Effects of bazedoxifene on bone mineral density,bone turnover,and safety in postmenopausal japanese women with osteoporosis

This randomized, double‐blind, placebo‐controlled, dose‐response late phase 2 study evaluated the efficacy and safety of bazedoxifene in postmenopausal Japanese women 85 years of age or younger with osteoporosis. Eligible subjects received daily treatment with oral doses of bazedoxifene 20 or 40 mg or placebo for 2 years. Efficacy assessments included bone mineral density (BMD) at the lumbar spine and other skeletal sites, bone turnover marker levels, lipid parameters, and incidence of new fractures. Of 429 randomized subjects, 387 were evaluable for efficacy, and 423 were included in the safety analyses (mean age, 64 years). At 2 years, the mean percent changes from baseline in lumbar spine BMD were significantly greater with bazedoxifene 20 and 40 mg (2.43% and 2.74%, respectively) than with placebo (?0.65%, p < .001 for both). Both bazedoxifene doses significantly improved BMD at the total hip, femoral neck, and greater trochanter compared with placebo (p < .001 for all). Decreases in bone turnover markers were observed with bazedoxifene 20 and 40 mg as early as 12 weeks (p < .05 for all) and were sustained throughout the study. Total and low‐density lipoprotein cholesterol levels were significantly decreased from baseline with both bazedoxifene doses compared with placebo (p < .05 for all). Incidences of new vertebral and nonvertebral fractures were similar among the bazedoxifene and placebo groups. Overall, the incidence of adverse events with bazedoxifene 20 and 40 mg was similar to that with placebo. Bazedoxifene significantly improved BMD, reduced bone turnover, and was well tolerated in postmenopausal Japanese women with osteoporosis. © 2011 American Society for Bone and Mineral Research.     

Two-year treatment with denosumab (AMG 162) in a randomized phase 2 study of postmenopausal women with low BMD.

Denosumab is a monoclonal antibody to RANKL. In this randomized, placebo-controlled study of 412 postmenopausal women with low BMD, subcutaneous denosumab given every 3 or 6 mo was well tolerated, increased BMD, and decreased bone resorption markers for up to 24 mo. Continued study of denosumab is warranted in the treatment of low BMD in postmenopausal women. INTRODUCTION: Denosumab is a fully human monoclonal antibody that inhibits RANKL, a key mediator of osteoclastogenesis and bone remodeling. This prespecified exploratory analysis evaluated the efficacy and safety of denosumab through 24 mo in the treatment of postmenopausal women with low BMD. MATERIALS AND METHODS: Four hundred twelve postmenopausal women with lumbar spine BMD T-scores of -1.8 to -4.0 or femoral neck/total hip T-scores of -1.8 to -3.5 were randomly assigned to receive double-blind, subcutaneous injections of placebo; denosumab 6, 14, or 30 mg every 3 mo; denosumab 14, 60, 100, or 210 mg every 6 mo; or open-label oral alendronate 70 mg once weekly. Outcome measures included BMD at the lumbar spine, total hip, distal one-third radius, and total body; bone turnover markers; and safety. RESULTS: Denosumab increased BMD at all measured skeletal sites and decreased concentrations of bone turnover markers compared with placebo at 24 mo. At the lumbar spine, BMD increases with denosumab ranged from 4.13% to 8.89%. BMD changes with denosumab 30 mg every 3 mo and > or =60 mg every 6 mo were similar to, or in some cases greater than, with alendronate. The incidence of adverse events was similar in the placebo, denosumab, and alendronate treatment groups. Exposure-adjusted adverse events over 2 yr of treatment were similar to those reported during the first year of treatment. CONCLUSIONS: In these postmenopausal women with low BMD, treatment with denosumab for 2 yr was associated with sustained increases in BMD and reductions in bone resorption markers compared with placebo.     

Once‐Weekly Risedronate in Men With Osteoporosis: Results of a 2‐Year,Placebo‐Controlled,Double‐Blind,Multicenter Study

