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Endocrine Care |
Chair of Obstetrics and Gynecology (S.P., T.S., F.Z.), University of Catanzaro, 88100 Catanzaro, Italy; Departments of Molecular and Clinical Endocrinology and Oncology (F.O., A.C., G.L.), and Gynecology, Obstetrics, and Human Reproduction (C.d.C.), University of Naples "Federico II", 80131 Naples, Italy; Department of Obstetrics and Gynecology (P.M.), University of Messina, 98100 Messina, Italy
Address all correspondence and requests for reprints to: Dr. Stefano Palomba, Via Nicolardi 188, Napoli 80131, Italy. E-mail: . stefanopalomba{at}tin.it
Abstract
This prospective randomized, double-blind, placebo-controlled, clinical trial was performed to evaluate the effectiveness of estrogens plus low-dose alendronate on bone metabolism. A total of 150 surgically postmenopausal women with osteoporosis were randomized in three groups: group A, micronized E2 (2 mg/d) plus standard-dose alendronate (10 mg/d); group B, micronized E2 plus low-dose alendronate (5 mg/d); and group C, micronized E2 plus placebo (one tablet per day). In all women, bone mineral density (BMD) and serum bone metabolism markers were assessed at admission and every 6 months for 2 yr.
After 2 yr, BMD significantly increased compared with baseline in all groups. The percentage BMD change was significantly higher in groups A and B than in group C. The differences in BMD detected between groups A and B were not statistically significant. Since the 6-month follow-up and throughout the study, serum osteocalcin and bone alkaline phosphatase levels and urinary deoxypyridinoline and pyrilinks-D excretion were significantly reduced in all groups. Serum bone alkaline phosphatase levels significantly decreased in groups A and B, without difference between them, in comparison with group C.
In conclusion, in surgically postmenopausal osteoporotic women treated with estrogen replacement, the addition of alendronate at a low dose of 5 mg daily induces a gain of bone mass not significantly different in comparison with that obtained using a standard dose of 10 mg daily.
ESTROGEN/HORMONE REPLACEMENT THERAPY (ERT/HRT) is widely considered the gold standard to prevent postmenopausal osteoporosis (1, 2, 3). Observational data suggest that long-term ERT/HRT maintains and even improves bone density, reducing the incidence of bone fractures (4, 5, 6, 7, 8, 9). However, the better effect of ERT/HRT on bone loss seems to be realized when the treatment is administered at the time of menopause and for a continuous period of treatment (2, 3, 4, 5, 6, 7, 8, 9, 10).
Few data are available in literature about the effectiveness of ERT/HRT in the treatment of women affected by osteoporosis (11). Recent data (12) have showed that the HRT did not induce any reduction in the incidence of fractures in women without osteoporosis.
Alendronate is a potent and specific inhibitor of osteoclast-mediated bone resorption, thus producing a significant increase in bone mineral density (BMD) (13, 14). It has been successfully used in preventing postmenopausal bone loss in women without osteoporosis (15), but also in women who have already developed osteoporosis (16, 17, 18, 19, 20, 21, 22). The use of alendronate reduces the incidence of fractures in postmenopausal osteoporotic women with or without pre-existing fractures (16, 17, 18, 19, 20, 21, 22).
Recent clinical trials (23, 24, 25) provided evidence that in postmenopausal osteoporotic women, the addition of 10 mg alendronate to HRT induced a higher increase of BMD at lumbar spine and hip than HRT alone.
At the same time, prolonged and continuous treatment with 5 mg alendronate was shown to be effective in preventing both postmenopausal (15, 26, 27, 28) and glucocorticoid-induced (29) bone loss. Furthermore, treatment with the low dose of 5 mg alendronate daily was shown to induce a BMD increase that was approximately 30% less than that obtained using the standard dose of 10 mg (14, 15, 28). In this view, the alendronate is currently used at the dosage of 10 mg daily (21).
This study was designed to compare the effect on bone metabolism of adding 5 and 10 mg alendronate to ERT in surgically postmenopausal women with osteoporosis.
Patients and Methods
The procedures used during the present study were in accordance with the guidelines of the Helsinki Declaration on human experimentation. The protocol was approved by the Local Ethic Committees. The purpose of the protocol was explained to all women attending the Departments of Gynecology of the Universities of Catanzaro, Messina, and Naples "Federico II" before they entered the study. Written informed consent was obtained from all subjects.
