Pediatric Drugs

, Volume 21, Issue 2, pp 95–106 | Cite as

Current and Emerging Therapeutic Options for the Management of Rare Skeletal Diseases

  • Oliver SemlerEmail author
  • Mirko Rehberg
  • Nava Mehdiani
  • Miriam Jackels
  • Heike Hoyer-Kuhn
Review Article


Increasing knowledge in the field of rare diseases has led to new therapeutic approaches in the last decade. Treatment strategies have been developed after elucidation of the underlying genetic alterations and pathophysiology of certain diseases (e.g., in osteogenesis imperfecta, achondroplasia, hypophosphatemic rickets, hypophosphatasia and fibrodysplasia ossificans progressiva). Most of the drugs developed are specifically designed agents interacting with the disease-specific cascade of enzymes and proteins involved. While some are approved (asfotase alfa, burosumab), others are currently being investigated in phase III trials (denosumab, vosoritide, palovarotene). To offer a multi-disciplinary therapeutic approach, it is recommended that patients with rare skeletal disorders are treated and monitored in highly specialized centers. This guarantees the greatest safety for the individual patient and offers the possibility of collecting data to further improve treatment strategies for these rare conditions. Additionally, new therapeutic options could be achieved through increased awareness, not only in the field of pediatrics but also in prenatal and obstetric specialties. Presenting new therapeutic options might influence families in their decision of whether or not to terminate a pregnancy with a child with a skeletal disease.


Compliance with Ethical Standards


Parts of this work were supported by “Deutsche Forschungsgemeinschaft” through Grant FOR 2722 to authors OS and MR.

Conflict of interest

HHK, MR and OS have received speaker’s fees and travel Grants from different companies in the past. HHK and OS have received research Grants from Amgen and Alexion. NM and MJ have not received any support from companies producing drugs mentioned in this article.