Male osteoporosis is increasingly recognized as a major public health issue. This multinational, 2‐yr, randomized, double‐blind, placebo‐controlled study was conducted to determine the efficacy and safety of 35 mg once‐a‐week risedronate in men with osteoporosis. Patients had to be men ≥30 yr old, with lumbar spine T‐score ≤ ?2.5 and femoral neck T‐score ≤ ?1 SD or lumbar spine T‐score ≤ ?1 and femoral neck T‐score ≤ ?2 SD (based on young normal men). Patients were randomized 2:1 to risedronate 35 mg once a week or placebo for 2 yr; all patients took 1000 mg elemental calcium and 400–500 IU vitamin D daily. Lumbar spine BMD at month 24 using last observation carried forward was the primary endpoint. Other endpoints included lumbar spine BMD at time points other than month 24, proximal femur BMD, bone turnover markers (BTMs), new vertebral fractures, clinical fractures, and adverse event (AE) assessment. There were 284 men enrolled in the study. Treatment with risedronate resulted in a significant increase from baseline to endpoint in lumbar spine BMD compared with placebo (4.5%; 95% CI: 3.5%, 5.6%; p < 0.001). Few new vertebral and nonvertebral fractures were reported, with no differences in fracture rates between the two groups. There was a significant (p < 0.01) reduction from baseline in BTMs for the risedronate group compared with placebo at all time points. No apparent differences in the pattern or distribution of AEs including serious and upper gastrointestinal AEs were observed. Risedronate therapy was well tolerated during this 2‐yr study and was rapidly effective as indicated by significant BTM decreases at month 3 and BMD increases at month 6 (the earliest time points tested). The effects of risedronate treatment on BMD and BTMs in this study were similar to those previously shown to be associated with fracture risk reductions in women with postmenopausal osteoporosis.     

Treatment of Postmenopausal Women with Osteoporosis or Low Bone Density with Raloxifene

Raloxifene, a selective estrogen receptor modulator (SERM), has been shown to improved bone mineral density (BMD) and serum lipid profiles in healthy postmenopausal women. The objective of this study was to examine the effects of raloxifene on BMD, biochemical markers of bone metabolism and serum lipids in postmenopausal women with low bone density or osteoporosis. This Phase II, multicenter, 24-month, double-masked study assessed the efficacy and safety of raloxifene in 129 postmenopausal women (mean age ± SD: 60.2 ± 6.7 years) with osteoporosis or low bone density (baseline mean lumbar spine BMD T-score: −2.8). Women were randomly assigned to one of three treatment groups: placebo, 60 mg/day raloxifene-HCl (RLX 60) or 150 mg/day raloxifene-HCl (RLX 150) and concomitantly received 1000 mg/day calcium and 300 U/day vitamin D₃. At 24 months, BMD was significantly increased in the lumbar spine (+3.2%), femoral neck (+2.1%), trochanter (+2.7%) and total hip (+1.6%) in the RLX 60 group compared with the placebo group (p<0.05). The RLX 150 group had increases in BMD similar to those observed with RLX 60. A greater percentage of raloxifene-treated patients, compared with those receiving placebo, had increased BMD (p<0.05). Serum bone-specific alkaline phosphatase activity, serum osteocalcin, and urinary type I collagen:creatinine ratio were significantly decreased in the RLX-treated groups, compared with the placebo group (p<0.01). RLX 60 treatment significantly decreased serum levels of triglycerides, and total- and LDL-cholesterol levels (p<0.01). The rates of patient discontinuation and adverse events were not significantly different among groups. In this study, raloxifene increased bone density, decreased bone turnover, and improved the serum lipid profile with minimal adverse events, and may be a safe and effective treatment for postmenopausal women with osteoporosis or low bone density. Received: 26 December 1998 / Accepted: 31 March 1999     

Epimedium-derived phytoestrogen flavonoids exert beneficial effect on preventing bone loss in late postmenopausal women: a 24-month randomized, double-blind and placebo-controlled trial.

Epimedium brevicornum maxim, a nonleguminous medicinal plant, has been found to be rich in phytoestrogen flavonoids. Results from a 24-month randomized double-blind placebo-controlled clinical trial showed that Epimedium-derived phytoestrogen flavonoids were able to exert beneficial effects on preventing bone loss in late postmenopausal women, without resulting in a detectable hyperplasia effect on the endometrium. INTRODUCTION: We performed a 24-mo randomized double-blind placebo-controlled clinical trial for evaluating the effect of the Epimedium-derived phytoestrogen flavonoids (EPFs) on BMD, bone turnover biochemical markers, serum estradiol, and endometrial thickness in postmenopausal women. MATERIALS AND METHODS: One hundred healthy late postmenopausal women, with a natural menopausal history within 10 approximately 18 yr and with a BMD T-score at the lumbar spine between -2 and -2.5 SD, were randomized into EPF treatment group (n = 50; a daily dose of 60 mg Icariin, 15 mg Daidzein, and 3 mg Genistein) or placebo control group (n = 50). All participants received 300 mg element calcium daily. BMD, bone turnover biochemical markers, serum estradiol, and endometrial thickness were measured at baseline and 12 and 24 mo after intervention. RESULTS: Eighty-five participants completed the trial. The patterns of BMD changes were significantly different between the EPF treatment group and placebo control group by repeated-measures ANOVA (p = 0.045 for interaction between time and group at femoral neck; p = 0.006 for interaction between time and group at lumbar spine). BMD was found with a decreased tendency in the placebo control group at 12 (femoral neck: -1.4%, p = 0.104; lumbar spine: -1.7%, p = 0.019) and 24 mo (femoral neck: -1.8%, p = 0.048; lumbar spine: -2.4%, p = 0.002), whereas EPF treatment maintained BMD at 12 (femoral neck: 1.1%, p = 0.285; lumbar spine:1.0%, p = 0.158) and 24 mo (femoral neck: 1.6%, p = 0.148; lumbar spine: 1.3%, p = 0.091). The difference in lumbar spine between the two groups was significant at both 12 (p = 0.044) and 24 mo (p = 0.006), whereas the difference in the femoral neck was marginal at 12 mo (p = 0.061) and significant at 24 mo (p = 0.008). Levels of bone biochemical markers did not change in the placebo control group. In contrast, EPF intervention significantly decreased levels of deoxypyrdinoline at 12 (-43%, p = 0.000) and 24 mo (-39%, p = 0.000), except for osteocalcin at 12 (5.6%, p = 0.530) and 24 mo (10.7%, p = 0.267). A significant difference in deoxypyrdinoline between the two groups was found at both 12 (p = 0.000) and 24 mo (p = 0.001). Furthermore, neither serum estradiol nor endometrial thickness was found to be changed in either groups during the clinical trial. CONCLUSIONS: EPFs exert a beneficial effect on preventing bone loss in late postmenopausal women without resulting in a detectable hyperplasia effect on the endometrium.     

