Efficacy and safety of ibandronate given by intravenous injection once every 3 months

Oral bisphosphonates are established therapeutics for postmenopausal osteoporosis. Alternative, simplified dosing regimens that improve tolerability and promote convenience may be advantageous. Ibandronate is a highly potent, nitrogen-containing bisphosphonate that can be administered as a convenient intravenous (i.v.) injection (over 15-30 s) in schedules featuring extended between-dose intervals. In a recent fracture prevention study, 1 and 0.5 mg i.v. ibandronate injections, given once every 3 months, were shown to dose-dependently increase lumbar spine and hip bone mineral density (BMD) and decrease biochemical markers of bone turnover in women with postmenopausal osteoporosis, but the overall magnitude of efficacy provided by both doses was suboptimal. In the present study (Intermittent Regimen intravenous Ibandronate Study: the IRIS study), the dose-response relationship with intermittent intravenous ibandronate injections was further evaluated in 520 postmenopausal osteoporotic women (aged 55-75 years, time since menopause >or= 5 years, lumbar spine [L1-L4] BMD T score < -2.5). At enrolment, participants were randomized to receive either 2 mg (n = 261) or 1 mg (n = 131) ibandronate or placebo (n = 128) intravenous injections, given once every 3 months. After 1 year, ibandronate therapy produced substantial and dose-dependent increases in lumbar spine and hip BMD, and decreases in biochemical markers of bone turnover, with the 2 mg dose providing significantly greater efficacy than the 1 mg dose. Most notably, lumbar spine BMD increased by 5.0% and 2.8% in the 2 and 1 mg groups, respectively, and decreased by 0.04% in the placebo group. Furthermore, total hip BMD increased by 2.9%, 2.2%, and 0.6%, respectively. Serum and urinary CTX, reflecting bone resorption, were decreased by 62.5% and 61%, respectively, with the 2 mg dose, and by 43.5% and 42%, respectively, with the 1 mg dose. Intravenous ibandronate was well tolerated with a similar incidence of adverse events to placebo. Importantly, no indicators of renal toxicity were reported. In summary, the 2 mg ibandronate regimen provides significantly greater BMD increases and significantly greater suppression of bone resorption markers than the 1 mg dose used in this study and in the previous fracture prevention study. Ongoing studies aim to further establish the efficacy and convenience of intermittent intravenous ibandronate injections in postmenopausal osteoporosis.     

Effects of oral ibandronate administered daily or intermittently on fracture risk in postmenopausal osteoporosis.

Oral daily (2.5 mg) and intermittent ibandronate (between-dose interval of >2 months), delivering a similar cumulative exposure, were evaluated in 2946 osteoporotic women with prevalent vertebral fracture. Significant reduction in incident vertebral fracture risk by 62% and 50%, respectively, was shown after 3 years. This is the first study to prospectively show antifracture efficacy for the intermittent administration of a bisphosphonate. INTRODUCTION: Bisphosphonates are important therapeutics in postmenopausal osteoporosis. However, they are currently associated with stringent dosing instructions that may impair patient compliance and hence therapeutic efficacy. Less frequent, intermittent administration may help to overcome these deficiencies. This study assessed the efficacy and safety of oral ibandronate administered either daily or intermittently with a dose-free interval of >2 months. MATERIALS AND METHODS: This randomized, double-blind, placebo-controlled, parallel-group study enrolled 2946 postmenopausal women with a BMD T score < or = -2.0 at the lumbar spine in at least one vertebra (L1-L4) and one to four prevalent vertebral fractures (T4-L4). Patients received placebo or oral ibandronate administered either daily (2.5 mg) or intermittently (20 mg every other day for 12 doses every 3 months). RESULTS AND CONCLUSIONS: After 3 years, the rate of new vertebral fractures was significantly reduced in patients receiving oral daily (4.7%) and intermittent ibandronate (4.9%), relative to placebo (9.6%). Thus, daily and intermittent oral ibandronate significantly reduced the risk of new morphometric vertebral fractures by 62% (p = 0.0001) and 50% (p = 0.0006), respectively, versus placebo. Both treatment groups also produced a statistically significant relative risk reduction in clinical vertebral fractures (49% and 48% for daily and intermittent ibandronate, respectively). Significant and progressive increases in lumbar spine (6.5%, 5.7%, and 1.3% for daily ibandronate, intermittent ibandronate, and placebo, respectively, at 3 years) and hip BMD, normalization of bone turnover, and significantly less height loss than in the placebo group were also observed for both ibandronate regimens. The overall population was at low risk for osteoporotic fractures. Consequently, the incidence of nonvertebral fractures was similar between the ibandronate and placebo groups after 3 years (9.1%, 8.9%, and 8.2% in the daily, intermittent, and placebo groups, respectively; difference between arms not significant). However, findings from a posthoc analysis showed that the daily regimen reduces the risk of nonvertebral fractures (69%; p = 0.012) in a higher-risk subgroup (femoral neck BMD T score < -3.0). In addition, oral ibandronate was well tolerated. Oral ibandronate, whether administered daily or intermittently with an extended between-dose interval of >2 months, is highly effective in reducing the incidence of osteoporotic fractures in postmenopausal women. This is the first time that significant fracture efficacy has been prospectively shown with an intermittently administered bisphosphonate in the overall study population of a randomized, controlled clinical trial. Thus, oral ibandronate holds promise as an effective and convenient alternative to current bisphosphonate therapies.     

