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Therapeutic equivalence of alendronate 35 milligrams once weekly and 5 milligrams daily in the prevention of postmenopausal osteoporosis
Therapeutic Equivalence of Alendronate 35 Milligrams Once Weekly and 5 Milligrams Daily in the Prevention of Postmenopausal Osteoporosis Marjorie M. Luckey, MD, Nigel Gilchrist, MBChB, Henry G. Bone, MD, Michael W. Davie, MD, Tobias J. de Villiers, MBChB, MMed, Mei Wu, MS, Anastasia G. Daifotis, MD, Arthur C. Santora, MD, PhD, and John J. Orloff, MD OBJECTIVE: To evaluate the efficacy and safety of alendronate 35 mg once weekly compared with alendronate 5 mg daily in the prevention of osteoporosis. METHODS: We compared the efficacy and safety of treatment with alendronate 35 mg once weekly (n ⴝ 362) and alendronate 5 mg daily (n ⴝ 361) in a 1-year, double-blind, multicenter study of postmenopausal women (6 months or greater), aged 40 –70 years, with lumbar spine and femoral neck bone mineral density T-scores between ⴚ2.5 and 1. The primary efficacy end point was the comparability of lumbar spine bone mineral density increases, defined by strict prespecified criteria. RESULTS: Mean increases in lumbar spine bone mineral density at 12 months were equivalent (difference between the alendronate 35-mg once-weekly group and the alendronate 5-mg daily group [90% confidence interval] at month 12 was ⴚ0.3% [ⴚ0.6, 0.1], well within the prespecified bounds of ⴞ1.0%). Bone mineral density increases at other skeletal sites and effects on bone turnover were also virtually identical for the two dosing regimens. Both treatment regimens were well tolerated, and the larger weekly unit dose was not associated with an increased frequency of upper gastrointestinal events. CONCLUSION: Alendronate 35 mg once weekly is therapeutically equivalent to alendronate 5 mg daily and provides patients with greater dosing convenience, in addition to the proven efficacy of alendronate and good tolerability. (Obstet Gynecol 2003;101:711–21. © 2003 by The American College of Obstetricians and Gynecologists.) From the Saint Barnabas Ambulatory Care Center, Livingston, New Jersey; Princess Margaret Hospital, Christchurch, New Zealand; Michigan Bone & Mineral Clinic, Detroit, Michigan; Jones and Hunt Orthopedic Hospital, Shropshire, United Kingdom; Panorama Medi-Clinic, Capetown, South Africa; and Merck Research Laboratories, Rahway, New Jersey. The authors thank Marianne Daley and Christine Peverly for their outstanding contributions in overseeing the conduct of this trial, and Douglas Tracey and Andrea Dynder for expert data coordination and statistical programming support.
After the onset of menopause, many women begin to experience accelerated bone loss due to estrogen deficiency, which poses a heightened risk of developing osteoporosis if intervention is not instituted. Osteoporotic fractures are one of the most common causes of morbidity and mortality in postmenopausal women. It is estimated that a 50-year-old postmenopausal white woman, irrespective of her bone mineral density, carries at least a 40% lifetime risk of fracture if left untreated.1,2 Fracture risk among osteoporotic women is about four times that among nonosteoporotic women in the same age group.3 Despite the availability of effective therapies to prevent osteoporosis, including the bisphosphonate alendronate, the use of such therapies in women at risk for osteoporosis has been relatively low.4 One of the reasons for this finding may be a perception of dosing inconvenience, particularly for bisphosphonates dosed as a daily regimen. Patients taking bisphosphonates are instructed to take the tablet fasting (with water only), to wait at least 30 minutes before the first food or other medication of the day, and to remain upright for at least 30 minutes postdose. These dosing requirements may be perceived by some patients, especially asymptomatic early postmenopausal women, as adding complexity to their daily routine. Thus, a less frequent dosing regimen, such as alendronate once weekly, would be a more attractive preventive therapy that may enhance long-term compliance. Animal studies have shown that larger doses of alenFinancial Disclosure This study was supported by funding from Merck Research Laboratories, Rahway, New Jersey. Mei Wu, Anastasias G. Daifotis, Arthur C. Santora, and John J. Orloff are employees of Merck & Co. Inc. and potentially own stock and/or hold stock options in the Company.
VOL. 101, NO. 4, APRIL 2003 © 2003 by The American College of Obstetricians and Gynecologists. Published by Elsevier.
0029-7844/03/$30.00 doi:10.1016/S0029-7844(03)00008-5
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dronate can be given less frequently and produce similar effects on bone mineral density, provided the same cumulative dose is maintained.5–7 This is supported by pharmacokinetic studies in animals and humans, which have demonstrated that the absorption, distribution, and elimination properties of alendronate lend themselves to less frequent dosing schedules.8 –10 Earlier clinical trials showed that higher doses of oral daily bisphosphonates were associated with upper gastrointestinal adverse events in a dose-dependent manner.11–13 Studies in animals, however, showed that once-weekly exposure to a high concentration of alendronate in an acid pH solution (to simulate refluxed gastric contents) over 4 weeks did not result in esophageal irritation, whereas daily dosing with lower concentrations of alendronate or risedronate was associated with esophagitis.14,15 These preclinical experiments predicted that once-weekly alendronate would have a similar, if not improved, safety and tolerability profile, compared with daily alendronate. To test the hypothesis that weekly and daily dosing regimens of alendronate are therapeutically equivalent, two multicenter, randomized studies were conducted to evaluate the efficacy and safety of once-weekly alendronate in comparison with daily alendronate in postmenopausal women. The recently published “treatment” study in postmenopausal women with osteoporosis showed that alendronate 70 mg once weekly and 35 mg twice weekly produced bone mineral density changes at the lumbar spine equivalent to that achieved with alendronate 10 mg daily, as determined by stringent, predefined equivalence criteria. Bone mineral density changes at other skeletal sites, including hip and total body, were also similar for all three treatment regimens.16 The overall safety profiles of the three treatment groups were very similar, and numerically lower incidences of upper gastrointestinal adverse experiences in several categories (gastroesophageal irritation and serious upper gastrointestinal adverse experiences) were observed in the weekly dosing group compared with the daily dosing group. Presented herein are results from a study comparing the efficacy and safety of alendronate 35 mg once weekly with 5 mg daily in postmenopausal women without osteoporosis. MATERIALS AND METHODS To be eligible for the study, women had to be 40 –70 years of age and postmenopausal, as diagnosed by a history of the absence of menstrual periods during the 6 months preceding randomization; for those women whose last menstrual period occurred 6 –12 months before study start, serum follicle-stimulating hormone levels were confirmed to be in the reference range for
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postmenopausal women. Other entry criteria included bone mineral density T-score (standard deviation difference from the normal young premenopausal mean) between ⫺2.5 and 1.0 at both the lumbar spine and the femoral neck, no history of osteoporotic fracture of the spine or hip, and no vertebral fracture as determined by lateral thoracolumbar spine radiographs evaluated locally. After randomization, baseline radiographs showing vertebral deformities were forwarded to a central radiologist (H.K. Genant, University of California, San Francisco) for further assessment and adjudication of potential vertebral fractures, using previously defined criteria.17 Subjects were not excluded on the basis of previous or active gastrointestinal disease, but they were excluded if there was a history of recent major upper gastrointestinal (esophagus, stomach, duodenum) mucosal erosive disease as defined by 1) significant upper gastrointestinal bleeding within the last year resulting in hospitalization and/or transfusion, 2) recurrent ulcer disease documented by radiographic or endoscopic means (two episodes in the last 2 years, or any documented ulcer in the preceding 3 months), 3) uncontrolled dyspepsia despite treatment on a daily basis, 4) esophageal or gastric variceal disease, or 5) esophageal stricture, achalasia, or severe esophageal motor dysfunction. Subjects were not excluded if symptoms of dyspepsia were controlled by daily medication, or because of a prior history of nonrecurrent peptic ulcer disease or concomitant use of aspirin or nonsteroidal antiinflammatory medications. Additional exclusion criteria included significant renal or hepatic dysfunction, myocardial infarction within the previous 6 months, uncontrolled hypertension, severe malabsorption, vitamin D deficiency, metabolic bone diseases (uncontrolled hypo- or hyperthyroidism, hypoor hyperparathyroidism, hypo- or hypercalcemia, Paget disease of bone, osteomalacia, or osteogenesis imperfecta). Women who had taken estrogen, calcitonin, or glucocorticoids within the preceding 6 months, or bisphosphonates or sodium fluoride (more than 1 mg per day) at any time were also excluded. This study was conducted at 43 centers in seven countries. Of the 1048 women screened, 723 were randomized. Randomization took place within each clinic. The number of women randomized in each center ranged from 3 to 37. Failure to meet one or more inclusion criteria accounted for 44% of those not randomized, whereas 20% of screening failures met one or more exclusion criteria. Of the screening failures, 36% were disqualified for reasons other than the inclusion/ exclusion criteria, including clinical adverse experiences (3%), laboratory adverse experiences (1%), withdrew consent (25%), lost to follow-up (2%), and protocol de-