Comparison of the Effect of Denosumab and Alendronate on BMD and Biochemical Markers of Bone Turnover in Postmenopausal Women With Low Bone Mass: A Randomized,Blinded, Phase 3 Trial

Denosumab is a fully human monoclonal antibody that inhibits bone resorption by neutralizing RANKL, a key mediator of osteoclast formation, function, and survival. This phase 3, multicenter, double‐blind study compared the efficacy and safety of denosumab with alendronate in postmenopausal women with low bone mass. One thousand one hundred eighty‐nine postmenopausal women with a T‐score ≤ ?2.0 at the lumbar spine or total hip were randomized 1:1 to receive subcutaneous denosumab injections (60 mg every 6 mo [Q6M]) plus oral placebo weekly (n = 594) or oral alendronate weekly (70 mg) plus subcutaneous placebo injections Q6M (n = 595). Changes in BMD were assessed at the total hip, femoral neck, trochanter, lumbar spine, and one‐third radius at 6 and 12 mo and in bone turnover markers at months 1, 3, 6, 9, and 12. Safety was evaluated by monitoring adverse events and laboratory values. At the total hip, denosumab significantly increased BMD compared with alendronate at month 12 (3.5% versus 2.6%; p < 0.0001). Furthermore, significantly greater increases in BMD were observed with denosumab treatment at all measured skeletal sites (12‐mo treatment difference: 0.6%, femoral neck; 1.0%, trochanter; 1.1%, lumbar spine; 0.6%, one‐third radius; p ≤ 0.0002 all sites). Denosumab treatment led to significantly greater reduction of bone turnover markers compared with alendronate therapy. Adverse events and laboratory values were similar for denosumab‐ and alendronate‐treated subjects. Denosumab showed significantly larger gains in BMD and greater reduction in bone turnover markers compared with alendronate. The overall safety profile was similar for both treatments.     

Odanacatib,a cathepsin‐K inhibitor for osteoporosis: A two‐year study in postmenopausal women with low bone density

Cathepsin K, a cysteine protease expressed in osteoclasts, degrades type 1 collagen. Odanacatib selectively and reversibly inhibited cathepsin K and rapidly decreased bone resorption in preclinical and phase I studies. A 1‐year dose‐finding trial with a 1‐year extension on the same treatment assignment was performed in postmenopausal women with low bone mineral density (BMD) to evaluate the safety and efficacy of weekly doses of placebo or 3, 10, 25, or 50 mg of odanacatib on BMD and biomarkers of skeletal remodeling. Women with BMD T‐scores of ?2.0 or less but not less than ?3.5 at the lumbar spine or femoral sites were randomly assigned to receive placebo or one of four doses of odanacatib; all received vitamin D with calcium supplementation as needed. The primary endpoint was percentage change from baseline lumbar spine BMD. Other endpoints included percentage change in BMD at hip and forearm sites, as well as changes in biomarkers of skeletal remodeling. Twenty‐four months of treatment produced progressive dose‐related increases in BMD. With the 50‐mg dose of odanacatib, lumbar spine and total‐hip BMD increased 5.5% and 3.2%, respectively, whereas BMD at these sites was essentially unchanged with placebo (?0.2% and ?0.9%). Biochemical markers of bone turnover exhibited dose‐related changes. The safety and tolerability of odanacatib generally were similar to those of placebo, with no dose‐related trends in any adverse experiences. In summary, 2 years of weekly odanacatib treatment was generally well‐tolerated and increased lumbar spine and total‐hip BMD in a dose‐related manner in postmenopausal women with low BMD. © 2010 American Society for Bone and Mineral Research     

Similar proportions of women lose bone mineral density with raloxifene or alendronate treatment.