Monthly oral ibandronate therapy in postmenopausal osteoporosis: 1-year results from the MOBILE study.

Once-monthly (50/50, 100, and 150 mg) and daily (2.5 mg; 3-year vertebral fracture risk reduction: 52%) oral ibandronate regimens were compared in 1609 women with postmenopausal osteoporosis. At least equivalent efficacy and similar safety and tolerability were shown after 1 year. INTRODUCTION: Suboptimal adherence to daily and weekly oral bisphosphonates can potentially compromise therapeutic outcomes in postmenopausal osteoporosis. Although yet to be prospectively shown in osteoporosis, evidence from randomized clinical trials in several other chronic conditions shows that reducing dosing frequency enhances therapeutic adherence. Ibandronate is a new and potent bisphosphonate with antifracture efficacy proven for daily administration and also intermittent administration with a dose-free interval of >2 months. This report presents comparative data on the efficacy and safety of monthly and daily oral ibandronate regimens. MATERIALS AND METHODS: MOBILE is a 2-year, randomized, double-blind, phase III, noninferiority trial. A total of 1609 women with postmenopausal osteoporosis were assigned to one of four oral ibandronate regimens: 2.5 mg daily, 50 mg/50 mg monthly (single doses, consecutive days), 100 mg monthly, or 150 mg monthly. RESULTS: After 1 year, lumbar spine BMD increased by 3.9%, 4.3%, 4.1%, and 4.9% in the 2.5, 50 /50, 100, and 150 mg arms, respectively. All monthly regimens were proven noninferior, and the 150 mg regimen superior, to the daily regimen. All monthly regimens produced similar hip BMD gains, which were larger than those with the daily regimen. All regimens similarly decreased serum levels of C-telopeptide, a biochemical marker of bone resorption. Compared with the daily regimen, a significantly larger proportion of women receiving the 100 and 150 mg monthly regimens achieved predefined threshold levels for percent change from baseline in lumbar spine (6%) or total hip BMD (3%). All regimens were similarly well tolerated. CONCLUSIONS: Monthly ibandronate is at least as effective and well tolerated as the currently approved daily ibandronate regimen in postmenopausal osteoporosis.     

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   

Ibandronate: a comparison of oral daily dosing versus intermittent dosing in postmenopausal osteoporosis.

