Skip to main content
Log in

Treatment considerations for the management of fibrodysplasia ossificans progressiva

  • Fibrodysplasia Ossificans Progressiva
  • Published:
Clinical Reviews in Bone and Mineral Metabolism Aims and scope Submit manuscript

Abstract

The ultimate goal of research on fibrodysplasia ossificans progressiva (FOP) is the development of treatments that will prevent, half, or even reverse the progression of the condition. Despite advances in understanding the pathophysiology of FOP, there are no therapies with scientifically proven benefits for the prevention or treatment of FOP. Insights obtained from the research laboratory and from the treatment of hundreds of patients world wide have allowed us to identify targets for potential therapies. Some of these therapies involve the use of currently available medications, whereas others involve novel therapeutic approaches that are in preclinical testing. In this article, we will review the scientific basis for considering various therapeutic options based on the known pathophysiology of FOP. Because there are presently no proven preventions or treatments for the condition, this article is intended to represent an opinion of the authors that may be helpful to others who face similar situations.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

References

  1. Glaser DL, Economides AN, Wang L, et al: 2003 In vivo somatic cell gene transfer of an engineered noggin mutein prevents BMP4-induced heterotopic ossification. J Bone Joint Surg Am 12:2332–2342.

    Google Scholar 

  2. Kan L, Hu M, Gomes WA, Kessler JA. 2004 Transgenic mice overexpressing BMP4 developa fibrodysplasia ossificans progressiva (FOP)-like phenotype. Am J Pathol 165:1107–1115.

    PubMed  CAS  Google Scholar 

  3. Connor JM, Evans, DA. 1982 Fibrodysplasia ossificans progressiva (FOP): the clinical features and natural history of 34 patients. J Bone Joint Surg Br 64:76–83.

    PubMed  CAS  Google Scholar 

  4. Connor JM. 1996 Fibrodysplasia ossificans progressiva— lessons from rare maladies. N Engl J Med 335:591–593.

    Article  PubMed  CAS  Google Scholar 

  5. Delatycki M, Rogers JG. 1998 The genetics of fibrodysplasia ossificans progressiva. Clin Orthop 346:1518.

    Google Scholar 

  6. Kaplan FS, Delatycki M, Gannon FH, Rogers JG, Smith R, Shore EM. 1998 Fibrodysplasia ossificans progressiva. In: Emery EH, ed. Neuromuscular Disorders: Clinical and Molecular Genetics. John Wiley & Sons, Chichester, NY, pp. 289–321.

    Google Scholar 

  7. Kaplan FS, Shore EM, Connor JM. 2002 Fibrodysplasia ossificans progressiva (FOP). In: Royce PM, Steinmann B, eds. Connective Tissue and Its Heritable Disorders. Wiley-Liss, John Wiley & Sons, New York, pp. 827–840.

    Chapter  Google Scholar 

  8. Kaplan FS, Glaser DL, Shore EM. 2005 The fourteenth annual report of the fibrodysplasia ossificans progressiva (FOP) collaborative research project. FOP Connection 16(2):1–20.

    Google Scholar 

  9. Xu M-Q, Feldman G, Le Merrer M, et al. 2000 Linkage exclusion and mutational analysis of the Noggin gene in patients with fibrodysplasia ossificans progressiva. Clin Genet 58:291–298.

    Article  PubMed  CAS  Google Scholar 

  10. Kaplan FS, Glaser DL, Shore EM. 2003 Fibrodysplasia (myositis) ossificans progressiva. In Favus MJ, ed. Primer on the Metabolic Bone Diseases and disorders of Mineral Metabolism, 5th Ed. The American Society for Bone and Mineral Research, Lippincott-Raven, Philadelphia, PA, pp. 513–516.

    Google Scholar 

  11. Scarlett RF, Rocke DM, Kantanie S, Patel JB, Shore EM, Kaplan FS, 2004 Influenza-like viral illnesses and flareups of fibrodysplasia ossificans progressiva. Clin Orthop 423: 275–279.

    Article  PubMed  Google Scholar 

  12. Lanchoney TF, Cohen RB, Rocke DM, Zasloff MA, Kaplan FS. 1995 Permanent heterotopic ossification at the injection site after diphtheria-tetanus-pertussis immunizations in children who have fibrodysplasia ossificans progressiva. J Pediatrics 126:762–764.

    Article  CAS  Google Scholar 

  13. Luchetti W, Cohen RB, Hahn GV, et al. 1996 Severe restriction in jaw movement after route injection of local anesthetic in patients who have fibrodysplasia ossificans progressiva. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 81:21–25.

    Article  PubMed  CAS  Google Scholar 

  14. Nussbaum BL, O'Hara, I, Kaplan FS, 1996 Fibrodysplasia ossificans progressiva (FOP): report of a case with guidelines for pediatric dental and anesthetic management. ASDC J Dent Child 63:448–450.

