Academic Unit of Bone Metabolism, University of Sheffield, Sheffield, UK.
Bone. 2009 Dec;45(6):1044-52. doi: 10.1016/j.bone.2009.07.089. Epub 2009 Aug 7.
Lasofoxifene is a novel selective estrogen receptor modulator that is being developed for the treatment of postmenopausal osteoporosis. Bone mineral density (BMD) measured by dual-energy X-ray absorptiometry (DXA) is currently used to diagnose osteoporosis. BMD response to therapy, however, is often not apparent until at least one year following start of treatment. Biochemical markers of bone turnover may provide an early indication of BMD response in individual patients. The aims of the study were: 1) to determine the variability in bone turnover markers (BTM) to estimate a value for least significant change (LSC); 2) to determine the number of subjects with a response to lasofoxifene greater than LSC; 3) to determine the number of subjects whose bone turnover is decreased to the lower half of the reference range and 4) to evaluate the use of bone turnover markers to predict the change in bone density in response to lasofoxifene. Fifty-one postmenopausal osteopenic women, ages 55 to 77 (mean 63.7) years, were recruited with 44 women completing the 2 year follow up. Participants received either lasofoxifene (0.25 mg/d) or placebo, in a 1:1 ratio. Duplicate measurements of BTM (bone alkaline phosphatase (bone ALP), N-terminal propeptide of type I collagen (PINP), serum beta crosslinked C-telopeptides of type I collagen (sbeta-CTX), urinary crosslinked N-telopeptides of type I collagen (U-NTX)) were made at baseline and 6 months with single measurements at 4, 8 and 12 weeks. Duplicate measurements of BMD at the lumbar spine (LS), total hip (TH) and distal forearm (DF) were made by DXA at baseline, one and two years in all subjects. Almost all women (92 to 96%), treated with lasofoxifene, had a reduction in serum-based bone turnover markers greater than LSC, and 52 to 80% had serum-based bone turnover markers in the lower half of the reference range, by six months of lasofoxifene therapy. The change in mean LSBMD from baseline, was significantly greater in the lasofoxifene group compared to placebo at 1 and 2 years (+2.5% and +3.4%, respectively, P<0.0001). Change in PINP and U-NTX at 6 months correlated inversely with change in LS and TH BMD at one and two years. The use of lasofoxifene therapy leads to significant decreases in bone turnover by 4 weeks of lasofoxifene therapy as a group, with a decrease in BTM greater than LSC occurring in almost all women taking lasofoxifene by 6 months. By this time, in over half of women taking lasofoxifene, BTM reached the lower half of the reference range. Our results suggest that bone turnover markers are useful for monitoring response to lasofoxifene. Changes occur early and relate to the BMD response.
拉索昔芬是一种新型的选择性雌激素受体调节剂，目前正在开发用于治疗绝经后骨质疏松症。双能 X 射线吸收法 (DXA) 测量的骨密度 (BMD) 目前用于诊断骨质疏松症。然而，骨密度对治疗的反应通常至少在治疗开始后一年才明显。骨转换标志物的生化标志物可能为个体患者的骨密度反应提供早期迹象。该研究的目的是：1) 确定骨转换标志物 (BTM) 的变异性，以估计最小显著变化 (LSC) 值；2) 确定有多少接受拉索昔芬治疗的患者的反应大于 LSC；3) 确定有多少患者的骨转换降低到参考范围的下半部分；4) 评估骨转换标志物在预测拉索昔芬对骨密度的反应中的作用。51 名绝经后骨质疏松的女性，年龄 55 至 77 岁（平均 63.7 岁），按 1:1 的比例随机接受拉索昔芬（0.25mg/d）或安慰剂治疗，44 名女性完成了 2 年的随访。在基线和 6 个月时，对骨碱性磷酸酶（骨 ALP）、I 型胶原 N 端前肽（PINP）、I 型胶原交联 C 端肽（sbeta-CTX）、I 型胶原交联 N 端肽（U-NTX）等 BTM 进行了双份测量，在 4、8 和 12 周时进行了单份测量。所有受试者在基线、1 年和 2 年均通过 DXA 测量腰椎（LS）、全髋（TH）和远端前臂（DF）的 BMD。基线时，几乎所有（92%至 96%）接受拉索昔芬治疗的女性的血清骨转换标志物均低于 LSC，且 52%至 80%的女性的血清骨转换标志物处于参考范围的下半部分，拉索昔芬治疗 6 个月后。与安慰剂相比，拉索昔芬组的平均 LS 骨密度从基线开始的变化在 1 年和 2 年时均显著更大（分别增加 2.5%和 3.4%，P<0.0001）。6 个月时 PINP 和 U-NTX 的变化与 1 年和 2 年时 LS 和 TH 骨密度的变化呈负相关。拉索昔芬治疗组在拉索昔芬治疗 4 周时，骨转换明显下降，几乎所有服用拉索昔芬的女性在 6 个月时，骨转换标志物均低于 LSC。此时，超过一半服用拉索昔芬的女性的 BTM 达到参考范围的下半部分。我们的研究结果表明，骨转换标志物可用于监测拉索昔芬的反应。变化发生得很早，与 BMD 反应有关。
