Journal of Inherited Metabolic Disease

, Volume 40, Issue 2, pp 219–226 | Cite as

Analysis of the functional muscle–bone unit of the forearm in patients with phenylketonuria by peripheral quantitative computed tomography

  • Daniela Choukair
  • Carolin Kneppo
  • Reinhard Feneberg
  • Eckhard Schönau
  • Martin Lindner
  • Stefan Kölker
  • Georg F. Hoffmann
  • Burkhard Tönshoff
Original Article


Bone disease in patients with phenylketonuria (PKU) is incompletely characterized. We therefore analyzed, in a cross-sectional study radius macroscopic bone architecture and forearm muscle size by peripheral quantitative computed tomography (pQCT) and muscle strength by hand dynamometry in a large cohort (n = 56) of adolescent and adult patients with PKU aged 26.0 ± 8.9 (range, 11.8–41.5) years. Data were compared with a reference population (n = 700) from the DONALD study using identical methodology. We observed a significant reduction of cortical thickness (z-score −1.01 ± 0.79), Strength–Strain Index (SSI) (z-score −0.81 ± 1.03), and total bone mineral density (BMD) of the distal radius (z-score −1.05 ± 1.00). Mean muscle cross-sectional area (z-score −0.98 ± 1.19) and muscle grip force (z-score −0.64 ± 1.26) were also significantly reduced, indicating an impaired muscular system as part of the clinical phenotype of PKU. SSI positively correlated (r = 0.53, P < 0.001) with the corresponding muscle cross-sectional area in the reference population; however, the regression line slope in PKU patients was less steep (P < 0.001), indicating that bone strength is not adequately adapted to muscle force. In conclusion, the radial bone in PKU patients is characterized by reduced bone strength in relation to muscular force, decreased cortical thickness, and impaired total BMD at the metaphyseal site. These alterations indicate a mixed bone defect in PKU, both of which are due to primary alterations of bone metabolism and to secondary alterations in response to neuromuscular abnormalities.


Bone Mineral Density Cortical Thickness Grip Force Peripheral Quantitative Compute Tomography Trabecular Bone Mineral Density 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



The authors thank Vassiliki Konstantopoulou and Ariane Kleiner for participation in recruitment of patients. We thank Friedrich Karl Trefz and Peter Burgard for critically reviewing the manuscript.

Details of funding

This study was supported by grants from the Dietmar Hopp Foundation and Milupa Nutricia GmbH Germany. The authors confirm independence from the sponsors; the content of the article was no influenced by the sponsors.

Compliance with ethical standards

Conflict of interest

Daniela Choukair, Carolin Kneppo, Reinhard Feneberg, Eckhard Schönau, Stefan Kölker, Georg F. Hoffmann, and Burkhard Tönshoff have no conflict of interest. Martin Lindner has received honoraria for educational lectures from Milupa Nutricia GmbH Germany.

Informed Consent

All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Declaration of Helsinki, 1975, as revised in 2000. Informed consent was obtained from all patients.

Supplementary material

10545_2016_2_MOESM1_ESM.docx (69 kb)
ESM 1 (DOCX 68 kb)