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viation (5%), all of which occurred during the placebo run-in period prior to randomization. Exclusion of subjects with adverse experiences during the placebo run-in period should not have any impact on efficacy or safety analyses, because these subjects were not yet randomized. The demographic characteristics of nonrandomized subjects did not differ substantially from those of randomized subjects. All subjects screened gave written, informed consent, and the study protocol was approved by institutional ethical review boards. This was a 1-year, multicenter, randomized, doubleblind study. Subjects were randomly assigned to receive either oral alendronate 5 mg daily or 35 mg once weekly. Treatment allocations were determined using a computer-generated allocation schedule. To maintain treatment blinding, a “double-placebo” treatment design (two different tablet images, only one of which contained alendronate for any given subject) was utilized. Subjects assigned to the 35-mg once-weekly group took an active 35-mg tablet each Tuesday and also took placebo matching the 5-mg tablet every day of the week, whereas subjects assigned to the 5-mg daily group took an active 5-mg tablet every day of the week, and also took placebo matching the 35-mg tablet each Tuesday. Before randomization, all subjects underwent a 14-day, single-blind placebo run-in period using placebo tablets matched to the two different tablet images. All subjects who were found to be less than 100% compliant with the 35-mg once-weekly placebo tablets or less than 80% compliant with the 5-mg daily placebo tablets, without a valid explanation, were excluded from randomization into the study. In addition to study medication, all subjects also received a supplement providing 500 mg per day of elemental calcium (as carbonate) and 250 IU per day of vitamin D. Subjects were instructed to take study medication in the morning with 6 – 8 oz water (at least 4 oz water were to have followed the last tablet on the day when two tablets were taken) at least 30 minutes before any other food or drink. They were also instructed to wait at least 30 minutes after dosing before taking other oral medications, including calcium supplements, and to remain upright for at least 30 minutes after dosing and until after the first food of the day. Bone mineral density was measured by dual-energy x-ray absorptiometry using Hologic (Hologic Corp., Bedford, MA) and Lunar (Lunar Corp., Madison, WI) densitometers. Results expressed as percentage changes in bone mineral density from these two densitometers were combined, as they are independent of the machine type.18 All bone mineral density analyses were performed by a central analysis facility that was blinded to treatment group and to other subject data. Daily mea-
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surements of bone mineral density phantoms by each dual-energy x-ray absorptiometry instrument detected no significant machine drift during the 1-year study, as determined by the bone mineral density Quality Control Center (Synarc Inc., DXA Centralized Analysis Facility, Portland, OR). Laboratory parameters used to evaluate changes in bone turnover were urinary N-telopeptides corrected for creatinine (Osteomark, Ostex, Seattle, WA) to assess the rate of bone resorption, and serum bone-specific alkaline phosphatase (Ostase, Beckman-Coulter, San Diego, CA) to assess the rate of bone formation. Assays were performed at a central laboratory (Mayo Clinical Laboratories, Rochester, MN). Safety was assessed on the basis of clinical evaluations and laboratory measurements, including serum chemistry, hematology, and urinalysis performed at each clinic visit at baseline and months 1, 3, 6, and 12. All clinical and laboratory adverse experiences, as well as concomitant medication use were recorded. Clinical adverse experiences were recorded on the basis of self-report. Clinical fractures were reported as adverse experiences. If a subject experienced clinical symptoms suggestive of an incident vertebral fracture, follow-up spine radiographs were obtained and sent, with the baseline spine radiograph, to the central facility (H.K. Genant, University of California, San Francisco) for fracture adjudication based on semi-quantitative assessment.17 The primary efficacy end point was the percent change from baseline at month 12 in lumbar spine bone mineral density (L1 to L4); safety and tolerability at month 12 was a co-primary end point. Secondary end points included percent changes from baseline at month 12 in bone mineral density of the hip (total hip, femoral neck, and trochanter) and total body, as well as in biochemical markers of bone turnover. The primary hypothesis was that 1 year of treatment with alendronate 35 mg once weekly would produce an increase in lumbar spine bone mineral density in postmenopausal women equivalent to that produced by alendronate 5 mg daily. The hypothesis was to be accepted if the 90% confidence interval (CI) of the between-treatment-group difference in mean percent change remained entirely within the equivalence range of ⫺1.0% to 1.0%. This range represents approximately 26% of the net treatment effect (alendronate 5 mg minus placebo percent change in lumbar spine bone mineral density) observed as the weighted average from two previous osteoporosis prevention studies,19,20 and any betweentreatment-group differences (and 90% CI) within this range are not likely to be clinically meaningful. The criterion is also consistent with standard recommendations for equivalence trials.21 Assuming a standard devi-
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ation of 2.61%, as was observed in a previous prevention study following 1 year of treatment with alendronate 5 mg daily,20 350 evaluable patients each in the alendronate 35-mg once-weekly and 5-mg daily groups would provide 99% (␣ ⫽ .05, two-tailed) power to demonstrate equivalence in lumbar spine bone mineral density, according to the above criterion. The percent changes in bone mineral density at the total hip, femoral neck, trochanter, and total body sites were evaluated to support the primary end point, but no clinical equivalence criteria were prespecified for these sites. The percent changes in bone mineral density were analyzed using an analysis of variance (ANOVA) model including treatment and study center as model factors. Subgroup analyses were performed for the percent change in lumbar spine bone mineral density to determine whether the treatment effect was different in prespecified subgroups, including baseline age, number of years since menopause, baseline lumbar spine bone mineral density, and baseline lumbar spine bone mineral density T-scores. The effect of subgroups was evaluated by the covariate by treatment interaction tests performed at the significance level of .05 (two-sided). For biochemical markers of bone turnover, the natural log fractions of on-treatment to baseline values at month 12 were analyzed using an ANOVA model including treatment and study center as model factors. This log transformation was used to normalize the distribution of the fractional change in biochemical markers. Geometric mean percent change from baseline was then calculated by back-transforming the arithmetic mean of the log fractions. The net result is identical to the percent change of the geometric mean of on-treatment values relative to the geometric mean of baseline values. Geometric means are more appropriate for analysis of biochemical markers, because the distribution of marker values in a postmenopausal population tends to be skewed. The primary analysis for bone mineral density change was performed using the completers’ approach, with all patients who have baseline and end-point data included in the analysis, because the intention-to-treat approach is not considered conservative in the context of an equivalence trial.21 Although subjects who discontinued the study because of adverse experiences were excluded from the completers’ analysis, similar proportions of subjects dropped out of the two treatment groups, so that their exclusion should not differentially influence the outcome of the analysis with respect to treatment group. The results of the completers’ analysis are presented in the section below, although intention-to-treat and per-protocol analyses were also performed for bone mineral density change and did not change the conclusions of the study. Biochemical markers were analyzed using only the per-protocol ap-
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proach. Fisher exact test was used to evaluate the between-treatment-group differences in the proportion of subjects with certain adverse experiences, with the primary focus being upper gastrointestinal adverse experiences. RESULTS Women randomized to the two treatment groups had similar baseline characteristics in terms of age, years since menopause, body mass index, dietary calcium intake, prior vertebral fracture, history of upper gastrointestinal disease, and prior nonsteroidal antiinflammatory drugs or aspirin use (Table 1). Although women with radiologic fractures of the lumbar spine were excluded at screening based on local review of spine radiographs, small, comparable proportions of women enrolled in the two treatment groups (5.5% and 3.6% in the 5-mg daily and 35-mg once-weekly groups, respectively) had baseline vertebral fractures as determined by central review of spine radiographs. These subjects were not discontinued from the study. At baseline, women in the two treatment groups had similar bone mineral density values at the lumbar spine and total hip, as well as similar rates of bone turnover, as indicated by levels of bone resorption and formation markers (Table 1). Of the 723 subjects randomized, 83.7% (82.5% and 84.8% in the alendronate 5-mg daily and 35-mg once-weekly groups, respectively) were included in the completers’ analysis of the primary end point. Reasons for exclusion from the completers’ analysis include discontinuation owing to clinical adverse experiences, lost to follow-up, withdrew consent, and protocol deviation. There was no apparent betweentreatment-group difference in the proportion of discontinued patients in each category. The primary end point was the change in lumbar spine bone mineral density from baseline at month 12. As shown in Figure 1 and Table 2, treatment with alendronate 35 mg once weekly and 5 mg daily over 12 months resulted in significant percentage increases from baseline in lumbar spine bone mineral density (2.9% and 3.2%, respectively, at month 12). The between-treatment-group difference in the percent change at month 12 (90% CI) was ⫺0.3% (⫺0.6, 0.1), with the 90% CI falling well within the prespecified bounds of ⫾1.0%, indicating that the two treatment regimens are equivalent with respect to the primary end point (Figure 2). Significant increases in bone mineral density from baseline were also observed at the total hip, femoral neck, trochanter, and total body in both treatment groups (Figure 1 and Table 2). There was no meaningful between-treatmentgroup difference in the percent change at month 12 at
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Table 1. Baseline Patient Characteristics Alendronate Variable Age (y)* Years since menopause* Body mass index (kg/m2)* Dietary calcium intake daily (mg)* Race: white (%)† Prior vertebral fracture (%) History of upper GI disease (%) Recent NSAID/aspirin use‡ (%) Bone mineral density (g/cm2) Lumbar spine Hologic densitometer* Lunar densitometer* Total hip Hologic densitometer* Lunar densitometer* Biochemical markers Urine NTx (nmol BCE/mmol creatinine)§ BAP (ng/mL)§
5 mg daily (n ⫽ 361)
35 mg once weekly (n ⫽ 362)
56.1 ⫾ 5.7 9.0 ⫾ 7.3 26.9 ⫾ 5.1 632.7 ⫾ 411.7 97.0 5.5 25.2 35.7
56.3 ⫾ 6.0 9.9 ⫾ 7.7 27.1 ⫾ 5.2 669.0 ⫾ 437.5 95.3 3.6 30.9 39.2
0.93 ⫾ 0.10 1.09 ⫾ 0.11
0.95 ⫾ 0.11 1.08 ⫾ 0.12
0.85 ⫾ 0.10 0.94 ⫾ 0.11
0.86 ⫾ 0.10 0.92 ⫾ 0.10
57.4 ⫾ 2.4 13.1 ⫾ 0.2
54.8 ⫾ 1.9 13.0 ⫾ 0.2
GI ⫽ gastrointestinal; NSAID ⫽ nonsteroidal antiinflammatory medication; NTx ⫽ N-telopeptides; BAP ⫽ bone-specific alkaline phosphatase. * Values are mean ⫾ standard deviation. † Twenty-eight patients not counted under “white” include the following ethnic groups: black (5), other (23). ‡ Two weeks before study start. § Values are geometric means ⫾ standard error.
