The mouse homozygous for a disruption of the klotho locus (KL ^−/− or klotho mouse) exhibited multiple pathological conditions resembling human aging. We observed osteopenia in KL ^−/− mice with a low bone turnover, in which the decrease in bone formation exceeded the decrease in bone resorption and resulted in net bone loss. This pathophysiology resembles closely that of senile osteoporosis in humans. Osteoblastic cells from KL ^−/− mice proliferated normally in vitro; however, they showed much lower alkaline phosphatase activity and mineralized matrix formation than those from control mice. Cultured osteoclastic cells from KL ^−/− mice had normal resorbing activity and survival rate, but the differentiation of osteoclastic cells from their precursors was significantly disturbed: in the co-culture of osteoblastic cells and osteoclast precursor cells, the formation of tartrate-resistant acid phosphatase-positive multinucleated osteoclastic cells was extremely poor only when osteoclast precursor cells orginated from KL ^−/− mice independently of the origin of the osteoblastic cells. In addition, we found that osteoprotegerin a secreted factor which inhibits osteoclastogenesis, was up-regulated in KL ^−/− mice. We conclude that a defect in klotho gene expression leads to the independent impairment of osteoblast and osteoclast differentiation, which can be a cause of low-turnover osteoporosis.