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Original Studies |
University of Vermont College of Medicine, Burlington, Vermont 05401
Address all correspondence and requests for reprints to: Dr. Richard P. Tonino, 1 South Prospect Street, Burlington, Vermont 05401. E-mail: richard.tonino{at}vtmednet.org
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Abstract |
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 Top Abstract IntroductionSubjects and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Alendronate is a potent inhibitor of bone resorption. It increases BMD, reduces bone turnover (as measured by biochemical markers of bone turnover and bone histomorphometry) to premenopausal levels, and substantially reduces the incidence of vertebral and nonvertebral fractures among postmenopausal women (8, 9, 10, 11, 12, 13). In patients with osteoporosis the incidence of new hip fractures is reduced by 63% within 18 months, the incidence of symptomatic new vertebral fractures is reduced by 59% within 12 months, and the incidence of multiple vertebral fractures is reduced by 90% (11, 14, 15). Alendronate has been studied in more than 17,000 participants in clinical trials and has been prescribed to more than 3 million patients worldwide as FOSAMAX (Merck & Co., Inc., Whitehouse Station, NJ).
Long-term treatment with antiresorptive therapy is probably needed by many patients, as current drugs for treatment of osteoporosis do not fully restore bone mass to healthy young adult levels. Therefore, it is important to evaluate the long-term safety and efficacy of antiresorptive agents. The initial placebo-controlled phase III studies of alendronate were designed to end after 3 yr (9). Although information from long-term follow-up to evaluate efficacy and safety would have been useful, it was no longer considered ethical to continue a placebo-controlled trial after the beneficial effects of alendronate to reduce fracture risk had been demonstrated. Thus, a 2-yr open label extension was conducted to increase the follow-up to 5 yr, with all women receiving alendronate (16). Treatment of postmenopausal osteoporotic women with alendronate (10 mg/day) for 5 yr produced progressive increases in BMD in the spine and hip and prevented bone loss in the forearm. At the end of 5 yr, BMD had increased at the lumbar spine, femoral neck, and trochanter relative to baseline by 9.4%, 4.8%, and 9.1%, respectively, among women taking continuous alendronate (10 mg/day) (16). Biochemical markers of bone turnover were decreased into the normal premenopausal range within 6 months and remained stable throughout the 5 yr among women taking alendronate. Safety and tolerability were similar between the 5- and 10-mg alendronate doses and were comparable to those for placebo during the initial 3 yr of the trial.
The primary objective of the current study was to examine the efficacy (as measured by changes in BMD and biochemical markers), safety, and tolerability of an additional 2 yr of alendronate treatment in these same patients, yielding a total of 7 yr of continuous alendronate treatment at doses of both 5 and 10 mg daily. A secondary objective was to examine skeletal changes occurring over 2 yr of alendronate discontinuation after 5 yr of continuous use.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Two nearly identical randomized, double blind,
placebo-controlled phase III clinical trials of 3-yr duration were
conducted in the United States (18 sites) and other countries (19 sites
in 15 countries) to evaluate the safety and efficacy of daily oral
alendronate (9). These studies enrolled a total of 994 postmenopausal
women with osteoporosis, as defined by spine BMD at least 2.5
SD below the mean for young healthy women (corresponding to
0.80 g/cm2 on Hologic, Inc., model
1000 densitometers, Waltham, MA). The women were randomized to receive
alendronate (5, 10, or 20 mg daily), or placebo of identical appearance
(Fig. 1
). The 20-mg dose was changed to 5
mg for yr 3, based on results from a separate study indicating that 20
mg was more than necessary to obtain maximal increases in BMD.
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A second 2-yr extension, from the end of yr 5 to the end of yr 7,
maintained the double blind treatment assignments from yr 3 for women
who were originally randomized to alendronate (5 or 10 mg). Women who
received alendronate (20 mg initially, then 5 mg in yr 3–5) received
placebo (designated 20/5/PBO) during this second extension (Fig. 1
).
Women from the original placebo group, who represented 40% of the
total, were ineligible for the second extension. The current report
describes data for the women who entered the second 2-yr extension for
yr 6 and 7 (n = 350, representing 59% of women originally
randomized to alendronate).
Participants were instructed to take the study medication each morning with 6–8 oz water at least 0.5 h before consuming any food or drink (except water). All patients received 500 mg/day calcium supplementation (as carbonate, OsCal; SmithKline Beecham, Pittsburgh, PA), and were instructed to take it with a meal, separate from the morning dose of alendronate. Participants taking vitamin D supplements were not excluded, and vitamin D supplements were not provided.
