70. Varenicline mitigates the increased risk of pseudarthrosis associated with nicotine

BACKGROUND CONTEXT Smoking is a predictor of poor outcomes in patients undergoing spinal fusion and has been associated with decreased satisfaction, decreased mobility, increased pain, and poor quality of life scores. Despite an abundance of counseling, long-term abstinence remains difficult for smokers undergoing spinal fusion. Most notably, high serum nicotine levels increase the risk of nonunion after spinal fusion. Varenicline, a pharmaceutical adjunct for smoking cessation, is a partial agonist designed to displace and outcompete nicotine at its receptor binding site, thereby limiting downstream activation. Recent investigations have discovered that all components of the nicotinic cholinergic system are also present in mammalian non-neuronal cells, including mesenchymal cells, and serve a critical regulator of bone metabolism. Accordingly, varenicline may outcompete nicotine in nAChR binding and therefore decrease the pseudarthrosis rate for patients unable to quit smoking in the perioperative period by limiting downstream activation of nicotinic pathways known to decrease trabecular bone volume, thickness, formation, and mineralization rate. PURPOSE To compare fusion rate and fusion mass characteristics between cohorts receiving nicotine, varenicline, or concurrent nicotine and varenicline after lumbar fusion. STUDY DESIGN/SETTING Rodent noninstrumented spinal fusion model. PATIENT SAMPLE Sixty 8-week-old male Sprague-Dawley rats weighing approximately 300 grams. OUTCOME MEASURES Manual palpation score, fusion score, bone fraction volume, bone mineral density, tissue mineral density, compressive modulus, and mineral apposition rate. METHODS Sixty rats underwent L4-5 posterolateral fusion (PLF) surgery. Four experimental groups (control: C, nicotine: N, varenicline: V, and combined: NV [nicotine and varenicline]) were included for analysis. Treatment groups received nicotine, varenicline, or a combination of nicotine and varenicline delivered through subcutaneous osmotic pumps beginning two weeks before surgery until the time of sacrifice 6 weeks postoperatively. Manual palpation testing, microCT imaging, bone histomorphometry, and biomechanical testing were performed on harvested spinal fusion segments. RESULTS Control (1.91, p=0.016) and combined (1.87, p=0.032) groups, when compared directly to the nicotine group (1.38), demonstrated significantly greater manual palpation scores. The fusion rate in the control (93.3%) and combined (93.3%) groups were significantly greater than that of the nicotine group (33.3%) (p=0.007, both). Biomechanical testing demonstrated greater Young's modulus of the fusion segment in the control (17.1 MPa) and combined groups (34.5 MPa) compared to the nicotine group (8.07 MPa) (p<0.001, both). MicroCT analysis demonstrated greater bone volume fraction (C:0.35 vs N:0.26 vs NV:0.33) (p<0.001, all) and bone mineral density (C:335 vs N:262 vs NV:328 mg Ha/cm3) (p<0.001, all) in the control and combined groups compared to the nicotine group. Histomorphometry demonstrated a greater mineral apposition rate in the combined group compared to the nicotine group (0.34 vs 0.24 µm/day, p=0.025). CONCLUSIONS In a rodent spinal fusion model, varenicline mitigates the adverse effects of high nicotine serum levels on the rate and quality of spinal fusion. Additionally, this is the first validation of a noninstrumented nicotine-nonunion model using the rodent lumbar spine, serving as a model for future research on nicotine and pseudarthrosis after spine surgery. FDA Device/Drug Status Varenicline (Approved for this indication) Smoking is a predictor of poor outcomes in patients undergoing spinal fusion and has been associated with decreased satisfaction, decreased mobility, increased pain, and poor quality of life scores. Despite an abundance of counseling, long-term abstinence remains difficult for smokers undergoing spinal fusion. Most notably, high serum nicotine levels increase the risk of nonunion after spinal fusion. Varenicline, a pharmaceutical adjunct for smoking cessation, is a partial agonist designed to displace and outcompete nicotine at its receptor binding site, thereby limiting downstream activation. Recent investigations have discovered that all components of the nicotinic cholinergic system are also present in mammalian non-neuronal cells, including mesenchymal cells, and serve a critical regulator of bone metabolism. Accordingly, varenicline may outcompete nicotine in nAChR binding and therefore decrease the pseudarthrosis rate for patients unable to quit smoking in the perioperative period by limiting downstream activation of nicotinic pathways known to decrease trabecular bone volume, thickness, formation, and mineralization rate. To compare fusion rate and fusion mass characteristics between cohorts receiving nicotine, varenicline, or concurrent nicotine and varenicline after lumbar fusion. Rodent noninstrumented spinal fusion model. Sixty 8-week-old male Sprague-Dawley rats weighing approximately 300 grams. Manual palpation score, fusion score, bone fraction volume, bone mineral density, tissue mineral density, compressive modulus, and mineral apposition rate. Sixty rats underwent L4-5 posterolateral fusion (PLF) surgery. Four experimental groups (control: C, nicotine: N, varenicline: V, and combined: NV [nicotine and varenicline]) were included for analysis. Treatment groups received nicotine, varenicline, or a combination of nicotine and varenicline delivered through subcutaneous osmotic pumps beginning two weeks before surgery until the time of sacrifice 6 weeks postoperatively. Manual palpation testing, microCT imaging, bone histomorphometry, and biomechanical testing were performed on harvested spinal fusion segments. Control (1.91, p=0.016) and combined (1.87, p=0.032) groups, when compared directly to the nicotine group (1.38), demonstrated significantly greater manual palpation scores. The fusion rate in the control (93.3%) and combined (93.3%) groups were significantly greater than that of the nicotine group (33.3%) (p=0.007, both). Biomechanical testing demonstrated greater Young's modulus of the fusion segment in the control (17.1 MPa) and combined groups (34.5 MPa) compared to the nicotine group (8.07 MPa) (p<0.001, both). MicroCT analysis demonstrated greater bone volume fraction (C:0.35 vs N:0.26 vs NV:0.33) (p<0.001, all) and bone mineral density (C:335 vs N:262 vs NV:328 mg Ha/cm3) (p<0.001, all) in the control and combined groups compared to the nicotine group. Histomorphometry demonstrated a greater mineral apposition rate in the combined group compared to the nicotine group (0.34 vs 0.24 µm/day, p=0.025). In a rodent spinal fusion model, varenicline mitigates the adverse effects of high nicotine serum levels on the rate and quality of spinal fusion. Additionally, this is the first validation of a noninstrumented nicotine-nonunion model using the rodent lumbar spine, serving as a model for future research on nicotine and pseudarthrosis after spine surgery.