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Prevention of Postmenopausal Bone Loss: Six-Year Results from the Early Postmenopausal Intervention Cohort Study

Oregon Osteoporosis Center (M.R.M.), Portland, Oregon 97213; Radiant Research-Honolulu (R.D.W.), Honolulu, Hawaii 96814; Nottingham City Hospital (D.J.H.), Nottingham, NG5 1PB, United Kingdom; Center for Clinical and Basic Research (C.C., P.R.), Ballerup DK-2750, Denmark; and Merck Research Laboratories (M.W., A.M.M, J.Y., P.D.R., A.C.S), Rahway, New Jersey 07065

Address all correspondence and requests for reprints to: Michael R. McClung, M.D., Oregon Osteoporosis Center, 5050 Northeast Hoyt, Suite 651, Portland, Oregon 97213. E-mail: mmcclung{at}orost.com.

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion References

 
We report the effect of continuous treatment with alendronate for 6 yr vs. placebo in the Early Postmenopausal Intervention Cohort study. A total of 1609 healthy, early postmenopausal women were recruited; we describe results for the 585 women who received continuous placebo or alendronate (2.5 or 5 mg) daily for 6 yr. Bone mineral density (BMD) was evaluated at the lumbar spine, hip, forearm, and total body at baseline and annually thereafter. Bone turnover markers were measured every 6 months from baseline to yr 2 and annually thereafter. Adverse experiences, including upper gastrointestinal events and fractures, were recorded throughout the study. Women receiving placebo experienced progressive decreases in BMD at all skeletal sites. Patients receiving alendronate experienced significant gains in spine and hip BMD that were maintained through yr 6. Significantly greater, dose-related decreases in bone turnover markers in the alendronate groups vs. placebo occurred within the first year and were sustained through yr 6. Women receiving alendronate had adverse experience incidences similar to those receiving placebo. Fractures occurred in 11.5, 10.3, and 8.9% of women taking placebo, 2.5 mg alendronate, or 5 mg alendronate daily, respectively. Therapy with alendronate is an effective and promising strategy for the prevention of postmenopausal osteoporosis.

	Introduction

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OSTEOPOROSIS IS A systemic skeletal disease characterized by low bone mass and microarchitectural deterioration of bone tissue (1). In the United States today, 10 million people have osteoporosis, and 34 million more have low bone mass, placing them at elevated risk for the disease (2). The consequences of osteoporosis include bone fragility and increased susceptibility to fracture. It has been estimated that half of all women of age 50 yr and older will sustain at least one osteoporotic fracture during their remaining lifetime (2). More than 1.5 million Americans experience osteoporotic fractures each year (2). In 2001, the estimated direct cost for osteoporotic and associated fractures was 17 billion dollars (2). However, the cost of osteoporosis is not merely economic; the societal costs are also great. For instance, only half of hip fracture patients regain the level of independence they had before the injury, and 12–40% die within 6 months (3). The future cost associated with this disease is expected to rise substantially as the proportion of the world’s population that is elderly increases. It has been estimated that the number of hip fractures will increase from 1.7 million in 1990 to 6.3 million in 2050, with an associated cost of $131 billion (4). Appropriate action to reduce the burden of osteoporosis is needed.

Intervention to prevent bone loss in early postmenopausal women is an effective approach to control the increasing incidence of osteoporosis. Such a strategy would avoid the accelerated bone loss and microarchitectural deterioration observed in the first decade after menopause. Indeed, by the time osteoporosis is diagnosed, subjects have generally lost in excess of 20% of their peak bone mass. Even with long-term effective therapy, it may not be fully possible to restore bone mass to peak levels, reverse architectural deterioration, and regain peak bone strength once such bone loss has occurred.

Hormone therapy (HT) had long been viewed as an appropriate strategy for the prevention of postmenopausal bone loss. However, recent data from randomized controlled trials have identified significant issues associated with prolonged HT, such as increased risks of breast and ovarian cancer, cardiovascular disease, stroke, and dementia (5, 6, 7, 8, 9). Moreover, in women without vasomotor symptoms, HT did not have a clinically meaningful effect on health-related quality of life (10). Because the risks of adverse events outweigh the potential benefits, prolonged use of HT is no longer recommended.