Patients
Between January 1997 and May 1998, 150 surgically postmenopausal women agreed to be enrolled in our study. Inclusion criteria were: 1) previous hysterectomy with bilateral oophorectomy performed before natural menopause, and 2) BMD values at least 2.5 SD below the mean bone density of the peak value for sex-matched healthy young adults (-2.5 T-score) at posterior-anterior lumbar spine. Exclusion criteria were: 1) active rheumatoid arthritis; 2) gastrointestinal or liver disease; 3) metabolic, neoplastic or endocrine diseases; 4) history of acute or recurrent vascular thrombosis; 5) secondary causes of osteoporosis, such as hyperparathyroidism, Paget’s disease of bone, or renal osteodystrophy; 6) previous treatment with bisphosphonates, sodium fluoride, calcitonin, estroprogestins or anabolic steroids, corticosteroids, calcium (Ca), vitamin D, phosphate (P), thiazidic diuretics, or other drugs interfering with bone metabolism; 7) abnormal serum levels of creatinine (Cr) (>133 µmol/liter), 25-OH-vitamin D (<20 µmol/liter), Ca (normal values, 2.2–2.6 mmol/liter), P (normal values, 1.0–1.4 mmol/liter), and PTH (normal values, 10–65 ng/liter); and 8) history of gastrointestinal side effects; and 10) body mass index (BMI) less than 18 kg/m2 or greater than 30 kg/m2. We also excluded women who regularly used any medication that had the potential to cause gastrointestinal irritation (such as nonsteroidal anti-inflammatory drugs) or drugs to inhibit gastric acid secretion, and women smoking more than 20 cigarettes per day or drinking more than 3 alcoholic beverages per day. Patients with BMD T-score values below 4.0 at posterior-anterior lumbar spine or with current/previous osteoporotic fractures were also excluded.
Treatment protocol
At the entry, all subjects were randomized in single blocks into a double-blind, placebo-controlled study design using a computer-generated randomization list. The subjects were assigned to 1 of 3 groups of 50 women each. All women received micronized 17ß-estradiol (Estrofem, Novo Nordisk, Rome, Italy) at a dose of 2 mg/d in association with or alendronate (Fosamax, Merck Sharp & Dhome, Rome, Italy) at a dose of 10 mg/d (group A), or alendronate at a dose of 5 mg/d (group B), or placebo tablets (1 tablet per day) (group C). Patients were instructed to take the medication (alendronate or placebo) orally in the morning at least 30 min before breakfast with abundant water and an empty stomach after an overnight fast and to remain upright for at least 30 min after dosing. The duration of the treatment was 24 months, and for this period double-blinding was maintained in all groups.
Study protocol
At baseline and every 6 months during treatment, BMD and bone metabolism were measured in all groups. Both patients and clinicians were blind in respect to these results throughout the study period.
At baseline and every 6 months during treatment, Ca intake, alcohol consumption, and physical activity were evaluated. Ca intake and alcohol consumption were assessed by a dietary history of patients using a semiquantitative diet questionnaire developed by our dieticians. Ca intake was expressed as a score ranging from 1–3, according to the following scale: 1, less than 500 mg/d; 2, 500-1000 mg/d; 3, more than 1000 mg/d. Alcohol consumption was also expressed as a score ranging from 1–3, according to the following scale: 1, less than 1000 mg/d; 2, 1000–2000 mg/d; 3, more than 2000 mg/d. A semiquantitative questionnaire was also used to evaluate patients’ daily physical activity, job, and daily activities. Physical activity was expressed as a score ranging from 1–3: 3 was assigned to women who exercised regularly (high physical activity); 2 was assigned to women who did not exercise regularly but participated daily in activities like cleaning house, climbing stairs, or walking to work, to the bus stop, or to a restaurant (moderate physical activity); 1 was assigned to women who did not participate in any of the activities mentioned above (low physical activity).
No dietary restrictions or changes were implemented during the study. To ensure adequate Ca intake, all patients with a Ca intake less than 1000 mg received daily supplements of elemental Ca in the form of an effervescent tablet composed of calcium carbonate (Cacit, Procter \|[amp ]\| Gamble, Rome, Italy) to achieve a total daily Ca intake of at least 1000 mg. This supplement was taken at lunch. A 1.25-dihydroxi-vitamin D (Rocaltrol, Roche, Milan, Italy) supplementation at the dose of 0.50 µg daily (one tablet per day) was also provided to all women and was taken at dinner.
