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Original Studies |
Michigan Bone and Mineral Clinic (H.G.B.), Detroit, Michigan 48236; General Clinical Research Center, Beth Israel Deaconess Medical Center (S.L.G.), Boston, Massachusetts 02215; ReSearch for Health (C.M.), Houston, Texas 77024; Veterans Administration Medical Center (N.B.), Charleston, South Carolina 29401; Chicago Center for Clinical Research (M.D.), Chicago, Illinois 60610; Medical College of Virginia (R.W.D.), Richmond, Virginia 23298; Bone Research Center (R.E.), Reading, Pennsylvania 19611; Edouard Herriot Hopital (P.J.M.), Lyon, France; SAM Clinical Research (S.S.M.), San Antonio, Texas 78229; Medical College of Georgia (A.L.M.), Augusta, Georgia 30912; Creighton University (R.R.R.), Omaha, Nebraska 68131; San Diego Endocrine Clinic (S.R.W.), San Diego, California 92108; and Merck Research Laboratories (N.H., T.M., S.S., A.J.Y., A.L.), Rahway, New Jersey 07065
Address all correspondence and requests for reprints to: Dr. Henry G. Bone, Michigan Bone and Mineral Clinic (H.G.B.), Detroit, Michigan 48236.
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Abstract |
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 Top Abstract IntroductionSubjects and MethodsResultsDiscussionReferences |
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Thus, alendronate and estrogen produced favorable effects on BMD. Combined use of alendronate and estrogen produced somewhat larger increases in BMD than either agent alone and was well tolerated.
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Alendronate is a potent bisphosphonate that has been shown to inhibit osteoclast activity at sites of bone resorption. Multicenter trials in postmenopausal women have demonstrated significant improvements in bone density, associated with a reduced incidence of hip, vertebral, and forearm fractures (1, 2, 3). Recent findings support the hypothesis that alendronate, like other nitrogen-containing bisphosphonates, inhibits a rate-limiting step in the mevalonic acid pathway that is essential for osteoclast function (4). In addition, bisphosphonates, including alendronate, appear to promote osteoclast apoptosis (5, 6).
The dominant effect of estrogen in the treatment of osteoporosis is a reduction in bone resorption attributed to decreased levels of cytokines associated with osteoclast stimulation (7). Estrogen therapy maintains or improves bone density (8, 9, 10) and appears to reduce vertebral fractures (11, 12). Although epidemiological studies have indicated reduced rates of nonvertebral fractures in estrogen users vs. nonusers (13), such effects remain to be confirmed in randomized controlled trials.
Because these antiresorptive agents have different mechanisms of action, we wished to determine whether combined use of alendronate and estrogens might lead to clinically meaningful increases in bone mass beyond those seen with the individual agents. Moreover, in view of the likelihood that alendronate and estrogen may be prescribed together, we were also interested in knowing whether there were any safety concerns associated with their combined use. Combined therapy may be considered in women who lose bone mass despite taking estrogens but may wish to consider estrogen therapy for other indications unrelated to osteoporosis, such as treatment of climacteric symptoms. Patients may fail to respond optimally to estrogen due to the presence of an untreated defect in bone or mineral metabolism or to individual variations in the absorption and metabolism of various estrogenic agents. However, in other cases accelerated bone resorption persists despite apparently normal mineral metabolism and adequate serum estradiol levels. Combination therapy may also be considered in women with severe osteoporosis, in whom the goal of therapy should be to maximally improve bone mineral density (BMD) and bone strength.
While the present study was being planned, a report was presented in abstract form on the positive effects of the combination of hormone replacement therapy (HRT) and another bisphosphonate, etidronate (14). During the course of the present study, additional data have been published on the additive effects of concomitant use of etidronate and estrogen (15, 16). The preliminary results of the present study were presented in part at the annual meeting of the American Society for Bone and Mineral Research (17), as was a report, subsequently published, that addition of alendronate to ongoing HRT in postmenopausal osteoporotic women produces increases in spine and hip BMD significantly greater than HRT alone (18).
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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This multicenter, double blind, randomized, 2-yr study enrolled 425 postmenopausal osteoporotic women, 42–82 yr of age, 92% of whom were Caucasians. Entry criteria included prior hysterectomy and a lumbar spine BMD below 0.862 g/cm2 for at least three evaluable vertebrae in the L1—L4 region, as measured by Hologic, Inc., densitometry equipment (Waltham, MA). Compared with the current reference range, the mean BMD (0.77 ± 0.07 g/cm2) observed in the patients enrolled corresponds to a mean t score of -2.5 ± 0.2.
