However, this Smad4 cKO phenotype is much more severe than that in our cKO mice and, although other Smad4 cKO mice also have osteoporosis, these mice later develop increased bone mass61, while targeted deletion of Smad3 in mice also results in osteopenia due to reduced bone formation, associated with increased osteocyte number62. Here, SMAD4 is linked to osteoporosis.