The objective of this study was to compare efficacy and safety of continuous versus intermittent oral dosing of ibandronate. Two hundred forty women aged 55-75 years with postmenopausal osteoporosis were randomized to active treatment or placebo. Similar total doses of ibandronate were provided by treatment regimens with either continuous 2.5 mg of ibandronate daily (n = 81) or intermittent 20 mg of ibandronate every other day for the first 24 days, followed by 9 weeks without active drug (n = 78). The placebo group (total, n = 81) was crossed over after 12 months to receive either continuous (n = 37) or intermittent ibandronate (n = 35). By 24 months, bone mineral density (BMD) had increased significantly relative to baseline in both active treatment groups. The continuous and intermittent groups showed statistically equivalent increases in lumbar spine BMD of +5.64% (+/-0.53) and +5.54% (+/-0.53) and in total hip of +3.35% (+/-0.40) and +3.41% (+/-0.40), respectively (per protocol population). Biochemical markers of bone turnover decreased significantly in both treatment groups. The level of marker suppression was similar, although the intermittent group displayed, as expected, more fluctuation over the treatment period. The frequency of adverse events was similar in the treatment groups. In conclusion, the intermittent and continuous regimens showed equivalent changes in BMD and bone turnover. These results confirm previous preclinical findings indicating that the efficacy of ibandronate depends on the total oral dose given rather than on the dosing schedule. This supports development of new flexible dosing regimens targeted to minimize the frequency of dosing, which are expected to improve convenience and lead to enhanced long-term patient compliance.     

The efficacy of 48-week oral ibandronate treatment in postmenopausal osteoporosis when taken 30 versus 60 minutes before breakfast

Since effective prevention and treatment of osteoporosis demands a high degree of long-term compliance, optimization of the dosing regimen in terms of efficacy and convenience of drug intake is a critical issue of oral bisphosphonate treatment. The purpose of the present study was to investigate whether the efficacy of the treatment with oral ibandronate, 2.5 mg daily, can be maintained if changing the postdose fast from 60 to 30 min. This was a 48-week, multicenter, open-label, randomized, parallel-group noninferiority study. Subjects were postmenopausal women 55-80 years old with lumbar spine (L1-L4) bone mineral density (BMD) corresponding to a T score < or =2.5. Women were randomly assigned to take 2.5 mg ibandronate exactly 30 or 60 min before breakfast. Lumbar spine and proximal femur (trochanter, femoral neck, total hip) BMD were measured by dual energy X-ray absorptiometry; serum osteocalcin and creatinine-corrected urinary C-telopeptide of type I collagen (u-CTX/Cr) excretion were measured by ELISA. After 48 weeks of treatment, the relative increase in lumbar spine BMD from baseline in the 30-min fast group was lower than that in the 60-min fast group (3.07% versus 4.95%, one-sided 97.5% CI = -2.89%) such that the prespecified noninferiority criteria were not met. The mean relative increases in BMD at the trochanter (3.04% versus 4.36%), femoral neck (1.82% versus 2.19%), and total hip (2.35% versus 3.21%) in the 30-min fast group were also lower than those in the 60-min fast group. Less suppression of the markers of bone turnover (u-CTX/Cr, -48.5% vs -61.8%; serum osteocalcin, -34.8% vs 43.8%) was observed in the 30-min compared with the 60-min group. In conclusion, if reducing the postdose fasting interval, dose-increase compensation would likely to be required to maintain efficacy of oral ibandronate treatment. Another potential solution for improving the convenience with bisphosphonate treatment is expected from weekly or monthly dosing regimens currently under clinical investigations.     

A systematic review of the effect of alendronate on bone mineral density in men.

Alendronate is known to increase bone mineral density (BMD) at the lumbar spine and hip in women, but less information is available in men. We conducted a systematic review of randomized controlled trials to determine whether oral alendronate improves BMD at the lumbar spine and hip in men with low bone mass or prevalent fractures, compared with men treated with placebo, calcium, or vitamin D. In three trials in men, BMD (measured by dual-energy X-ray absorptiometry) increased at 2-3 yr (compared to baseline) at the lumbar spine and femoral neck in alendronate-treated patients compared to controls. The pooled estimates of changes in BMD with 10 mg of alendronate daily compared to controls were as follows: 7.8% over 2-3 yr (95% confidence interval [CI] = 4.8- 10.8) at the lumbar spine and 3.8% (95% CI = 2.3-5.3) at the femoral neck (p < 0.001 for treatment effect in each analysis). Statistically significant heterogeneity of treatment effect was noted between trials. We conclude that 10 mg of oral daily alendronate is significantly associated with increase in BMD at the lumbar spine and hip in men over 2-3 yr and that these changes are similar to those previously observed in postmenopausal women.     