The ISCD recommends that bone mineral density (BMD) be monitored in patients undergoing antiresorptive therapy to identify patients with a significant BMD loss. This analysis compares the proportions of postmenopausal women treated with raloxifene 60 mg/d (n=82) or alendronate 10 mg/d (n=83) who had significant BMD loss in a randomized, double-blind, placebo-controlled trial that assessed changes in lumbar spine and femoral neck BMD from baseline to 1 yr, measured using dual-energy X-ray absorptiometry. According to ISCD criteria, significant BMD loss was defined as greater than the least significant change, calculated as precision multiplied by 2.77 (95% confidence interval). Assuming a 1% precision at the lumbar spine, the proportions of women with a loss of BMD greater than the least significant change (3%) were similar (p>0.05) between the raloxifene (3%) and alendronate (2%) groups. Assuming 2% precision at the femoral neck, the proportions of women with a loss greater than the least significant change (6%) were similar (p>0.05) between the raloxifene (1%) and alendronate (2%) groups. In conclusion, similar proportions of women did not respond to raloxifene or alendronate therapy, as measured by changes in lumbar spine or femoral neck BMD, when precision error was taken into account.     

Effect of raloxifene after recombinant teriparatide [hPTH(1–34)] treatment in postmenopausal women with osteoporosis

Summary Loss of bone mineral density occurs after discontinuation of teriparatide, if no subsequent treatment is given. Sequential raloxifene prevented rapid bone loss at lumbar spine and further increased bone mineral density (BMD) at femoral neck, whether raloxifene was started immediately or after a one-year delay following teriparatide treatment. Introduction We compared the sequential effects of raloxifene treatment with a placebo on teriparatide-induced increases in bone mineral density (BMD). A year of open-label raloxifene extended the study to assess the response with and without delay after discontinuation of teriparatide. Methods Following a year of open-label teriparatide 20 μg/day treatment, postmenopausal women with osteoporosis were randomly assigned to raloxifene 60 mg/day (n = 157) or a placebo (n = 172) for year 2, followed by a year of open-label raloxifene. BMD was measured by dual energy x-ray absorptiometry. Results The raloxifene and placebo groups showed a decrease in lumbar spine (LS) BMD in year 2 for raloxifene and placebo groups (−1.0 ± 0.3%, P = 0.004; and −4.0 ± 0.3%, P < 0.001, respectively); the decrease was less with raloxifene (P < 0.001). Open-label raloxifene treatment reversed the LS BMD decrease with a placebo, resulting in similar decreases 2 years after randomization (−2.6 ± 0.4% (raloxifene-raloxifene) and −2.7 ± 0.4% (placebo-placebo). At study end, LS and femoral neck (FN) BMD were higher than pre-teriparatide levels, with no significant differences between the raloxifene-raloxifene and placebo-raloxifene groups, respectively (LS: 6.1 ± 0.5% vs. 5.1 ± 0.5%; FN: 3.4 ± 0.6% vs. 3.0 ± 0.5%). Conclusion Sequential raloxifene prevented rapid bone loss at the LS and increased FN BMD whether raloxifene was started immediately or after a one-year delay following teriparatide treatment. Preliminary data presented previously at the International Osteoporosis Foundation World Congress on Osteoporosis, Toronto Canada June 2–6, 2006, abstract published: Adami S, Munoz-Torres M, Econs MJ, Sipos A, Xie L, Dalsky GP, McClung M, Felsenberg D, Brown JP, Brandi ML, San Martin J. Effect of raloxifene after teriparatide treatment in postmenopausal women with osteoporosis. Osteoporos Int. 2006;17(Suppl 2):S137.     

Effect of low‐dose calcium supplements on bone loss in perimenopausal and postmenopausal Asian women: A randomized controlled trial