  1. Adamczyk P, Morawiec-Knysak A, Pludowski P, Banaszak B, Karpe J, Pluskiewicz W (2011) Bone metabolism and the muscle–bone relationship in children, adolescents and young adults with phenylketonuria. J Bone Miner Metab 29(2):236–244CrossRefPubMedGoogle Scholar
  2. Allen JR, Humphries IR, Waters DL et al (1994) Decreased bone mineral density in children with phenylketonuria. Am J Clin Nutr 59(2):419–422PubMedGoogle Scholar
  3. Brandt I, Reinken L (1988) The growth rate of healthy children in the first 16 years: Bonn-Dortmund longitudinal developmental study. Klin Padiatr 200(6):451–456CrossRefPubMedGoogle Scholar
  4. de Groot MJ, Hoeksma M, van Rijn M, Slart RH, van Spronsen FJ (2012) Relationships between lumbar bone mineral density and biochemical parameters in phenylketonuria patients. Mol Genet Metab 105(4):566–570CrossRefPubMedGoogle Scholar
  5. Demirdas S, Coakley KE, Bisschop PH, Hollak CE, Bosch AM, Singh RH (2015) Bone health in phenylketonuria: a systematic review and meta-analysis. Orphanet J Rare Dis 10:17CrossRefPubMedPubMedCentralGoogle Scholar
  6. Frost HMF (1995) Introduction to a new skeletal physiology. The Pajaro Group, Inc., PuebloGoogle Scholar
  7. Frost HM, Schonau E (2001) On longitudinal bone growth, short stature, and related matters: insights about cartilage physiology from the Utah paradigm. J Pediatr Endocrinol Metab: JPEM 14(5):481–496CrossRefPubMedGoogle Scholar
  8. Greeves LG, Carson DJ, Magee A, Patterson CC (1997) Fractures and phenylketonuria. Acta paediatrica (Oslo, Norway : 1992) 86(3):242–244CrossRefGoogle Scholar
  9. Hansen KE, Ney D (2014) A systematic review of bone mineral density and fractures in phenylketonuria. J Inherit Metab Dis 37(6):875–880CrossRefPubMedPubMedCentralGoogle Scholar
  10. Holick MF (2008) Vitamin D: a D-Lightful health perspective. Nutr Rev 66(10 Suppl 2):S182–S194CrossRefPubMedGoogle Scholar
  11. Lage S, Bueno M, Andrade F et al (2010) Fatty acid profile in patients with phenylketonuria and its relationship with bone mineral density. J Inherit Metab Dis 33(Suppl 3):S363–S371CrossRefPubMedGoogle Scholar
  12. Leonard MB, Bachrach LK (2001) Assessment of bone mineralization following renal transplantation in children: limitations of DXA and the confounding effects of delayed growth and development. Am J Transplant Off J Am Soc Transplant Am Soc Transplant Surg 1(3):193–196CrossRefGoogle Scholar
  13. Moisio KC, Podolskaya G, Barnhart B, Berzins A, Sumner DR (2003) pQCT provides better prediction of canine femur breaking load than does DXA. J Musculoskel Neuronal Interact 3(3):240–245Google Scholar
  14. Neu CM, Manz F, Rauch F, Merkel A, Schoenau E (2001a) Bone densities and bone size at the distal radius in healthy children and adolescents: a study using peripheral quantitative computed tomography. Bone 28(2):227–232CrossRefPubMedGoogle Scholar
  15. Neu CM, Rauch F, Manz F, Schoenau E (2001b) Modeling of cross-sectional bone size, mass and geometry at the proximal radius: a study of normal bone development using peripheral quantitative computed tomography. Osteopor Int: J established Result Cooperation Between Eur Found Osteoporos Nat Osteoporos Found USA 12(7):538–547CrossRefGoogle Scholar
  16. Rauch F, Schoenau E (2001) The developing bone: slave or master of its cells and molecules? Pediatr Res 50(3):309–314CrossRefPubMedGoogle Scholar
  17. Rauch F, Neu C, Manz F, Schoenau E (2001) The development of metaphyseal cortex--implications for distal radius fractures during growth. J Bone Miner Res Off J Am Soc Bone Miner Res 16(8):1547–1555CrossRefGoogle Scholar
  18. Roricht S, Meyer BU, Irlbacher K, Ludolph AC (1999) Impairment of callosal and corticospinal system function in adolescents with early-treated phenylketonuria: a transcranial magnetic stimulation study. J Neurol 246(1):21–30CrossRefPubMedGoogle Scholar
  19. Ruth EM, Weber LT, Schoenau E et al (2004) Analysis of the functional muscle–bone unit of the forearm in pediatric renal transplant recipients. Kidney Int 66(4):1694–1706CrossRefPubMedGoogle Scholar
  20. Schiessl HFJ, Tysarczyk-Niemeyer G, Willnecker J (1996) Noninvasive bone strength index as analyzed by peripheral quantitative computed tomography (pQCT. In: Paediatric osteology: newdevelopments in diagnostics and therapy. Elsevier, Amsterdam, pp 141–146Google Scholar
  21. Schoenau E, Neu CM, Mokov E, Wassmer G, Manz F (2000) Influence of puberty on muscle area and cortical bone area of the forearm in boys and girls. J Clin Endocrinol Metab 85(3):1095–1098CrossRefPubMedGoogle Scholar
  22. Schoenau E, Neu CM, Rauch F, Manz F (2001) The development of bone strength at the proximal radius during childhood and adolescence. J Clin Endocrinol Metab 86(2):613–618CrossRefPubMedGoogle Scholar
  23. Schonau E (1998) Problems of bone analysis in childhood and adolescence. Pediatric Nephrol (Berlin, Germany) 12(5):420–429CrossRefGoogle Scholar
  24. Schonau E, Werhahn E, Schiedermaier U et al (1996) Influence of muscle strength on bone strength during childhood and adolescence. Horm Res 45(Suppl 1):63–66PubMedGoogle Scholar
  25. Schwahn B, Mokov E, Scheidhauer K, Lettgen B, Schonau E (1998) Decreased trabecular bone mineral density in patients with phenylketonuria measured by peripheral quantitative computed tomography. Acta Paediatr (Oslo, Norway : 1992) 87(1):61–63CrossRefGoogle Scholar
  26. Solverson P, Murali SG, Litscher SJ, Blank RD, Ney DM (2012) Low bone strength is a manifestation of phenylketonuria in mice and is attenuated by a glycomacropeptide diet. PLoS One 7(9), e45165CrossRefPubMedPubMedCentralGoogle Scholar
  27. Tanner JM (1962) Growth at adolescence. Blackwell, OxfordGoogle Scholar
  28. Trefz F, Maillot F, Motzfeldt K, Schwarz M (2011) Adult phenylketonuria outcome and management. Mol Genet Metab 104(Suppl):S26–S30CrossRefPubMedGoogle Scholar
  29. Zeman J, Bayer M, Stepan J (1999) Bone mineral density in patients with phenylketonuria. Acta paediatrica (Oslo, Norway : 1992) 88(12):1348–1351CrossRefGoogle Scholar

Copyright information

© SSIEM 2016

Authors and Affiliations

  1. 1.Department of Pediatrics IUniversity Children’s Hospital HeidelbergHeidelbergGermany
  2. 2.ICON Clinical Research GmbHLangenGermany
  3. 3.University Children’s Hospital CologneCologneGermany
  4. 4.Division of Neuropediatrics and Metabolic Medicine, Department of Pediatrics IUniversity Children’s Hospital HeidelbergHeidelbergGermany
  5. 5.University Children’s Hospital FrankfurtFrankfurt am MainGermany

Personalised recommendations