Long-term cannabidiol treatment did not restore bone microstructural defects in skeletally mature ovariectomized Sprague-Dawley rats

Cannabidiol (CBD) effects on bone metabolism in postmenopausal osteoporosis remain unclear. While endocannabinoids and phytocannabinoids bind to receptors in bone cells, direct evidence of CBD's bone-protective effects is lacking. We evaluated the effects of CBD on bone metabolism in ovariectomized (OVX) rat model of estrogen deficiency. Twelve-week study with treatment initiated 2 wk after the surgery was conducted. Five experimental groups were established: sham-operated with vehicle (SHM/VEH), sham with CBD (SHM/CBD5), OVX with vehicle (OVX/VEH), OVX with 17β-estradiol (OVX/E2), and OVX with CBD (OVX/CBD5). Cannabidiol was administered at 5 mg/kg/d via osmotic pumps. Micro-CT of the distal femur revealed that trabecular bone mass in OVX/CBD5 decreased similarly to OVX/VEH, indicating no protective effect. Serum bone turnover markers showed increased bone resorption in OVX/CBD5 compared to OVX/VEH. Gene expression analysis revealed that estrogen significantly reduced <i>Ctsk</i> gene expression compared to OVX/VEH, while CBD showed no significant differences. No significant changes were observed in cannabinoid receptor expression or bone metabolism in sham-operated rats receiving CBD. While CBD (5 mg/kg/d) was well-tolerated, it did not mitigate OVX-induced bone loss in skeletally mature rats. Consequently, CBD should not be considered a monotherapy for postmenopausal osteoporosis, though it appears safe for other potential medical applications.