Alendronate in early postmenopausal women: effects on bone mass during long-term treatment and after withdrawal. Alendronate Osteoporosis Prevention Study Group

We studied the effect on bone mass of alendronate treatment for 5 yr and its withdrawal. Four hundred and forty-seven postmenopausal women with normal bone mass entered a 3-yr randomized trial followed by a 2-yr open label extension. Three hundred and eleven women completed the first 3 yr, and 263 consented to continue and completed the extension. We are reporting data from groups using the dose of alendronate currently approved for osteoporosis prevention (5 mg) or from the group in which alendronate treatment was withdrawn: 52 women received alendronate (5 mg) for 5 yr (group I), 56 received 3 yr of placebo followed by alendronate (5 mg) for 2 yr (group II), and 52 received alendronate (20 mg) for 2 yr followed by 3 yr off therapy (group III). In group I, alendronate (5 mg) increased bone mineral density (BMD) at the spine and trochanter by 2.5-3.2% (P < 0.001 vs. baseline) and stabilized total body and femoral neck BMD (change vs. baseline, P = NS) over 5 yr. By the end of 5 yr, BMD was comparable at the spine, hip, and total body in groups I and III. The 3-yr decrease in BMD after withdrawal of alendronate (20 mg) in group III was 1.8-5.7% (P < 0.01 vs. baseline) and similar to the 3-yr decrease in BMD in group II during the initial 3 yr. In conclusion, alendronate (5 mg) for 5 yr or alendronate (20 mg) for 2 yr followed by 3 yr off therapy prevented postmenopausal bone loss. After withdrawal of alendronate (20 mg), bone loss resumed at the normal early postmenopausal rate.     

Prevention of bone loss with tibolone in postmenopausal women: results of two randomized, double-blind, placebo-controlled, dose-finding studies

Tibolone, a novel compound with tissue-specific effects, has been found to have antiresorptive properties in bone. To confirm the efficacy of tibolone and determine its minimum effective dose for prevention of bone loss in early postmenopausal women, two randomized, double-blind, placebo-controlled, dose-finding studies were performed. Seven hundred seventy healthy women postmenopausal within 1-4 yr, with normal bone density for their age, were treated for 2 yr with 0.3, 0.625, 1.25, or 2.5 mg tibolone daily or placebo. All subjects took supplemental calcium carbonate (500 mg daily). Bone mineral density (BMD) of the lumbar spine and right proximal femur was measured by dual-energy x-ray absorptiometry for up to 2 yr. At each dose level, except the lowest (0.3 mg), tibolone produced a progressive increase in lumbar spine and total hip BMD over the 2-yr treatment period; at 0.3 mg, total hip density was maintained. However, only the doses 1.25 mg and 2.5 mg produced a progressive increase in femoral neck BMD. The differences in mean percent change from baseline in spine and total hip density were significant (P < 0.05) for all tibolone dose groups compared with placebo at all time points. Tibolone was well tolerated, with a similar overall incidence of adverse events compared with placebo. Tibolone 1.25 mg per day is recommended because it shows a positive and statistically significant change in BMD of spine and femoral neck.     

Effects of resistance and aerobic exercise on physical function, bone mineral density, OPG and RANKL in older women

This study compared the effects of a resistance training protocol and a moderate-impact aerobic training protocol on bone mineral density (BMD), physical ability, serum osteoprotegerin (OPG), and receptor activator of nuclear factor kappa B ligand (RANKL) levels. Seventy-one older women were randomly assigned to resistance exercise (RE), aerobic exercise (AE) or a control group (CON). Both interventions were conducted 3 times per week for 8 months. Outcome measures included proximal femur BMD, muscle strength, balance, body composition, serum OPG, and RANKL levels. Potential confounding variables included dietary intake, accelerometer-based physical activity (PA), and molecularly defined lactase nonpersistence. After 8 months, only RE group exhibited increases in BMD at the trochanter (2.9%) and total hip (1.5%), and improved body composition. Both RE and AE groups improved balance. No significant changes were observed in OPG and RANKL levels, and OPG/RANKL ratio. Lactase nonpersistence was not associated with BMD changes. No group differences were observed in baseline values or change in dietary intakes and daily PA. Data suggest that 8 months of RE may be more effective than AE for inducing favourable changes in BMD and muscle strength, whilst both interventions demonstrate to protect against the functional balance control that is strongly related to fall risk.     