any skeletal site, although no comparability criteria were prespecified for the hip and total body sites. All 90% CIs of the differences included zero (data not shown), suggesting that there were no significant differences in treatment effect at any skeletal site measured. Although analysis of bone mineral density change was performed using the completers’ approach, intention-to-treat and per-protocol analyses yielded similar results at all skeletal sites. The mean lumbar spine bone mineral density percent changes from baseline at month 12 in the alendronate 35-mg once-weekly and 5-mg daily groups were 2.8% and 3.1%, respectively, based on the intention-to-treat analysis, and 2.8% and 3.2%, respectively, based on the per-protocol analysis. An overwhelming majority of the women experienced an increase in bone mineral density (more than 0% change) at the lumbar spine and total hip in both treatment groups (Table 3); at month 12, the proportions of women experiencing any increase in lumbar spine bone mineral density were 88.6% and 90.2% in the 5-mg daily and the 35-mg once-weekly groups, respectively. There was no meaningful between-treatment-group difference in the proportion of women with any increase in bone mineral density at either skeletal site. The proportions of women experiencing more than 2% gain, less than 2% change, and more than 2% loss at the lumbar spine and total hip were similar between treatment groups (Figure 3); at month 12, the proportions of women with a bone
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mineral density gain of more than 2% at the lumbar spine were 71.1% and 66.8% in the 5-mg daily and the 35-mg once-weekly groups, respectively. Prespecified subgroup analyses indicated that the increases in lumbar spine bone mineral density were similar between treatment groups regardless of age (less than 65 or more than 65 years), years since menopause (less than 3, 3–10, 10 or more years), and baseline lumbar spine bone mineral density T-score (within the interval of [⫺2.5, ⫺1] or greater than ⫺1) (Figure 4). There were no significant subgroup-by-treatment interactions for any of the subgroups (P ⬎ .200). Treatment with alendronate 5 mg daily and 35 mg once weekly also produced similar effects on the rate of bone turnover. Marked reductions from baseline in urinary N-telopeptides were observed in both treatment groups as early as 1 month, and treatment with both regimens further reduced the levels of N-telopeptides to approach the middle of the premenopausal reference range22 at month 12 (P ⬍ .001 for within-group change from baseline at month 12) (Figure 5). There were no significant between-treatment-group differences in the effect on urinary N-telopeptides; at month 12, the geometric mean percent changes from baseline were ⫺48.0 and ⫺48.2% in the 5-mg daily and the 35-mg onceweekly groups, respectively. Significant reductions in serum bone-specific alkaline phosphatase were also seen in both treatment groups over the 1-year period, with
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Table 2. Percent Change From Baseline in Bone Mineral Density at Month 12 Alendronate Site
5 mg daily
35 mg once weekly
Lumbar spine Total hip Femoral neck Trochanter Total body
3.2 (2.9, 3.5) 1.8 (1.4, 1.9) 1.4 (1.0, 1.8) 2.7 (2.2, 3.0) 0.7 (0.5, 1.0)
2.9 (2.6, 3.2) 1.5 (1.2, 1.7) 1.4 (1.1, 1.9) 2.3 (1.9, 2.7) 0.5 (0.3, 0.8)
Values presented are means (95% confidence intervals). All changes are significant increases from baseline (P ⬍.001).
levels approaching the middle of the premenopausal reference range22 at month 12 (P ⬍ .001 for within-group change from baseline at month 12) (Figure 5). The geometric mean percent changes from baseline at month 12 were ⫺31.5% and ⫺27.5% in the 5-mg daily and 35-mg once-weekly groups, respectively; although the difference between treatment groups was statistically significant (P ⫽ .028), it was small relative to the overall treatment effect. Both the 5-mg daily and 35-mg onceweekly groups experienced small yet significant decreases (P ⬍ .001) from baseline in serum calcium and phosphate; the geometric mean percent changes at month 12 in serum calcium were ⫺1.6% and ⫺1.9%, respectively, and those in serum phosphate were ⫺5.4% and ⫺5.7%, respectively. The between-treatment-group differences were not statistically significant. Overall, the safety profiles of alendronate 35 mg once weekly and 5 mg daily were excellent and similar to each other. The proportions of subjects having any adverse experiences, drug-related adverse experiences, and serious adverse experiences were comparable between the two treatment groups. No serious drug-related adverse experiences or deaths occurred in either group. The
Figure 1. Mean (⫾ standard error) percent change in bone mineral density of the spine, total hip, femoral neck, and trochanter over 12 months. Triangles ⫽ alendronate 5 mg daily; circles ⫽ alendronate 35 mg once weekly. Luckey. Alendronate 35 mg Once Weekly. Obstet Gynecol 2003.
Figure 2. Between-treatment-group difference (with 90% confidence interval [CI]) of mean percent changes in lumbar spine bone mineral density from baseline at month 12. Circle ⫽ alendronate 35 mg once weekly ⫺ alendronate 5 mg daily. Luckey. Alendronate 35 mg Once Weekly. Obstet Gynecol 2003.
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Table 3. Proportion of Patients With Any Increase in Bone Mineral Density at Different Skeletal Sites ⱕ3 y postmenopause
⬎3 y postmenopause
Overall
Skeletal site
ALN 5 mg daily
ALN 35 mg once weekly
ALN 5 mg daily
ALN 35 mg once weekly
ALN 5 mg daily
ALN 35 mg once weekly
Lumbar spine BMD Total hip BMD
87.1 66.7
91.0 71.1
89.2 85.5
89.9 79.2
88.6 80.2
90.2 76.8
ALN ⫽ alendronate; BMD ⫽ bone mineral density. Values are %.
proportion of subjects discontinuing from the study therapy because of a clinical adverse experience was lower in the 35-mg once-weekly group than in the 5-mg daily group (5.2% and 9.4%, respectively, P ⫽ .049).
Similar proportions of subjects experienced one or more upper gastrointestinal adverse experiences, none of which were serious, in the 5-mg daily and the 35-mg once-weekly groups (24.1% and 25.1%, respectively). The rates of discontinuation due to upper gastrointestinal adverse experiences were also comparable between treatment groups. Abdominal pain, acid regurgitation, nausea, and dyspepsia were the most common upper gastrointestinal adverse experiences; no clinically meaningful between-treatment-group differences were observed in any specific upper gastrointestinal adverse experiences (Table 4). There were no cases of esophagitis in either group, and only one subject experienced a gastric ulcer. More than half of the subjects used nonsteroidal antiinflammatory medications and/or aspirin (56.5% and 53.0% in the 5-mg daily and 35-mg once-weekly groups, respectively) at some time during the study. An analysis of the potential interaction between non-
Figure 3. Proportions of women with more than 2% loss, less than 2% change, and more than 2% gain in bone mineral density (BMD) of the lumbar spine and total hip. ALN ⫽ alendronate.
Figure 4. Mean percent change from baseline at month 12 in lumbar spine bone mineral density (BMD) by subgroups. ALN ⫽ alendronate.
Luckey. Alendronate 35 mg Once Weekly. Obstet Gynecol 2003.
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Table 4. Upper Gastrointestinal Adverse Experiences Alendronate Adverse experience category
5 mg daily (n ⫽ 361)
35 mg once weekly (n ⫽ 362)
Patients with one or more upper GI adverse experiences Discontinued from therapy due to an upper GI adverse experience Abdominal pain Abdominal distention Acid regurgitation Dyspepsia Nausea Vomiting Gastric ulcer
87 (24.1)
91 (25.1)
16 (4.4)
13 (3.6)
21 (5.8) 12 (3.3) 22 (6.1) 16 (4.4) 22 (6.1) 18 (5.0) 0
26 (7.2) 10 (2.8) 25 (6.9) 16 (4.4) 14 (3.9) 9 (2.5) 1 (0.3)
GI ⫽ gastrointestinal. Values are n (%). Although a patient may have two or more adverse experiences within the same category, the patient is counted only once within that category. The same patient may appear in different categories.
Figure 5. Geometric mean values for urinary N-telopeptides (NTx) and serum bone-specific alkaline phosphatase (BAP) by time point, with premenopausal reference ranges21 denoted by horizontal lines (mean ⫾ 2 standard deviations). Triangles ⫽ alendronate 5 mg daily; circles ⫽ alendronate 35 mg once weekly. Luckey. Alendronate 35 mg Once Weekly. Obstet Gynecol 2003.
steroidal antiinflammatory medications and either dosing regimen of alendronate showed that, although nonsteroidal antiinflammatory medication/aspirin use increased the overall incidence of upper gastrointestinal adverse experiences, the relative risk of upper gastrointestinal adverse experiences was not increased for the alendronate 35-mg once-weekly group compared with the 5-mg daily group during the period of nonsteroidal antiinflammatory medication use (relative risk [95% CI] was 1.05 [0.62, 1.79] during the “on-use” period and 0.88 [0.59, 1.30] during the “off-use” period). No subjects experienced a clinical vertebral fracture during the study. Nonvertebral fracture adverse experiences were reported in 2.5% of the 5-mg daily group and 1.4% of the 35-mg once-weekly group. None of the subjects experienced a hip fracture. There were no meaningful between-treatment-group differences in the incidence or skeletal distribution of nonvertebral fracture adverse events.