  1. 1.
    Evangelista T, et al. The context for the thematic grouping of rare diseases to facilitate the establishment of European Reference Networks. Orphanet J Rare Dis. 2016;11:17.Google Scholar
  2. 2.
    Heon-Klin V. European Reference networks for rare diseases: what is the conceptual framework? Orphanet J Rare Dis. 2017;12(1):137.Google Scholar
  3. 3.
    Nampoothiri S, et al. Eight years experience from a skeletal dysplasia referral center in a tertiary hospital in Southern India: a model for the diagnosis and treatment of rare diseases in a developing country. Am J Med Genet A. 2014;164A(9):2317–23.Google Scholar
  4. 4.
    Ben Amor IM, Glorieux FH, Rauch F. Genotype-phenotype correlations in autosomal dominant osteogenesis imperfecta. J Osteoporos. 2011;2011:540178.Google Scholar
  5. 5.
    Caparros-Martin JA, et al. Clinical and molecular analysis in families with autosomal recessive osteogenesis imperfecta identifies mutations in five genes and suggests genotype-phenotype correlations. Am J Med Genet A. 2013;161A(6):1354–69.Google Scholar
  6. 6.
    Hofmann C, et al. Unexpected high intrafamilial phenotypic variability observed in hypophosphatasia. Eur J Hum Genet. 2014;22(10):1160–4.Google Scholar
  7. 7.
    Al Kaissi A, et al. The Diversity of the clinical phenotypes in patients with fibrodysplasia ossificans progressiva. J Clin Med Res. 2016;8(3):246–53.Google Scholar
  8. 8.
    Yeh P, et al. Accuracy of prenatal diagnosis and prediction of lethality for fetal skeletal dysplasias. Prenat Diagn. 2011;31(5):515–8.Google Scholar
  9. 9.
    Cozzolino M, et al. Ultrasonographic early diagnosis of osteogenesis imperfecta type I: implications for pre and post-natal therapy. Arch Gynecol Obstet. 2016;294(1):215–6.Google Scholar
  10. 10.
    Bellur S, et al. Cesarean delivery is not associated with decreased at-birth fracture rates in osteogenesis imperfecta. Genet Med. 2016;18(6):570–6.Google Scholar
  11. 11.
    Savarirayan R, et al. Best practice guidelines regarding prenatal evaluation and delivery of patients with skeletal dysplasia. Am J Obstet Gynecol. 2018;219(6):545–62.Google Scholar
  12. 12.
    Bonafe L, et al. Nosology and classification of genetic skeletal disorders: 2015 revision. Am J Med Genet A. 2015;167A(12):2869–92.Google Scholar
  13. 13.
    Fratzl-Zelman N, et al. Classification of osteogenesis imperfecta. Wien Med Wochenschr. 2015;165(13–14):264–70.Google Scholar
  14. 14.
    Becker J, et al. Exome sequencing identifies truncating mutations in human SERPINF1 in autosomal-recessive osteogenesis imperfecta. Am J Hum Genet. 2011;88(3):362–71.Google Scholar
  15. 15.
    Hoyer-Kuhn H, Rehberg M, Semler O. Angeborene Skeletterkrankungen. Monatsschrift Kinderheilkunde. 2017;165(8):663–71.Google Scholar
  16. 16.
    Beccard R, et al. Do bone mineral density, bone geometry and the functional muscle-bone unit explain bone fractures in healthy children and adolescents? Horm Res Paediatr. 2010;74(5):312–8.Google Scholar
  17. 17.
    Schonau E, et al. Influence of muscle strength on bone strength during childhood and adolescence. Horm Res. 1996;45(Suppl 1):63–6.Google Scholar
  18. 18.
    Rittweger J, et al. Muscle atrophy and bone loss after 90 days’ bed rest and the effects of flywheel resistive exercise and pamidronate: results from the LTBR study. Bone. 2005;36(6):1019–29.Google Scholar
  19. 19.
    Shore EM, et al. A recurrent mutation in the BMP type I receptor ACVR1 causes inherited and sporadic fibrodysplasia ossificans progressiva. Nat Genet. 2006;38(5):525–7.Google Scholar
  20. 20.
    Komarova SV, et al. Mathematical model for bone mineralization. Front Cell Dev Biol. 2015;3:51.Google Scholar
  21. 21.
    Roschger P, et al. Changes in the degree of mineralization with osteoporosis and its treatment. Curr Osteoporos Rep. 2014;12(3):338–50.Google Scholar
  22. 22.
    van Meurs JB, et al. Role of epigenomics in bone and cartilage disease. J Bone Miner Res. 2019;34(2):215–30.Google Scholar
  23. 23.
    Morris JA, et al. Epigenome-wide association of DNA methylation in whole blood with bone mineral density. J Bone Miner Res. 2017;32(8):1644–50.Google Scholar
  24. 24.
    Fernandez-Rebollo E, et al. Primary osteoporosis is not reflected by disease-specific DNA methylation or accelerated epigenetic age in blood. J Bone Miner Res. 2018;33(2):356–61.Google Scholar
  25. 25.
    Ward LM, Rauch F. Anabolic therapy for the treatment of osteoporosis in childhood. Curr Osteoporos Rep. 2018;16(3):269–76.Google Scholar
