Stuart R. Weiss

Effect of Oral Alendronate on Bone Mineral Density and the Incidence of Fractures in Postmenopausal Osteoporosis

BACKGROUND Postmenopausal osteoporosis is a serious health problem, and additional treatments are needed. METHODS We studied the effects of oral alendronate, an aminobisphosphonate, on bone mineral density and the incidence of fractures and height loss in 994 women with postmenopausal osteoporosis. The women were treated with placebo or alendronate (5 or 10 mg daily for three years, or 20 mg for two years followed by 5 mg for one year); all the women received 500 mg of calcium daily. Bone mineral density was measured by dual-energy x-ray absorptiometry. The occurrence of new vertebral fractures and the progression of vertebral deformities were determined by an analysis of digitized radiographs, and loss of height was determined by sequential height measurements. RESULTS The women receiving alendronate had significant, progressive increases in bone mineral density at all skeletal sites, whereas those receiving placebo had decreases in bone mineral density. At three years, the mean (+/- SE) differences in bone mineral density between the women receiving 10 mg of alendronate daily and those receiving placebo were 8.8 +/- 0.4 percent in the spine, 5.9 +/- 0.5 percent in the femoral neck, 7.8 +/- 0.6 percent in the trochanter, and 2.5 +/- 0.3 percent in the total body (P < 0.001 for all comparisons). The 5-mg dose was less effective than the 10-mg dose, and the regimen of 20 mg followed by 5 mg was similar in efficacy to the 10-mg dose. Overall, treatment with alendronate was associated with a 48 percent reduction in the proportion of women with new vertebral fractures (3.2 percent, vs. 6.2 percent in the placebo group; P = 0.03), a decreased progression of vertebral deformities (33 percent, vs. 41 percent in the placebo group; P = 0.028), and a reduced loss of height (P = 0.005) and was well tolerated. CONCLUSIONS Daily treatment with alendronate progressively increases the bone mass in the spine, hip, and total body and reduces the incidence of vertebral fractures, the progression of vertebral deformities, and height loss in postmenopausal women with osteoporosis.

Efficacy and safety of ezetimibe added to ongoing statin therapy for treatment of patients with primary hypercholesterolemia.

Ezetimibe is a lipid-lowering drug that inhibits the intestinal absorption of dietary and biliary cholesterol by blocking passage across the intestinal wall. The efficacy and safety of adding ezetimibe to ongoing statin therapy in patients with primary hypercholesterolemia was evaluated in a randomized, double-blind, placebo-controlled study. The study group included 769 adults (aged > or =18 years) with primary hypercholesterolemia who had not achieved National Cholesterol Education Program (NCEP) Adult Treatment Panel II goals with dietary alteration and statin monotherapy. Patients receiving a stable dose of a statin for > or =6 weeks were randomized to receive concurrent treatment with placebo (n = 390) or ezetimibe (n = 379), 10 mg/day, in addition to continuing their open-label statin for 8 weeks. The primary efficacy variable was the percent change in low-density lipoprotein (LDL) cholesterol from baseline with statin monotherapy to end point after intervention (secondary variables: high-density lipoprotein [HDL] cholesterol and triglycerides). Ongoing statin therapy plus ezetimibe led to changes of -25.1% for LDL cholesterol (HDL cholesterol +2.7%; triglycerides -14.0%) compared with LDL cholesterol -3.7% (p <0.001), HDL cholesterol +1.0% (p <0.05), and triglycerides -2.9% (p <0.001) for placebo added to ongoing statin therapy. Among patients not at LDL cholesterol goal at on-statin baseline, 71.5% receiving statin plus ezetimibe versus 18.9% receiving statin plus placebo reached goal at end point (odds ratio 23.7; p <0.001). The co-administration of statin and ezetimibe was generally well tolerated. Adding ezetimibe to ongoing statin therapy led to substantial additional reduction in LDL cholesterol levels, facilitating attainment of NCEP goals. Ezetimibe offers a new therapeutic option for patients receiving statins who require further reduction in LDL cholesterol.

Reduction of LDL Cholesterol by 25% to 60% in Patients With Primary Hypercholesterolemia by Atorvastatin, a New HMG-CoA Reductase Inhibitor

This 6-week, double-blind clinical trial evaluated lipid parameter responses to different dosages of atorvastatin in patients with primary hypercholesterolemia. Atorvastatin is a new 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor under development. After completing an 8-week placebo-baseline dietary phase, 81 patients were randomly assigned to receive either placebo or 2.5, 5, 10, 20, 40, or 80 mg atorvastatin once daily for 6 weeks. Plasma LDL cholesterol reductions from baseline were dose related, with 25% to 61% reduction from the minimum dose to the maximum dose of 80 mg atorvastatin once a day. Plasma total cholesterol and apo B reductions were also dose related. Previously, reductions in LDL cholesterol of the magnitude observed in this study have been seen only with combination drug therapy. In this study, atorvastatin was well tolerated by hyperlipidemic patients, had an acceptable safety profile, and provided greater reduction in cholesterol than other previously reported HMG-CoA reductase inhibitors.