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DISCUSSION In two major studies employing daily regimens of alendronate enrolling a total of 2056 postmenopausal women without osteoporosis, treatment with alendronate 5 mg daily resulted in significant increases in lumbar spine bone mineral density (an average increase of 3% in the first year, which was maintained in subsequent years of treatment), as well as smaller yet significant increases in hip and total body bone mineral density. By contrast, the placebo groups experienced progressive bone loss at all skeletal sites relative to baseline.19,20 Although the above studies have shown that the daily regimen of oral alendronate is highly efficacious and generally well tolerated in the prevention of bone loss, the current study is the first to demonstrate that alendronate once weekly provides an equally efficacious alternative to the daily regimen while providing similar safety and tolerability. The primary efficacy end point of the current study was percent change in lumbar spine bone mineral density after 1 year of treatment. The lumbar spine was chosen because at this site, alendronate 5 mg produces the highest ratio of bone mineral density increase to the coefficient of variation of the measurement of change.11,19,20,23 One year was considered an adequate period for establishing therapeutic equivalence of alendronate 35 mg once weekly to 5 mg daily, because most of the increase in lumbar spine bone mineral density had been observed during the first year of treatment in prior studies.19,20 At the end of 1 year, treatment with both
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alendronate 35 mg once weekly and 5 mg daily resulted in percentage increases in lumbar spine bone mineral density similar to those observed for 5 mg daily in the two previous prevention studies, and the difference between the two groups was not significant, satisfying stringent, prespecified equivalence criteria. The similarity in treatment effect on lumbar spine bone mineral density was consistent across prespecified patient subgroups, although the ability to detect subtle differences in treatment response was limited by the sample size in each subgroup. Although no predefined equivalence hypotheses were established for other skeletal sites, the two treatment regimens also produced similar bone mineral density increases at the hip and total body, and the changes observed at these sites were in the range of those seen previously.19,20 It is worth noting that the current study did not include a placebo group and, therefore, does not illustrate the true bone mineral density “treatment effect” (difference between treatment and placebo) of the two dosing regimens, which is expected to be greater in magnitude than the difference from baseline, because the placebo groups in previous prevention studies generally experienced a 1% loss or more at the lumbar spine after 1 year.19,20 The equivalence hypothesis was supported further by the demonstration that similar proportions of subjects in the two treatment groups experienced some gain (more than 0% change) in lumbar spine and total hip bone mineral density, with a great majority of women experiencing bone gain regardless of the number of years since menopause. In addition, the proportions of subjects experiencing more than 2% loss, less than 2% change, and more than 2% gain at the lumbar spine and total hip were similar between the two treatment groups and comparable to those observed after 2 years of treatment with alendronate 5 mg daily in a previous prevention study.20 Similar time–response curves for the reduction in biochemical markers of bone resorption (urinary Ntelopeptides) and bone formation (serum bone-specific alkaline phosphatase) were seen in both treatment groups, with the decrease in urinary N-telopeptides occurring more rapidly than the decrease in serum bonespecific alkaline phosphatase, consistent with the known mechanism of action of alendronate—inhibition of osteoclast function. The mean urinary N-telopeptide and serum bone-specific alkaline phosphatase levels at baseline were elevated compared with the premenopausal reference mean, which is consistent with the estrogen deficiency state of the postmenopausal women in this study. Treatment with both dosing regimens after 1 year
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brought the marker levels down to the middle of the premenopausal reference ranges, as seen with alendronate 5 mg daily in a previous prevention study,19 and is responsible for and compatible with the significant bone mineral density increases seen in both treatment groups at 1 year. Although the reduction of serum bone-specific alkaline phosphatase at the end of 1 year was slightly lower in the 35-mg once-weekly group, the difference was small and not likely to be clinically significant. Further, the reductions in N-telopeptides were nearly indistinguishable between the two groups, and no appreciable difference in bone mineral density change at any skeletal site was observed. In addition to proven efficacy, a long-term preventive therapy also must have an excellent safety and tolerability profile to be accepted by asymptomatic women. In previous studies using daily alendronate, the safety and tolerability profiles of alendronate 5 mg daily were shown to be comparable to those of placebo, and no increased incidence of upper gastrointestinal adverse experiences was associated with alendronate use.19,20 The present study showed that alendronate 35 mg once weekly was similarly safe and well tolerated. No serious upper gastrointestinal adverse experience occurred in either group. It is worth noting that 28.1% of subjects had a history of upper gastrointestinal diseases. In addition, approximately 37% and 55% of subjects were using nonsteroidal antiinflammatory medications or aspirin before and during the study, respectively. Analysis of upper gastrointestinal adverse experiences among nonsteroidal antiinflammatory medication users showed that the relative risk for upper gastrointestinal adverse experiences during the period of nonsteroidal antiinflammatory medication use was not higher for the 35-mg once-weekly group compared with the 5-mg daily group, suggesting that the weekly regimen is not more likely to cause upper gastrointestinal irritation than the daily regimen, even in patients receiving nonsteroidal antiinflammatory medications. Although fracture was not an end point in this study, clinical fractures were captured as adverse experiences for the purpose of safety assessment. No clinical vertebral fractures occurred in either treatment group. The incidences of nonvertebral fractures were very low and similar in the two treatment groups; approximately half of the fractures were due to excessive trauma. Given the therapeutic equivalence and similar safety profile of the two dosing regimens, the less frequent once-weekly alendronate should be more readily accepted by women contemplating preventive therapy for osteoporosis. Past studies have indicated higher dosing frequency to be a contributing factor to the lack of
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compliance with and adherence to antihypertensive therapy.24,25 For chronic therapies in general, studies have shown that compliance is substantially improved when dosing frequency is reduced from three or four times daily to once daily.26 A recent study to assess the preference, convenience, and overall compliance of alendronate 70 mg once weekly compared with 10 mg daily showed that an overwhelming majority of patients (more than 85% for each parameter) found the weekly regimen to be preferable, more convenient, and easier to comply with.27 In addition, the rate of compliance with onceweekly fluoxetine has been found to be significantly higher than that with once-daily fluoxetine in the treatment of depression.28 Thus, studies of patient compliance to date strongly support the hypothesis that alendronate 35 mg once weekly, by providing women with greater flexibility and convenience in dosing, will be a more acceptable alternative to daily therapy in the prevention of postmenopausal osteoporosis.
