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University of California (S.T.H.), San Francisco, California 94117; University of Aarhus (E.F.E.), Aarhus, DK-8000 Denmark; Chicago Center for Clinical Research (M.D.), Chicago, Illinois 60610; Clinical Research Center of South Florida (M.P.E.), Stuart, Florida 34996, and (A.H.M.) Leesburg, Florida 34748; Jerry L. Pettis Veteran’s Affairs Medical Center (D.J.B.), Loma Linda, California 92357; and Procter & Gamble Pharmaceuticals (C.E.C., A.A.C.), Cincinnati, Ohio 45040
Address all correspondence and requests for reprints to: Dr. Steven T. Harris, University of California Osteoporosis Programs, 350 Parnassus Avenue, Suite 706, San Francisco, California 94117-3608.
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Abstract |
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 Top Abstract IntroductionSubjects and MethodsResultsDiscussionReferences |
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This was a 1-yr, double blind, placebo-controlled study in which 524 postmenopausal women received daily treatment with conjugated equine estrogens (0.625 mg) alone or in combination with risedronate (5 mg). Women who had not undergone hysterectomy received medroxyprogesterone acetate (up to 5 mg, daily or cyclically) at the discretion of the investigator. The primary efficacy end point was the percent change from baseline in mean lumbar spine bone mineral density (BMD) at 1 yr. Changes in BMD at the proximal femur and forearm, bone turnover markers, and histology and histomorphometry were also assessed.
At 12 months, significant (P < 0.05) increases from baseline in lumbar spine BMD were observed in both treatment groups (HRT-only, 4.6%; combined risedronate-HRT, 5.2%); the difference between the two groups was not statistically significant. Both therapies led to significant increases in BMD at 12 months at the femoral neck (1.8% and 2.7%, respectively), femoral trochanter (3.2% and 3.7%), distal radius (1.7% and 1.6%), and midshaft radius (0.4% and 0.7%). The differences between groups were statistically significant (P < 0.05) at the femoral neck and midshaft radius. Both combined risedronate-HRT and HRT-only produced significant decreases in the biochemical markers of bone turnover, with somewhat greater decreases in the combined treatment group. Bone biopsy data showed normal bone structure and normal mineralization with either treatment. Expected decreases in bone turnover were observed and were greater in the combined treatment group (68–79% reduction relative to baseline values, P < 0.005). Overall, combined treatment had a safety profile similar to that of HRT-only, including bone and gastrointestinal safety profiles.
In conclusion, the combined treatment with risedronate and HRT had a favorable effect on BMD similar to that of HRT alone at the lumbar spine and slightly, but significantly, greater than that of HRT alone at the femoral neck and midshaft radius. The combined treatment was well tolerated, and there were no adverse effects on the skeleton.
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Bisphosphonates are an effective alternative to HRT in the management of postmenopausal osteoporosis and are becoming widely used as first choice treatment, especially in women for whom HRT is unattractive or contraindicated (1). In addition, some women lose bone despite HRT. It has been shown that 23% of postmenopausal women may experience bone loss in the lumbar spine, and 33% may experience bone loss in the femoral neck despite HRT (7). Therefore, combining HRT with a bisphosphonate in clinical practice is likely to control menopausal symptoms and to protect bone from fracture. Bisphosphonates have been shown to increase bone mineral density (BMD) and significantly reduce the risk of osteoporotic fractures (1, 8, 9, 10, 11). A few studies combining HRT and bisphosphonate have been conducted with alendronate (12, 13) and etidronate (14, 15). These studies demonstrated a greater increase in bone density with such regimens.
Risedronate is a potent pyridinyl bisphosphonate that has been shown to induce a biochemical remission in Paget’s disease of bone (16, 17), decrease bone turnover and increase bone density in multiple myeloma (18, 19), reduce the incidence of vertebral fractures in corticosteroid-induced osteoporosis (20), and reduce the risk of vertebral and nonvertebral fractures, including hip fractures, in women with postmenopausal osteoporosis (21, 22, 23). To date, no data from combined therapy with risedronate and HRT have been reported. The present study was conducted to determine the safety and efficacy of a combined regimen of risedronate and HRT in postmenopausal women.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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The patient population included 524 ambulatory women at 25 study
centers in North America. To be eligible, women had to be at least 12
months postmenopausal or, if the date of the last menstrual period was
uncertain, to have FSH and serum estradiol values within the
postmenopausal range. Participants were stratified by duration of
menopause (
5 yr or >5 yr). Women who had received HRT for more than
1 month within the past 12 months were excluded. Other exclusion
criteria were recent therapy with drugs known to affect bone turnover,
evidence of metabolic bone disease, abnormal Pap smear or mammogram,
any significant organic or psychiatric disease that could affect
participation or interfere with the interpretation of data, and
physical characteristics or abnormalities on the anterior/posterior
spinal radiographs that could preclude precise dual x-ray
absorptiometry (DXA) measurements. The protocol was approved by the
respective institutional review boards, and all patients gave informed
consent.