Exclusion criteria included evidence of metabolic bone disease (other than postmenopausal osteoporosis), a low serum 25-hydroxyvitamin D concentration [<10 ng/mL (25 nmol/L)], concomitant therapy with drugs that affect bone turnover (including bisphosphonates, calcitonin, or fluo-ride), renal insufficiency, severe cardiac disease, or history of recent major upper gastrointestinal mucosal erosive disease (including significant upper gastrointestinal bleeding, recurrent peptic ulcer disease, and esophageal or gastric varices). However, a history of other gastrointestinal diseases or chronic use of nonsteroidal antiinflammatory agents were not considered reasons for exclusion. Women were not eligible for entry into the study if they had an underlying condition that would contraindicate randomization to estrogen, including active thrombophlebitis or history of prior thromboembolic disease, history of unexplained genital bleeding within the preceding year, increased risk for breast cancer, or fasting serum triglycerides more than 400 mg/dL. Women were also excluded from entering the study if within 6 months before entry into the study they had taken any form of systemic HRT. The study was limited to women who had undergone hysterectomy to avoid any possible confounding effects of progestin therapy or withdrawal bleeding. The protocol was approved by the institutional review boards of the participating institutions, and all of the patients provided informed consent.
Study design
Four-hundred and twenty-five patients were randomized to one of four treatment regimens: placebo alendronate/placebo conjugated equine estrogen (CEE; n = 50), alendronate (10 mg/day) and placebo CEE (n = 92), CEE (0.625 mg/day) and placebo alendronate (n = 143), or alendronate (10 mg/day) and CEE (0.625 mg/day; n = 140), using a computer-generated randomization schedule with a 1:2:3:3 ratio for these treatments. Patients also received 500 mg elemental calcium daily. The CEE preparation was Premarin (Wyeth-Ayerst Laboratories, Inc., Marietta, PA).
Outcome measurements
The patients were seen at baseline and at 3, 6, 12, 18, and 24 months. The BMDs of the lumbar spine, hip [femoral neck, trochanter, and total proximal femur (total hip)], and total body regions were measured at baseline and at 6, 12, 18, and 24 months by dual energy x-ray absorptiometry using Hologic, Inc., QDR 1000W, 1500, and 2000 series instruments (Waltham, MA). Regular instrument and operator quality control measures were carried out and analyzed by Medical Data Management (Waltham, MA). A standard phantom was used at all sites for cross-calibration.
Serum and urine samples were obtained at baseline and at 3, 6, 12, 18, and 24 months. In addition to standard safety measurements, specimens were assayed for biochemical markers of bone turnover. These included serum bone-specific alkaline phosphatase (BSAP), urinary excretion of cross-linked N-telopeptides of type I collagen corrected for creatinine (NTx), which were analyzed at a central reference laboratory (Mayo Medical Laboratories, Rochester, MN). The Osteomark enzyme-linked immunoassay (Ostex International, Inc., Seattle, WA) was used for the measurement of NTx, whereas the Tandem-R Ostase immunoradiometric assay (Hybritech, San Diego, CA) was used to measure BSAP. The NTx values were expressed as nanomoles of bone collagen equivalent (BCE) per mmol creatinine. The normal range for this assay is 5–65 nmol BCE/mmol creatinine. The BSAP values were expressed as nanograms per mL. The normal range for this assay is 2.9–14.5 ng/mL.
Iliac crest bone biopsies for histomorphometric analysis were obtained after at least 18 months of blinded treatment. The specimens were analyzed by two separate laboratories (Creighton University, Omaha, NE; and Hopital Edouard Herriot, Lyon, France). The primary purpose of the histomorphometric analysis was to assess safety by examining the effects of treatment on different parameters of bone turnover and to rule out mineralization defects or other histological abnormalities.
