New insights on olpadronate effects on bone material and structural properties related to strength

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

Rio de Janeiro (Brasil)

Congreso; IOF World Congress on Osteoporosis; 2004

International Osteoporosis Foundation

   Doses of 45-90 mg/kg/d of OPD (IG-8801, Gador SA, Buenos Aires, carcinogenicity dose-range finding study) were orally given during 3 months 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 by increasing 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 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 ultimate load (bone "toughness"; 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 pre-yield bone behavior 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 bone mechanostat theory). The large effects on bones´ post-yield behavior and ultimate strength should be assigned to changes in some "creeping" factors not determined in the study, affecting crack progress within cortical tissue (“plastic” deformation period, bone toughness) previously to fracture. Failure of BSI to predict ultimate strength suggests that the observed bone strengthening would have been determined chiefly through changes in some 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.