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Original Studies |
Helen Hayes Hospital (R.L., F.C.), West Haverstraw, New York 10993; Columbia University College of Physicians and Surgeons (R.A.L.), New York, New York 10032; Brigham and Women’s Hospital (B.W.W.), Boston, Massachusetts 02115; University of California at San Francisco (S.T.H.), San Francisco, California 94117; and Merck & Co., Inc. (J.E.R., C.L.L., M.E.M., C.A.B.), West Point, Pennsylvania 19486
Address all correspondence and requests for reprints to: Christine A. Byrnes, M.D., Merck & Co., Inc., P.O. Box 4, HM-214, West Point, Pennsylvania 19486. E-mail: christine_byrnes{at}merck.com
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Abstract |
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A total of 428 postmenopausal women with osteoporosis, who had been receiving HRT for at least 1 yr, were randomized to receive either alendronate (10 mg/day) or placebo. HRT was continued in both groups. Changes in bone mineral density (BMD) and biochemical markers of bone turnover were assessed.
Compared with HRT alone, at 12 months, alendronate plus HRT produced significantly greater increases in BMD of the lumbar spine (3.6% vs. 1.0%, P < 0.001) and hip trochanter (2.7% vs. 0.5%, P < 0.001); however, the between-group difference in BMD at the femoral neck was not significant (1.7% vs. 0.8%, P = 0.072). Biochemical markers of bone turnover (serum bone-specific alkaline phosphatase and urine N-telopeptide) decreased significantly at 6 and 12 months with alendronate plus HRT, and they remained within premenopausal levels. Addition of alendronate to ongoing HRT was generally well tolerated, with no significant between-group differences in upper gastrointestinal adverse events or fractures.
This study demonstrated that, in postmenopausal women with low bone density despite ongoing treatment with estrogen, alendronate added to HRT significantly increased bone mass at both spine and hip trochanter and was generally well tolerated.
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Introduction |
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The nitrogen-containing bisphosphonate alendronate is also a highly effective therapy for postmenopausal osteoporosis. Several large prospective clinical trials have demonstrated that alendronate increases bone mass and significantly decreases the incidence of osteoporotic fractures (16, 17, 18, 19, 20, 21, 22). In postmenopausal women with osteoporosis, alendronate produced increases in BMD of approximately 3.5–6% at the lumbar spine and 2–3% at the femoral neck, after 1 yr of therapy, compared with baseline (20, 21, 22).
The primary mechanism by which estrogen and bisphosphonates are thought to affect bone density is through inhibition of bone resorption by osteoclasts. Although it may seem unlikely that combination therapy with two antiresorptive agents would provide additive efficacy, two small clinical trials (4–19 patients per group) of combination therapy showed that intermittent cyclic etidronate therapy and HRT produced greater increases in bone mass than either therapy alone at both the lumbar spine and hip in postmenopausal women (23, 24). To date, no studies of combination therapy with alendronate and HRT have been reported.
The purpose of this study was to evaluate the effect on BMD of adding alendronate to ongoing HRT in postmenopausal women with osteoporosis. The primary hypothesis was that the addition of alendronate to ongoing HRT would produce a mean increase, from baseline, in lumbar spine BMD that was greater than that observed with continued HRT alone.
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Subjects and Methods |
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Eligible subjects included women who were at least 40 yr of age (or at least 25 yr of age if surgically menopausal); postmenopausal for at least 5 yr; and receiving ongoing HRT for at least 1 yr before study entry. The estrogen component of the HRT regimen had to be at least the lowest dose recommended by the manufacturer for management of osteoporosis or approximately equivalent to at least 0.625 mg/day of conjugated equine estrogens. Participants were required to have a BMD measurement by dual x-ray absorptiometry at the lumbar spine or femoral neck that was at least 2 SD below the mean for a reference population of young women; BMD at the other site had to be at least 1.5 SD below the mean. Subjects were excluded from the study for any of the following: contraindications to HRT; treatment with any agent other than HRT that might influence bone turnover; untreated hyperthyroidism; disorders of bone mineralization; conditions that affected esophageal emptying; or dosages of any drug that might alter calcium metabolism. Ethics committee approval was obtained at all sites, and informed consent was obtained from all patients before any study procedures being performed.
Treatment
A total of 1855 postmenopausal women at 38 United States
investigative sites were screened by dual x-ray absorptiometry, and 565
met the BMD inclusion criteria for the study (Fig. 1
). A total of 428 women who continued to
meet all of the inclusion and none of the exclusion criteria (after
medical history, physical examination, and laboratory assessment) and
who were at least 80% compliant with study medication, during a 2-week
single-blind placebo run-in period, were randomized in a 1:1 ratio to
receive either 10 mg alendronate daily or placebo in addition to their
previously prescribed HRT regimen. Blinded allocation number assignment
was stratified, according to the duration of previous HRT therapy, to
ensure an equal distribution between treatment groups of subjects who
had received HRT for at least 2 yr or less than 2 yr. Patients were
instructed to take alendronate or placebo in the morning, at least 30
min before the first meal of the day, with 6–8 ounces of plain water
and to remain upright for at least 30 min after dosing.
