Ronald Emkey

Two-year effects of alendronate on bone mineral density and vertebral fracture in patients receiving glucocorticoids: A randomized, double-blind, placebo-controlled extension trial

OBJECTIVE To evaluate the continued efficacy and safety of alendronate (ALN) for up to 2 years in patients receiving glucocorticoids. METHODS This is a 12-month extension of a previously completed 1-year trial of daily ALN, performed to evaluate the effects of ALN over a total of 2 years in 66 men and 142 women continuing to receive at least 7.5 mg of prednisone or equivalent daily. All patients received supplemental calcium and vitamin D. The primary end point was the mean percentage change in lumbar spine bone mineral density (BMD) from baseline to 24 months. Other outcomes included changes in hip and total body BMD, biochemical markers of bone turnover, radiographic joint damage of the hands, and vertebral fracture incidence. RESULTS The mean (+/-SEM) lumbar spine BMD increased by 2.8 +/- 0.6%, 3.9 +/- 0.7%, and 3.7 +/- 0.6%, respectively, in the groups that received 5 mg, 10 mg, and 2.5/10 mg of ALN daily (P < or = 0.001) and decreased by -0.8 +/- 0.6% in the placebo group (P not significant) over 24 months. In patients receiving any dose of ALN, BMD was increased at the trochanter (P < or = 0.05) and maintained at the femoral neck. Total body BMD was increased in patients receiving 5 or 10 mg ALN (P < or = 0.01). These 2 dose levels of ALN were more effective than placebo at all sites (P < or = 0.05). Bone turnover markers (N-telopeptides of type I collagen and bone-specific alkaline phosphatase) decreased 60% and 25%, respectively, during treatment with ALN (P < or = 0.05). There were fewer patients with new vertebral fractures in the ALN group versus the placebo group (0.7% versus 6.8%; P = 0.026). The safety profile was similar between treatment groups. CONCLUSION Alendronate is an effective, well-tolerated therapy for the prevention and treatment of glucocorticoid-induced osteoporosis, with sustained treatment advantages for up to 2 years.

Significant Differential Effects of Alendronate, Estrogen, or Combination Therapy on the Rate of Bone Loss after Discontinuation of Treatment of Postmenopausal Osteoporosis: A Randomized, Double-Blind, Placebo-Controlled Trial

