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.     

Effects of raloxifene on bone mineral metabolism in postmenopausal Japanese women on hemodialysis

In addition to renal osteodystrophy, postmenopausal women on hemodialysis are at high risk for osteoporosis. Recent studies reported the effects of raloxifene, a selective estrogen receptor modulator for osteoporosis, in postmenopausal women. The present study evaluated the efficacy of raloxifene and its effects on bone mineral metabolism in postmenopausal Japanese patients on dialysis. In a prospective, multicentre study, 17 postmenopausal women on chronic hemodialysis with severe osteoporosis (bone mineral density [BMD]≤2 SD by bone densitometry) were treated with 60 mg/day raloxifene hydrochloride for 12 months. The study also included 10 age-matched control women. Vitamin D and calcium salts were not changed during the study. Intact parathyroid hormone (iPTH), serum calcium and phosphorus, and bone resorption marker (NTx) were measured, and BMD were determined by DEXA, at 0, 6, and 12 months after administration of raloxifene. The mean lumbar spine BMD at baseline was similar in the two groups. Raloxifene therapy (for 12 months) improved lumbar spine BMD (by 2.6%) in 53% of the patients, while 70% of the control group showed a reduction in BMD (by 4.0%). Raloxifene significantly decreased serum calcium and increased iPTH. Our results suggested that raloxifene improved trabecular BMD in postmenopausal Japanese women on hemodialysis. The effects of raloxifene on serum calcium and serum iPTH level suggest it improves bone resorption. Vitamin D and/or calcium salts should be added to raloxifene treatment to avoid secondary hyperparathyroidism.     

Comparison of alendronate and intranasal calcitonin for treatment of osteoporosis in postmenopausal women

This study compared the effects of oral alendronate and intranasal calcitonin for treatment of osteoporosis in postmenopausal women. Women at least 5 yr postmenopause (n = 299) were randomized to either 10 mg alendronate, matching alendronate placebo, or open-label intranasal calcitonin 200 IU daily for 12 months. Hip and spine bone mineral density (BMD) and markers of bone turnover were measured, and safety and tolerability were assessed. Alendronate produced greater increases in BMD than calcitonin at 12 months at the lumbar spine (5.16% vs. 1.18%; P < 0.001), trochanter (4.73% vs. 0.47%; P < 0.001), and femoral neck (2.78% vs. 0.58%; P < 0.001). Changes in BMD with calcitonin were greater than with placebo at the femoral neck, but were not different from placebo at either the trochanter or lumbar spine. Greater decreases in bone turnover were seen with alendronate than with calcitonin (serum bone-specific alkaline phosphatase, 43% vs. 9%, P < 0.001; urinary N-telopeptide, 62% vs. 11%, P < 0.001). Similar percentages of patients in each group reported an adverse experience during the study. We conclude that, in postmenopausal women with osteoporosis, 12 months of therapy with alendronate produced significantly greater increases in BMD of the hip and spine and greater decreases in bone turnover than intranasal calcitonin.     

Alendronate prevents loss of bone density associated with discontinuation of hormone replacement therapy: a randomized controlled trial

BACKGROUND: Many women using hormone replacement therapy (HRT) will discontinue HRT and lose its bone-protective effect. Methods to preserve bone density in these women need to be explored. This multicenter, international, randomized, blinded, 12-month study was conducted to assess the effect of alendronate sodium on bone density in women who had recently discontinued HRT. METHODS: The 144 postmenopausal women included in the study were diagnosed as having low bone mineral density (BMD) and had recently discontinued HRT. They were randomized to receive either a daily dose of 10 mg of alendronate sodium or matching placebo. The main outcome measures were spine, hip, and total body BMD; biochemical markers of bone turnover; and tolerability. RESULTS: Alendronate treatment was associated with a 2.3% mean increase (95% confidence interval [CI], 1.7%-3.0%) in spine BMD compared with a mean loss of 3.2% (95% CI, - 4.6% to - 1.7%) in patients receiving placebo, for a difference of 5.5% (95% CI, 4.2%-6.8%) between alendronate and placebo. Greater hip and total body BMD preservation was also observed with alendronate use. Bone turnover decreased significantly with alendronate (bone-specific alkaline phosphatase levels decreased by 20% and urinary N-telopeptide/creatinine ratio by 47%), but increased in the placebo group (by 18% and 36%, respectively). Alendronate was well tolerated, with no increase in adverse events compared with placebo. CONCLUSIONS: A high rate of bone loss was observed in the first 12 to 15 months after discontinuation of HRT in postmenopausal women with low BMD. Treatment with alendronate increased or maintained both spine and hip BMD and prevented the increase in bone resorption seen with withdrawal of HRT in this population.     