Statistical analysis
The primary efficacy end point was the difference between groups in the percent change in lumbar spine BMD from baseline at 24 months. Secondary efficacy end points were the percent changes in hip and total body BMD and biochemical markers of bone turnover. The results were analyzed on an intention to treat basis. The primary comparisons were between baseline and month 24. If month 24 data were unavailable, the last postrandomization measurement was carried forward. Patients were excluded from the intention to treat analysis if BMD data were not available for the baseline and at least one additional visit after initiation of treatment. For analyses of biochemical markers we used the log-transformed fraction of the baseline value at month 24. This transformation was preplanned, as noted in the data analysis section of the study protocol. Data from the patients who violated the protocol were excluded from the biochemical markers analysis. Pairwise comparisons were made using ANOVA techniques. Treatment, center, treatment by center, and treatment by prior use of conjugated estrogens were used as factors. Prior use of estrogen was defined as estrogen use for at least 30 days 6 months before randomization. The assumption of homoscedasticity for the ANOVA model was assessed by Levene’s test, and the normality assumption was assessed by the Shapiro-Wilk test. If the assumptions were violated, a nonparametric method was used. In such cases, the nonparametric method was considered the primary analysis. Fisher’s exact test was used for comparing treatment groups for adverse experience rates and the proportion of patients who exceeded predefined limits of change in laboratory safety parameters.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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The baseline characteristics of the 425 patients are shown in
Table 1
by treatment group. Baseline
demographic characteristics were similar in all treatment groups. The
mean lumbar spine BMD for these subjects was approximately 2.5
SD below the normal reference young adult mean.
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Thirty-nine patients discontinued from the study due to an adverse experience: 5 (10%) in the placebo group, 6 (6%) in the alendronate group, 14 (10%) in the CEE group, and 13 (9%) in the combination group. In addition, 40 patients withdrew their consent: 7 (14%) in the placebo group, 10 (11%) in the alendronate group, 12 (8%) in the CEE group, and 11 (8%) in the combination group. Seventeen patients were lost to follow-up (4, 5, 5, and 3 in the placebo, alendronate, CEE, and combination groups, respectively), and 9 patients were discontinued due to protocol violation (0, 3, 3, and 3 in the placebo, alendronate, CEE, and combination groups, respectively). Thus, 75.3% of subjects completed the study, with no significant differences between groups.
BMD
Mean changes in BMD relative to baseline after 2 yr are shown in
Table 2, and the time course is shown in
Fig. 1 (A–D). At the end of month
24, the BMD increases relative to baseline seen in the combination
group at both the lumbar spine and the femoral neck were significantly
greater than those in either the alendronate (P <
0.001 and P = 0.022, respectively) or CEE
(P < 0.001 and P = 0.003,
respectively) group. The effects of the combination were significantly
greater than those of CEE alone at the total hip (P =
0.001) and trochanter hip subregion, (P < 0.001), but
were not significantly different from those of alendronate alone. All
three active treatments produced significant increases relative to
baseline in total body BMD, but there were no significant differences
between the active treatment groups. The effects on BMD of alendronate
alone did not differ significantly from those of CEE alone at any site,
with the exception of the femoral trochanter, where the increase
relative to baseline produced by alendronate (+5.9%) was significantly
greater than that produced by CEE (+4.3%; P = 0.004).
The increases in the active treatment groups appeared to be progressive
through the end of yr 2, without evidence of a plateau having been
reached. As expected, however, most of the increases in BMD took place
during the first year of the study.
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A significant reduction in urinary NTx was seen in the
alendronate, CEE, and combination groups, reaching a nadir by 6 or 12
months and remaining stable thereafter, as shown in Fig. 2A.
A transient, but significant, 20% reduction was also seen in the
placebo group by month 6; this decrease had abated by the end of yr 1.
At the end of yr 2, the mean changes from baseline in urinary NTx were
-61% (P = 0.005), -52% (P <
0.001), and -70% (P < 0.001) in the alendronate,
CEE, and combination groups, respectively. The effect of alendronate
was greater than that of CEE alone, and the combination regimen
produced a greater decrease in this marker of bone turnover than either
agent alone. In all treatment groups, the mean absolute values of
urinary NTx remained within the normal premenopausal range (5–65 nmol
BCE/mmol creatinine) (19). Significant reductions in serum BSAP were
seen in the three active treatment groups, reaching a nadir by month
18, as shown in Fig. 2B. At the end of yr 2, serum BSAP was
unchanged in the placebo group and decreased by 50% (P
= 0.002), 49% (P < 0.001), and 60%
(P < 0.001) in the alendronate, CEE, and combination
groups, respectively. The effect of alendronate was similar to that of
CEE, and the combination produced a greater decrease in serum BSAP than
either treatment alone. The mean absolute values of serum BSAP remained
within the normal premenopausal range (2.9–14.5 ng/mL) (19).
