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

  • Janet M. Pritchard
  • Thomas L. WillettEmail author
Reference work entry
Part of the Biomarkers in Disease: Methods, Discoveries and Applications book series (BDMDA)


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.


Pentosidine Bone quality Fracture Fracture risk Osteoporosis Biomarker Bone turnover markers Advanced glycation end product Nonenzymatic cross-link 

List of Abbreviations


Advanced glycation end product


Serum bone-specific alkaline phosphatase


Bone mineral density


C-terminal cross-linking telopeptide of type 1 collagen










Dual x-ray absorptiometry


Enzyme-linked immunosorbent assay


High-performance liquid chromatography


Hazard ratio


Lysyl oxidase


Odds ratio


Procollagen type 1 N propeptide of type 1 collagen






Relative risk


Urinary N-terminal telopeptide of type 1 collagen


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© Springer Science+Business Media Dordrecht 2017

Authors and Affiliations

  1. 1.Biomedical Engineering Program, Department of Systems Design EngineeringUniversity of WaterlooWaterlooCanada
  2. 2.Kinesiology and Interdisciplinary ScienceMcMaster UniversityHamiltonCanada

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