Mineral density and bone strength are dissociated in long bones of rat osteopetrotic mutations

Bone mineral density (BMD) and mechanical strength generally show strong po sitive correlations. However, osteopetrosis is a metabolic bone disease wit h increased skeletal density radiographically and increased risk of fractur e. We have evaluated mechanical strength and mineral density in three osteo petrotic mutations in the rat (incisors-absent [ia/ia], osteopetrosis [op/o p], and toothless [tl/tl]) to test the hypothesis that reduced bone resorpt ion in one or more of these mutations results in weaker bones in the presen ce of greater mineral density and skeletal mass. Peripheral quantitative co mputed tomography (pQCT) was used to analyze BMD and cross-sectional geomet ry in the tibial diaphysis and metaphysis as well as the femoral diaphysis and femoral neck, The bending breaking force of tibial and femoral midshaft s was obtained using the three-point bending test and femoral neck strength was tested by axial loading. Osteopetrotic mutants were significantly smal ler than their normal littermates (NLMs) in each stock. The pQCT analysis s howed that BMD and bone mineral content (BMC) were higher than or equal to NLMs in all skeletal sites measured in the osteopetrotic mutants. However, the mechanical breaking force was equal to or lower than their NLMs in all sites. The cross-sectional structure of long bone shafts was markedly diffe rent in osteopetrotic mutants, having a thin cortex and a medullary area fi lled with primary trabecular bone, These results indicate that osteopetroti c mutations in the rat increase bone density and decrease bone strength. Th e tibial diaphysis was significantly weaker in tl/tl and ia/ia mutants and the tibial metaphysis showed the greatest increase in BMD in all mutants. T hese data are another illustration that an increased BMD does not necessari ly lead to stronger bones.