Effects of physical exercise on sex hormone binding globulin, high density lipoprotein cholesterol, total cholesterol and triglycerides in postmenopausal women.

This study was performed on 18 postmenopausal female volunteers in order to examine changes in sex hormone binding globulin (SHBG), high density lipoprotein cholesterol (HDLC), total cholesterol (TC) and serum triglyceride (TG) levels in a period of four months of moderate physical exercise. While SHBG decreased significantly (from 55.3 +/- 20.9 to 48.3 +/- 21.0 nM, P < 0.05), TG increased significantly (from 87 +/- 41.7 to 120.5 +/- 57.5 mg/dl, P < 0.001). These changes were accompanied by a significant decrease (P < 0.001) in body fat content. Other parameters such as HDL-cholesterol, TC and BMI did not change significantly. Plasma levels of SHBG were negatively correlated to serum TG both at the beginning (r = 0.492, P < 0.05) and at the end (r = 0.538, P < 0.05) of the period of moderate exercise. Also, changes in SHBG were negatively correlated with changes in BMI (r = 0.585, P < 0.05) and this could indicate that SHBG levels are more related to nutritional status than androgen/estrogen imbalance.     

Long-term effects of raloxifene on bone mineral density, bone turnover, and serum lipid levels in early postmenopausal women: three-year data from 2 double-blind, randomized, placebo-controlled trials

BACKGROUND: In postmenopausal women, raloxifene hydrochloride has favorable effects on bone and lipid metabolism and does not stimulate reproductive tissues. The studies reported herein evaluated the long-term (3-year) effects of raloxifene treatment on bone mineral density (BMD), serum lipid levels, and drug tolerability in healthy postmenopausal women. METHODS: A total of 1145 healthy European and North American postmenopausal women aged 45 through 60 years were enrolled in 2 parallel, double-blind, randomized, placebo-controlled trials of identical design and randomly assigned to receive raloxifene hydrochloride, 30, 60, or 150 mg, or placebo daily; all groups received 400 to 600 mg of elemental calcium. Assessments included measurements for BMD by dual-energy x-ray absorptiometry, markers of bone turnover, and serum lipid levels. RESULTS: Lumbar spine BMD changed from baseline to 36 months as follows: placebo (mean percentage change + SE), -1. 32% +0.22%; raloxifene, 30 mg, 0.71% +0.23%; raloxifene, 60 mg, 1. 28% +0.23%; and raloxifene, 150 mg, 1.20% +0.24%. Comparable BMD changes were observed in the hip and total body. Biochemical markers of bone turnover were suppressed by raloxifene to normal premenopausal ranges through 3 years. Serum low-density lipoprotein cholesterol was reduced 7% to 12% below baseline through 3 years. Study withdrawals due to any reason (37%) and withdrawals due to adverse events (14%) were not different among groups. The only significant adverse effect of therapy was hot flashes (25% in the 60-mg raloxifene group vs 18% in the placebo group); hot flashes were typically reported as mild and were not associated with study withdrawal (1.7% for 60-mg raloxifene vs 2.4% for placebo). CONCLUSIONS: Raloxifene preserves BMD at important skeletal sites, lowers serum low-density lipoprotein cholesterol levels, and has a tolerability profile comparable to placebo. These results indicate a favorable benefit-risk profile of raloxifene for long-term use in healthy postmenopausal women. Arch Intern Med. 2000;160:3444-3450.     

