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A systematic review of bone mineral density and fractures in phenylketonuria

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Journal of Inherited Metabolic Disease

Abstract

Introduction

Our objective was to systematically review and analyze published data on bone mineral density (BMD) and fracture rates in patients with phenylketonuria (PKU), and relationships between BMD and phenylalanine levels.

Methodology

We searched PubMed, CINAHL, and Cochrane databases from January 1966 to November 2013 for studies of spine BMD or fracture in PKU and control subjects. We excluded studies assessing skeletal health by ultrasound or peripheral quantitative computer tomography. Both authors reviewed abstracts for inclusion, and read full text papers to extract data.

Results

Sixteen studies met eligibility criteria. Meta-analysis of three studies found that spine BMD was 0.100 g/cm2 lower (95% CI, -0.110, -0.090 g/cm2) in 67 subjects with PKU, compared to 161 controls. Among six studies, 20% (53 of 263) of PKU subjects experienced clinical fractures. In the single study with controls, the fracture rate was 2.6 fold higher (95% CI, 1.1-6.1) after age 8 in PKU subjects, compared to healthy sibling controls. When considering a total of 12 studies in 412 subjects, nine or 75% of studies representing 71% of studied subjects reported no association between phenylalanine levels and BMD.

Summary

Spine BMD is lower in PKU than control subjects, but only one study controlled for smaller body size. Existing studies suggest a clinical fracture rate of 20% among PKU subjects, but fracture rates in controls are lacking. Finally, existing data shows no consistent relationship between phenylalanine levels and BMD. Future studies are needed to clarify the etiology and health consequences of low BMD in PKU.

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References

  • Adamczyk P, Morawiec-Knysak A, Pludowski P et al (2010) Bone metabolism and the muscle-bone relationship in children, adolescents and young adults with phenylketonuria. J Bone Miner Metab 29(2):236–244

    Article  PubMed  Google Scholar 

  • Allen JR, Humphries IR, Waters DL et al (1994) Decreased bone mineral density in children with phenylketonuria. Am J Clin Nutr 59(2):419–422

    PubMed  CAS  Google Scholar 

  • Al-Qadreh A, Schulpis KH, Athanasopoulou H et al (1998) Bone mineral status in children with phenylketonuria under treatment. Acta Paediatr 87(11):1162–1166

    Article  PubMed  CAS  Google Scholar 

  • Barat P, Barthe N, Redonnet-Vernhet I et al (2002) The impact of the control of serum phenylalanine levels on osteopenia in patients with phenylketonuria. Eur J Pediatr 161(12):687–688

    Article  PubMed  CAS  Google Scholar 

  • Bickel H, Gerrard J, Hickmans EM (1953) Influence of phenylalanine intake on phenylketonuria. Lancet 265(6790):812–813

    Article  PubMed  CAS  Google Scholar 

  • Carson DJ, Greeves LG, Sweeney LE et al (1990) Osteopenia and phenylketonuria. Pediatr Radiol 20(8):598–599

    Article  PubMed  CAS  Google Scholar 

  • de Groot MJ, Hoeksma M, van Rijn M et al (2012) Relationships between lumbar bone mineral density and biochemical parameters in phenylketonuria patients. Mol Genet Metab 105(4):566–570

    Article  PubMed  Google Scholar 

  • Fölling A (1934) Über Ausscheidung von Phenylbrenztraubensäure in den Harn als Stoffwechselanomalie in Verbindung mit Imbezillität. Hoppe-Seyler’s Zeitschrift für physiologische Chemie 227(1–4):169–181

    Article  Google Scholar 

  • Gordon CM, Bachrach LK, Carpenter TO et al (2008) Dual energy X-ray absorptiometry interpretation and reporting in children and adolescents: the 2007 ISCD Pediatric Official Positions. J Clin Densitom Off J Int Soc Clin Densitom 11(1):43–58

    Article  Google Scholar 

  • Greeves LG, Carson DJ, Magee A et al (1997) Fractures and phenylketonuria. Acta Paediatr 86(3):242–244

    Article  PubMed  CAS  Google Scholar 

  • Higgins JP, Thompson SG, Deeks JJ et al (2003) Measuring inconsistency in meta-analyses. BMJ 327(7414):557–560

    Article  PubMed  PubMed Central  Google Scholar 

  • Hillman L, Schlotzhauer C, Lee D et al (1996) Decreased bone mineralization in children with phenylketonuria under treatment. Eur J Pediatr 155(Suppl 1):S148–S152

