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Clinical Research Center of North Texas (S.B.), Denton, Texas 76210; Division of Clinical Immunology and Rheumatology (K.G.S.), University of Alabama at Birmingham, Birmingham, Alabama 35294; Beth Israel Deaconess Medical Center and Harvard Medical School (D.P.K.), Boston, Massachusetts 02215; Oregon Osteoporosis Center (M.M.), Portland, Oregon 97213; University of Maryland School of Medicine (M.H.), Baltimore, Maryland 21201; Endocrine Unit (S.-A.M.B.), Massachusetts General Hospital, Boston, Massachusetts 02114; Arthritis Associates (A.S.), Palm Harbor, Florida 34684; Foundation for Osteoporosis Research and Education (R.K.), Oakland, California 94612; and Merck & Co., Inc. (E.C. D.E.T., A.E.d.P.), West Point, Pennsylvania 19486
Address all correspondence and requests for reprints to: Dr. Sydney Bonnick, Clinical Research Center of North Texas, 2921 Country Club Road, Suite 101, Denton, Texas 76210. E-mail: sbonnick{at}msn.com.
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Abstract |
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Design: This was a randomized, double-blind extension conducted at 72 U.S. sites.
Patients and Methods: Of the 1053 women who completed yr 1, 833 postmenopausal women with low BMD entered the extension, continuing their same treatment allocation [once-weekly (OW) alendronate 70 mg or OW risedronate 35 mg]. Changes in BMD at the hip trochanter, total hip, femoral neck, and lumbar spine and in markers of bone turnover were compared at 24 months. Tolerability was assessed by adverse experience reporting.
Results: Alendronate produced greater increases from baseline in BMD at 24 months than did risedronate at the trochanter (alendronate, 4.6%; risedronate, 2.5%, P < 0.001) as well as at all other BMD sites. Significantly more alendronate than risedronate patients had measured BMD increases of 0% or more and 3% or more at all BMD sites (P < 0.001), and fewer alendronate patients had measured decreases of 3% or more at all BMD sites. Significantly greater reductions in all biochemical markers of bone turnover occurred with alendronate, compared with risedronate. No differences were seen in occurrence or discontinuations due to upper gastrointestinal adverse experiences.
Conclusions: Patients receiving 70 mg OW alendronate had greater gains in BMD, were more likely to maintain or gain BMD, and had greater reductions in bone turnover markers than patients receiving 35 mg OW risedronate after 24 months, with no differences in upper gastrointestinal tolerability.
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Introduction |
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A 1-yr extension of FACT was completed to determine whether the differences in BMD and bone turnover persisted over 2 yr and whether tolerability remained similar. This report provides the results from this extension of the original study, encompassing 2 yr of treatment.
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Patients and Methods |
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Participants in FACT were community-dwelling, ambulatory, postmenopausal (at least 6 months) women 40 yr of age or older (
25 yr if surgically menopausal) with a BMD 2.0 SD or more below young normal mean bone density in at least one of four sites [total hip, hip trochanter, femoral neck, or posteroanterior lumbar spine (L1 to L4)]. Women were required to be in good general health, with hip and spinal anatomy suitable for dual-energy x-ray absorptiometry. In accordance with alendronate prescribing information, individuals with a history of abnormalities of the esophagus that delay esophageal emptying, such as stricture or achalasia, were excluded, as were those unable to remain upright for 30 min after dosing. The specific exclusion criteria have been published previously (6). Women with hypocalcemia, hypovitaminosis D (serum 25 hydroxyvitamin D < 10 ng/ml), or metabolic bone diseases other than postmenopausal osteoporosis were excluded.
Study design
The extension (protocol 211–10) was a double-blind, active-controlled, multicenter study during which all eligible women maintained their original randomized, blinded treatment allocation (oral alendronate 70 mg OW or oral risedronate 35 mg OW) from yr 1 for an additional 12 months. Seventy-two of the original 78 sites within the United States chose to participate in the extension study. The study was conducted in accordance with consideration for the protection of patients, as outlined in the Declaration of Helsinki, and was approved by the appropriate institutional review boards. All participants gave written, informed consent before entering the study extension.