Time-dependent effects of vitamin K2 (menatetrenone) on bone metabolism in postmenopausal women

Vitamin K is known to mediate carboxylation of glutamyl residues of osteocalcin. We evaluated the effects of vitamin K2 (menatetrenone) treatment (45 mg/day) for 48 weeks on the markers of bone formation and resorption, bone mineral density (BMD), and the incidence of vertebral fractures in 34 Japanese postmenopausal women (aged 48-82 years). Serum levels of alkaline phosphatase (ALP) increased gradually and became significant at 48 weeks after menatetrenone treatment, while urinary excretion of deoxypyridinoline (DPD) decreased transiently but significantly at 4 weeks. Serum levels of both intact osteocalcin (OC) and carboxylated OC (Gla-OC) increased rapidly and significantly within 4 weeks and sustained their high values up to 48 weeks after the treatment, while those of undercarboxylated OC (Glu-OC) decreased reciprocally. These results can be interpreted to suggest that Glu-OC was converted to Gla-OC in vivo. On the other hand, lumbar BMD values showed no significant change and only one subject with a previous vertebral fracture had one newly occurring vertebral fracture. These results indicate that menatetrenone treatment of postmenopausal women constantly elevates bone formation markers as well as converts Glu-OC to Gla-OC. Thus, vitamin K2 treatment may promote bone formation, at least as measured biochemically in these subjects.     

Alendronate produces greater effects than raloxifene on bone density and bone turnover in postmenopausal women with low bone density: results of EFFECT (Efficacy of FOSAMAX versus EVISTA Comparison Trial) International

OBJECTIVES: Alendronate and raloxifene are antiresorptive agents with different mechanisms of action, each used to treat osteoporosis in postmenopausal women. This study was undertaken to compare the efficacy and tolerability of alendronate to raloxifene in postmenopausal women with low-bone density. DESIGN: Randomized, double-masked, double-dummy multicentre international study. SETTING: Clinical trial centres in Europe, South America and Asia-Pacific. SUBJECTS: A total of 487 postmenopausal women with low bone density, based on bone mineral density (BMD) of the lumbar spine or hip (T-score < or =-2.0). Interventions. Patients received either alendronate 70 mg once weekly and daily placebo identical to raloxifene or raloxifene 60 mg daily and weekly placebo identical to alendronate for 12 months. MAIN OUTCOME MEASURES: Evaluations included BMD of the lumbar spine and hip and markers of bone turnover at 6 and 12 months and adverse event reporting. RESULTS: Alendronate demonstrated substantially greater increases in BMD than raloxifene at both lumbar spine and hip sites at 12 months. Lumbar spine BMD increased 4.8% with alendronate vs. 2.2% with raloxifene (P < 0.001). The increase in total hip BMD was 2.3% with alendronate vs. 0.8% with raloxifene (P < 0.001). Reductions in bone turnover were significantly larger with alendronate than raloxifene. Overall tolerability was similar, however, the proportion of patients reporting vasomotor events was significantly higher with raloxifene (9.5%) than with alendronate (3.7%, P = 0.010). The proportion of patients reporting gastrointestinal events was similar between groups. CONCLUSION: In postmenopausal women with low bone density, improvements in BMD and markers of bone turnover were substantially greater during treatment with alendronate compared to raloxifene.     

Long-term 1,25(OH)2 vitamin D therapy increases bone mineral density in osteopenic women. Comparison with the effect of plain vitamin D

BACKGROUND AND AIMS: Although the bone protective effect of vitamin D has been studied intensively, the usefulness of 1,25(OH)2D3 in treating osteoporosis is still questionable. The aim of the present prospective study was to evaluate the effect of a standard pharmacological dose of 1,25(OH)2D3 in postmenopausal unsubstituted women. METHODS: Our study group comprised 52 post-menopausal women with low normal or osteopenic values of bone mineral density (BMD). Thirty-two of them were treated with 1,25(OH)2D3 for 3 years. In parallel, another group of women was treated with cholecalciferol (n=20). Vitamin D adequacy before administration of 1,25(OH)2D3 and compliance with treatment were checked by serum PTH levels, which were assessed at the start and three times in the course of treatment. RESULTS: Increase in BMD at the spine at the end of the 1st, 2nd and 3rd years of treatment with 1,25(OH)2D3 (expressed as a percentage of the value before treatment) was higher, but did not significantly differ from the effect of plain vitamin D. A significant increase in BMD at the hip at the end of the 3rd (but not the 1st and 2nd) year of treatment with 1,25(OH)2D3 was found (p<0.05, compared with the effect of plain vitamin D). The protective effect of cholecalciferol was found only on spine but not hip BMD. CONCLUSION: The study supports the hypothesis that long-term administration of 1,25(OH)2D3 is effective in treating low bone mass in postmenopausal women.     

