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Dissecting the relationship between high-sensitivity serum C-reactive protein and increased fracture risk: the Rotterdam Study

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Abstract

Summary

Serum high-sensitivity C-reactive protein (CRP) is an inflammatory biomarker. We investigated the relationship between CRP and bone health in the Rotterdam Study. Serum high-sensitivity CRP was associated with fracture risk and lower femoral neck bending strength. Mendelian randomization analyses did not yield evidence for this relationship being causal.

Introduction

Inflammatory diseases are associated with bone pathology, reflected in a higher fracture risk. Serum high-sensitivity CRP is an inflammatory biomarker. We investigated the relationship between CRP and bone mineral density (BMD), hip bone geometry, and incident fractures in the Rotterdam Study, a prospective population-based cohort.

Methods

At baseline, serum high-sensitivity CRP was measured. A weighted genetic risk score was compiled for CRP based on published studies (29 polymorphisms; Illumina HumanHap550 Beadchip genotyping and HapMap imputation). Regression models were reported per standard deviation increase in CRP adjusted for sex, age, and BMI. Complete data was available for 6,386 participants, of whom 1,561 persons sustained a fracture (mean follow-up, 11.6 years).

Results

CRP was associated with a risk for any type of fracture [hazard ratio (HR) = 1.06; 95 % confidence interval (CI), 1.02–1.11], hip fractures (HR = 1.09; 1.02–1.17) and vertebral fractures [odds ratio (OR) = 1.34; 1.14–1.58]. An inverse relationship between CRP levels and section modulus (−0.011 cm3; −0.020 to −0.003 cm3) was observed. The combined genetic risk score of CRP single nucleotide polymorphisms (SNPs) was associated with serum CRP levels (p = 9 × 10−56), but not with fracture risk (HR = 1.00; 0.99–1.00; p = 0.23).

Conclusions

Serum high-sensitivity CRP is associated with fracture risk and lower bending strength. Mendelian randomization analyses did not yield evidence for this relationship being causal. Future studies might reveal what factors truly underlie the relationship between CRP and fracture risk.

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Acknowledgments

The Rotterdam Study is funded by the Erasmus Medical Center and Erasmus University, Rotterdam; the Netherlands Organization for the Health Research and Development (ZonMw); the Research Institute for Diseases in the Elderly (014-93-015; RIDE2, RIDE), the Ministry of Education, Culture and Science, the Ministry for Health, Welfare and Sports; the European Commission (DG XII); and the Municipality of Rotterdam. The authors are grateful to the study participants, the staff from the Rotterdam Study, and the participating general practitioners and pharmacists. We also thank Dr. Eugene McCloskey for the assessment of vertebral fractures. The generation and management of GWAS genotype data for the Rotterdam Study is supported by the Netherlands Organisation of Scientific Research NWO Investments (nr. 175.010.2005.011, 911-03-012). We thank Pascal Arp, Mila Jhamai, Marijn Verkerk, Lizbeth Herrera, and Marjolein Peters for their help in creating the GWAS database and Karol Estrada and Maksim V. Struchalin for their support in creation and analysis of imputed data.

Conflicts of interest

The authors state that they have no conflicts of interest.

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Authors and Affiliations

  1. Department of Internal Medicine, Erasmus MC, P.O. Box 2040 ee5-79, 3000 CA, Rotterdam, The Netherlands

    L. Oei, N. Campos-Obando, A. Dehghan, L. Stolk, J. B. J. van Meurs, A. G. Uitterlinden, M. C. Zillikens & F. Rivadeneira

  2. Department of Epidemiology, Erasmus MC, P.O. Box 2040 ee5-79, 3000 CA, Rotterdam, The Netherlands

    L. Oei, A. Dehghan, L. Stolk, A. Hofman, A. G. Uitterlinden, O. H. Franco & F. Rivadeneira

  3. Netherlands Genomics Initiative (NGI)‐Sponsored Netherlands Consortium for Healthy Aging (NCHA), Rotterdam, The Netherlands

    L. Oei, N. Campos-Obando, A. Dehghan, L. Stolk, J. B. J. van Meurs, A. Hofman, A. G. Uitterlinden, O. H. Franco, M. C. Zillikens & F. Rivadeneira

  4. Department of Radiology, Erasmus MC, Rotterdam, The Netherlands

    E. H. G. Oei

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  1. L. Oei
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  2. N. Campos-Obando
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  4. E. H. G. Oei
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  10. M. C. Zillikens
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Correspondence to F. Rivadeneira.

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Oei, L., Campos-Obando, N., Dehghan, A. et al. Dissecting the relationship between high-sensitivity serum C-reactive protein and increased fracture risk: the Rotterdam Study. Osteoporos Int 25, 1247–1254 (2014). https://doi.org/10.1007/s00198-013-2578-0

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