Context Alendronate and conjugated estrogen therapy both increase bone mineral density in postmenopausal women, but is the rate of bone loss greater when alendronate or estrogen therapy is discontinued? Contribution The discontinuation phase of this double-blind, placebo-controlled trial showed loss of spine and trochanter bone mass in postmenopausal women 1 year after withdrawal of estrogen and no such loss after withdrawal of either alendronate or combination therapy with alendronate and estrogen therapy. Cautions The study was not large or long enough to show whether discontinuation of estrogen therapy is associated with more fractures than discontinuation of either alendronate or combination therapy. The Editors Several antiresorptive agents have been shown to increase bone mass and reduce osteoporotic fractures (1-3). Because greater improvements in bone mass in women using therapy are associated with greater reductions in fracture (4, 5), investigators have begun to examine combinations of antiresorptive therapies to achieve more substantial gains in bone mass. Lindsay and colleagues demonstrated that addition of alendronate to hormone replacement therapy in postmenopausal women resulted in greater increases in bone mass than did maintenance of estrogen therapy alone (6). We previously showed that administration of alendronate and estrogen for 2 years in postmenopausal women with low bone mass resulted in statistically significantly greater increases in bone mass at the lumbar spine and femoral neck than those seen in women taking either agent alone (7). Furthermore, combination therapy was safe and resulted in normal findings on histologic examination of bone. In clinical practice, a key concern is the potential for accelerated bone loss when antiresorptive therapy is discontinued. Approximately one third of women discontinue hormone replacement therapy within 1 year of initiation (8). Older studies have demonstrated significant losses in bone mass after discontinuation of hormone replacement therapy (9-11). In contrast, when therapy with oral alendronate, 10 mg/d, is discontinued after osteoporosis treatment, bone mass at the hip and spine are maintained for 1 year (12). However, no head-to-head comparison of hormone replacement therapy and alendronate or the combination of antiresorptive therapy after discontinuation has been done. In addition, future losses in bone mass when patients discontinue therapy must be considered in management of osteoporosis in postmenopausal women. We therefore sought to examine the rate of bone loss after discontinuation of 2 years of alendronate therapy, hormone replacement therapy, or combination therapy. A subset of participants continued to take combination therapy for a third year to determine whether prolonged therapy remained beneficial. Methods Study Participants Four hundred twenty-five postmenopausal women 42 to 82 years of age who had low bone mass were enrolled in a 2-year randomized, double-blind, placebo-controlled clinical trial conducted at 18 centers in the United States (7). Participants were recruited from clinics, private practices, newspaper advertisements, and targeted mailings. All participants who completed the initial study were asked to enroll in the 1-year extension. Participants were told that if they were taking active treatment, they might be randomly allocated to receive placebo or treatment for the third year and that if they were taking placebo, they would continue to do so. Entry criteria for the initial study are described elsewhere (7). All women had had hysterectomy and had a bone mineral density at the lumbar spine that was less than or equal to a T score of 2.0 SDs below the peak bone mass in young adults. Data on presence or absence of ovaries were not collected. Exclusion criteria were metabolic bone disease, a low serum 25-hydroxyvitamin D level, use of medications known to affect bone turnover, renal insufficiency, severe cardiac disease, and recent major upper gastrointestinal disease. The institutional review board at each clinical site approved the extension protocol. After signing the extension consent form and undergoing baseline evaluation for the extension, participants were allocated to blinded treatment on the basis of their original treatment in the first 2 years of the study. The randomization process was centrally determined by a statistician; as in the initial study, treatment allocation was concealed. Design As described for the initial study at each center, patients were randomly allocated to one of four treatment groups: placebo (n = 50); alendronate, 10 mg/d (n = 92); conjugated estrogen, 0.625 mg/d (n = 143); or alendronate, 10 mg/d, plus conjugated estrogen, 0.625 mg/d (n = 140) (Figure 1). The conjugated estrogen used was Premarin (Wyeth-Ayerst, Philadelphia, Pennsylvania). All women received calcium carbonate to provide 500 mg of elemental calcium daily. Figure 1. Design of original 2-year study and reallocation to extension phase for year 3. At the end of the second year, 244 of the 425 women (57%) continued in a 1-year extension of the study (Figure 1). Of these women, 28 who previously received placebo continued to do so. Women who were taking combination therapy were reallocated to continue taking combination therapy (n = 44) or switch to placebo (n = 41). In addition, 50 participants taking alendronate alone and 81 participants taking conjugated estrogen alone for the first 2 years were assigned to placebo for the third year. All patients and investigators remained blinded to medication allocation. Patients continued to receive calcium supplementation during the third year. Outcome Measures Women were examined at month 24 (baseline of the 1-year extension), month 30, and month 36. Bone mineral density of the lumbar spine, hip (femoral neck, trochanter, total hip), and total body were assessed by using dual-energy x-ray absorptiometry with QDR-1000W, QDR-1500, or QDR-2000 series bone densitometers (Hologic, Inc., Bedford, Massachusetts). A standard phantom was used for cross-calibration at all sites. Serum and urine samples were also obtained at months 24, 30, and 36 for assessment of biochemical markers of bone turnover, namely bone-specific alkaline phosphatase and urinary N-telopeptide cross-links of collagen type I, corrected for creatinine. Statistical Analysis We used SAS software, version 6.12, TSLevel 0060, PROCedureGLM (SAS Institute, Inc., Cary, North Carolina) to analyze the data. The primary efficacy end point was the mean difference between groups in the percentage change in bone mineral density at the lumbar spine from month 24 to month 36. Secondary efficacy end points were the mean percentage changes in bone mineral density of the hip and total body and biochemical markers of bone turnover. Overall percentage changes from month 0 to 36 in spine, hip, and total-body bone mineral density were also analyzed. The prespecified analysis was based on an intention-to-treat approach. At study design, we prespecified that all patients who had a baseline measurement and at least one measurement during treatment would be included in the analysis according to the group to which they were randomly allocated. The missing data were approximated by carrying forward the last available value on treatment forward to the missing time point. No data from the original 2-year study were carried forward to the extension period for any assessment of change. Women who violated the protocol were excluded from analysis of biochemical markers, as previously reported (7). Between-group comparisons of bone mineral density and biochemical measures were made by using analysis of variance techniques, with treatment, center, and treatment-by-center as factors. The assumption of homoscedasticity for the analysis of variance model was assessed by using the Levene test, and the normality assumption was assessed by using the ShapiroWilk test (13). If the assumptions were violated, a nonparametric method was used to corroborate the parametric results. The Fisher exact test was used to compare treatment groups for the proportion of participants who exceeded predefined limits of change in laboratory safety variables (13). Power calculations based on estimated sample sizes of 56 and 84 participants in the alendronate/placebo and estrogen/placebo treatment groups, respectively, yielded an estimate of 92% power to detect a 1.5% difference between mean percentage changes from month 24 to month 36 in bone mineral density at the lumbar spine ( = 0.05, two-tailed test). As requested by the journal editors, data on bone mineral density were also analyzed by using a mixed-model analysis, and results of this analysis are presented. An appropriate curvilinear function was fitted to the actual data, and the function was estimated by using all data available across time points for each participant. A model that regressed bone mineral density versus log (month + 1) provided the appropriate fit for the 3-year data and was used to analyze these data. The variable log (month + 1) was used because log (month) is undefined when month is 0, and log (month + 1) yields the value 0 at baseline. The fitted values from the model were used to obtain the percentage change during the period of interest. Data on bone mineral density from the mixed-model analyses are presented unless otherwise specified. Role of the Funding Source Data were collected by investigators at each study site with the support of Merck Research Laboratories, Rahway, New Jersey. Analyses were performed by statisticians at Merck & Co., Inc. Data were interpreted by the authors, who submitted the manuscript for publication. Results Patient Characteristics and Retention Baseline randomization characteristics did not differ between participants who entered the extension phase and those who did not. Baseline demographic characteristics of the 244 women who entered the extension phase were s