BMD measurement
The BMD was determined by dual energy x-ray absorptiometry (Dexa QDR 1000, Hologic, Inc., Waltham, MA) at posterior-anterior lumbar spine (vertebrae L1–L4) and at hip (trochanter and femoral neck). The precision of the measurements expressed as coefficient of variation (CV) in vitro for repeated BMD determinations in two standard phantoms in our laboratory was 0.42%. The CV in vivo had been evaluated comparing 2 measurements performed at 7-d intervals in 33 volunteers, and was 1.2, 1.9, and 1.0% for lumbar spine, trochanter, and femoral neck, respectively. An instrument calibration with a standard phantom was obtained every day at all sites examined. We used the mean of three scans to calculate bone mineral content. The BMD values were calculated by the software of the bone densitometer dividing the bone mineral content (grams per centimeter) for the bone width (centimeters) and expressed directly as an index (grams per square centimeter).
The absorptiometries were examined by the same observer who was blind in respect to different treatment regimens. The primary endpoint was lumbar spine BMD. Hip trochanter and femoral neck BMD were considered as secondary endpoints. Absorptiometric findings were expressed as percentage change of baseline values.
Biochemical assays
At entry, serum FSH and E2 levels were assayed in all women. The bone metabolism was evaluated at entry and every 6 months for 24 months by determining the serum levels of Ca and P, PTH, osteocalcin (OC), and bone alkaline phosphatase (BAP) levels as markers of bone formation, and urinary Cr-corrected free deoxypyridinoline (DPD) and pyrilinks-D (PYD) as markers of bone resorption. Blood and 24-h urine samples were collected after an overnight fasting between 0830 and 0930 h to avoid the interference of circadian changes. Patients were asked to refrain from eating foods containing fat or gelatin within 12 h of their clinic visit. Serum samples were separated within 1 h of collection and kept frozen at -80 C, and urine was stored at -20 C until biochemical analysis. All samples from the same woman were analyzed in the same assay and were analyzed blind by a central laboratory.
Serum Ca levels (reference range, 2.2–2.6 mmol/liter) and P levels (reference range, 1.0–1.4 mmol/liter) were assessed by spectrophotometry. Serum FSH, E2, Ca, P, PTH, OC, and BAP, and urinary Cr, DPD, and PYD levels were measured with commercial kits. Serum FSH levels (reference range for postmenopausal women, >40 IU/liter) were determined with a RIA (DiaSorin, Inc., Saluggia, Italy) with a sensitivity of 0.2 IU/liter and an intra-assay and interassay CV of 1.4 and 4.2%, respectively. Serum E2 levels (reference range for postmenopausal women: < 70 pmol/liter) were determined using a RIA (Eurogenetics Italy, Turin, Italy) with a sensitivity of 0 pmol/liter, and an intra-assay and interassay CV of 3.7 and 5.8%, respectively. Serum PTH levels (reference range, 10–65 ng/liter) were determined using an intact PTH immunoradiometric assay (Diagnostics Systems Laboratories, Inc., Webster, TX) with a sensitivity of 1.0 ng/liter and an intra-assay and interassay CV of 7.1 and 3.5%, respectively. Serum OC levels (reference range, 3.1–13.7 ng/ml) were assayed by an immunoradiometric assay (Diagnostic Products Corporation, Los Angeles, CA) with a sensitivity of 0.1 ng/ml and an intra-assay and interassay CV of 4.5 and 3.5%, respectively. Serum BAP levels (reference range for postmenopausal women, 14.8–43.4 IU/liter) were measured using an immunoenzymatical assay (EIA) (Metra Biosystems, Milan, Italy) with a sensitivity of 0.7 IU/liter and an intra-assay and interassay CV of 5.2 and 5.0%, respectively. Urinary DPD concentrations (reference range normalized for Cr levels, 3.0–7.4 nmol/mmol) were assayed by an EIA (Metra Biosystems) with a sensitivity of 1.1 nmol/liter and an intra-assay and interassay CV of 7.6 and 5.5%, respectively. Urinary PYD concentrations (reference range normalized for Cr levels, 16.0–37.0 nmol/mmol) were assayed by an EIA (Metra Biosystems) with a sensitivity of 7.5 nmol/liter and an intra-assay and interassay CV of 8.5 and 6.8%, respectively. Urinary concentrations of Cr (reference range, 8.8–14.1 mmol/24 h) were measured with the use of an autoanalyzer (Monarch 1000, Instrumentation Laboratory, Milan, Italy). Cr-corrected values were calculated by dividing DPD and PYD by urinary Cr measured using a standard colorimetric assay (DPD/Cr and PYD/Cr). The biochemical data of bone turnover markers were also expressed as the percentage change from the baseline values.