The primary efficacy end point in these studies was change in lumbar spine BMD. The secondary end point was BMD changes at the proximal femur hip (femoral neck, trochanter, and Ward’s triangle). Additional secondary end points included changes in forearm and total body BMD, and changes in biochemical markers of bone resorption [urinary N-telopeptides of type I collagen corrected for creatinine (NTX)] and bone formation [serum bone-specific alkaline phosphatase (BSAP)].
Measurements
BMD was measured by dual energy x-ray absorptiometry using Hologic, Inc., QDR, Lunar Corp. DPX-L (Madison, WI), or Norland XR-26 (Fort Atkinson, WI) densitometers, using prespecified standard operating procedures. All BMD scans were reviewed at the study site and by a quality assurance center (Hologic, Inc., MDM/Synarc,), while maintaining the double blind. Measurements of a BMD calibration phantom that was circulated to all sites were used to monitor calibration of dual energy x-ray absorptiometry instruments during the study, and each site measured a spine BMD phantom at routine intervals; no corrections for changes in calibration during the study were necessary.
Serum and urinary biochemical markers of bone turnover were measured at a central laboratory (Medical Research Laboratories, Cincinnati, OH). Urinary NTX, a marker of bone resorption, was measured using Osteomark kits (Ostex International, Inc., Seattle, WA). Serum BSAP, a marker of bone formation, was measured using Ostase kits (Beckman Coulter, Inc.-Coulter, San Diego, CA). Stature was measured annually to the nearest millimeter using a Harpenden stadiometer (Seritex, Inc., Carlstadt, NJ), because decreases in height are a surrogate measure of new vertebral fractures. The value for height was the average of three to five measurements obtained at each visit.
Analyses
The data from the two multicenter studies (U.S. and other countries) were pooled, as the designs and subject characteristics of the two studies were nearly identical. Study and treatment center interactions were examined in analyses where appropriate. Summary statistics and analyses of change in efficacy and safety parameters during this extension study are limited to the 350 women who were enrolled into the second 2-yr extension study (yr 6–7). Therefore, changes during the first 3 and 5 yr of treatment reported here are similar, but not identical, to those previously reported for all patients initially enrolled (9, 16).
Percent changes from month 60 and baseline were used to assess the effect of treatment on BMD, stature, and biochemical markers at month 84. The intention to treat principle was used in analyses of BMD and stature; data from the last point of evaluation were carried forward in patients who withdrew from the second extension study before study completion or for whom follow-up measurements were inadequate. Thus, analyses included all patients who had at least one measurement after month 60. Due to the changes in treatments and medication doses in some groups, biochemical marker analyses were performed per protocol, with no data carried forward from subjects who discontinued before the end of the study, as these markers were included to evaluate the clinical pharmacology of alendronate and may not be adequate surrogates for clinical efficacy. A natural log transformation was used to normalize the distribution of the changes in biochemical parameters (fraction of value at month 0) for analysis.
ANOVA was used to examine treatment effect. Within each treatment group, changes were tested using paired t tests. A least squares mean change and its confidence interval (CI) was computed for all treatment groups, adjusted for study and clinical center.
Safety and tolerability were evaluated based on original treatment group randomization. All clinical and laboratory adverse experiences were reviewed, including those that were considered serious or drug related (i.e. rated by the investigator as possibly, probably, or definitely drug related) or that resulted in patient withdrawal from the study. Fisher’s exact test was used to compare proportions of patients with clinical adverse experiences between 5- and 10-mg treatment groups. Fisher’s test was not used for comparisons to placebo because the 20/5/PBO group did not take placebo continuously for all 7 yr, and prior exposure to alendronate may have influenced outcomes such as fracture, thereby complicating interpretation. Safety was also assessed by analyzing weight, blood pressure, and pulse rate for within- and between-group differences in changes from baseline and by analyzing the proportions of patients with laboratory parameters exceeding predefined limits (or changes) in laboratory variables. All reported symptomatic nonvertebral and vertebral fractures were considered adverse experiences, with no attempt to exclude those fractures related to excessive trauma. All fractures were confirmed by radiographs.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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At baseline (month 0), the 350 women in the current extension study (yr 6–7) had a mean age of 63 yr and were 16 yr postmenopause. Their mean spinal BMD was 0.71 (SD = 0.08) g/cm2 (measured on Hologic, Inc., and Norland densitometers), and 21% had existing vertebral fractures at baseline. The geometric mean urinary NTX/creatinine was 87.5 nmol Bone Collagen Equivalents/mmol creatinine, and the mean BSAP was 18.1 ng/mL. Mean dietary calcium intake was 734 mg/day, and mean body mass index was 24 kg/m2. In general, the baseline characteristics of the patients who did not enter the current extension study were similar to those of the patients who entered the extension (data not shown). Among those who entered the current extension, the treatment groups were generally comparable to each other at baseline (month 0), except that the prevalence of vertebral fracture was 23.4%, 14.8%, and 26.4% in the 5 mg, 10 mg, and 20/5/PBO groups, respectively. Additional details of baseline patient characteristics were provided in a previous report for all patients enrolled (9).
