The Cannabinoid Pharmacology of Bone Healing: Developments in Fusion Medicine
Abstract
1. Introduction
2. Epidemiology
3. Current Clinical Evidence in Spine Surgery
4. Endocannabinoid Physiology and Bony Healing/Fusion
5. CB1 Receptor
Genotype | Phenotype/Effect | Murine Strain | Sex | Age | Citations |
---|---|---|---|---|---|
CB1 Related Knock-Outs | |||||
CB1−/− | Elevated trabecular & cortical bone mass (young adults) | C57BL/6J | M/F | 8–11 weeks | Idris 2005 [52] |
CB1−/− | Age-related osteoporosis with low bone formation and fatty marrow | C57BL/6J | M/F | 12 months | Idris 2009 [46] |
CB1−/− | Suppressed bone formation via heightened sympathetic tone | C57BL/6J | M/F | 3 months | Tam 2008 [47] |
CB1−/− | Elongated femur & tibia from growth-plate expansion | C57BL/6J | M/F | 6 weeks | Wasserman 2015 [53] |
CB2 Related Knock-Outs | |||||
CB2−/− | Accelerated trabecular bone loss | C57BL/6J | M/F | 8–11 weeks or 51 weeks | Ofek 2006 [54] |
CB2−/− | Accelerated Cortical Expansion | C57BL/6J | M/F | 8–11 weeks or 51 weeks | Ofek 2006 [54] |
CB2−/− | Increased activity of Trabecular Osteoblasts | C57BL/6J | M/F | 8–11 weeks or 51 weeks | Ofek 2006 [54] |
CB2−/− | Increased Activity of Osteoclasts | C57BL/6J | M/F | 8–11 weeks or 51 weeks | Ofek 2006 [54] |
CB2−/− | Decreased Diaphyseal Osteoblast precursors | C57BL/6J | M/F | 8–11 weeks or 51 weeks | Ofek 2006 [54] |
CB2−/− | Increased Cortical Bone | C57BL/6 | M/F | 3 months | Khalid 2015 [55] |
CB2−/− | Reduced capacity to form bone & no protective effects from CB2 agonists | C57BL/6 | F | 8 weeks | Sophocleous 2011 [56] |
CB2−/− | Low Bone Turnover & High Trabecular Bone Mass–In young females | CD1 | M/F | 12 Months | Sophocleous 2014 [57] |
P62 KO | Osteoanabolic Effect | Pg62 Mice | M/F | 3 months | Keller 2022 [44] |
P62 KO | Increased number of Osteoblasts and Osteoclasts | Pg62 Mice | M/F | 3 months | Keller 2022 [44] |
CB2−/− | Young female mice had higher trabecular bone mass but lost more with age. | CD1 Mice | M/F | 3 months | Sophocleous 2014 [57] |
CB2−/− | Similar bone volume decrease compared to wild-type & bone mass reduced with age. | C57BL/6 Mice | M/F | 3 months | Sophocleous 2014 [57] |
Study Design | Strain | Sex | Age | Receptor | Ligand | Agonist or Antagonist | Phenotype/Effect | Citation |
---|---|---|---|---|---|---|---|---|
CB1 Related In Vivo Models | ||||||||
Ovariectomy-induced bone loss (global KO ± rimonabant) | C57BL/6J | F | Adult | CB1 | Rimonabant | Antagonist | Bone mass preserved; osteoclast suppression | Idris 2005 [52] |
Mild TBI remote bone-gain model | C57BL/6J | M | 12 weeks | CB1 | 2-AG | Agonist | CB1-dependent bone formation; absent in KO | Tam 2008 [47] |
Glucocorticoid osteoporosis (methyl-pred ± rimonabant) | Sprague-Dawley | M | 3–4 mo. & 12–14 mo. | CB1 | Rimonabant | Antagonist | Antagonist prevents loss in young; worsens loss in old | Samir 2014 [58] |
Calvarial TBI bone-gain model ± rimonabant | ICR & C57BL/6J | M | 6 & 12 weeks | CB1 | Rimonabant | Antagonist | Skull bone gain CB1-dependent; Antagonist blocks | Eger 2019 [59] |
Diabetic bone loss, renal-tubule CB1 KO | C57BL/6J | M | Adult | CB1 | CB1 antag | Antagonist | KO/antagonist prevent loss via increased EPO and formation | Baraghithy 2021 [60] |
CB2 Related In Vivo Models | ||||||||
Ovariectomy-Induced Bone Loss | C57BL/J | M/F | 3 vs. 6 months | CB2 | OGP | Agonist & Allosteric Modulator | Age-Related Decline in Bone Mass | Rapheal-Mizrahi 2022 [45] |
Glucocorticoid induced Osteonecrosis | Sprague Dawley | M | 10 weeks | CB2 | JWH133 | Agonist | Alleviation of Glucocorticoid induced Osteonecrosis | Sun 2021 [61] |
Glucocorticoid induced Osteonecrosis | Sprague Dawley | M | 10 weeks | CB2 | JWH133 | Agonist | Osteogenic protection via GSK/3B/B-Catenin signaling pathway | Sun 2021 [61] |
Glucocorticoid induced Osteonecrosis | Sprague Dawley Rat | M | 10 weeks | CB2 | JWH133 | Agonist | Stimulation of Angiogenesis | Sun 2021 [61] |
Ovariectomy-Induced Bone Loss | C57BL/6J Mice | M/F | 10 weeks | CB2 | HU-308 | Agonist | Protective of Bone Loss | Smoum 2015 [62] |
Ovariectomy-Induced Bone Loss | C57BL/6J Mice | M/F | 10 weeks | CB2 | HU- 433 | Agonist | Protective of Bone Loss (3–4 order of magnitude more potent) | Smoum 2015 [62] |