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.     

Long-term administration of quarterly IV ibandronate is effective and well tolerated in postmenopausal osteoporosis: 5-year data from the DIVA study long-term extension

Summary

Long-term bone mineral density (BMD) gains, bone marker levels, and safety of 3?mg quarterly intravenous (IV) ibandronate were studied in this 3-year extension to the Dosing IntraVenous Administration (DIVA) trial. Quarterly IV ibandronate consistently increased lumbar spine bone mineral density measured with dual-energy X-ray absorptiometry (DXA-BMD) over 5?years (8.1%) and was well tolerated in women with postmenopausal osteoporosis.

Introduction

Treatment with IV ibandronate regimens, 2?mg bimonthly and 3?mg quarterly, has been studied for up to 5?years in a long-term extension (LTE) to the 2-year DIVA trial.

Methods

DIVA LTE is an open-label extension to a 2-year randomized, double-blind, double-dummy, noninferiority, phase III study (DIVA core). DIVA LTE involved postmenopausal women who had completed 2?years of DIVA core, comparing daily oral and IV ibandronate (≥75% adherence with IV ibandronate in year?2 of DIVA). Patients previously treated with 2?mg bimonthly or 3?mg quarterly IV ibandronate continued on the same regimen; patients who had received 2.5?mg daily oral ibandronate and placebo IV in DIVA core were switched to IV ibandronate.

Results

Pooled analysis of 497 intent-to-treat (ITT) patients receiving IV ibandronate from DIVA core baseline showed consistent increases over 5?years in lumbar spine DXA-BMD (8.4% [95% confidence interval (CI)?=?7.5, 9.3] with 2?mg bimonthly and 8.1% [95% CI?=?7.2, 8.9] with 3?mg quarterly). Three-year data relative to DIVA LTE baseline in the full ITT population (756 patients randomized or reallocated from DIVA, including those previously on daily treatment) showed maintenance of DXA-BMD gains from DIVA core with further gains in lumbar spine DXA-BMD. These benefits are supported by sustained reductions in markers of bone metabolism. No tolerability concerns or new safety signals were observed.

Conclusions

Treatment with IV ibandronate 2?mg bimonthly or 3?mg quarterly is effective and well tolerated for up to 5?years in women with postmenopausal osteoporosis.     

Apolipoprotein E gene polymorphism and bone loss: estrogen status modifies the influence of apolipoprotein E on bone loss.

The identification of genes that contribute to bone mineral density (BMD) and bone loss has widespread implications for the understanding and prevention of osteoporosis. The objective of this study was to examine the relationship between the presence and absence of the apolipoprotein E*4 (APOE*4) allele and both BMD and annualized percentage rate of change in BMD at the lumbar spine and hip in a population of 392 healthy, pre-, peri-, and postmenopausal white women participating in the Women's Healthy Lifestyle Project. APOE genotype was analyzed by restriction enzyme analysis from genomic DNA. BMD at the lumbar spine and hip was measured at baseline and after a mean of 2.5 years using dual-energy X-ray absorptiometry (DXA). In premenopausal women, there were no significant differences in BMD or in the annualized percentage rate of change in BMD at the spine or hip when comparing women with and without the APOE*4 allele. In contrast, spine bone loss was significantly greater in peri- and postmenopausal women having an APOE*4 allele than in women without this allele (-1.75 + 1.5% per year vs. -0.98 +/- 1.4% per year, respectively, p = 0.018). Among peri- and postmenopausal women currently using hormone replacement therapy (HRT), there were no differences in the annualized percentage rate of change in spine BMD; whereas, among non-HRT users, there was a 2-fold higher rate of spine bone loss in women with an APOE*4 allele compared with women without this allele (-2.31 +/- 1.5% per year vs. -1.27 +/- 1.3% per year, respectively, p = 0.033; APOE*4 x HRT interaction, p = 0.076). In conclusion, this study shows the importance of APOE*4 allele in spine bone loss in peri- and postmenopausal women and, more importantly, it provides evidence for a genetic and lifestyle interaction in modulating spine bone loss.     