Effect of continued alendronate
Seven years of treatment resulted in a total lumbar spine
BMD increase of 11.4% for the 10 mg group and 8.2% for the 5 mg group
compared to baseline (month 0). Lumbar spine BMD increased
significantly by 1.6% in the 10-mg group and 1.5% in the 5-mg group
treated with alendronate during yr 6–7, relative to that at the 60
month point (Fig. 2 and Table 1). The increase in BMD appeared to be
linear after 18 months (based on visual inspection) for the continuous
administration groups, as shown in Fig. 2. Linear regression was used
to estimate the slope of mean change in BMD vs. time between
18 and 84 months. The slope indicates that each additional year of
treatment increases spine BMD by 0.83% (SE =
0.07) for the 10-mg dose and 0.58% (0.05) for the 5-mg dose. The
proportion of women whose spine BMD increased relative to that at month
0 was 97% for the 10 mg group, and 88% for the 5 mg group.
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and 4 and Table 1). Overall, larger BMD
increases were observed at the hip trochanter than the femoral neck. At
the end of 7 yr, trochanter BMD had increased 9.5% for the 10 mg group
and 5.6% for the 5 mg group, compared to 4.9% and 2.6%,
respectively, at the femoral neck, relative to baseline (Figs. 3 and 4
and Table 1). The increase in total body BMD and prevention of loss of
forearm BMD through yr 5 were maintained, but did not change, with both
alendronate groups (5 and 10 mg) over yr 6 and 7 (Table 1).
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and 6).
Within 3 months, urinary NTX was reduced to approximately -75%
relative to baseline in the 10 mg group and remained relatively stable
in subsequent years. NTX in the 5-mg dose group was initially reduced
to approximately -65%, and gradually declined further to coincide
with mean NTX levels of the 10 mg group at the end of 84 months,
-71.3% (95% CI, -66.8, -75.9) for 5 mg and -71.9% (-68.4,
-75.5) for 10 mg. Serum BSAP was reduced to approximately -55% for
the 10 mg group, with a final value of -52.3% (-48.8, -55.8) at
month 84. For the 5 mg group, BSAP was reduced to approximately -40%
relative to baseline within 6 months and then declined to approximately
-50% after 36 months, with a final value of -44.6% (-40.9, -48.2)
at month 84.
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There were no significant changes in BMD at the spine and hip
during yr 6–7 in the 20/5/PBO group (switched to placebo after 5 yr of
alendronate treatment; 2 yr of 20 mg, followed by 3 yr of 5 mg),
although there were small, nonsignificant declines at the hip based on
visual inspection (Table 1, Figs. 3 and 4). Small, but significant,
declines in BMD occurred at total body and forearm. At the end of 84
months, BMD in the 20/5/PBO group was higher than baseline by 8.9% at
the spine, 6.8% at the trochanter, and 3.2% at the femoral neck
(Table 1 and
Figs. 2–4). These values were intermediate between the
groups that had received 5 and 10 mg alendronate continuously for 7 yr,
reflecting the cumulative alendronate exposure of these three
groups.
Discontinuation of alendronate resulted in small increases in urinary
NTX and serum BSAP in yr 6–7 compared to levels observed during
treatment (Figs. 5 and 6). NTX remained stable, however, between months
72 and 84, after increasing from approximately -73% at 60 months to a
final value of -57.9% (95% CI, -52.6, -63.1). Serum BSAP also
remained well below baseline, increasing gradually over time from
approximately -55% at month 60 to -36.7% (-32.4, -40.9) at the
end of 7 yr.
