| Abstract |
Alendronate is an aminobisphosphonate with potent antiresorptive action on bone. Continuous oral administration of ALN in late menopausal women with low bone density, suppresses bone turnover [261] and induces significant and progressive [265] increase in bone density (7,4-9,6% in lumbar spine and 3,5-5,8% in femoral neck in 3 years [261-264]. As a result ALN reduces the fracture risk about 50% in osteoporotic women after menopause [264,274]. Aim of this study was to evaluate the effect of ALN on bone metabolism and bone loss in early postmenopausal period and on prevention of bone loss that follows after a hip fracture in postmenopausal women. In addition, after having studied the specific mode of action of ALN, we suggested that intermittent oral administration may suppress bone turnover efficiently and prevent bone loss, with lower cumulative dosing intake. Thus, we studied the results of intermittent cyclic administration of 10mg ALN per day for two months followed by another two months without therapy, on bone metabolism and bone density in early and late postmenopausal period. In this study, bone turnover was measured by biochemical methods and use of newer markers of bone formation and resorption. We studied menopausal bone turnover and investigated the correlation between bone markers and uncoupling index and Body mass index (BMI) after menopause. In particular, BMI was evaluated as a factor that predisposes to osteoporosis and osteoporotic hip fractures. For the previous purposes, we studied the results of ALN treatment in three different groups of menopausal women and parallel controls, who were of different age and severity of bone loss, resulting in different therapeutic goals. These groups were: a) early menopausal women with low BMD (-1,5SD T-score), where the therapeutic aim was mainly prevention of bone loss, b) >5 years menopausal women with osteoporosis, with aim to increase bone density and c) menopausal women with hip fracture, which is an osteoporotic fracture and its presence increases the risk of a new osteoporotic fracture. In particular: A) 36 early postmenopausal women, with mean age 49,28±3,5 and low BMD (<-1,5SD σε T-score) were randomly ascribed in three groups; receiving 10mg ALN and 500mg calcium per day continuously, 10mg ALN intermittently (for two months followed by another two months without therapy) and 500mg calcium daily or controls receiving daily 500mg calcium, for two years. In women on continuous therapy, BMDLS and BMDFN was significantly increased (3,93±1,86% (P=0,022) and 2,12±1,9% (Ρ=0,037), paired t-test respectively) in one year. In the intermittent group only BMDLS was slightly increased compared to controls (0,93±2,01% vs -1,94±1,73, P=0,042, ANOVA). Progressive increase during the 2nd year was observed only in BMDLS of the 1st group (0,89±1,62%, Ρ=0,047 ANOVA). Continuous dosing induced significant suppression of all bone markers about 30-50% on 12th month, while significant decrease in S-OC, U-DPD και U-NTX-I compared to controls (Ρ<0,05, ANOVA) was observed in the intermittent group on month 12. B) 45 late postmenopausal women, with mean age 64,35±6,2 and osteoporosis (BMD<-2,5SD σε T-score) were randomly allocated in three groups; receiving 10mg ALN and 500mg calcium per day continuously, 10mg ALN intermittently (for two months followed by another two months without therapy) and 500mg calcium daily or controls receiving daily 500mg calcium. After 2 years, the effect of continuous administration of ALN was +7,2±2,01% and +2,64±2,01% increase in BMDLS and BMDFN respectively compared to pre-treatment measurements (paired t-test Ρ=0,0001). Intermittent dosing increased BMDLS about 5,02±3,6% (paired t-test Ρ=0,013) and prevented bone loss in femoral neck (2,08±2,01%, paired t-test Ρ>0.05). During continuous administration, bone markers decreased early (3rd month) about 30-60% and on 2nd year they were still decreased compared to pretreatment levels (Ρ<0,038, paired t-test). During intermittent administration, bone markers showed their nadir late on month 12 and on 2nd year most of them were not significantly reduced. C) 40 postmenopausal women with recent hip fracture either received 10mg ALN and 500mg calcium per day continuously or 500mg calcium daily for one year. In women with hip fracture who received ALN, bone loss was prevented and BMDLS increased significantly compared to initial measurement (3,2+/-0,8%, paired t-test P=0,02). BMDTH was significantly increased compared to controls, who demonstrated -3,2±1,7 (P<0,018 t-test) decrease in total hip and -2,3+/-0,93% (Ρ<0,02 t-test) in spine. D) In 130 healthy postmenopausal women we investigated the correlation of BMI with bone markers, bone uncoupling index and bone density. BMDFN (P<0,0001), age (Ρ<0,0012) and BMDSP (Ρ<0,001) were positively correlated with ΒΜΙ, while S-PICP (Ρ=0,0017, R2=0,088) and age-adjusted S-OC (r=-0,185, P=0,048) were negatively correlated with BMI. Bone uncoupling indices zOC-zDPD, zPICP-zDPD, zPICP-zPYD, zPICP-zNTX-I correlated negatively with BMDLS. Uncoupling indices (zPICP-zDPD) and (zPICP-zPYD) correlated negatively with BMI (r= -0,25, P=0,01 και r= -0,21, P=0,037). Women were classified in normal (ΒΜΙ<25kg/m2), overweight (BMI=25-30kg/m2) and obese (ΒΜΙ> 30kg/m2) according to their BMI. Overweight and obese had 30% lower S-PICP levels (68,11±24,85ng/ml and 66,41±24,93ng/ml vs 97,47±23,36ng/ml P=0,0001). Obese women had also lower levels of zPICP-zDPD, zPICP-zPYD, zPICP-zCTX-Ι (ANOVA, Ρ=0,027, Ρ=0,0028, Ρ=0,02) and higher BMDLS and BMDTH compared to normals (ANOVA, Ρ=0,0004 και Ρ<0,001). In addition, 40 postmenopausal women with hip fracture were compared to 40 age-matched healthy postmenopausal women and they had significant lower BMI, BMDLS and BMDTH (t-test, P<0,0001). From the data reported above, we conclude that continuous administration of alendronate induces early and sustained suppression of bone turnover and produces significant increase in bone density, in postmenopausal women with osteoporosis and early postmenopausal women with osteopenia. Alendronate also prevents bone loss that follows a hip fracture and increases bone density in postmenopausal women with hip fracture. Intermittent administration of the same daily dose of ALN, induces smaller increase in lumbar spine and prevents bone loss from femoral neck, during the 1st year of treatment. Bone markers show smaller, delayed reduction and wider variation between subsequent measurements compared to continuous treatment. However, their levels were still reduced during the intervals without treatment, and it seems that antiresorptive action is sustained even during the free intervals. Intermittent cyclic dosing with 2 months period for one year may be used when the aim is prevention of bone and stabilization of bone density. Nevertheless our study shows that increased BMI exerts a positive effect on bone density, while decreased BMI is a predisposing factor for hip fracture. Overweight and obese women have reduced collagen I formation, as was measured by S-PICP, and reduced uncoupling indices. Since these findings are not coupled by according reduction in bone density, it seems that extraskeletal collagen formation is more sensitive in BMI variation.
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Η χρήση των νεοτέρων διφωσφονικών (Alendronate) στη θεραπεία και πρόληψη της οστεοπόρωσης