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Efficacy and safety measurements
All efficacy and safety measurements were obtained at baseline and after 6 and 12 months of therapy. Measurements of BMD were determined using either Hologic, Inc. (Waltham, MA) or Lunar Corp. (Madison, WI) densitometers. Normative values provided by Hologic, Inc. were used for determination of T-scores (a comparison to a gender-matched young normal reference population) and patient eligibility based on the mean and SD of this manufacturer’s reference population. Comparable values for measurements of lumbar spine and femoral neck BMD made on Lunar Corp. densitometers were approximated from cross-calibration equations derived from linear regression analyses (26). All patients had their BMD measurements performed using the same densitometer for the full duration of the study. Measurements of BMD were analyzed, in a blinded fashion, by a central quality assurance center (BonaFide, Ltd., Madison, WI).
All serum and urine specimens were collected in the morning, after an overnight fast, and were analyzed by a central laboratory (Mayo Medical Labs, Rochester, MN). Serum bone-specific alkaline phosphatase (BAP) was measured, as a marker of bone formation, using the Tandem-R Ostase kit (Hybritech, Inc., San Diego, California) (27). Urinary N-telopeptide (NTX) of type I collagen was measured, as a marker of bone resorption, with the Osteomark enzyme-linked immunoassay (Ostex International, Inc., Seattle, Washington) (28, 29).
Participants were assessed for clinical adverse experiences (AEs) at each study visit. An AE was considered serious by the investigator if it resulted in 1) death; 2) permanent or substantial disability; 3) inpatient hospitalization; 4) prolongation of an existing hospitalization; or was 5) cancer; 6) a result of an overdose; or 7) life-threatening. Information on clinically apparent fractures was collected through AE reporting.
Statistical analysis
Baseline demographic and clinical characteristics were compared using t tests (continuous data) and Fisher’s exact test (dichotomous data).
The mean percent change, from baseline, in lumbar spine BMD after 1 yr of treatment was the primary endpoint. Secondary endpoints included the mean percent change in BMD, from baseline, at the hip trochanter and femoral neck. ANOVA was employed to make comparisons between treatment groups, with respect to BMD endpoints. The ANOVA model included terms for treatment, site, stratum at least 2 yr of prior HRT therapy vs. less than 2 yr of prior HRT therapy, as noted previously in the randomization strategy), and all two-way interactions with treatment. Paired t tests were used to compare baseline BMD to both the 6-month and end-of-study BMD values within treatment groups.
An all-patients-treated approach was employed in the analysis. That is, all patients who had at least one dose of therapy, a baseline measurement, and at least one posttreatment observation were included in the analysis. In the event of missing data at month 12, the month-6 value was carried forward for analysis at this timepoint. Less than 5% of the data at month 12 was carried forward.
ANOVA was also used to compare treatments with regard to the biochemical markers of bone turnover (BAP, NTX). Because the mean percent changes in BAP and NTX values were not normally distributed, an ANOVA on the ranked values was performed. Medians are reported as the measure of central tendency.
Differences in the overall incidence of AEs, as well as individual AEs, were compared between treatment groups, employing Fisher’s exact test. Analyses were conducted on all reported AEs, as well as those considered drug-related by the investigator (rating of possibly, probably, or definitely drug-related). Special attention was given to fractures and gastrointestinal AEs, using Fisher’s exact test to assess between-group differences. All patients randomized were included in the analysis of safety.
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Results |
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). Approximately 85% of
the women in each treatment group had received HRT for 2 yr or longer.
Mean duration of HRT use was approximately 10 yr. Over half of the
women in each treatment group had not undergone hysterectomy and were
receiving a progestin. The most commonly used estrogen preparations
were conjugated equine estrogens (75%), micronized estradiol (10%),
and transdermal estradiol (8%). Over 90% of the women in each
treatment group were at least 90% compliant with both study drug
therapy and HRT. Approximately 2% of the participants discontinued
therapy with study drug but continued in the trial on HRT: four
patients in the alendronate-plus-HRT group and five patients in the
HRT-alone group discontinued study drug after an average of 6 months
and 8 months of therapy, respectively.
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Endpoints
At both 6 and 12 months, the mean percent increases in lumbar
spine BMD in the alendronate-plus-HRT group were significantly greater
than those in the group treated with HRT alone (Fig. 2). Mean percent increases in hip
trochanter BMD were also significantly greater in the
alendronate-plus-HRT group (Fig. 3). The
between-group difference in mean percent change in femoral neck BMD at
12 months was not significant (P = 0.072) (Fig. 4). Subgroup analyses of BMD change, by
age decade and HRT strata (less than 2 yr and at least 2 yr), indicated
that patients responded similarly to treatment regardless of age or
duration of previous HRT.
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and 6. In
both treatment groups the median level of BAP at baseline was near the
premenopausal mean (7.75 ug/L and 8.20 ug/L in the alendronate-plus-HRT
and HRT-alone groups, respectively) (30). Median baseline values for
NTX were also at the premenopausal mean for this marker in both
treatment groups (34.0 nmol of bone collagen equivalent per mmol
creatinine in both groups) (32). Alendronate-plus-HRT produced
significantly greater decreases in BAP and NTX from baseline than
HRT-alone at both 6 and 12 months. Values for BAP and NTX in the group
treated with HRT alone were not significantly changed from baseline at
either timepoint.
