Department of Anatomy, Cell Biology, and Physiology, Indiana University School of Medicine, 635 Barnhill Drive, MS 5045, Indianapolis, IN, 46202, USA.
Department of Pharmacology & Toxicology, Indiana University School of Medicine, Indianapolis, IN, 46202, USA.
Calcif Tissue Int. 2024 Aug;115(2):174-184. doi: 10.1007/s00223-024-01239-8. Epub 2024 Jun 10.
Patients with chronic kidney disease (CKD) report high pain levels, but reduced renal clearance eliminates many analgesic options; therefore, 30-50% of CKD patients have chronic opioid prescriptions. Opioid use in CKD is associated with higher fracture rates. Opioids may directly alter bone turnover directly through effects on bone cells and indirectly via increasing inflammation. We hypothesized that continuous opioid exposure would exacerbate the high bone turnover state of CKD and be associated with elevated measures of inflammation. Male C57Bl/6J mice after 8 weeks of adenine-induced CKD (AD) and non-AD controls (CON) had 14-day osmotic pumps (0.25-µL/hr release) containing either saline or 50-mg/mL oxycodone (OXY) surgically implanted in the subscapular region. After 2 weeks, all AD mice had elevated blood urea nitrogen, parathyroid hormone, and serum markers of bone turnover compared to controls with no effect of OXY. Immunohistochemical staining of the distal femur showed increased numbers of osteocytes positive for the mu opioid and for toll-like receptor 4 (TLR4) due to OXY. Osteocyte protein expression of tumor necrosis factor-α (TNF-α) and RANKL were higher due to both AD and OXY so that AD + OXY mice had the highest values. Trabecular osteoclast-covered surfaces were also significantly higher due to both AD and OXY, resulting in AD + OXY mice having 4.5-fold higher osteoclast-covered surfaces than untreated CON. These data demonstrate that opioids are associated with a pro-inflammatory state in osteocytes which increases the pro-resorptive state of CKD.
患有慢性肾病（CKD）的患者报告疼痛水平较高，但肾脏清除率降低会消除许多镇痛选择；因此，30-50%的 CKD 患者有慢性阿片类药物处方。CKD 患者使用阿片类药物与更高的骨折率有关。阿片类药物可能通过直接作用于骨细胞或间接增加炎症来直接改变骨转换。我们假设持续的阿片类药物暴露会加剧 CKD 的高骨转换状态，并与炎症标志物的升高相关。8 周腺嘌呤诱导的 CKD（AD）和非 AD 对照组（CON）雄性 C57Bl/6J 小鼠接受手术植入肩胛下区的 14 天渗透泵（0.25-µL/hr 释放），内含盐水或 50-mg/mL 羟考酮（OXY）。2 周后，所有 AD 小鼠的血尿素氮、甲状旁腺激素和血清骨转换标志物均高于对照组，而 OXY 无影响。对远端股骨的免疫组织化学染色显示，由于 OXY，骨细胞中 mu 阿片受体和 toll 样受体 4（TLR4）阳性的骨细胞数量增加。由于 AD 和 OXY，骨细胞中肿瘤坏死因子-α（TNF-α）和 RANKL 的蛋白表达增加，因此 AD+OXY 小鼠的表达水平最高。由于 AD 和 OXY，破骨细胞覆盖的小梁表面也显著增加，导致 AD+OXY 小鼠的破骨细胞覆盖表面是未处理的 CON 的 4.5 倍。这些数据表明，阿片类药物与骨细胞中的促炎状态相关，从而增加了 CKD 的促吸收状态。