Safety evaluation
Standard clinical evaluations and laboratory analyses, including hematologic, renal function, and liver function tests, measurements of serum Ca and P concentrations, and microscopic examinations of sediment from midstream urine specimens were performed before treatment and after every 6 months. A mammography was performed before and yearly during treatment.
The subjects were instructed to report in a daily diary the appearance of adverse experiences (AEs). The AEs were defined as any undesirable clinical experience occurring to patients during the study, whether or not related to the drugs administrated. A serious AE was defined as death, overdose, diagnosis of cancer, or any event that was life-threatening, permanently disabling or requiring hospitalization. From the time the patients received the first dose of the drugs, all subjects were seen every 3 months to check the personal diary. All patient data were carefully considered to establish the severity, duration, seriousness, and a possible cause-effect relationship.
Statistical analysis
On the basis of previous data (30), the sample size required was calculated to be of 40 subjects per group to detect an effect (2% difference in the mean percentage change from baseline in lumbar spine BMD within- and between-group) on the size of two SD with an 
value of 0.05 (two-sided) and a power 1-
of 0.8. After evaluating our expected dropout rate, we enrolled 50 subjects per group. The power analysis of the present study showed a value of ß = 0.855.
Repeated measures ANOVA followed by the Newman-Keuls multiple range test was used to compare multiple measures of age, time since menopause, BMI, BMD, and biochemical data. Wilcoxon’s signed rank test was used to compare parity, cigarettes smoked, alcohol consumption, calcium intake, and physical activity. The proportion of women receiving Ca supplements in the three groups of treatment was compared using the 
2 test. The Fisher’s exact test was used to compare the incidence of AEs between treatment groups. The statistical analysis was performed using the SPSS 9.0 (SPSS, Inc., Chicago, IL). Data were normally distributed and were expressed as mean ± SD.
Results
Demographic data
One hundred twenty-nine of the 150 enrolled patients completed the study.
A profile of the patients is shown in Table 1
. At study entry, the three groups were similar for age, time since menopause, parity, BMI, cigarettes smoked, Ca intake, alcohol consumption, physical activity, and serum FSH and E2 levels (Table 1). The proportion of women receiving Ca supplements was similar at baseline between the groups (Table 1) and throughout the 24 months of treatment (data not shown).
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At baseline, lumbar spine, trochanter, and femoral neck BMD were similar in the three groups (Table 1
). Since the 6-month follow-up and throughout the study, lumbar spine, trochanter, and femoral neck BMD were significantly increased (P < 0.05) compared with baseline in groups A and B, whereas only the lumbar spine BMD was significantly (P < 0.05) increased in group C (Fig. 1). In addition, at the 6-month follow-up, lumbar spine, trochanter, and femoral neck BMD increase was significantly (P < 0.05) higher in group A than in groups B and C, without any difference between them (Fig. 1). Since the 12-month follow-up and throughout the study, the percentage change of lumbar spine BMD was significantly higher (P < 0.05) in groups A and B than in group C (Fig. 1). No significant difference was found between groups A and B (Fig. 1).
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At baseline, the biochemical parameters of bone turnover were similar in the three groups (Table 1). Serum Ca, P, and PTH levels were unchanged in all groups throughout the study period. Since the 6-month follow-up and throughout the study, serum OC and BAP levels and urinary DPD and PYD excretion were significantly (P < 0.05) reduced in all groups (Fig. 2). After 12 and 24 months of treatment, the percentage decrease of BAP levels was higher (P < 0.05) in groups A and B, without any difference between them, than in group C (Fig. 2).
