Archives of Osteoporosis

, 13:93 | Cite as

Progressive bone impairment with age and pubertal development in neurofibromatosis type I

  • Giulia Rodari
  • G. Scuvera
  • F. M. Ulivieri
  • E. Profka
  • F. Menni
  • V. Saletti
  • S. Esposito
  • S. Bergamaschi
  • E. Ferrante
  • C. Eller-Vainicher
  • S. Esposito
  • M. Arosio
  • C. Giavoli
Original Article



Bone density impairment represents an established complication in adults with neurofibromatosis type 1, while few data exist in the pediatric population. Age- and gender-adjusted bone mass decreases with age and pubertal development, identifying childhood as the best time frame to introduce prevention strategies aiming at peak bone mass achievement.


The present study aims at evaluating bone mineral density (BMD) in a population of children with neurofibromatosis type I (NF-1), with particular focus on changes occurring during growth and pubertal development.


Bone metabolic markers and bone status [by dual-energy X-ray absorptiometry scans (DXA) of the total body and lumbar spine with morphometric analysis] were assessed in 50 children (33 males; mean age ± SD, 11.6 ± 4 years). Bone mineral apparent density (BMAD), trabecular bone score (TBS), and bone strain (BS) of the lumbar spine (LS) DXA were also obtained.


In our cohort areal BMD (aBMD) Z-score was below the mean in 88% of the patients at LS (70% after correction for bone size) and in 86% considering total body (TB) DXA. However, aBMD Z-score was < − 2 in 12% after correction for bone size at LS and TB, respectively. Lumbar spine aBMD Z-score (r = − 0.54, P < 0.0001), LS BMAD Z-score (r = − 0.53, P < 0.0001), and TB Z-score (r = − 0.39, P = 0.005) showed a negative correlation with growth and pubertal development (P = 0.007, P = 0.02, P = 0.01, respectively), suggesting that patients failed to gain as much as expected for age.


Bone density impairment becomes more evident with growth and pubertal development in NF-1 patients, thus identifying childhood as the best time frame to introduce prevention strategies aiming at peak bone mass achievement. TBS and BS, providing bone DXA qualitative information, could be useful during longitudinal follow-up for better characterizing bone impairment in these patients.


Bone mineral density Neurofibromatosis type 1 Peak bone mass Pubertal development Pediatrics Trabecular bone score Bone strain 


