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Original Studies |
University Department of Endocrinology and Metabolism (L.M., P.C.), Aarhus Amtssygehus, Aarhus, Denmark; Procter & Gamble Pharmaceuticals (P.J.B., J.D.), Cincinnati, Ohio 45242; Indiana University School of Medicine (C.C.J.), Indianapolis, Indiana 46202.
Address correspondence and requests for reprints to: Lene Mortensen, MD, PhD, University Department of Endocrinology and Metabolism, Aarhus Amtssygehus, Tage Hansensgade 2, DK-8000, Aarhus C, Denmark.
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Abstract |
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Introduction |
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Risedronate, or 1-hydroxy-2-(3-pyridinyl)ethylidene bisphosphonic acid monosodium salt, is a potent pyridinyl bisphospho-nate currently under clinical development for the treatment and prevention of postmenopausal osteoporosis and secondary osteoporosis such as corticosteroid-induced osteoporosis, as well as for the treatment of other bone diseases such as Paget’s disease of bone. It is an antiresorptive agent that inhibits osteoclastic bone resorption (6). It has been demonstrated to be effective in normalizing bone turnover and increasing bone mass in patients with multiple myeloma (7), in decreasing serum calcium in patients with primary hyperparathyroidism (8), and in decreasing pain and the biochemical indicators of disease activity in patients with Paget’s disease (9, 10).
The objectives of this study were to determine 1) the efficacy of 24 months of oral risedronate therapy on bone loss in women in early postmenopause, 2) the effect on bone mass when risedronate treatment is stopped, and 3) the safety and tolerance of risedronate in this asymptomatic patient population.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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This double-blind, placebo-controlled study was conducted at two study centers: Indiana University School of Medicine, Indianapolis, Indiana, and the Department of Endocrinology, Aarhus Amtssygehus, Aarhus, Denmark. Patients were stratified based on calcium intake and then randomly assigned to receive oral placebo, 5 mg oral risedronate cyclically, the "cyclic group" (risedronate daily for the first 2 weeks of every calendar month and placebo daily for the rest of the month), or 5 mg of oral risedronate daily, the "daily group." There were three calcium intake strata: 1) less than 400 mg daily, 2) 400–650 mg daily, and 3) between 650 and 1500 mg daily. This was done because calcium intake might affect response to therapy. The average daily dose of risedronate in the cyclic group was 2.3 mg. After 1 yr of participation in the study, patients were offered three options: 1) to discontinue from the study, 2) to complete a second year without therapy, or 3) to continue the blinded study for an additional year and to complete 1 yr without treatment thereafter. The blind-regarding-treatment assignment was maintained throughout the study.
Patients
Women with normal lumbar spine bone mass (within 2
SD of age-matched mean bone mass) who were 6–60 months
postmenopausal qualified for enrollment. Patients’ estradiol levels
had to be at least 40 pg/mL and FSH at least 20 U/L, and they had to be
ambulatory and active, weigh at least 45 kg and no more than 90 kg, and
be within 25% of normal weight and height values as determined by the
investigator based on standard weight tables (i.e., 1983
Metropolitan Life Insurance tables). Patients also had to be willing
and able to participate in the study and to provide written informed
consent. Ineligible patients included those who took any
bisphosphonate, thyroid hormone therapy, glucocorticoids (
5 mg
prednisone per day), anabolic agents, calcitonin, vitamin D (>400 IU
per day), high-dose calcium (>1,500 mg per day), diuretics, or
anticonvulsants for more than 1 month within the previous 6 months,
estrogens and/or progestogens for more than 1 month within the past
year, or fluoride for more than 1 month ever in the past; had a history
of any generalized bone disease, including hyperparathyroidism,
Paget’s disease of bone, renal osteodystrophy, or any other acquired
or congenital bone disease, a documented history of alcohol or drug
abuse, or evidence of significant organic or psychiatric disease; any
evidence of established osteoporosis, such as an atraumatic vertebral
deformity documented by spinal x-ray, or a history of
osteoporosis-related fracture of the hip or wrist; or who underwent
bilateral oophorectomy or had any other type of artificially induced
menopause.