Women were eligible to enter the extension study if they completed the original 12-month study, described by Rosen et al. (6). They were to begin treatment within 7 d after their final yr 1 study visit and take their dose on the same day each week. In addition to study medication, all patients were instructed to consume 1000 mg of elemental calcium and 400 IU vitamin D daily, from either their preexisting diet or a supplement provided by the sponsor (Os-cal 500+D; SmithKline Beecham, Pittsburgh, PA) with their noon or evening meals. Women recorded medication use during the 24 months of treatment.
Assessment of outcomes
BMD was measured by dual-energy x-ray absorptiometry using Hologic (Bedford, MA) or Lunar (Madison, WI) densitometers on the same machine during baseline and all follow-up visits to the investigational site through month 24. Instrument quality control and all BMD analyses were performed by a central analysis facility (Bio-Imaging Technologies, Inc., Newtown, PA) blinded to treatment allocation. No significant machine drifts or shifts occurred during the 2-yr study based on phantom BMD measurements on each dual-energy x-ray absorptiometer.
Two markers each of bone resorption and bone formation were used to evaluate changes in bone turnover. Bone resorption was measured by urinary N-telopeptide of type I human collagen (NTX) corrected for creatinine (Ortho Vitros; Ortho Clinical Diagnostics, Amersham, UK) and serum C-telopeptide (CTX; measured on the Elecsys 2010 automated analyzer, Roche Elecsys, Mannheim, Germany). Bone formation was measured by bone-specific alkaline phosphatase (BSAP; Access OSTASE assay; Beckman-Coulter, Fullerton, CA) and serum N-terminal propeptide of type 1 procollagen (P1NP; Intact P1NP, P1NP RIA; Orion Diagnostic, Espoo, Finland). Samples for serum biochemical markers and a fasting second-morning void for urinary N-telopeptide were obtained at 24 months. Stored samples were analyzed in batches by time point at the end of the study. The intraassay and interassay coefficient of variation ranged from 1.9 to 2.4% for BSAP, 3.4 to 9.6% for P1NP, 1.6 to 5.0% for NTX, and less than 8% for CTX.
Efficacy and safety evaluations
The primary efficacy end point was the comparison of the mean percentage change from baseline in trochanteric BMD at 24 months between the two treatment groups. As noted in the report of the yr 1 results, this site was chosen as the primary end point because of both the precision at measuring BMD at this site and the rapid and large gains in BMD seen at this site in response to bisphosphonate therapy (6). Secondary BMD end points included a comparison of the mean percentage change from baseline in total hip, femoral neck, and lumbar spine BMD at 24 months between the two treatment groups and the proportion of patients with predefined increases of trochanteric and lumbar spine BMD 0% or more and 3% or more from baseline at 24 months. Additional secondary end points were a comparison of the mean percentage change from baseline in biochemical markers of bone turnover (NTX, CTX, BSAP, and P1NP) at 24 months between the two treatment groups. Other prespecified analyses included determination of the proportion of women with BMD increases 0% or more, 1, 2, 3, 4, and 5% from baseline at each BMD site at 24 months and an analysis of the proportion of women with BMD losses 3% or more at each BMD site.
Safety was monitored by investigators, who recorded clinical and laboratory adverse experiences (AEs) during study visits. Patients could report AEs in person or by phone at any time during the study.
Statistical methods
The hypothesis of the extension study stated that, in postmenopausal women with osteoporosis, treatment with oral alendronate 70 mg OW will produce a mean percent increase from baseline in hip trochanter BMD at 24 months that is greater than that observed with oral risedronate 35 mg OW. All statistical analyses were conducted by Merck & Co., Inc. Treatment effect at 6, 12, and 24 months on BMD for all women entering the extension study was assessed by an ANOVA on percentage change from baseline using a linear model that included terms for treatment and study center. Treatment differences were estimated by differences in least squares means from the ANOVA model, and the 95% confidence intervals (CIs) were calculated. All patients who were enrolled in the 12-month extension who had a baseline BMD, a BMD measurement in the extension, and took at least one dose of study drug in the extension were included in the modified intention-to-treat (mITT) analysis. Patients were analyzed according to the group to which they were randomized. Missing values were imputed by carrying the last postbaseline value forward to the 24-month time point.
