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Orphanet Journal of Rare Diseases

, 10:17

First Online: 15 February 2015Received: 22 September 2014Accepted: 25 January 2015DOI: 10.1186-s13023-015-0232-y

Cite this article as: Demirdas, S., Coakley, K.E., Bisschop, P.H. et al. Orphanet J Rare Dis 2015 10: 17. doi:10.1186-s13023-015-0232-y


Patients with Phenylketonuria PKU reportedly have decreased bone mineral density BMD. The primary aim of this study was to perform a systematic review and meta-analysis to determine the extent and significance of low BMD in early treated patients with PKU. Secondary aims were to assess other bone status indicators including bone turnover markers BTM and to define areas for future research. Two research teams Amsterdam, Netherlands and Atlanta, USA performed literature searches for articles reporting data on BMD, osteopenia and osteoporosis, BTM or other bone indicators in patients with PKU. Included articles were compared between research teams and assessed for quality and risk of bias. A total of 13 unique articles were included; 11-13 articles reported BMD including a total of 360 patients. Ten out of 11 articles found BMD was significantly lower in patients with PKU. Meta-analyses for total BMD TBMD; 3 studies; n = 133, lumbar spine BMD LBMD; 7 studies; n = 247, and femoral neck BMD FBMD; 2 studies; n = 78 Z-scores were performed. Overall effect sizes were: TBMD −0.45 95% CI −0.61, −0.28; LBMD −0.70 95% CI −0.82, −0.57; FBMD −0.96 95% CI −1.42, −0.49. Definitions of osteopenia and osteoporosis were highly heterogeneous between studies and did not align with World Health Organization standards and the International Society for Clinical Densitometry positions on BMD measurement. Despite individual study findings of low BMD indicating higher risk of osteoporosis, pooled available data suggest reduction in BMD is not clinically important when using standard definitions of low BMD. Results from studies evaluating BTM are inconclusive. Phenylalanine concentration, vitamin D, PTH, and nutrient intake do not correlate with BMD or BTM. We recommend forthcoming studies use standard definitions of low BMD to determine clinical implications of BMD Z-scores below 0, explore cause of low BMD in the subset of patients with low BMD for chronological age Z-score < −2 and assess fracture risk in patients with PKU.

KeywordsPhenylketonuria PKU Bone mineral density BMD Bone turnover markers Phenylalanine Osteopenia Osteoporosis Meta-analysis Systematic review AbbreviationsANDThe academy of nutrition and dietetics

AND EA ProcessThe academy of nutrition and dietetics evidence analysis process

BMCBone mineral content

BMDBone mineral density

BTMBone turnover markers

CDCCenters for disease control and prevention

DXADual-energy X-ray absorptiometry

FBMDFemoral bone mineral density

ISCDInternational society for clinical densitometry

LBMLean body mass

LBMDLumbar bone mineral density

NHANESNational health and nutrition examination survey



pQUSPeripheral quantitative ultrasound

PRISMAPreferred reporting items for systematic reviews and meta-analyses

PROSPEROInternational prospective register of systematic reviews

PTHParathyroid hormone

QCCQuality criteria checklist

SDsStandard deviations

SIGNScottish intercollegiate guidelines network

TBMDTotal bone mineral density

WHOWorld health organization

Serwet Demirdas, Katie E Coakley, Annet M Bosch and Rani H Singh contributed equally to this work.

Electronic supplementary materialThe online version of this article doi:10.1186-s13023-015-0232-y contains supplementary material, which is available to authorized users.

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Autor: Serwet Demirdas - Katie E Coakley - Peter H Bisschop - Carla E M Hollak - Annet M Bosch - Rani H Singh


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