REFERENCES 1. Chrischilles EA, Butler CD, Davis CS, Wallace RB. A model of lifetime osteoporosis impact. Arch Intern Med 1991;151:2026–32. 2. Melton LJ III, Chrischilles EA, Cooper C, Lane AW, Riggs BL. How many women have osteoporosis? J Bone Miner Res 1992;7:1005–10. 3. Ross PD, Davis JW, Epstein RS, Wasnich RD. Pre-existing fractures and bone mass predict vertebral fracture incidence in women. Ann Intern Med 1991;114:919–23. 4. Gehlbach SH, Fournier M, Bigelow C. Recognition of osteoporosis by primary care physicians. Am J Public Health 2002;92:271–3. 5. Seedor JG, Quartuccio HA, Thompson DD. The bisphosphonate alendronate (MK-217) inhibits bone loss due to ovariectomy in rats. J Bone Miner Res 1991;6:339–46. 6. Balena R, Toolan BC, Shea M, Markatos A, Myers ER, Lee SC, et al. The effects of 2-year treatment with the aminobisphosphonate alendronate on bone metabolism, bone histomorphometry, and bone strength in ovariectomized nonhuman primates. J Clin Invest 1993;92: 2577–86. 7. Rodan GA, Seedor JG, Balena R. Preclinical pharmacology of alendronate. Osteoporos Int 1993;3 Suppl 3:S7–12. 8. Khan SA, Kanis JA, Vasikaran S, Kline WF, Matuszewski BK, McCloskey EV, et al. Elimination and biochemical responses to intravenous alendronate in postmenopausal osteoporosis. J Bone Miner Res 1997;12:1700–7. 9. Gertz BJ, Holland SD, Kline WF, Matuszewski BK, Porras
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AG. Clinical pharmacology of alendronate sodium. Osteoporos Int 1993;3 Suppl 3:S13–6. Porras AG, Holland SD, Gertz BJ. Pharmacokinetics of alendronate. Clin Pharmacokinet 1999;36:315–28. Tucci JR, Tonino RP, Emkey RD, Peverly CA, Kher U, Santora AC. Effect of three years of oral alendronate treatment in postmenopausal women with osteoporosis. Am J Med 1996;101:488–501. Chesnut CH 3rd, McClung MR, Ensrud KE, Bell NH, Genant HK, Harris ST, et al. Alendronate treatment of the postmenopausal osteoporotic woman: Effect of multiple dosages on bone mass and bone remodeling. Am J Med 1995;99:144–52. Lufkin EG, Argueta R, Whitaker MD, Cameron AL, Wong VH, Egan KS, et al. Pamidronate: An unrecognized problem in gastrointestinal tolerability. Osteoporos Int 1994;4:320–2. Peter CP, Handt LK, Smith SM. Esophageal irritation due to alendronate sodium tablets: Possible mechanisms. Dig Dis Sci 1998;43:1998–2002. Bone HG, Adami S, Rizzoli R, Favus M, Ross PD, Santora A, et al. Weekly administration of alendronate: Rationale and plan for clinical assessment. Clin Ther 2000;22:15–28. Schnitzer T, Bone HG, Crepaldi G, Adami S, McClung M, Kiel D, et al. Therapeutic equivalence of alendronate 70 mg once-weekly and alendronate 10 mg daily in the treatment of osteoporosis. Aging Clin Exp Res 2000;12: 1–12. Genant HK, Wu CY, Van Kuijk C, Nevitt MC. Vertebral fracture assessment using a semiquantitative technique. J Bone Miner Res 1993;8:1137–48. Faulkner KG, McClung MR. Quality control of DXA instruments in multicenter trials. Osteoporos Int 1995;5: 218–27. McClung M, Clemmesen B, Daifotis A, Gilchrist NL, Eisman J, Weinstein RS, et al. Alendronate prevents postmenopausal bone loss in women without osteoporosis: A double-blind, randomized, controlled trial. Ann Intern Med 1998;128:253–61. Hosking D, Chilvers CE, Christiansen C, Ravn P, Wasnich R, Ross P, et al. Prevention of bone loss with alendronate in postmenopausal women under 60 years of age. N Engl J Med 1998;338:485–92. Jones B, Jarvis P, Lewis JA, Ebbutt AF. Trials to assess equivalence: The importance of rigorous methods. BMJ 1996;313:36–39. Garnero P, Sornay-Rendu E, Delmas PD. Decreased bone turnover in oral contraceptive users. Bone 1995;16: 499–503. Liberman UA, Weiss SR, Broll J, Minne HW, Quan H, Bell NH, et al. Effect of oral alendronate on bone mineral density and the incidence of fractures in postmenopausal osteoporosis. N Engl J Med 1995;333:1437–43. Bailey JE, Lee MD, Somes GW, Graham RL. Risk factors
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for antihypertensive medication refill failure by patients under medicaid managed care. Clin Ther 1996;18: 1252–62. 25. Hamilton RA, Briceland LL. Use of prescription-refill records to assess patient compliance. Am J Hosp Pharm 1992;49:1691–6. 26. Sbarbaro JA. Strategies to improve compliance with therapy. Am J Med 1985;79:34–7. 27. Simon JA, Lewiecki EM, Smith ME, Petruschke RA, Wang L, Palmisano JJ. Patient preference for once-weekly alendronate 70 mg versus once-daily alendronate 10 mg: A multicenter, randomized, open-label, crossover study. Clin Ther 2002;24:1871–86.
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28. Claxton A, de Klerk E, Parry M, Robinson JM, Schmidt ME. Patient compliance to a new enteric-coated weekly formulation of fluoxetine during continuation treatment of major depressive disorder. J Clin Psychiatry 2000;61: 928–32. Address reprint requests to: Marjorie Luckey, MD, St. Barnabas Ambulatory Care Center, Osteoporosis Center, 200 South Orange Avenue, Livingston, NJ 07039; E-mail: [email protected]. Received June 3, 2002. Received in revised form October 31, 2002. Accepted November 7, 2002.
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Guidelines for three different types of articles have been adopted by Obstetrics & Gynecology as policy: 1. CONSORT (Consolidation of Standards of Reporting Trials) standards for reporting randomized trials 2. QUOROM (Quality of Reporting of Meta-analyses) guidelines for meta-analyses and systematic reviews of randomized trials 3. MOOSE (Meta-analysis of Observational Studies in Epidemiology) guidelines for meta-analyses and systematic reviews of observational studies Investigators who are planning, conducting, or reporting randomized trials or meta-analyses of randomized trials or meta-analyses of observational studies should be thoroughly familiar with these sets of standards. NOW AVAILABLE ONLINE www.greenjournal.org Summaries of the guidelines may also be obtained by contacting the Editorial Office (Phone: 202-314-2317; FAX: 202-479-0830; E-mail: [email protected]).
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After the onset of menopause, many women begin to experience accelerated bone loss due to estrogen deficiency, which poses a heightened risk of developing osteoporosis if intervention is not instituted. Osteoporotic fractures are one of the most common causes of morbidity and mortality in postmenopausal women. It is estimated that a 50-year-old postmenopausal white woman, irrespective of her bone mineral density, carries at least a 40% lifetime risk of fracture if left untreated.1,2 Fracture risk among osteoporotic women is about four times that among nonosteoporotic women in the same age group.3 Despite the availability of effective therapies to prevent osteoporosis, including the bisphosphonate alendronate, the use of such therapies in women at risk for osteoporosis has been relatively low.4 One of the reasons for this finding may be a perception of dosing inconvenience, particularly for bisphosphonates dosed as a daily regimen. Patients taking bisphosphonates are instructed to take the tablet fasting (with water only), to wait at least 30 minutes before the first food or other medication of the day, and to remain upright for at least 30 minutes postdose. These dosing requirements may be perceived by some patients, especially asymptomatic early postmenopausal women, as adding complexity to their daily routine. Thus, a less frequent dosing regimen, such as alendronate once weekly, would be a more attractive preventive therapy that may enhance long-term compliance. Animal studies have shown that larger doses of alenFinancial Disclosure This study was supported by funding from Merck Research Laboratories, Rahway, New Jersey. Mei Wu, Anastasias G. Daifotis, Arthur C. Santora, and John J. Orloff are employees of Merck & Co. Inc. and potentially own stock and/or hold stock options in the Company.
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dronate can be given less frequently and produce similar effects on bone mineral density, provided the same cumulative dose is maintained.5–7 This is supported by pharmacokinetic studies in animals and humans, which have demonstrated that the absorption, distribution, and elimination properties of alendronate lend themselves to less frequent dosing schedules.8 –10 Earlier clinical trials showed that higher doses of oral daily bisphosphonates were associated with upper gastrointestinal adverse events in a dose-dependent manner.11–13 Studies in animals, however, showed that once-weekly exposure to a high concentration of alendronate in an acid pH solution (to simulate refluxed gastric contents) over 4 weeks did not result in esophageal irritation, whereas daily dosing with lower concentrations of alendronate or risedronate was associated with esophagitis.14,15 These preclinical experiments predicted that once-weekly alendronate would have a similar, if not improved, safety and tolerability profile, compared with daily alendronate. To test the hypothesis that weekly and daily dosing regimens of alendronate are therapeutically equivalent, two multicenter, randomized studies were conducted to evaluate the efficacy and safety of once-weekly alendronate in comparison with daily alendronate in postmenopausal women. The recently published “treatment” study in postmenopausal women with osteoporosis showed that alendronate 70 mg once weekly and 35 mg twice weekly produced bone mineral density changes at the lumbar spine equivalent to that achieved with alendronate 10 mg daily, as determined by stringent, predefined equivalence criteria. Bone mineral density changes at other skeletal sites, including hip and total body, were also similar for all three treatment regimens.16 The overall safety profiles of the three treatment groups were very similar, and numerically lower incidences of upper gastrointestinal adverse experiences in several categories (gastroesophageal irritation and serious upper gastrointestinal adverse experiences) were observed in the weekly dosing group compared with the daily dosing group. Presented herein are results from a study comparing the efficacy and safety of alendronate 35 mg once weekly with 5 mg daily in postmenopausal women without osteoporosis. MATERIALS AND METHODS To be eligible for the study, women had to be 40 –70 years of age and postmenopausal, as diagnosed by a history of the absence of menstrual periods during the 6 months preceding randomization; for those women whose last menstrual period occurred 6 –12 months before study start, serum follicle-stimulating hormone levels were confirmed to be in the reference range for
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postmenopausal women. Other entry criteria included bone mineral density T-score (standard deviation difference from the normal young premenopausal mean) between ⫺2.5 and 1.0 at both the lumbar spine and the femoral neck, no history of osteoporotic fracture of the spine or hip, and no vertebral fracture as determined by lateral thoracolumbar spine radiographs evaluated locally. After randomization, baseline radiographs showing vertebral deformities were forwarded to a central radiologist (H.K. Genant, University of California, San Francisco) for further assessment and adjudication of potential vertebral fractures, using previously defined criteria.17 Subjects were not excluded on the basis of previous or active gastrointestinal disease, but they were excluded if there was a history of recent major upper gastrointestinal (esophagus, stomach, duodenum) mucosal erosive disease as defined by 1) significant upper gastrointestinal bleeding within the last year resulting in hospitalization and/or transfusion, 2) recurrent ulcer disease documented by radiographic or endoscopic means (two episodes in the last 2 years, or any documented ulcer in the preceding 3 months), 3) uncontrolled dyspepsia despite treatment on a daily basis, 4) esophageal or gastric variceal disease, or 5) esophageal stricture, achalasia, or severe esophageal motor dysfunction. Subjects were not excluded if symptoms of dyspepsia were controlled by daily medication, or because of a prior history of nonrecurrent peptic ulcer disease or concomitant use of aspirin or nonsteroidal antiinflammatory medications. Additional exclusion criteria included significant renal or hepatic dysfunction, myocardial infarction within the previous 6 months, uncontrolled hypertension, severe malabsorption, vitamin D deficiency, metabolic bone diseases (uncontrolled hypo- or hyperthyroidism, hypoor hyperparathyroidism, hypo- or hypercalcemia, Paget disease of bone, osteomalacia, or osteogenesis imperfecta). Women who had taken estrogen, calcitonin, or glucocorticoids within the preceding 6 months, or bisphosphonates or sodium fluoride (more than 1 mg per day) at any time were also excluded. This study was conducted at 43 centers in seven countries. Of the 1048 women screened, 723 were randomized. Randomization took place within each clinic. The number of women randomized in each center ranged from 3 to 37. Failure to meet one or more inclusion criteria accounted for 44% of those not randomized, whereas 20% of screening failures met one or more exclusion criteria. Of the screening failures, 36% were disqualified for reasons other than the inclusion/ exclusion criteria, including clinical adverse experiences (3%), laboratory adverse experiences (1%), withdrew consent (25%), lost to follow-up (2%), and protocol de-
