“Bone is a complex tissue of the with unique properties such as high strength and regeneration capabilities while carrying out multiple functions. Bone regeneration occurs both in physiological situations (bone turnover) and pathological situations (e.g. fractures), being performed by osteoblasts and osteoclasts. If this process is inadequate, fracture nonunion or aseptic loosening of implants occurs and requires a complex treatment.
Exogenous factors are currently used to increase bone regeneration process when needed, such as bisphosphonates and vitamin D, but limitations do exist. Cannabinoid system has been shown to have positive effects on bone metabolism. Cannabinoids at bone level mainly act on two receptors called CB-1 and CB-2, but GPR55, GPR119, TPRV1, TPRV4 receptors may also be involved. The CB-2 receptors are found in bone cells at higher levels compared to other receptors.
Endocannabinods represented by anandamide and 2-arachidonoylglycerol, can stimulate osteoblast formation, bone formation and osteoclast activity. CB-2 agonists including HU-308, HU-433, JWH133 and JWH015 can stimulate osteoblast proliferation and activity, while CB-2 antagonists such as AM630 and SR144528 can inhibit osteoclast differentiation and function. CB-1 antagonist AM251 has been shown to inhibit osteoclast differentiation and activity, while GPR55 antagonist cannabidiol increases osteoblast activity and decreases osteoclast function.
An optimal correlation of dose, duration, moment of action and affinity can lead to an increased bone regeneration capacity, with important benefits in many pathological situations which involve bone tissue. As adverse reactions of cannabinoids haven’t been described in patients under controlled medication, cannabinoids can represent future treatment for bone regeneration.”
https://www.ncbi.nlm.nih.gov/pubmed/30702341
https://www.tandfonline.com/doi/abs/10.1080/03602532.2019.1574303?journalCode=idmr20
“Osteosarcoma is the most common primary malignant tumor of bone in children and adolescents.
Bortezomib (BTZ) is an approved anticancer drug, classified as a selective reversible inhibitor of the ubiquitin-dependent proteasome system, that leads to cancer cell cycle arrest and apoptosis reducing the invasion ability of Osteosarcoma cells in vitro. It also regulates the RANK/RANKL/OPG system, involved in the pathogenesis of bone tumors and in cell migration.
A side effect of BTZ is to induce painful sensory peripheral neuropathy which lead to cessation of therapy or dose reduction.
Recently BTZ has been evaluated in combination with 
“The endocannabinoid system has emerged as a considerable target for the treatment of diverse diseases.
In addition to the well-established palliative effects of 
“Many malignant cancers, including breast cancer, have a propensity to invade bones, leading to excruciating bone pain.
Opioids are the primary analgesics used to alleviate this cancer-induced bone pain (CIBP) but are associated with numerous severe side effects, including enhanced bone degradation, which significantly impairs patients’ quality of life.
In contrast, agonists activating only peripheral CB1 receptors (CB1Rs) have been shown to effectively alleviate multiple chronic pain conditions with limited side effects, yet no studies have evaluated their role(s) in CIBP.
Here, we demonstrate for the first time that a peripherally selective CB1R agonist can effectively suppress CIBP.
Overall, our studies demonstrate that CIBP can be effectively managed by using a peripherally restricted CB1R agonist, PrNMI, without inducing dose-limiting central side effects.
Thus, targeting peripheral CB1Rs could be an alternative therapeutic strategy for the treatment of CIBP.”
“Endocannabinoids are bioactive lipids that modulate various physiological processes through G-protein-coupled receptors (CB1 and CB2) and other putative targets. By sharing the activation of the same receptors, some phytocannabinoids and a multitude of synthetic 
“Cannabis use is rising in the USA. Its relationship to 