A long-term study of bone mineral density in patients with phenylketonuria under diet therapy

Koura, Hala M.; Ismail, Nagwa Abdallah; Kamel, Ashraf; Ahmed, Azza A Ali Hebatalla I; Saad-Hussein, Amal; Effat, Laila K.

doi:10.5114/aoms.2011.23417

Cited by 29 publications

(31 citation statements)

References 33 publications

(42 reference statements)

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“…We found no difference in BMD Z-score by PAH deficiency severity, similar to what has been reported in two recent studies (de Groot et al 2012; Miras et al 2013), and in contrast to the previously held belief that more severe patients will have lower BMD (Zeman et al 1999;Koura et al 2011). In addition, there was no difference in BMD Z-score by age category, as reported by other studies in the literature (Zeman et al 1999;de Groot et al 2012).…”

Section: Discussionsupporting

confidence: 92%

Modeling correlates of low bone mineral density in patients with phenylalanine hydroxylase deficiency

Coakley

Douglas

Goodman

et al. 2016

J of Inher Metab Disea

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Phenylalanine hydroxylase (PAH) deficiency is an inherited metabolic disorder requiring life-long restriction of dietary protein and phenylalanine-free medical food. Low bone mineral density (BMD) is reported, but factors associated with BMD Z-score (standard deviations from normal) are unknown. We examined associations between clinical and dietary parameters and total BMD Z-score in PAH deficiency patients, and developed models to predict Z-score. Data collected from patients >4 years of age (n = 88; mean age = 18.8 y; 61 % female) included demographic, clinical, laboratory, and dietary intakes. Adjusted Spearman's correlation coefficients were calculated between parameters and TBMD Z-score, measured by dual energy x-ray absorptiometry (DXA). Parameters approaching significance (p-value < 0.10) were candidate predictors for four linear regression models predicting TBMD Z-score. To validate, model-predicted Z-scores were compared to DXA Z-scores. Mean TBMD Z-score was -0.326; 18 (20.4 %) had Z-score < -1. Z-scores were positively correlated with dietary vitamin D, calcium, and medical food intake and compliance with prescription, and negatively with dietary carbohydrate, sugar, caffeine intake, glycemic load, and prescribed medical food (grams protein/day; p-value < 0.05). The best model included medical food compliance, medical food intake, caffeine intake, and bone-specific alkaline phosphatase (r-square = 0.364). This model predicted Z-score category [normal or low (<-1)] with sensitivity = 66.7 %, likelihood ratio = 14.7, and AUC = 0.83 compared to DXA Z-score. No subjects had low BMD for chronological age (Z-score ≤ -2). Compliance with medical food prescription was the strongest predictor of TBMD Z-score. One model, if validated in a separate sample of patients with more cases of low BMD, showed potential to estimate TBMD Z-score using routine clinical patient parameters.

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Section: Discussionsupporting

confidence: 92%

Modeling correlates of low bone mineral density in patients with phenylalanine hydroxylase deficiency

Coakley

Douglas

Goodman

et al. 2016

J of Inher Metab Disea

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“…Higher intake of food phenylalanine correlated to a BTM ratio favoring resorption (p-value ¼ 0.017) while better compliance with medical food correlated to a BTM ratio favoring formation (p-value ¼ 0.056) suggesting following diet is critical. DXA showed normal BMD for age in all subjects and a mean total BMD Z-score of 0.045 (range À1.9-2.3) contradicting low BMD found in previous studies (Carson et al 1990;Zeman et al 1999;Perez-Duenas et al 2002;Koura et al 2011) but in line with more recent reports (Demirdas et al 2015;Geiger et al 2016). We defined low BMD by ISCD criteria (Z-score <À2) instead of alternative definitions used in previous studies (Demirdas et al 2015).…”

