Does Bone Resorption Stimulate Periosteal Expansion? A Cross-Sectional Analysis of β-C-telopeptides of Type I Collagen (CTX), Genetic Markers of the RANKL Pathway, and Periosteal Circumference as Measured by pQCT

Authors

  • John P Kemp,

    1. MRC Centre for Causal Analyses in Translational Epidemiology, University of Bristol, Bristol, UK
    2. School of Social and Community Medicine, University of Bristol, Bristol, UK
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  • Adrian Sayers,

    1. School of Social and Community Medicine, University of Bristol, Bristol, UK
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  • Lavinia Paternoster,

    1. MRC Centre for Causal Analyses in Translational Epidemiology, University of Bristol, Bristol, UK
    2. School of Social and Community Medicine, University of Bristol, Bristol, UK
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  • David M Evans,

    1. MRC Centre for Causal Analyses in Translational Epidemiology, University of Bristol, Bristol, UK
    2. School of Social and Community Medicine, University of Bristol, Bristol, UK
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  • Kevin Deere,

    1. MRC Centre for Causal Analyses in Translational Epidemiology, University of Bristol, Bristol, UK
    2. School of Social and Community Medicine, University of Bristol, Bristol, UK
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  • Beate St Pourcain,

    1. MRC Centre for Causal Analyses in Translational Epidemiology, University of Bristol, Bristol, UK
    2. School of Social and Community Medicine, University of Bristol, Bristol, UK
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  • Nicholas J Timpson,

    1. MRC Centre for Causal Analyses in Translational Epidemiology, University of Bristol, Bristol, UK
    2. School of Social and Community Medicine, University of Bristol, Bristol, UK
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  • Susan M Ring,

    1. School of Social and Community Medicine, University of Bristol, Bristol, UK
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  • Mattias Lorentzon,

    1. Center for Bone and Arthritis Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
    2. Geriatric Medicine, Department of Internal Medicine and Clinical Nutrition, University of Gothenburg, Gothenburg, Sweden
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  • Terho Lehtimäki,

    1. Department of Clinical Chemistry, Fimlab Laboratories, and University of Tampere School of Medicine, Tampere, Finland
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  • Joel Eriksson,

    1. Center for Bone and Arthritis Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
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  • Mika Kähönen,

    1. Department of Clinical Physiology, University of Tampere School of Medicine and Tampere University Hospital, Tampere, Finland
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  • Olli Raitakari,

    1. Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, and the Department of Clinical Physiology and Nuclear Medicine, Turku University Hospital, Turku, Finland
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  • Marika Laaksonen,

    1. Department of Food and Environmental Sciences, University of Helsinki, Helsinki, Finland
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  • Harri Sievänen,

    1. The UKK Institute for Health Promotion Research, Tampere, Finland
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  • Jorma Viikari,

    1. Department of Medicine, University of Turku and Turku University Hospital, Turku, Finland
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  • Leo-Pekka Lyytikäinen,

    1. Department of Clinical Chemistry, Fimlab Laboratories, and University of Tampere School of Medicine, Tampere, Finland
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  • George Davey Smith,

    1. MRC Centre for Causal Analyses in Translational Epidemiology, University of Bristol, Bristol, UK
    2. School of Social and Community Medicine, University of Bristol, Bristol, UK
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  • William D Fraser,

    1. Norwich Medical School, University of East Anglia, East Anglia, UK
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  • Liesbeth Vandenput,

    1. Center for Bone and Arthritis Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
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  • Claes Ohlsson,

    1. Center for Bone and Arthritis Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
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  • Jon H Tobias

    Corresponding author
    1. School of Clinical Sciences, University of Bristol, Bristol, UK
    • Address correspondence to: Jon Tobias, MD, PhD, Musculoskeletal Research Unit, Avon Orthopaedic Centre, Southmead Hospital, Bristol BS10 5NB, United Kingdom. E-mail: Jon.Tobias@bristol.ac.uk

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ABSTRACT

We hypothesized that bone resorption acts to increase bone strength through stimulation of periosteal expansion. Hence, we examined whether bone resorption, as reflected by serum β-C-telopeptides of type I collagen (CTX), is positively associated with periosteal circumference (PC), in contrast to inverse associations with parameters related to bone remodeling such as cortical bone mineral density (BMDC). CTX and mid-tibial peripheral quantitative computed tomography (pQCT) scans were available in 1130 adolescents (mean age 15.5 years) from the Avon Longitudinal Study of Parents and Children (ALSPAC). Analyses were adjusted for age, gender, time of sampling, tanner stage, lean mass, fat mass, and height. CTX was positively related to PC (β = 0.19 [0.13, 0.24]) (coefficient = SD change per SD increase in CTX, 95% confidence interval)] but inversely associated with BMDC (β = –0.46 [–0.52,–0.40]) and cortical thickness [β = –0.11 (–0.18, –0.03)]. CTX was positively related to bone strength as reflected by the strength-strain index (SSI) (β = 0.09 [0.03, 0.14]). To examine the causal nature of this relationship, we then analyzed whether single-nucleotide polymorphisms (SNPs) within key osteoclast regulatory genes, known to reduce areal/cortical BMD, conversely increase PC. Fifteen such genetic variants within or proximal to genes encoding receptor activator of NF-κB (RANK), RANK ligand (RANKL), and osteoprotegerin (OPG) were identified by literature search. Six of the 15 alleles that were inversely related to BMD were positively related to CTX (p < 0.05 cut-off) (n = 2379). Subsequently, we performed a meta-analysis of associations between these SNPs and PC in ALSPAC (n = 3382), Gothenburg Osteoporosis and Obesity Determinants (GOOD) (n = 938), and the Young Finns Study (YFS) (n = 1558). Five of the 15 alleles that were inversely related to BMD were positively related to PC (p < 0.05 cut-off). We conclude that despite having lower BMD, individuals with a genetic predisposition to higher bone resorption have greater bone size, suggesting that higher bone resorption is permissive for greater periosteal expansion. © 2014 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals, Inc. on behalf of the American Society for Bone and Mineral Research. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

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