  26. 26.
    Forlino A, Marini JC. Osteogenesis imperfecta. Lancet. 2016;387(10028):1657–71.Google Scholar
  27. 27.
    Marini JC, et al. Osteogenesis imperfecta. Nat Rev Dis Primers. 2017;3:17052.Google Scholar
  28. 28.
    Mueller B, et al. Consensus statement on physical rehabilitation in children and adolescents with osteogenesis imperfecta. Orphanet J Rare Dis. 2018;13(1):158.Google Scholar
  29. 29.
    Hoyer-Kuhn H, et al. A specialized rehabilitation approach improves mobility in children with osteogenesis imperfecta. J Musculoskelet Neuronal Interact. 2014;14(4):445–53.Google Scholar
  30. 30.
    Hogler W, et al. The effect of whole body vibration training on bone and muscle function in children with osteogenesis imperfecta. J Clin Endocrinol Metab. 2017;102(8):2734–43.Google Scholar
  31. 31.
    Ruck J, et al. Fassier–Duval femoral rodding in children with osteogenesis imperfecta receiving bisphosphonates: functional outcomes at one year. J Child Orthop. 2011;5(3):217–24.Google Scholar
  32. 32.
    Ashby E, et al. Functional outcome of humeral rodding in children with osteogenesis imperfecta. J Pediatr Orthop. 2018;38(1):49–53.Google Scholar
  33. 33.
    Wirth T. Osteogenesis imperfecta. Orthopade. 2012;41(9):773–82 (quiz 83–4).Google Scholar
  34. 34.
    Franzone JM, Kruse RW. Intramedullary nailing with supplemental plate and screw fixation of long bones of patients with osteogenesis imperfecta: operative technique and preliminary results. J Pediatr Orthop B. 2018;27(4):344–9.Google Scholar
  35. 35.
    Astrom E, Soderhall S. Beneficial effect of bisphosphonate during five years of treatment of severe osteogenesis imperfecta. Acta Paediatr. 1998;87(1):64–8.Google Scholar
  36. 36.
    Glorieux FH, et al. Cyclic administration of pamidronate in children with severe osteogenesis imperfecta. N Engl J Med. 1998;339(14):947–52.Google Scholar
  37. 37.
    Gatti D, et al. Intravenous neridronate in children with osteogenesis imperfecta: a randomized controlled study. J Bone Miner Res. 2005;20(5):758–63.Google Scholar
  38. 38.
    Antoniazzi F, et al. Early bisphosphonate treatment in infants with severe osteogenesis imperfecta. J Pediatr. 2006;149(2):174–9.Google Scholar
  39. 39.
    Adami S, et al. Intravenous neridronate in adults with osteogenesis imperfecta. J Bone Miner Res. 2003;18(1):126–30.Google Scholar
  40. 40.
    Semler O, et al. Reshaping of vertebrae during treatment with neridronate or pamidronate in children with osteogenesis imperfecta. Horm Res Paediatr. 2011;76(5):321–7.Google Scholar
  41. 41.
    Panigrahi I, et al. Response to zolendronic acid in children with type III osteogenesis imperfecta. J Bone Miner Metab. 2010;28(4):451–5.Google Scholar
  42. 42.
    Kumar C, et al. Zoledronate for osteogenesis imperfecta: evaluation of safety profile in children. J Pediatr Endocrinol Metab. 2016;29(8):947–52.Google Scholar
  43. 43.
    Saraff V, et al. Efficacy and treatment costs of zoledronate versus pamidronate in paediatric osteoporosis. Arch Dis Child. 2018;103(1):92–4.Google Scholar
  44. 44.
    Dwan K, et al. Bisphosphonate therapy for osteogenesis imperfecta. Cochrane Database Syst Rev. 2016;10:CD005088.Google Scholar
  45. 45.
    Glorieux FH, et al. Osteogenesis imperfecta type VI: a form of brittle bone disease with a mineralization defect. J Bone Miner Res. 2002;17(1):30–8.Google Scholar
  46. 46.
    Land C, et al. Osteogenesis imperfecta type VI in childhood and adolescence: effects of cyclical intravenous pamidronate treatment. Bone. 2007;40(3):638–44.Google Scholar
  47. 47.
    Semler O, et al. First use of the RANKL antibody denosumab in osteogenesis imperfecta type VI. J Musculoskelet Neuronal Interact. 2012;12(3):183–8.Google Scholar
  48. 48.
    Hoyer-Kuhn H, et al. Two years’ experience with denosumab for children with osteogenesis imperfecta type VI. Orphanet J Rare Dis. 2014;9(1):145.Google Scholar
  49. 49.
    Hoyer-Kuhn H, et al. Safety and efficacy of denosumab in children with osteogenesis imperfect—a first prospective trial. J Musculoskelet Neuronal Interact. 2016;16(1):24–32.Google Scholar
  50. 50.
    Grasemann C, et al. Effects of RANK-ligand antibody (denosumab) treatment on bone turnover markers in a girl with juvenile Paget’s disease. J Clin Endocrinol Metab. 2013;98(8):3121–6.Google Scholar
  51. 51.