    Article  PubMed  Google Scholar 

  • Koura HM, Abdallah Ismail N, Kamel AF et al (2011) A long-term study of bone mineral density in patients with phenylketonuria under diet therapy. Arch Med Sci 7(3):493–500

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • 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):363–371

    Article  Google Scholar 

  • McMurry MP, Chan GM, Leonard CO et al (1992) Bone mineral status in children with phenylketonuria--relationship to nutritional intake and phenylalanine control. Am J Clin Nutr 55(5):997–1004

    PubMed  CAS  Google Scholar 

  • Millet P, Vilaseca MA, Valls C et al (2005) Is deoxypyridinoline a good resorption marker to detect osteopenia in phenylketonuria? Clin Biochem 38(12):1127–1132

    Article  PubMed  CAS  Google Scholar 

  • Modan-Moses D, Vered I, Schwartz G et al (2007) Peak bone mass in patients with phenylketonuria. J Inherit Metab Dis 30(2):202–208

    Article  PubMed  CAS  Google Scholar 

  • Moher D, Liberati A, Tetzlaff J et al (2009) Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. Ann Intern Med 151(4):264–269, W264

    Article  PubMed  Google Scholar 

  • Perez-Duenas B, Cambra FJ, Vilaseca MA et al (2002) New approach to osteopenia in phenylketonuric patients. Acta Paediatr 91(8):899–904

    Article  PubMed  CAS  Google Scholar 

  • Porta F, Spada M, Lala R et al (2008) Phalangeal quantitative ultrasound in children with phenylketonuria: a pilot study. Ultrasound Med Biol 34(7):1049–1052

    Article  PubMed  Google Scholar 

  • Porta F, Mussa A, Zanin A et al (2011) Impact of metabolic control on bone quality in phenylketonuria and mild hyperphenylalaninemia. J Pediatr Gastroenterol Nutr 52(3):345–350

    Article  PubMed  CAS  Google Scholar 

  • R Core Development Team (2008) R: A language and environment for statistical computing. R. F. f. S. Computing, Vienna, Austria

    Google Scholar 

  • Vockley J, Andersson HC, Antshel KM et al (2014) Phenylalanine hydroxylase deficiency: diagnosis and management guideline. Genet Med Off J Am Coll Med Genet 16(2):188–200

    CAS  Google Scholar 

  • Zhang F, Whyte MP, Wenkert D (2012) Dual-energy X-ray absorptiometry interpretation: a simple equation for height correction in preteenage children. J Clin Densitom Off J Int Soc Clin Densitom 15(3):267–274

    Article  Google Scholar 

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Compliance with Ethics Guidelines

Conflicts of interest

Karen Hansen is a consultant to Takeda Pharmaceuticals and Deltanoid Pharmaceuticals.

Denise Ney is a co-inventor on US Patent 8,604,168 B2, Glycomacropeptide Medical Foods for Nutritional Management of Phenylketonuria and other Metabolic Disorders, held by the Wisconsin Alumni Research Foundation and licensed to Cambrooke Therapeutics, LLC.

Informed consent

This article does not contain any studies with human or animal subjects performed by the any of the authors.

Animal rights

This article does not contain any studies with human or animal subjects performed by the any of the authors.

Funding

KEH received support from NIH (R01 AG028739, NIA and ODS) during the conduct of this study. DMN received support from FDA (R01 FD003711) and the United States Department of Agriculture Hatch grant WISO 1517 during the conduct of this study. No agency funded the current project.

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Authors and Affiliations

  1. Department of Medicine, Division of Rheumatology, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA

    Karen E. Hansen

  2. Department of Nutritional Sciences, College of Agricultural & Life Sciences, Madison, WI, USA

    Denise Ney

  3. Rheumatology Division, University of Wisconsin School of Medicine & Public Health, Room 4124 MFCB, 1685 Highland Avenue, Madison, WI, 53705-2281, USA

    Karen E. Hansen

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  1. Karen E. Hansen
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  2. Denise Ney
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Correspondence to Karen E. Hansen.

Additional information

Communicated by: Peter Burgard

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Hansen, K.E., Ney, D. A systematic review of bone mineral density and fractures in phenylketonuria. J Inherit Metab Dis 37, 875–880 (2014). https://doi.org/10.1007/s10545-014-9735-2

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  • DOI: https://doi.org/10.1007/s10545-014-9735-2

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