Lees Cynthia, Shen Victor, Brommage Robert
Department of Pathology, Section on Comparative Medicine, Winston Salem, NC, USA.
Menopause. 2007 Jan-Feb;14(1):97-105. doi: 10.1097/01.gme.0000227858.50473.69.
The purpose of this study was to evaluate the effects on bone of two doses of the selective estrogen receptor modulator lasofoxifene in surgically postmenopausal cynomolgus monkeys for 24 months. The primary endpoint of this study was biomechanical testing of animals treated for 2 years.
The design of the study was a five-group (sham-ovariectomy, ovariectomy, conjugated [0.02 mg/kg], and two doses of lasofoxifene [1.0 and 5.0 mg/kg]), parallel arm design, with the treatments lasting for 24 months. Bone biomarker and estradiol data were collected at baseline and 3, 6, 12, 18, and 24 months after surgery. Vertebral bone mineral density was determined at baseline and every 6 months after ovariectomy. Hip bone density was determined at baseline and 12 and 24 months postovariectomy. Iliac bone biopsies were collected at 7 months, and the second lumbar vertebra and left femur were collected at 24 months after initiation of treatment for histomorphometric examination. The third lumbar vertebra and right femur were tested for mechanical strength after 24 months of treatment.
Lasofoxifene and conjugated estrogens prevented ovariectomy-induced increases in serum alkaline phosphatase and CrossLaps and resulted in increased vertebral (all three treatments) and hip (conjugated estrogens and high-dose lasofoxifene only) bone mineral density, although both doses of lasofoxifene exceeded the doses projected to be used in women. In the 7-month iliac biopsy specimens, both doses of lasofoxifene reduced bone turnover rates. These histomorphometric changes were not present in either the vertebral or femoral compartments measured after 24 months of treatment. Lasofoxifene-treated animals did not differ from ovariectomized controls in mechanical strength testing of either the third lumbar vertebra or right femur.
Lasofoxifene prevented ovariectomy-induced increased bone turnover and loss of bone mineral density without having a detrimental effect on bone strength.
本研究旨在评估两种剂量的选择性雌激素受体调节剂拉索昔芬对手术绝经后的食蟹猴骨骼的影响，为期24个月。本研究的主要终点是对接受2年治疗的动物进行生物力学测试。
该研究采用五组（假卵巢切除、卵巢切除、共轭雌激素[0.02mg/kg]以及两种剂量的拉索昔芬[1.0和5.0mg/kg]）平行组设计，治疗持续24个月。在基线以及术后3、6、12、18和24个月收集骨生物标志物和雌二醇数据。在基线以及卵巢切除术后每6个月测定椎体骨矿物质密度。在基线以及卵巢切除术后12和24个月测定髋部骨密度。在治疗开始后7个月采集髂骨活检样本，在治疗24个月后采集第二腰椎和左股骨进行组织形态计量学检查。在治疗24个月后对第三腰椎和右股骨进行力学强度测试。
拉索昔芬和共轭雌激素可预防卵巢切除引起的血清碱性磷酸酶和交联C端肽增加，并导致椎体（所有三种治疗）和髋部（仅共轭雌激素和高剂量拉索昔芬）骨矿物质密度增加，尽管两种剂量的拉索昔芬均超过预计用于女性的剂量。在7个月时的髂骨活检样本中，两种剂量的拉索昔芬均降低了骨转换率。在治疗24个月后测量的椎体或股骨部分中未出现这些组织形态计量学变化。在第三腰椎或右股骨的力学强度测试中，接受拉索昔芬治疗的动物与卵巢切除对照组无差异。
拉索昔芬可预防卵巢切除引起的骨转换增加和骨矿物质密度丢失，且对骨强度无不利影响。