The log-transformed fraction of baseline value (calculated by dividing the on-treatment value by the baseline value and then applying the natural log) was applied to normalize the distribution of changes in biochemical markers before comparisons of alendronate and risedronate were assessed using the same model as in the BMD analyses. The delta method was used to estimate a 95% CI of the treatment difference in percentage change from baseline from the above ANOVA model. For the biochemical marker data at 24 months, the primary analysis was based on a per-protocol (PP) approach, with no data being carried forward. All patients or time points with important protocol violations were excluded from the PP analyses. The same cohort of patients included in the 24-month analyses were used for analyses at 3, 6, and 12 months if they were not protocol violators at the specific time point.
Because the primary analysis of treatment effect on BMD was performed only on data from the women who continued into the extension at the completion of yr 1 (extension cohort, n = 833), which is a subset of all randomized patients, a post hoc supportive analysis was performed for all randomized patients (original cohort, n = 1053) during the entire 2-yr treatment period. If patients discontinued during the first 12 months or completed the first 12 months but did not enter the extension, the last on-treatment measurements were carried forward to 24 months. Treatment effect in the original cohort was analyzed in the same manner as described above for the extension cohort.
The safety analysis included all patients who received at least one dose of study medication in the extension in either treatment group. Differences in proportions of patients with any AEs, serious AEs, and discontinuations due to AEs were analyzed using Fisher’s exact test. The treatment groups were also compared for the proportion of patients with UGI AEs using Fisher’s exact test.
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Results |
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Of the 892 eligible women who completed the baseline study, 833 (79.1%) enrolled in the 1-yr extension (Fig. 1
). The completion rates for the extension were similar in the two treatment groups (alendronate 92.3%; risedronate 91.6%).
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Demographics and baseline characteristics
There were no meaningful differences in baseline characteristics between the alendronate and risedronate treatment groups in the extension (Table 1). The demographics of the extension cohort were similar to those of the 1053 women in the yr 1 study cohort and to the 220 women who were not eligible or chose not to enroll in the extension.
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Increases from baseline in BMD at month 24 were significantly (P < 0.001) greater in alendronate patients than in risedronate patients at all sites measured: the trochanter, total hip, femoral neck, and lumbar spine (Fig. 2). At month 24, the treatment differences were 2.1% (95% CI 1.4–2.8%) at the trochanter, 1.7% (95% CI 1.3–2.2%) at the total hip, 1.9% (95% CI 1.2–2.5%) at the femoral neck, and 1.8% (95% CI 1.2–2.5%) at the lumbar spine. The differences increased with time at all sites (Fig. 2). The increases in BMD from baseline at all time points were significant for both treatment groups.
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and Table 2). Regardless of the level used to categorize gains in BMD, the differences in the proportions between the two treatment groups achieving the respective levels consistently favored alendronate. Alendronate-treated patients were 1.4–1.7 times more likely than risedronate-treated patients to show a gain of 3% or more in BMD. In general, the higher the cut point, the greater the relative BMD response favoring alendronate (e.g. for trochanter, 86%/75% = 1.15 for 0%, 67%/45% = 1.49 for 3%, 49%/30% = 1.63 for 5%).
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and Table 2). Biochemical markers of bone turnover
Both treatments significantly reduced bone resorption, as measured by percent reduction from baseline in urine NTX (Fig. 4) and serum CTX. After 24 months of therapy, alendronate reduced NTX and CTX by 56.6 and 73.4%, respectively, whereas the corresponding reductions for risedronate were 43.9 and 53.1%. The differences between the two treatment groups were significant by as early as 3 months and were maintained at 24 months (P < 0.001).