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viation (5%), all of which occurred during the placebo run-in period prior to randomization. Exclusion of subjects with adverse experiences during the placebo run-in period should not have any impact on efficacy or safety analyses, because these subjects were not yet randomized. The demographic characteristics of nonrandomized subjects did not differ substantially from those of randomized subjects. All subjects screened gave written, informed consent, and the study protocol was approved by institutional ethical review boards. This was a 1-year, multicenter, randomized, doubleblind study. Subjects were randomly assigned to receive either oral alendronate 5 mg daily or 35 mg once weekly. Treatment allocations were determined using a computer-generated allocation schedule. To maintain treatment blinding, a “double-placebo” treatment design (two different tablet images, only one of which contained alendronate for any given subject) was utilized. Subjects assigned to the 35-mg once-weekly group took an active 35-mg tablet each Tuesday and also took placebo matching the 5-mg tablet every day of the week, whereas subjects assigned to the 5-mg daily group took an active 5-mg tablet every day of the week, and also took placebo matching the 35-mg tablet each Tuesday. Before randomization, all subjects underwent a 14-day, single-blind placebo run-in period using placebo tablets matched to the two different tablet images. All subjects who were found to be less than 100% compliant with the 35-mg once-weekly placebo tablets or less than 80% compliant with the 5-mg daily placebo tablets, without a valid explanation, were excluded from randomization into the study. In addition to study medication, all subjects also received a supplement providing 500 mg per day of elemental calcium (as carbonate) and 250 IU per day of vitamin D. Subjects were instructed to take study medication in the morning with 6 – 8 oz water (at least 4 oz water were to have followed the last tablet on the day when two tablets were taken) at least 30 minutes before any other food or drink. They were also instructed to wait at least 30 minutes after dosing before taking other oral medications, including calcium supplements, and to remain upright for at least 30 minutes after dosing and until after the first food of the day. Bone mineral density was measured by dual-energy x-ray absorptiometry using Hologic (Hologic Corp., Bedford, MA) and Lunar (Lunar Corp., Madison, WI) densitometers. Results expressed as percentage changes in bone mineral density from these two densitometers were combined, as they are independent of the machine type.18 All bone mineral density analyses were performed by a central analysis facility that was blinded to treatment group and to other subject data. Daily mea-
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surements of bone mineral density phantoms by each dual-energy x-ray absorptiometry instrument detected no significant machine drift during the 1-year study, as determined by the bone mineral density Quality Control Center (Synarc Inc., DXA Centralized Analysis Facility, Portland, OR). Laboratory parameters used to evaluate changes in bone turnover were urinary N-telopeptides corrected for creatinine (Osteomark, Ostex, Seattle, WA) to assess the rate of bone resorption, and serum bone-specific alkaline phosphatase (Ostase, Beckman-Coulter, San Diego, CA) to assess the rate of bone formation. Assays were performed at a central laboratory (Mayo Clinical Laboratories, Rochester, MN). Safety was assessed on the basis of clinical evaluations and laboratory measurements, including serum chemistry, hematology, and urinalysis performed at each clinic visit at baseline and months 1, 3, 6, and 12. All clinical and laboratory adverse experiences, as well as concomitant medication use were recorded. Clinical adverse experiences were recorded on the basis of self-report. Clinical fractures were reported as adverse experiences. If a subject experienced clinical symptoms suggestive of an incident vertebral fracture, follow-up spine radiographs were obtained and sent, with the baseline spine radiograph, to the central facility (H.K. Genant, University of California, San Francisco) for fracture adjudication based on semi-quantitative assessment.17 The primary efficacy end point was the percent change from baseline at month 12 in lumbar spine bone mineral density (L1 to L4); safety and tolerability at month 12 was a co-primary end point. Secondary end points included percent changes from baseline at month 12 in bone mineral density of the hip (total hip, femoral neck, and trochanter) and total body, as well as in biochemical markers of bone turnover. The primary hypothesis was that 1 year of treatment with alendronate 35 mg once weekly would produce an increase in lumbar spine bone mineral density in postmenopausal women equivalent to that produced by alendronate 5 mg daily. The hypothesis was to be accepted if the 90% confidence interval (CI) of the between-treatment-group difference in mean percent change remained entirely within the equivalence range of ⫺1.0% to 1.0%. This range represents approximately 26% of the net treatment effect (alendronate 5 mg minus placebo percent change in lumbar spine bone mineral density) observed as the weighted average from two previous osteoporosis prevention studies,19,20 and any betweentreatment-group differences (and 90% CI) within this range are not likely to be clinically meaningful. The criterion is also consistent with standard recommendations for equivalence trials.21 Assuming a standard devi-
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ation of 2.61%, as was observed in a previous prevention study following 1 year of treatment with alendronate 5 mg daily,20 350 evaluable patients each in the alendronate 35-mg once-weekly and 5-mg daily groups would provide 99% (␣ ⫽ .05, two-tailed) power to demonstrate equivalence in lumbar spine bone mineral density, according to the above criterion. The percent changes in bone mineral density at the total hip, femoral neck, trochanter, and total body sites were evaluated to support the primary end point, but no clinical equivalence criteria were prespecified for these sites. The percent changes in bone mineral density were analyzed using an analysis of variance (ANOVA) model including treatment and study center as model factors. Subgroup analyses were performed for the percent change in lumbar spine bone mineral density to determine whether the treatment effect was different in prespecified subgroups, including baseline age, number of years since menopause, baseline lumbar spine bone mineral density, and baseline lumbar spine bone mineral density T-scores. The effect of subgroups was evaluated by the covariate by treatment interaction tests performed at the significance level of .05 (two-sided). For biochemical markers of bone turnover, the natural log fractions of on-treatment to baseline values at month 12 were analyzed using an ANOVA model including treatment and study center as model factors. This log transformation was used to normalize the distribution of the fractional change in biochemical markers. Geometric mean percent change from baseline was then calculated by back-transforming the arithmetic mean of the log fractions. The net result is identical to the percent change of the geometric mean of on-treatment values relative to the geometric mean of baseline values. Geometric means are more appropriate for analysis of biochemical markers, because the distribution of marker values in a postmenopausal population tends to be skewed. The primary analysis for bone mineral density change was performed using the completers’ approach, with all patients who have baseline and end-point data included in the analysis, because the intention-to-treat approach is not considered conservative in the context of an equivalence trial.21 Although subjects who discontinued the study because of adverse experiences were excluded from the completers’ analysis, similar proportions of subjects dropped out of the two treatment groups, so that their exclusion should not differentially influence the outcome of the analysis with respect to treatment group. The results of the completers’ analysis are presented in the section below, although intention-to-treat and per-protocol analyses were also performed for bone mineral density change and did not change the conclusions of the study. Biochemical markers were analyzed using only the per-protocol ap-
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proach. Fisher exact test was used to evaluate the between-treatment-group differences in the proportion of subjects with certain adverse experiences, with the primary focus being upper gastrointestinal adverse experiences. RESULTS Women randomized to the two treatment groups had similar baseline characteristics in terms of age, years since menopause, body mass index, dietary calcium intake, prior vertebral fracture, history of upper gastrointestinal disease, and prior nonsteroidal antiinflammatory drugs or aspirin use (Table 1). Although women with radiologic fractures of the lumbar spine were excluded at screening based on local review of spine radiographs, small, comparable proportions of women enrolled in the two treatment groups (5.5% and 3.6% in the 5-mg daily and 35-mg once-weekly groups, respectively) had baseline vertebral fractures as determined by central review of spine radiographs. These subjects were not discontinued from the study. At baseline, women in the two treatment groups had similar bone mineral density values at the lumbar spine and total hip, as well as similar rates of bone turnover, as indicated by levels of bone resorption and formation markers (Table 1). Of the 723 subjects randomized, 83.7% (82.5% and 84.8% in the alendronate 5-mg daily and 35-mg once-weekly groups, respectively) were included in the completers’ analysis of the primary end point. Reasons for exclusion from the completers’ analysis include discontinuation owing to clinical adverse experiences, lost to follow-up, withdrew consent, and protocol deviation. There was no apparent betweentreatment-group difference in the proportion of discontinued patients in each category. The primary end point was the change in lumbar spine bone mineral density from baseline at month 12. As shown in Figure 1 and Table 2, treatment with alendronate 35 mg once weekly and 5 mg daily over 12 months resulted in significant percentage increases from baseline in lumbar spine bone mineral density (2.9% and 3.2%, respectively, at month 12). The between-treatment-group difference in the percent change at month 12 (90% CI) was ⫺0.3% (⫺0.6, 0.1), with the 90% CI falling well within the prespecified bounds of ⫾1.0%, indicating that the two treatment regimens are equivalent with respect to the primary end point (Figure 2). Significant increases in bone mineral density from baseline were also observed at the total hip, femoral neck, trochanter, and total body in both treatment groups (Figure 1 and Table 2). There was no meaningful between-treatmentgroup difference in the percent change at month 12 at
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Table 1. Baseline Patient Characteristics Alendronate Variable Age (y)* Years since menopause* Body mass index (kg/m2)* Dietary calcium intake daily (mg)* Race: white (%)† Prior vertebral fracture (%) History of upper GI disease (%) Recent NSAID/aspirin use‡ (%) Bone mineral density (g/cm2) Lumbar spine Hologic densitometer* Lunar densitometer* Total hip Hologic densitometer* Lunar densitometer* Biochemical markers Urine NTx (nmol BCE/mmol creatinine)§ BAP (ng/mL)§
5 mg daily (n ⫽ 361)
35 mg once weekly (n ⫽ 362)
56.1 ⫾ 5.7 9.0 ⫾ 7.3 26.9 ⫾ 5.1 632.7 ⫾ 411.7 97.0 5.5 25.2 35.7
56.3 ⫾ 6.0 9.9 ⫾ 7.7 27.1 ⫾ 5.2 669.0 ⫾ 437.5 95.3 3.6 30.9 39.2
0.93 ⫾ 0.10 1.09 ⫾ 0.11
0.95 ⫾ 0.11 1.08 ⫾ 0.12
0.85 ⫾ 0.10 0.94 ⫾ 0.11
0.86 ⫾ 0.10 0.92 ⫾ 0.10
57.4 ⫾ 2.4 13.1 ⫾ 0.2
54.8 ⫾ 1.9 13.0 ⫾ 0.2
GI ⫽ gastrointestinal; NSAID ⫽ nonsteroidal antiinflammatory medication; NTx ⫽ N-telopeptides; BAP ⫽ bone-specific alkaline phosphatase. * Values are mean ⫾ standard deviation. † Twenty-eight patients not counted under “white” include the following ethnic groups: black (5), other (23). ‡ Two weeks before study start. § Values are geometric means ⫾ standard error.
