Cannabinoid receptors as target for treatment of osteoporosis: a tale of two therapies.

The central nervous system plays an important role in regulating bone metabolism in health and in disease with a number of neurotransmitters been reported to influence bone cell activity through a central relay. In keeping with this, recent studies demonstrated that endocannabinoids and their receptors are involved in the pathogenesis of osteoporosis. The endocannabinoids anandamide and 2-arachidonylglycerol are found in the skeleton and numerous studies also showed that bone cells express the cannabinoid receptors CB1 and CB2 and the orphan receptor GPR55. Pharmacological and genetic inactivation of CB1, CB2 and GPR55 in adult mice suppress bone resorption, increase bone mass and protect against bone loss, suggesting that inverse agonists/antagonists of these receptors may serve as anti-resorptive agents. In the ageing skeleton however CB1 and CB2 receptors have a protective effect against age-dependent bone loss in both male and female mice. CB1 receptor deficiency in aged mice results in accelerated age-dependent osteoporosis due to marked increase in bone resorption and significant reduction in bone formation coupled to enhanced adipocyte accumulation in the bone marrow compartment. Similar acceleration of bone loss was also reported in CB2 deficient mice of similar age but found to be associated with enhanced bone turnover. This review summarises in vitro and in vivo findings relating to the influence of cannabinoid ligands on bone metabolism and argues in favour of the exploitation of cannabinoid receptors as targets for both anabolic and anti-resorptive therapy for treatment of complex multifaceted bone diseases such as osteoporosis.