Treatment of Severe Osteogenesis Imperfecta: Functional Outcomes at Skeletal Maturity. Arch Phys Med Rehabil. 2015;96(10):1834–9.
  18. Zeitlin L, Fassier F, Glorieux FH. Modern approach to children with osteogenesis imperfecta. J Pediatr Orthop B. 2003;12(2):77–87.
  19. Aubry-Rozier B, Unger S, Bregou A, Freymond Morisod M, Vaswani A, Scheider P, et al. News in osteogenesis imperfecta: from research to clinical management. Rev Med Suisse. 2015;11(466):657–8, 660–2. French.
  20. Ruck J, Dahan-Oliel N, Montpetit K, Rauch F, Fassier F. Fassier-Duval femoral rodding in children with osteogenesis imperfecta receiving bisphosphonates: functional outcomes at one year. J Child Orthop. 2011;5(3):217–24.
  21. Sinikumpu JJ, Ojaniemi M, Lehenkari P, Serlo W. Severe osteogenesis imperfecta Type-III and its challenging treatment in newborn and preschool children. A systematic review. Injury. 2015;46(8):1440–6.
  22. Carmel AS,, Shieh A, Bang H, Bockman RS. The 25(OH)D level needed to maintain a favorable bisphosphonate response is >/=33 ng/ml. Osteoporos Int. 2012;23(10):2479–87.
  23. Kusumi K, Ayoob R, Bowden SA, Ingraham S, Mahan JD. Beneficial effects of intravenous pamidronate treatment in children with osteogenesis imperfecta under 24 months of age. J Bone Miner Metab. 2015;33(5):560–8.
  24. Lindahl K, Kindmark A, Rubin CJ, Malmgren B, Grigelioniene G, Söderhäll S, et al. Decreased fracture rate, pharmacogenetics and BMD response in 79 Swedish children with osteogenesis imperfecta types I, III and IV treated with Pamidronate. Bone. 2016;87:11–8.
  25. Palomo T, Fassier F, Ouellet J, Sato A, Montpetit K, Glorieux FH, et al. Intravenous Bisphosphonate Therapy of Young Children with Osteogenesis Imperfecta: Skeletal Findings During Follow Up Throughout the Growing Years. J Bone Miner Res. 2015;30(12):2150–7.
  26. Rijks EB, Bongers BC, Vlemmix MJ, Boot AM, van Dijk AT, Sakkers RJ, et al. Efficacy and Safety of Bisphosphonate Therapy in Children with Osteogenesis Imperfecta: A Systematic Review. Horm Res Paediatr. 2015;84(1):26–42.
  27. Dwan K, Phillipi CA, Steiner RD, Basel D. Bisphosphonate therapy for osteogenesis imperfecta. Cochrane Database Syst Rev. 2014;7: CD005088.
  28. Glorieux FH, Bishop NJ, Plotkin H, Chabot G, Lanoue G, Travers R. Cyclic administration of pamidronate in children with severe osteogenesis imperfecta. N Engl J Med. 1998;339(14):947–52.
  29. Marini JC. Bone: Use of bisphosphonates in children-proceed with caution. Nat Rev Endocrinol. 2009;5(5):241–3.
  30. Uveges TE, Kozloff KM, Ty JM, Ledgard F, Raggio CL, Gronowicz G, et al. Alendronate treatment of the brtl osteogenesis imperfecta mouse improves femoral geometry and load response before fracture but decreases predicted material properties and has detrimental effects on osteoblasts and bone formation. J Bone Miner Res. 2009;24(5):849–59.
  31. Munns CF, Rauch F, Zeitlin L, Fassier F, Glorieux FH. Delayed osteotomy but not fracture healing in pediatric osteogenesis imperfecta patients receiving pamidronate. J Bone Miner Res. 2004;19(11):1779–86.
  32. Anam EA, Rauch F, Glorieux FH, Fassier F, Hamdy R. Osteotomy Healing in Children With Osteogenesis Imperfecta Receiving Bisphosphonate Treatment. J Bone Miner Res. 2015;30(8):1362–8.
  33. Shane E, Burr D, Abrahamsen B, Adler RA, Brown TD, Cheung AM, et al. Atypical subtrochanteric and diaphyseal femoral fractures: second report of a task force of the American Society for Bone and Mineral Research. J Bone Miner Res. 2014;29(1):1–23.
  34. Schilcher J, Koeppen V, Ranstam J, Skripitz R, Michaëlsson K, Aspenberg P. Atypical femoral fractures are a separate entity, characterized by highly specific radiographic features. A comparison of 59 cases and 218 controls. Bone. 2013;52(1):389–92.
