Division of Diagnostic and Surgical Sciences, UCLA School of Dentistry, Los Angeles, CA, USA.
Comparative Biology and Safety Sciences, Amgen Inc., Thousand Oaks, CA, USA.
J Bone Miner Res. 2019 Jan;34(1):171-181. doi: 10.1002/jbmr.3581. Epub 2018 Sep 24.
Antiresorptive agents, such as bisphosphonates and denosumab, are frequently used for the management of osteoporosis. Indeed, both medications decrease the risk of osteoporotic fractures; however, these medications are associated with rare but potentially severe side effects, such as osteonecrosis of the jaw (ONJ). ONJ, defined as an area of exposed bone in the maxillofacial region that lasts for 8 weeks, often presents with significant pain and infection and can lead to serious complications. Interestingly, other treatments for osteoporosis have been developed, such as antibodies against the osteocyte-secreted protein, sclerostin. Sclerostin functions to inhibit the Wnt signaling cascade, leading to inhibition of bone formation. In clinical trials, a sclerostin antibody (romosozumab, Amgen Inc., UCB Brussels) increases bone formation and lowers the risk of osteoporotic fractures. However, in conjunction with increased osteoblastic activity, a reduction in bone resorption markers is observed. This antiresorptive effect raises the concern of possible ONJ development in patients treated with sclerostin antibodies. Here, utilizing ligature-induced experimental periodontitis (EP), we evaluated the effects of sclerostin inhibition on the development of ONJ-like lesions in ovariectomized rats. Beginning 8 weeks post-ovariectomy, rats were treated for 22 weeks with weekly injections of vehicle (Veh), 200 μg/kg zoledronic acid (ZA), a potent bisphosphonate at 100-fold the osteoporosis dose, or 5 mg/kg sclerostin antibody (Scl-Ab) at the osteoporotic dose. EP was initiated at week 12 and maintained for the remainder of the study. Scl-Ab treatment transiently increased serum P1NP, a bone formation marker, increased BV/TV, and decreased eroded surfaces in lumbar vertebrae. ZA-treated rats developed histologic features of ONJ, whereas Veh-treated controls did not. Scl-Ab animals lost less periodontal bone in sites with EP. However, these animals presented with no histologic signs of ONJ. In conclusion, sclerostin inhibition enhanced structural bone parameters, without inducing ONJ-like lesions, in ovariectomized rats with EP. © 2018 American Society for Bone and Mineral Research.
抗吸收剂，如双磷酸盐和地舒单抗，常用于骨质疏松症的治疗。事实上，这两种药物都降低了骨质疏松性骨折的风险;然而，这些药物与罕见但潜在严重的副作用有关，如颌骨坏死（ONJ）。ONJ 的定义为颌面部持续 8 周的暴露骨区域，常伴有明显的疼痛和感染，并可导致严重的并发症。有趣的是，已经开发出其他骨质疏松症的治疗方法，如针对骨细胞分泌蛋白硬骨素的抗体。硬骨素的作用是抑制 Wnt 信号级联反应，从而抑制骨形成。在临床试验中，一种硬骨素抗体（罗莫索单抗，安进公司，UCB 布鲁塞尔）增加了骨形成并降低了骨质疏松性骨折的风险。然而，随着成骨细胞活性的增加，观察到骨吸收标志物减少。这种抗吸收作用引起了人们的关注，即接受硬骨素抗体治疗的患者可能会发生 ONJ。在这里，我们利用结扎诱导的实验性牙周炎（EP），评估了硬骨素抑制对去卵巢大鼠 ONJ 样病变发展的影响。从卵巢切除术后 8 周开始，大鼠每周接受一次注射，持续 22 周，注射物（Veh）、200μg/kg 唑来膦酸（ZA），一种骨质疏松症剂量的 100 倍的强力双磷酸盐，或 5mg/kg 硬骨素抗体（Scl-Ab），骨质疏松症剂量。EP 在第 12 周开始，并持续到研究结束。Scl-Ab 治疗可短暂增加血清 P1NP，一种骨形成标志物，增加 BV/TV，并减少腰椎的侵蚀表面。ZA 治疗的大鼠出现了 ONJ 的组织学特征，而 Veh 治疗的对照组则没有。在有 EP 的部位，Scl-Ab 动物的牙周骨丢失较少。然而，这些动物没有出现 ONJ 的组织学迹象。总之，在 EP 的去卵巢大鼠中，硬骨素抑制增强了结构骨参数，而没有诱导出 ONJ 样病变。
