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


BACKGROUND
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.


CONCLUSIONS
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.
Tang
S Y
SY
Department of Biomedical Engineering, Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, Troy, NY 12180, USA.
Allen
M R
MR
Phipps
R
R
Burr
D B
DB
Vashishth
D
D
D019386:Alendronate / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D001696:Biomechanical Phenomena; D015519:Bone Density / Q000187:drug effects*; D050071:Bone Density Conservation Agents / Q000008:administration & dosage / Q000494:pharmacology*; D001857:Bone Matrix / Q000187:drug effects*; D004164:Diphosphonates / Q000008:administration & dosage / Q000494:pharmacology*; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D012968:Etidronic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D005260:Female; D017127:Glycation End Products, Advanced / Q000378:metabolism*; D023421:Models, Animal; D010024:Osteoporosis / Q000188:drug therapy*; D000068296:Risedronic Acid
D050071:Bone Density Conservation Agents; D004164:Diphosphonates; D017127:Glycation End Products, Advanced; D000068296:Risedronic Acid; D012968:Etidronic Acid; D019386:Alendronate