Addition of alendronate to ongoing hormone replacement therapy in the treatment of osteoporosis: a randomized, controlled clinical trial.

Alendronate and estrogen are effective therapies for postmenopausal osteoporosis, but their efficacy and safety as combined therapy are unknown. The objective of this study was to evaluate the addition of alendronate to ongoing hormone replacement therapy (HRT) in the treatment of postmenopausal women with osteoporosis. A total of 428 postmenopausal women with osteoporosis, who had been receiving HRT for at least 1 yr, were randomized to receive either alendronate (10 mg/day) or placebo. HRT was continued in both groups. Changes in bone mineral density (BMD) and biochemical markers of bone turnover were assessed. Compared with HRT alone, at 12 months, alendronate plus HRT produced significantly greater increases in BMD of the lumbar spine (3.6% vs. 1.0%, P < 0.001) and hip trochanter (2.7% vs. 0.5%, P < 0.001); however, the between-group difference in BMD at the femoral neck was not significant (1.7% vs. 0.8%, P = 0.072). Biochemical markers of bone turnover (serum bone-specific alkaline phosphatase and urine N-telopeptide) decreased significantly at 6 and 12 months with alendronate plus HRT, and they remained within premenopausal levels. Addition of alendronate to ongoing HRT was generally well tolerated, with no significant between-group differences in upper gastrointestinal adverse events or fractures. This study demonstrated that, in postmenopausal women with low bone density despite ongoing treatment with estrogen, alendronate added to HRT significantly increased bone mass at both spine and hip trochanter and was generally well tolerated.     

Additional beneficial effects of alendronate in growth hormone (GH)-deficient adults with osteoporosis receiving long-term recombinant human GH replacement therapy: a randomized controlled trial.

We conducted a randomized controlled trial in osteoporotic adult GH-deficient (GHD) patients to assess whether additional treatment with a bisphosphonate would further favorably influence parameters of bone turnover and bone mineral density measurements (BMD). All patients were receiving stable recombinant human (rhGH) replacement therapy for 4 yr at the start of the study. Eighteen GHD patients with osteoporosis were randomized to continue their rhGH maintenance dose or to receive combination therapy with rhGH and alendronate for 12 months. All patients were calcium and vitamin replete, and there were no changes in calcium, vitamin D, or hormone replacement therapy for the duration of the study. At baseline there were no significant differences between the alendronate and the control group in parameters of bone turnover, BMD, or prevalence of vertebral fractures. Childhood-onset and adult-onset GHD were equally distributed between the groups, with no statistical differences in age and gender or other parameters between groups. Mean serum osteocalcin, serum bone-specific alkaline phosphatase, and urinary N-telopeptide/creatinine ratio were within the normal range at the start of the study. In the alendronate group all measured parameters of bone turnover, i.e. bone-specific alkaline phosphatase, osteocalcin, and urinary N-telopeptide/creatinine ratio, significantly decreased after 6 months, with no further decrease thereafter. No changes were observed in the control group. In the alendronate-treated patients serum bone-specific alkaline phosphatase decreased from 10.9 +/- 0.9 to 6.8 +/- 0.7 microg/L at 6 months (P < 0.001), serum osteocalcin decreased from 3.9 +/- 0.4 to 1.7 +/- 0.3 microg/L (P < 0.001), and the urinary N-telopeptide/creatinine ratio decreased from 27.3 +/- 7.0 to 6.4 +/- 0.8 nmol/mmol (P = 0.01). In this group, lumbar spine BMD significantly increased from baseline by 3.4% at 6 months (P = 0.001) and by 4.4% at 12 months (P < 0.001) of treatment, with no further significant increase between 6 and 12 months (P = 0.217). No changes in lumbar spine BMD were observed in the control group. There were no significant changes in femoral neck BMD in either group for the duration of the study. No incident vertebral or peripheral fractures were documented in either group at the end of the study. In summary, this is the first report indicating that treatment with alendronate was able to significantly increase BMD at the lumbar spine in GHD patients with osteoporosis receiving stable rhGH replacement for 4 yr. This increase was significantly greater in alendronate-treated patients than in patients maintained on rhGH. The increase in lumbar spine BMD in the alendronate-treated patients was associated with a decrease in the measured markers of bone turnover, whereas these markers did not change further in the patients maintained on rhGH. This controlled study suggests that additional treatment with alendronate in GHD patients with osteoporosis receiving stable rhGH replacement therapy is effective in increasing BMD at the lumbar spine. Further investigation is required to assess whether rhGH replacement alone or combined treatment with rhGH and alendronate is able to reduce the increased fracture risk associated with GHD.     