Current standard‐dose calcium supplements (eg, 1000 mg/d) may increase the risk for cardiovascular events. Effectiveness of lower‐dose supplements in preventing bone loss should thus be considered. This study aimed to assess whether calcium supplements of 500 or 250 mg/d effectively prevent bone loss in perimenopausal and postmenopausal Japanese women. We recruited 450 Japanese women between 50 and 75 years of age. They were randomly assigned to receive 500 mg of calcium (as calcium carbonate), 250 mg of calcium, or placebo daily. Medical examinations conducted three times over a 2‐year follow‐up period assessed bone mineral density (BMD) of the lumbar spine and femoral neck. One‐factor repeated measures ANOVA was used for statistical tests. Subgroup analyses were also conducted. Average total daily calcium intake at baseline for the 418 subjects who underwent follow‐up examinations was 493 mg/d. Intention‐to‐treat analysis showed less dramatic decreases in spinal BMD for the 500‐mg/d calcium supplement group compared to the placebo group (1.2% difference over 2 years, p = 0.027). Per‐protocol analysis (≥80% compliance) revealed that spinal BMD for the 500‐mg/d and 250‐mg/d calcium supplement groups decreased less than the placebo group (1.6%, p = 0.010 and 1.0%, p = 0.078, respectively), and that femoral neck BMD for the 500‐mg/d calcium supplement group decreased less relative to the placebo group (1.0%, p = 0.077). A low‐dose calcium supplement of 500 mg/d can effectively slow lumbar spine bone loss in perimenopausal and postmenopausal women with habitually low calcium intake, but its effect on the femoral neck is less certain. Calcium supplementation dosage should thus be reassessed. (Clinical Trials Registry number: UMIN000001176). © 2012 American Society for Bone and Mineral Research.     

Oral daily ibandronate prevents bone loss in early postmenopausal women without osteoporosis.

Oral daily ibandronate was investigated for the prevention of bone loss in postmenopausal women without osteoporosis (n = 653). BMD at the lumbar spine and hip were significantly increased (3.1% and 1.8%, respectively; p < or = 0.0001 versus placebo) with 2.5 mg ibandronate after 24 months. Oral ibandronate is a promising option for the prevention of postmenopausal bone loss. INTRODUCTION: Further strategies to manage patients most at risk from developing postmenopausal osteoporosis are required. The objectives of this multicenter, double-blind, randomized, placebo-controlled study were to examine the efficacy, tolerability, and optimal dose of oral daily ibandronate in the prevention of bone loss in postmenopausal women. MATERIALS AND METHODS: In total, 653 women (mean bone mineral density [BMD] T-score > -2.5 at the lumbar spine), who had been postmenopausal for at least 1 year, were allocated to one of four strata based on time since menopause and baseline lumbar spine BMD. Women were randomized to receive calcium (500 mg daily) plus either placebo (n = 162) or ibandronate 0.5 mg (n = 162), 1 mg (n = 166), or 2.5 mg (n = 163) as once-daily oral treatment for 2 years. The primary endpoint was the mean percent change in lumbar spine BMD with ibandronate versus placebo. RESULTS AND CONCLUSIONS: After 2 years, oral daily ibandronate produced a dose-related and sustained maintenance or increase in BMD at the lumbar spine and hip (total hip, femoral neck, trochanter), together with a dose-related reduction in the rate of bone turnover. The greatest nominal increases in spinal and hip BMD were observed with the 2.5-mg dose, which produced statistically significant BMD gains compared with placebo at 6 months and all subsequent time-points at the spine and hip (3.1% and 1.8% increase in lumbar spine and total hip BMD, respectively, versus placebo; p < or = 0.0001 after 24 months). Oral daily ibandronate was well tolerated with an incidence of upper gastrointestinal adverse events similar to placebo. No safety concerns were identified. In summary, oral daily ibandronate 2.5 mg decreases bone turnover, preserves or increases BMD in the spine and proximal femur, and is well tolerated. Oral ibandronate provides a promising option for the prevention of bone loss in postmenopausal women.     

Efficacy and safety of bazedoxifene in postmenopausal Asian women

Summary

This 6-month study examined the efficacy and safety of bazedoxifene 20?mg in postmenopausal Asian women. Bazedoxifene showed statistically significant improvements over placebo in bone mineral density at all skeletal sites evaluated. Bazedoxifene significantly reduced bone turnover and had favorable effects on lipid parameters. Bazedoxifene was safe and well tolerated.

Introduction

This 6-month, randomized, double-blind, placebo-controlled phase 3 study conducted in China, Korea, and Taiwan evaluated the efficacy and safety of bazedoxifene in postmenopausal Asian women.

Methods

Generally, healthy postmenopausal Asian women (N?=?487; mean age, 57.2?years; mean lumbar spine bone mineral density [BMD], ?1.1) were randomized to daily therapy with bazedoxifene 20?mg or placebo; all subjects received daily supplemental calcium carbonate 600?mg. The changes from baseline in BMD at the lumbar spine (primary end point) and at other skeletal sites, bone turnover markers, and lipid parameters were evaluated at 6?months. Safety assessments included adverse event (AE) reporting and physical/gynecologic examination.