Comparative efficacy of hormone replacement therapy, etidronate, calcitonin, alfacalcidol, and vitamin K in postmenopausal women with osteoporosis: The Yamaguchi Osteoporosis Prevention Study

PURPOSE: To assess the comparative effectiveness of several medications on bone mineral density, biochemical bone markers, and the incidence of vertebral fractures in postmenopausal women with osteoporosis. METHODS: A total of 396 postmenopausal women, aged 50 to 75 years, were allocated randomly to six equal-sized groups: hormone replacement therapy, etidronate, eel calcitonin, alfacalcidol, vitamin K (menatetrenone), or control (no treatment). Thoracic and lumbar spine radiographs, bone mineral density at the distal radius, and markers of bone turnover were assessed at baseline and every 3 months during the 2-year study. RESULTS: Compared with baseline, the 2-year mean changes in bone mineral density were 2.0% for hormone replacement therapy, -0.5% for etidronate, 1.6% for calcitonin, -3.6% for alfacalcidol, -1.9% for vitamin K, and -3.3% for control. Seventeen (26%) of the 66 control patients developed new vertebral fractures. Compared with controls, the relative risks of vertebral fracture were 0.35 (95% confidence interval [CI]: 0.14 to 0.83) for hormone replacement therapy, 0.40 (95% CI: 0.17 to 0.92) for etidronate, 0.41 (95% CI: 0.17 to 0.93) for calcitonin, 0.56 (95% CI: 0.26 to 1.12) for alfacalcidol, and 0.44 (95% CI: 0.20 to 0.99) for vitamin K. CONCLUSION: We observed significant reductions in the incidence of vertebral fractures with hormone replacement therapy, etidronate, and calcitonin, and significant improvements in bone mineral density with hormone replacement therapy and calcitonin.     

绝经后妇女体力活动与桡骨骨密度、皮质厚度和相关骨代谢指标关系的研究

目的　探讨绝经后女性日常体力活动与桡骨骨密度 (BMD)、皮质厚度和相关骨代谢指标的关系。　方法　以单纯随机抽样的方法 ,抽取江门市 12家工厂和企事业单位自然绝经的女性职工 137名作为研究对象 ,采用标准化的体力活动问卷MOSPA评价其体力活动水平 ,并测量有关桡骨皮质骨结构指标和相关骨代谢指标。　结果　在校正年龄、体质指数 (BMI)、血清雌二醇、膳食钙和维生素D摄入水平等因素后 ,高体力活动组女性的桡骨BMD〔分别为 (0 5 88± 0 0 0 7)、(0 6 34±0 0 0 4 )g/cm2 〕和骨皮质指数均高于低体力活动组 ,而其骨髓腔宽度则低于低体力活动组 (P <0 0 5 ) ,但两组间的血清钙、磷、碱性磷酸酶 (AKP)、抗酒石酸盐酸性磷酸酶 (TRAP)以及空腹尿钙和肌酐比较 ,差异均无显著性 (P >0 0 5 )。与低体力活动组相比较 ,高体力活动组的TRAP有下降趋势。　结论　绝经后妇女体力活动与桡骨BMD、骨皮质厚度呈正相关关系     

Homocysteine, bone mineral density, and fracture risk over 2 years of followup in women with and without systemic lupus erythematosus