甲状旁腺素1-34对骨质疏松大鼠治疗作用的实验研究

目的探讨甲状旁腺素134(hPTH134)对骨质疏松的治疗作用以及与血钙、磷、维生素D代谢和生长因子的关系。方法用摘除大鼠双侧卵巢的方式制备骨质疏松模型(OVX),实验动物分为4个组:模型对照组(OVX组,摘除大鼠双侧卵巢不作任何处理);hPTH134治疗组(PTH组,摘除大鼠双侧卵巢12w后用hPTH134治疗8w);盐酸雷洛昔芬治疗组(摘除大鼠双侧卵巢12w后用雷洛昔芬治疗8w);假手术组(Sham组,仅切除卵巢周围的脂肪组织约3g,术后12w纳入实验)。应用HOLOGIC第4代双能X线4500W骨密度仪测大鼠腰椎、股骨上段骨密度值(BMD);以骨形态计量学测股骨骨小梁面积、矿化沉积率;用ELISA法测定血清IGF1水平和血清25OHVitD浓度以及血淋巴细胞VitD受体(VDR)含量。结果hPTH134治疗组、盐酸雷洛昔芬治疗组均较OVX组腰椎、股骨上段骨密度增高,组间比较差异有显著性(P<0.01)。hPTH134治疗组较盐酸雷洛昔芬治疗组股骨上段骨密度增高,两组之间差异有显著性(P<0.01)。hPTH134治疗组骨小梁面积明显增加、矿化沉积率增高。hPTH134治疗组、盐酸雷洛昔芬治疗组血清IGF1浓度值、血清25OHVitD浓度值升高,与OVX组比较差异有显著性(P<0.01)。各组血淋巴细胞VDR含量无明显变化,与OVX组比较差异无显著性(P>0.05)。结论hPTH134能够预防腰椎、股骨上段骨密度丢失,使骨小梁面积明显增加、矿化沉积率增高并且血清IGF1及血清25OHVitD浓度值升高,但对VDR含量无明显作用。     

Effects of alendronate on bone mineral density and bone metabolic markers in postmenopausal asthmatic women treated with inhaled corticosteroids

We have recently shown that long-term use of inhaled corticosteroids decreases bone mineral density (BMD) of the lumbar spine in postmenopausal asthmatic women. The present study aimed to evaluate the efficacy of alendronate in comparison with that of alfacalcidol (1-alpha-hydroxyvitamin D(3)) for the treatment of BMD reduction in postmenopausal asthmatic patients who had inhaled corticosteroid therapy without regular use of systemic corticosteroids. Twenty-eight postmenopausal asthmatic patients with BMD T score of -1.0 or less were randomized to receive alendronate (5 mg/d) or alfacalcidol (1 microg/d). Bone mineral density was determined at baseline and 12 months after the treatment, and biochemical markers of bone metabolism were measured at baseline and after 6 and 12 months of treatment. The mean (+/-SD) BMD values at the lumbar spine, the total hip, and the Ward's triangle significantly increased by 4.9 +/- 4.5% (P = .0005), 2.4 +/- 2.2% (P = .0005), and 3.6 +/- 5.2% (P = .02) at 12 months in the alendronate group, whereas the corresponding values did not significantly change in the alfacalcidol group. In the alendronate group, urinary N-telopeptide (NTx), serum osteocalcin, and serum alkaline phosphatase concentrations significantly decreased, and serum intact parathyroid (PTH) level significantly increased, from baseline at both 6 and 12 months. In the alfacalcidol group, urinary NTx showed modest but significant decrease, although the extent of the change was smaller than that in the alendronate group. We concluded that alendronate was effective to improve reduced BMD in postmenopausal asthmatic patients on inhaled corticosteroid therapy through the mechanism of inhibiting bone resorption.     