Oral alendronate (a potent and selective inhibitor of osteoclast-mediated bone resorption) has been shown to be generally well tolerated and highly effective in the treatment of osteoporosis in postmenopausal women. Well-controlled, randomized, multinational studies have shown that alendronate induces progressive increases in bone mass of normal quality and reduces the incidence of fractures in women with postmenopausal osteoporosis (11, 12, 13, 14, 15). Alendronate is also an established therapy for the prevention of osteoporosis (16, 17, 18, 19). Among women in the Early Postmenopausal Intervention Cohort (EPIC), alendronate (5 mg for 4 yr) increased bone mineral density (BMD) and then maintained bone mass at the spine and hip sites (17). The EPIC study was designed to continue for a total of 6 yr; the current report describes the efficacy, safety, and tolerability of alendronate vs. placebo over the full 6 yr in the EPIC study.

	Subjects and Methods

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Subjects

The EPIC study enrolled 1609 women across four centers (Portland, OR; Honolulu, HI; Nottingham, UK; and Ballerup, Denmark). The women were 45–59 yr old, in good general health, and at least 6 months postmenopausal at baseline. To ensure that few women who entered the study had osteoporosis, baseline BMD at the spine was 0.8 g/cm² or greater in approximately 90% of patients (18). The study was approved by the local ethics committees and institutional review boards at each center.

Treatment

After a 2-wk, single-blind, placebo run-in period, consenting subjects were randomized to treatment. The treatment groups were divided into two strata (Fig. 1). The specifics of treatment allocation and the results of the EPIC study through 4 yr were previously reported (16, 17). This report focuses on the patients who were randomized to receive the same dose of alendronate (2.5 or 5 mg daily) or placebo continuously for 6 yr of the study (n = 585). Results for patients in other treatment groups who discontinued treatment at 2 or 4 yr according to study design are presented in a separate report (19).

View larger version (28K): [in this window] [in a new window]   FIG. 1. Treatment allocation and sample sizes, by stratum and year of study, for the treatment groups described in this report. The numbers enrolled are shown on the left. There were approximately equal numbers of participants at each of the four sites (two U.S. sites and two European sites). In stratum 1, women were randomized to receive placebo, 2.5 or 5 mg alendronate daily, or open-label estrogen-progestin. Women who had undergone hysterectomy or for whom estrogen-progestin was contraindicated or unacceptable were enrolled in stratum 2, which randomized women to placebo or 2.5 or 5 mg alendronate daily. S1, Stratum 1; PBO, placebo; ALN, alendronate; E/P, estrogen-progestin.

BMD

BMD of the lumbar spine, total hip, femoral neck, trochanter, forearm, and total body was measured by dual-energy x-ray absorptiometry using a Hologic (Bedford, MA) QDR 2000 densitometer. Measurements were taken twice at baseline and then annually. Synarc (Maynard, MA) was responsible for all aspects of quality assurance for BMD measurements, including calibration of machines, training of technicians, assessment of machine performance, adequacy of the scans obtained, analysis performed at various sites, and data management without knowledge of treatment assignment.

Biochemical markers

To examine bone resorption, urine N-telopeptide cross-links of type 1 collagen (NTx) (Ostex, Seattle, WA), corrected for creatinine excretion, was measured every 6 months from baseline to month 72 in fasting morning urine samples. Data on the bone formation marker, bone specific alkaline phosphatase, were only collected for the initial 3 yr of the study, and results were reported previously (17).

Safety evaluations

Subjects were clinically evaluated every 3 months. All unfavorable and unintended clinical events, including fractures (regardless of cause) and laboratory abnormalities, were considered adverse experiences and were evaluated for severity, duration, potential relationship to study drug, and outcome.