    PubMed  CAS  Google Scholar 

  15. Glaser DL, Rocke DM, Kaplan FS. 1998 Catastrophic falls in patients who have fibrodysplasia ossificans progressiva. Clin Orthop 346:110–116.

    PubMed  Google Scholar 

  16. Gannon FH, Valentine BA, Shore EM, Zasloff MA, Kaplan FS. 1998 Acute lymphocytic infiltration in an extremely early lesion of fibrodysplasia ossificans progressiva. Clin Orthop 346:19–25.

    PubMed  Google Scholar 

  17. Gannon FH, Glaser D, Caron R, Thompson LDR, Shore EM, Kaplan FS. 2001 Mast cell involvement in fibrodysplasia ossificans progressiva (FOP). Hum Pathol 32: 842–848.

    Article  PubMed  CAS  Google Scholar 

  18. Janoff HB, Zasloff MA, Kaplan FS. 1996 Submandibular swelling in patients with fibrodysplasia ossificans progressiva. Otolaryngol Head Neck Surg 114:599–604.

    Article  PubMed  CAS  Google Scholar 

  19. Kaplan AP. 2002 Chronic urticaria an dangioedema. N Engl J Med 346:175–179.

    Article  PubMed  Google Scholar 

  20. Simmons FER. 2004 Advances in H1-Antihistamines. N Engl J Med 351:2203–2217.

    Article  Google Scholar 

  21. DiCesare PE, Nimni ME, Pen L, Yazdi M, Cheung DT. 1991 Effects of Indomethacin on demineralized bone-induced heterotopic ossification in the rat. J Orthop Res 9: 855–861.

    Article  PubMed  CAS  Google Scholar 

  22. Weinreb M, Suponitsky I, Keila S. 1997 Systemic administration of an anabolic dose of PGE2 in young rats increases the osteogenic capacity of bone marrow. Bone 20: 521–526.

    Article  PubMed  CAS  Google Scholar 

  23. Zhang X, Schwarz EM, Young DA, Puzas E, Rosier RN, O'Keefe RJ. 2002 Cyclo-oxygenase-2 regulates mesenchymal cell differentiation into the osteoblast lineage and is critically involved in bone repair. J Clin Invest 109: 1405–1415.

    Article  PubMed  CAS  Google Scholar 

  24. Jones, MK, Wang H, Peskar BM, et al. 1999 Inhibition of angiogenesis by nonsteroidal anti-inflammatory drugs: insight into mechanisms and implications for cancer growth and ulcer healing. Nat Med 5:1418–1423.

    Article  PubMed  CAS  Google Scholar 

  25. Couzin J, Drugsafety. 2004 Withdrawal of Vioxx casts a shadow over COX-2 inhibitors. Science 306:384–385.

    Article  PubMed  CAS  Google Scholar 

  26. Fitzgerald GA. 2004 Coxibs and cardiovascular disease. N Engl J Med 351:1709–1711.

    Article  PubMed  CAS  Google Scholar 

  27. White WB, Faich G, Whelton A, et al. 2002 Comparison of thromboembolic events in patients treated with celexoxib, a cyclo-oxygenase-2 specific inhibitor, versus ibuprofen or diclofenac. Am J Cardiol 89:425–430.

    Article  PubMed  CAS  Google Scholar 

  28. White WB, Faich G, Borer JS, Makuch RW. 2003 Cardiovascular thrombotic events in arthritis trials of the cyclo-oxygenase-2 inhibitor celecoxib. Am J Cardiol 92: 411–418.

    Article  PubMed  CAS  Google Scholar 

  29. Altschuler EL. 2001 Question: Bone marrow transplant for fibrodysplasia ossificans progressiva: has the hour arrived? Clin Orthop 392:450–451.

    Article  PubMed  Google Scholar 

  30. Altschuler EL. 2004 Bone marrow transplantation in a patient with fibrodysplasia ossificans progressiva. Clin Orthop 422:277–278.

    Article  PubMed  Google Scholar 

  31. Emerson SG, Kaplan FS. 2001 Marrow stem cell transplantation in fibrodysplasia ossificans progressiva. Clin Orthop 392:451–455.

    Article  PubMed  Google Scholar 

  32. Kaplan FS, Glaser DL, Shore EM, Emerson SG. 2004 Bone marrow transplantation in a patient with fibrodysplasia ossificans progressiva. Clin Orthop 422:278.

    Article  Google Scholar 

  33. Shafritz AB, Shore EM, Gannon FH, et al. 1996 Overexpression of an osteogenic morphogen in fibrodysplasia ossificans progressiva (FOP). N Engl J Med 335: 555–561.