OBJECTIVE: To examine the relationship of baseline homocysteine levels with bone mineral density (BMD) and incidence of fractures over 2 years in women with and without systemic lupus erythematosus (SLE). METHODS: Women with SLE (n = 100) and without SLE (n = 100) were matched according to age (+/- 5 yrs), race, and menopausal status. Data were collected from 1997 to 2004, including hip, lumbar spine (L-spine), and distal forearm BMD, serum homocysteine levels, and a self-administered questionnaire on osteoporosis risk factors, medications and symptomatic fractures at baseline and 2-year followup. Analyses were performed to compare homocysteine levels, BMD, and incident fractures and to evaluate the relationship of homocysteine with BMD and incident fractures in both groups. RESULTS: Mean homocysteine +/- SD was higher (p < 0.001) in women with SLE (9.88 +/- 3.8 micromol/l) than in women without SLE (7.98 +/- 2.6 micromol/l). Women with SLE had significantly lower L-spine BMD Z-scores, while hip BMD Z-scores and distal forearm BMD T-scores were nonsignificantly lower than in women without SLE. No significant correlations were observed between homocysteine and BMD in either group. Thirteen women with SLE experienced new fractures, while 4 women without SLE had new fractures over 2 years (p = 0.035); however, there was no association between homocysteine levels and incident fractures in either group. CONCLUSION:Women with SLE had significantly greater baseline homocysteine, lower L-spine BMD, and more new fractures over 2 years, compared with women without SLE. Homocysteine levels were not significantly associated with BMD and did not predict new fractures in women with or without SLE over 2 years.     

Prevalence of depressive symptoms in postmenopausal women with low bone mineral density and/or prevalent vertebral fracture: results from the Multiple Outcomes of Raloxifene Evaluation (MORE) study

OBJECTIVE: To examine the prevalence of depressive symptoms in a cross-sectional study of postmenopausal women with osteoporosis with and without prevalent vertebral fracture. METHODS: Participants were a subset of English-speaking women (n = 3798, mean age 66.7 yrs) from the Multiple Outcomes of Raloxifene Evaluation trial, who had low bone mineral density (BMD) and/or prevalent vertebral fractures. Vertebral fractures were measured at baseline by radiography using a semiquantitative technique. Depressive symptoms were assessed at baseline using the Geriatric Depression Scale (GDS), a valid and reliable scale for depression screening in elderly patients. Women were considered as probably depressed if > or = 6 symptoms of depression were reported. RESULTS: Postmenopausal women with prevalent vertebral fracture reported more depressive symptoms as assessed by the GDS than women without prevalent vertebral fracture (1.54 vs 1.26; p = 0.001). There was an absolute increase of 2.5% (p = 0.008) in the prevalence of probable depression (GDS score > or = 6) in women with prevalent fracture compared to those without prevalent fracture. The prevalence of probable depression was 4.1% among women without prevalent vertebral fracture and 6.6% in women with a prevalent vertebral fracture. The prevalence of probable depression was 3-fold higher in women with at least 3 prevalent vertebral fractures compared to women without prevalent fracture (12.8% vs 4.1%; p < 0.001). CONCLUSION: Postmenopausal women with prevalent vertebral fractures had greater prevalence of depressive symptoms and probable depression as assessed by the GDS than women without vertebral fracture with low BMD. The dual diagnosis of depression and osteoporosis may mean worse health outcomes. Patients with prevalent vertebral fractures may be considered not only for interventions that address fracture risk reduction, but also for psychosocial interventions that address depressive symptoms.     

Long-term effects of exercise on blood pressure and lipids in healthy women aged 40-65 years: The Sedentary Women Exercise Adherence Trial (SWEAT)