Statistical analysis

The primary endpoint was percent change in lumbar spine BMD from baseline to month 72 using a modified intention-to-treat approach: subjects were followed regardless of whether they continued to take the study medication, and the last available measurement after baseline was carried forward in patients who dropped out of the study before month 72. Secondary endpoints included changes in BMD at other sites and biochemical markers of bone turnover. Prespecified analyses of BMD changes among subgroups of baseline age, years since menopause, BMD, and body mass index (BMI) were also performed. A patient was excluded from the intention-to-treat analysis for one or both of the following reasons: 1) no efficacy data at baseline; or 2) no efficacy data after baseline. Treatment effects were evaluated by ANOVA, including treatment, study center, and stratum. The treatment-by-stratum and treatment-by-center interactions were also examined. Between-treatment comparisons of adjusted means were performed using ANOVA. A confirmatory per-protocol analysis was also conducted, which only included subjects who completed the 6-yr study and complied with the prespecified per-protocol rules regarding adherence to medication use and inclusion/exclusion criteria. All statistical tests were two-sided; significance was defined as P < 0.05. Adjustments for multiple comparisons were not performed; this was specified in advance, because there was only one primary endpoint and one primary comparison [alendronate (5 mg) vs. placebo].

	Results

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Baseline characteristics

The disposition of participants in the groups that received continuous treatment is shown, by year of the study, in Table 1. Among the 428 women who participated in yr 4 of the study, 348 (81.3%) continued into yr 5, and 305 (71.3%) completed all 6 yr. Among the participants who continued into yr 5, all study groups had similar demographic characteristics and lumbar spine bone density values at baseline [T = –0.8 (SD = 0.9)] (Table 2).

Table 3 presents the mean change in BMD from baseline at the end of 6 yr. Postmenopausal women treated with placebo for 6 yr experienced significant progressive decreases in BMD of the spine, hip, forearm, and total body (all P values 0.001). In contrast, women who received 6 yr of treatment with alendronate (2.5 or 5 mg daily) experienced significant gains vs. baseline values in mean lumbar spine, trochanter, and total hip BMD (P 0.001) (Table 3 and Fig. 2). In addition, women who received continuous 5 mg alendronate for 6 yr experienced a significant increase in BMD at the femoral neck vs. baseline values (P 0.01). The treatment-by-stratum and treatment-by-center interactions were found to be either nonsignificant (NS) (P > 0.10) or nonqualitative in nature. The results of the intention-to-treat analysis were generally very similar to those from the confirmatory per-protocol approach (data not shown). Changes in BMD at the total body and trochanter tended to be somewhat greater in magnitude for the per-protocol analysis when compared with the intention-to-treat analysis, but the patterns of differences between treatment groups were similar in both analyses.

View larger version (24K): [in this window] [in a new window]   FIG. 2. Mean changes from baseline in BMD of the lumbar spine (A), total hip (B), total body (C), and distal one third forearm (D) in groups taking placebo, 2.5 mg alendronate for 6 yr, and 5 mg alendronate for 6 yr. Bars, SE.

Patients who received placebo for 6 yr experienced a small mean decrease in urinary NTx levels (approximately 25% at 6 months) followed by a progressive further decline until approximately 3 yr. The levels remained relatively stable from then to the end of 6 yr, resulting in a final value 37.9% below baseline. In the groups receiving alendronate, 2.5 mg and 5 mg daily for 6 yr, there was a much greater dose-related decrease in mean urinary NTx during the first year of treatment followed by a further small decline up to yr 3, and then it remained relatively stable within the normal premenopausal range (20, 21). At the end of 6 yr, the mean percent changes from baseline were –63.9 and –68.0% for the 2.5-mg and 5-mg alendronate groups, respectively. The decreases in bone resorption in the two alendronate groups were significantly (P < 0.001) different from the placebo group at the end of yr 6 (Fig. 3).

View larger version (19K): [in this window] [in a new window]   FIG. 3. Mean changes from baseline in urine N-telopeptides in groups taking placebo, 2.5 mg alendronate for 6 yr, and 5 mg alendronate for 6 yr groups. Bars, SE.

