Both aerobic glycolysis and mitochondrial respiration are required for osteoclast differentiation.

Excessive bone resorption over bone formation is the root cause for bone loss leading to osteoporotic fractures. Development of new antiresorptive therapies calls for a holistic understanding of osteoclast differentiation and function. Although much has been learned about the molecular regulation of osteoclast biology, little is known about the metabolic requirement and bioenergetics during osteoclastogenesis. Here, we report that glucose metabolism through oxidative phosphorylation (OXPHOS) is the predominant bioenergetic pathway to support osteoclast differentiation. Meanwhile, increased lactate production from glucose, known as aerobic glycolysis when oxygen is abundant, is also critical for osteoclastogenesis. Genetic deletion of Glut1 in osteoclast progenitors reduces aerobic glycolysis without compromising OXPHOS, but nonetheless diminishes osteoclast differentiation in vitro. Glut1 deficiency in the progenitors leads to osteopetrosis due to fewer osteoclasts specifically in the female mice. Thus, Glut1-mediated glucose metabolism through both lactate production and OXPHOS is necessary for normal osteoclastogenesis.