Efficacy and safety of raloxifene 60 milligrams/day in postmenopausal Asian women

In healthy Caucasian postmenopausal women, raloxifene increases bone mineral density (BMD), decreases biochemical markers of bone turnover, and lowers low-density lipoprotein (LDL) cholesterol, without effects on high-density lipoprotein (HDL) cholesterol and triglycerides. This randomized, double-blind study examines the effects of raloxifene 60 mg/d (n = 483) or placebo (n = 485) in healthy postmenopausal Asian women (mean age 57 yr) from Australia, Hong Kong, India, Indonesia, Malaysia, Pakistan, Philippines, Singapore, Taiwan, and Thailand. Serum osteocalcin, serum N-telopeptide, total cholesterol, HDL cholesterol, LDL cholesterol, and triglycerides were assessed at baseline and 6 months. Lumbar spine BMD was measured at baseline and 1 yr in 309 women from 4 countries. Clinical adverse events were recorded at each interim visit. At 6 months, raloxifene 60 mg/d significantly decreased osteocalcin, N-telopeptide, total cholesterol, and LDL cholesterol by medians of 15.9%, 14.6%, 5.3%, and 7.7%, respectively, from placebo. Changes in HDL cholesterol and triglycerides were similar between raloxifene and placebo. Raloxifene 60 mg/d increased mean lumbar spine BMD (1.9%) from placebo at 1 yr (P = 0.0003). The incidences of hot flashes (placebo 3.5%, raloxifene 5.6%, P = 0.12), and leg cramps (placebo 2.7%, raloxifene 4.3%, P = 0.16) were not different between groups. No case of venous thromboembolism was reported. The effects of raloxifene 60 mg/d on bone turnover, BMD, and serum lipids in healthy postmenopausal Asian women were similar to that previously reported in Caucasian women.     

Raloxifene to prevent gonadotropin-releasing hormone agonist-induced bone loss in men with prostate cancer: a randomized controlled trial

GnRH agonists decrease bone mineral density and increase fracture risk in men with prostate cancer. Raloxifene increases bone mineral density in postmenopausal women, but its efficacy in hypogonadal men is not known. In a 12-month open-label study, men with nonmetastatic prostate cancer (n = 48) who were receiving a GnRH agonist were assigned randomly to raloxifene (60 mg/d) or no raloxifene. Bone mineral densities of the posteroanterior lumbar spine and proximal femur were measured by dual energy x-ray absorptiometry. Mean (+/-se) bone mineral density of the posteroanterior lumbar spine increased by 1.0 +/- 0.9% in men treated with raloxifene and decreased by 1.0 +/- 0.6% in men who did not receive raloxifene (P = 0.07). Bone mineral density of the total hip increased by 1.1 +/- 0.4% in men treated with raloxifene and decreased by 2.6 +/- 0.7% in men who did not receive raloxifene (P < 0.001). Similar between-group differences were observed in the femoral neck (P = 0.06) and trochanter (P < 0.001). In men receiving a GnRH agonist, raloxifene significantly increases bone mineral density of the hip and tends to increase bone mineral density of the spine.     

Aging bone and osteoporosis: strategies for preventing fractures in the elderly

As the older population increases, the incidence of osteoporotic fractures is expected to dramatically rise during the next few decades. Older patients are much more susceptible to fracture at any given bone mineral density (BMD) than are younger patients because of various factors, including the quality of aging bone, which involves more than BMD. Suppression of increased bone turnover by antiresorptive therapies, even with only small changes in BMD, can reduce fracture risk, especially in the lumbar spine. Bisphosphonate treatment can significantly reduce vertebral and nonvertebral fractures, including hip fractures, even in the very elderly. Prospective analyses show that risedronate therapy consistently and significantly reduces the risk of new morphometric vertebral fractures after 1 year in postmenopausal women. Post hoc analyses report significant reductions in the risk of 1 new clinical vertebral fracture after 6 months of risedronate therapy and after 1 year of alendronate therapy. Oral raloxifene therapy and salmon calcitonin nasal spray therapy have been shown to reduce the risk of vertebral fracture after 3 and 5 years, respectively, and post hoc data show a significant reduction in clinical vertebral fracture risk at 1 year with raloxifene use. However, neither raloxifene therapy nor calcitonin therapy reduce the risk of nonvertebral and hip fractures at currently approved doses. Bisphosphonates have been shown to be safe and efficacious with 7 years' risedronate sodium and 10 years' alendronate sodium data published, and bisphosphonates reduce bone turnover and increase BMD to a greater degree than raloxifene and calcitonin, which may partly account for their nonvertebral and hip fracture reduction effect. Therefore, bisphosphonate therapy with risedronate or alendronate should be considered in patients with low BMD at the hip and in older patients with osteoporosis and osteopenia, particularly those with an existing fracture.     