Study design
This was a double blind, placebo-controlled, parallel group study. Patients were randomly assigned to receive either 0.625 mg conjugated equine estrogens plus 5 mg risedronate (263 patients) or 0.625 mg conjugated equine estrogens plus placebo (261 patients) daily for a period of 12 months. Risedronate was administered as a cellulose film-coated tablet prepared by Procter & Gamble Pharmaceuticals (Cincinnati, OH). Patients were instructed to take their medication with 240 mL water 30–60 min before breakfast and to avoid lying down for 1 h after taking the tablet. The estrogen was supplied as Premarin (Wyeth-Ayerst Laboratories, Inc., Philadelphia, PA). Women who had not undergone hysterectomy also received medroxyprogesterone acetate (up to 5 mg, daily or cyclically) at the discretion of the investigator. All patients received 1 g elemental calcium daily (Os-Cal, SmithKline Beecham, Pittsburgh, PA) either with lunch or the evening meal. Patients with 25-hydroxyvitamin D levels below 39.9 nmol/L at screening were supplemented with oral vitamin D, not exceeding 500 IU/day, throughout the study.
Methods
The primary efficacy end point was the difference between groups in percent change from baseline in mean lumbar spine BMD at 12 months. In addition, BMD was evaluated at the femoral neck, femoral trochanter, distal radius, and midshaft (one third) radius. Bone densitometry measurements were performed at baseline and at 6 and 12 months by DXA using either Lunar Corp. (Madison, WI) or Hologic, Inc. (Waltham, MA), densitometers. Baseline and 12 month BMD values were the average of duplicate DXA measurements. Baseline lumbar spine BMD values were standardized to adjust for machine type. Data were analyzed at the Oregon Osteoporosis Center (Portland, OR). DXA phantom data were analyzed for consistent instrument performance throughout the study (24).
Biochemical markers of bone formation [serum bone-specific alkaline phosphatase (BAP)] and bone resorption [deoxypyridinoline (Dpyr) and N-telopeptide (NTx), both adjusted for creatinine excretion] were collected at baseline and at 1, 3, 6, and 12 months (baseline, 3 months, and 12 months for NTx). Serum BAP was measured using the Tandem-R Ostase immunoradiometric assay (Hybritech, San Diego, CA). Urinary Dpyr was measured by high pressure liquid chromatography, and NTx was measured by enzyme-linked immunosorbent assay (Ostex International, Inc., Seattle, WA).
Lateral spinal radiographs (T4 to L4) were obtained at baseline and 12 months and were analyzed at a central facility for prevalence and incidence of vertebral fractures. The assessment of vertebral fractures was made using quantitative morphometry, in accordance with the recommendations of the Working Group on Vertebral Fractures (25). A vertebra was considered to be fractured at baseline (prevalent fracture) if any of the vertebral height ratios fell more than 3 SD below the mean for the study population, as described by Melton et al. (26). A new (incident) vertebral fracture was defined as a decrease of at least 15% (for intact vertebrae at baseline) or at least 4 mm (for fractured vertebrae at baseline) in any of the measured vertebral heights (anterior, middle, or posterior). In addition, all vertebral fractures identified by morphometry were verified visually by a qualified skeletal radiologist (Massachusetts General Hospital, Boston, MA).
Bone biopsies for histology and histomorphometry measurements were obtained at baseline and 12 months in a subset of patients. Samples were taken from the ileum after double tetracycline labeling and analyzed by one of the authors (E.F.E.), as previously described (27, 28), using standardized nomenclature (29).
Adverse events (AEs) were recorded at all postbaseline visits, and their severity and relationship to treatment were evaluated by the investigators. An upper gastrointestinal endoscopy was requested (but not required) for all patients with moderate to severe upper gastrointestinal AEs. Moderate to severe events were defined as those in which symptoms were frequent (more than three times per day) and lasted longer than 1 h, required prescription or frequent (more than three times per week) over the counter medications, resulted in impairment of normal activities, or resulted in incapacity and/or hospitalization. All patients underwent a mammogram and Pap smear at baseline and 12 months.