    Article  PubMed  CAS  Google Scholar 

  34. Kitterman JA, Kantanie S, Rocke DM, Kaplan FS. 2005 latrogenic harm caused by diagnostic errors in fibrodysplasia ossificans progressiva. Pediatrics, in press.

  35. Kussmaul WG, Esmail AN, Sagar Y, Ross J, Gregory S, Kaplan FS. 1998 Pulmonary and cardiac function in advanced fibrodysplasia ossificans progressiva. Clin Orthop 346:104–109.

    PubMed  Google Scholar 

  36. Kaplan FS, Sawyer J, Connors S, et al. 1998. Urinary basic fibroblast growth factor: a biochemical marker for preosseous fibroproliferative lesions in patients with FOP. Clin Orthop 346:59–65.

    PubMed  Google Scholar 

  37. Kaplan FS, Tabas J, Gannon FH, Finkel G, Hahn GV, Zasloff MA. 1993 The histopathology of fibrodysplasia ossificans progressiva: an endoc hondral process. J Bone Joint Surg Am 75-A:220–230.

    Google Scholar 

  38. Langenfeld EM, Langenfeld J. 2004 Bone morphogenetic protein-2 simulates angiogenesis in developing tumors. Mol Cancer Res 2(3):141–149.

    PubMed  CAS  Google Scholar 

  39. Huang J, Frischer JS, Serur A, et al. 2003 Regression of established tumors and metastases by potent vascular endothelial grown factor blockade. Proc Natl Acad Sci USA 100:7785–7790.

    Article  PubMed  CAS  Google Scholar 

  40. Stephens T, Brynner R. 2001 Dark Remedy: The impact of Thalidomide and its Revival as a Vital Medicine. Perseus Publishing, New York.

    Google Scholar 

  41. Brantus JF, Meunier PJ. 1998 Effects of intravenous etidronate and oral corticosteroids in fibrodysplasia ossificans progressiva. Clin Orthop 346:117–120.

    PubMed  Google Scholar 

  42. Schuetz P, Mueller B, Christ-Crain M, Dick W, Haas H. 2005 Amino-bisphosphonates in heterotopic ossification: first experience in five consecutive cases. Spinal Cord, in press.

  43. Still K, Phipps RJ, Scutt A. 2003 Effects of risedronate, alendronate, and etidronate on the viability and activity of rat bone marrow stromal cells in vitro. Calcif Tissue Int 72: 143–150.

    Article  PubMed  CAS  Google Scholar 

  44. Dunford JE, Thompson K, Coxon FP, et al. 2001 Structure-activity relationships for inhibition or farnesyl diphosphate synthase in vitro and inhibition of bone resorption in vivo by nitrogen-containing bisphosphonates. J Pharmacol Exp Therap 296:235–242.

    CAS  Google Scholar 

  45. Wood J, Bonjean K, Ruetz S, et al. 2002 Novel antiangiogenic effects of the bisphosphonate compound zoledronic acid. J Pharmacol Exp Therap 302:1055–1061.

    Article  CAS  Google Scholar 

  46. Santini D, Vincenzi B, Avvisati G, et al. 2002 Pamidronate induces modifications of circulating angiogenetic factors in cancer patients. Clin Cancer Res: 8:1080–1084.

    PubMed  CAS  Google Scholar 

  47. Green JR. 2002 Preclinical pharmacology of zoledronic acid. Semin Oncol 29 (6 Suppl 21):3–11.

    Article  PubMed  CAS  Google Scholar 

  48. Green JR. 2003 Antitumor effects of bisphosphonates. Cancer 97 (Suppl):840–847.

    Article  PubMed  Google Scholar 

  49. Pechersturfer M, Jilch R, Sauty A, et al. 2000 Effect of first treatment with aminobisphosphonates pamidronate and ibandronate on circulating lymphocyte subpopulations. J Bone Miner Res 15:147–154.

    Article  Google Scholar 

  50. Zasloff MA, Rocke DM, Crofford LJ, Hahn GV, Kaplan FS. 1998 Treatment of patients who have fibrodysplasia ossificans progressiva with isotretinoin. Clin Orthop 346: 121–129.

    PubMed  Google Scholar 

  51. Serrano de la Pena L, Billings PC, Fiori JL, Ahn J, Kaplan FS, Shore EM. 2005 Fibrodysplasia ossificans progressiva (FOP), a disorder of ectopic osteogenesis, misregulates cell surface expression and trafficking of BMPRIA. J Bone Miner Res 20:1168–1176.

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Frederick S. Kaplan MD.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Glaser, D.L., Kaplan, F.S. Treatment considerations for the management of fibrodysplasia ossificans progressiva. Clinic Rev Bone Miner Metab 3, 243–250 (2005). https://doi.org/10.1385/BMM:3:3-4:243

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1385/BMM:3:3-4:243

Key Words

Navigation