A Randomized, Double-Blind, Single-Dose, Crossover Study to Demonstrate the Bioequivalence of 2 Formulations of Albiglutide in Healthy Adult Participants.

Albiglutide, developed for treatment of type 2 diabetes mellitus, is provided in a dual-chamber cartridge (DCC) single-dose pen-injector containing lyophilized drug that must be reconstituted with diluent prior to use. A liquid formulation of albiglutide has been developed that does not require mixing. In this 2-period, randomized, crossover, double-blind, phase I study (NCT02660736) in 59 healthy volunteers, pharmacokinetic parameters were determined and the bioequivalence of the 2 formulations was assessed. Participants received injections from each type of pen-injector, one containing albiglutide 50 mg and one containing placebo, followed by an 8-week washout period between regimens: albiglutide 50-mg liquid formulation from an auto-injector and lyophilized placebo from a DCC pen-injector (Regimen A), or placebo liquid from an auto-injector and lyophilized albiglutide 50 mg from a DCC pen-injector (Regimen B). Geometric mean total exposures (area under the drug concentration-time curve [AUC](0-t) [1345.4 vs 1426.9 (µg · h/mL)], AUC(0-∞) [1376.2 vs 1454.6 (µg · h/mL)], and maximum concentration of drug in blood plasma [4968.5 vs 5314.7 ng/mL]) were comparable between Regimens A and B. Ratios of geometric least square means (90% confidence interval) were 95.3% (89.49-101.52) for AUC(0-∞) , 95.1% (89.12-101.49) for AUC(0-t) , and 93.2% (86.76-100.17) for maximum concentration of drug in blood plasma, falling within the 90% confidence interval of 0.80 to 1.25 for bioequivalence. No new safety concerns were observed.

Evaluation of Quantitative Computed Tomography Cortical Hip Quadrant in a Clinical Trial With Rosiglitazone: A Potential New Study Endpoint.

Quantitative computed tomography (QCT) measurements have been used extensively to ascertain information about bone quality and density due to the 3-dimensional information provided and the ability to segment out trabecular and cortical bones. QCT imaging helps to improve our understanding of the role that each bone compartment plays in the pathogenesis and prognosis of fracture. This study was conducted to explore longitudinal changes in femoral neck (FN) cortical bone structure using both volumetric bone mineral density (vBMD) and cortical shell thickness assessments via QCT in a double-blind, randomized, multicenter clinical trial in postmenopausal women with type 2 diabetes mellitus. This study also examined whether treatment-associated changes in the cortical bone vBMD and thickness in femoral neck quadrants could be evaluated. Subjects were randomized to rosiglitazone (RSG) or metformin (MET) for 52 wk followed by 24 wk of open-label MET. A subset of 87 subjects underwent QCT scans of the hip at baseline, after 52 wk of double-blind treatment, and after 24 wk of treatment with MET using standard full-body computed tomography scanners. All scans were evaluated and analyzed centrally. Cortical vBMD at the FN was precisely segmented from trabecular bone and used to assess a possible therapeutic effect on this bone compartment. QCT analysis showed reductions in adjusted mean percentage change in vBMD and in absolute cortical thickness occurred with RSG treatment from baseline to week 52, whereas changes with MET were generally minimal. The reductions observed during RSG treatment for 1 yr appeared to partially reverse during the open-label MET phase from weeks 52 to 76. The femoral neck quadrant may provide utility as a potential endpoint in clinical trials for the understanding of the therapeutic effect of new entities on cortical bone vs trabecular bone; however, further clinical validation is needed. TRIAL REGISTRATION: The protocol (GSK study number AVD111179) was registered on ClinicalTrials.gov as NCT00679939.

A randomized placebo-controlled trial of the efficacy of denosumab in Indian postmenopausal women with osteoporosis.

INTRODUCTION: Osteoporosis is a serious condition affecting up to 50% of Indian postmenopausal women. Denosumab reduces bone resorption by targeting the receptor activator of nuclear factor-κB ligand. This study assessed the efficacy and safety of denosumab in Indian postmenopausal women with osteoporosis. MATERIALS AND METHODS: In this double-blind, multicenter, phase 3 study, 250 Indian postmenopausal women aged 55 to 75 years (T-score <-2.5 and >-4.0 at the lumbar spine or total hip; serum 25(OH) D levels ≥20 ng/mL) were randomized to receive one subcutaneous dose of denosumab 60 mg or placebo. All subjects received oral calcium ≥1000 mg and vitamin D3 ≥ 400 IU daily. The primary end point was mean percent change in bone mineral density (BMD) at the lumbar spine from baseline to Month 6. Secondary end points included mean percent change from baseline in BMD at total hip, femoral neck, and trochanter at Month 6 and median percent change from baseline in bone turnover markers at Months 1, 3, and 6. RESULTS: Total 225 subjects (denosumab = 111, placebo = 114) completed the six-month study. Baseline demographics were similar between groups. A 3.1% (95% confidence interval, 1.9%, 4.2%) increase favoring denosumab versus placebo was seen for the primary end point (P < 0.0001). Denosumab demonstrated a significant treatment benefit over placebo for the secondary end points. There were no fractures or withdrawals due to adverse events. CONCLUSIONS: Consistent with results from studies conducted in other parts of the world, denosumab was well tolerated and effective in increasing BMD and decreasing bone turnover markers over a six-month period in Indian postmenopausal women.

