Translating evidence to practice: a systematic and clinical analysis of bone health in phenylketonuria Open Access

Coakley, Katie (2015)

Permanent URL:


Since the 1960s, newborn screening has allowed early detection of phenylketonuria (PKU), an inborn error of metabolism characterized by the inability to break down phenylalanine. Patients are treated immediately and for life with a low-protein diet and elemental medical food. Secondary effects of PKU are surfacing including low bone mineral density (BMD). A systematic review of 13 studies examining BMD in early-treated patients found lower mean BMD Z-score than normal, but within normal range defined by the International Society for Clinical Densitometry (ISCD) as Z-scores>-2. Most studies used incorrectly applied definitions for osteopenia and osteoporosis. To assess characteristics associated with BMD Z-score in patients with PKU, a study of 88 patients was conducted. BMD Z-score was positively associated with dietary vitamin D, calcium and medical food intake and compliance with medical food prescription. BMD Z-score was negatively correlated with dietary carbohydrate, sugar, caffeine, glycemic load and prescribed medical food. Models were developed to estimate BMD Z-score using predictors significantly correlated with BMD Z-score (p-value<0.10) and estimates were compared to DXA Z-scores. One model predicted Z-scores with 66.7% sensitivity and an AUC of 0.83 and included medical food compliance, medical food intake, caffeine intake, and blood bone-specific alkaline-phosphatase. The model must be validated in a separate set of patients before being used clinically to screen for patients that need DXA scans. Primary data were collected from 44 patients with PKU to examine unreported exposures, bone turnover markers (BTM), and BMD. All patients had normal BMD; however, 67% had elevated bone resorption but normal formation suggesting uncoupling of bone turnover. Nutrient intake met requirements for nutrients except vitamin D. The majority of protein, vitamin D, calcium and zinc intake came from medical food. Two dietary patterns were developed and the pattern considered compliant with medical food was associated with lower bone turnover. Physical activity was not associated with BTM or BMD. Together, results suggest BMD is not as compromised as hypothesized in patient with PKU, and well within the normal range for age and sex. Dietary intake and body composition drive variation in BMD instead of PKU related factors like phenylalanine concentrations.

Table of Contents

Chapter 1. Introduction. 1

1.1 Background and Significance. 1

1.2 Focus of the Investigation. 10

Chapter 2. Nutrition management of patients with phenylketonuria. 12

2.1 Overall Goals of Treatment1. 12

2.2 Phenylalanine Tolerance and Medical Food Prescription. 12

2.3 Nutrition Management over the Lifespan. 15

2.4 Medical Treatment Options. 18

2.5 Other Considerations. 19

Chapter 3. Methods. 22

3.1 Literature Review. 22

3.2 Reporting of Bone Health in the Literature. 25

3.3 Developing a Predictive Model to Estimate BMD. 28

3.4 Survey of Metabolic Dietitians to Assess Current Monitoring of Bone Health. 29

3.5 Primary Data Collection. 30

3.6 Dissertation Hypotheses. 32

Chapter 4. Bone health in phenylketonuria: a systematic review and meta-analysis. 35

4.1 Abstract. 36

4.2 Introduction. 37

4.3 Materials and Methods. 39

4.4 Results. 51

4.5 Discussion. 72

4.6 References. 81

Chapter 5. Modeling correlates of low bone mineral density in patients with

phenylalanine hydroxylase deficiency. 85

5.1 Abstract. 86

5.2 Introduction. 87

5.3 Methods. 90

5.4 Results. 94

5.5 Conclusions. 97

5.6 References. 111

5.7 Other Important Results. 115

Chapter 6. Relationship between dietary intake and source of nutrition on bone health in patients with PKU. 122

6.1 Abstract. 123

6.2 Introduction. 124

6.3 Patients and Methods. 128

6.4 Results. 135

6.5 Conclusions and References. 151

6.6 References. 161

Chapter 7. Discussion of Results and Conclusions. 166

7.1 Assumptions and Limitations. 168

7.2 External Validation of Predictive Models. 171

7.3 Clinical Implications for Patients with PKU. 172

7.4 Future Research. 173

7.5 Next Steps. 174

7.6 Final Conclusion. 174

Cited Literature. 176

About this Dissertation

Rights statement
  • Permission granted by the author to include this thesis or dissertation in this repository. All rights reserved by the author. Please contact the author for information regarding the reproduction and use of this thesis or dissertation.
  • English
Research Field
Committee Chair / Thesis Advisor
Committee Members
Last modified

Primary PDF

Supplemental Files