Study drug
Study drug was provided as 2.5 mg standard hard gelatin capsules. The placebo capsules were identical in appearance to the risedronate capsules. All test materials were prepared by Procter & Gamble Pharmaceuticals. Each patient was supplied 2 bottles of study drug per month that contained the proper amount and type of study medication appropriate for the patient’s assigned study group. The 2 bottles for each month were labeled Bottle 1 and Bottle 2. Bottle 1 contained 28 capsules, enough to last through 2 weeks of dosing (patients took 2 capsules per day), and Bottle 2 contained 40 capsules, enough to last through a 31-day month plus 3 additional days for any delayed study visits. Patients in the placebo group took 2 placebo capsules daily throughout the active phase of the study; patients in the cyclic group took two 2.5 mg capsules daily for 2 weeks and then 2 placebo capsules for the remainder of each calendar month; and patients in the daily group took two 2.5 mg risedronate capsules daily. Patients were instructed to take the study drug with at least 8 ounces of water, 2 h before bedtime and 2 h after a meal. Patients were also instructed not to take dairy products, vitamins, or antacids containing calcium, iron, magnesium, or aluminum within 2 h of dosing. They were allowed only water in this 4-hour window. Patients were not required to take supplemental calcium as part of the study requirements.
Efficacy measures
The primary efficacy end point was percentage change in lumbar spine bone mineral density (BMD) at 24 months as measured by dual x-ray absorptiometry (DXA, Hologic QDR 1000, Hologic, Waltham, MA). BMD of the proximal femur (neck, trochanter, and Ward’s triangle) was also monitored over the course of the study. Changes in bone turnover were assessed by monitoring urinary deoxypyridinoline/creatinine, pyridinoline/creatinine (bone resorption markers), and total alkaline phosphatase (bone formation marker).
Safety measures
Adverse events, regardless of severity, were recorded at all patient visits. The investigator recorded adverse events reported by patients, as well as those that he or she observed. Vital sign assessments, physical examinations, hematology, and serum and urine chemistry (liver tests, renal function, bone metabolism) were conducted periodically throughout the study. Radiographs of the thoracic and lumbar spine were taken before the study, at months 7, 13, and 25, and at 12 months after cessation of treatment. They were evaluated for the appearance of vertebral deformities for safety purposes. Vertebral deformities were defined as 25% or more decrease in anterior, mid, and/or posterior height of a vertebral body compared to baseline.
DXA methodology
Lumbar spine (L1-L4) BMD and BMC were measured using Hologic QDR 1000 densitometers that were cross-calibrated between centers. Fractured vertebrae were excluded from analysis. BMD of proximal hip was measured at the same side in the same position at each visit.
Sample collection procedures and assay methodology
Urine for the collagen crosslinks (deoxypyridinoline and pyridinoline) was collected as a 2-h morning sample (after first morning void). Samples were kept frozen at -70 C until time of assay, which was conducted at the Corning Nichols Institute using HPLC. The normal range for deoxypyridinoline/creatinine was 5–34 pmol/µmol creatinine. Serum alkaline phosphatase was measured using an assay with a normal range of 25–125 U/L at the Indianapolis center and a normal range of 80–250 U/L at the Aarhus center. The alkaline phosphatase data were transformed to standard scores and were calculated as fraction of study site range because of this difference between the two assays. The arbitrary standard score was calculated as fraction of study site range and had a normal range of -1 to +1, corresponding to the lower and upper limits of the reference range at each study center, respectively.
Statistical analyses
The population of primary interest for effectiveness and safety was the "intent-to-treat" population, which included all available data from patients randomized into the study. The primary assessment of the effectiveness of risedronate was based on an overall comparison of the three treatment groups with respect to percentage change from baseline in BMD of the lumbar spine at the 2-yr visit. The comparability of the treatment groups was determined by using a 3-way analysis of variance (ANOVA) at the 2-yr visit. Treatment was the main effect; center and calcium intake stratum were the blocking factors, and all the interactions were included. Because very few patients were included in the lowest calcium intake stratum, the two lower calcium intake strata were combined for the analyses. After examining the interactions, the ANOVA was recalculated without these interaction terms, and the treatment differences were assessed using the main effects ANOVA model. Pairwise comparisons of the treatment groups were done using the Fisher’s protected LSD test (pairwise comparisons were performed only if the ANOVA detected a significant treatment group difference). If the ANOVA model assumptions were not tenable, the 3-way ANOVA was replaced by the Kruskal-Wallis test, and the Fisher’s protected LSD test was replaced by the Wilcoxon rank-sum test.
