Bisphosphonates alter trabecular bone collagen cross-linking and isomerization in beagle dog vertebra.
Changes in organic matrix may contribute to the anti-fracture efficacy of anti-remodeling agents. Following one year of treatment in beagle dogs, bisphosphonates alter the organic matrix of vertebral trabecular bone, while raloxifene had no effect. These results show that pharmacological suppression of turnover alters the organic matrix component of bone.


BACKGROUND
The collagen matrix contributes significantly to a bone's fracture resistance yet the effects of anti-remodeling agents on collagen properties are unclear. The goal of this study was to assess changes in collagen cross-linking and isomerization following anti-remodeling treatment.


METHODS
Skeletally mature female beagles were treated for one year with oral doses of vehicle (VEH), risedronate (RIS; 3 doses), alendronate (ALN; 3 doses), or raloxifene (RAL; 2 doses). The middle dose of RIS and ALN and the lower dose of RAL approximate doses used for treatment of post menopausal osteoporosis. Vertebral trabecular bone matrix was assessed for collagen isomerization (ratio of alpha/beta C-telopeptide [CTX]), enzymatic (pyridinoline [PYD] and deoxypyridinoline [DPD]), and non-enzymatic (pentosidine [PEN]) cross-links.


RESULTS
All doses of both RIS and ALN increased PEN (+34-58%) and the ratio of PYD/DPD (+14-26%), and decreased the ratio of alpha/beta CTX (-29-56%) compared to VEH. RAL did not alter any collagen parameters. Bone turnover rate was significantly correlated to PEN (R = -0.664), alpha/beta CTX (R = 0.586), and PYD/DPD (R = -0.470).


CONCLUSIONS
Bisphosphonate treatment significantly alters properties of bone collagen suggesting a contribution of the organic matrix to the anti-fracture efficacy of this drug class.
Allen
M R
MR
Department of Anatomy and Cell Biology, MS 5035, Indiana University School of Medicine, 635 Barnhill Dr., Indianapolis, IN 46202, USA. matallen@iupui.edu
Gineyts
E
E
Leeming
D J
DJ
Burr
D B
DB
Delmas
P D
PD
D019386:Alendronate / Q000494:pharmacology; D000596:Amino Acids / Q000378:metabolism; D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives / Q000378:metabolism; D050071:Bone Density Conservation Agents / Q000494:pharmacology*; D016723:Bone Remodeling / Q000187:drug effects; D003094:Collagen / Q000378:metabolism*; D004164:Diphosphonates / Q000494:pharmacology*; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D012968:Etidronic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D005260:Female; D008159:Lumbar Vertebrae / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D008239:Lysine / Q000031:analogs & derivatives / Q000378:metabolism; D020849:Raloxifene Hydrochloride / Q000494:pharmacology; D000068296:Risedronic Acid
D000596:Amino Acids; D050071:Bone Density Conservation Agents; D004164:Diphosphonates; D020849:Raloxifene Hydrochloride; C015484:pyridinoline; C036020:deoxypyridinoline; D003094:Collagen; D001120:Arginine; C062187:pentosidine; D008239:Lysine; D000068296:Risedronic Acid; D012968:Etidronic Acid; D019386:Alendronate