Comparison of Antiresorptive Therapies in Head-to-Head Trials and the EVista and Alendronate Comparison Trial
Several head-to-head comparisons of the effects of antiresorptive therapies on surrogate markers of bone efficacy have been performed to date. These studies essentially confirm results from placebo-controlled trials in terms of magnitude of effects on surrogate markers. Similar increases in lumbar spine BMD and decreases in bone turnover were observed for alendronate (10 mg/day) and conjugated equine estrogen (CEE) (0.625 mg/day) in postmenopausal women with low BMD. However, CEE was associated with greater gains in BMD than alendronate when it was compared with lower doses of alendronate (5 or 2.5 mg/day) in healthy young postmenopausal women. Alendronate produced greater increases in BMD and greater decreases in bone turnover than did intranasal calcitonin in two separate head-to-head studies.[39,40] Greater increases in BMD and decreases in bone turnover have been also observed with CEE (0.625 mg/day) plus medroxyprogesterone[41,42] or alendronate (10 mg/day), as compared with raloxifene (60 mg/day).
Given the difficulties in comparing results across clinical trials with fracture as an endpoint, as well as interpreting the results of head-to-head trials with surrogate markers of bone efficacy as an endpoint, a head-to-head comparison of antiresorptive agents with the endpoint of total fracture would assist the physician in making informed therapeutic decisions. The measurement of total fracture risk reduction is a more clinically relevant endpoint than either vertebral or nonvertebral fractures alone, because radiographic and clinical vertebral fractures and nonvertebral fractures are associated with increased morbidity and mortality[5,6,44,45] and a majority of the patients are treated with antiresorptive agents with the goal of preventing any fracture, not a specific fracture type. Given the importance of preventing the first vertebral fracture,[5-9] patients with osteoporosis by BMD definitions who have not yet sustained a vertebral fracture are particularly well suited for study in such a trial. Therefore, a fracture endpoint trial, the Evista Alendronate Comparison (EVA) trial, is currently underway to compare directly the osteoporotic fracture risk reduction efficacy of raloxifene and alendronate in postmenopausal women with osteoporosis as defined by BMD. In addition to a direct comparison of the bone efficacy of these drugs, this trial will also allow comparison of extraskeletal effects and the safety of the two therapies. Because of the lack of anti-fracture efficacy data of the alendronate 70 mg weekly formulation, the alendronate 10 mg/day dosage was selected for comparison to raloxifene.
The EVA trial is a multi-center, double-blind, double-dummy, randomized clinical trial with two active treatment arms. After giving informed consent, approximately 3000 patients will be randomly assigned to one of two treatment groups: raloxifene HCl 60 mg/day or alendronate Na 10 mg/day. We calculate that with 1500 patients per arm there will be more than 90% power to establish the equivalence of raloxifene to alendronate with an equivalence margin of 30% at 5 years of treatment. All patients will also receive approximately 500 mg elemental calcium and 400 IU of vitamin D daily as supplements to their usual daily intake. The study will consist of two phases: a screening phase and a treatment phase lasting 5 years.
The study endpoints are shown in Table 2. The primary endpoint of this study is to compare the effects of treatment with raloxifene with those of alendronate in postmenopausal women with osteoporosis on the number of patients who experience at least one new osteoporotic fracture (vertebral or nonvertebral). Secondary objectives of this study include a comparison of the effects of the two treatments on the number of woman with any osteoporotic fracture at a particular site (such as vertebral, hip, wrist, etc.), on the incidence of newly diagnosed breast cancer, integrated measures of health utility scores, height loss, percentage change in lumbar spine or femoral neck BMD.
Bone mineral density measurements will be performed using dual-energy X-ray absorptiometry (DXA) in the spine and hip at baseline and again at 2 years. Lateral thoracic and lumbar spine radiographs will be obtained at baseline and at 3 and 5 years. Vertebral osteoporotic fractures will be determined from lateral spine radiographs using semiquantitative analysis. Nonvertebral fractures will be collected and confirmed via radiograph or written report. Mammograms will be performed at baseline and annually. Adverse events and height measurements will be made at baseline and annually.
Eligible participants are ambulatory postmenopausal women, 50-80 years of age, with osteoporosis defined by femoral neck BMD T-score between -4.0 and -2.5 using the NHANES reference database and no prior vertebral fracture. This age range was chosen because this is when most osteoporotic fractures are likely to occur. Patients over 80 years were not included because of issues related to life expectancy in a 5-year trial. Among the important exclusion criteria are a history of estrogen-dependent neoplasia, a history of venous thromboembolism, long-term treatment with glucocorticoids, diseases that affect calcium or skeletal metabolism, and recent treatment with bone active drugs. Investigators may also exclude any patients in whom a disease of any kind could compromise the safety or evaluation of this study.
This is the first comparative study of two drugs known to be effective against osteoporotic fracture, raloxifene and alendronate, with fracture as a primary endpoint. By studying both drugs in one large, well-defined population of postmenopausal women with osteoporosis, we can expect to overcome many of the problems inherent in comparing their overall safety and efficacy from separate studies. Data obtained from this study will thus permit more informed judgment by practitioners and provider groups concerning the relative clinical utility of these two drugs.
Address for correspondence: Dr Edward Gwynne Lufkin, Lilly Research Laboratories, Lilly Corporate Center , DC 4109, Eli Lilly and Company, Indianapolis, IN 46285, USA. Tel.: +1-317-277-3187; Fax: +1-317-277-3743; email: email@example.comPrevious PageSection 4 of 4Curr Med Res Opin 20(3):351-357, 2004. © 2004 Librapharm Limited
This is a part of article Antiresorptive Treatment of Postmenopausal Osteoporosis: Review Taken from "Danazol Danocrine" Information Blog