To assess separation among the treatment groups at other time points, the percentage change from baseline in BMD of the lumbar spine at the 3-, 6-, 9-, 12-, and 18-month time points was analyzed in the same manner described for the primary analysis. To determine within-treatment-group responses, the actual values for BMD of the lumbar spine at months 3, 6, 9, 12, 18, 24, and 36 were compared with baseline values within each treatment group by using a paired t test. For certain parameters, paired t tests were performed within each treatment group between the baseline and 36-month data as well as the 24- and 36-month data to evaluate the treatment-free follow-up year response.
Secondary effectiveness measurements included percentage change from baseline in BMD of the femoral neck, the trochanteric region, and the Ward’s triangle region of the proximal femur. The percentage change from baseline in BMD for each of the three sites was analyzed separately at each visit for treatment effects in the manner described for the lumbar spine, and within-treatment-group comparisons were done using paired t tests. Bone markers were analyzed similarly.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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shows the patient accountability.
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, were similar among
treatment groups. Participants were, on average, within 3 yr of
menopause. The mean calcium intake was high, approximately 1 g per
day. From Table 2, it can also be seen that patients had normal bone
mass for this age group.
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and Table 3 show the lumbar spine BMD results over
the 3 yr of the study. From Table 3, it can be seen that the patient
population that completed all 3 yr of this study had similar BMD
results as the intent-to-treat population shown in Fig. 1. Lumbar spine
BMD in both risedronate treatment groups was significantly higher at
all time points during the first 2 yr compared with placebo
(P < 0.05). On average, the placebo control group lost
4.3% (0.04 g/cm2) bone mass at the lumbar spine by the end
of the 2-yr treatment period. This occurred despite a high mean calcium
intake, assuming the calcium intake did not change from baseline (see
Table 2
). In the 5 mg cyclic group, risedronate treatment prevented
most of the bone loss (mean % change, -1.6%; actual mean change,
-0.01 g/cm2). Since patients were taking 5 mg of
risedronate daily for 2 weeks and were then without therapy for the
remainder of a calendar month, the mean daily dose taken by patients in
this group was approximately 2.3 mg. The group that received 5 mg daily
of risedronate showed a statistically significant mean increase of
1.4% (0.01 g/cm2) in lumbar spine bone mass at the end of
24 months (paired t test). Patients in the 2 calcium intake
strata had similar responses across treatment groups. Referring to Fig. 1, 1 year after risedronate treatment was discontinued, the increase in
bone mass was relatively well maintained in the active-treatment groups
compared with the placebo group, even though the size of the effect was
diminished. The amount of bone lost at the lumbar spine during the
follow-up year in the 5 mg daily group was similar to the loss that
occurred in the placebo group during the first year of the study. The
rate of loss appeared to be greater in the first 6 months of follow-up
in the 5 mg daily group than in the last 6 months. Even though there
were statistically significant differences between the cyclic
risedronate and placebo groups during the 2-yr treatment period, this
significance was not maintained during the follow-up year.
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, the femoral neck and
trochanter BMD data are shown. In the placebo group, there were
statistically significant mean decreases of 2.4% (0.02
g/cm2) and 2.8% (0.02 g/cm2) at the femoral
neck and trochanter, respectively, after 24 months (paired t
test). This bone loss was prevented in the active-treatment groups. In
fact, there were statistically significant increases of BMD at the
femoral trochanter at 2 yr (2.6%; 0.02 g/cm2) and femoral
neck at 9 months (1.3%; 0.01 g/cm2) (paired t
test) in the daily group. A daily dose of 5 mg also seemed to be more
effective than a cyclic regimen at these sites. There was a 7% (0.04
g/cm2) mean increase from baseline and an 8.2% (0.04
g/cm2) difference from placebo at the Ward’s triangle
femoral site in the 5 mg daily group at the end of 24 months. The
cyclic group showed a 3.1% (0.01 g/cm2) increase and the
placebo group a 1.2% (0.01 g/cm2) decrease from baseline
at 24 months. These changes were statistically significantly different
from each other (P = 0.001, Kruskal-Wallis test,
normality assumption not met). Interestingly, statistically significant
differences in bone mass at the femoral trochanter between the
active-treatment groups and the placebo group were maintained during
the follow-up year. However, a significant loss in bone mass was also
observed at this site in the 5 mg daily group at the end of the
treatment-free follow-up year.