  35. Hegazy A, Kenawey M, Sochett E, Tile L, Cheung AM, Howard AW. Unusual Femur Stress Fractures in Children With Osteogenesis Imperfecta and Intramedullary Rods on Long-term Intravenous Pamidronate Therapy. J Pediatr Orthop. 2015 June 8. [Epub ahead of print]
  36. Nicolaou N, Agrawal Y, Padman M, Fernandes JA, Bell MJ. Changing pattern of femoral fractures in osteogenesis imperfecta with prolonged use of bisphosphonates. J Child Orthop. 2012;6(1):21–7.
  37. Ben Amor IM, Roughley P, Glorieux FH, Rauch F. Skeletal clinical characteristics of osteogenesis imperfecta caused by haploinsufficiency mutations in COL1A1. J Bone Miner Res. 2013;28(9):2001–7.
  38. Anissipour AK, Hammerberg KW, Caudill A, Kostiuk T, Tarima S, Zhao HS, et al. Behavior of scoliosis during growth in children with osteogenesis imperfecta. J Bone Joint Surg Am. 2014;96(3):237–43.
  39. Engelbert RH, Uiterwaal CS, van der Hulst A, Witjes B, Helders PJ, Pruijs HE. Scoliosis in children with osteogenesis imperfecta: influence of severity of disease and age of reaching motor milestones. Eur Spine J. 2003;12(2):130–4.
  40. Benson DR, Newman DC. The spine and surgical treatment in osteogenesis imperfecta. Clin Orthop Relat Res. 1981(159):147–53.
  41. Yong-Hing K, MacEwen GD. Scoliosis associated with osteogenesis imperfecta. J Bone Joint Surg Br. 1982;64(1):36–43.
  42. Janus GJ, Finidori G, Engelbert RH, Pouliquen M, Pruijs JE. Operative treatment of severe scoliosis in osteogenesis imperfecta: results of 20 patients after halo traction and posterior spondylodesis with instrumentation. Eur Spine J. 2000;9(6):486–91.
  43. Amako M, Fassier F, Hamdy RC, Aarabi M, Montpetit K, Glorieux FH. Functional analysis of upper limb deformities in osteogenesis imperfecta. J Pediatr Orthop. 2004;24(6):689–94.
  44. Fassier AM, Rauch F, Aarabi M, Janelle C, Fassier F. Radial head dislocation and subluxation in osteogenesis imperfecta. J Bone Joint Surg Am. 2007;89(12):2694–704.
  45. Fassier F, Sardar Z, Aarabi M, Odent T, Haque T, Hamdy R. Results and complications of a surgical technique for correction of coxa vara in children with osteopenic bones. J Pediatr Orthop. 2008;28(8):799–805.
  46. Aarabi M, Rauch F, Hamdy RC, Fassier F. High prevalence of coxa vara in patients with severe osteogenesis imperfecta. J Pediatr Orthop. 2006;26(1):24–8.
  47. Lee JH, Gamble JG, Moore RE, Rinsky LA. Gastrointestinal problems in patients who have type-III osteogenesis imperfecta. J Bone Joint Surg Am. 1995;77(9):1352–6.
  48. Violas P, Fassier F, Hamdy R, Duhaime M, Glorieux FH. Acetabular protrusion in osteogenesis imperfecta. J Pediatr Orthop. 2002;22(5):622–5.
  49. Gerber LH, Binder H, Weintrob J, Grange DK, Shapiro J, Fromherz W, et al. Rehabilitation of children and infants with osteogenesis imperfecta. A program for ambulation. Clin Orthop Relat Res. 1990(251):254–62.
  50. Brizola E, Staub AL, Felix TM. Muscle strength, joint range of motion, and gait in children and adolescents with osteogenesis imperfecta. Pediatr Phys Ther. 2014;26(2):245–52.
  51. Engelbert RH, Uiterwaal CS, Gerver WJ, van der Net JJ, Pruijs HE, Helders PJ. Osteogenesis imperfecta in childhood: impairment and disability. A prospective study with 4-year follow-up. Arch Phys Med Rehabil. 2004;85(5):772–8.
  52. Pouliot-Laforte A, Veilleux LN, Rauch F, Lemay M. Physical activity in youth with osteogenesis imperfecta type I. J Musculoskelet Neuronal Interact. 2015;15(2):171–6.
  53. Van Brussel M, Takken T, Uiterwaal CS, Pruijs HJ, Van der Net J, Helders PJ, et al. Physical training in children with osteogenesis imperfecta. J Pediatr. 2008;152(1):111–6, 116 e1.
  54. Montpetit K, Dahan-Oliel N, Ruck-Gibis J, Fassier F, Rauch F, Glorieux F. Activities and participation in young adults with osteogenesis imperfecta. J Pediatr Rehabil Med. 2011;4(1):13–22.