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) and P1NP (–62% alendronate, –46% risedronate, P < 0.001) after 24 months. The differences between the two treatment groups favoring alendronate were significant at 24 months (P < 0.001) and at all earlier time points. Comparison of original and extension cohorts
The 12-month treatment differences for the extension cohort (n = 833) differed slightly from those reported at the end of yr 1 for the original cohort (n = 1053). At the end of yr 1 in the extension cohort, the treatment differences were 1.6% (95% CI 1.0–2.2%) at the trochanter, 1.3% (95% CI 0.8–1.8%) at the lumbar spine, 1.2% (95% CI 0.8–1.7%) at the total hip, and 0.8% (95% CI 0.3–1.4%) at the femoral neck. In comparison, the treatment differences reported at the end of yr 1 in the original cohort were 1.4, 1.2, 1.0, and 0.7%, respectively (6). These differences were all within the respective 95% CIs for the extension cohort. An analysis of the original cohort was also performed, carrying all data forward to 24 months. The treatment differences at 24 months were also within the 95% CIs for the treatment differences of the extension cohort at 24 months (data not shown).
Safety
There were no significant differences between treatment groups in the overall rate of clinical AEs at 24 months: 87.1% alendronate-treated and 86.5% risedronate-treated women reported one or more clinical AEs. There were no significant differences between the treatment groups in the incidence of serious AEs (12.4% alendronate, 13.5% risedronate) or discontinuations due to AEs (2.2% in each group). Similarly, over 24 months, there were no significant differences in UGI AEs between the two treatment groups (24.8% alendronate, 22.9% risedronate) or in the proportion of women discontinuing due to an UGI AE (1.7% alendronate, 1.2% risedronate; Table 3). The most common UGI AEs reported overall were dyspepsia (7.0%), nausea (6.7%), and reflux disease (4.0%). The differences between the treatment groups were not significant. There was a single death due to a serious UGI AE (hemorrhagic duodenal ulcer) that occurred in the risedronate treatment group during the extension study.
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Discussion |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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There has been much debate about the clinical utility of changes in BMD and biochemical markers observed during clinical trials (7, 8, 9, 10). Multiple analyses using individual patient data from clinical trials have shown that gains in BMD and reductions in bone turnover markers are associated with decreases in both vertebral and nonvertebral fractures (11, 12, 13, 14). It is well known, however, that changes in BMD during antiresorptive therapy do not account for all of the observed reduction in fracture risk, with the proportion varying, depending on the analysis design and statistical methodology used (9, 15, 16). Similarly, changes in bone turnover markers in response to antiresorptive therapy have been shown to predict fracture reduction (7, 11, 12). Although the complete nature of this relationship is unknown, there is no evidence for a threshold effect for nonvertebral fractures for either agent (11, 12). Because head-to-head trials of antiosteoporosis drugs from the same class are not likely to include fracture end points, for reasons previously discussed (6, 17), surrogate or intermediate end points are the best tools currently available to compare the relative effects of two agents with similar mechanisms of action (18).
BMD nonresponse to therapy is of potential concern to clinicians and patients alike (19). The analysis presented here focuses on comparing BMD response to therapy between the two bisphosphonates. Not only were there greater increases seen in BMD overall with alendronate, but there were also greater responses at all the prespecified levels of BMD at each site of interest. Importantly, there was a significant difference between the two agents in preventing a decrease in BMD, regardless of the BMD site measured. Women treated with risedronate were 1.2–1.3 times more likely to show a measured decrease in BMD than those treated with alendronate. This ratio became more pronounced when the proportion of women losing 3% or more were compared between the two treatment groups.