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

The Efficacy and Six-Week Tolerability of Simvastatin 80 and 160 mg/Day

The hydroxymethylglutaryl coenzyme A reductase inhibitor simvastatin is the most effective of the currently approved hypolipidemic drugs and has been shown to reduce mortality and coronary morbidity in patients with coronary artery disease. For these patients the United States National Cholesterol Education Program advocates reducing low-density lipoprotein (LDL) cholesterol to <100 mg/dl. However, in some patients this cannot be achieved using monotherapy with simvastatin 40 mg/day, the current maximal recommended dose. To evaluate the effectiveness of extending the dosage range, 156 subjects with LDL cholesterol >160 mg/dl and triglycerides (TG) <350 mg/dl were randomized to simvastatin at doses of 40, 80, and 160 mg/day in a 26 week, double-blind, 3-period, complete block crossover study. Each active treatment period was 6 weeks in duration with intervening 2 week washout periods. Median reductions from baseline in LDL cholesterol were 41%, 47%, and 53% in the 40-, 80-, and 160-mg groups, respectively. The corresponding reductions in plasma TG were 21%, 23%, and 33%. High-density lipoprotein (HDL) cholesterol increased by 6% to 8% in each group. One patient (0.7%) taking 160 mg developed myopathy; 1 patient (0.7%) taking 80 mg, and 3 (2.1%) taking 160 mg had transaminase elevations > 3 times the upper limit of normal. No new or unexpected adverse effects were observed. We conclude that simvastatin at doses of 80 and 160 mg/day provides additional efficacy with a low short-term incidence of adverse effects; our results support the continued investigation of simvastatin at these doses.

A randomized trial of the effects of atorvastatin and niacin in patients with combined hyperlipidemia or isolated hypertriglyceridemia

BACKGROUND To assess the lipid-lowering effects and safety of atorvastatin and niacin in patients with combined hyperlipidemia or isolated hypertriglyceridemia. METHODS We performed a randomized, open-label, parallel-design, active-controlled, study in eight centers in the United States. We enrolled 108 patients with total cholesterol (TC) of > or =200 mg/dL, serum triglycerides (TG) > or =200 and < or =800 mg/dL, and apolipoprotein B (apo B) > or =110 mg/dL. Patients were randomly assigned to receive atorvastatin 10 mg once daily (n=55) or immediate-release niacin 1 g three times daily for 12 weeks (n=53). Patients were stratified based on low-density lipoprotein cholesterol (LDL-C): Patients with LDL-C > or =135 mg/dL were considered to have combined hyperlipidemia and patients with LDL-C <135 mg/dL were considered to have isolated hypertriglyceridemia. The primary outcome measure was percent change from baseline in LDL-C. Other lipid levels were evaluated as secondary parameters. RESULTS Atorvastatin reduced LDL-C 30% and TC 26% from baseline, and increased high-density lipoprotein cholesterol (HDL-C) 4%. Total TG were reduced 17%. Niacin reduced LDL-C 2%, TC 7%, increased HDL-C 25%, and reduced total TG 29% from baseline. There was a significant difference in LDL-C reduction, the primary efficacy parameter, between the two treatment groups (P <0.05, favoring atorvastatin), as well as a significant difference in the improvement in HDL-C (P <0.05, favoring niacin). The effect of atorvastatin was relatively consistent between patients with combined hyperlipidemia and isolated hypertriglyceridemia, whereas there was more variability between these strata in the niacin treatment group. Atorvastatin was better tolerated than niacin. CONCLUSION Atorvastatin may allow patients with combined hyperlipidemia to be treated with monotherapy and offers an efficacious and well-tolerated alternative to niacin for the treatment of patients with isolated hypertriglyceridemia.

Efficacy and safety of Simvastatin 80 mg/day in hypercholesterolemic patients

Abstract This randomized, multicenter, double-blind parallel-group study was performed to evaluate the lipid-altering efficacy and safety of simvastatin 80 mg/day, a dose twice the current maximum recommended dose. At 20 centers in the United States, 521 male and female hypercholesterolemic patients were randomly assigned in a ratio of 2:3 to receive simvastatin 40 or 80 mg once daily, respectively, for 24 weeks in conjunction with a lipid-lowering diet. Patients met National Cholesterol Education Program (NCEP) low-density lipoprotein (LDL) cholesterol criteria for pharmacologic treatment. The mean percentage reductions (95% confidence intervals) from baseline in LDL cholesterol averaged at weeks 18 and 24 were 38% (−40 to −36) and 46% (−47 to −45) for the 40- and 80-mg groups, respectively (p

The Cost of Reaching National Cholesterol Education Program (NCEP) Goals in Hypercholesterolaemic Patients A Comparison of Atorvastatin, Simvastatin, Lovastatin and Fluvastatin

AbstractObjective: Recognising the importance of treating hyperlipidaemia, the National Cholesterol Education Program (NCEP) has established widely accepted treatment goals for low density lipoprotein cholesterol (LDL-C). Medications used most commonly to achieve these LDL-C goals are HMG-CoA reductase inhibitors. The relative resource utilisation and cost associated with the use of reductase inhibitors of different LDL-C lowering efficacy are unknown, but are major health and economic concerns. The objective of this study was to determine the mean total cost of care to reach NCEP goals with various reductase inhibitors. Design: In a randomised, 54-week, 30-centre controlled trial we compared resources used and costs associated with treating patients to achieve NCEP goals using 4 reductase inhibitors: atorvastatin, simvastatin, lovastatin and fluvastatin. Patients and Participants: The trial studied 662 patients; 318 had known atherosclerotic disease. Interventions: Reductase inhibitor therapy was initiated at recommended starting doses and increased according to NCEP guidelines and package insert information. For patients who did not reach the goal at the highest recommended dose of each reductase inhibitor, the resin colestipol was added. Main outcome measures and results: Patients treated with atorvastatin, compared with other reductase inhibitors, were more likely to reach NCEP goals during treatment (p < 0.05), required fewer office visits (p < 0.001) and less adjuvant colestipol therapy (p = 0.001). Consequently, the mean total cost of care (1996 values) to reach NCEP goals was lower with atorvastatin [

Effects of simvastatin and prevastatin on gonadal function in male hypercholesterolemic patients

US1064; 95% confidence interval (CI):

The lipid-lowering effects of atorvastatin, a new HMG-CoA reductase inhibitor: results of a randomized, double-masked study

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