Patient preference for once-monthly ibandronate versus once-weekly alendronate in a randomized, open- label, cross-over trial : the Boniva Alendronate Trial in Osteoporosis (BALTO)

ABSTRACT Objective: Ibandronate, a potent nitrogen-containing bisphosphonate, can be administered with extended interval dosing. Patient preferences were assessed for once-monthly versus once-weekly bisphosphonate treatment using a previously developed, open-label, cross-over trial design. Research design and methods: This was a 6‐month, prospective, randomized, open-label, multi-center study with a two-period and two-sequence cross-over treatment design. After screening, eligible patients (postmenopausal women with osteoporosis) were randomized to once-monthly ibandronate 150 mg followed by once-weekly alendronate 70 mg for a total of 6 months (Sequence A) or once-weekly alendronate followed by once-monthly ibandronate for a total of 6 months (Sequence B). The primary objective was to evaluate patient-reported preference for either the once-monthly ibandronate regimen or the once-weekly alendronate regimen based on responses to a preference questionnaire. Results: A total of 342 patients were enrolled into this study (Sequence A, 170; Sequence B, 172). In the primary analysis of patient preference, 71.4% of women selected once-monthly ibandronate and 28.6% of women selected once-weekly alendronate. Overall, 66.1% preferred the once-monthly ibandronate regimen to the once-weekly alendronate regimen (26.5%) and 7.4% of participants stated no preference for either regimen. The preference rate for once-monthly ibandronate was statistically significant ( p < 0.0001). ‘Ease of following a treatment regimen for a long time’ was the most common reason given for patient preference for both the once-monthly ibandronate (61%, 169/276) and once-weekly alendronate (25%, 70/276) regimens. Additionally, 17% (47/276) of patients who preferred once-monthly ibandronate chose ‘it is easier to tolerate side effects’ as did 4.3% (12/276) of patients who preferred alendronate. Significantly more women found once-monthly ibandronate to be more convenient ( p < 0.0001). Conclusions: Significantly more women with postmenopausal osteoporosis preferred once-monthly ibandronate therapy to once-weekly alendronate therapy, and found the once-monthly regimen to be more convenient. Ease of following a treatment regimen for a long time was the most common reason given for the patients’ preferences.

