Changes in the RANK ligand/osteoprotegerin system are correlated to changes in bone mineral density in bisphosphonate-treated osteoporotic patients
Changes in the RANK ligand/osteoprotegerin system are correlated to changes in bone mineral density in bisphosphonate-treated osteoporotic patients
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DOI：
10.1007/s00198-005-0035-4
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发表时间：
2006-05-01
影响因子：
4
通讯作者：
Fahrleitner-Pammer, A
中科院分区：
文献类型：
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作者：
Dobnig, H;Hofbauer, LC;Fahrleitner-Pammer, A
导言：由于nf - κ B配体的可溶性受体激活剂（sRANKL）和内源性抗骨吸收细胞因子骨保护素（OPG）是由成骨细胞产生的，并且考虑到这些细胞在抗骨吸收治疗过程中发生了显著的变化，我们假设用双膦酸盐（BP）治疗会伴随血清OPG和sRANKL水平的变化。方法：在一项前瞻性，随机对照试验中，未经治疗的绝经后骨质疏松症妇女，口服BP治疗（每日剂量10mg阿仑膦酸盐或5mg利塞膦酸盐）联合钙/维生素D与单独钙/维生素D治疗（对照组）进行比较。56例患者分别于2、6、12个月完成随访。基线时进行标准化脊柱x线检查，基线时和1年后分别对股骨颈和股骨粗隆进行DEXA测量。采用基于多克隆抗体的ELISA系统检测血清OPG和sRANKL水平。结果：1年后，CTR组颈、粗隆骨密度（BMD）无明显下降，联合BP组平均升高3.3%、4.6% （p < 0.0001）。CTR组12个月时血清I型胶原c端末端肽（sCTX）和骨钙素水平分别下降12%和10%，联合BP组分别下降43%和23%（均有统计学意义）。CTR组OPG血清水平在2个月时显著下降9% (p < 0.005)，在较晚时间点仍低于治疗前水平。阿仑膦酸钠和利塞膦酸钠治疗的患者组在2个月后的OPG水平没有变化，但在6个月和12个月时，他们的血清水平明显升高。在整个治疗期间，sRANKL的水平没有变化。单因素回归分析显示，与sCTX相比，BP治疗12个月后血清OPG水平的变化与BMD变化呈正相关（转子：r= 0.59, p < 0.0001；颈部：r= 0.50, p < 0.001），与BMD变化呈预期的负相关（转子：r= -0.35, p=0.03；颈部：r= -0.23, p=0.16）。经过12个月的多元回归分析，当OPG和sCTX联合使用时，粗隆BMD 1年变化的R-2值从0.33（单独使用OPG）和0.23（单独使用sCTX）显著提高到0.57 （p < 0.001）。股骨颈的结果也有统计学意义（R-2=0.35, p < 0.001）。CTR组BMD和OPG变化无相关性。结论：我们得出结论，在BP治疗中，血清OPG水平的变化与BMD反应的变化呈正相关，而与sCTX水平的变化不同。治疗期间bp相关的血清OPG水平变化可能是由于对破骨细胞生成和破骨细胞凋亡的影响以及对成骨细胞OPG生成的直接刺激作用。这些OPG水平的变化可用于预测患者对BP治疗的个体反应。
Introduction: Since the soluble receptor activator of the NF-kappa B ligand (sRANKL) as well as the endogenous anti-resorptive cytokine osteoprotegerin (OPG) are produced by osteoblasts and given that these cells undergo significant changes during antiresorptive treatment, we hypothesized that treatment with bisphosphonates (BP) would be accompanied by changes in serum OPG and sRANKL levels. Methods: In a prospective, randomized controlled trial of previously untreated postmenopausal women with osteoporosis, oral BP therapy (daily doses of either 10 mg alendronate or 5 mg risedronate) in combination with calcium/vitamin D was compared to calcium/vitamin D treatment alone (control group). Follow-up at 2, 6 and 12 months was completed for 56 patients. Standardized spinal X-rays were performed at baseline, and DEXA measurements at the femoral neck and trochanter were made at baseline and after 1 year. Serum OPG and sRANKL levels were measured with a polyclonal antibody-based ELISA system. Results: After 1 year, there was a non-significant loss in neck and trochanteric bone mineral density (BMD) in the CTR group and a mean increase of 3.3% and 4.6% in the combined BP group (both p < 0.0001), respectively. Serum levels of C-terminal telopeptides of type I collagen (sCTX) and osteocalcin decreased by 12% and 10% at 12 months in the CTR group and by 43% and 23% in the combined BP group, respectively (all significant). OPG serum levels in the CTR group decreased significantly by 9% at 2 months (p < 0.005) and remained below pre-treatment levels at later time points. Both the alendronate- and risedronate-treated patient groups showed unaltered OPG levels after 2 months, but they had significantly increased serum levels at 6 and 12 months. Levels of sRANKL were unchanged throughout the treatment period. Univariate regression analysis demonstrated that changes in serum OPG levels after 12 months of BP treatment were positively and better correlated to BMD changes (trochanter: r= 0.59, p < 0.0001; neck: r= 0.50, p < 0.001) than those of sCTX, which showed the expected negative correlation to BMD change (trochanter: r= -0.35, p=0.03; neck: r= -0.23, p=0.16). With multiple regression analyses at 12 months, R-2 values for 1-year changes in trochanteric BMD of 0.33 (OPG alone) and 0.23 (sCTX alone) were significantly improved to the 0.57 when OPG and sCTX changes were combined (p < 0.001). Results for the femoral neck were also statistically significant R-2=0.35, p < 0.001). BMD and OPG changes in the CTR group were not correlated with each other. Conclusions: We conclude that with BP treatment, changes in serum OPG levels, unlike changes in sCTX levels, are positively correlated to changes in BMD response. The BP-related changes in serum OPG levels during treatment could result from effects on osteoclastogenesis and osteoclast apoptosis as well as from a direct stimulatory effect on osteoblastic OPG production. These changes in OPG levels may be used to predict the individual response of patients to BP treatment.