Statistical analysis
Analyses were conducted on the intent to treat population comprised of the randomized patients who took at least one dose of study drug. All statistical analyses were performed at the 5% significance level (two-sided). Within-treatment group analyses were carried out using the one-sample paired t test. Between-treatment comparisons were carried out using a three-way ANOVA model, including treatment group, investigator, and stratum as factors. A three-way ANOVA with factors such as center, treatment group, and concomitant use of medroxyprogesterone was performed to determine the effect of medroxyprogesterone treatment on BMD. Fisher’s exact test was used to compare the incidence of vertebral fractures between treatment groups. Histomorphometric parameters were summarized using median and interquartile range (between the 25th and 75th percentiles) for baseline and postbaseline values, and comparisons with baseline values within each treatment group were performed using the signed rank test. Data are shown as the mean ± SEM unless otherwise specified.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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). Women in the
HRT-only group were slightly older (mean age ± SD,
59.8 ± 7.99 vs. 58.0 ± 8.18 yr;
P = 0.005). Most (76%) had undergone menopause more
than 5 yr before study entry. Medroxyprogesterone acetate was used by
48% of the patients throughout the study.
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The mean baseline bone turnover marker values and 25-hydroxyvitamin D levels were comparable between groups. A similar number of women in each group had 25- hydroxyvitamin D levels below 39.9 nmol/L [38 (14.7%) in the HRT-only group and 37 (14.2%) in the combined risedronate-HRT group]. At 6 months, 15 (7.5%) women in the HRT-only group and 16 (7.4%) women in the combined group had 25-hydroxyvitamin D levels below 39.9 nmol/L.
BMD
At 12 months, both HRT-only and combined rised ronate-HRT produced
significant increases from baseline in mean BMD at the lumbar spine,
femoral neck, trochanter, midshaft radius, and distal radius (Table 2 and Figs. 1 and 2).
Patients receiving combined therapy had a slightly greater increase
from baseline in BMD at most skeletal sites except the distal radius.
The differences in BMD between the HRT-only and combined
risedronate-HRT groups were statistically significant at the lumbar
spine at 6 months and at the femoral neck and midshaft radius at 12
months. The differences in BMD between the two treatment groups were
not statistically significant at the lumbar spine, trochanter, and
distal radius at 12 months. The consistency of the findings was
examined by performing analyses on absolute changes in BMD from
baseline values. The results were similar to those observed for percent
change in BMD from baseline values across all skeletal sites (data not
shown).
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). The increases in BMD at the hip
and radius were similar between the two strata, and no significant
treatment by stratum effect was observed for any BMD site at a
significance level of 0.1. The percent increase from baseline in lumbar
spine BMD at 12 months was not significantly different between women
treated with medroxyprogesterone and women who did not receive that
treatment [4.8% (0.23) vs. 4.8% (0.28), respectively;
P = 0.9]. Fractures
At 12 months, new vertebral fractures were found in 4 of 155 (2.6%) patients with evaluable radiographs in the HRT-only group and 3 of 168 (1.8%) patients in the combined risedronate-HRT group (P = 0.625).
Seven patients (2.7%) in the HRT-only group had sustained a total of nine nonvertebral fractures by 12 months, whereas two patients (0.8%) in the combined risedronate-HRT group had two nonvertebral fractures. All but one of the nonvertebral fractures were traumatic; that one fracture occurred in a women receiving HRT-only. The two fractures in patients receiving combined regimen were toe fractures. Nonvertebral fractures in the HRT-only group involved the carpus (n = 1), humerus (n = 2), metatarsus (n = 2), pelvis (n = 1), radius (n = 1), ribs (n = 1), and wrist (n = 1).
Biochemical markers of bone turnover
Biochemical markers of bone formation (serum BAP) and resorption
(urinary Dpyr/Cr and NTx/Cr) decreased significantly from baseline at
all time points in both treatment groups (Fig. 3). The decrease in bone turnover markers
was significantly greater at most time points in the combined
risedronate-HRT group than in the HRT-only group.
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Bone histology and histomorphometry
In 47 women (HRT-only group, 24; risedronate-HRT group, 23)
bone biopsy specimens had adequate material for histomorphometric
and/or histological evaluation after 12 months of treatment. In a
subset of these 47 women, paired bone biopsies (baseline and 12 months)
were analyzed (HRT-only group, 16; risedronate-HRT group, 16); selected
histomorphometric parameters for these biopsies are shown in Table 3.