Prevention of bone loss in postmenopausal women treated with lasofoxifene compared with raloxifene

Objective: Osteoporosis is a significant health problem in postmenopausal women. Consequently, new and effective therapies are being sought to preserve bone mass and prevent osteoporosis in this population of women. The objective of this study was to compare the effects of lasofoxifene with raloxifene and placebo on indices of bone health in postmenopausal women. Design: A randomized, double-blind, placebo- and active treatment-controlled study of 2 years duration was conducted. Women included 410 postmenopausal women aged 47 to 74 years. The four treatment groups were: lasofoxifene 0.25 mg/day, or 1.0 mg/day, raloxifene 60 mg/day, or placebo daily. All women received daily calcium and vitamin D supplements. The primary endpoint was percent change from baseline to 2 years in lumbar spine bone mineral density (BMD) in all women having baseline and at least one follow-up bone density measurement. Total hip BMD, biochemical markers of bone turnover, low-density lipoprotein cholesterol, and safety were also evaluated in all women. Results: Both doses of lasofoxifene significantly increased lumbar spine BMD compared with raloxifene (P ≤ 0.05) and with placebo treatment (P ≤ 0.05). Least squares mean increases (95% CI) from baseline in lumbar spine BMD, compared with placebo, were 3.6% (1.9, 5.2) for lasofoxifene 0.25 mg/day, 3.9% (2.4, 5.5) for lasofoxifene 1.0 mg/day, and 1.7% (0.3, 3.0) for raloxifene. The two doses of lasofoxifene and raloxifene were equally effective at increasing total hip BMD. Lasofoxifene and raloxifene significantly reduced the levels of biochemical markers of bone turnover compared with placebo. In general, the effects of lasofoxifene were greater than the responses to raloxifene. At 2 years, lasofoxifene significantly (P ≤ 0.05) reduced low-density lipoprotein cholesterol levels by 20.6% and 19.7% with 0.25 mg/day and 1 mg/day, respectively, compared with raloxifene (12.1%) and placebo (3.2%). Lasofoxifene and raloxifene had a similar adverse event profile with low rate of discontinuations due to adverse events. Conclusions: Lasofoxifene may be an effective and well-tolerated treatment option for the prevention of bone loss in postmenopausal women.

Ibandronate produces significant, similar antifracture efficacy in North American and European women: new clinical findings from BONE.

ABSTRACT Objectives: BONE (oral iBandronate Osteoporosis vertebral fracture trial in North America and Europe) determined whether less frequent dosing of ibandronate (dose-free interval > 2 months) provided similar antifracture efficacy to daily dosing. As osteoporosis medications must be effective across different populations, an additional objective of BONE was to investigate and report the effect of oral ibandronate in North American and European women, as described here. Patients and methods: BONE was a randomized, double-blind, placebo-controlled, fracture-prevention study in 2946 postmenopausal women (age 55 years−80 years; ≥ 5 years since menopause) with osteoporosis (low lumbar spine bone mineral density and one to four prevalent vertebral fractures [T4−L4]). Participants received daily calcium (500 mg) and vitamin D (400 IU) plus either placebo, oral daily ibandronate (2.5 mg) or oral intermittent ibandronate (20 mg every other day for 12 doses every 3 months). The efficacy and tolerability of ibandronate were assessed independently in both North American and European populations. Results: Consistent, significant efficacy was observed in the North American (new vertebral fracture risk reduction: 60% and 54% with daily and intermittent ibandronate, respectively) and European patient populations (50% and 48%, respectively). Both ibandronate regimens also significantly reduced the incidence of new, worsening, and acute clinical, vertebral fractures. Daily and intermittent ibandronate significantly increased bone density at the spine in both North American (5.4% and 4.4% vs. baseline with daily and intermittent ibandronate, respectively) and European (7.1% and 6.3% vs. baseline, respectively) populations. Significant increases were also observed for total hip bone density (2.6% and 3.7% vs. baseline for daily, and 2.5% and 3.1% for intermittent; North American and European populations, respectively). Comparable, significant decreases in biochemical markers of bone turnover (reductions in urinary excretion of C-telopeptide levels of 53.5% and 67.1% vs. baseline for daily, and 50.0% and 53.8% for intermittent; North American and European populations, respectively) were also observed in both populations ( p < 0.004 for all cited measurements in each ibandronate group vs. placebo). Oral ibandronate was well tolerated in both North American and European patients, with a safety profile similar to placebo. Conclusions: Oral ibandronate, administered daily or intermittently, effectively reduced vertebral fracture risk in North American and European women with postmenopausal osteoporosis. These results demonstrate the efficacy of ibandronate administered with extended dose-free intervals, regardless of patients’ geographical origin. Research investigating other less frequent ibandronate regimens, such as once-monthly oral administration, is underway.