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Throughout the 2-yr observation, the three treatment schedules were well tolerated. The total incidence of all AEs was not significantly different between the three groups (28, 28, and 22% for groups A, B, and C, respectively). The incidence of AEs that were drug-related was low and not significantly different between the three groups (14, 12, and 10% for groups A, B, and C, respectively). In particular, both doses of alendronate were equally well tolerated, and their safety profile was similar to that of placebo.
There was also no significant difference in the incidence of clinical effects and/or laboratory abnormalities between the three groups of treatment (data not shown).
The numbers of withdrawals were similar in the three groups (eight, six, and seven women in groups A, B, and C, respectively). Dropouts were due to lack of compliance to the treatment in nine patients (four, two, and three patients in groups A, B, and C, respectively) and to upper gastrointestinal symptoms in eight patients (three, three, and two patients in groups A, B, and C, respectively). The upper gastrointestinal AEs consisted of gastralgia (two, one, and one case in groups A, B, and C, respectively), nausea (one case in groups A and C), and vomiting (one case in groups B and C). Three patients (one and two patients in groups A and C, respectively) dropped from the study for the appearance of breast tenderness. Only one serious AE was reported (a patient of group B died because of an acute myocardial infarction).
Throughout the study, no woman had vertebral or nonvertebral fractures.
Discussion
The most frequent treatment received by women to alleviate the postmenopausal symptoms soon after surgical menopause is ERT (1). Furthermore, few data are still available in the literature concerning the long-term effect of ERT on bone density and fracture risk (11). On the contrary, many trials (13, 14, 15, 16, 17, 18, 19, 20, 21) have showed that alendronate administration induces a bone gain and a reduction of the bone fracture risk.
The results of the present prospective randomized double-blind placebo-controlled clinical trial confirm that ERT effectively increases BMD in surgically postmenopausal women with osteoporosis (1, 2, 3, 4, 5, 6, 7, 8, 9, 10) and that the combined ERT/HRT plus alendronate therapy induces a significantly higher increase of BMD than ERT/HRT alone (1, 23, 24, 25).
It is well known that alendronate and ERT act on bone as two antiresorptive agents inducing an inhibition of osteoclastic activity with an effect mediated by a different mechanism of action (31, 32, 33, 34). Alendronate addition to ERT increases significantly the bone gain at all sites examined in comparison with ERT alone, showing that these two antiresorptive drugs have an additive effect on bone density when used in combination. This effect was observed on the axial and peripheral skeleton. Furthermore, the beneficial effect was stronger on lumbar spine than on trochanter and femoral neck. Changes of BMD were greater in bone regions containing larger proportions of cancellous bone at higher turnover such as at lumbar spine.
Our findings on ERT plus standard-dose alendronate administration are similar to those obtained previously in postmenopausal osteoporotic women (23, 25). Lindsay et al. (23) showed that in postmenopausal osteoporotic women ongoing HRT, the addition of 10 mg alendronate daily induced a significant increase in BMD when compared with HRT alone. In this last study (23), however, no data on BMD and bone metabolism during different treatment schedules were available. On the contrary, we enrolled only women who had undergone hysterectomy with bilateral oophorectomy to avoid any possible confounding effect of progestin therapy on bone metabolism. In addition, the endogenous E2 levels that were assayed gave results not significantly different among groups, ruling out any effect of endogenous hormone concentrations on the bone (35).
The data collected in our prospective double-blind placebo-controlled study confirmed the significant increase of BMD observed after 2 yr of treatment with the association conjugated equine estrogens plus 10 mg alendronate daily in comparison with conjugated equine estrogens alone (24). Recently, Tiras et al. (25) also reported a beneficial effect in BMD after 1 yr of treatment with HRT plus 10 mg daily compared with 10 mg alendronate daily alone.
An important limitation of our study was the absence of an alendronate 10 mg only arm. In this view, it was not possible to demonstrate whether the combination of ERT plus alendronate 5 mg is more effective than alendronate 10 mg alone.
Moreover, our study provides evidence that there is no statistically significant difference between a long-term treatment with alendronate at doses of 10 or 5 mg when administered in surgically postmenopausal osteoporotic women treated with ERT. Indeed, a significant difference between the groups treated with standard-dose and low-dose alendronate daily was observed only after 6 months of treatment, and this difference remained significant after 12 months of treatment only for the trochanter and femoral neck sites. After 18 months of treatment, however, no significant difference between the two doses of alendronate was detected in lumbar, femoral neck, and trochanter BMD as well as in the biochemical markers of bone metabolism.
