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Original Studies |
Department of Nuclear Medicine (I.F.), Guy’s Hospital, London SE1 9RT, United Kingdom; Department of Endocrinology (C.R.), Hospital Rangueil, Toulouse 31403, France; Oxford Health Management Ltd. (R.S.), Acland Hospital, Oxford S10 2RX, United Kingdom; Procter & Gamble Pharmaceuticals (D.E., E.S.), Mason, Ohio 45040; and Bone/Cartilage Metabolism Unit (J.-Y.R.), Polycliniques L. Brull, 4020 Liege, Belgium
Address correspondence and requests for reprints to: Ignac Fogelman, Department of Nuclear Medicine, Guy’s Hospital, St. Thomas Street, London SE1 9RT, United Kingdom.
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Abstract |
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Women with a mean lumbar spine T-score of -2 or less (n = 543) received 24 months of placebo or risedronate (2.5 or 5 mg/day). All received calcium (1 g/day). The principal outcome measures were bone mineral density (BMD) at the lumbar spine, femoral neck, and femoral trochanter.
At 24 months, lumbar spine BMD increased from baseline by 4% with 5 mg risedronate and 1.4% in the 2.5-mg group, compared with no change with placebo. Efficacy was similar in women who were less than 5 yr and more than 5 yr postmenopausal. At 24 months, risedronate (5 mg) had also increased BMD at the femoral neck and trochanter, whereas BMD decreased in the placebo group. BMD increases were seen at all three sites with risedronate (5 mg) after only 6 months of therapy. Risedronate was well tolerated; upper gastrointestinal adverse events were similar to placebo.
We conclude that risedronate (5 mg) increases BMD rapidly and effectively and is well tolerated in postmenopausal women with low bone mass, regardless of time since menopause.
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Osteoporosis is a major cause of morbidity in the elderly. The fractures associated with osteoporosis cause considerable disability and loss of quality of life and can be fatal (6). The annual cost of treating osteoporotic fractures has been estimated to be £727 million ($1.2 billion equivalent) in the UK and $13.8 billion in the US (7, 8).
Several therapeutic options are available for the treatment or prevention of postmenopausal osteoporosis. Estrogen replacement is the most frequently prescribed therapy for prevention of postmenopausal osteoporosis and has been shown to reduce the risk of vertebral and hip fractures (9, 10). However, this therapy is contraindicated in some patients and is unacceptable to many others, and long-term adherence to therapy is poor (11, 12). Raloxifene, a selective estrogen receptor modulator, has been shown to modestly increase bone mineral density (BMD) and decrease the incidence of vertebral fracture but has not demonstrated significant effects in reducing nonvertebral fractures (13, 14).
Clearly, there is a need to develop alternative, effective therapies for the prevention and treatment of postmenopausal osteoporosis. Guidelines for the management of postmenopausal osteoporosis (15, 16) list bisphosphonates as a useful therapeutic option for the treatment of these conditions. Etidronate and alendronate have been shown to be effective in increasing or maintaining BMD in early postmenopausal women (17, 18, 19). Both of these bisphosphonates have also been shown to increase BMD and reduce fracture risk in postmenopausal women with established osteoporosis (20, 21, 22).
Risedronate is a potent pyridinyl bisphosphonate currently licensed in the US for the treatment of Paget’s disease of bone and is under development for the treatment and prevention of osteoporosis. It has been shown to be effective in the treatment of Paget’s disease of bone (23, 24), and it improves or maintains bone mass in patients with postmenopausal and corticosteroid-induced osteoporosis (25, 26).
Our aim was to assess the efficacy and tolerability of risedronate (2.5 mg and 5 mg) in preventing or reversing the loss of BMD in early and late postmenopausal women with low bone mass.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Patients
Women up to 80 yr of age were eligible to participate in the
study if they had been postmenopausal for at least 1 yr, based on the
date of their last menstrual period, and had a mean lumbar spine
(L1–L4) T-score of -2 or less. Patients were excluded from the
study if they had hyperparathyroidism, hyperthyroidism, or osteomalacia
within a year before the study; a history of cancer; or abnormalities
that would interfere with the measurement of lumbar spine BMD by
dual-energy x-ray absorptiometry (DXA). Patients were also excluded if
they had taken (within 6–12 months, depending on the medication) or
were still taking treatment known to affect bone metabolism, including
an injection of vitamin D 
10,000 IU. Prior or concomitant use
of nonsteroidal antiinflammatory drugs (NSAIDs) or aspirin was
permitted. Patients with previous or ongoing upper gastrointestinal
disease were not excluded.