  55. Gatti D, Rossini M, Viapiana O, Povino MR, Liuzza S, Fracassi E, et al. Teriparatide treatment in adult patients with osteogenesis imperfecta type I. Calcif Tissue Int. 2013;93(5):448–52.
  56. Orwoll ES, Shapiro J, Veith S, Wang Y, Lapidus J, Vanek C, et al. Evaluation of teriparatide treatment in adults with osteogenesis imperfecta. J Clin Invest. 2014;124(2):491–8.
  57. Cummings SR, San Martin J, McClung MR, Siris ES, Eastell R, Reid IR, et al. Denosumab for prevention of fractures in postmenopausal women with osteoporosis. N Engl J Med. 2009;361(8):756–65.
  58. Hoyer-Kuhn H, Netzer C, Koerber F, Schoenau E, Semler O. Two years’ experience with denosumab for children with osteogenesis imperfecta type VI. Orphanet J Rare Dis. 2014;9:145.
  59. Semler O, Netzer C, Hoyer-Kuhn H, Becker J, Eysel P, Schoenau E. First use of the RANKL antibody denosumab in osteogenesis imperfecta type VI. J Musculoskelet Neuronal Interact. 2012;12(3):183–8.
  60. Sinder BP, Lloyd WR, Salemi JD, Marini JC, Caird MS, Morris MD, et al. Effect of anti-sclerostin therapy and osteogenesis imperfecta on tissue-level properties in growing and adult mice while controlling for tissue age. Bone. 2016;84:222–229.
  61. Hoyer-Kuhn H, Franklin J, Allo G, Kron M, Netzer C, Eysel P, Hero B, et al. Safety and efficacy of denosumab in children with osteogenesis imperfecta – a first prospective trial. J Musculoskelet Neuronal Interact. 2016;16(1):24–32.
  62. Marini JC, Reich A, Smith SM. Osteogenesis imperfecta due to mutations in non-collagenous genes: lessons in the biology of bone formation. Curr Opin Pediatr. 2014;26(4):500–7.
  63. Chamberlain JR,, Deyle DR, Schwarze U, Wang P, Hirata RK, Li Y, et al. Gene targeting of mutant COL1A2 alleles in mesenchymal stem cells from individuals with osteogenesis imperfecta. Mol Ther. 2008;16(1):187–93.
  64. Chamberlain JR, Schwarze U, Wang PR, Hirata RK, Hankenson KD, Pace JM, et al. Gene targeting in stem cells from individuals with osteogenesis imperfecta. Science. 2004;303(5661):1198–201.
  65. Li F, Wang X, Niyibizi C. Bone marrow stromal cells contribute to bone formation following infusion into femoral cavities of a mouse model of osteogenesis imperfecta. Bone. 2010;47(3):546–55.
  66. Guillot PV, Abass O, Bassett JH, Shefelbine SJ, Bou-Gharios G, Chan J, et al. Intrauterine transplantation of human fetal mesenchymal stem cells from first-trimester blood repairs bone and reduces fractures in osteogenesis imperfecta mice. Blood. 2008;111(3):1717–25.
  67. Vanleene M, Saldanha Z, Cloyd KL, Jell G, Bou-Gharios G, Bassett JH, et al. Transplantation of human fetal blood stem cells in the osteogenesis imperfecta mouse leads to improvement in multiscale tissue properties. Blood. 2011;117(3):1053–60.
  68. Horwitz EM, Prockop DJ, Fitzpatrick LA, Koo WW, Gordon PL, Neel M, et al. Transplantability and therapeutic effects of bone marrow-derived mesenchymal cells in children with osteogenesis imperfecta. Nat Med. 1999;5(3):309–13.
  69. Horwitz EM, Gordon PL, Koo WK, Marx JC, Neel MD, McNall RY, et al. Isolated allogeneic bone marrow-derived mesenchymal cells engraft and stimulate growth in children with osteogenesis imperfecta: Implications for cell therapy of bone. Proc Natl Acad Sci U S A. 2002;99(13):8932–7.
  70. Le Blanc K, Götherström C, Ringdén O, Hassan M, McMahon R, Horwitz E, et al. Fetal mesenchymal stem-cell engraftment in bone after in utero transplantation in a patient with severe osteogenesis imperfecta. Transplantation. 2005;79(11):1607–14.
  71. Pioletti DP, Montjovent MO, Zambelli PY, Applegate L. Bone tissue engineering using foetal cell therapy. Swiss Med Wkly. 2006;136(35–36):557–60.
  72. Montjovent MO, Burri N, Mark S, Federici E, Scaletta C, Zambelli PY, et al. Fetal bone cells for tissue engineering. Bone. 2004;35(6):1323–33.

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