Effects of Bazedoxifene on BMD and Bone Turnover in Postmenopausal Women: 2‐Yr Results of a Randomized,Double‐Blind,Placebo‐, and Active‐Controlled Study

Osteoporosis is an increasingly common health concern in postmenopausal women. In a 2‐yr phase III study, bazedoxifene prevented bone loss, reduced bone turnover, and was well tolerated in early postmenopausal women with normal or low BMD. Introduction : Bazedoxifene is a novel selective estrogen receptor modulator that has increased BMD and bone strength in experimental models, without stimulating breast or uterus. This 24‐mo, randomized, double‐blind study assessed the efficacy and safety of three doses of bazedoxifene compared with placebo and raloxifene in the prevention of postmenopausal osteoporosis. Materials and Methods : Healthy postmenopausal women with a BMD T‐score at the lumbar spine or femoral neck between –1.0 and ?2.5 or clinical risk factors for osteoporosis were randomly assigned to one of five groups: bazedoxifene 10, 20, or 40 mg/d, placebo, or raloxifene 60 mg/d. All women received elemental calcium. Efficacy outcomes included changes from baseline through 24 mo in BMD of the lumbar spine, hip, femoral neck, and femoral trochanter and biomarkers of bone metabolism. Results : The intent‐to‐treat population included 1434 women (mean age, 58 yr; mean time from last menstrual period, 11 yr). All doses of bazedoxifene and raloxifene prevented bone loss, whereas in the placebo group, there was significant loss of BMD at all skeletal sites. Mean differences in percent change in lumbar spine BMD from baseline to 24 mo relative to placebo were 1.08 ± 0.28%, 1.41 ± 0.28%, 1.49 ± 0.28%, and 1.49 ± 0.28% for 10, 20, and 40 mg bazedoxifene and 60 mg raloxifene, respectively (p < 0.001 for all comparisons). Comparable BMD responses were observed at other body sites. Significant and comparable decreases in serum osteocalcin and C‐telopeptide levels from baseline and relative to placebo with active treatment were observed as early as 3 mo and were sustained through study conclusion (p < 0.001). Overall incidences of adverse events, serious adverse events, and discontinuations caused by adverse events were similar between groups. The most common adverse events included headache, infection, arthralgia, pain, hot flush, and back pain. Conclusions : Treatment with bazedoxifene prevented bone loss and reduced bone turnover equally as well as raloxifene and was generally well tolerated in postmenopausal women with normal/low BMD.     

Clodronate reduces vertebral fracture risk in women with postmenopausal or secondary osteoporosis: results of a double-blind, placebo-controlled 3-year study.

The efficacy of oral clodronate 800 mg daily to reduce vertebral fractures was studied in 593 women with postmenopausal or secondary osteoporosis. The incidence of vertebral fractures was significantly reduced by 46%. The effect was not modified by the underlying cause of osteoporosis or other baseline factors including bone mineral density, QUS, weight, and smoking. INTRODUCTION: This study aimed to determine if the bisphosphonate, clodronate (Bonefos), reduced the incidence of vertebral fractures in osteoporotic women. MATERIALS AND METHODS: Women fulfilling the WHO criteria for osteoporosis at the lumbar spine (T-score 相似文献   

Bone Mineral Density and Bone Turnover 10 Years After a Single 5 mg Dose or Two 5-Yearly Lower Doses of Zoledronate in Osteopenic Older Women: An Open-Label Extension of a Randomized Controlled Trial

