Abstract：
BACKGROUND: The opioid epidemic is a public health crisis affecting spine care and pain management. Medical marijuana is a potential nonopioid analgesic yet to be studied in the surgical setting since its effects on bone healing are not fully understood. Studies have demonstrated analgesic and potentially osteoinductive properties of cannabinoids with endocannabinoid receptor expression in bone tissue.
OBJECTIVE: We hypothesize that tetrahydrocannabinol (THC) and cannabidiol (CBD) will not decrease bone healing in spinal fusion.
METHODS: Seventy-eight adult Sprague-Dawley rats were used for this study. Utilizing allogenic bone grafts (6 donor rats), posterolateral inter-transverse lumbar fusion at the L4-L5 level was performed. The animals were equally divided into four treatment groups, each receiving 0.1 ml intraperitoneal injections weekly as follows: placebo (saline), 5 mg/kg THC, 5 mg/kg CBD, and a combination of 5 mg/kg THC and 5mg/kg CBD (Combo).
METHODS: Callus tissue was harvested 2- and 8-weeks postsurgery for qPCR assessment to quantify changes in the expression of osteogenic genes. Manual palpation was done to assess the strength of the L4-L5 arthrodesis on all rats. μCT image-based callus analysis and histology were performed. One-way ANOVA followed by post hoc comparisons was performed.
RESULTS: μCT demonstrated no significant differences. Treatment groups had slightly increased bone volume and density compared to control. qPCR at 2 weeks indicated downregulated RANKL/OPG ratios skewing towards osteogenesis in the CBD group, with the THC and CBD+THC groups demonstrating a downward trend (p>.05). ALPL, BMP4, and SOST were significantly higher in the CBD group, with CTNNB1 and RUNX2 also showing an upregulating trend. The CBD group showed elevation in Col1A1 and MMP13. Data at eight weeks showed ALPL, RUNX2, BMP4, and SOST were downregulated for all treatment groups. In the CBD+THC group, RANK, RANKL, and OPG were downregulated. OPG downregulation reached significance for the THC and CBD+THC group compared to saline. Interestingly, the RANKL/OPG ratio showed upregulation in the CBD and CBD+THC groups. RANKL showed upregulation in the CBD group. At 2 and 8 weeks, the CBD treatment group showed superior histological progression, increasing between time points.
CONCLUSIONS: This study demonstrates that CBD and THC have no adverse effect on bone healing and the rate of spinal fusion in rats. Osteogenic factors were upregulated in the CBD-treated groups at 2 weeks, which indicates a potential for bone regeneration. In this group, compared to control, the RANKL/OPG ratio at the early healing phase demonstrates the inhibition of osteoclast differentiation, enhancing bone formation. Interestingly, it shows promoted osteoclast differentiation at the later healing phase, enhancing bone remodeling. This aligns with the physiological expectation of a lower ratio in the early phases and a higher ratio in the later remodeling phases.
CONCLUSIONS: CBD and THC showed no inhibitory effects on bone healing in a spinal fusion model. Moreover, histologic and gene expression analysis demonstrated that CBD may, in fact, enhance bone healing. Further research is needed to confirm the safe usage of THC and CBD in the postoperative setting following spinal fusions.
OBJECTIVE: We hypothesize that tetrahydrocannabinol (THC) and cannabidiol (CBD) will not decrease bone healing in spinal fusion.
METHODS: Seventy-eight adult Sprague-Dawley rats were used for this study. Utilizing allogenic bone grafts (6 donor rats), posterolateral inter-transverse lumbar fusion at the L4-L5 level was performed. The animals were equally divided into four treatment groups, each receiving 0.1 ml intraperitoneal injections weekly as follows: placebo (saline), 5 mg/kg THC, 5 mg/kg CBD, and a combination of 5 mg/kg THC and 5mg/kg CBD (Combo).
METHODS: Callus tissue was harvested 2- and 8-weeks postsurgery for qPCR assessment to quantify changes in the expression of osteogenic genes. Manual palpation was done to assess the strength of the L4-L5 arthrodesis on all rats. μCT image-based callus analysis and histology were performed. One-way ANOVA followed by post hoc comparisons was performed.
RESULTS: μCT demonstrated no significant differences. Treatment groups had slightly increased bone volume and density compared to control. qPCR at 2 weeks indicated downregulated RANKL/OPG ratios skewing towards osteogenesis in the CBD group, with the THC and CBD+THC groups demonstrating a downward trend (p>.05). ALPL, BMP4, and SOST were significantly higher in the CBD group, with CTNNB1 and RUNX2 also showing an upregulating trend. The CBD group showed elevation in Col1A1 and MMP13. Data at eight weeks showed ALPL, RUNX2, BMP4, and SOST were downregulated for all treatment groups. In the CBD+THC group, RANK, RANKL, and OPG were downregulated. OPG downregulation reached significance for the THC and CBD+THC group compared to saline. Interestingly, the RANKL/OPG ratio showed upregulation in the CBD and CBD+THC groups. RANKL showed upregulation in the CBD group. At 2 and 8 weeks, the CBD treatment group showed superior histological progression, increasing between time points.
CONCLUSIONS: This study demonstrates that CBD and THC have no adverse effect on bone healing and the rate of spinal fusion in rats. Osteogenic factors were upregulated in the CBD-treated groups at 2 weeks, which indicates a potential for bone regeneration. In this group, compared to control, the RANKL/OPG ratio at the early healing phase demonstrates the inhibition of osteoclast differentiation, enhancing bone formation. Interestingly, it shows promoted osteoclast differentiation at the later healing phase, enhancing bone remodeling. This aligns with the physiological expectation of a lower ratio in the early phases and a higher ratio in the later remodeling phases.