Compliance with ethical standards

Conflicts of interest



  1. 1.
    Evans DG, Howard E, Giblin C, Clancy T, Spencer H, Huson SM, Lalloo F (2010) Birth incidence and prevalence of tumor-prone syndromes: estimates from a UK family genetic register service. Am J Med Genet A 152A:327–332. CrossRefPubMedGoogle Scholar
  2. 2.
    Ratner N, Miller SJ (2015) A RASopathy gene commonly mutated in cancer: the neurofibromatosis type 1 tumour suppressor. Nat Rev Cancer 15:290–301. CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Gutmann DH, Aylsworth A, Carey JC, Korf B, Marks J, Pyeritz RE, Rubenstein A, Viskochil D (1997) The diagnostic evaluation and multidisciplinary management of neurofibromatosis 1 and neurofibromatosis 2. JAMA 278:51–57. CrossRefPubMedGoogle Scholar
  4. 4.
    Lynch TM, Gutmann DH (2002) Neurofibromatosis 1. Neurol Clin 20:841–865. CrossRefPubMedGoogle Scholar
  5. 5.
    Ward BA, Gutmann DH (2005) Neurofibromatosis 1: from lab bench to clinic. Pediatr Neurol 32:221–228. CrossRefPubMedGoogle Scholar
  6. 6.
    Stevenson DA, Viskochil DH, Carey JC (2007) Neurofibromatosis type 1 is a genetic skeletal disorder. Am J Med Genet A 143:2082–2083. CrossRefGoogle Scholar
  7. 7.
    Yilmaz K, Ozmen M, Bora Goksan S, Eskiyurt N (2007) Bone mineral density in children with neurofibromatosis 1. Acta Paediatr 96:1220–1222. CrossRefPubMedGoogle Scholar
  8. 8.
    Stevenson DA, Moyer-Mileur LJ, Murray M, Slater H, Sheng X, Carey JC, Dube B, Viskochil DH (2008) Bone mineral density in children and adolescents with neurofibromatosis type 1. J Pediatr 150:83–88. CrossRefGoogle Scholar
  9. 9.
    Dulai S, Briody J, Schindeler A, North KN, Cowell CT, Little DG (2007) Decreased bone mineral density in neurofibromatosis type 1: results from a pediatric cohort. J Pediatr Orthop 27:472–475. CrossRefPubMedGoogle Scholar
  10. 10.
    Duman O, Ozdem S, Turkkaharaman D, Olgac ND, Gungor F, Haspolat S (2008) Bone metabolism markers and bone mineral density in children with neurofibromatosis type-1. Brain and Development 30:584–588. CrossRefPubMedGoogle Scholar
  11. 11.
    Brunetti-Pierri N, Doty SB, Hicks J, Phan K, Mendoza-Londono R, Blazo M, Tran A, Carter S, Lewis RA, Plon SE, Phillips WA, O’Brian Smith E, Ellis KJ, Lee B (2008) Generalized metabolic bone disease in neurofibromatosis type I. Mol Genet Metab 94:105–111. CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Caffarelli C, Gonnelli S, Tanzilli L, Vivarelli R, Tamburello S, Balestri P, Nuti R (2010) Quantitative ultrasound and dual-energy x-ray absorptiometry in children and adolescents with neurofibromatosis of type 1. J Clin Densitom 13:77–83. CrossRefPubMedGoogle Scholar
  13. 13.
    Lodish MB, Dagalakis U, Sinali N, Bornstein E, Kim A, Lokie KB, Baldwin AM, Reynolds JC, Dombi E, Stratakis CA, Widemann BC (2012) Bone mineral density in children and young adults with neurofibromatosis type 1. Endocr Relat Cancer 19:817–825. CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Bachrach LK (2001) Acquisition of optimal bone mass in childhood and adolescence. Trends Endocrinol Metab 12:22–28. CrossRefPubMedGoogle Scholar
  15. 15.
    Rizzoli R, Bianchi ML, Garabèdian M, McKay HA, Moreno LA (2010) Maximizing bone mineral mass gain during growth for the prevention of fractures in the adolescents and the elderly. Bone 46:294–305. CrossRefPubMedGoogle Scholar
  16. 16.
    George-Abraham JK, Martin LJ, Kalkwarf HJ, Rieley MB, Stevenson DA, Viskochil DH, Hopkin RJ, Stevens AM, Hanson H, Schorry EK (2013) Fractures in children with neurofibromatosis type 1 from two NF clinics. Am J Med Genet A 161:921–926. CrossRefGoogle Scholar
  17. 17.
    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. CrossRefPubMedGoogle Scholar
  18. 18.
    2013 ISCD Official Positions - Paediatric - International Society for Clinical Densitometry (ISCD). Accessed 13 Sept 2016
  19. 19.
    National Institutes of Health Consensus Development Conference (1988) Neurofibromatosis. NIH Consens Statement 1987 Jul 13–15; 6:1–19Google Scholar
  20. 20.
    Tanner JM, Whitehouse RH (1976) Clinical longitudinal standards for height, weight, height velocity, weight velocity, and the stages of puberty. Arch Dis Child 51:170–179. CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Greulich WW, Pyle SL (1959) Radiographic atlas of skeletal development of the hand and wrist, 2nd edn. Stanford University Press, StanfordGoogle Scholar
  22. 22.
    Institute of Medicine (IOM) (2011) Dietary reference intakes for calcium and vitamin D. The National Academies Press, Washington, pp 260–262Google Scholar
  23. 23.
    Payne RB (1198) Renal tubular reabsorption of phosphate, (TmP/GFR): indications and interpretation. Ann Clin Biochem 35:201–206CrossRefGoogle Scholar
  24. 24.
    Ward KA, Ashby RL, Roberts SA, Adams JE, Zulf Mughal M (2007) UK reference data for the Hologic QDR Discovery dual-energy x ray absorptiometry scanner in healthy children and young adults aged 6–17 years. Arch Dis Child 92:53–59. CrossRefPubMedGoogle Scholar
  25. 25.
    Pothuaud L, Carceller P, Hans D (2008) Correlations between grey-level variations in 2D projection images (TBS) and 3D microarchitecture: applications in the study of human trabecular bone microarchitecture. Bone 42:775–787CrossRefGoogle Scholar
  26. 26.
    Pohuaud L, Barthe N, Krieg MA, Mehsen N, Carceller P, Hans D (2009) Evaluation of the potential use of trabecular bone score to complement bone mineral density in the diagnosis of osteoporosis: a preliminary spine BMD-matched, case-control study. J Clin Densitom 12(2):170–176. CrossRefGoogle Scholar