Comparative screening for thyroid disorders in old age in areas of iodine deficiency, long-term iodine prophylaxis and abundant iodine intake

OBJECTIVE The bisphosphonates have proven efficacy in the management of post-menopausal osteoporosis. However, the benefits of prolonged (<2 years) administration and the effects of discontinuation of bisphosphonate treatment are not clear. DESIGN We have previously reported a 2-year, randomized, double-blind, placebo-controlled trial of pamidronate therapy (150mg/day) in women with established post-menopausal osteoporosis. We now report the bone mineral density (BMD) changes in those women who continued for a third year of active treatment and were then observed off therapy for a further 12 months. PATIENTS Twenty-two women (mean age 66 years) continued on pamidronate in year 3, and in 16 of these the effects of subsequent discontinuation of therapy for 12 months were studied. MEASUREMENTS BMD was measured in the total body, lumbar spine and proximal femur using a Lunar DPX-L dual-energy, X-ray absorptiometer. RESULTS The third year of therapy with pamidronate was associated with a significant further gain in BMD only at the lumbar spine (2.1±0.8%, P=0.003), resulting in a total gain of 9.5±1.0% at that site over 3 years of treatment. In the total body, BMD tended to decline (?0.6±0.3%) in year 3. One year after discontinuation of pamidronate, there were significant losses of BMD in the total body (?1.9±0.3%, P<0.0001) and femoral trochanter (?2.7±0.9%, P=0.01), and non-significant changes at the lumbar spine (?0.9±0.8%), femoral neck (?0.5±1.6%), and Ward's triangle (?2.9±3.7%). By the end of one year off therapy, BMD was greater than baseline only in the lumbar spine (71±1.1%, P<0.0001) and femoral trochanter (4.5±1.88%, P<0.03). In the total body, BMD was 0.3±0.7% below the values at the trial’s inception (P=0.7). CONCLUSIONS These data demonstrate that the rate of bone gain associated with bisphosphonate use slows over time, and that significant bone loss follows withdrawal of these agents. These findings have important implications for the duration of use of these novel drugs in the therapy of osteoporosis and suggest a need for close observation following their discontinuation.     

Skeletal benefits of alendronate: 7-year treatment of postmenopausal osteoporotic women. Phase III Osteoporosis Treatment Study Group

We report here the second 2-yr extension of a clinical trial among postmenopausal women; 235 women continued blinded treatment with 5 or 10 mg alendronate daily, and 115 women who had been treated with alendronate for 5 yr were switched to blinded placebo. Continuous treatment with alendronate (10 mg daily) for 7 yr increased lumbar spine bone mineral density (BMD) by 11.4% compared to baseline. After the initial 18 months, each additional year of treatment through yr 7 increased spine BMD by 0.8% for the 10-mg dose and 0.6% for the 5-mg dose, with significant increases during yr 6-7. Previously reported increases in BMD at other skeletal sites and decreases in biochemical markers of bone turnover remained stable during yr 6-7. Among women previously taking alendronate for 5 yr who were switched to placebo, there was no significant decline in BMD at the spine or hip, whereas small, but significant, decreases in BMD at the forearm and total body and small increases in biochemical markers were observed. The safety and tolerability profiles were similar to those of placebo. This is the largest published long-term study of antiresorptive therapy. Our findings indicate that long-term alendronate treatment is well tolerated and effective for 7 yr. Increases in spinal BMD continue for at least 7 yr, and other skeletal benefits are maintained. Discontinuation does not lead to accelerated bone loss, but continuous treatment yields better skeletal benefits than shorter treatment.     

Comparison of weekly treatment of postmenopausal osteoporosis with alendronate versus risedronate over two years

OBJECTIVE: A 1-yr extension of the Fosamax Actonel Comparison Trial was completed to compare changes in bone mineral density (BMD), bone turnover, and upper gastrointestinal tolerability over 2 yr of treatment. DESIGN: This was a randomized, double-blind extension conducted at 72 U.S. sites. PATIENTS AND METHODS: Of the 1053 women who completed yr 1, 833 postmenopausal women with low BMD entered the extension, continuing their same treatment allocation [once-weekly (OW) alendronate 70 mg or OW risedronate 35 mg]. Changes in BMD at the hip trochanter, total hip, femoral neck, and lumbar spine and in markers of bone turnover were compared at 24 months. Tolerability was assessed by adverse experience reporting. RESULTS: Alendronate produced greater increases from baseline in BMD at 24 months than did risedronate at the trochanter (alendronate, 4.6%; risedronate, 2.5%, P < 0.001) as well as at all other BMD sites. Significantly more alendronate than risedronate patients had measured BMD increases of 0% or more and 3% or more at all BMD sites (P < 0.001), and fewer alendronate patients had measured decreases of 3% or more at all BMD sites. Significantly greater reductions in all biochemical markers of bone turnover occurred with alendronate, compared with risedronate. No differences were seen in occurrence or discontinuations due to upper gastrointestinal adverse experiences. CONCLUSIONS: Patients receiving 70 mg OW alendronate had greater gains in BMD, were more likely to maintain or gain BMD, and had greater reductions in bone turnover markers than patients receiving 35 mg OW risedronate after 24 months, with no differences in upper gastrointestinal tolerability.     

