Alendronate effects on pre- and post-yield behavior of cortical bone in ovariectomized rats may be independent of bone mineralization

MARIA ANGELINA CHIAPPE; GUSTAVO ROBERTO COINTRY; RICARDO FRANCISCO CAPOZZA; GABRIEL IORIO; ENRIQUE ALVAREZ; 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

   To describe ALN effects on cortical bone, fourty 3-month old rats were OX and treated immediately with 0 (OX-C, n=13), 5 (OX-5, n=13) or 25 ug/kg sc (OX-25, n=14) 2/wk for 6 months, keeping further 15 as sham controls. Their femurs were scanned by pQCT and tested in bending.    Despite not affecting bone mineralization (volumetric cortical BMD) and cross-sectional geometry (diameters, bone area, moment of inertia -MI-), OX impaired the stiffness of both cortical tissue (elastic modulus, E) and diaphyses (load/deformation ratio), and reduced the loads supported at yield (Wy) and at fracture (Wf). Strikingly, the post-yield fraction of Wf (Wp = Wf -Wy, indicative of bone toughness) was significantly enhanced by OX, perhaps because of the naturally inverse relationship between the tissue’s ability to prevent crack generation (impaired) and progress (improved). The highest ALN dose prevented all negative effects of OX and improved Wf over sham values. No changes in Wy were observed in treated rats (no effect on crack generation). However, Wp (bone toughness) was enhanced in a similar proportion than it was in OX rats. The naturally negative correlations between MI (y, an indicator of the efficiency of diaphyseal design) and E (x, an indicator of bone material’s “quality”) showed “anti-anabolic” shifts (to lower-left region of the graph) for OX-C and “anti-catabolic” displacements (to upper-right regions) in OX-5 or -25 rats with respect to sham controls. This would reflect negative or positive interactions of OX and ALN, respectively, with the feed-back control of bone architecture (spatial orientation of bone modeling) as a function of bone stiffness and mechanical usage of the skeleton (bone mechanostat theory).    In agreement with previous observations in intact rats treated with Olpadronate, lack of effects on bone mineralization and geometry in this study suggests that both OX and ALN treatment would have improved Wp (and additionally ALN would have improved Wf) by affecting some microstructural determinant(s) of bone material’s stiffness and toughness (creeping factors) independently of bone mineralization. These novel effects of bisphosphonates may explain the striking dissociation observed between induced improvements in BMD and fracture incidence in large studies with post-menopausal osteoporotic wom