Section: Discussioncontrasting

confidence: 37%

Impact of Dietary Intake on Bone Turnover in Patients with Phenylalanine Hydroxylase Deficiency

et al. 2017

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Phenylalanine hydroxylase (PAH) deficiency is a genetic disorder characterized by deficiency of the PAH enzyme. Patients follow a phenylalanine-restricted diet low in intact protein, and must consume synthetic medical food (MF) to supply phenylalanine-free protein. We assessed relationships between dietary intake and nutrient source (food or MF) on bone mineral density (BMD) and bone turnover markers (BTM) in PAH deficiency. Blood from 44 fasted females 11-52 years of age was analyzed for plasma phenylalanine, serum BTM [CTx (resorption), P1NP (formation)], vitamin D, and parathyroid hormone (PTH). BTM ratios were calculated to assess resorption relative to formation (CTx/P1NP). Dual energy X-ray absorptiometry measured total BMD and age-matched Zscores. Three-day food records were analyzed for total nutrient intake, nutrients by source (food, MF), and compliance with MF prescription. Spearman's partial coefficients (adjusted for age, BMI, energy intake, blood phenylalanine) assessed correlations. All had normal BMD for age (Z-score >À2). Sixty-four percent had high resorption and normal formation indicating uncoupled bone turnover. CTx/P1NP was positively associated with food phenylalanine (r 2 ¼ 0.39; p-value ¼ 0.017), energy (r 2 ¼ 0.41; p-value ¼ 0.011) and zinc (r 2 ¼ 0.41; pvalue ¼ 0.014). CTx/P1NP was negatively associated with MF fat (r 2 ¼ À0.44; p-value ¼ 0.008), MF compliance (r 2 ¼ À0.34; p-value ¼ 0.056), and positively with food sodium (r 2 ¼ 0.43; p-value ¼ 0.014). CTx/ P1NP decreased significantly with age (p-value ¼ 0.002) and higher PTH (p-value ¼ 0.0002). Phenylalanine was not correlated with any bone indicator. Females with PAH deficiency had normal BMD but elevated BTM, particularly resorption. More favorable ratios were associated with nutrients from MF and compliance. Younger females had less favorable BTM ratios. Promoting micronutrient intake through compliance with MF may impact bone metabolism in patients with PAH deficiency. Synopsis: Bone mineral density was normal in 44 females with PAH deficiency; however, bone turnover markers suggested uncoupling of bone resorption and formation, particularly in younger patients. Adequate nutrient intake from medical food and overall medical food compliance may positively impact bone turnover.

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“…Three studies (Allen et al 1994; Hillman et al 1996; Koura et al 2011) reported spine BMD in 67 individuals with PKU and 161 healthy age and gender matched controls (Table 1). A Forest plot of these three studies (Figure 2) demonstrated that spine BMD was 0.100 g/cm 2 lower (95% CI, −0.110, −0.090 g/cm 2 ) in subjects with PKU, compared to controls.…”

Section: Resultsmentioning

confidence: 99%

“…Twelve studies (McMurry et al 1992; Allen et al 1994; Hillman et al 1996; Al-Qadreh et al 1998; Barat et al 2002; Perez-Duenas et al 2002; Millet et al 2005; Modan-Moses et al 2007; Adamczyk et al 2010; Lage et al 2010; Koura et al 2011; de Groot et al 2012) in 412 PKU patients evaluated correlations between BMD and phenylalanine levels (Table 3). Three of 12 studies (McMurry et al 1992; Al-Qadreh et al 1998; Adamczyk et al 2010) in 119 of 412 (29%) PKU patients reported an inverse association between phenylalanine and BMD.…”

Section: Resultsmentioning

confidence: 99%

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A systematic review of bone mineral density and fractures in phenylketonuria

Hansen

Ney²

2014

J of Inher Metab Disea

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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 3 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 6 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, 9 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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A long-term study of bone mineral density in patients with phenylketonuria under diet therapy

Cited by 29 publications

References 33 publications

Modeling correlates of low bone mineral density in patients with phenylalanine hydroxylase deficiency

Modeling correlates of low bone mineral density in patients with phenylalanine hydroxylase deficiency

Impact of Dietary Intake on Bone Turnover in Patients with Phenylalanine Hydroxylase Deficiency

A systematic review of bone mineral density and fractures in phenylketonuria

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