Ibandronate dose response is associated with increases in bone mineral density and reductions in clinical fractures: Results of a meta-analysis

This meta-analysis pooled data from the four phase III clinical trials of ibandronate to assess the relationship between ibandronate dose, changes in bone mineral density, and rates of both clinical and non-vertebral fractures. Individual patient data from the intent-to-treat population of the BONE, IV fracture prevention, MOBILE, and DIVA studies were included for analysis. The relationship between ibandronate dose and bone mineral density at both the lumbar spine and at the total hip was assessed qualitatively. The relationship between lumbar spine bone mineral density and clinical fracture rate, and the relationship between total hip bone mineral density and non-vertebral fracture rate, were assessed both qualitatively and using mathematical models. A total of 8710 patients were included in this analysis. Both lumbar spine and total hip bone mineral density were observed to increase with increasing ibandronate dose. The incidence of all clinical fractures was observed to decrease as lumbar spine bone mineral density increased. A statistically significant inverse linear relationship was observed between percent change in lumbar spine bone mineral density and the rate of clinical fractures (P=0.005). A non-significant curvilinear relationship was observed between percent change in total hip bone mineral density and non-vertebral fracture rate. Increased ibandronate exposure is associated with increasing gains in the lumbar spine bone mineral density and decreasing clinical fracture rates. A non-linear relationship may exist between increases in the total hip bone mineral density and non-vertebral fracture rate.

Alendronate with and without cholecalciferol for osteoporosis: results of a 15‐week randomized controlled trial

ABSTRACT Objective: Many osteoporosis patients have low 25-hydroxyvitamin D (25OHD) and do not take recommended vitamin D amounts. A single tablet containing both cholecalciferol (vitamin D3) and alendronate would improve vitamin D status concurrently, with a drug shown to reduce fracture risk. This study assessed the efficacy, safety, and tolerability of a once-weekly tablet containing alendronate 70 mg and cholecalciferol 70 μg (2800 IU) (ALN + D) versus alendronate 70 mg alone (ALN). Methods: This 15‐week, randomized, double-blind, multi-center, active-controlled study was conducted during a season when 25OHD levels are declining, and patients were required to avoid sunlight and vitamin D supplements for the duration of the study. Men ( n = 35) and postmenopausal women (n = 682) with osteoporosis and 25OHD ≥ 9 ng/mL were randomized to ALN + D ( n = 360) or ALN (n = 357). Main outcome measures: Serum 25OHD, parathyroid hormone, bone-specific alkaline phosphatase (BSAP), and urinary N‐telopeptide collagen cross-links (NTX). Results: Serum 25OHD declined from 22.2 to 18.6 ng/mL with ALN (adjusted mean change = –3.4;95% confidence interval [CI]: –4.0 to –2.8), and increased from 22.1 to 23.1 ng/mL with ALN + D (adjusted mean change = 1.2; 95% CI: 0.6 to 1.8). At 15 weeks, adjusted mean 25OHD was 26% higher ( p < 0.001, ALN + D versus ALN), the adjusted relative risk (RR) of 25OHD < 15 ng/mL (primary endpoint) was reduced by 64% (incidence 11% vs. 32%; RR = 0.36; 95% CI: 0.27 to 0.48 [ p < 0.001]), and the RR of 25OHD < 9 ng/mL (a secondary endpoint) was reduced by 91% (1% vs. 13%; RR = 0.09; 95% CI: 0.03 to 0.23 [ p < 0.001]). Antiresorptive efficacy was unaltered, as measured by reduction in bone turnover (BSAP and NTX). Conclusion: In osteoporosis patients who avoided sunlight and vitamin D supplements, this once-weekly tablet containing alendronate and cholecalciferol provided equivalent antiresorptive efficacy, reduced the risk of low serum 25OHD, improved vitamin D status over 15 weeks, and was not associated with hypercalcemia, hypercalciuria or other adverse findings, versus alendronate alone. Trial registration: ClinicalTrials.gov identifier: NCT00092066.