Rosiglitazone decreases bone mineral density and increases bone turnover in postmenopausal women with type 2 diabetes mellitus.

CONTEXT: Postmenopausal status and type 2 diabetes mellitus (T2DM) are independent risk factors for fractures. An increased fracture risk has been observed with rosiglitazone (RSG), a thiazolidinedione, in patients with T2DM. DESIGN AND SETTING: This was a randomized, double-blind study in postmenopausal women with T2DM. A 52-week double-blind phase (RSG or metformin [MET]) was followed by a 24-week open-label phase, during which time all patients received MET. MAIN OUTCOME MEASURES: The primary endpoint was to assess the mean percentage change in bone mineral density (BMD) at the femoral neck (FN) by dual-energy x-ray absorptiometry from baseline to week 52 in the RSG treatment group. Key secondary objectives included assessment of changes in BMD at the total hip, trochanter, and lumbar spine and to evaluate RSG effects on bone turnover markers. RESULTS: From baseline to week 52, RSG was associated with a reduction in FN BMD by dual-energy x-ray absorptiometry (-1.47%). During the open-label phase (weeks 52-76), no further loss in FN BMD was observed. A decrease in BMD occurred at the total hip during RSG or MET treatment at 52 weeks (-1.62 and -0.72%, respectively). Total hip BMD loss by RSG was attenuated after switching to MET and was similar between treatment groups at the end of the open-label phase. From baseline to week 52, bone turnover markers significantly increased with RSG compared with MET, but decreased significantly during the open-label phase. CONCLUSIONS: RSG for 52 weeks in postmenopausal women with T2DM was associated with small reductions in FN, total hip, and lumbar spine BMD and increased bone turnover markers. These effects are attenuated after cessation of RSG treatment.

Mechanism of action study to evaluate the effect of rosiglitazone on bone in postmenopausal women with type 2 diabetes mellitus: rationale, study design and baseline characteristics.

OBJECTIVES: Post-hoc analyses have shown an increase incidence of fractures among type 2 diabetes (T2DM) patients treated with thiazolidinediones (TZDs). The mechanisms by which TZDs may be associated with increased fracture risk is not well understood. This article describes the study design and baseline characteristics for a prospective, randomized, double-blind, active-controlled trial to evaluate the effects of rosiglitazone on changes in measures of skeletal structure, surrogates of bone strength and metabolism. METHODS: Postmenopausal women without osteoporosis and diagnosed with T2DM were randomized in a double-blind design to either rosiglitazone or metformin for 52 weeks, then all subjects received open-label metformin for 24 weeks. Study endpoints included changes in bone mineral density (BMD), quantitative computed tomography (QCT), digitized hip radiography (HXR) and high resolution magnetic resonance imaging (hrMRI). Serum markers of bone metabolism and indices of glycemic control were assessed within and between treatment groups. RESULTS: A total of 226 subjects were randomized. Baseline characteristics included: age 63.8 ± 6.5 years; years postmenopausal 16.9 ± 8.4; duration of diabetes 3.5 (1.8-7.8) years; body mass index (BMI) 31.4 ± 5.9 kg/m(2); and glycated hemoglobin (HbA1c) 6.4 ± 0.65%. At baseline, mean T-scores were -0.95 ± 0.91 at the femoral neck, -0.02 ± 0.97 at the total hip and -0.55 ± 1.25 at the total spine. Since there are no well recognized techniques to determine bone mass and structure at the distal limbs (cortical bone sites where fractures were reported in RSG subjects), using the femoral neck as a surrogate for these areas may be a potential limitation of the study. CONCLUSION: This is the first randomized trial utilizing multiple techniques to evaluate bone mass, structure, serum markers of bone remodeling, and potential reversibility of changes after discontinuation of rosiglitazone. This study will provide information about RSG bone effects in a population of postmenopausal women at risk for bone loss and subsequent fracture. CLINICALTRIALSGOV NUMBER: NCT00679939.

Teriparatide for acceleration of fracture repair in humans: a prospective, randomized, double-blind study of 102 postmenopausal women with distal radial fractures.

