Combined deficiency of the Cnr1 and Cnr2 receptors protects against age‐related bone loss by osteoclast inhibition

The endocannabinoid system plays a role in regulating bone mass and bone cell activity and inactivation of the type 1 (Cnr1) or type 2 (Cnr2) cannabinoid receptors influences peak bone mass and age‐related bone loss. As the Cnr1 and Cnr2 receptors have limited homology and are activated by different ligands, we have evaluated the effects of combined deficiency of Cnr1 and 2 receptors (Cnr1/2^?/?) on bone development from birth to old age and studied ovariectomy induced bone loss in female mice. The Cnr1/2^?/? mice had accelerated bone accrual at birth when compared with wild type littermates, and by 3 months of age, they had higher trabecular bone mass. They were also significantly protected against ovariectomy‐induced bone loss due to a reduction in osteoclast number. The Cnr1/2^?/? mice had reduced age‐related bone loss when compared with wild‐type due to a reduction in osteoclast number. Although bone formation was reduced and bone marrow adiposity increased in Cnr1/2^?/? mice, the osteoclast defect outweighed the reduction in bone formation causing preservation of bone mass with aging. This contrasts with the situation previously reported in mice with inactivation of the Cnr1 or Cnr2 receptors individually where aged‐related bone loss was greater than in wild‐type. We conclude that the Cnr1 and Cnr2 receptors have overlapping but nonredundant roles in regulating osteoclast and osteoblast activities. These observations indicate that combined inhibition of Cnr1 and Cnr2 receptors may be beneficial in preventing age‐related bone loss, whereas blockade of individual receptors may be detrimental.