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Follow-Up of Six Patients with Neurofibromatosis 1-Related Osteoporosis Treated with Alendronate for 23 Months

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Abstract

This is the first prospective follow-up study to describe the effects of oral alendronate medication on neurofibromatosis 1 (NF1)-related osteoporosis. NF1 is a neurocutaneous skeletal syndrome associated with increased fracture risk and high frequency of osteopenia and osteoporosis. Alendronate is a bisphosphonate drug which inhibits the function of bone-resorbing osteoclasts, ultimately leading to an increase in bone mineral density (BMD) and reduction in fracture risk. However, in vitro studies have shown that NF1 osteoclasts display insensitivity to apoptotic signals caused by bisphosphonates. Our aim was to monitor the effects of alendronate medication in patients with NF1. Five men and one woman, aged 28–76 years, with NF1-related osteoporosis were enrolled to the study. Study participants did not have other conditions and were not taking any medication known to affect bone. The medication included a weekly dose of 70 mg alendronate and a daily 20 μg vitamin D supplementation. After 23 months of follow-up, BMD was increased in five out of six patients, but the increase was not statistically significant. Serum levels of the bone turnover markers CTX and PINP were reduced, suggesting slower bone remodeling, as expected. An unexpected result was that serum levels of the osteoclast activity marker TRAP5b did not change during the follow-up. One new stress fracture of the tibia was documented during the alendronate therapy. Even though the study group was small, the findings of the current study (one new fracture and one patient with decreased BMD) call for a larger study to assess the efficacy of bisphosphonates in NF1-related osteoporosis.

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Abbreviations

NF1:

Neurofibromatosis type 1

CTX:

Collagen type I C-terminal telopeptide

TRACP5b:

Tartrate-resistance acid phosphatase 5b

PINP:

Procollagen type I N-terminal propeptide

References

  1. Riccardi V, Eichner J (1986) Neurofibromatosis: phenotype, natural history and pathogenesis. Johns Hopkins University Press, Baltimore

    Google Scholar 

  2. Huson S (2008) The neurofibromatoses: classification, clinical features and genetic counseling. In: Kaufmann D (ed) Neurofibromatoses. Monographs in human genetics, Karger, pp 1–20

    Chapter  Google Scholar 

  3. Jouhilahti EM, Peltonen S, Heape A, Peltonen J (2011) Pathoetiology of neurofibromatosis. Am J Pathol 178:1932–1939

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  4. Xu G, O’Connell P, Viskochil D, Cawthon R, Robertson M, Culver M, Dunn D, Stevens J, Gesteland R, White R (1990) The neurofibromatosis type 1 gene encodes a protein related to GAP. Cell 62:599–608

    Article  CAS  PubMed  Google Scholar 

  5. Stumpf D, Annergers J, Brown S, Conneally P, Housman D, Leppert M, Miller J, Moss M, Pileggi A, Rapin I, Strohman R, Swanson L, Zimmersman A (1988) Neurofibromatosis. Conference statement. National Institutes of Health Consensus Development Conference. Arch Neurol 45:575–578

    Article  Google Scholar 

  6. Peltonen S, Poyhonen M (2012) Clinical diagnosis and atypical forms of NF1. In: Upadhyaya M, Cooper D (eds) Neurofibromatosis type 1: molecular and cellular biology. Springer, Berlin, pp 17–30

    Chapter  Google Scholar 

  7. Elefteriou F, Kolanczyk M, Schindeler A et al (2009) Skeletal abnormalities in neurofibromatosis type 1: approaches to therapeutic options. Am J Med Genet A 149:2327–2338

    Article  Google Scholar 

  8. Kuorilehto T, Pöyhönen M, Bloigu R, Heikkinen J, Väänänen K, Peltonen J (2005) Decreased bone mineral density and content in neurofibromatosis type 1: lowest local values are located in the load-carrying parts of the body. Osteoporos Int 16:928–936

    Article  CAS  PubMed  Google Scholar 

  9. Brunetti-Pierri N, Doty S, Hicks J, Phan K, Mendoza-Londono R, Blazo M, Tran A, Carter S, Lewis R, Plon S, Phillips W, O’Brian Smith E, Ellis K, Lee B (2008) Generalized metabolic bone disease in neurofibromatosis type I. Mol Genet Metab 94:105–111