Results

At 6?months, women who received bazedoxifene 20?mg had significantly greater BMD compared with those receiving placebo at the lumbar spine (0.41% vs ?0.32%, P?<?0.01), femoral neck (?0.08% vs ?0.69%, P?=?0.014), trochanter (0.50% vs ?0.23%, P?=?0.010), and total hip (?0.03% vs ?0.77%, P?<?0.001), respectively. Bazedoxifene 20?mg was also associated with significant differences from placebo in median percent reductions from baseline in serum C-telopeptide (?21.8%, P?<?0.001) and osteocalcin (?12.9%, P?<?0.001) levels and total (?5.0%, P?<?0.001) and low-density lipoprotein cholesterol (?9.5%, P?<?0.001) levels. The incidence of AEs was not different between subjects treated with bazedoxifene and those who received placebo.

Conclusion

Bazedoxifene was generally safe and effective in preventing bone loss in this short-term study of postmenopausal Asian women.     

The effect of raloxifene treatment in postmenopausal women with CKD

It is unknown whether treatment for osteoporosis with raloxifene is safe or effective in those with chronic kidney disease (CKD). With data from a multicenter, randomized, placebo-controlled trial of 7705 postmenopausal women with osteoporosis, the effect of raloxifene on rate of change of bone mineral density (BMD), incidence of fractures, and adverse events by stage of CKD was examined over 3 yr. Baseline serum creatinine values were available for 7316 women, and these values were used to assign a category of creatinine clearance (CrCl) using the Cockcroft-Gault formula (CrCl < 45, 45 to 59, and > or = 60 ml/min). BMD was measured at baseline and annually by dual x-ray absorptiometry. Within the placebo group, lower baseline CrCl was associated with a trend for higher annual losses of BMD at the femoral neck; however, within the raloxifene group, lower baseline CrCl was associated with greater increases in femoral neck BMD. This interaction between category of CrCl and treatment assignment was significant for rate of change of BMD at the hip. Irrespective of kidney function, raloxifene treatment was associated with a greater increase in spine BMD, a reduction in vertebral fractures, and no effect on nonvertebral fractures compared with placebo. Within each category of kidney function, adverse events were similar between the raloxifene and placebo groups. In conclusion, raloxifene increases BMD at both the hip and the spine and reduces the risk for vertebral fractures among individuals with CKD. The effect ofraloxifene on hip BMD is greater among those with mild to moderate CKD.     

Effects of tibolone and raloxifene on bone mineral density in osteopenic postmenopausal women

SUMMARY: A randomized trial was conducted in osteopenic postmenopausal women to compare the efficacy of tibolone versus raloxifene on BMD of the lumbar spine and hip. Tibolone increased lumbar spine and total hip BMD to a statistically significantly greater extent than raloxifene after two years of treatment. INTRODUCTION: Both tibolone, a selective tissue estrogenic activity regulator (STEAR), and raloxifene, a selective estrogen receptor modulator (SERM), are known to prevent postmenopausal bone loss. However, no head-to-head studies to compare the efficacy on bone have been performed. METHODS: A double-blind, randomized trial was conducted in osteopenic postmenopausal women aged 60-79 years to compare the effects of tibolone 1.25 mg/day to raloxifene 60 mg/day on bone mineral density (BMD). Serum osteocalcin and serum type I collagen C-telopeptides were measured as biochemical markers of bone metabolism. RESULTS: Three hundred and eight subjects were allocated to treatment. Both treatments significantly increased lumbar spine BMD, however the increase was significantly larger after tibolone treatment than after raloxifene treatment (at year 1: 2.2% versus 1.2%, p<0.01 and at year 2: 3.8% versus 2.1%, p<0.001). After 2 years of treatment, the increase in total hip BMD in the tibolone group was significantly larger than in the raloxifene group (p<0.05). Both treatments significantly reduced type I collagen C-telopeptides and osteocalcin levels when compared to baseline. CONCLUSIONS: Tibolone 1.25 mg/day for 2 years prevents postmenopausal bone loss in older women and results in a larger increase of BMD both at the lumbar spine and hip than raloxifene.     

Effect of 1 year of discontinuation of raloxifene or estrogen therapy on bone mineral density after 5 years of treatment in healthy postmenopausal women