    Trejo P, Rauch F, Ward L. Hypercalcemia and hypercalciuria during denosumab treatment in children with osteogenesis imperfecta type VI. J Musculoskelet Neuronal Interact. 2018;18(1):76–80.Google Scholar
  52. 52.
    Bandeira F, et al. Multiple severe vertebral fractures during the 3-month period following a missed dose of denosumab in a postmenopausal woman with osteoporosis previously treated with alendronate. Int J Clin Pharmacol Ther. 2019;57(3):163–6.Google Scholar
  53. 53.
    Cummings SR, et al. Vertebral fractures after discontinuation of denosumab: a post hoc analysis of the randomized placebo-controlled FREEDOM trial and its extension. J Bone Miner Res. 2018;33(2):190–8.Google Scholar
  54. 54.
    Florez H, et al. Spontaneous vertebral fractures after denosumab discontinuation: a case collection and review of the literature. Semin Arthritis Rheum. 2019. Scholar
  55. 55.
    Perosky JE, et al. Single dose of bisphosphonate preserves gains in bone mass following cessation of sclerostin antibody in Brtl/+ osteogenesis imperfecta model. Bone. 2016;93:79–85.Google Scholar
  56. 56.
    Williams BO. Insights into the mechanisms of sclerostin action in regulating bone mass accrual. J Bone Miner Res. 2014;29(1):24–8.Google Scholar
  57. 57.
    McClung MR. Sclerostin antibodies in osteoporosis: latest evidence and therapeutic potential. Ther Adv Musculoskelet Dis. 2017;9(10):263–70.Google Scholar
  58. 58.
    Sinder BP, et al. Sclerostin antibody improves skeletal parameters in a Brtl/+ mouse model of osteogenesis imperfecta. J Bone Miner Res. 2013;28(1):73–80.Google Scholar
  59. 59.
    Glorieux FH, et al. BPS804 anti-sclerostin antibody in adults with moderate osteogenesis imperfecta: results of a randomized phase 2a trial. J Bone Miner Res. 2017;32(7):1496–504.Google Scholar
  60. 60.
    Horwitz EM, 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 USA. 2002;99(13):8932–7.Google Scholar
  61. 61.
    Horwitz EM, et al. Transplantability and therapeutic effects of bone marrow-derived mesenchymal cells in children with osteogenesis imperfecta. Nat Med. 1999;5(3):309–13.Google Scholar
  62. 62.
    Le Blanc K, 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.Google Scholar
  63. 63.
    Chan JK, Gotherstrom C. Prenatal transplantation of mesenchymal stem cells to treat osteogenesis imperfecta. Front Pharmacol. 2014;5:223.Google Scholar
  64. 64.
    Gotherstrom C, et al. Pre- and postnatal transplantation of fetal mesenchymal stem cells in osteogenesis imperfecta: a two-center experience. Stem Cells Transl Med. 2014;3(2):255–64.Google Scholar
  65. 65.
    Westgren M, Gotherstrom C. Stem cell transplantation before birth—a realistic option for treatment of osteogenesis imperfecta? Prenat Diagn. 2015;35(9):827–32.Google Scholar
  66. 66.
    Chitty LS, et al. EP21.04: BOOSTB4: a clinical study to determine safety and efficacy of pre- and/or postnatal stem cell transplantation for treatment of osteogenesis imperfecta. Ultrasound Obstet Gynecol. 2016;48(Suppl 1):356.Google Scholar
  67. 67.
    Pauli RM. Achondroplasia: a comprehensive clinical review. Orphanet J Rare Dis. 2019;14(1):1.Google Scholar
  68. 68.
    Ceroni JRM, et al. Natural history of 39 patients with achondroplasia. Clinics (Sao Paulo). 2018;73:e324.Google Scholar
  69. 69.
    Zaffanello M, et al. Sleep disordered breathing in children with achondroplasia. World J Pediatr. 2017;13(1):8–14.Google Scholar
  70. 70.
    Park KW, et al. Limb lengthening in patients with achondroplasia. Yonsei Med J. 2015;56(6):1656–62.Google Scholar
  71. 71.
    Nadel JL, et al. Screening and surgery for foramen magnum stenosis in children with achondroplasia: a large, national database analysis. J Neurosurg Pediatr. 2018;23(3):374–80.Google Scholar
  72. 72.
    Miccoli M, Bertelloni S, Massart F. Height outcome of recombinant human growth hormone treatment in achondroplasia children: a meta-analysis. Horm Res Paediatr. 2016;86(1):27–34.Google Scholar
  73. 73.
    Lorget F, et al. Evaluation of the therapeutic potential of a CNP analog in a Fgfr3 mouse model recapitulating achondroplasia. Am J Hum Genet. 2012;91(6):1108–14.Google Scholar
  74. 74.
    Krejci P. The paradox of FGFR3 signaling in skeletal dysplasia: why chondrocytes growth arrest while other cells over proliferate. Mutat Res Rev Mutat Res. 2014;759:40–8.Google Scholar
  75. 75.
    Legeai-Mallet L. C-type natriuretic peptide analog as therapy for achondroplasia. Endocr Dev. 2016;30:98–105.Google Scholar
  76. 76.