Drug treatment
Initially, eligible patients were randomized in a 1:1:1 ratio to receive daily risedronate (2.5 mg or 5 mg) or placebo; within each center, the randomization was stratified according to the time since menopause (5 yr or less, or more than 5 yr). The 2.5-mg risedronate group was discontinued by protocol amendment at 9 of the 13 centers, on the basis of efficacy and safety assessments from other randomized, placebo-controlled clinical trials (25, 27). Patients were instructed to take their medication with at least 240 mL of water on an empty stomach, 30–60 min before breakfast, to ingest the tablet in an upright position, and to remain upright for 1 h after dosing. Patients were also instructed not to consume dairy or other calcium-containing products at the same time as study medication. All patients were required to take elemental calcium (1 g/day), as calcium carbonate, at a different time of day from the study drug, preferably with food. Treatment was continued for 24 months.
Assessments
Previous therapy for osteoporosis and prior or concomitant use of NSAIDs or aspirin were recorded at baseline and after 1, 3, 6, 9, 12, 15, 18, 21, and 24 months of treatment.
BMD was measured at the lumbar spine, femoral neck, and femoral trochanter (by DXA) at baseline and after 6, 12, 18, and 24 months. Only Lunar Corp. (Madison, WI, USA) or Hologic, Inc. (Waltham, MA) densitometers were used, and each study center used only one model of instrument. Lumbar spine and femoral neck BMD values were standardized to account for differences between the densitometers, according to the equations of Genant et al. (28). No standardization was available for the femoral trochanter; baseline values for the two densitometers are quoted separately. DXA scans were analyzed by the Osteoporosis Research Center, Portland, OR. Longitudinal correction factors were generated from phantom DXA data by the Osteoporosis Research Center to compensate for variations between instruments (29).
Normal values of lumbar spine BMD for young females were provided by the manufacturers of the densitometers. These values were means of the values for all four vertebrae (L1–L4). T-scores were calculated only in those patients in whom all four lumbar vertebrae were intact (i.e. not fractured) at baseline.
Biochemical markers of bone resorption and formation were assessed to provide a measure of bone turnover. N-telopeptide is a marker of bone resorption and was measured using the Osteomark enzyme-linked immunosorbent assay (Ostex International, Inc. Seattle, WA). Serum bone-specific alkaline phosphatase is a marker of bone formation and was assessed using the Tandem R-Ostase immunoradiometric assay (Beckman Coulter, Inc. Diagnostics Hybritech, Inc., San Diego, CA).
Safety was evaluated by assessment of adverse events (including nonvertebral fractures and vertebral fractures), vital signs, and clinical laboratory tests. Information on adverse events was obtained throughout the study, from spontaneous reports and by direct questioning. Odds ratios were calculated to determine whether the risk of upper gastrointestinal adverse events was increased in patients using NSAIDs or aspirin.
Vertebral fractures were assessed from thoracic and lumbar (T4–L4) lateral and anterior-posterior spinal radiographs taken at baseline, and from lateral spinal radiographs taken at the end of the study. Potential fractures were identified by quantitative morphometry, according to the guidelines of the US National Osteoporosis Foundation Working Group on Vertebral Fractures (30), and subsequent visual verification of incident fractures was performed by a qualified radiologist. A vertebral body was considered to be fractured if any of the vertebral height ratios fell below 3 SD of the mean for the study population, as described previously (31). Standard hematology and clinical chemistry tests were performed at baseline and after 6, 12, and 24 months.
A full physical examination was performed at the beginning and end of the study, and vital signs (heart rate and seated blood pressure) were measured at all scheduled visits.
Statistical methods
We calculated that, with an anticipated 25% dropout rate at 24
months, a sample size of 180 patients per group would provide
sufficient power to detect either a 6% difference between the placebo
and risedronate groups in the change in BMD from baseline to 24 months,
or a 2.5% difference between the groups in the change in BMD during
the second year of the study, with 90% power for each test and a
two-sided 
= 0.05 significance level.
Data were analyzed on an intention-to-treat basis, including all patients randomized to treatment and who had received at least one dose of study medication. Homogeneity among the three groups at baseline was tested by ANOVA, with factors for center and time since menopause. In addition, homogeneity for dichotomous variables (such as smoking, previous osteoporosis treatment, and the presence of vertebral fractures) was tested by logistic regression analysis.
The principal efficacy analysis was based on the change in BMD at the lumbar spine from baseline to month 24. Differences in this variable between the groups were compared by ANOVA, adjusted for center and stratum. Changes within treatment groups, and between the placebo and 5-mg risedronate treatment groups, were assessed by calculating 95% confidence intervals (CIs). Changes in BMD at the femoral neck and femoral trochanter were compared by ANOVA.