Safety and tolerability
Alendronate (both 5 and 10 mg) was well tolerated during yr 6–7;
the safety and tolerability profiles were similar to those of placebo
(Table 2). In particular, the incidence
of upper gastrointestinal adverse events, both overall and those
considered by the investigator to be drug related (possibly, probably,
or definitely), was similar to that of placebo for both the 5- and
10-mg doses (Table 3). Two patients
withdrew due to upper gastrointestinal adverse events in the placebo
group compared to zero and one patient, respectively, in the 5 and 10
mg groups. No patients died during yr 6–7 in any group.
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Once incorporated into mineralized bone, alendronate has a long residence with a half-life measured in years, similar to calcium and other bone minerals. Osteoclasts may resorb less bone when they encounter alendronate in mineralized tissue. Alendronate released during bone resorption may also enter the circulation, where it would be available to inhibit bone resorption at other remodeling sites. Thus, it is possible that the alendronate present in bone from the previous 5 yr of treatment in the 20/5/PBO group may have slowed the rate of BMD declines in yr 6–7 (after discontinuation). Although the current study suggests that discontinuation of alendronate may result in some reversal of skeletal benefits, the effect is much less than that observed after estrogen withdrawal (19, 20).
BMD remained relatively stable over 2 yr after stopping alendronate in this study, although there was a small rise in bone turnover, as measured by NTX and BSAP. Similar findings have been reported in two other studies of alendronate discontinuation over 1 yr (20, 21). In contrast, estrogen discontinuation results in a rapid decline in BMD and increase in bone turnover (20, 22, 23). A substantial increase in bone turnover may have a deleterious effect on fracture risk, as the additional resorption pits may create local areas of weakness in trabeculae or perforate trabecular struts with irreparable damage (17). This may explain why the antifracture efficacy of estrogen diminishes markedly or disappears within several years after discontinuing estrogen treatment (24, 25).
Interpreting the incidence of new fractures and stature loss in the current study is complicated by the lack of a continuous placebo group. However, there is no evidence of an increase in fractures or height loss upon discontinuing alendronate compared to those in subjects continuing alendronate. There is some concern that excessive inhibition of bone turnover might impair bone strength and increase fracture risk. For example, a recent study of dogs found that microcracks accumulated in the ribs of dogs treated with 5 times the usual human dose of risedronate and alendronate (26). Cortical remodeling was suppressed up to 68% compared to that in untreated dogs. However, the relevance to humans is unknown, because this study did not use a high turnover osteoporosis model and unusually high doses were used. In an ovariectomized baboon model of high turnover, alendronate reduced turnover to control (nonovariectomized) levels or lower, and increased BMD, resulting in an increase in bone strength (27). Among human patients treated with alendronate, bone turnover markers return to within the premenopausal range and are not excessively suppressed. Thus, continued monitoring of long-term safety is prudent, but existing evidence indicates that there is a considerably wide safety margin of decreased bone turnover, and that alendronate treatment reduces the risk of osteoporotic fractures (28).
The average increase in BMD compared to placebo during the initial 2 yr of this trial was nearly 7% during treatment with 10 mg alendronate daily and about 5% with 5 mg daily. These findings are very consistent with those reported previously for these doses (9, 10, 11, 12). During 7 yr of treatment with 10 mg alendronate daily, spine BMD increased from baseline (month 0) by an average of 11%. Although there was no continuous placebo group for comparison during the final 2 yr, a progressive decline in BMD of 0.5–1%/yr would be expected for such a group from previous experience in clinical trials and epidemiological studies (1, 2, 3, 4, 9). Although increases in soft tissue calcification with age may sometimes cause spine BMD to be overestimated, the original placebo group in this study lost approximately 1–2% at all measured sites during the first 3 yr, and there was no evidence of an increase in BMD during yr 6–7 in the 20/5/PBO group (9). As a result, the expected difference for 10 mg alendronate relative to placebo would be greater than 11% after 7 yr.
The mechanism by which inhibition of resorption by alendronate increases BMD rather than simply prevents further declines is not completely understood. The current theory is that the amount of bone resorbed is less than the amount subsequently formed, leading to continued positive bone balance and increases in BMD beyond the 1–2 yr needed to refill existing resorption sites in some studies (29, 30, 31, 32). The current study indicates that increases in spine BMD may continue for at least 7 yr. Inhibiting excessive resorption may also allow compromised bone to respond to mechanical demands, preferentially thickening critical trabeculae, and helping to compensate for reduced connectivity (29, 33). Furthermore, reducing the rate of bone turnover allows more complete mineralization of bone tissue (34, 35). Each of these three mechanisms would increase BMD and might also improve bone strength and reduce fracture risk (17).