Intravenous zoledronate reduces fracture risk (5 mg at 18-month intervals) and prevents bone loss (doses of 1 to 5 mg for 3 to >5 years), but the duration of action of a single 5 mg dose and the effects of lower doses beyond 5 years are unknown. We report the second open-label extension (years 5 to 10) of a 2-year randomized, multidose, placebo-controlled, double-blinded trial. A total of 116 older women who completed 5 years of participation either continued observation without further treatment (zoledronate 5 mg and placebo at baseline) or received repeat doses of 1 or 2.5 mg zoledronate (zoledronate 1 mg and zoledronate 2.5 mg at baseline, respectively). Outcomes were spine, hip, and total body bone mineral density (BMD) and serum markers of bone turnover. After a single 5 mg dose of zoledronate, mean BMD at the lumbar spine and total hip was maintained at or above baseline levels for 9 and 10 years, respectively. The mean level of the bone resorption marker β-C-terminal telopeptide of type I collagen (β-CTX) was at least 25% lower than that in the placebo group for 9 years. In women administered 5-yearly doses of 2.5 mg zoledronate, mean BMD at the total hip and lumbar spine was maintained at or above baseline levels for 9 and 10 years, respectively. Redosing with 1 or 2.5 mg zoledronate at 5 years reduced bone turnover markers for 3 to 4 years. BMD increased for 3 to 4 years after redosing with 1 mg zoledronate. In the group given 5-yearly 2.5 mg zoledronate, β-CTX was at least 20% lower than that in the placebo group for 10 years. Both a single baseline 5 mg dose of zoledronate and 5-yearly doses of 1 and 2.5 mg zoledronate prevented bone loss at hip and spine for 8 to 10 years in older postmenopausal women. Clinical trials to evaluate the effects on fracture risk of these very infrequent and lower doses of zoledronate are justified. © 2021 American Society for Bone and Mineral Research (ASBMR).     

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.     

Insufficiently dosed intravenous ibandronate injections are associated with suboptimal antifracture efficacy in postmenopausal osteoporosis

Less frequent bisphosphonate dosing in women with postmenopausal osteoporosis has the potential to promote therapy adherence through improved convenience. Ibandronate is a highly potent nitrogen-containing bisphosphonate, proven to significantly increase vertebral and nonvertebral bone mineral density (BMD) when administered as a convenient intravenous injection. A recent double-blind, placebo-controlled, randomized phase III study explored the antifracture efficacy and safety of 1 and 0.5 mg iv ibandronate injections, given once every 3 months, in 2862 women (55-76 years) with postmenopausal osteoporosis [one to four prevalent vertebral fractures and lumbar spine (L1-L4) BMD T score of less than -2.0 and greater than -5.0 in >or=1 vertebra]. All participants received daily vitamin D (400 IU) and calcium (500 mg) supplementation. The primary endpoint was the incidence of new morphometric vertebral fractures after 3 years. However, although a consistent trend toward a reduction in the incidence of new morphometric vertebral fracture was observed in the active treatment arms compared with placebo (9.2% vs. 8.7% vs. 10.7% in the 1 mg, 0.5 mg and placebo groups, respectively), as well as in the incidence of nonvertebral and hip fractures, the magnitude of fracture reduction was suboptimal and was insufficient to achieve statistical significance. At the studied doses, intravenous ibandronate injections also produced dose-dependent, but comparatively small, increases in lumbar spine BMD (4.0% and 2.9%, respectively) and decreases in biochemical markers of bone resorption and formation, relative to placebo. Optimal fracture efficacy likely requires more substantial increases in BMD and more pronounced suppression of bone turnover. In light of the clear dose-response relationship observed in this and other studies, this is likely to be achieved with higher intravenous doses of ibandronate. The results of a recent phase II/III study (Intermittent Regimen Intravenous Ibandronate Study: the IRIS study) provide support for this hypothesis.     

