Effects of high doses of olpadronate on the elastic (pre-yield) and plastic (post-yield) behavior of cortical bone in normal rats

GUSTAVO ROBERTO COINTRY; NÉLIDA MONDELO; RICARDO FRANCISCO CAPOZZA; JOSÉ LUIS FERRETTI

Davos (Suiza)

Congreso; VII Workshop on Bisphosphonates What is new in bisphosphonates? - From the laboratory to the patient; 2004

International Bone and Mineral Society

   High doses of OPD (Gador SA, Buenos Aires; 45-90 mg/kg/d x 3 months, from a carcinogenicity dose-range finding study) were orally given to 20 male and 24 female rats 4-5-sem old (7 & 9 controls). The cortical vBMD, cross-sectional perimeters (PM), area (CSA) and moment of inertia (MI) of femur diaphyses and their structural stiffness (load/deformation ratio) and strength during the successive “elastic”, reversible (pre-yield, no microcracks) and “plastic”, irreversible (post-yield, microcrack accumulation) deformation periods were determined by pQCT and bending tests. The pre-yield stiffness of cortical tissue (elastic modulus, E) and a Bone Strength Index, BSI = vBMD * MI (which can predict ultimate strength but does not capture any microstructural indicator of cortical tissue) were calculated from those data.     No effects on growth were observed. Treatment improved significantly CSA and MI as a function of increases in both endosteal and periosteal PMs, more evidently in male than female rats, with no effects on cortical vBMD and E. As a result, mild increases in structural diaphyseal stiffness and strength at yield (only significant in males) were observed. Diaphyseal ultimate strength was substantially enhanced (males, +38%, p<0.001; females, +17%, p<0.01) chiefly because of a large increase in the post-yield fraction of the ultimate load (males, +300%, p<0.001; females, +80%, p<0.05). The BSI failed to predict ultimate load in treated animals.    The positive effects of the assayed OPD doses on the pre-yield behavior of bones would reflect an anabolic improvement in diaphyseal geometry induced independently of bone material’s mineralization and elastic stiffness (i.e., beyond the homeostatic control of bone structure as predicted by the mechanostat theory). The large effects on post-yield behavior and ultimate strength of the bones should be assigned to changes in other factors (not determined in the study) affecting the progress of cracks within cortical tissue (“plastic” deformation period) previously to fracture. Failure of BSI to predict ultimate strength suggests that the observed bone strengthening would have been determined chiefly by mineralization-unrelated, microstructural factors in this study. These results point out some novel bisphosphonate effects on bone strength and mechanism of fracture with no apparent involvement of bone mineralization.