The incidences of the most frequent adverse events and of nonvertebral fractures in the three groups were compared by Fisher’s exact test. A significance level of 0.05 was used for all analyses.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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A total of 543 women were enrolled in the study: 180 were
randomized to receive placebo; 184, risedronate (2.5 mg); and 179,
risedronate (5 mg). Two patients in the 5-mg risedronate group were
excluded from the intention-to-treat analysis because they did not
receive study medication. A total of 355 patients completed 24 months
of treatment: 143 in the placebo group, 73 in the risedronate 2.5-mg
group, and 139 in the 5-mg risedronate group. In the 2.5-mg risedronate
group, 76 patients were withdrawn before the end of the trial because
of protocol amendment, on the basis of efficacy and safety assessments,
from other randomized, placebo-controlled clinical trials (25, 27). The
three groups were well matched at baseline, with regard to demographic
characteristics and medical history (Table 1
), although a higher proportion of
patients in the 5-mg risedronate group than in the other groups had
received previous treatment for osteoporosis; this difference was not
statistically significant (P = 0.12, Fisher’s exact
test).
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). T-scores were not calculated in
16 patients in the placebo group, 20 in the 2.5-mg risedronate group,
and 31 in the 5-mg risedronate group, because of fractures in 1 or more
of the lumbar vertebrae (L1–L4). There were no significant differences
in baseline BMD at the lumbar spine, femoral neck, or femoral
trochanter (Table 1). Efficacy of risedronate
Primary efficacy analyses. BMD at the lumbar spine
increased from baseline by 4% at month 24 in patients treated with 5
mg risedronate, in contrast to no-change in the placebo group (Table 2). The differences in percentage change
from baseline, between the 5-mg risedronate and placebo groups were
also statistically significant at months 6, 12, and 18. BMD at the
lumbar spine also increased from baseline in patients receiving 2.5 mg
risedronate, although the increases were smaller at all time points
than those recorded with 5 mg risedronate.
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). Baseline measurements of lumbar spine
BMD were made in 62 women who had been postmenopausal for 5 yr or less.
In these women, BMD at the lumbar spine increased significantly, by
4.2 ± 0.8% (within-group 95% CI 2.5–5.9) from baseline,
after 24 months of treatment with 5 mg risedronate. In contrast, there
was a mean decrease of 2.4 ± 1.2% in the placebo group
(between-group 95% CI 3.8–10.2). Lumbar spine BMD was measured at
baseline in 364 women who had been postmenopausal for more than 5 yr .
In these women, BMD at the lumbar spine increased significantly, by
4.0 ± 0.4% (within-group 95% CI 3.3–4.8) from baseline, after
24 months of treatment with5 mg risedronate . In contrast, lumbar spine
BMD decreased by 0.4 ± 0.3% in the placebo group (between-group
95% CI 2.6–4.6).
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). The differences in the percentage change from baseline,
between the placebo and 5-mg risedronate groups, approached statistical
significance at month 6 and were statistically significant at months
12, 18, and 24. Similarly, BMD at the femoral trochanter increased from
baseline by almost 3% after 24 months of treatment with 5 mg
risedronate but decreased slightly in the placebo group (Table 2). The
differences in the percentage change from baseline between the placebo
and 5-mg risedronate groups were statistically significant at 6, 12,
18, and 24 months. The effect of risedronate treatment on BMD at both
sites in the proximal femur was similar in those women who were
postmenopausal for 5 yr or less and those who were postmenopausal for
more than 5 yr. Biochemical markers
In patients receiving 5 mg risedronate, serum bone-specific
alkaline phosphatase concentrations decreased from baseline by
approximately 22% after 24 months, compared with a mean increase of
8% in the placebo group (Fig. 2a). The
differences in the percentage changes from baseline between the
treatment groups were statistically significant at months 3, 6, 12, and
24.
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). The
differences in percentage changes from baseline, between the placebo
and 5-mg risedronate treatment groups, were statistically significant
at all time points. Safety and tolerability
Bone safety. This study was not statistically powered to detect effects on vertebral or nonvertebral fractures, but positive trends toward reductions in fracture incidence were recorded. At the end of the study, vertebral fractures were present in 17 of 125 patients with known fracture status (14%) in the placebo group, 8 of 60 patients (13%) in the 2.5-mg risedronate group, and 8 of 112 patients (7%) in the 5-mg risedronate group. Nonvertebral fractures occurred in 13 patients (9%) in the placebo group, compared with 4 (5%) in the 2.5-mg risedronate group and 7 (5%) in the 5-mg risedronate group.
Adverse events. There were no differences in the overall
incidence of adverse events among the three treatment groups (Table 3). The incidence of serious adverse
events and patient withdrawal attributable to adverse events was
similar in all three treatment groups. The incidence of upper
gastrointestinal adverse events among the patients receiving 5 mg
risedronate was similar to that in the placebo group, but the incidence
in the 2.5-mg risedronate group was slightly greater (Table 3).
Abdominal pain and dyspepsia were the most frequent upper
gastrointestinal adverse events and were evenly distributed among the
treatment groups. There were no differences between treatment groups in
the distribution of the other upper gastrointestinal adverse events.