An analysis by Watts et al. (20) using data from the two Vertebral Efficacy with Risedronate Therapy trials (3, 4) and the Hip Intervention Program (5) showed that, among patients treated with 2.5 or 5 mg of risedronate daily, those who had measured increases in BMD at the spine were less likely to suffer vertebral fracture than patients who had a measured loss of BMD. Similar findings have been reported from studies with alendronate (21). Both Hochberg et al. (21) and Bauer et al. (12) have shown that greater increases in BMD at the lumbar spine or hip among alendronate-treated patients resulted in a lower risk of vertebral fractures. These studies demonstrate that there is clinical benefit in terms of fracture risk reduction in having patients experience measured increases in BMD, rather than measured decreases. In another analysis, Chapurlat et al. (22) suggested that women losing up to 4% of BMD at the lumbar spine or total hip during treatment with alendronate still had a significantly decreased risk of vertebral fracture, compared with women in the placebo group who had a similar decrease in BMD. The authors noted that this magnitude of change was likely to be less than the least significant change needed to conclude that the BMD had actually changed (22). Declines in BMD greater than 4% in the alendronate-treated women in that study were not associated with significant reductions in spine fracture risk vs. the placebo-treated women with similar declines. This suggests that stability of the bone mass on antiresorptive therapy results in spine fracture risk reduction, compared with similar stability in BMD in placebo-treated women. Consequently, the findings from Chapurlat et al. (22) do not negate the greater benefit of gaining bone density on therapy, compared with losing it. Thus, reducing BMD loss should be seen as advantageous to patients.
In the present study, the effectiveness of alendronate and risedronate on maintaining or increasing BMD and decreasing bone turnover marker levels was compared. Previous placebo-controlled studies have shown that these two agents are effective in reducing the risk of vertebral and nonvertebral fractures (1, 3). As has been previously reported, the sample size required to make meaningful comparisons in fracture risk reduction is not consistent with the size of this study (6). The results presented here do not address the question of whether the differences observed in this study in BMD and bone turnover markers translate into more effective protection from fracture with alendronate. Although claims have been made from nonfracture studies regarding fracture risk reductions, most, if not all, of these studies compared an active agent vs. a placebo (23, 24). Whether the differences in antiresorptive efficacy observed in the current trial are due to differences in dose or reflect true differences in the in vivo potency of the two agents also cannot be answered from this study. Although other noninvasive techniques may become available to identify and quantify factors other than BMD and bone turnover that contribute to fracture risk, at present, changes in BMD and bone turnover are used to explain, in part, the decreased fracture risk achieved with antiresorptive agents (14, 16).
In clinical trials, neither OW alendronate nor OW risedronate has been documented to induce more UGI side effects than seen in placebo groups. This is the first study to assess the UGI tolerability of the two OW bisphosphonates in a direct comparator fashion over 24 months using doses approved for the treatment of postmenopausal osteoporosis. The UGI intolerance was low and similar in both treatment groups.
Conclusion
In this cohort of postmenopausal women with osteoporosis followed up for 2 yr in the 1-yr FACT and 1-yr extension, alendronate 70 mg OW produced significantly greater gains in BMD at all skeletal sites and significantly greater reduction of all bone turnover markers, compared with risedronate 35 mg OW, with equal tolerability. Alendronate was more effective than risedronate in reducing the risk of bone loss. These findings may be useful to clinicians in making prescribing and management decisions for their patients.
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Acknowledgments |
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Footnotes |
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Disclosure: S.B., K.G.S., D.P.K., M.M., M.H., A.S., and R.K. have received consulting fees or paid advisory board and lecture fees from Merck & Co., Inc. E.C., D.E.T., and A.E.d.P. are employees of Merck & Co., Inc. and may own Merck & Co., Inc. stock.
National Clinical Trial (NCT) 00092014; http://www.clinicaltrials.gov/ct/show/NCT00092014?order=25
First Published Online April 24, 2006
Abbreviations: AE, Adverse experience; BMD, bone mineral density; BSAP, bone-specific alkaline phosphatase; CI, confidence interval; CTX, C-telopeptide; FACT, Fosamax Actonel Comparison Trial; mITT, modified intention-to-treat; NTX, N-telopeptide of type I human collagen; OW, once-weekly; PA, posteroanterior; P1NP, N-terminal propeptide of type 1 procollagen; PP, per-protocol; UGI, upper gastrointestinal.
Received November 30, 2005.
Accepted April 18, 2006.
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