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, the 2-yr changes from baseline
in lumbar spine, femoral neck, and trochanter are shown for the
risedronate groups relative to the changes in the placebo group. This
clearly indicates a dose response at the predominantly trabecular bone
sites (lumbar spine and femoral trochanter). At the femoral neck, the
changes were similar in the two risedronate groups.
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, data from the bone resorption
marker, urinary deoxypyridinoline/creatinine (d-pyr/creat), and the
bone formation marker, serum alkaline phosphatase (AP), are shown.
There was a rapid mean decrease in d-pyr/creat within 14 days following
the start of treatment in the 5 mg daily group. After 6 months, there
was no further significant decrease in d-pyr/creat, and there seemed to
be a new lower steady state in bone turnover. By the end of 24 months,
there was a mean decrease from baseline of 31% in the daily group. In
the 5 mg cyclic group, there was a sharp initial decrease in mean
d-pyr/creat (at the 2-week time point), but then a return toward the
mean baseline level when treatment was discontinued after the first 14
days. Nevertheless, by the end of 24 months of treatment, there was
still a statistically significant 15% decrease from baseline in the
cyclic group. As expected, the placebo group did not show any
significant change over time. Changes in pyridinoline/creatinine were
very similar to d-pyr/creat (data not shown). There was a greater
reduction in mean AP in the daily risedronate group compared with the
cyclic risedronate and placebo groups. The initial decrease in AP
levels was not as rapid as observed with d-pyr/creat. By the end of 24
months, there was a statistically significant difference between the
daily and cyclic groups. The cyclic group, although statistically
different from the placebo group from months 6–24, showed a smaller
initial decrease in mean AP with a plateau thereafter, whereas the
placebo group increased slightly from the baseline level; at the
24-month point, there was a significant increase compared with baseline
(paired t test).
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There was a slight decrease in serum calcium and phosphorus within 2–4 weeks after initiating risedronate treatment (data not shown). These decreases were not clinically significant. There was a significant initial mean increase in serum intact PTH (i-PTH) after only 2 weeks in the 5 mg daily group (data not shown). The cyclic group showed a smaller initial increase in mean i-PTH compared with the daily group. By the end of 24 months, however, the mean levels among the 3 groups were very similar. The 1,25-(OH)2D3 results corresponded to the pattern observed with i-PTH, while 25OHD2 levels remained close to baseline levels throughout the study (data not shown).
Overall, risedronate was very well tolerated. There was no difference in incidence of adverse events among drug and placebo treatment groups. Three patients each in the placebo and cyclic groups and two in the daily group withdrew from the study due to adverse events. One of these events, hip arthralgia, reported early in the study at week 17 in the cyclic risedronate group, was considered by the investigator as possibly drug related. Reports of arthralgia throughout the study remained low and were similar in the placebo and risedronate treatment groups. The other reports of arthralgia were not considered causally related by the investigators.
Patients with a previous history of upper gastrointestinal disease were not excluded from this study. At study entry, 6 patients in the placebo group (17%), 5 in the 5 mg cyclic group (13%), and 6 in the 5 mg daily group (16%) had a history of upper gastrointestinal pathology (esophageal, gastric, or duodenal). Despite this, there was no increased incidence of frequently observed gastrointestinal adverse events such as abdominal pain (placebo, 11%; 5 mg cyclic, 13%; 5 mg daily, 8%) and dyspepsia (placebo, 28%; 5 mg cyclic, 24%; 5 mg daily, 16%) in the risedronate groups compared with placebo.
Two patients had vertebral fractures during the study. One was in the cyclic group (L2 fracture at 6 months and L1 fracture at 12 months following cessation of drug treatment), and the other was in the daily group (T7 at 12 months following cessation of drug therapy). Six patients had nonvertebral fractures as the result of accidental traumatic events. One patient in the placebo group fractured her metacarpal bones, a second patient her index finger, and a third patient her small finger. One patient in the cyclic risedronate group fractured a rib, another patient her wrist, and a third patient fractured her ankle. No patients in the daily risedronate group had a nonvertebral fracture. Overall, there was no clinical relevance to these fracture findings, and all fractures healed normally while the patients continued participation in the study.