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A similar proportion of clinical AEs in each group was considered by the investigators as possibly, probably, or definitely drug-related (alendronate-plus-HRT, 21%; HRT-alone, 20%). Incidence of drug-related gastrointestinal AEs was identical in both groups (10.7%). There was no difference between groups in incidence of serious AEs (alendronate-plus-HRT, 6%; HRT-alone, 8%), and none was considered drug-related. More patients experienced fractures in the alendronate-plus-HRT group than in the group receiving HRT alone (15 vs. 9 patients, respectively). The difference in fracture incidence between treatment groups was not significant (P = 0.293). Sites of fractures reported for patients in the alendronate-plus-HRT group were: foot/toe (n = 8), ankle (n = 1), rib (n = 3), patella (n = 1), wrist (n = 1), and hand (n = 1). For patients in the HRT-alone group, reported fractures were: foot/toe (n = 4), ankle (n = 1), tibia (n = 1), rib (n = 1), arm (n = 1), and wrist (n = 1). No patient in either group experienced hip fracture or symptomatic vertebral fracture during the study period. Two fractures in the HRT-alone group were considered serious AEs by the investigators.
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Discussion |
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The additive effect of combination antiresorptive therapy observed in this study is consistent with the results reported from two small studies where combination therapy with estrogen and the bisphosphonate etidronate produced greater increases in bone mass at the lumbar spine and hip than those observed with either therapy alone (23, 24). Although it is known that both estrogen and bisphosphonates increase bone mass by decreasing bone resorption, they seem to act by different mechanisms. Alendronate’s effect on resorption occurs primarily through alteration in the structure and function of the osteoclast, probably by interference with enzymes in the cholesterol biosynthetic pathway (32, 33). The precise mechanism of estrogen’s effect on the skeleton is still not known (34). Current evidence suggests that estrogen may block production of cytokines in the bone microenvironment that increase formation of osteoclasts and extend their life span (35). Thus, use of two antiresorptive agents may produce greater inhibition of osteoclastic activity, leading to greater increases in bone mass, than those produced with single agents.
The well-known effect of estrogen to increase calcium absorption may explain the BMD increases noted in this study in the group treated with HRT alone after the provision of supplemental calcium and Vitamin D (13, 36). Though biochemical markers of bone turnover did not decrease in the group treated with HRT alone, the observed increase in bone mass is consistent with an increase in bone mineralization. The alendronate-plus-HRT group, on the other hand, may have benefited from both enhanced mineralization and further decreases in bone turnover. Improved compliance with HRT in the study setting is another possible explanation for the findings in the group receiving HRT alone.
Although the increases in BMD in the alendronate-plus-HRT group were greater than those seen in the group receiving HRT alone, the magnitude of the increases demonstrated in the present study were less than those reported in previous trials of estrogen and alendronate monotherapy (4, 6, 13–16, 20–22). However, the patients in this study differed significantly from those included in previous trials, in that patients in the present study had been receiving antiresorptive therapy with HRT for an average of 10 yr. Thus, this population would not be expected to show the dramatic increases in BMD demonstrated when antiresorptive therapy is initiated in treatment-naive patients, where filling in of remodeling space may contribute to the BMD increases noted in the first 1–2 yr of therapy. Nonetheless, the present study demonstrates the ability of alendronate to produce further increase in bone mass in postmenopausal osteoporotic women who have been receiving estrogen.
This study also demonstrated that the combination of alendronate and HRT was generally well tolerated. Gastrointestinal tolerability was similar in both groups. Biochemical markers were significantly decreased in the combination group and remained within the normal premenopausal range for these indices of bone turnover (30, 31). Though no hip fractures or symptomatic vertebral fractures occurred in this trial, larger studies of longer duration will be necessary to fully define both the long-term safety profile and any additive benefit in preventing fractures when antiresorptive therapies are combined.
The present study was not designed to determine optimal dosages of estrogen and alendronate when used in combination. The estrogen dosage chosen reflected the dose most commonly recommended and used in clinical practice for management of osteoporosis. The alendronate dosage used has been demonstrated to produce maximal increases in bone mass while maintaining a favorable tolerability profile, and it is the dose currently recommended for treatment of osteoporosis in postmenopausal women (22). Whether similar increases in BMD would be seen using lower dosages of these agents in combination is not known.
This study also did not address the efficacy of estrogen in the long-term prevention or treatment of osteoporosis. However, the characteristics of the postmenopausal women screened for participation in this trial suggest that, despite several years of ongoing estrogen therapy, many women receiving HRT may continue to have low bone mass and osteoporosis and so remain at high risk for subsequent osteoporotic fracture. Our results suggest that many of these women may benefit from follow-up bone mass measurement and consideration of add-on therapy with alendronate to achieve further increases in bone mass.
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Acknowledgments |
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Footnotes |
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Received March 9, 1999.
Revised April 14, 1999.
Accepted June 9, 1999.
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References |
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