Alendronate in primary hyperparathyroidism: a double-blind, randomized, placebo-controlled trial

Primary hyperparathyroidism (PHPT) is often associated with reduced bone mineral density (BMD). A randomized, double-blind, placebo-controlled trial was conducted to determine whether alendronate (ALN), 10 mg daily, maintains or improves BMD in patients with PHPT. Eligible patients had asymptomatic PHPT and did not meet surgical guidelines or refused surgery. Forty-four patients randomized to placebo or active treatment arms were stratified for gender. At 12 months, patients taking placebo crossed over to active treatment. All patients were on active treatment in yr 2. The primary outcome index, BMD, at the lumbar spine (LS), femoral neck, total hip, and distal one third radius was measured every 6 months by dual-energy x-ray absorptiometry. Calcium, phosphorous, PTH, bone-specific alkaline phosphatase (BSAP) activity, urinary calcium, and urinary N-telopeptide (NTX) excretion were monitored every 3 months. Treatment with alendronate over 2 yr was associated with a significant (6.85%; micro(d) = 0.052; +/-0.94% se; P < 0.001) increase in LS BMD in comparison with baseline. Total hip BMD increased significantly at 12 months with alendronate by 4.01% (micro(d) = 0.027; +/-0.77% se; P < 0.001) from baseline and remained stable over the next 12 months of therapy. BMD at the one third radius site did not show any statistically significant change in the alendronate-treated group at 12 or 24 months of therapy. At 24 months, the alendronate-treated group showed a 3.67% (micro(d) = 0.022; +/-1.63% se; P = 0.038) gain in bone density at the femoral neck site in comparison with baseline. The placebo group, when crossed over to alendronate at 12 months, showed a significant change of 4.1% (micro(d) = 0.034; +/-1.12% se; P = 0.003) in the LS BMD and 1.7% (micro(d) = 0.012; +/-0.81% se; P = 0.009) at the total hip site in comparison with baseline. There was no statistically significant change seen in the placebo group at 12 months at any BMD site and no significant change at 24 months for the distal one third radius or femoral neck sites. Alendronate was associated with marked reductions in bone turnover markers with rapid decreases in urinary NTX excretion by 66% (micro(d) = -60.27; +/-13.5% se; P < 0.001) at 3 months and decreases in BSAP by 49% at 6 months (micro(d) = -15.98; +/-6.32% se; P < 0.001) and by 53% at 9 and 12 months (micro(d) = -17.11; +/-7.85% se; P < 0.001; micro(d) = -17.36; +/-6.96% se; P < 0.001, respectively) of therapy. In the placebo group, NTX and BSAP levels remained elevated. Serum calcium (total and ionized), PTH, and urine calcium did not change with alendronate therapy. In PHPT, alendronate significantly increases BMD at the LS at 12 and 24 months from baseline values. Significant reductions in bone turnover occur with stable serum calcium and PTH levels. Alendronate may be a useful alternative to parathyroidectomy in asymptomatic PHPT among those with low BMD.     

几种治疗绝经后妇女骨量减少干预方案疗效及安全性的比较

200例骨量减少、年龄在45～80岁的绝经后妇女随机分为4组,进行不同干预方案治疗,治疗12个月后,双膦酸盐(固邦)组骨密度提高最明显(腰椎为3.5%,全髋为2.6%,均P＜0.05),选择性雌激素受体调节剂(贝邦)组(腰椎为2.0%,P＜0.05),骨转换指标均改善(均P＜0.05),活性维生素D(萌格旺)和钙剂(钙尔奇D)组骨密度和骨转换指标均无明显改变.

Abstract：

Two hundreds postmenopausal women with osteopenia, aged 45-80, were randomly divided into 4 groups, and received different drug interventions. After treatment for 12 months, the lumbar spine bone mineral density(BMD)and total hip BMD in alendronate group increased significantly(3.5% and 2.6%, both P＜0.05), the lumbar spine BMD raised 2.0% in selective estrogen receptor regulator group(P＜0.05). Bone turnover indices improved in both groups(all P＜0.05). No change in BMD or bone turnover indices was found in patients treated with active vitamin D3and calcium.     