    Yamanaka S, et al. Circulatory CNP rescues craniofacial hypoplasia in achondroplasia. J Dent Res. 2017;96(13):1526–34.Google Scholar
  77. 77.
    Garcia S, et al. Postnatal soluble FGFR3 therapy rescues achondroplasia symptoms and restores bone growth in mice. Sci Transl Med. 2013;5(203):203ra124.Google Scholar
  78. 78.
    Pavone V, et al. Hypophosphatemic rickets: etiology, clinical features and treatment. Eur J Orthop Surg Traumatol. 2015;25(2):221–6.Google Scholar
  79. 79.
    Shimada T, et al. Targeted ablation of Fgf23 demonstrates an essential physiological role of FGF23 in phosphate and vitamin D metabolism. J Clin Investig. 2004;113(4):561–8.Google Scholar
  80. 80.
    Verge CF, et al. Effects of therapy in X-linked hypophosphatemic rickets. N Engl J Med. 1991;325(26):1843–8.Google Scholar
  81. 81.
    Makitie O, et al. Early treatment improves growth and biochemical and radiographic outcome in X-linked hypophosphatemic rickets. J Clin Endocrinol Metab. 2003;88(8):3591–7.Google Scholar
  82. 82.
    Carpenter TO, et al. Randomized trial of the anti-FGF23 antibody KRN23 in X-linked hypophosphatemia. J Clin Investig. 2014;124(4):1587–97.Google Scholar
  83. 83.
    Carpenter TO, et al. Burosumab therapy in children with X-linked hypophosphatemia. N Engl J Med. 2018;378(21):1987–98.Google Scholar
  84. 84.
    Whyte MP, et al. Efficacy and safety of burosumab in children aged 1–4 years with X-linked hypophosphataemia: a multicentre, open-label, phase 2 trial. Lancet Diabetes Endocrinol. 2019;7(3):189–99.Google Scholar
  85. 85.
    Whyte MP. Hypophosphatasia—aetiology, nosology, pathogenesis, diagnosis and treatment. Nat Rev Endocrinol. 2016;12(4):233–46.Google Scholar
  86. 86.
    Mornet E, et al. Clinical utility gene card for: hypophosphatasia—update 2013. Eur J Hum Genet. 2014. Scholar
  87. 87.
    Whyte MP. Hypophosphatasia: an overview for 2017. Bone. 2017;102:15–25.Google Scholar
  88. 88.
    Whyte MP, Wenkert D, Zhang F. Hypophosphatasia: natural history study of 101 affected children investigated at one research center. Bone. 2016;93:125–38.Google Scholar
  89. 89.
    Zierk J, et al. Pediatric reference intervals for alkaline phosphatase. Clin Chem Lab Med. 2017;55(1):102–10.Google Scholar
  90. 90.
    Whyte MP, et al. Enzyme-replacement therapy in life-threatening hypophosphatasia. N Engl J Med. 2012;366(10):904–13.Google Scholar
  91. 91.
    Whyte MP, et al. Asfotase alfa treatment improves survival for perinatal and infantile hypophosphatasia. J Clin Endocrinol Metab. 2016;101(1):334–42.Google Scholar
  92. 92.
    Kitaoka T, et al. Safety and efficacy of treatment with asfotase alfa in patients with hypophosphatasia: Results from a Japanese clinical trial. Clin Endocrinol (Oxf). 2017;87(1):10–9.Google Scholar
  93. 93.
    Hofmann CE, et al. Efficacy and safety of asfotase alfa in infants and young children with hypophosphatasia: a phase 2 open-label study. J Clin Endocrinol Metab. 2019. Scholar
  94. 94.
    Shore EM, Kaplan FS. Inherited human diseases of heterotopic bone formation. Nat Rev Rheumatol. 2010;6(9):518–27.Google Scholar
  95. 95.
    Kaplan FS, et al. Fibrodysplasia ossificans progressiva. Best Pract Res Clin Rheumatol. 2008;22(1):191–205.Google Scholar
  96. 96.
    Shimono K, et al. Potent inhibition of heterotopic ossification by nuclear retinoic acid receptor-gamma agonists. Nat Med. 2011;17(4):454–60.Google Scholar
  97. 97.
    Wentworth KL, Masharani U, Hsiao EC. Therapeutic advances for blocking heterotopic ossification in fibrodysplasia ossificans progressiva. Br J Clin Pharmacol. 2018. Scholar
  98. 98.
    Luo Y, et al. Development of new therapeutic agents for fibrodysplasia ossificans progressiva. Curr Mol Med. 2016;16(1):4–11.Google Scholar
  99. 99.
    Kaplan FS, et al. Palovarotene reduces new heterotopic ossification in fibrodysplasia ossificans progressiva (FOP). JBMR. 2018;33(Suppl 1):MON-1066.Google Scholar
  100. 100.
    Inubushi T, et al. Palovarotene inhibits osteochondroma formation in a mouse model of multiple hereditary exostoses. J Bone Miner Res. 2018;33(4):658–66.Google Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Centre for Rare Skeletal Diseases in childhood, Children’s HospitalUniversity of CologneCologneGermany
  2. 2.Children’s and Adolescent’s HospitalUniversity of CologneCologneGermany
  3. 3.Centre for Prevention and Rehabilitation, UnirehaUniversity of CologneCologneGermany

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