Over the entire 6-yr follow-up, the groups treated with alendronate had incidences of clinical (including upper gastrointestinal), drug-related, serious, or laboratory-related adverse experiences similar to those of the group receiving continuous placebo (Table 6). There were no serious drug-related adverse experiences. Moreover, discontinuation of therapy due to adverse events occurred at similar rates in the placebo and alendronate groups. Overall, fractures occurred in 61 patients [53 nonvertebral and eight vertebral fractures (Table 6)], and the lowest incidence was observed in the alendronate 5-mg group (NS).

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

Alendronate is also an established therapy for the prevention of osteoporosis where the goals of therapy are to stabilize bone density, maintain biochemical indices of bone turnover in the premenopausal range, and prevent fracture risk from increasing subsequently. Indeed, low bone mass and increased turnover are important contributors to fracture risk. Previously, we reported that alendronate prevented bone loss and maintained bone mass in healthy postmenopausal women in the EPIC for up to 4 yr (17, 18). The present study marks the completion of the original study and confirms continued prevention of bone loss in these same women through 6 yr.

Our results show that postmenopausal women randomized to placebo for 6 yr experienced progressive decreases in BMD of the spine, hip, forearm, and total body. Six years of treatment with alendronate (2.5 or 5 mg daily) produced initial increases in BMD and prevented subsequent postmenopausal bone loss at the lumbar spine, femoral neck, total hip, and trochanter. Although all groups experienced BMD losses at the distal one third forearm site, alendronate reduced the loss relative to placebo. Moreover, the decline in forearm BMD observed from baseline to yr 4 in women treated with continuous alendronate leveled off in yr 5 and 6. The findings reported here differ somewhat, compared with those reported recently in which BMD increases continued for a longer time, and were larger in older women who received 5 mg or 10 mg alendronate daily for 10 yr (22).

In a previous report on older women with osteoporosis, the 10-mg daily dose of alendronate produced greater effects on BMD and bone markers than the 5-mg dose (22). The effects of alendronate on BMD were also dose-related in the current study of early postmenopausal women. Overall, 5 mg alendronate daily was more effective than the 2.5-mg dose at all measured sites. A similar osteoporosis prevention study, investigating varying doses of alendronate, support the finding that alendronate at dosages of 5 mg daily or greater prevented postmenopausal bone loss (23). Moreover, a once-weekly formulation is now available and provides greater dosing convenience, a key element in the long-term management of osteoporosis (24).

The positive benefit of alendronate on BMD changes over 6 yr was evident in all risk factor subgroups, relative to placebo. For example, the response to treatment with alendronate in the subgroups of women with lower BMD was similar to those with higher BMD at baseline. As reported earlier, we observed greater declines in BMD among thinner (lower BMI) women in the placebo group compared with other women, but alendronate produced positive effects that were similar in magnitude to those seen in every subgroup category, relative to placebo (25).

It has recently been recognized that elevated bone turnover adversely influences bone mass and fracture risk (26). Bone turnover accelerates at the time of menopause (27) and remains elevated thereafter (28, 29, 30, 31). In the present study, the rate of bone loss was greater among younger women and during the first few years after menopause, consistent with previous reports (32, 33, 34). Reduction in biochemical markers of bone turnover has been correlated with increases in bone density and reduced fracture risk (35). During the first year of treatment with alendronate, biochemical markers of bone turnover decreased in a dose-dependent manner and remained within the normal premenopausal range (18, 19) through 6 yr of follow-up, suggesting an appropriate reduction of bone turnover. Similar findings have recently been reported for up to 10 yr with alendronate doses of 5 mg and 10 mg (22). Women randomized to continuous placebo experienced small decreases in biochemical markers of bone turnover, which may be due to the increased dietary intake of supplemental calcium, decreased resorption after the perimenopausal period, a subtle drift in the calibration of the assay, or other unidentified factors.