The use of risedronate did not increase the odds ratio (OR) for the
association between upper gastrointestinal adverse events and NSAIDs
[OR: placebo 1.4 (95% CI 0.7–2.7), 5 mg risedronate 1.4 (95% CI
0.7–2.9)] or aspirin [OR: placebo 1.5 (95% CI 0.7–3.3), 5 mg
risedronate 0.8 (95% CI 0.3–2.1)]. The tolerability of risedronate
was similar to placebo, even in patients with previous or ongoing
gastrointestinal disease.
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In the placebo group, one patient had esophageal erosion and a hiatal hernia, three had stomach ulceration, and two had esophageal and stomach ulceration. In the 2.5-mg risedronate group, one patient had lower esophageal and stomach ulceration; one had lower esophageal ulceration, an unspecified duodenal abnormality, and a hiatal hernia; and one had stomach ulceration. Two patients in the 5-mg risedronate group had stomach ulceration, and three had esophageal ulceration and hiatal hernias.
Clinical laboratory evaluations. No clinically relevant changes from baseline in blood pressure, pulse rate, height, weight, or the findings of other physical examinations occurred during the study. There were no clinically relevant differences in hematology variables between the placebo and risedronate groups. No significant differences in markers of hepatic and renal function were recorded. Serum calcium and phosphorus concentrations and total alkaline phosphatase activities in the treatment groups remained within the normal ranges throughout the study. Total alkaline phosphatase activity decreased from baseline in both risedronate groups, with the larger decrease in the 5-mg risedronate group.
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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BMD increased in patients treated with 5 mg risedronate but not in those receiving placebo, despite the fact that both groups received supplemental calcium. This finding is consistent with the results of an earlier study (25) and indicates that calcium alone is insufficient to treat postmenopausal bone loss. Bone mass increased rapidly in patients treated with risedronate, with significant increases, compared with placebo at the lumbar spine and femoral trochanter, after 6 months of therapy. At 12 months, these differences remained statistically significant; and, in addition, there was a significant increase in femoral neck BMD with 5 mg risedronate, compared with the placebo group. The rapid effect of 5 mg risedronate is confirmed by the observation that the biochemical markers of bone formation and resorption (bone-specific alkaline phosphatase and N-telopeptide/creatinine ratio) were reduced after 1–3 months of treatment.
The beneficial effect of risedronate on BMD was independent of the time since menopause; significant increases were seen in women who had experienced menopause more than 5 yr before entry to the study and in women with a more recent menopause. The ability of risedronate to reduce early postmenopausal bone loss has important implications for the management of osteoporosis. Ideally, treatment for osteoporosis should be started as early as possible, before significant bone loss has occurred and trabecular architecture has been disrupted (15).
The femoral neck and trochanter are both sites at which fractures occur frequently, so the ability of risedronate to increase BMD at these locations is clinically significant. Furthermore, the femoral neck consists of approximately 75% cortical bone, whereas the femoral trochanter is composed predominantly of trabecular bone. The results show that risedronate increases BMD in both types of bone.
Similar improvements in BMD have been observed after long-term therapy with etidronate (20, 21), and in several extensive trials of alendronate (22, 34, 35). The increases in BMD that we observed with 5 mg risedronate compare favorably with those recorded in a trial of the selective estrogen receptor modulator raloxifene (2–3% at the spine and femoral neck and trochanter) (13).
Risedronate was well tolerated by postmenopausal women in our study. The adverse-event profile of risedronate was similar to that of placebo. Particular attention was given to gastrointestinal safety, because of the observation of gastrointestinal adverse events during clinical use of some other bisphosphonates (36, 37, 38). Overall, risedronate was not associated with an increased incidence of upper gastrointestinal adverse events and did not increase the risk of gastrointestinal adverse events in patients reporting a history of gastrointestinal disease or in those who had previously taken or who were currently using NSAIDs or aspirin or were smokers or alcohol consumers. These populations are likely to be encountered frequently in routine clinical practice and may be particularly prone to adverse gastrointestinal effects.
In conclusion, risedronate provided rapid and effective therapy for postmenopausal osteoporosis, with significant increases in BMD that were maintained throughout 24 months of treatment. The beneficial effect of risedronate was independent of the time since menopause. Risedronate was well tolerated, and the incidence of gastrointestinal adverse events did not differ significantly from the placebo group.
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Acknowledgments |
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Footnotes |
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2 The principal investigators at each study center are listed in
Acknowledgments.
Received September 29, 1999.
Revised January 11, 2000.
Accepted January 12, 2000.
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References |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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), 2.5 mg risedronate (
), or
placebo (
), stratified into: a) 
5 yr postmenopausal or b) >5 yr
postmenopausal. ***, P < 0.001 vs.
placebo. Values are means ± SEM.