There were no clinically relevant risedronate-related changes in hepatic, renal, and hematologic parameters or vital signs during the study.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Once-daily therapy with risedronate 5 mg increased bone mass in early postmenopausal women with normal BMD. In fact, women in this treatment group had significant mean percentage increases in BMD of the lumbar spine from baseline at all visits during the 24 months of treatment. The overall treatment effect was significant at all visits during the 24-month treatment period. Women in the placebo group lost bone mass as expected. Cyclic treatment with risedronate (5 mg of risedronate once daily for 2 weeks, followed by placebo for approximately 2 weeks) did not completely prevent the loss of bone mass, although the difference in bone mass between the cyclic risedronate and placebo groups was statistically significant at 24 months. This statistically significant benefit of cyclic therapy (during which patients took 5 mg of risedronate daily approximately half of the time) vs. placebo indicates that risedronate is of value even in patients in whom compliance may be severely compromised.
Risedronate also had a positive effect at the proximal femur. This is potentially important in terms of protecting against hip fractures. Large long-term prospective clinical trials are currently underway that are designed to provide clinical evidence that treatment with risedronate reduces fracture risk.
Risedronate treatment caused expected decreases in urinary d-pyr/creat and serum AP values in as little as 2 weeks in this patient population. This rapid decrease in bone biomarkers is similar to what has been observed with risedronate in patients with other bone diseases (7). Importantly, there was no evidence of oversuppression of bone turnover.
The results from the nontreatment follow-up year suggest that bone turnover returns toward its increased state and bone mass is not maintained at the same level. However, by the end of the follow-up year, BMD of the lumbar spine and proximal femur were still higher relative to the placebo group, clearly indicating a persistent overall benefit. Bone turnover also did not quite return to baseline levels. These data suggest that if treatment is discontinued in an early postmenopausal population, the patient’s bone mass should be followed to determine whether retreatment is indicated. This is similar to what is observed after stopping estrogen replacement therapy, when bone mass is lost at least at the same rate as after ovariectomy (13, 14, 15). From this study, it can be concluded that the rate of bone loss after discontinuing risedronate in an early postmenopausal population is similar to the rate of loss in the placebo group during the first year of the study.
Several other observed changes in bone metabolism parameters also reflect the pharmacology of risedronate. Initial decreases in serum calcium lead to an increase in serum i-PTH, which activates 25OHD3 to 1,25-(OH)2D3. This leads to a correction in serum calcium, possibly through increased absorption of calcium from the intestine and renal tubular reabsorption.
Risedronate was well tolerated across the two treatment groups. This tolerance is especially important for a therapy such as risedronate, which might be administered chronically. Specifically, the most frequently observed gastrointestinal adverse events such as abdominal pain and dyspepsia were similarly distributed among the risedronate and placebo treatment groups. This suggests that risedronate is well tolerated, even by patients with a history of upper gastrointestinal pathology (such as esophageal reflux, gastritis, esophageal stricture, and ulcers) who participated in this study.
In conclusion, in early postmenopausal women with age-matched normal bone mass at baseline, risedronate therapy resulted in a significant increase in BMD of the lumbar spine after 24 months of treatment with 5 mg daily. A cyclic regimen of 5 mg per day for the first 2 weeks of each month was also effective in preventing bone loss relative to placebo control. Importantly, bone turnover was decreased without interfering with the bone renewal process. When treatment was discontinued, bone turnover increased within 6 months toward baseline levels, and bone mass decreased significantly within 1 yr. Risedronate was also safe and well tolerated in this study population. This pyridinyl bisphosphonate could provide a useful treatment alternative to prevent bone loss in early postmenopausal women.
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Acknowledgments |
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Footnotes |
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Received July 11, 1997.
Revised October 29, 1997.
Accepted November 5, 1997.
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| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Endocrinology | Endocrine Reviews | J. Clin. End. & Metab. |
| Molecular Endocrinology | Recent Prog. Horm. Res. | All Endocrine Journals |
, placebo group;
•, 5 mg cyclic risedronate group; 
, 5 mg daily risedronate group.
Error bars represent SEM. *, statistically
significant differences from placebo (ANOVA P <
0.05); 
, an increase compared with baseline (paired t
test P < 0.05); à, statistically significant
differences from the cyclic group (ANOVA P <
0.05); §, a decrease compared with baseline (paired t
test P < 0.05); xx, a decrease compared with month
24 (paired t test P < 0.05).
