Recker Robert R, Delmas Pierre D, Halse Johan, Reid Ian R, Boonen Steven, García-Hernandez Pedro A, Supronik Jerzy, Lewiecki E Michael, Ochoa Luis, Miller Paul, Hu Huilin, Mesenbrink Peter, Hartl Florian, Gasser Juerg, Eriksen Erik F
School of Medicine, Creighton University, Omaha, Nebraska 68131, USA.
J Bone Miner Res. 2008 Jan;23(1):6-16. doi: 10.1359/jbmr.070906.
In a substudy of the HORIZON pivotal fracture trial, in which yearly intravenous zoledronic acid 5 mg was found to significantly reduce risk of various fracture types in patients with postmenopausal osteoporosis, 152 patients underwent bone biopsy. Zoledronic acid reduced bone turnover by 63% and preserved bone structure and volume, with evidence of ongoing bone remodeling in 99% of biopsies obtained.
In the HORIZON pivotal fracture trial (PFT), enrolling 7,736 women with postmenopausal osteoporosis, three annual intravenous infusions of the bisphosphonate zoledronic acid (5 mg) significantly reduced morphometric vertebral, clinical vertebral, hip, and nonvertebral fractures by 70%, 77%, 41%, and 25%, respectively. Whereas 79% of patients received zoledronic acid/placebo only (stratum I, n = 6,113), 21% received concomitant treatment with other antiresorptive drugs, excluding other bisphosphonates, PTH, and strontium (stratum II, n = 1,652).
To determine effects on bone remodeling and bone architecture, iliac crest bone biopsies were obtained in 152 patients on active treatment or placebo at 3 yr after double tetracycline labeling. In five patients, only qualitative histology was performed, leaving 147 biopsy cores (79 on active treatment and 68 on placebo) for microCT analysis and histomorphometry.
Analysis of bone structure by microCT revealed higher trabecular bone volume (BV/TV) in the zoledronic acid group (median, 16.6% versus 12.8%; p = 0.020). In addition, patients treated with zoledronic acid exhibited higher trabecular numbers (p = 0.008), decreased trabecular separation (p = 0.011), and a trend toward improvement in connectivity density (p = 0.062), all indicating better preservation of trabecular structure after treatment with zoledronic acid. Qualitative analysis revealed presence of tetracycline label in 81 of 82 biopsies from patients on zoledronic acid and all 70 biopsies from placebo patients, indicative of continued bone remodeling. No bone pathology was observed. Zoledronic acid induced a 63% median (71% mean) reduction of the activation frequency (Ac.f; p < 0.0001) and reduced mineralizing surface (MS/BS; p < 0.0001) and volume referent bone formation rate (BFR/BV) versus placebo, indicating reduced bone turnover. Mineral appositional rate was higher in the zoledronic acid group (p = 0.0002), suggesting improved osteoblast function compared with placebo. Mineralization lag time was similar in the two groups, whereas osteoid volume (OV/BV; p < 0.0001) and osteoid thickness (O.Th; p = 0.0094) were lower in zoledronic acid-treated patients, indicating normal osteoid formation and mineralization of newly formed bone. Concomitant administration of other antiresorptive osteoporosis therapies (e.g., raloxifene, tamoxifen, tibolone, ipriflavone) did not significantly alter the tissue level response to zoledronic acid.
Annual dosing for 3 yr with zoledronic acid 5 mg intravenously resulted in a median 63% (mean, 71%) reduction of bone turnover and preservation of bone structure and mass without any signs of adynamic bone. Concomitant treatment with other osteoporosis therapies did not significantly affect the bone response to zoledronic acid.
在HORIZON关键骨折试验的一项子研究中，发现每年静脉注射5毫克唑来膦酸可显著降低绝经后骨质疏松症患者各种骨折类型的风险，152例患者接受了骨活检。唑来膦酸使骨转换降低了63%，并保留了骨结构和骨量，在99%的活检样本中都有持续骨重塑的证据。
在HORIZON关键骨折试验（PFT）中，纳入了7736例绝经后骨质疏松症女性，每年静脉输注三次双膦酸盐唑来膦酸（5毫克）分别使形态计量学椎体骨折、临床椎体骨折、髋部骨折和非椎体骨折显著降低了70%、77%、41%和25%。79%的患者仅接受唑来膦酸/安慰剂治疗（I组，n = 6113），21%的患者接受了其他抗吸收药物的联合治疗，不包括其他双膦酸盐、甲状旁腺激素和锶（II组，n = 1652）。
为了确定对骨重塑和骨结构的影响，在双四环素标记后3年，对152例接受活性治疗或安慰剂治疗的患者进行了髂嵴骨活检。5例患者仅进行了定性组织学检查，留下147个活检芯（79个接受活性治疗，68个接受安慰剂治疗）用于显微CT分析和组织形态计量学分析。
通过显微CT对骨结构进行分析，发现唑来膦酸组的小梁骨体积（BV/TV）更高（中位数，16.6%对12.8%；p = 0.020）。此外，接受唑来膦酸治疗的患者小梁数量更多（p = 0.008），小梁间距减小（p = 0.011），连接密度有改善趋势（p = 0.062），所有这些都表明唑来膦酸治疗后小梁结构得到更好的保留。定性分析显示，82例接受唑来膦酸治疗患者的活检样本中有81例存在四环素标记，安慰剂组的70例活检样本全部存在四环素标记，表明骨重塑持续存在。未观察到骨病理改变。与安慰剂相比，唑来膦酸使活化频率（Ac.f；p < 0.0001）中位数降低了63%（平均值为71%），矿化表面（MS/BS；p < 0.0001）和体积参考骨形成率（BFR/BV）降低，表明骨转换减少。唑来膦酸组的矿化沉积率更高（p = 0.0002），表明与安慰剂相比成骨细胞功能有所改善。两组的矿化延迟时间相似，而唑来膦酸治疗患者中的类骨质体积（OV/BV；p < 0.0001）和类骨质厚度（O.Th；p = 0.0094）较低，表明新形成骨的类骨质形成和矿化正常。同时给予其他抗吸收性骨质疏松症治疗（如雷洛昔芬、他莫昔芬、替勃龙、依普黄酮）并未显著改变组织水平对唑来膦酸的反应。
每年静脉注射5毫克唑来膦酸，连续给药3年，可使骨转换中位数降低63%（平均值为71%），并保留骨结构和骨量，且无骨无动力的任何迹象。同时给予其他骨质疏松症治疗对骨对唑来膦酸的反应无显著影响。