The beneficial effects of hormone replacement therapy (HRT), selective estrogen receptor modulators (SERMs), or bisphosphonates in the prevention and treatment of osteoporosis in postmenopausal women have been well established. However, little is known about the effects of discontinuation of treatment on bone mineral density. We investigated the effect of 1 year of discontinuation of the SERM raloxifene (Ral; 60 mg and 150 mg), conjugated equine estrogen (CEE; 0.625 mg), and placebo after 5 years of treatment in a double-blind, randomized study. Thirty-eight of 59 healthy and hysterectomized postmenopausal women (mean age 55 years) completed the treatment and 1 year follow-up period. Lumbar spine and femoral neck bone mineral density (BMD) were performed with dual-energy X-ray absorptiometry, before, during, and at the end of treatment, as well as after 1 year of discontinuation of therapy. One year of discontinuation significantly reduced the mean lumbar spine BMD in the raloxifene- and estrogen-treated women (p < 0.05), whereas mean femoral neck BMD was reduced significantly only in women treated with 60 mg Ral (p < 0.05). The mean percentage change (+/-SD) in lumbar spine BMD was: CEE, -6.2% (+/-3.7%); Ral 60 mg, -2.4% (+/-2.4%); Ral 150 mg, -2.6% (+/-3.1%); and placebo, -1.6% (+/-4.3%). Our results show that 5 years of treatment with either Ral or CEE did not protect against bone loss after 1 year of withdrawal of therapy, and that the rate of bone loss was not significantly different from that of placebo-treated women.     

Effects of raloxifene,hormone replacement therapy,and placebo on bone turnover in postmenopausal women

Raloxifene, a nonsteroidal selective estrogen receptor modulator (SERM), increases bone mineral density (BMD), decreases biochemical markers of bone turnover, and prevents incident vertebral fractures in postmenopausal women, while sparing the breast and endometrium from the undesirable stimulation caused by estrogen. How the long-term beneficial effects of raloxifene on bone turnover, as assessed by bone histomorphometry, compare with hormone replacement therapy (HRT) and placebo are not known. We studied 66 healthy postmenopausal women (age 55 to 75 years, mean 63 years) who were randomized to either raloxifene 150 mg/day, HRT (Premarin 0.625 mg/day, and Provera 2.5 mg/day), or placebo for 1 year. All women received 1–1.5 g of calcium/day. Following double tetracycline labeling, transiliac bone biopsies were obtained at baseline and 1 year and analyzed for changes in histologic indexes of bone remodeling on the cancellous surface as well as at the endocortical subdivision of the endosteal envelope, the location of the greatest fraction of postmenopausal bone loss. BMD and biochemical markers of bone turnover were also determined at baseline and 1 year. Four paired biopsies were obtained in the HRT group, six in the raloxifene group, and five in the placebo group. The frequency of remodeling events on cancellous bone and rate of bone formation in both cancellous and endocortical bone increased in the placebo group, while these measurements decreased in both drug treatment groups. Using analysis of mean percentage changes, when compared with the placebo group, these changes were significantly different for both raloxifene and HRT treatment groups (p<0.02). In all subjects, the bone was lamellar with discrete tetracycline labels and there was no evidence of marrow fibrosis or abnormal bone cells. BMD increased from baseline at the lumbar spine (p<0.05 in the HRT group) and in the total body (p<0.05 for both raloxifene and HRT). Compared with that of the raloxifene group, the increase in BMD was greater in the HRT group at the lumbar spine but not in the total body. Serum bone alkaline phosphatase, serum osteocalcin, and urine C-terminal cross-linking telopeptide of type I collagen significantly decreased (p<0.05) in both active treatment groups, changes significantly different from those seen with placebo. Overall, these results support the hypothesis that raloxifene preserves bone mass by reducing the elevated bone turnover found in postmenopausal women receiving placebo, by mechanisms similar to those operative in postmenopausal women receiving HRT.     

Multinational, Placebo-Controlled, Randomized Trial of the Effects of Alendronate on Bone Density and Fracture Risk in Postmenopausal Women with Low Bone Mass: Results of the FOSIT Study

This randomized, double-masked, placebo-controlled trial evaluated the safety, tolerability and effects on bone mineral density (BMD) of alendronate in a large, multinational population of postmenopausal women with low bone mass. At 153 centers in 34 countries, 1908 otherwise healthy, postmenopausal women with lumbar spine BMD 2 standard deviations or more below the premenopausal adult mean were randomly assigned to receive oral alendronate 10 mg (n = 950) or placebo (n = 958) once daily for 1 year. All patients received 500 mg elemental calcium daily. Baseline characteristics of patients in the two treatment groups were similar. At 12 months, mean increases in BMD were significantly (p相似文献   

A Randomized,Double‐Blind Phase 2 Clinical Trial of Blosozumab,a Sclerostin Antibody,in Postmenopausal Women with Low Bone Mineral Density