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Histomorphometry
Bone biopsies were obtained from 98 patients after at least 18
months of treatment. Ninety-two specimens were suitable for
histomorphometric evaluation. No qualitative abnormalities were found.
As shown in Table 3, osteoid thickness
and osteoid volume were not increased and, in fact, declined in the
active treatment groups relative to placebo group values, consistent
with the decrease in turnover. The mineral apposition rate was
unchanged in all treatment groups. There was no indication that any
treatment produced impairment of bone mineralization. As expected, the
mineralizing surface was significantly decreased in all active
treatment groups relative to that in the placebo group, consistent with
a decrease in bone turnover. All biopsies had evidence of turnover in
cortical bone, as shown by the presence of tetracycline label. In
addition, cancellous bone label was observed in 89 of the 92 biopsies.
The 3 specimens without detectable cancellous label were obtained from
patients who received combination therapy. This was not an unexpected
finding, as tetracycline label may occasionally not be detected even in
bone biopsies from normal individuals (20).
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The tolerability profile of combined alendronate and estrogen was
favorable and consistent with those of the individual treatments, as
shown in Table 4. Upper gastrointestinal
adverse experiences occurred with a similar frequency in the different
treatment groups. Only 1 (1%) of 92 alen-dronate-treated patients
discontinued therapy due to an upper gastrointestinal adverse
experience vs. none in the placebo group, 3 (2%) of 143 in
the CEE group, and 2 (1%) of 140 in the combination group. As
expected, CEE treatment, alone or in combination with alendronate, was
frequently associated with complaints such as breast pain and weight
gain. However, the only group with a significant increase in mean body
weight was the placebo group (data not shown).
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, fractures occurred in 4 of 50 placebo patients (8%),
10 of 143 CEE patients (7%), 5 of 92 alendronate patients (5%), and 8
of 140 combination patients (6%). As expected in view of the small
number of events, there were no significant differences in fracture
incidence among the treatment groups. |
Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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The clinical relevance of the greater increase in bone mass with combination treatment needs to be considered in the light of previous studies, in which both BMD and fracture incidence were measured as outcomes. Several other studies of alendronate have shown significant and clinically important reductions in the incidence of vertebral, hip, and any nonvertebral clinical fractures (2, 3). Hochberg and colleagues have also shown that greater increases in BMD are associated with greater decreases in vertebral fractures in postmenopausal women receiving alendronate therapy (21). This suggests that the slightly greater increases in BMD produced by combined alendronate and estrogen therapy may result in additional antifracture efficacy, especially in women with inadequate responses to estrogen treatment and in those with extremely low BMD. However, the current study was far too small to detect such an effect.
Decreases in bone turnover with alendronate or CEE monotherapy, as reflected by biochemical markers, were consistent with the effects previously reported for these agents (1, 6). Alendronate alone decreased urinary NTx, a marker of bone resorption, to a slightly greater extent than estrogen alone (60% vs. 50%), but the effects of alendronate and estrogen on BSAP, a marker of bone formation, were indistinguishable (both produced a 50% decrease from baseline). Combined treatment with alendronate and estrogen produced a slightly greater decrease in bone markers than either treatment alone. However, the mean absolute values for both serum BSAP and urinary NTx remained within the range for premenopausal women. Thus, although the combination of alendronate and estrogen treatment decreased biochemical markers of bone turnover to a somewhat greater extent than either treatment alone, it did not give rise to excessive suppression.
The baseline turnover markers were not strongly predictive of the response to treatment. The reductions in the levels of turnover markers in all active treatment groups were significantly, but only weakly, correlated with the increases in bone mass. Thus, these tests provide an indication of the response to treatment, but cannot be relied upon clinically to predict the magnitude of BMD response in individual patients.
The mineralizing surface in iliac trabecular bone, an index of the local rate of bone turnover, decreased by more than 90% in the alendronate-treated group, by approximately 75% in the CEE group, and by approximately 95% in the combined alendronate and CEE group, in parallel with the 50–70% decrease in urinary NTx and the 50–60% decrease in BSAP. The reduction seen in the alendronate group is consistent with the results of previous studies in postmenopausal osteoporosis (22). The presence of tetracycline label in cortical bone in all specimens indicates that although the combination produced a greater reduction in mineralizing surface than either agent alone, no treatment group experienced complete suppression of bone turnover. Histomorphometry also showed normal mineralization, normal lamellar bone, and normal bone quality, consistent with previous studies of alendronate (22).