Ovariectomy-Induced Bone Loss | Mice | F | 10 weeks | CB2 | 2-AG | Agonist | Up-regulated Notch 1 Expression and promoted differentiation of hbMSCSs | Tian 2021 [63] |
Ovariectomy-Induced Bone Loss | C3H Mice | F | 8 or 51 weeks | CB2 | HU-308 | Agonist | Attenuates Bone loss, stimulated cortical thickness, suppresses osteoclast number and stimulates endocortical bone formation. Suppressed Osteoclast genesis. By reducing the availability of RANKL. | Ofek 2006 [54] |
Cell Line | Cell-Type | Receptor | Ligand | Agonist or Antagonist | Effect | Citation |
---|---|---|---|---|---|---|
PDLSCs | MSCs (periodontal) | CB1 | R(+)-Methanandamide | Agonist | Increased osteogenic differentiation (TNF/IFN-resistant) | Yan 2019 [49] |
hBMSCs | MSCs (bone marrow) | CB1 | CB1 over-expression | Genetic OE | Increased mineralization; rescued TNF/IFN inhibition | Yan 2022 [50] |
Mouse BMSCs | MSCs (bone marrow) | CB1 | SR141716A (Rimonabant) | Antagonist | Induced apoptosis; decreased mineralized matrix | Gowran 2013 [51] |
CD14⁺-derived OCs | Osteoclasts | CB1 | Anandamide (AEA) | Agonist | Increased osteoclast formation + resorption | |
BMSCs | MSCs (bone marrow) | CB2 | JWH133 | Agonist | Osteogenic protection Via GSK/3B/B-Catenin signaling pathway | Sun 2021 [61] |
BMSCs | MSCs (bone marrow) | CB2 | JWH133 | Agonist | Stimulation of Angiogenesis Via endothelial cell migration & VEGF | Sun 2021 [61] |
C57BL/6 Mice | BMSCs | CB2 | CBD | Agonist | Osteogenic Differentiation Via p38 MAPK signaling pathway | Li 2022 [64] |
Human Bone Marrow | Osteoblasts | CB2 | JWH-133 | Agonist | Improves Osteogenesis | Rossi 2015 [65] |
Mouse Calvarial cells | Osteoblasts | CB2 | HU-308/HU-433 | Agonist | Protection of Bone Loss | Smoum 2015 [62] |
MC3T3 E1 | Osteoblasts | CB2 | HU-308 | Agonist | Osteoblast Proliferation Via Erk1/2 phosphorylation and Map-kapk2 protein synthesis in G protein cyclin D1 mitogenic axis | Ofek 2011 [66] |
BMSCs & RAW264.7 cell line | Osteoblasts & Osteoclasts | CB2 | Desmethoxyyangoni, Flavokawain A, Echinatin, Mangiferin, 11-keto-B-boswelic acid | Agonist | Promote Osteogeneis & Inhibit Osteoclast Differentiation | Hu 2022 [67] |
Human Osteoblasts | Osteoblasts | CB2 | OGP | Agonist | Proliferation of Osteoblasts | Raphael-Mizrahi 2022 [45] |
Mouse BDMS | BDMS | CB2 | OGP | Agonist | Attenuation of Osteoclast Differentiation | Raphael-Mizrahi 2022 [45] |
Mouse BDMS | BDMS | CB2 | OGP | Agonist | Anti-Inflammatory Activity in Macrophages | Raphael-Mizrahi 2022 [45] |
Mouse BMDS | BDMS & Osteoblasts | CB2 | HU-308 | Agonist | Direct stimulation of stromal cells/osteoblasts and inhibition of monocytes/osteoclasts by direct inhibition of RANKL expression | Ofek 2006 [54] |
Human Bone Marrow | Osteoblasts | TRPV1 | Resiniferatoxin (RTX) | Agonist | Improves Osteogenesis | Rossi 2015 [68] |
6. CB2 Receptor
6.1. Cannabidiol (CBD)
6.2. Cannabigerol (CBG)
6.3. Tetrahydrocannabinol (THC)
7. Conclusions
Funding
Conflicts of Interest
References
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Urreola, G.; Le, M.; Harris, A.; Castillo, J.A., Jr.; Saiz, A.M.; Shahzad, H.; Martin, A.R.; Kim, K.D.; Khan, S.; Price, R. The Cannabinoid Pharmacology of Bone Healing: Developments in Fusion Medicine. Biomedicines 2025, 13, 1891. https://doi.org/10.3390/biomedicines13081891
Urreola G, Le M, Harris A, Castillo JA Jr., Saiz AM, Shahzad H, Martin AR, Kim KD, Khan S, Price R. The Cannabinoid Pharmacology of Bone Healing: Developments in Fusion Medicine. Biomedicines. 2025; 13(8):1891. https://doi.org/10.3390/biomedicines13081891
Chicago/Turabian StyleUrreola, Gabriel, Michael Le, Alan Harris, Jose A. Castillo, Jr., Augustine M. Saiz, Hania Shahzad, Allan R. Martin, Kee D. Kim, Safdar Khan, and Richard Price. 2025. "The Cannabinoid Pharmacology of Bone Healing: Developments in Fusion Medicine" Biomedicines 13, no. 8: 1891. https://doi.org/10.3390/biomedicines13081891
APA StyleUrreola, G., Le, M., Harris, A., Castillo, J. A., Jr., Saiz, A. M., Shahzad, H., Martin, A. R., Kim, K. D., Khan, S., & Price, R. (2025). The Cannabinoid Pharmacology of Bone Healing: Developments in Fusion Medicine. Biomedicines, 13(8), 1891. https://doi.org/10.3390/biomedicines13081891