A comparison of the effects of raloxifene and estrogen on bone in postmenopausal women

Raloxifene HCl, a selective estrogen receptor modulator, has been shown to increase bone mineral density (BMD) and decrease biochemical markers of bone turnover in postmenopausal women without stimulatory effects on the breast and uterus. However, it is not known whether the changes in BMD and bone turnover are associated with changes at the tissue level, nor how changes with raloxifene compare with estrogen. In this randomized, double blind study, we evaluated the effects of raloxifene (Evista, 60 mg/day) or conjugated equine estrogens (CEE; Premarin, 0.625 mg/day) on bone architecture, bone turnover, and BMD. Iliac crest bone biopsies were obtained at baseline and at the end of the study after double tetracycline labeling and were analyzed for standard histomorphometric indexes. Serum and urinary biochemical markers of bone turnover were measured at baseline and at 4, 10, 18, and 24 weeks of treatment. Total body, lumbar spine, and hip BMD were measured at baseline and at the end of the study by dual energy x-ray absorptiometry. Activation frequency and bone formation rate/bone volume were significantly decreased from baseline in the CEE, but not in the raloxifene, group. Bone mineralization did not change in either group. Most markers of bone resorption and formation decreased in both groups, but to a greater degree in the CEE group (P < .05). Total body and lumbar spine BMD increased from baseline in both groups, with a greater increase in the CEE group (P < 0.05). Hip BMD significantly increased from baseline in the raloxifene group, but the change was not different from that in the CEE group. These results suggest that raloxifene reduces bone turnover and increases bone density, although to a lesser extent than CEE. Thus, raloxifene is an alternative to CEE for the prevention and treatment of osteoporosis in postmenopausal women.     

A comparison of the effects of raloxifene and conjugated equine estrogen on bone and lipids in healthy postmenopausal women

BACKGROUND: Although many studies have assessed the effects of estrogen and raloxifene hydrochloride on bone mineral density and serum lipid concentrations, there are few direct comparative data. METHODS: Randomized placebo-controlled trial for 3 years, intention-to-treat analysis. Six hundred nineteen postmenopausal women with prior hysterectomy (mean age, 53.0 years) were studied in 38 centers in Europe, North America, Australasia, and South Africa. They were randomized to 60 mg/d or 150 mg/d of raloxifene, 0.625 mg/d of conjugated equine estrogen (CEE), or placebo. Bone density of the lumbar spine and proximal femur, biochemical markers of bone turnover, and fasting serum lipid concentrations were assessed for 3 years. RESULTS: Compared with baseline, bone density in the lumbar spine progressively declined by 2.0% in the placebo group (P <.05), was stable in the 2 raloxifene groups, and increased 4.6% in the subjects receiving CEE (P <.001). Effects in both raloxifene groups were different from those observed in the CEE and placebo groups (P <.001). Bone density in the total hip showed similar results. Conjugated equine estrogen produced significantly greater depression of serum osteocalcin, bone-specific alkaline phosphatase, and urine C-telopeptide, compared with raloxifene. Each of the active treatments caused comparable depression of low-density lipoprotein cholesterol below placebo levels (P <.001 at most time points). Raloxifene did not affect high-density lipoprotein cholesterol, whereas CEE increased it by 13.4% compared with placebo at 3 years (P <.001). Triglyceride concentrations increased 24.6% in the CEE group at 3 years (P <.003), a significantly greater change than in the raloxifene groups, which were 4.9% and 8.0% above baseline (P < or =.002) but not different from placebo. Urinary incontinence was reported in 11 women receiving CEE, but in only 1 or 2 in each of the other groups (P < or =.01 compared with the other groups). Hernias occurred less frequently in those receiving 150 mg/d of raloxifene or CEE (P =.03 vs placebo). CONCLUSIONS: Raloxifene and CEE have beneficial effects on bone density and bone turnover, although effects of CEE are more marked. Raloxifene and CEE produce different patterns of lipid responses and have distinct adverse effect profiles.     