Efficacy of monthly oral ibandronate is sustained over 5 years: the MOBILE long-term extension study

Summary

The long-term efficacy and safety of once-monthly ibandronate were studied in this extension to the 2-year Monthly Oral Ibandronate in Ladies (MOBILE) trial. Over 5?years, lumbar spine bone mineral density (BMD) increased from baseline with monthly ibandronate 150?mg (8.4%). Long-term monthly ibandronate is effective and well tolerated for up to 5?years in women with postmenopausal osteoporosis.

Introduction

Once-monthly therapy with ibandronate has been studied for up to 5?years in a long-term extension (LTE) to the 2?year MOBILE trial.

Methods

This multicenter, double-blind extension study of monthly ibandronate involved postmenopausal women who had completed 2?years of the MOBILE core study, with ≥75% adherence. Patients were reallocated, or were randomized from daily therapy, to ibandronate 100?mg monthly or 150?mg monthly for a further 3?years.

Results

A pooled intent-to-treat (ITT) analysis of 344 patients receiving monthly ibandronate from the core MOBILE baseline showed increases over 5?years in lumbar spine BMD (8.2% with 100?mg and 8.4% with 150?mg). Three-year data relative to MOBILE LTE baseline in the full ITT population of all 698 patients randomized or reallocated from MOBILE (including those previously on daily treatment) showed, on average, maintenance of proximal femur BMD gains achieved in the core 2-year study, with further small gains in lumbar spine BMD. In general, maintenance of efficacy was also indicated by markers of bone metabolism.

Conclusions

There were no tolerability concerns or new safety signals. Monthly treatment with ibandronate 100 and 150?mg is effective and well tolerated for up to 5?years in women with postmenopausal osteoporosis.     

Daily and intermittent oral ibandronate normalize bone turnover and provide significant reduction in vertebral fracture risk: results from the BONE study

Increasing evidence suggests that a high rate of bone turnover is associated with low bone mineral density (BMD) and is strongly linked to fracture risk. Measurement of biochemical markers of bone turnover is therefore becoming a more widely used endpoint in clinical trials in postmenopausal osteoporosis. This multinational double-blind, fracture-prevention study enrolled 2946 postmenopausal women with osteoporosis. Patients were randomized to receive placebo or oral ibandronate administered daily (2.5 mg/day) or intermittently (20 mg every other day for 12 doses every 3 months). The primary endpoint was the incidence of new vertebral fractures after 3 years. Secondary outcome measures included changes in the rate of bone turnover as assessed by biochemical markers and increases in spinal and hip BMD. Daily and intermittent oral ibandronate significantly reduced the risk of vertebral fractures by 62% and 50%, respectively, and produced significant and sustained reductions in all the measured biochemical markers of bone turnover. By 3 months, the rate of bone turnover was reduced by approximately 50–60%, and this level of suppression was sustained throughout the remainder of the study. In summary, oral ibandronate, given daily or with a between-dose interval of >2 months, normalizes the rate of bone turnover, provides significant increases in BMD and a marked reduction in the incidence of vertebral fractures. Thus, intermittent ibandronate has potential to become an important alternative to currently licensed bisphosphonates in postmenopausal osteoporosis.     

The efficacy and tolerability of risedronate on bone mineral density and bone turnover markers in osteoporotic Chinese women: a randomized placebo-controlled study

Osteoporosis has become an important health problem in postmenopausal Asian populations as the prevalence of hip and vertebral fractures in some Asian countries has risen to approach that of Caucasian populations. Risedronate, a pyridinyl-bisphosphonate agent, is a potent inhibitor of bone resorption. Risedronate increases bone mineral density (BMD), reduces markers of bone turnover, and reduces the risk of fractures in Caucasian postmenopausal women. To determine the efficacy and tolerability of risedronate in Chinese, a multicenter, randomized, double blind, placebo controlled study was performed in Hong Kong. Sixty-five (65) postmenopausal osteoporotic Southern Chinese women, aged 67+/-6 years, were randomly assigned to receive either risedronate 5 mg daily (n=31) or placebo (n=34) for 12 months. All women received calcium carbonate 500 mg daily and vitamin D 400 IU daily. Mean baseline BMD T-score at the spine and total hip was -3.4 and -2.6, respectively. A significant increase in spine BMD was already evident at month 3 of risedronate treatment (P<0.001). Risedronate significantly increased BMD and reduced bone turnover markers as compared with placebo. The risedronate group had significant increase in BMD at 12 months at both the spine and hip when compared with the placebo group (L1-4 6.6% vs. 0.4%, P<0.001; total hip 2.7% vs. 0.3, P<0.0001; femoral neck 1.8% vs. 1.1%, P<0.02; trochanter 4% vs. 1.1%, P<0.0001, respectively). Significant changes in urine N-telopeptide (NTx) and serum osteocalcin were evident as early as 1 and 3 months, respectively, with risedronate treatment. No significant changes were seen in both BMD and bone markers in the placebo group. Risedronate was well tolerated without major adverse effects. We conclude that risedronate is an effective and well-tolerated agent for the treatment of postmenopausal osteoporosis in Asian population.     