Two recent independent meta-analyses of all long-term, placebo-controlled clinical trials of antiresorptive drugs concluded that larger increases in BMD during antiresorptive therapy are associated with greater reductions in vertebral fracture risk (17, 36). Based on the relationship observed, a BMD increase of 12–14% (vs. placebo, as predicted after 7 yr of alendronate treatment) would correspond to as much as a 64% reduction in fracture risk.
Limited data are available regarding the long-term efficacy of other antiresorptive agents in randomized trials. Up to 7 yr of follow-up have been reported for a smaller study of cyclical etidronate therapy, with 3 yr of blinded treatment followed by 2 yr of open label treatment and 2 additional yr of blinded treatment (31). Women who received cyclical etidronate continuously for the full 7 yr (n = 51) had final BMD values approximately 7.5% above baseline. Bone density appeared to remain stable at the spine and hip for up to 2 yr after discontinuation of 5 yr of etidronate treatment (n = 46).
Most long-term clinical trials of estrogen have involved early postmenopausal women, and therefore may not be comparable to our findings. One open label (double blind for the first 2 yr) study of women less than 2 yr postmenopause reported the effect of 2 mg estradiol (plus progestin) daily for 10 yr on BMD of the spine and distal forearm (37). However, a large proportion (50–61%) of women dropped out, and the analysis was not by intention to treat. Among those who remained on treatment or placebo for 10 yr (n = 64), spine BMD increased 13.1% compared to a -4.7% loss in the untreated group, and forearm BMD remained stable at -0.7% compared to a 17.6% loss. A second study (n = 129 completed) reported the effect of high dose (2.5 mg conjugated estrogen, 2–4 times the currently recommended dose) estrogen treatment for 10 yr on bone mass at the metacarpal among women without osteoporosis (38). Women less than 3 yr postmenopause had increases of 8.7% at the metacarpal, but women more than 3 yr postmenopause had no increase relative to baseline; women taking placebo had BMD declines of approximately 10% (38). A study of mestranol treatment of ovariectomized women (n = 58) reported slight decreases in metacarpal (-1.9%) and radius (-2.2%) bone mass after an average of 9 yr of follow-up; bone mass changes in the placebo group (n = 42) were -9.5% at the radius and -13.9 at the metacarpal (39). As with the other estrogen studies, intention to treat analysis was not performed. A 5-yr open label study of women 2 yr or less postmenopause reported an 0.8% increase in spine BMD and a 1.4% decrease at the hip among 232 women receiving estrogen, compared to decreases of 4.3–4.5% in the placebo group (n = 116) (40).
Thus, our findings suggest that of the agents with long-term data (alendronate, etidronate, estrogen), alendronate yields the best demonstrated large increases in BMD among women with osteoporosis. These increases with alendronate are consistent across trials and progressive at the spine through 7 yr. Increases in BMD at the hip, total body, and forearm during the first few years are maintained in later years, even with discontinuation of therapy. Changes in biochemical markers were not available in other studies for comparison.
It is important to increase or preserve BMD for the purpose of reducing fracture risk among women with osteoporosis or osteopenia (17, 18). Estrogen may increase BMD initially, but there is evidence that long-term estrogen use may only slow bone loss (19, 38, 40). Epidemiological studies suggest that at least 6 yr of estrogen treatment may be required to achieve a significant reduction in fracture risk (24, 25, 42). This may partly explain why some women taking estrogen were found to have low BMD and experience fractures (43, 44). As a result, the National Osteoporosis Foundation recommends that BMD be measured in women who have been using estrogen for long periods (3). Recent studies also show that addition of alendronate can augment BMD increases among estrogen-treated women whose BMD values remain in the osteoporotic range (45, 46).
We conclude that spinal BMD continues to increase throughout 7 yr of alendronate treatment, and BMD remains stable at other sites after rising during the first few years. Biochemical markers of bone turnover remained stable during the sixth and seventh years of treatment with alendronate, well below baseline. Bone density remained stable for 2 yr after discontinuing alendronate. Although there was a small increase in biochemical markers of bone turnover when treatment was discontinued, turnover remained well below baseline levels. The safety and tolerability of alendronate in yr 6 and 7 were similar to those of placebo. These findings should reassure clinicians that long-term alendronate treatment is very effective and generally well tolerated through at least 7 yr. The results indicate that discontinuation does not lead to accelerated bone loss as seen with estrogen, so accrued BMD gains will continue to play a role, as will the lower levels of bone turnover.
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Footnotes |
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Received January 20, 2000.
Revised May 12, 2000.
Accepted May 18, 2000.
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References |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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