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Pentosidine as a Biomarker for Poor Bone Quality and Elevated Fracture Risk

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Biomarkers in Bone Disease

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Abstract

The purpose of this chapter is to explore the concept of pentosidine, an advanced glycation end product, as a biomarker of bone quality and bone fragility. Bone quality is a term used to describe the many factors that contribute to fracture risk that are not necessarily captured during clinical fracture assessment. Pentosidine formation in the body requires glycation and oxidation of proteins. In bone, the protein that is most affected is type 1 collagen. Pentosidine forms divalent cross-links between adjacent type 1 collagen molecules. Pentosidine content can be assessed in systemic fluids (urine and serum) and in bone tissue using various methods, including high-performance liquid chromatography (HPLC) and more recently, mass spectrometry (MS). When assessed in urine and serum, most studies report an association between pentosidine and prevalent or incident fracture. The risk of incident fracture appears to be 3–42 % higher for elevated levels of pentosidine in serum or urine. However, these results may be confounded by overall bone turnover rate, as gold standard bone turnover markers, procollagen type 1 N propeptide of type 1 collagen (P1NP), and C-terminal cross-linking telopeptide of type 1 collagen (CTX) are not accounted for in regression models. There are other inconsistencies in the results related to disease status (i.e., type 2 diabetes diagnosis), ethnicity (i.e., Japanese vs. Caucasian), and sex. When assessed in bone samples, pentosidine accumulation in cortical bone is negatively related to measures of bone toughness (such as ductility, work-to-fracture), but inconsistent results have been reported in trabecular bone. Also, correlation is not causation and in vitro models do not completely account for all changes occurring in the bone material with aging and disease. Pentosidine content in bone tends to increase in an age-dependent manner, and different diseases can accelerate the accumulation of pentosidine. Studies in animal models of type 2 diabetes, type 1 diabetes, low and high turnover chronic kidney disease, and postmenopausal osteoporosis have shown elevated levels of bone pentosidine and altered amounts of enzymatic cross-links (lysyl oxidase [LOX]-dependent cross-links). As these diseases are also associated with higher fracture risk, the hypothesis is that pentosidine contributes to fracture risk. However, whether pentosidine plays a causal role in degrading bone mechanical properties and increasing fracture risk remains to be elucidated. The role of pentosidine as a biomarker for bone quality and fracture risk requires more research in the areas of determining whether systemic pentosidine is better at predicting fractures and is superior to other gold standard bone turnover markers (s-CTX, s-P1NP), determining whether the link between bone-specific pentosidine and bone mechanical properties is consistent in trabecular and cortical bone, determining relationships between bone-specific and systemic pentosidine in diseases with high and low bone turnover, and accounting for differences in resorption rate, ethnicity, and sex. In addition, standard quality assurance measures must be addressed (i.e., specimen stability, variability) for pentosidine to be a biomarker for bone quality and fracture risk.

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Abbreviations

AGE:

Advanced glycation end product

BAP:

Serum bone-specific alkaline phosphatase

BMD:

Bone mineral density

CTX:

C-terminal cross-linking telopeptide of type 1 collagen

deH-DHLNL:

Dehydro-dihydroxylysinonorleucine

deH-HLNL:

Dehydro-hydroxylysinonorleucine

DPD:

Deoxypyridinoline

DPL:

Deoxypyrrololine

DXA:

Dual x-ray absorptiometry

ELISA:

Enzyme-linked immunosorbent assay

HPLC:

High-performance liquid chromatography

HR:

Hazard ratio

LOX:

Lysyl oxidase

OR:

Odds ratio

P1NP:

Procollagen type 1 N propeptide of type 1 collagen

PYD:

Pyridinoline

PYL:

Pyrrololine

RR:

Relative risk

u-NTX:

Urinary N-terminal telopeptide of type 1 collagen

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Authors and Affiliations

  1. Biomedical Engineering Program, Department of Systems Design Engineering, University of Waterloo, 200 University Avenue West, N2L 3G1, Waterloo, ON, Canada

    Thomas L. Willett

  2. Kinesiology and Interdisciplinary Science, McMaster University, 1280 Main St W., L8S 4L8, Hamilton, Ontario, Canada

    Janet M. Pritchard

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  1. Sciences Division, King's College, London, United Kingdom

    Victor R. Preedy

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Pritchard, J.M., Willett, T.L. (2016). Pentosidine as a Biomarker for Poor Bone Quality and Elevated Fracture Risk. In: Preedy, V. (eds) Biomarkers in Bone Disease. Biomarkers in Disease: Methods, Discoveries and Applications. Springer, Dordrecht. https://doi.org/10.1007/978-94-007-7745-3_32-1

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