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  10. Tucker T, Schnabel C, Hartmann M, Friedrich R, Frieling I, Kruse H, Mautner V, Friedman J (2009) Bone health and fracture rate in individuals with neurofibromatosis 1 (NF1). J Med Genet 46:259–265

    Article  CAS  PubMed  Google Scholar 

  11. Petramala L, Giustini S, Zinnamosca L, Marinelli C, Colangelo L, Cilenti G, Formicuccia M, D’Erasmo E, Calvieri S, Letizia C (2012) Bone mineral metabolism in patients with neurofibromatosis type 1 (von Recklinghausen disease). Arch Dermatol Res 304:325–331

    Article  CAS  PubMed  Google Scholar 

  12. Heervä E, Peltonen S, Svedström E, Aro HT, Väänänen K, Peltonen J (2012) Osteoclasts derived from patients with neurofibromatosis 1 (NF1) display insensitivity to bisphosphonates in vitro. Bone 50:798–803

    Article  PubMed  Google Scholar 

  13. Heervä E, Leinonen P, Kuorilehto T, Peltonen S, Pöyhönen M, Väänänen K, Peltonen J (2013) Neurofibromatosis 1–related osteopenia often progresses to osteoporosis in 12 years. Calcif Tissue Int 92:23–27

    Article  PubMed  Google Scholar 

  14. Heervä E, Koffert A, Jokinen E, Kuorilehto T, Peltonen S, Aro HT, Peltonen J (2012) A controlled register-based study of 460 neurofibromatosis 1 patients: increased fracture risk in children and adults over 41 years of age. J Bone Miner Res 27:2333–2337

    Article  PubMed  Google Scholar 

  15. George-Abraham J, Martin L, Kalkwarf H, Rieley M, Stevenson D, Viskochil D, Hopkin R, Stevens A, Hanson H, Schorry E (2013) Fractures in children with neurofibromatosis type 1 from two NF clinics. Am J Med Gen A 161:921–926

    Article  CAS  Google Scholar 

  16. NIH Consensus Development Panel on Osteoporosis Prevention, Diagnosis, and Therapy (2001) Osteoporosis prevention, diagnosis, and therapy. JAMA 285:785–795

    Article  Google Scholar 

  17. Lewiecki E, Gordon C, Baim S, Binkley N, Bilezikian J, Kendler D, Hans D, Silverman S, Bishop N, Leonard M, Bianchi M, Kalkwarf H, Langman C, Plotkin H, Rauch F, Zemel B (2008) Special report on the 2007 adult and pediatric Position Development Conferences of the International Society for Clinical Densitometry. Osteoporos Int 19:1078–1369

    Google Scholar 

  18. Bergstrom J, Bostedor R, Masarachia P, Reszka A, Rodan G (2000) Alendronate is a specific, nanomolar inhibitor of farnesyl diphosphate synthase. Arch Biochem Biophys 373:231–234

    Article  CAS  PubMed  Google Scholar 

  19. Dunford J, Rogers M, Ebetino F, Phipps R, Coxon F (2006) Inhibition of protein prenylation by bisphosphonates causes sustained activation of Rac, Cdc42, and Rho GTPases. J Bone Miner Res 21:684–694

    Article  PubMed  Google Scholar 

  20. Gallacher S, Dixon T (2010) Impact of treatments for postmenopausal osteoporosis (bisphosphonates, parathyroid hormone, strontium ranelate, and denosumab) on bone quality: a systematic review. Calcif Tissue Int 87:469–484

    Article  CAS  PubMed  Google Scholar 

  21. Reginster J (2011) Antifracture efficacy of currently available therapies for postmenopausal osteoporosis. Drugs 71:65–78

    Article  CAS  PubMed  Google Scholar 

  22. Vasikaran S, Eastell R, Bruyère O, Foldes A, Garnero P, Griesmacher A, McClung M, Morris H, Silverman S, Trenti T, Wahl D, Cooper C, Kanis J (2011) Markers of bone turnover for the prediction of fracture risk and monitoring of osteoporosis treatment: a need for international reference standards. Osteoporos Int 22:391–420