  27. 27.
    Del Rio LM, Winzenrieth R, Cormier C (2013) Di Gregorio, S. Is bone microarchitecture status of the lumbar spine assessed by TBS related to femoral neck fracture? A Spanish case-control study. Osteoporos Int 24:991–998CrossRefGoogle Scholar
  28. 28.
    Silva BC, Broy SB, Boutroy S, Schousboe JT, Shepherd JA, Leslie WD (2015) Fracture risk prediction by non-BMD DXA measures: the 2015 ISCD official positions part 2: trabecular bone score. J Clin Densitom 18(3):309–330. CrossRefPubMedGoogle Scholar
  29. 29.
    Martineau P, Silva BC, Leslie WD (2017) Utility of trabecular bone score in the evaluation of osteoporosis. Curr Opin Endocrinol Diabetes Obes 24(6):402–410. CrossRefPubMedGoogle Scholar
  30. 30.
    Hans D, Goertzen AL, Krieg MA, Leslie WD (2011) Bone microarchitecture assessed by TBS predicts osteoporotic fractures independent of bone density: the Manitoba study. J Bone Miner Res Off J Am Soc Bone Miner Res 26:2762–2769CrossRefGoogle Scholar
  31. 31.
    Gockenbach MS (2008) Understanding and Implementing the finite element method. Society for Industrial and Applied MathematicsGoogle Scholar
  32. 32.
    Zienkiewicz O (2005) The finite element method for solid and structural mechanics. Butterworth-Heinemann, OxfordGoogle Scholar
  33. 33.
    Yang L, Palermo L, Black DM, Eastell R (2014) Prediction of incident hip fracture with the estimated femoral strength by finite element analysis of DXA scans in the study of osteoporotic fractures. J Bone Miner Res 29:2594–2600. CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Orwoll ES, Marshall LM, Nielson CM, Cummings SR, Lapidus J, Cauley JA, Ensrud K, Lane N, Hoffmann PR, Kopperdahl DL, Keaveny TM, for the Osteoporotic Fractures in Men (MrOS) Study Group (2009) Finite element analysis of the proximal femur and hip fracture risk in older men. J Bone Miner Res 24:475–483. CrossRefPubMedGoogle Scholar
  35. 35.
    Wu X, Estwick SA, Chen S, Yu M, Ming W, Nebesio TD, Li Y, Yuan J, Kapur R, Ingram D, Yoder MC, Yang FC (2006) Neurofibromin plays a critical role in modulating osteoblast differentiation of mesenchymal stem/progenitor cells. Hum Mol Genet 15:2837–2845. CrossRefPubMedGoogle Scholar
  36. 36.
    Shawwa K, Arabi A, Nabulsi M, Maalouf J, Salamoun M, Choucair M, Hans D, El-Hajj Fuleihan G (2016) Predictors of trabecular bone score in school children. Osteoporos Int 27:703–710. CrossRefPubMedGoogle Scholar
  37. 37.
    Heervä E, Alanne MH, Peltonen S, Kuorilehto T, Hentunen T, Väänänen K, Peltonen J (2010) Osteoclasts in neurofibromatosis type 1 display enhanced resorption capacity, aberrant morphology, and resistance to serum deprivation. Bone 47:583–590. CrossRefPubMedGoogle Scholar
  38. 38.
    Li H, Liu Y, Zhang Q, Jing Y, Chen S, Song Z, Yan J, Li Y, Wu X, Zhang X, Zhang Y, Case J, Yu M, Ingram DA, Yang FC (2009) Ras dependent paracrine secretion of osteopontin by Nf1+/- osteoblasts promote osteoclast activation in a neurofibromatosis type I murine model. Pediatr Res 65:613–618. CrossRefPubMedGoogle Scholar
  39. 39.
    Yu X, Chen S, Potter OL, Murthy SM, Li J, Pulcini JM, Ohashi N, Winata T, Everett ET, Ingram D, Clapp WD, Hock JM (2005) Neurofibromin and its inactivation of Ras are prerequisites for osteoblast functioning. Bone 36:793–802. CrossRefPubMedGoogle Scholar
  40. 40.
    Wu X, Chen S, He Y, Rhodes SD, Mohammad KS, Li X, Yang X, Jiang L, Nalepa G, Snider P, Robling AG, Clapp DW, Conway SJ, Guise TA, Yang FC (2011) The haploinsufficient hematopoietic microenvironment is critical to the pathological fracture repair in murine models of neurofibromatosis type 1. PLoS One 6:e24917. CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Yang FC, Chen S, Robling AG, Yu X, Nebesio TD, Yan J, Morgan T, Li X, Yuan J, Hock J, Ingram DA, Clapp DW (2006) Hyperactivation of p21 ras and PI3K cooperate to alter murine and human neurofibromatosis type 1- haploinsufficient osteoclast functions. J Clin Invest 116:2880–2891. CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Poyrazoğlu HG, Baş VN, Arslan A, Bastug F, Canpolat M, Per H, Gümüs H, Kumandas S (2017) Bone mineral density and bone metabolic markers' status in children with neurofibromatosis type 1. J Pediatr Endocrinol Metab 30(2):175–180. CrossRefPubMedGoogle Scholar
  43. 43.
    Lammert M, Kappler M, Mautner VF, Lammert K, Störkel S, Friedman JM, Atkins D (2005) Decreased bone mineral density in patients with neurofibromatosis 1. Osteoporos Int 16:1161–1166. CrossRefPubMedGoogle Scholar
  44. 44.
    Stevenson DA, Viskochil DH, Carey JC, Sheng X, Murray M, Moyer-Mileur L, Shelton J, Roberts WL, Bunker AM, Hanson H, Bauer S, D'Astous JL (2011) Pediatric 25-hydroxyvitamin D concentrations in neurofibromatosis type 1. J Pediatr Endocrinol Metab 24(3–4):169–174. CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Hockett CW, Eelloo J, Huson SM, Roberts SA, Berry JL, Chaloner C, Rawer R, Mughal MZ (2013) Vitamin D status and muscle function in children with neurofibromatosis type 1 (NF1). J Musculoskelet Neuronal Interact 13:111–119PubMedGoogle Scholar
  46. 46.
    Schnabel C, Dahm S, Streichert T, Thierfelder W, Kluwe L, Mautner VF (2014) Differences of 25-hydroxyvitamin D3 concentrations in children and adults with neurofibromatosis type 1. Clin Biochem 47:560–563. CrossRefPubMedGoogle Scholar