Sclerostin, a SOST protein secreted by osteocytes, negatively regulates formation of mineralized bone matrix and bone mass. We report the results of a randomized, double‐blind, placebo‐controlled multicenter phase 2 clinical trial of blosozumab, a humanized monoclonal antibody targeted against sclerostin, in postmenopausal women with low bone mineral density (BMD). Postmenopausal women with a lumbar spine T‐score –2.0 to –3.5, inclusive, were randomized to subcutaneous blosozumab 180 mg every 4 weeks (Q4W), 180 mg every 2 weeks (Q2W), 270 mg Q2W, or matching placebo for 1 year, with calcium and vitamin D. Serial measurements of spine and hip BMD and biochemical markers of bone turnover were performed. Overall, 120 women were enrolled in the study (mean age 65.8 years, mean lumbar spine T‐score –2.8). Blosozumab treatment resulted in statistically significant dose‐related increases in spine, femoral neck, and total hip BMD as compared with placebo. In the highest dose group, BMD increases from baseline reached 17.7% at the spine, and 6.2% at the total hip. Biochemical markers of bone formation increased rapidly during blosozumab treatment, and trended toward pretreatment levels by study end. However, bone specific alkaline phosphatase remained higher than placebo at study end in the highest‐dose group. CTx, a biochemical marker of bone resorption, decreased early in blosozumab treatment to a concentration less than that of the placebo group by 2 weeks, and remained reduced throughout blosozumab treatment. Mild injection site reactions were reported more frequently with blosozumab than placebo. In conclusion, treatment of postmenopausal women with an antibody targeted against sclerostin resulted in substantial increases in spine and hip BMD. These results support further study of blosozumab as a potential anabolic therapy for osteoporosis. © 2014 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research (ASBMR)     

BMD changes and predictors of increased bone loss in postmenopausal women after a 5‐year course of alendronate

Management of women discontinuing bisphosphonates after 3 to 5 years of treatment is controversial. Little is known about how much bone mineral density (BMD) is lost after discontinuation or whether there are risk factors for greater rates of bone loss post‐discontinuation. We report patterns of change in BMD and prediction models for the changes in BMD in postmenopausal women during a 5‐year treatment‐free period after alendronate (ALN) therapy. We studied 406 women enrolled in the Fracture Intervention Trial (FIT) who had taken ALN for a mean of 5 years and were then enrolled in the placebo arm of the FIT Long‐Term Extension (FLEX) trial for an additional 5 years, describing 5‐year percent changes in total hip, femoral neck, and lumbar spine BMD over the treatment‐free period. Prediction models of 5‐year percent changes in BMD considered all linear combinations of candidate risk factors for bone loss such as BMD at the start of the treatment‐free period, the change in BMD on ALN, age, and fracture history. Serum for three markers of bone turnover was available in 76 women, and these bone turnover markers were included as candidate predictors for these 76 women. Mean 5‐year BMD changes were –3.6% at the total hip, –1.7% at the femoral neck, and 1.3% at the lumbar spine. Five‐year BMD losses of >5% were experienced by 29% of subjects at the total hip, 11% of subjects at the femoral neck, and 1% of subjects at the lumbar spine. Several risk factors such as age and BMI were associated with greater bone loss, but no models based on these risk factors predicted bone loss rates. Although about one‐third of women who discontinued ALN after 5 years experienced >5% bone loss at the total hip, predicting which women will lose at a higher rate was not possible.     

Effect of raloxifene on bone mineral density and biochemical markers of bone turnover in Japanese postmenopausal women with osteoporosis: results from a randomized placebo-controlled trial

The safety and efficacy of raloxifene, a selective estrogen receptor modulator (SERM), has been studied extensively in large, global clinical trials. However, the effect of raloxifene on bone mineral density (BMD) and on biochemical markers of bone turnover in Japanese postmenopausal women with osteoporosis has not been rigorously evaluated. This study was designed to assess the safety and efficacy of raloxifene in Japanese postmenopausal women with osteoporosis following 1 year of therapy. Participants in this multicenter trial were randomly assigned to receive placebo, raloxifene 60 mg/day (RLX60), or raloxifene 120 mg/day (RLX120). Lumbar spine BMD was measured at baseline, 24, 40, and 52 weeks, and biochemical markers of bone turnover were assessed at baseline, 12, 24, and 52 weeks. Serum lipids were assessed at baseline, 12, 24, 40, and 52 weeks, and breast examinations and transvaginal ultrasound of the endometrium were performed at enrollment and 52 weeks. Compared with baseline, women taking RLX60 had significant increases in lumbar spine (L2-L4) BMD at 24 weeks (+3.3%, p<0.001) through 52 weeks (+3.5%, p<0.001) of therapy, and similar results were observed in the RLX120 group. Markers of bone turnover and total cholesterol and LDL-C were significantly reduced, and no significant treatment-group difference was observed for patients reporting at least one adverse event following randomization. In addition, there were no reported venous thromboembolic events (VTE) in any treatment group. The results of this study demonstrate that raloxifene is associated with early increases in lumbar spine BMD, has favorable effects on biochemical markers of bone turnover and lipid profile, and is well tolerated in postmenopausal Japanese women.The named authors wrote this article on behalf of the Japan Clinical Trial Research Group.