    Article  CAS  PubMed  Google Scholar 

  23. Cummings S, Black D, Thompson D, Applegate W, Barrett-Connor E, Musliner T, Palermo L, Prineas R, Rubin S, Scott J, Vogt T, Wallace R, Yates A, LaCroix A (1998) Effect of alendronate on risk of fracture in women with low bone density but without vertebral fractures: results from the Fracture Intervention Trial. JAMA 280:2077–2082

    Article  CAS  PubMed  Google Scholar 

  24. Tonino R, Meunier P, Emkey R, Rodriguez-Portales J, Menkes C, Wasnich R, Bone H, Santora A, Wu M, Desai R, Ross P (2000) Skeletal benefits of alendronate: 7-year treatment of postmenopausal osteoporotic women. Phase III Osteoporosis Treatment Study Group. J Clin Endocrinol Metab 85:3109–3115

    CAS  PubMed  Google Scholar 

  25. Bone H, Hosking D, Devogelaer J, Tucci J, Emkey R, Tonino R, Rodriguez-Portales J, Downs R, Gupta J, Santora A, Liberman U (2004) Alendronate Phase III Osteoporosis Treatment Study Group. Ten years’ experience with alendronate for osteoporosis in postmenopausal women. N Engl J Med 350:1189–1199

    Article  CAS  PubMed  Google Scholar 

  26. Rosen C, Hochberg M, Bonnick S, McClung M, Miller P, Broy S, Kagan R, Chen E, Petruschke R, Thompson D, de Papp A (2005) Treatment with once-weekly alendronate 70 mg compared with once-weekly risedronate 35 mg in women with postmenopausal osteoporosis: a randomized double-blind study. J Bone Miner Res 20:141–151

    Article  CAS  PubMed  Google Scholar 

  27. Nenonen A, Cheng S, Ivaska K, Alatalo S, Lehtimäki T, Schmidt-Gayk H, Uusi-Rasi K, Heinonen A, Kannus P, Sievänen H, Vuori I, Väänänen K, Halleen J (2005) Serum TRAP 5b is a useful marker for monitoring alendronate treatment: comparison with other markers of bone turnover. J Bone Miner Res 20:1804–1812

    Article  CAS  PubMed  Google Scholar 

  28. Birke O, Schindeler A, Ramachandran M, Cowell C, Munns C, Bellemore M, Little D (2010) Preliminary experience with the combined use of recombinant bone morphogenetic protein and bisphosphonates in the treatment of congenital pseudarthrosis of the tibia. J Child Orthop 4:507–517

    Article  PubMed Central  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Cell Biology and Anatomy, University of Turku, Kiinamyllynkatu 10, 20520, Turku, Finland

    Eetu Heervä & Juha Peltonen

  2. Department of Dermatology, Medical Research Center, Oulu University Hospital and University of Oulu, 90220, Oulu, Finland

    Laura Huilaja & Pekka Leinonen

  3. Department of Dermatology, Kainuu Central Hospital, 87140, Kajaani, Finland

    Pekka Leinonen

  4. Department of Dermatology, Turku University Hospital and University of Turku, 20521, Turku, Finland

    Sirkku Peltonen

Authors
  1. Eetu Heervä
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  2. Laura Huilaja
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  3. Pekka Leinonen
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  4. Sirkku Peltonen
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  5. Juha Peltonen
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Corresponding author

Correspondence to Juha Peltonen.

Additional information

Eetu Heervä, Laura Huilaja, Pekka Leinonen, Sirkku Peltonen and Juha Peltonen declare that they have no conflict of interest.

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Heervä, E., Huilaja, L., Leinonen, P. et al. Follow-Up of Six Patients with Neurofibromatosis 1-Related Osteoporosis Treated with Alendronate for 23 Months. Calcif Tissue Int 94, 608–612 (2014). https://doi.org/10.1007/s00223-013-9835-2

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  • DOI: https://doi.org/10.1007/s00223-013-9835-2

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