Animal experiments show a dramatic improvement in skeletal repair by teriparatide. We tested the hypothesis that recombinant teriparatide, at the 20 microg dose normally used for osteoporosis treatment or higher, would accelerate fracture repair in humans. Postmenopausal women (45 to 85 years of age) who had sustained a dorsally angulated distal radial fracture in need of closed reduction but no surgery were randomly assigned to 8 weeks of once-daily injections of placebo (n = 34) or teriparatide 20 microg (n = 34) or teriparatide 40 microg (n = 34) within 10 days of fracture. Hypotheses were tested sequentially, beginning with the teriparatide 40 microg versus placebo comparison, using a gatekeeping strategy. The estimated median time from fracture to first radiographic evidence of complete cortical bridging in three of four cortices was 9.1, 7.4, and 8.8 weeks for placebo and teriparatide 20 microg and 40 microg, respectively (overall p = .015). There was no significant difference between the teriparatide 40 microg versus placebo groups (p = .523). In post hoc analyses, there was no significant difference between teriparatide 40 microg versus 20 microg (p = .053); however, the time to healing was shorter in teriparatide 20 microg than placebo (p = .006). The primary hypothesis that teriparatide 40 microg would shorten the time to cortical bridging was not supported. The shortened time to healing for teriparatide 20 microg compared with placebo still may suggest that fracture repair can be accelerated by teriparatide, but this result should be interpreted with caution and warrants further study.

Active comparator trial of teriparatide vs alendronate for treating glucocorticoid-induced osteoporosis: results from the Hispanic and non-Hispanic cohorts.

Glucocorticoid use is a leading cause of secondary osteoporosis. This post hoc analysis compared teriparatide vs alendronate on bone mineral density (BMD) in Hispanic and non-Hispanic patients with glucocorticoid-induced osteoporosis. The 18-mo results from all patients (N=428) in a double-blind trial of teriparatide (20 microg/d) and alendronate (10 mg/d) who had taken glucocorticoids for >or=3 mo were reported (Saag et al. N Engl J Med 2007). The present study analyzed results from the Hispanic (n=61) and non-Hispanic (n=367) cohorts. The BMD was measured by dual-energy X-ray absorptiometry (DXA). In the Hispanic cohort at 18 mo, there were significantly greater increases from baseline in the teriparatide vs alendronate group in lumbar spine BMD (9.8%+/-1.7% vs 4.2%+/-1.4%; p<0.001; mean+/-SE) and total hip BMD (5.9%+/-1.6% vs 1.3%+/-1.3%, p<0.001), with no significant difference between groups at the femoral neck (4.3%+/-2.2% vs 2.0%+/-1.8%, p=0.228). Within each treatment group, the BMD responses were not significantly different in the Hispanic vs non-Hispanic cohort. The number of patients reporting >or=1 adverse event was not significantly different between treatments in either cohort, with more patients reporting nausea in the teriparatide group. In summary, teriparatide was more efficacious than alendronate in increasing BMD in Hispanic and non-Hispanic patients with glucocorticoid-induced osteoporosis. Both treatments were generally well tolerated.

Predictors of hot flushes in postmenopausal women who receive raloxifene therapy.

OBJECTIVE: In a previous report, we described the results of a randomized, controlled trial that evaluated the potential of raloxifene to induce or exacerbate hot flushes. Here, we provide additional analyses that were undertaken to identify potential predictors of hot flushes and to assess the clinical usefulness of various therapeutic strategies for the reduction of hot flushes in postmenopausal women who receive raloxifene therapy. STUDY DESIGN: In this randomized, double-blind, placebo-controlled study, 487 unselected postmenopausal women were assigned randomly to receive treatment for 8 months with raloxifene, which was administered either at a dose of 60 mg/d every other day for 2 months followed by 60 mg/d (slow-dose escalation) or 60 mg/d throughout (raloxifene), or placebo. Data on the number, duration, intensity, and severity of hot flushes and awakenings because of night sweats were collected. Logistic regression models were used to examine the predictive value of various demographic and menopausal factors on the development or worsening of hot flushes. RESULTS: At baseline, 40.4% of all randomly assigned patients had hot flushes. The mean number of hot flushes (3-5 per week) was low. Fewer years postmenopause, surgical menopause, and previous estrogen or estrogen/progestin therapy were significant predictors of hot flushes at baseline but were not predictive of incident hot flushes during treatment with raloxifene. Of the women who received raloxifene therapy who had pre-existing hot flushes at baseline, 36% women had none at the end point. Early postmenopause and surgical menopause were significant predictors of a biologically relevant increase in hot flushes (>/=14 flushes/week). Early postmenopause, previous estrogen/progestin therapy, high body mass index, and greater duration of hot flushes at baseline were significant predictors of the need for symptomatic treatment. After 2 months of treatment, women in early postmenopause had significantly more hot flushes with raloxifene therapy than with slow-dose escalation ( P = .042), whereas there was no significant difference between raloxifene therapy and slow-dose escalation among women in later postmenopause. In the 50 patients who requested symptomatic treatment during the study, phytohormones or veralipride did not reduce the number of hot flushes markedly. CONCLUSION: A shorter time since menopause and surgical menopause are important predictors of hot flushes both before and during treatment with raloxifene. Previous estrogen/progestin therapy also increases the risk of hot flushes at baseline. For women in early postmenopause, slow-dose escalation of raloxifene therapy may be a suitable therapeutic strategy for the reduction of the risk of hot flushes.