Effect of alendronate and MK-677 (a growth hormone secretagogue), individually and in combination, on markers of bone turnover and bone mineral density in postmenopausal osteoporotic women

GH increases bone turnover and stimulates osteoblast activity. We hypothesized that administration of MK-677, an orally active GH secretagogue, together with alendronate, a potent inhibitor of bone resorption, would maintain a higher bone formation rate relative to that seen with alendronate alone, thereby generating greater enhancement of bone mineral density (BMD) in women with postmenopausal osteoporosis. We determined the individual and combined effects of MK-677 and alendronate administration on insulin-like growth factor I levels and biochemical markers of bone formation (osteocalcin and bone-specific alkaline phosphatase) and resorption [urinary N-telopeptide cross-links (NTx)] for 12 months and BMD for 18 months. In a multicenter, randomized, double blind, placebo-controlled, 18-month study, 292 women (64-85 yr old) with low femoral neck BMD were randomly assigned in a 3:3:1:1 ratio to 1 of 4 daily treatment groups for 12 months: MK-677 (25 mg) plus alendronate (10 mg); alendronate (10 mg); MK-677 (25 mg); or a double dummy placebo. Patients who received MK-677 alone or placebo through month 12 received MK-677 (25 mg) plus alendronate (10 mg) from months 12-18. All other patients remained on their assigned therapy. All patients received 500 mg/day calcium. The primary results, except for BMD, are provided for month 12. MK-677, with or without alendronate, increased insulin-like growth factor I levels from baseline (39% and 45%; P < 0.05 vs. placebo). MK-677 increased osteocalcin and urinary NTx by 22% and 41%, on the average, respectively (P < 0.05 vs. placebo). MK-677 and alendronate mitigated the reduction in bone formation compared with alendronate alone based on mean relative changes in serum osteocalcin (-40% vs. -54%; P < 0.05, combination vs. alendronate) and reduced the effect of alendronate on resorption (NTx) as well (-52% vs. -61%; P < 0.05, combination vs. alendronate). MK-677 plus alendronate increased BMD at the femoral neck (4.2% vs. 2.5% for alendronate; P < 0.05). However, similar enhancement was not seen with MK-677 plus alendronate in BMD of the lumbar spine, total hip, or total body compared with alendronate alone. GH-mediated side effects were noted in the groups receiving MK-677, although adverse events resulting in discontinuation from the study were relatively infrequent. In conclusion, the anabolic effect of GH, as produced through the GH secretagogue MK-677, attenuated the indirect suppressive effect of alendronate on bone formation, but did not translate into significant increases in BMD at sites other than the femoral neck. Although the femoral neck is an important site for fracture prevention, the lack of enhancement in bone mass at other sites compared with that seen with alendronate alone is a concern when weighed against the potential side effects of enhanced GH secretion.     

Additive effects of raloxifene and alendronate on bone density and biochemical markers of bone remodeling in postmenopausal women with osteoporosis

Both raloxifene (RLX) and alendronate (ALN) can treat and prevent new vertebral fractures, increase bone mineral density (BMD), and decrease biochemical markers of bone turnover in postmenopausal women with osteoporosis. This phase 3, randomized, double-blind 1-yr study assessed the effects of combined RLX and ALN in 331 postmenopausal women with osteoporosis (femoral neck BMD T-score, less than -2). Women (aged < or = 75 yr; > or = 2 yr since their last menstrual period) received placebo, RLX 60 mg/d, ALN 10 mg/d, or RLX 60 mg/d and ALN 10 mg/d combined. At baseline, 6 and 12 months, BMD was measured by dual x-ray absorptiometry. The bone turnover markers serum osteocalcin, bone-specific alkaline phosphatase, and urinary N- and C-telopeptide corrected for creatinine were measured. The effects of RLX and ALN were considered to be independent and additive if the interaction effect was not statistically significant (P > 0.10) in a two-way ANOVA model. All changes in BMD and bone markers at 12 months were different between placebo and each of the active treatment groups, and between the RLX and RLX+ALN groups (P < 0.05). On average, lumbar spine BMD increased by 2.1, 4.3, and 5.3% from baseline with RLX, ALN, and RLX+ALN, respectively. The increase in femoral neck BMD in the RLX+ALN group (3.7%) was greater than the 2.7 and 1.7% increases in the ALN (P = 0.02) and RLX (P < 0.001) groups, respectively. The changes from baseline to 12 months in bone markers ranged from 7.1 to -16.0% with placebo, -23.8 to -46.5% with RLX, -42.3 to -74.2% with ALN, and -54.1 to -81.0% in the RLX+ALN group. RLX and ALN increased lumbar spine and femoral neck BMD, and decreased osteocalcin and C-telopeptide corrected for creatinine in an additive and independent manner, because the interaction effects were not significant. Although the ALN group had changes in BMD and bone markers that were approximately twice the magnitude as in the RLX group, it is not known how well these changes correlate to the clinical outcome of fracture. RLX+ALN reduced bone turnover more than either drug alone, resulting in greater BMD increment, but whether this difference reflects better fracture risk reduction was not assessed in this study.