CONCLUSIONS: CBD and THC showed no inhibitory effects on bone healing in a spinal fusion model. Moreover, histologic and gene expression analysis demonstrated that CBD may, in fact, enhance bone healing. Further research is needed to confirm the safe usage of THC and CBD in the postoperative setting following spinal fusions.
摘要：
背景：阿片类药物流行是影响脊柱护理和疼痛管理的公共卫生危机。医用大麻是一种潜在的非阿片类镇痛药，尚未在手术环境中进行研究，因为尚未完全了解其对骨骼愈合的影响。研究已经证明了在骨组织中具有内源性大麻素受体表达的大麻素的镇痛和潜在的骨诱导特性。
目的：我们假设四氢大麻酚（THC）和大麻二酚（CBD）不会降低脊柱融合术中的骨愈合。
方法：本研究使用78只成年Sprague-Dawley大鼠。利用同种异体骨移植（6只供体大鼠），在L4-L5水平进行后外侧横向腰椎间融合术.将动物平均分为四个治疗组，每个人每周接受0.1ml腹膜内注射，如下：安慰剂（盐水），5mg/kgTHC，5mg/kgCBD，和5mg/kgTHC和5mg/kgCBD（组合）的组合。
方法:在手术后2周和8周收获愈伤组织用于qPCR评估以定量成骨基因表达的变化。进行手动触诊以评估所有大鼠的L4-L5关节固定术的强度。进行基于μCT图像的骨痂分析和组织学。进行单因素方差分析,然后进行事后比较。
结果：μCT显示无显著差异。与对照组相比,治疗组具有略微增加的骨体积和密度。2周时的qPCR表明RANKL/OPG比率下调，在CBD组中朝着成骨方向倾斜，THC和CBD+THC组呈下降趋势(P>0.05)。ALPL,在CBD组中，BMP4和SOST明显更高，CTNNB1和RUNX2也显示出上调趋势。CBD组显示Col1A1和MMP13升高。八周的数据显示ALPL，所有治疗组的RUNX2、BMP4和SOST均下调。在CBD+THC组中，RANK,RANKL,OPG下调。与盐水相比,THC和CBD+THC组的OPG下调达到显著性。有趣的是,RANKL/OPG比值在CBD和CBD+THC组中显示上调.RANKL在CBD组中显示上调。在2周和8周，CBD治疗组表现出优越的组织学进展，在时间点之间增加。
结论：这项研究表明，CBD和THC对大鼠的骨愈合和脊柱融合率没有不利影响。在CBD治疗组中，成骨因子在两周时上调，这表明了骨骼再生的潜力。在这个群体中,与对照相比，早期愈合阶段的RANKL/OPG比值证明了破骨细胞分化的抑制作用，增强骨形成。有趣的是,它显示在愈合后期促进的破骨细胞分化，增强骨骼重塑。这与在早期阶段较低比率和在后期重塑阶段较高比率的生理预期一致。
结论：CBD和THC对脊柱融合模型的骨愈合无抑制作用。此外，组织学和基因表达分析表明，CBD可能，事实上,增强骨骼愈合。需要进一步的研究来确认THC和CBD在脊柱融合后的术后环境中的安全使用。
目的：我们假设四氢大麻酚（THC）和大麻二酚（CBD）不会降低脊柱融合术中的骨愈合。
方法：本研究使用78只成年Sprague-Dawley大鼠。利用同种异体骨移植（6只供体大鼠），在L4-L5水平进行后外侧横向腰椎间融合术.将动物平均分为四个治疗组，每个人每周接受0.1ml腹膜内注射，如下：安慰剂（盐水），5mg/kgTHC，5mg/kgCBD，和5mg/kgTHC和5mg/kgCBD（组合）的组合。
方法:在手术后2周和8周收获愈伤组织用于qPCR评估以定量成骨基因表达的变化。进行手动触诊以评估所有大鼠的L4-L5关节固定术的强度。进行基于μCT图像的骨痂分析和组织学。进行单因素方差分析,然后进行事后比较。
结果：μCT显示无显著差异。与对照组相比,治疗组具有略微增加的骨体积和密度。2周时的qPCR表明RANKL/OPG比率下调，在CBD组中朝着成骨方向倾斜，THC和CBD+THC组呈下降趋势(P>0.05)。ALPL,在CBD组中，BMP4和SOST明显更高，CTNNB1和RUNX2也显示出上调趋势。CBD组显示Col1A1和MMP13升高。八周的数据显示ALPL，所有治疗组的RUNX2、BMP4和SOST均下调。在CBD+THC组中，RANK,RANKL,OPG下调。与盐水相比,THC和CBD+THC组的OPG下调达到显著性。有趣的是,RANKL/OPG比值在CBD和CBD+THC组中显示上调.RANKL在CBD组中显示上调。在2周和8周，CBD治疗组表现出优越的组织学进展，在时间点之间增加。
结论：这项研究表明，CBD和THC对大鼠的骨愈合和脊柱融合率没有不利影响。在CBD治疗组中，成骨因子在两周时上调，这表明了骨骼再生的潜力。在这个群体中,与对照相比，早期愈合阶段的RANKL/OPG比值证明了破骨细胞分化的抑制作用，增强骨形成。有趣的是,它显示在愈合后期促进的破骨细胞分化，增强骨骼重塑。这与在早期阶段较低比率和在后期重塑阶段较高比率的生理预期一致。
结论：CBD和THC对脊柱融合模型的骨愈合无抑制作用。此外，组织学和基因表达分析表明，CBD可能，事实上,增强骨骼愈合。需要进一步的研究来确认THC和CBD在脊柱融合后的术后环境中的安全使用。