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). The latter reflects the rate at which bone
is being mineralized. Cancellous bone volume did not change in the
HRT-only group, whereas a trend toward an increase was seen with the
combined treatment (median increase, 11.7%; P =
0.075). Total erosion surfaces and osteoid surfaces decreased
significantly in both treatment groups, reflecting decreased bone
turnover (Table 3). Activation frequency, which reflects tissue level bone turnover, decreased from baseline by 31% (median; P = 0.59) in the HRT-only group and by 68% (median, P = 0.004) in the combined risedronate-HRT group. Mineralizing surface decreased by 50% (P = 0.2) and 79% (P < 0.001) in the HRT-only and combined groups, respectively. Cancellous tetracycline label, an indicator of continuous bone turnover, was present in all biopsy specimens in the risedronate-HRT group. In the HRT-only group, cancellous tetracycline label was present in all but one specimen. In the latter specimen, the examination of the cortex was also negative for the presence of a tetracycline label.
AEs
The incidence of serious AEs and those leading to withdrawal was
slightly greater in patients receiving HRT-only treatment than in those
receiving combined risedronate-HRT. Table 4 displays the most common and the
clinically relevant AEs. The leading causes for patient discontinuation
from the study in the HRT-only group were vaginal hemorrhage (10
patients), breast pain (5 patients), abdominal pain, asthenia, nausea,
and metrorrhagia (4 patients each). In combined risedronate-HRT
patients, the most common reasons for discontinuation were breast pain
(3 patients), vaginal hemorrhage, headache, and abdominal pain (2
patients each).
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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The effects of other bisphosphonates in combination with HRT have been recently reported. In two relatively small studies, etidronate and HRT administered in combination for 4 yr to early postmenopausal women with normal BMD (15) or to late postmenopausal women with established osteoporosis (14) produced greater increases in BMD at the lumbar spine and hip than did either therapy alone. Similarly, Bone and colleagues reported that combined alendronate and estrogen therapy administered for 2 yr was associated with greater increases in spine and hip BMD than either alendronate or estrogen alone in a population of osteoporotic women (mean T-score, -2.5) (13). Although the results of our study are, in general, consistent with these recent reports, a direct comparison with other studies is difficult. In studies with combined etidronate-HRT, BMD was not measured before 2 yr of treatment (14, 15). In the study with combined alendronate and estrogen therapy statistical analysis was not reported at 1 yr (13). In addition, the population in the latter study had a substantially lower BMD and more years since menopause than the population in our study.
The effect of combined risedronate-HRT on BMD at the femoral neck and midshaft radius, sites that are rich in cortical bone, is of particular interest. The combined treatment resulted in significantly greater increases in BMD at those two sites compared with HRT-only. This suggests that combined treatment with risedronate and HRT may have a more pronounced effect in the appendicular skeleton than in the axial skeleton, although longer-term studies are needed to confirm this observation and to determine the clinical relevance in terms of fracture risk reduction.
Although there was a significantly greater decrease in biochemical markers of bone turnover in the combined risedronate-HRT group than in the HRT-only group, the differences between the two groups were relatively small and of uncertain clinical significance. However, the maximum reduction in the bone formation marker (44%) and bone resorption markers (40–63%) in the combined treatment produced mean values that were still within the normal range for premenopausal women. This was consistent with the bone histomorphometric data demonstrating ongoing bone turnover without excessive suppression.
The bone safety of the combined risedronate-HRT regimen was examined by obtaining bone biopsies, most of them paired, from a subset of patients. This allowed not only comparison between the treatment groups, but also assessment of changes over time within the groups. With an antiresorptive treatment, there are three potential bone safety concerns to be addressed: structural abnormalities, defective mineralization, and excessive suppression of bone turnover. There were no structural abnormalities in either treatment group; bone was of normal lamellar structure without evidence of woven bone. Bone mineralization, as assessed by measuring osteoid thickness and mineral apposition rate, was similar between the treatment groups and, importantly, did not change significantly during the 12-month treatment period. In a recent study, combined treatment with alendronate and estrogen was not associated with any structural or mineralization abnormalities (13).
