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A systematic review of bone mineral density and fractures in phenylketonuria.

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/cm(2) lower (95% CI, -0.110, -0.090 g/cm(2)) 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. 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.

SUBMITTER: Hansen KE

PROVIDER: S-EPMC4208974 | biostudies-literature | 2014 Nov

REPOSITORIES: biostudies-literature

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A systematic review of bone mineral density and fractures in phenylketonuria.

Hansen Karen E KE Ney Denise D

Journal of inherited metabolic disease 20140709 6

<h4>Introduction</h4>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.<h4>Methodology</h4>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 comput ...[more]

PMID: 25005329

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Project description:IntroductionAbdominal aortic calcification (AAC) is associated with low bone mass and increased fracture risk. Two previous meta-analyses have investigated the association between AAC and fracture. However, these meta-analyses only identified articles until December 2016, undertook limited searches and did not explore potential sources of between-study heterogeneity. We aim to undertake a sensitive and comprehensive assessment of the relationship between AAC, bone mineral density (BMD) as well as prevalent and incident fractures.MethodsWe will search MEDLINE, EMBASE, Web of Science core collection and Google Scholar (top 200 articles sorted by relevance) from their inception to 1 June 2018. Reference lists of included studies and previous systematic reviews will be hand searched for additional eligible studies. Retrospective and prospective cohort studies (cross-sectional, case-control and longitudinal) reporting the association between AAC, BMD and fracture at any site will be included. At least two investigators will independently: (A) evaluate study eligibility and extract data, with a third investigator to adjudicate when discrepancies occur, (B) assess study quality by the Newcastle-Ottawa Scale for each cohort/study. The meta-analysis will be reported in adherence to the Meta-analysis of Observational Studies in Epidemiology criteria. AAC will be grouped as either: (1) AAC present or absent, (2) AAC categorised as 'low' (referent-lowest reported group) versus 'high' (all other groups) or (3) dose-response when AAC was assessed in ?3 groups. Where primary event data were reported in individual studies, pooled risk differences and risk ratios with 95%?CI will be calculated, from which, a summary estimate will be determined using DerSimonian-Laird random effects models. For the AAC and BMD pooled analyses, estimates will be expressed as standardised mean difference with 95%?CI. We will examine the likelihood of publication bias and where possible, investigate potential reasons for between-study heterogeneity using subgroup analyses and meta-regression.Ethics and disseminationThe study will be submitted to a peer- reviewed journal and disseminated via research presentations.Prospero registration numberCRD42018088019.

Project description:BackgroundOsteoporosis is diagnosed by the measurement of bone mineral density, which is a highly heritable and multifactorial trait. We aimed to identify genetic loci that are associated with bone mineral density.MethodsIn this genome-wide association study, we identified the most promising of 314 075 single nucleotide polymorphisms (SNPs) in 2094 women in a UK study. We then tested these SNPs for replication in 6463 people from three other cohorts in western Europe. We also investigated allelic expression in lymphoblast cell lines. We tested the association between the replicated SNPs and osteoporotic fractures with data from two studies.FindingsWe identified genome-wide evidence for an association between bone mineral density and two SNPs (p<5x10(-8)). The SNPs were rs4355801, on chromosome 8, near to the TNFRSF11B (osteoprotegerin) gene, and rs3736228, on chromosome 11 in the LRP5 (lipoprotein-receptor-related protein) gene. A non-synonymous SNP in the LRP5 gene was associated with decreased bone mineral density (rs3736228, p=6.3x10(-12) for lumbar spine and p=1.9x10(-4) for femoral neck) and an increased risk of both osteoporotic fractures (odds ratio [OR] 1.3, 95% CI 1.09-1.52, p=0.002) and osteoporosis (OR 1.3, 1.08-1.63, p=0.008). Three SNPs near the TNFRSF11B gene were associated with decreased bone mineral density (top SNP, rs4355801: p=7.6x10(-10) for lumbar spine and p=3.3x10(-8) for femoral neck) and increased risk of osteoporosis (OR 1.2, 95% CI 1.01-1.42, p=0.038). For carriers of the risk allele at rs4355801, expression of TNFRSF11B in lymphoblast cell lines was halved (p=3.0x10(-6)). 1883 (22%) of 8557 people were at least heterozygous for these risk alleles, and these alleles had a cumulative association with bone mineral density (trend p=2.3x10(-17)). The presence of both risk alleles increased the risk of osteoporotic fractures (OR 1.3, 1.08-1.63, p=0.006) and this effect was independent of bone mineral density.InterpretationTwo gene variants of key biological proteins increase the risk of osteoporosis and osteoporotic fracture. The combined effect of these risk alleles on fractures is similar to that of most well-replicated environmental risk factors, and they are present in more than one in five white people, suggesting a potential role in screening.

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Project description:ImportanceDespite the reassuring emerging evidence on the lack of a causal relationship between sun protection and vitamin D deficiency, there is scarce data on whether multimodal sun protection is associated with reduced bone mineral density (BMD) and/or increased prevalence of osteoporotic bone fractures. This lack of data may lead to worry and decreased sun-protective behaviors on the part of patients.ObjectiveTo investigate the association of sun-protective behaviors with BMD z scores and the prevalence of osteoporotic fractures.Design, setting, and participantsThis population-based cross-sectional study included data from US adults who participated in the 2017 to 2018 cycle of the National Health and Nutrition Examination Survey (NHANES). Data were analyzed between September and November 2020.Main outcomes and measuresDefinition of sun-protective behaviors (staying in the shade, wearing long sleeves, and sunscreen use), site-specific and total BMD, and osteoporotic fractures (hip, wrist, and spine) in the NHANES data.ResultsData from 3418 adults 20 years and older (average age, 39.5 [95% CI, 38.6-40.4] years; 1612 [47.2%] men and 1806 [52.9%] women) who completed the NHANES dermatology questionnaire were included in this study. The prevalence of frequent staying in the shade, wearing of long sleeves, and sunscreen use were 31.6% (95% CI, 27.8%-35.7%), 11.8% (95% CI, 10.6%-13.1%), and 26.1% (95% CI, 23.5%-28.8%), respectively. The use of individual sun-protective behaviors was not associated with diminished site-specific and total BMD z scores in the multivariate models (estimate, -0.23 [95% CI, -0.47 to 0.02], P = .18; -0.08 [-0.27 to 0.12], P = .72; and -0.10 [-0.32 to 0.13], P = .15 for frequent staying in the shade, wearing of long sleeves, and sunscreen use, respectively). Moderate to frequent staying in the shade was associated with reduced prevalence of spine fractures in the multivariate model (odds ratio, 0.19 [95% CI, 0.04-0.86], P = 0.02).Conclusion and relevanceIn this cross-sectional study, routine use of sun-protective behaviors among the US adult population was not associated with decreased BMD or increased risk of osteoporotic fracture. Sun protection may be associated with a modest decrease in the prevalence of osteoporotic fractures, possibly owing to risk-averse behaviors. These reassuring findings add to the growing body of evidence on the safety of sun protection, with no considerable negative association with bone health.

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A systematic review of bone mineral density and fractures in phenylketonuria.

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A systematic review of bone mineral density and fractures in phenylketonuria.

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