Genetic interaction between ATF4 and Hop2 was best demonstrated by osteopenia (low bone mass) in the Atf4+/−:Hop2+/− double heterozygous (het) mice, which is identical to a low bone mass in Hop2−/− mice and milder than osteoporosis in Atf4−/− mice (23, 28). This evidence concerns the gene ATF4 and osteoporosis.