Copyright information

© International Osteoporosis Foundation and National Osteoporosis Foundation 2018

Authors and Affiliations

  • Giulia Rodari
    • 1
  • G. Scuvera
    • 2
  • F. M. Ulivieri
    • 3
  • E. Profka
    • 1
  • F. Menni
    • 2
  • V. Saletti
    • 4
  • S. Esposito
    • 4
  • S. Bergamaschi
    • 1
  • E. Ferrante
    • 1
  • C. Eller-Vainicher
    • 1
  • S. Esposito
    • 5
  • M. Arosio
    • 1
  • C. Giavoli
    • 1
  1. 1.Endocrinology Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico; Department of Clinical Sciences and Community HealthUniversity of MilanMilanItaly
  2. 2.Pediatric Highly Intensive Care Unit, Department of Pathophysiology and Transplantation, Fondazione IRCCS Ca’ Granda Ospedale Maggiore PoliclinicoUniversity of MilanMilanItaly
  3. 3.Bone Metabolic Unit, Division of Nuclear MedicineFondazione IRCCS Ca’ Granda Ospedale Maggiore PoliclinicoMilanItaly
  4. 4.Developmental Neurology UnitFondazione IRCCS Istituto Neurologico Carlo BestaMilanItaly
  5. 5.Pediatric Clinic, Department of Surgical and Biomedical SciencesUniversità degli Studi di PerugiaPerugiaItaly

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