any skeletal site, although no comparability criteria were prespecified for the hip and total body sites. All 90% CIs of the differences included zero (data not shown), suggesting that there were no significant differences in treatment effect at any skeletal site measured. Although analysis of bone mineral density change was performed using the completers’ approach, intention-to-treat and per-protocol analyses yielded similar results at all skeletal sites. The mean lumbar spine bone mineral density percent changes from baseline at month 12 in the alendronate 35-mg once-weekly and 5-mg daily groups were 2.8% and 3.1%, respectively, based on the intention-to-treat analysis, and 2.8% and 3.2%, respectively, based on the per-protocol analysis. An overwhelming majority of the women experienced an increase in bone mineral density (more than 0% change) at the lumbar spine and total hip in both treatment groups (Table 3); at month 12, the proportions of women experiencing any increase in lumbar spine bone mineral density were 88.6% and 90.2% in the 5-mg daily and the 35-mg once-weekly groups, respectively. There was no meaningful between-treatment-group difference in the proportion of women with any increase in bone mineral density at either skeletal site. The proportions of women experiencing more than 2% gain, less than 2% change, and more than 2% loss at the lumbar spine and total hip were similar between treatment groups (Figure 3); at month 12, the proportions of women with a bone
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mineral density gain of more than 2% at the lumbar spine were 71.1% and 66.8% in the 5-mg daily and the 35-mg once-weekly groups, respectively. Prespecified subgroup analyses indicated that the increases in lumbar spine bone mineral density were similar between treatment groups regardless of age (less than 65 or more than 65 years), years since menopause (less than 3, 3–10, 10 or more years), and baseline lumbar spine bone mineral density T-score (within the interval of [⫺2.5, ⫺1] or greater than ⫺1) (Figure 4). There were no significant subgroup-by-treatment interactions for any of the subgroups (P ⬎ .200). Treatment with alendronate 5 mg daily and 35 mg once weekly also produced similar effects on the rate of bone turnover. Marked reductions from baseline in urinary N-telopeptides were observed in both treatment groups as early as 1 month, and treatment with both regimens further reduced the levels of N-telopeptides to approach the middle of the premenopausal reference range22 at month 12 (P ⬍ .001 for within-group change from baseline at month 12) (Figure 5). There were no significant between-treatment-group differences in the effect on urinary N-telopeptides; at month 12, the geometric mean percent changes from baseline were ⫺48.0 and ⫺48.2% in the 5-mg daily and the 35-mg onceweekly groups, respectively. Significant reductions in serum bone-specific alkaline phosphatase were also seen in both treatment groups over the 1-year period, with
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Table 2. Percent Change From Baseline in Bone Mineral Density at Month 12 Alendronate Site
5 mg daily
35 mg once weekly
Lumbar spine Total hip Femoral neck Trochanter Total body
3.2 (2.9, 3.5) 1.8 (1.4, 1.9) 1.4 (1.0, 1.8) 2.7 (2.2, 3.0) 0.7 (0.5, 1.0)
2.9 (2.6, 3.2) 1.5 (1.2, 1.7) 1.4 (1.1, 1.9) 2.3 (1.9, 2.7) 0.5 (0.3, 0.8)
Values presented are means (95% confidence intervals). All changes are significant increases from baseline (P ⬍.001).
levels approaching the middle of the premenopausal reference range22 at month 12 (P ⬍ .001 for within-group change from baseline at month 12) (Figure 5). The geometric mean percent changes from baseline at month 12 were ⫺31.5% and ⫺27.5% in the 5-mg daily and 35-mg once-weekly groups, respectively; although the difference between treatment groups was statistically significant (P ⫽ .028), it was small relative to the overall treatment effect. Both the 5-mg daily and 35-mg onceweekly groups experienced small yet significant decreases (P ⬍ .001) from baseline in serum calcium and phosphate; the geometric mean percent changes at month 12 in serum calcium were ⫺1.6% and ⫺1.9%, respectively, and those in serum phosphate were ⫺5.4% and ⫺5.7%, respectively. The between-treatment-group differences were not statistically significant. Overall, the safety profiles of alendronate 35 mg once weekly and 5 mg daily were excellent and similar to each other. The proportions of subjects having any adverse experiences, drug-related adverse experiences, and serious adverse experiences were comparable between the two treatment groups. No serious drug-related adverse experiences or deaths occurred in either group. The
Figure 1. Mean (⫾ standard error) percent change in bone mineral density of the spine, total hip, femoral neck, and trochanter over 12 months. Triangles ⫽ alendronate 5 mg daily; circles ⫽ alendronate 35 mg once weekly. Luckey. Alendronate 35 mg Once Weekly. Obstet Gynecol 2003.
Figure 2. Between-treatment-group difference (with 90% confidence interval [CI]) of mean percent changes in lumbar spine bone mineral density from baseline at month 12. Circle ⫽ alendronate 35 mg once weekly ⫺ alendronate 5 mg daily. Luckey. Alendronate 35 mg Once Weekly. Obstet Gynecol 2003.
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Table 3. Proportion of Patients With Any Increase in Bone Mineral Density at Different Skeletal Sites ⱕ3 y postmenopause
⬎3 y postmenopause
Overall
Skeletal site
ALN 5 mg daily
ALN 35 mg once weekly
ALN 5 mg daily
ALN 35 mg once weekly
ALN 5 mg daily
ALN 35 mg once weekly
Lumbar spine BMD Total hip BMD
87.1 66.7
91.0 71.1
89.2 85.5
89.9 79.2
88.6 80.2
90.2 76.8
ALN ⫽ alendronate; BMD ⫽ bone mineral density. Values are %.
proportion of subjects discontinuing from the study therapy because of a clinical adverse experience was lower in the 35-mg once-weekly group than in the 5-mg daily group (5.2% and 9.4%, respectively, P ⫽ .049).
Similar proportions of subjects experienced one or more upper gastrointestinal adverse experiences, none of which were serious, in the 5-mg daily and the 35-mg once-weekly groups (24.1% and 25.1%, respectively). The rates of discontinuation due to upper gastrointestinal adverse experiences were also comparable between treatment groups. Abdominal pain, acid regurgitation, nausea, and dyspepsia were the most common upper gastrointestinal adverse experiences; no clinically meaningful between-treatment-group differences were observed in any specific upper gastrointestinal adverse experiences (Table 4). There were no cases of esophagitis in either group, and only one subject experienced a gastric ulcer. More than half of the subjects used nonsteroidal antiinflammatory medications and/or aspirin (56.5% and 53.0% in the 5-mg daily and 35-mg once-weekly groups, respectively) at some time during the study. An analysis of the potential interaction between non-
Figure 3. Proportions of women with more than 2% loss, less than 2% change, and more than 2% gain in bone mineral density (BMD) of the lumbar spine and total hip. ALN ⫽ alendronate.
Figure 4. Mean percent change from baseline at month 12 in lumbar spine bone mineral density (BMD) by subgroups. ALN ⫽ alendronate.
Luckey. Alendronate 35 mg Once Weekly. Obstet Gynecol 2003.
Luckey. Alendronate 35 mg Once Weekly. Obstet Gynecol 2003.