In the past, many experts believed that the most effective way for women to prevent osteoporosis was to initiate HT immediately after menopause and continue its use throughout their lives (36). Although short-term HT is still recommended for the treatment of vasomotor symptoms, recent clinical trial data suggest that the risks associated with prolonged HT outweigh the benefits (5, 6, 7). Moreover, many women cannot or will not use HT because of contraindications or such side effects as breast tenderness, fluid retention, and uterine bleeding (37, 38). In contrast to HT, alendronate had a safety and tolerability profile similar to that of placebo in this study and earlier reports. Women treated for 6 yr with alendronate in the EPIC study had an overall incidence of clinical adverse experiences similar to that of the group receiving placebo. In particular, there were no serious drug-related adverse events, and the number of upper gastrointestinal adverse events was similar in the alendronate and placebo groups. The safety and tolerability profile was similar for both doses of alendronate studied.

Overall, 61 women in the continuous-treatment groups sustained a fracture during the study, none of which was considered to be drug related: 29 (11.5%) in the placebo group, 17 (10.3%) in the 2.5-mg alendronate group, and 15 (8.9%) in the alendronate 5-mg group. The EPIC study was not designed to evaluate the effect of alendronate on fracture risk, because the incidence of osteoporotic fractures in healthy, younger, recently postmenopausal women is low, and a much larger study would be necessary (39). However, the documented association between increased BMD and reduced bone turnover with reduced susceptibility to fractures (35, 40) suggests that, because alendronate effectively maintained bone mass, it will likely confer protection against fractures as well.

Our study has several strengths and limitations. To our knowledge, this is the largest and longest randomized controlled trial examining the effects of nonestrogen therapy in the prevention of postmenopausal osteoporosis. Objective, blinded measures of BMD and biochemical markers with centralized quality control help reduce the potential for bias. Like many multiyear studies, patients in this study represented a self-selected cohort due to patient reconsent for the follow-up visits. However, these patients still provide valuable medical information that warrants reporting.

In summary, treatment of early postmenopausal women with daily 2.5 and 5 mg alendronate effectively normalized bone resorption and increased and maintained bone density at the lumbar spine, hip femoral neck, hip trochanter, and total hip over 6 yr. Treatment was associated with a favorable safety and tolerability profile and adverse experience incidences similar to placebo. Therapy with alendronate is effective in preserving bone mass in postmenopausal women and is a promising strategy for the prevention of postmenopausal osteoporosis.

	Acknowledgments

 
Christine Sisk provided assistance with preparation of the manuscript.

	Footnotes

 
This work was supported by Merck Research Laboratories in the form of research grants to the individual study sites.

The EPIC Study Group is made up of the following: R. D. Wasnich, D. S. Uyeda, R. Ali, J. L. Ruckle, H. Souza, and M. T. Afaga (Radiant Research-Honolulu); C. Christiansen, P. Alexandersen, L. B. Tanko, P. Ravn, B. J. Riis, L. Warming, Y. Z. Bagger, and T. F. Nielsen (Center for Clinical and Basic Research); D. Hosking, S. Cawte, C. E. D. Chilvers, S. Cliffe, C. A. Coupland, Y. San, K. Dove, and B. Horton (Bone and Mineral Unit, Nottingham City Hospital and Department of Public Health Medicine and Epidemiology, Nottingham Medical School, Nottingham, UK); M. R. McClung, M. K. N. Omizo, E. Steffens, P. Workman, and D. Conn (Oregon Osteoporosis Center, Portland, OR); A. Santora, J. Yates, A. Maragoto, C. Yacik, P. Ross, A. M. Mantz, and M. S. Daley (Merck Research Laboratories, Rahway, NJ); J. Cole, C. Davies-Wilkie, K. McFerran, A. Prosper, and A. Colley (Merck Research Laboratories, Hoddesdon, UK); M. Busch-Sørensen, P. Trøgaard, and B. Lohse Hansen (Merck Research Laboratories, Copenhagen, Denmark); and E. Yapchian and K. Rodriguez Amaya (Synarc, Bedford, MA).

Abbreviations: BMD, Bone mineral density; BMI, body mass index; EPIC, Early Postmenopausal Intervention Cohort; HT, hormone therapy; NS, nonsignificant; NTx, N-telopeptide cross-links of type 1 collagen.

Received September 30, 2003.

Accepted June 22, 2004.

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