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Glucocorticoid-Induced Osteoporosis: Sustained use of glucocorticoids is commonly associated with development of osteoporosis and resulting fractures (especially vertebral, hip, and rib). It occurs in both males and females of all ages. The relative risk of a hip fracture in patients on >7.5 mg/ day prednisone is more than doubled (RR = 2.27); the relative risk of vertebral fracture is increased 5-fold (RR = 5.18). Bone loss occurs most rapidly during the first 6 months of therapy with persistent but slowing bone loss for as long as glucocorticoid therapy continues. Osteoporosis occurs as a result of inhibited bone formation and increased bone resorption resulting in net bone loss. ACTONEL decreases bone resorption without directly inhibiting bone formation. In two 1-year clinical trials in the treatment and prevention of glucocorticoid-induced osteoporosis, ACTONEL 5 mg decreased urinary collagen cross-linked N-telopeptide (a marker of bone resorption), and serum bone specific alkaline phosphatase (a marker of bone formation) by 50% to 55% and 25% to 30%, respectively, within 3 to 6 months after initiation of therapy. Text Continues Below
Paget's Disease: Paget's disease of bone is a chronic, focal skeletal disorder characterized by greatly increased and disordered bone remodeling. Excessive osteoclastic bone resorption is followed by osteoblastic new bone formation, leading to the replacement of the normal bone architecture by disorganized, enlarged, and weakened bone structure. Clinical manifestations of Paget's disease range from no symptoms to severe bone pain, bone deformity, pathological fractures, and neurological disorders. Serum alkaline phosphatase, the most frequently used biochemical marker of disease activity, provides an objective measure of disease severity and response to therapy. In pagetic patients treated with ACTONEL 30 mg/ day for 2 months, bone turnover returned to normal in a majority of patients as evidenced by significant reductions in serum alkaline phosphatase (a marker of bone formation), and in urinary hydroxyproline/ creatinine and deoxypyridinoline/ creatinine (markers of bone resorption). Radiographic structural changes of bone lesions, especially improvement of a majority of lesions with an osteolytic front in weight-bearing bones, were also observed after ACTONEL treatment. In addition, histomorphometric data provide further support that ACTONEL can lead to a more normal bone structure in these patients. Radiographs taken at baseline and after 6 months from patients treated with ACTONEL 30 mg daily demonstrate that ACTONEL decreases the extent of osteolysis in both the appendicular and axial skeleton. Osteolytic lesions in the lower extremities improved or were unchanged in 15/ 16 (94%) of assessed patients; 9/ 16 (56%) patients showed clear improvement in osteolytic lesions. No evidence of new fractures was observed. CLINICAL STUDIES Treatment of Osteoporosis in Postmenopausal Women: The fracture efficacy of ACTONEL 5 mg daily in the treatment of postmenopausal osteoporosis was demonstrated in 2 large, randomized, placebo-controlled, double-blind studies that enrolled a total of almost 4000 postmenopausal women under similar protocols. The Multinational study (VERT MN) (ACTONEL 5 mg, n = 408) was conducted primarily in Europe and Australia; a second study was conducted in North America (VERT NA) (ACTONEL 5 mg, n = 821). Patients were selected on the basis of radiographic evidence of previous vertebral fracture, and therefore, had established disease. The average number of prevalent vertebral fractures per patient at study entry was 4 in VERT MN, and 2.5 in VERT NA, with a broad range of baseline bone mineral density (BMD) levels. All patients in these studies received supplemental calcium 1000 mg/ day. Patients with low vitamin D levels (approximately 40 nmol/ L or less) also received supplemental vitamin D 500 IU/ day. Positive effects of ACTONEL treatment on BMD were also demonstrated in each of 2 large, randomized, placebo-controlled trials (BMD MN and BMD NA) in which almost 1200 postmenopausal women (ACTONEL 5 mg, n = 394) were recruited on the basis of low lumbar spine bone mass (more than 2 SD below the premenopausal mean) rather than a history of vertebral fracture. ACTONEL 35-mg once a week (n = 485) was shown to be therapeutically equivalent to ACTONEL 5-mg daily (n = 480) in a 1-year, double-blind, multicenter study of postmenopausal women with osteoporosis. In the primary efficacy analysis of completers, the mean increases from baseline in lumbar spine BMD at 1 year were 4. 0% (3. 7, 4. 3; 95% confidence interval [CI]) in the 5-mg daily group (n = 391) and 3.9% (3. 6, 4. 3; 95% CI) in the 35-mg once a week group (n = 387) and the mean difference between 5 mg daily and 35 mg weekly was 0.1%(-0. 42, 0.55;
