Osteoporosis is a common complication in cystic fibrosis (CF) patients. In this study, we performed a histomorphometric analysis of the bones of a mouse genetic model of human CF in which both copies of the cystic fibrosis transmembrane conductance regulator (CFTR) gene are inactivated. We find that, even in the absence of obvious nutritional and therapeutic differences, the CFTR mutation is associated with severe osteopenia. Bone mineral density (BMD) of total body and of individual bones is significantly diminished. CFTR mutants display a striking significant (50%) reduction of cortical bone width and thinner trabeculae. Analysis of dynamic parameters indicates a significant reduction of bone formation and a concomitant strong increase in bone resorption. Active osteoclasts where found mostly associated with cortical bone. Our data support the concept that CF-associated osteoporosis is part of the syndromic symptoms associated with the CFTR mutation.