Excessive suppression of bone turnover could potentially lead to
accumulation of microdamage that, in turn, could result in increased
bone fragility. Indeed, a recent study in dogs demonstrated that high
doses of alendronate and risedronate (
5 times the clinical dose)
increased microdamage accumulation (30). Although bone
strength and stiffness were not significantly affected by either
treatment in this dog model, bone toughness (the amount of energy a
bone can absorb before it breaks) declined significantly with
alendronate treatment. In our study, combined treatment with
risedronate and HRT was associated with a 68–79% reduction in bone
turnover, as assessed by activation frequency and mineralizing surface,
respectively. Nevertheless, the median mineralizing surface of 1.3%
after 12 months of treatment in the combined group was equal to that in
the HRT-only group. Tetracycline labels were present in all biopsy
specimens in the combined group, indicating the continuous bone
turnover needed for the repair of potential microdamage. In a similar
study, combined treatment with alendronate and estrogen reduced bone
turnover, as assessed by mineralizing surface, by about 98%, relative
to placebo, after approximately 18–24 months (13). The
mineralizing surface was 5% in patients who received placebo, 1.2% in
patients who received estrogen alone, and 0.1% in patients who
received combined therapy with alendronate and estrogen. The clinical
relevance of this marked suppression of bone turnover with the
combination of alendronate and estrogen is unclear, but no increase in
fracture rate was noted in this 2-yr study.
The number of vertebral and nonvertebral fractures was nominally lower in the combined risedronate-HRT group than in the group receiving HRT alone, supporting the bone safety of the combined treatment. Although the study did not have statistical power to detect differences in fracture rates between treatment groups, these results are encouraging. Bone and colleagues also reported a slightly lower incidence of fractures in the recent study with combined alendronate and estrogen treatment compared with estrogen alone (6% vs. 7%, respectively) (13). However, in a study in which alendronate therapy was added to ongoing, long-term HRT in postmenopausal women, there was a nominally slightly higher incidence of fractures in the combined alendronate-HRT group (7%) compared with the HRT-only group (4.2%) (12). However, the study again lacked statistical power to detect differences in fracture rates between the two groups.
These studies of combined HRT and bisphosphonate therapy are generally supportive of bone safety. However, longer- term studies, ideally with each individual bisphosphonate, would be necessary to detect the effect of combined therapy on the incidence of fractures.
The current study enrolled a large number of patients to evaluate the overall safety of combined risedronate-HRT administration compared with treatment with HRT alone. Overall, both HRT-only and combined risedronate-HRT were well tolerated and had a similar adverse event profile. Discontinuation of therapy in both groups was largely due to adverse events attributable to HRT, including breast pain and vaginal hemorrhage. The incidence of upper gastrointestinal adverse events was similar in both treatment groups. In the risedronate-HRT group, none of the abnormalities found during endoscopy for upper gastrointestinal complaints resulted in study withdrawal.
The present study is not without limitations. The study was of 1-yr duration and longer-term effects on BMD remain to be established. A risedronate-only arm was not included in the study, and it is therefore not possible to separate the combined risedronate-HRT effect from the effect of treatment with risedronate alone. Most importantly, this study, as was true for the other similar studies with combined bisphosphonate-hormone replacement treatment (13, 14, 15), was not designed to determine whether the combined regimen leads to a greater reduction in fracture risk than does either therapy alone. BMD was the primary end point in these studies. The clinical relevance of greater increases in BMD at the femoral neck and distal radius with combined treatment remains to be determined.
In conclusion, combined treatment with risedronate and HRT is well tolerated, has an overall safety profile comparable to that of HRT-only without adverse effects on the skeleton, and produces increases in BMD at all skeletal sites. The increases were similar at the lumbar spine and slightly, but significantly, larger at the femoral neck and midshaft radius than those observed in women receiving HRT alone.
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Acknowledgments |
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Other investigators participating in the study were: John Assini, Schenectady, NY; Arthur D. Bankhurst, Albuquerque, NM; Marshall B. Block, Phoenix, AZ; Stanley Feld, Dallas, TX; Kathleen Fitzgerald, Providence, RI; Marc Gittelman, N. Miami, FL; Diane Koster, Albuquerque, NM; Thomas Littlejohn, Winston-Salem, NC; Morris Notelovitz, Gainesville, FL; Sam A. Pasquale, New Brunswick, NJ; Sanford Plevin, Clearwater, FL; David A. Podlecki, Longmont, CO; Elliott N. Schwartz, Oakland, CA; Sherwyn Schwartz, San Antonio, TX; Simon Scumpia, Austin, TX; Melvin Stjernholm, Boulder, CO; Randall Stoltz, Evansville, IN; Richard D. Wasnich, Honolulu, HI; Stuart R. Weiss, San Diego, CA; and Thomas M. Zizic, Baltimore, MD.
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Footnotes |
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Received August 25, 2000.
Revised December 14, 2000.
Revised February 1, 2001.
Accepted February 6, 2001.
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) or risedronate-HRT
(•). #, P < 0.05 vs. baseline; *,
P < 0.05, between-group comparison.