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Table 4. Upper Gastrointestinal Adverse Experiences Alendronate Adverse experience category
5 mg daily (n ⫽ 361)
35 mg once weekly (n ⫽ 362)
Patients with one or more upper GI adverse experiences Discontinued from therapy due to an upper GI adverse experience Abdominal pain Abdominal distention Acid regurgitation Dyspepsia Nausea Vomiting Gastric ulcer
87 (24.1)
91 (25.1)
16 (4.4)
13 (3.6)
21 (5.8) 12 (3.3) 22 (6.1) 16 (4.4) 22 (6.1) 18 (5.0) 0
26 (7.2) 10 (2.8) 25 (6.9) 16 (4.4) 14 (3.9) 9 (2.5) 1 (0.3)
GI ⫽ gastrointestinal. Values are n (%). Although a patient may have two or more adverse experiences within the same category, the patient is counted only once within that category. The same patient may appear in different categories.
Figure 5. Geometric mean values for urinary N-telopeptides (NTx) and serum bone-specific alkaline phosphatase (BAP) by time point, with premenopausal reference ranges21 denoted by horizontal lines (mean ⫾ 2 standard deviations). Triangles ⫽ alendronate 5 mg daily; circles ⫽ alendronate 35 mg once weekly. Luckey. Alendronate 35 mg Once Weekly. Obstet Gynecol 2003.
steroidal antiinflammatory medications and either dosing regimen of alendronate showed that, although nonsteroidal antiinflammatory medication/aspirin use increased the overall incidence of upper gastrointestinal adverse experiences, the relative risk of upper gastrointestinal adverse experiences was not increased for the alendronate 35-mg once-weekly group compared with the 5-mg daily group during the period of nonsteroidal antiinflammatory medication use (relative risk [95% CI] was 1.05 [0.62, 1.79] during the “on-use” period and 0.88 [0.59, 1.30] during the “off-use” period). No subjects experienced a clinical vertebral fracture during the study. Nonvertebral fracture adverse experiences were reported in 2.5% of the 5-mg daily group and 1.4% of the 35-mg once-weekly group. None of the subjects experienced a hip fracture. There were no meaningful between-treatment-group differences in the incidence or skeletal distribution of nonvertebral fracture adverse events.
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DISCUSSION In two major studies employing daily regimens of alendronate enrolling a total of 2056 postmenopausal women without osteoporosis, treatment with alendronate 5 mg daily resulted in significant increases in lumbar spine bone mineral density (an average increase of 3% in the first year, which was maintained in subsequent years of treatment), as well as smaller yet significant increases in hip and total body bone mineral density. By contrast, the placebo groups experienced progressive bone loss at all skeletal sites relative to baseline.19,20 Although the above studies have shown that the daily regimen of oral alendronate is highly efficacious and generally well tolerated in the prevention of bone loss, the current study is the first to demonstrate that alendronate once weekly provides an equally efficacious alternative to the daily regimen while providing similar safety and tolerability. The primary efficacy end point of the current study was percent change in lumbar spine bone mineral density after 1 year of treatment. The lumbar spine was chosen because at this site, alendronate 5 mg produces the highest ratio of bone mineral density increase to the coefficient of variation of the measurement of change.11,19,20,23 One year was considered an adequate period for establishing therapeutic equivalence of alendronate 35 mg once weekly to 5 mg daily, because most of the increase in lumbar spine bone mineral density had been observed during the first year of treatment in prior studies.19,20 At the end of 1 year, treatment with both
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alendronate 35 mg once weekly and 5 mg daily resulted in percentage increases in lumbar spine bone mineral density similar to those observed for 5 mg daily in the two previous prevention studies, and the difference between the two groups was not significant, satisfying stringent, prespecified equivalence criteria. The similarity in treatment effect on lumbar spine bone mineral density was consistent across prespecified patient subgroups, although the ability to detect subtle differences in treatment response was limited by the sample size in each subgroup. Although no predefined equivalence hypotheses were established for other skeletal sites, the two treatment regimens also produced similar bone mineral density increases at the hip and total body, and the changes observed at these sites were in the range of those seen previously.19,20 It is worth noting that the current study did not include a placebo group and, therefore, does not illustrate the true bone mineral density “treatment effect” (difference between treatment and placebo) of the two dosing regimens, which is expected to be greater in magnitude than the difference from baseline, because the placebo groups in previous prevention studies generally experienced a 1% loss or more at the lumbar spine after 1 year.19,20 The equivalence hypothesis was supported further by the demonstration that similar proportions of subjects in the two treatment groups experienced some gain (more than 0% change) in lumbar spine and total hip bone mineral density, with a great majority of women experiencing bone gain regardless of the number of years since menopause. In addition, the proportions of subjects experiencing more than 2% loss, less than 2% change, and more than 2% gain at the lumbar spine and total hip were similar between the two treatment groups and comparable to those observed after 2 years of treatment with alendronate 5 mg daily in a previous prevention study.20 Similar time–response curves for the reduction in biochemical markers of bone resorption (urinary Ntelopeptides) and bone formation (serum bone-specific alkaline phosphatase) were seen in both treatment groups, with the decrease in urinary N-telopeptides occurring more rapidly than the decrease in serum bonespecific alkaline phosphatase, consistent with the known mechanism of action of alendronate—inhibition of osteoclast function. The mean urinary N-telopeptide and serum bone-specific alkaline phosphatase levels at baseline were elevated compared with the premenopausal reference mean, which is consistent with the estrogen deficiency state of the postmenopausal women in this study. Treatment with both dosing regimens after 1 year
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brought the marker levels down to the middle of the premenopausal reference ranges, as seen with alendronate 5 mg daily in a previous prevention study,19 and is responsible for and compatible with the significant bone mineral density increases seen in both treatment groups at 1 year. Although the reduction of serum bone-specific alkaline phosphatase at the end of 1 year was slightly lower in the 35-mg once-weekly group, the difference was small and not likely to be clinically significant. Further, the reductions in N-telopeptides were nearly indistinguishable between the two groups, and no appreciable difference in bone mineral density change at any skeletal site was observed. In addition to proven efficacy, a long-term preventive therapy also must have an excellent safety and tolerability profile to be accepted by asymptomatic women. In previous studies using daily alendronate, the safety and tolerability profiles of alendronate 5 mg daily were shown to be comparable to those of placebo, and no increased incidence of upper gastrointestinal adverse experiences was associated with alendronate use.19,20 The present study showed that alendronate 35 mg once weekly was similarly safe and well tolerated. No serious upper gastrointestinal adverse experience occurred in either group. It is worth noting that 28.1% of subjects had a history of upper gastrointestinal diseases. In addition, approximately 37% and 55% of subjects were using nonsteroidal antiinflammatory medications or aspirin before and during the study, respectively. Analysis of upper gastrointestinal adverse experiences among nonsteroidal antiinflammatory medication users showed that the relative risk for upper gastrointestinal adverse experiences during the period of nonsteroidal antiinflammatory medication use was not higher for the 35-mg once-weekly group compared with the 5-mg daily group, suggesting that the weekly regimen is not more likely to cause upper gastrointestinal irritation than the daily regimen, even in patients receiving nonsteroidal antiinflammatory medications. Although fracture was not an end point in this study, clinical fractures were captured as adverse experiences for the purpose of safety assessment. No clinical vertebral fractures occurred in either treatment group. The incidences of nonvertebral fractures were very low and similar in the two treatment groups; approximately half of the fractures were due to excessive trauma. Given the therapeutic equivalence and similar safety profile of the two dosing regimens, the less frequent once-weekly alendronate should be more readily accepted by women contemplating preventive therapy for osteoporosis. Past studies have indicated higher dosing frequency to be a contributing factor to the lack of
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compliance with and adherence to antihypertensive therapy.24,25 For chronic therapies in general, studies have shown that compliance is substantially improved when dosing frequency is reduced from three or four times daily to once daily.26 A recent study to assess the preference, convenience, and overall compliance of alendronate 70 mg once weekly compared with 10 mg daily showed that an overwhelming majority of patients (more than 85% for each parameter) found the weekly regimen to be preferable, more convenient, and easier to comply with.27 In addition, the rate of compliance with onceweekly fluoxetine has been found to be significantly higher than that with once-daily fluoxetine in the treatment of depression.28 Thus, studies of patient compliance to date strongly support the hypothesis that alendronate 35 mg once weekly, by providing women with greater flexibility and convenience in dosing, will be a more acceptable alternative to daily therapy in the prevention of postmenopausal osteoporosis.
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for antihypertensive medication refill failure by patients under medicaid managed care. Clin Ther 1996;18: 1252–62. 25. Hamilton RA, Briceland LL. Use of prescription-refill records to assess patient compliance. Am J Hosp Pharm 1992;49:1691–6. 26. Sbarbaro JA. Strategies to improve compliance with therapy. Am J Med 1985;79:34–7. 27. Simon JA, Lewiecki EM, Smith ME, Petruschke RA, Wang L, Palmisano JJ. Patient preference for once-weekly alendronate 70 mg versus once-daily alendronate 10 mg: A multicenter, randomized, open-label, crossover study. Clin Ther 2002;24:1871–86.
S TANDARDS
28. Claxton A, de Klerk E, Parry M, Robinson JM, Schmidt ME. Patient compliance to a new enteric-coated weekly formulation of fluoxetine during continuation treatment of major depressive disorder. J Clin Psychiatry 2000;61: 928–32. Address reprint requests to: Marjorie Luckey, MD, St. Barnabas Ambulatory Care Center, Osteoporosis Center, 200 South Orange Avenue, Livingston, NJ 07039; E-mail: [email protected]. Received June 3, 2002. Received in revised form October 31, 2002. Accepted November 7, 2002.
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