Weekly Oral Alendronic Acid in Male Osteoporosis

AbstractObjective: To evaluate the efficacy and tolerability of alendronic acid 70mg once weekly for the treatment of male osteoporosis. Patients and methods: This randomised, double-blind, placebo-controlled, 12-month trial compared the effect of alendronic acid 70mg once weekly or placebo (randomised 2: 1) on bone mineral density (BMD) in 167 men with spine or hip BMD at least 2 standard deviations (SD) below the mean for young normal white males or nontraumatic fracture. All patients received calcium and vitamin D (colecalciferol). We measured lumbar spine, hip and total body BMD, and biochemical markers of bone turnover. Fractures were collected as adverse events. Results: Alendronic acid 70mg once weekly produced significant BMD increases from baseline of 4.3% at the spine, 2.1% at the femoral neck, 2.4% at the trochanter, and 1.4% at the total body, which were all significantly greater than placebo (p < 0.05). The increase at the lumbar spine was significant relative to baseline and placebo after 6 months of treatment (p < 0.001). The treatment effect was consistent regardless of BMD, age, height, weight, body mass index (BMI) and hypogonadal status at baseline. Alendronic acid significantly decreased biochemical markers of bone turnover relative to baseline and placebo. Alendronic acid was generally well tolerated, with an incidence of gastrointestinal adverse events similar to placebo. Conclusion: Alendronic acid 70mg administered once weekly is an effective and convenient alternative to daily dosing for the treatment of male osteoporosis.

Efficacy and tolerability of once-monthly oral ibandronate (150 mg) and once-weekly oral alendronate (70 mg): additional results from the Monthly Oral Therapy With Ibandronate For Osteoporosis Intervention (MOTION) study.

BACKGROUND The MOTION (Monthly Oral Therapy with Ibandronate for Osteoporosis Intervention) study reported that once-monthly ibandronate was noninferior to once-weekly alendronate in terms of increasing bone mineral density (BMD) at the lumbar spine and total hip over 12 months. On analysis of secondary and exploratory end points in MOTION, which included trochanter and femoral neck BMD, monthly ibandronate was found to be noninferior to weekly alendronate. The coprimary, secondary, and exploratory BMD end points from MOTION have been previously reported. OBJECTIVE This report presents additional results from the MOTION study, including response rates in terms of lumbar spine and total hip BMD gains above baseline; findings from a comparison of serum concentrations of bone turnover markers; and tolerability analysis, including adverse events that led to withdrawal and gastrointestinal (GI) adverse events. METHODS MOTION was a 12-month (with 15-day follow-up), randomized, multinational, multicenter, double-blind, double-dummy, parallel-group, noninferiority study in postmenopausal women aged 55 to <85 years with osteoporosis. Patients were randomly assigned to receive 150-mg-monthly oral ibandronate and weekly alendronate-matched placebo, or 70-mg-weekly oral alendronate and monthly ibandronate-matched placebo, for 12 months. At baseline, day 7 of treatment, 3 and 6 months, 6 months + 7 days, and 12 months, serum concentrations of markers of bone resorption (C-telopeptide of the a chain of type 1 collagen [sCTX]) and bone formation (serum N-terminal propeptides of type 1 collagen) were measured in a subset of the total trial population. At baseline and month 12, BMD was measured using dual-energy x-ray absorptiometry. Exploratory analyses of patients whose spine, total hip, and trochanter BMD at 12 months were above baseline (responders) were also performed. RESULTS A total of 1760 women were enrolled (ibandronate, 887 patients; alendronate, 873). The median changes in the trough concentrations of sCTX were -75.5% with monthly ibandronate and -81.2% with weekly alendronate. The percentage of patients with mean lumbar spine and total hip BMD gains above baseline (responders) were 90% and 87%, respectively, for ibandronate and 92% and 90%, respectively, for alendronate. GI adverse events were reported in <or=30% of patients per group during this 1-year study. CONCLUSION The data from these postmenopausal women with osteoporosis suggest that once-monthly 150-mg ibandronate therapy provided clinically comparable efficacy in terms of BMD response, reductions in bone turnover, and GI tolerability similar to that of weekly 70-mg alendronate.

