Association of cannabinoid receptor modulation with normal and abnormal skeletal remodelling: A systematic review and meta-analysis of in vitro, in vivo and human studies

To address the inconsistent findings from studies that used different models to explore the role of classical cannabinoid type 1 (CB1) and 2 (CB2) receptors in skeletal remodelling, we searched Medline, Web of Science and Embase for relevant studies from inception to June 23, 2020. We identified 38 in vitro, 34 in vivo and 9 human studies. A meta-analysis of in vitro studies showed that exposure to the inverse-agonists AM251 (mean difference [MD]:−26.75, 95% confidence interval [CI]:−45.36,−8.14, p = 0.005), AM630 (standardised[std.] MD:−3.11, CI:−5.26,−0.97, p = 0.004; SR144528, std.MD:−4.88, CI −7.58,−2.18, p = 0.0004) and CBD (std.MD:−1.39, CI −2.64,−0.14, p = 0.03) is associated with reduced osteoclastogenesis, whereas the endocannabinoid 2-AG (std.MD:2.00, CI:0.11–3.89, p = 0.04) and CB2-selective agonist HU308 (MD:19.38, CI:11.75–27.01, p < 0.00001) were stimulatory. HU308 also enhanced osteoblast differentiation (std.MD:2.22, CI:0.95–3.50, p = 0.0006) and activity (std.MD:2.97, CI:1.22–4.71, p = 0.0008). In models of bone loss, CB1/2 deficiency enhanced peak bone volume (std.MD:3.70, CI:1.77–5.63, p = 0.0002) but reduced bone formation (std.MD:−0.54, CI:−0.90,−0.17, p = 0.004) in female mice. In male rats, CB1/2 deficiency (std.MD:2.31, CI:0.30–4.33, p = 0.02) and AM251 or CBD treatments (std.MD:2.19, CI:0.46–3.93, p = 0.01) enhanced bone volume. CB1/2 deficiency (std.MD:9.78, CI:4.96–14.61, p < 0.0001) and AM251 or AM630 treatments (std.MD:28.19, CI:19.13–37.25, p < 0.0001) were associated with osteoprotection. The CB2-selective agonists JWH133 and 4Q3C enhanced bone volume in arthritic rodents (std.MD:14.45, CI:2.08–26.81, p = 0.02). In human, CB2 SNPs (AA:rs2501431, MD:−0.28, CI:−0.55,−0.01, p = 0.04; CC:rs2501432, MD:−0.29, CI:−0.56,−0.02, p = 0.03) were associated with reduced bone mineral density, however the association of Marijuana use remains unclear. Thus, CB1/2 modulation is associated with altered bone metabolism, however findings are confounded by low study number and heterogenicity of models.