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Changes in non-enzymatic glycation and its association with altered mechanical properties following 1-year treatment with risedronate or alendronate

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Abstract

Summary

One year of high-dose bisphosphonate (BPs) therapy in dogs allowed the increased accumulation of advanced glycation end-products (AGEs) and reduced postyield work-to-fracture of the cortical bone matrix. The increased accumulation of AGEs in these tissues may help explain altered bone matrix quality due to the administration of BPs in animal models

Introduction

Non-enzymatic glycation (NEG) is a posttranslational modification of the organic matrix that results in the formation of advanced glycation end-products (AGEs). In bone, the accumulation of AGEs play an important role in determining fracture resistance, and elevated levels of AGEs have been shown to adversely affect the bone’s propensity to brittle fracture. It was thus hypothesized that the suppression of tissue turnover in cortical bone due to the administration of bisphosphonates would cause increased accumulation of AGEs and result in a more brittle bone matrix.

Methods

Using a canine animal model (n = 12), we administered daily doses of a saline vehicle (VEH), alendronate (ALN 0.20, 1.00 mg/kg) or risedronate (RIS 0.10, 0.50 mg/kg). After a 1-year treatment, the mechanical properties, intracortical bone turnover, and the degree of nonenzymatic cross-linking of the organic matrix were measured from the tibial cortical bone tissue of these animals.

Results

There was a significant accumulation of AGEs at high treatment doses (+49 to + 86%; p < 0.001), but not at doses equivalent to those used for the treatment of postmenopausal osteoporosis, compared to vehicle. Likewise, postyield work-to-fracture of the tissue was significantly reduced at these high doses (−28% to −51%; p < 0.001) compared to VEH. AGE accumulation inversely correlated with postyield work-to-fracture (r 2 = 0.45; p < 0.001), suggesting that increased AGEs may contribute to a more brittle bone matrix.

Conclusion

High doses of bisphosphonates result in the accumulation of AGEs and a reduction in energy absorption of cortical bone. The increased accumulation of AGEs in these tissues may help explain altered bone matrix quality due to the administration of BPs in animal models.

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Acknowledgements

The authors gratefully thank Glenn Berard and Joseph Said for assistance in sample preparation. This work is supported by NIH grants AG20618, AR047838, and AR007581; and a research grant from The Alliance for Better Bone Health (P&G Pharmaceuticals and Sanofi-Aventis). Merck and Co. provided the alendronate. This investigation utilized an animal facility constructed with support from Research Facilities Improvement Program Grant Number C06RR10601 from the NIH National Center for Research Resources.

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Author notes

  1. S. Y. Tang

    Present address: Department of Orthopaedic Surgery, School of Medicine, University of California San Francisco, San Francisco, CA, USA

Authors and Affiliations

  1. Department of Biomedical Engineering, Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, Troy, NY, USA

    S. Y. Tang & D. Vashishth

  2. Department of Anatomy and Cell Biology, Indiana University-Purdue University Indianapolis, Indianapolis, IN, USA

    M. R. Allen & D. B. Burr

  3. Procter and Gamble Pharmaceuticals, Inc., Mason, OH, USA

    R. Phipps

  4. 3137 BT—Center for Biotechnology and Interdisciplinary Studies, Department of Biomedical Engineering, Rensselaer Polytechnic Institute, Troy, NY, 12180, USA

    D. Vashishth

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Correspondence to D. Vashishth.

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Tang, S.Y., Allen, M.R., Phipps, R. et al. Changes in non-enzymatic glycation and its association with altered mechanical properties following 1-year treatment with risedronate or alendronate. Osteoporos Int 20, 887–894 (2009). https://doi.org/10.1007/s00198-008-0754-4

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