Denosumab versus risedronate in glucocorticoid-induced osteoporosis: a multicentre, randomised, double-blind, active-controlled, double-dummy, non-inferiority study

BACKGROUND Glucocorticoid-induced osteoporosis is the most common form of secondary osteoporosis and is associated with an estimated annual fracture rate of 5%. We aimed to assess the efficacy and safety of denosumab compared with risedronate in glucocorticoid-induced osteoporosis. METHODS We did a 24-month, double-blind, active-controlled, double-dummy, non-inferiority study at 79 centres in Europe, Latin America, Asia, and North America. Eligible patients were aged 18 years or older and were receiving glucocorticoids (≥7·5 mg prednisone daily, or equivalent) for at least 3 months (glucocorticoid continuing) or less than 3 months (glucocorticoid initiating) before screening. Patients younger than 50 years needed to have a history of osteoporosis-related fracture; glucocorticoid-continuing patients aged 50 years or older needed a lumbar spine, total hip, or femoral neck bone mineral density T score of -2·0 or less, or -1·0 or less if they had a history of osteoporosis-related fracture. Participants were randomly assigned (1:1) to either 60 mg subcutaneous denosumab every 6 months and oral placebo daily for 24 months, or 5 mg oral risedronate daily and subcutaneous placebo every 6 months for 24 months. Randomisation was stratified by sex within each subpopulation, and was done with an interactive voice-response system. Active drugs and corresponding placebos had identical packaging, labels, and appearance. The primary outcome was non-inferiority of denosumab to risedronate in terms of percentage change from baseline in lumbar spine bone mineral density at 12 months based on non-inferiority margins (-0·7 and -1·1 percentage points for the glucocorticoid-continuing and glucocorticoid-initiating subpopulations, respectively). Superiority was also assessed as a secondary outcome. The primary efficacy set included all randomly assigned participants who had a baseline and postbaseline lumbar spine bone mineral density measurement, and was analysed according to randomised treatment assignment. The safety analysis set included all randomly assigned participants who received at least one dose of investigational product, and was analysed by actual treatment received. This study is registered with ClinicalTrials.gov (NCT01575873) and is completed. FINDINGS Between March 28, 2012, and June 30, 2015, 795 patients, 505 of whom were glucocorticoid continuing and 290 of whom were glucocorticoid initiating, were enrolled and randomly assigned (398 to denosumab, 397 to risedronate). Denosumab was both non-inferior and superior to risedronate at 12 months for effect on bone mineral density at the lumbar spine in both glucocorticoid-continuing (4·4% [95% CI 3·8-5·0] vs 2·3% [1·7-2·9]; p<0·0001) and glucocorticoid-initiating (3·8% [3·1-4·5] vs 0·8% [0·2-1·5]; p<0·0001) subpopulations. Incidence of adverse events, serious adverse events (including infections), and fractures was similar between treatment groups. The most common adverse events were back pain (17 [4%] patients in the risedronate group and 18 [5%] in the denosumab group) and arthralgia (21 [5%] patients in the risedronate group and 17 [4%] in the denosumab group). Serious infection occurred in 15 (4%) patients in the risedronate group and 17 (4%) patients in the denosumab group. INTERPRETATION Denosumab could be a useful treatment option for patients newly initiating or continuing glucocorticoids who are at risk of fractures. FUNDING Amgen.