The clinical and laboratory adverse experience profiles of combined use of alendronate and estrogen were consistent with those of the individual agents. The selection of a cohort of hysterectomized, postmenopausal women avoided withdrawal bleeding, which is a common reason for bias and subject withdrawal in studies involving HRT. As a result, approximately 75% of the patients completed the study, with a similar retention rate in each group. No clinically meaningful differences in adverse experience profile were seen relative to that in the placebo group with either treatment, used alone or in combination. Because the study was performed in women who had undergone hysterectomy, the results relating to estrogen use may not necessarily be generalized to all postmenopausal women or other types of estrogen or estrogen/progestin therapy.
In summary, in postmenopausal women with low bone mass concomitantly taking calcium, combined use of alendronate and estrogen produced additive effects on bone mass compared with the effect of either agent alone. Over 2 yr of exposure, the combination therapy was well tolerated, and no adverse effects on bone mineralization or bone fragility were observed.
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Footnotes |
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2 Members of the Alendronate/Estrogen Trial Research Group: Clinical
centers: Arthur Bankhurst, University of New Mexico School of Medicine
(Albuquerque, NM); Norman Bell, V.A. Medical Center (Charleston, SC);
Michael Bolognese, Osteoporosis Analysis Clinic (Gaithersburg, MD);
Henry G. Bone, Michigan Bone and Mineral Clinic (Detroit, MI); Alan
Burshell, Ochsner Clinic (New Orleans, LA); Michael Davidson, Chicago
Center for Clinical Research (Chicago, IL); Michael Davis, Coastal
Clinical Research, Inc. (Mobile, AL); Robert W. Downs, Medical College
of Virginia (Richmond, VA); Ronald Emkey, Bone
Research Center (Reading, PA); Marlene Garone, Western PennsylvaniaHospital (Pittsburgh, PA); Susan L Greenspan, General Clinical Research Center, Beth Israel Deaconess Medical Center (Boston, MA); Maria Greenwald, Osteoporosis Medical Center (Palm Springs, CA); Angelo Licata, Cleveland Clinic Foundation (Cleveland, OH); Harris McIlwain, Tampa Medical Group (Tampa, FL); Clark McKeever, ReSearch for Health (Houston, TX); Samuel A. Miller, SAM Clinical Research (San Antonio, TX); Anthony L. Mulloy, Medical College of Georgia (Augusta, GA); Joseph R. Tucci, Roger Williams Medical Center (Providence, RI); and Stuart R. Weiss, San Diego Endocrine Clinic (San Diego, CA). Histomorphometry laboratories: Pascale Chavassieux and Pierre J. Meunier, Hopital Edouard Herriot (Lyon, France); and Robert R. Recker, Creighton University (Omaha, NE). Sponsors: Tersit Biftu, Anastasia Daifotis, Norman Heyden, Don Kimmel, Antonio Lombardi, Thomas Musliner, Shailaja Suryawanshi, and A. John Yates, Merck Research Laboratories (Rahway, NJ).
Received May 6, 1999.
Revised November 4, 1999.
Accepted November 8, 1999.
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References |
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S. T. Harris, E. F. Eriksen, M. Davidson, M. P. Ettinger, A. H. Moffett Jr., D. J. Baylink, C. E. Crusan, and A. A. Chines Effect of Combined Risedronate and Hormone Replacement Therapies on Bone Mineral Density in Postmenopausal Women J. Clin. Endocrinol. Metab., May 1, 2001; 86(5): 1890 - 1897. [Abstract] [Full Text]
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D. Altkorn and T. Vokes Treatment of Postmenopausal Osteoporosis JAMA, March 21, 2001; 285(11): 1415 - 1418. [Full Text] [PDF]
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C. Crandall Risedronate: A Clinical Review Arch Intern Med, February 12, 2001; 161(3): 353 - 360. [Abstract] [Full Text] [PDF]
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 Estrogen, Alendronate, or Both for Osteoporosis? Journal Watch Women's Health, June 1, 2000; 2000(601): 6 - 6. [Full Text]
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 Estrogen, Alendronate, or Both for Osteoporosis? Journal Watch Gastroenterology, May 1, 2000; 2000(501): 19 - 19. [Full Text]
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 Estrogen, Alendronate, or Both for Osteoporosis? Journal Watch (General), March 14, 2000; 2000(314): 1 - 1. [Full Text]
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), alendronate
(ALN; 
), CE (
), and ALN plus CE (
) treatment groups.