No other data are currently available in literature regarding the addition of low-dose alendronate to ERT/HRT.
Previous studies evaluating the efficacy of different doses of alendronate in the prevention and treatment of postmenopausal osteoporosis have demonstrated a dose-dependent action (30, 36). The minimum dose demonstrating a significant increase in BMD was 2.5 mg daily, and the maximal increase in BMD was observed at 10 mg daily. In contrast, our data showed after a 2-yr follow-up no significant dose-dependent increase in BMD when alendronate is administered in postmenopausal osteoporotic women treated with micronized E2. It is possible that long-term ERT plus alendronate 5 mg administration induces a maximal anti-reabsorbing effect on bone, not increasing with higher alendronate doses. In other words, it seems that there is a threshold effect on bone turnover when estrogens and alendronate are administrated in association.
After 6 months of treatment, the biochemical bone metabolism markers were significantly decreased in all groups compared with baseline, indicating the effectiveness of the three regimens of treatment. Moreover, the bone turnover marker values detected during the study were in normal range and not suppressed at low level. The significant decrease in bone turnover markers observed after administration of ERT plus alendronate was due to high bone turnover marker values at entry in the surgically postmenopausal women enrolled.
An early and transient rise of PTH and a decrease of Ca levels was observed during 10 mg alendronate treatment. The serum BAP resulted to be the more sensitive marker of action of alendronate on bone turnover with particular regard to the different dose of alendronate. In fact, we observed in women treated with ERT plus alendronate a significantly higher suppression only of serum BAP levels than in those treated with ERT alone.
An important issue is the possibility that the association of anti-reabsorbing drugs might induce a high suppression of bone turnover, a skeletal microdamage, and an increase in bone fragility. Anyway, as highlighted before, the bone turnover markers showed a significant reduction, but their values remained in the normal premenopausal range. In addition, the use of low-dose alendronate in ERT users may add a beneficial effect on BMD, avoiding the risk of a stronger suppression of bone turnover.
As previously reported (28), the tolerability of alendronate during our study was very good, and it was similar between 10 or 5 mg alendronate doses. Indeed, the rates of AEs and of AE-related dropouts were similar among groups. The side effects observed in the groups treated with alendronate plus ERT were similar to those of the group treated with ERT plus placebo.
Alendronate is an expensive antiosteoporotic drug, and its addition to ERT increases significantly the costs of the treatment. Indeed, the observation that in surgically postmenopausal osteoporotic women treated with ERT the addition of 5 mg alendronate daily induces a net gain in bone mass, not significantly different in comparison with the addition of 10 mg alendronate daily, may have a positive impact in terms of pharmaceutical costs.
Because the ultimate goal of treatment for postmenopausal women is the reduction of fracture risk, it would be very interesting to evaluate the effect on risk of fractures of alendronate plus ERT treatments. Considering that in postmenopausal women a clear relationship between BMD and fracture risk was shown (37, 38, 39) and larger increases in BMD have been associated with reduced fracture risk (40, 41), it is tempting to hypothesize a favorable effect of low-dose of alendronate in association with ERT on fracture risk.
Finally, our data demonstrate that in postmenopausal women with osteoporosis treated with ERT, the addition of 5 mg alendronate daily did not have a significant long-term effect in terms of bone gain in comparison with a dose of 10 mg daily. Considering the data available at the present, 10 mg alendronate daily remains the gold standard for the treatment of postmenopausal osteoporosis. Furthermore, in postmenopausal women with osteoporosis treated with ERT/HRT for climacteric complaints, the addition of 5 mg alendronate daily seems to be sufficient to achieve a maximal anti-reabsorbing effect on bone tissue.
Acknowledgments
Footnotes
Abbreviations: AE, Adverse experience; BAP, bone alkaline phosphatase; BMD, bone mineral density; BMI, body mass index; Ca, calcium; Cr, creatinine; CV, coefficient of variation; DPD, deoxypyridinoline; EIA, immunoenzymatical assay; ERT, estrogen replacement therapy; HRT, hormone replacement therapy; OC, osteocalcin; P, phosphate; PYD, pyrilinks-D.
Received February 16, 2001.
Accepted November 19, 2001.
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, P < 0.05 vs. baseline. 
, Group A; 
, group B, 
, group C.