Efficacy and safety of oral recombinant calcitonin tablets in postmenopausal women with low bone mass and increased fracture risk: a randomized,placebo-controlled trial

Summary

The effect of an investigational oral calcitonin tablet upon bone mineral density (BMD) of the spine was investigated in postmenopausal women with low bone mass and at increased risk of fracture. Compared to placebo, calcitonin tablets increased lumbar spine BMD. This agent may provide an additional choice for patients.

Introduction

An investigational oral salmon calcitonin preparation was previously shown to increase lumbar spine BMD in postmenopausal women with osteoporosis. Our objective was to evaluate the use of this agent in postmenopausal women with low bone mass and at increased fracture risk but not meeting BMD criteria for osteoporosis.

Methods

Treatment-naïve women were randomized to receive oral recombinant salmon calcitonin tablets or placebo once daily for 1 year. Dual-energy X-ray absorptiometry was performed at baseline and at study weeks 28 and 54. CTx-1, a bone resorption marker, was obtained at the same time points. Subjects returned periodically for tolerability assessment and adverse event (AE) recording.

Results

One hundred twenty-nine women in the USA were randomized, 86 to calcitonin and 43 to placebo. Calcitonin recipients experienced a significant increase from baseline in lumbar spine BMD; the difference compared with placebo was significant. Dosing at bedtime or with dinner was equally effective. CTx-1 was suppressed in calcitonin recipients but not in placebo subjects. Gastrointestinal AEs were common, but the overall safety profile was comparable between groups.

Conclusions

Oral calcitonin may provide a useful therapeutic alternative for some women with low bone mass.     

Matrix Delivery Transdermal 17β-Estradiol for the Prevention of Bone Loss in Postmenopausal Women

A total of 277 early postmenopausal women were enrolled in this placebo-controlled 2-year study to examine the efficacy of a matrix transdermal 17β-estradiol system, at three different dosages (25, 50 and 75 mg/day) combined with sequential oral dydrogesterone 20 mg/day, in preventing bone loss. At 2 years, the difference from placebo in percentage change from baseline of L1–4 lumbar spine bone mineral density (BMD) (assessed by dual-energy X-ray absorptiometry) was 4.7%± 0.7% with estradiol 25 mg/day, 7.3%± 0.7% with estradiol 50 mg/day and 8.7%± 0.7% with estradiol 75 mg/day (all values mean ± SEM). There were also significant increases in femoral neck, trochanter and total hip BMD with all doses of estradiol compared with placebo. Additionally, most patients had a significant gain (increase greater than 2.08%) in lumbar spine bone mass compared with placebo. Patients who received estradiol also experienced clinically significant and dose-related decreases in total serum osteocalcin, serum bone alkaline phosphatase and urinary C-telopeptide, with all three markers of bone turnover returning to premenopausal levels. Estradiol was well tolerated during the 2-year treatment period. Transdermal estradiol is effective and well tolerated at dosages between 25–75 mg/day in the prevention of bone loss in postmenopausal women; 25 mg/day offers an effective option for those women who cannot tolerate higher doses. Received: 30 June 1998 / Accepted: 22 September 1998