OBJECTIVES: To evaluate the long-term effects of regular moderate or vigorous intensity exercise on blood pressure and blood lipids in previously sedentary older women. DESIGN: Subjects were randomly assigned to either a supervised centre-based (CB) or a minimally supervised home-based (HB) exercise program, initially for 6 months. Within each program, subjects were further randomized to exercise either at moderate (40-55% heart rate reserve, HRres) or vigorous intensity (65-80% HRres). After 6 months, all groups continued a HB moderate or vigorous exercise program for another 12 months. METHODS: Healthy, sedentary women (aged 40-65 years) (n = 126) were recruited from the community. Subjects exercised three times per week for 30 min. They were evaluated at baseline, 6, 12 and 18 months. RESULTS: There was a significant fall of 2.81 mmHg in systolic blood pressure (P = 0.049) and 2.70 mmHg in diastolic blood pressure (P = 0.004) after correction for age and baseline values with moderate exercise, but not with vigorous-intensity exercise. When this analysis was repeated with the change in body mass included, the results were unchanged. After correction for potential confounding factors, there was a significant fall in total cholesterol and low density lipoprotein cholesterol with vigorous but not moderate exercise at 6 months (P < 0.05) but not at 18 months. CONCLUSIONS: In this largely normotensive population of older women, a moderate, but not vigorous exercise program, achieved sustained falls in resting systolic and diastolic blood pressure over 18 months. The study demonstrates that, in older women, moderate intensity exercise is well accepted, sustainable long-term and has the health benefit of reduced blood pressure.     

The association between physical activity, cardiorespiratory fitness, and lipoprotein(a) concentrations in a tri-ethnic sample of women: The Cross-Cultural Activity Participation Study

The purpose of this cross-sectional study was threefold: (1) to examine ethnic differences in plasma lipoprotein(a) [Lp(a)] concentrations; (2) to examine the relationship between physical activity levels (moderate, moderate-vigorous, and total MET-min/day) and Lp(a) concentrations; and (3) to determine the relationship between maximal treadmill time and Lp(a) concentrations among African-American, Native American, and Caucasian women (n=140, ages 40-70 years: 54.5+/-10.7). Physical activity records were kept for two 4-day periods, scheduled 1 month apart, a total of 8 days, and each activity was assigned a code from the 'Compendium of physical activity'. Subjects completed a graded exercise test to determine maximal treadmill time, and a fasted blood sample was collected to quantify Lp(a) concentration. Lp(a) concentrations were negatively skewed with a geometric mean of 28.3 mg/dl (25-75%: 10.4-43.1 mg/dl) in African-Americans (n=47), 2.9 mg/dl (25-75%: 1.2-7.4 mg/dl) in Native Americans (n=45), and 9.4 mg/dl (25-75%: 2.6-22.4 mg/dl) in Caucasians (n=48). African-American women had significantly higher (p<0.05) Lp(a) concentrations than either Native Americans or Caucasians. No relationships were observed among moderate, moderate-vigorous, and total MET-min/day of physical activity, maximal treadmill time, and Lp(a) concentrations. Significant ethnic differences in Lp(a) concentrations were found, with African-American women having higher Lp(a) concentrations than Native American and Caucasian women. Lp(a) concentrations were not associated with any physical activity variables. Therefore, physical activity and maximal treadmill time did not influence Lp(a) concentrations in this tri-ethnic population of women.     

The relationship of total body bone mineral (TBBMC) to anthropometric variables in postmenopausal women,and contribution of chronological age and years since menopause to TBBMC loss

Summary Dual energy X-ray absorptiometry measurements of total body bone mineral content (TBBMC), fat body mass (FBM) and fat mass percentage (%FM), lean body mass (LBM) and body weight (BW) were performed on 168 normal postmenopausal females. They were matched regarding life style and habits and had body mass index under 30. Their TBBMCs were correlated with these measurements, with chronological age (CA) and with the number of years since menopause (YSM).There was no correlation between TBBMC and %FM and LBM, but there was with BW (p<0.001). There was a significant and negative correlation (r=–0.453, p<0.01) between TBBMC and CA and to a higher range (r=–0.697, p<0.001) with YSM. Menopausal females over 60 (n=87) presented less bone mass than younger females (n=81) (p<0.01). These data suggest that regarding TBBMC, menopausal onset is a more important factor in bone mass loss, which persists rather markedly even during periods of time far from menopause and that TBBMC depends more on BW than on LBM and FM in women.