95% CI). The results of the intent-to-treat analysis with the last observation carried forward were consistent with the primary efficacy analysis of completers. The 2 treatment groups were also similar with regard to BMD increases at other skeletal sites. The safety and efficacy of once weekly ACTONEL 35 mg in women without osteoporosis are currently being studied, but data are not yet available. Effect on Vertebral Fractures: Fractures of previously undeformed vertebrae (new fractures) and worsening of pre-existing vertebral fractures were diagnosed radiographically; some of these fractures were also associated with symptoms (i. e., clinical fractures). Spinal radiographs were scheduled annually and prospectively planned analyses were based on the time to a patient's first diagnosed fracture. The primary endpoint for these studies was the incidence of new and worsening vertebral fractures across the period of 0 to 3 years. ACTONEL 5 mg daily significantly reduced the incidence of new and worsening vertebral fractures and of new vertebral fractures in both VERT NA and VERT MN at all time points (Table 1). The reduction in risk seen in the subgroup of patients who had 2 or more vertebral fractures at study entry was similar to that seen in the overall study population. Table 1 The Effect of ACTONEL on the Risk of Vertebral Fractures
Proportion of Patients
with Fracture (%) a VERT NA
Placebo
n = 678
ACTONEL 5 mg
n = 696
Absolute Risk
Reduction (%)
Relative Risk
Reduction (%)
New and Worsening
0 -1 Year 7.2 3.9 3.3 49
0 -2 Years 12.8 8.0 4.8 42
0 -3 Years 18.5 13.9 4.6 33
New
0 -1 Year 6.4 2.4 4.0 65
0 -2 Years 11.7 5.8 5.9 55
0 -3 Years 16.3 11.3 5.0 41 VERT MN
Placebo
n = 346
ACTONEL 5 mg
n = 344
Absolute Risk
Reduction (%)
Relative Risk
Reduction (%)
New and Worsening
0 -1 Year 15.3 8.2 7.1 50
0 -2 Years 28.3 13.9 14.4 56
0 -3 Years 34.0 21.8 12.2 46
New
0 -1 Year 13.3 5.6 7.7 61
0 -2 Years 24.7 11.6 13.1 59
0 -3 Years 29.0 18.1 10.9 49 a Calculated by Kaplan-Meier methodology. Effect on Osteoporosis-Related Nonvertebral Fractures: In VERT MN and VERT NA, a prospectively planned efficacy endpoint was defined consisting of all radiographically confirmed fractures of skeletal sites accepted as associated with osteoporosis. Fractures at these sites were collectively referred to as osteoporosis-related nonvertebral fractures. ACTONEL 5 mg daily significantly reduced the incidence of nonvertebral osteoporosis-related fractures over 3 years in VERT NA (8% vs. 5%; relative risk reduction 39%) and reduced the fracture incidence in VERT MN from 16% to 11%. There was a significant reduction from 11% to 7% when the studies were combined, with a corresponding 36% reduction in relative risk. Figure 1 shows the overall results as well as the results at the individual skeletal sites for the combined studies. Placebo ACTONEL 5 mg
0
2
4
6
8
10
12 All Wrist
Humerus Hip Pelvis Clavicle
%
of
Patients
Leg Figure 1 Nonvertebral Osteoporosis-Related Fractures
Cumulative Incidence Over 3 Years Combined VERT MN and VERT NA
Effect on Height: In the two 3-year osteoporosis treatment studies, standing height was measured yearly by stadiometer. Both ACTONEL and placebo-treated groups lost height during the studies.
Patients who received ACTONEL had a statistically significantly smaller loss of height than those who received placebo. In VERT MN, the median annual height change was -1. 3 mm/ yr in the ACTONEL 5-mg daily group compared to -2. 4 mm/ yr in the placebo group. In VERT NA, the median annual height change was -0. 7 mm/ yr in the ACTONEL 5-mg daily group compared to -1. 1 mm/ yr in the placebo group.
Effect on Bone Mineral Density: The results of 4 randomized, placebo-controlled trials in women with postmenopausal osteoporosis (VERT MN, VERT NA, BMD MN, BMD NA) demonstrate that ACTONEL 5 mg daily increases BMD at the spine, hip, and wrist compared to the effects seen with placebo. Table 2 displays the significant increases in BMD seen at the lumbar spine, femoral neck, femoral trochanter, and midshaft radius in these trials compared to placebo. Thus, overall ACTONEL reverses the loss of BMD, a central factor in the progression of osteoporosis. In both VERT studies (VERT MN and VERT NA), ACTONEL 5 mg daily produced increases in lumbar spine BMD that were progressive over the 3 years of treatment, and were statistically significant relative to baseline and to placebo at 6 months and at all later time points. Table 2 Mean Percent Increase in BMD from Baseline in Patients
Taking ACTONEL 5 mg or Placebo at Endpoint a
VERT MN b VERT NA b BMD MN c BMD NA c
Placebo
n = 323
5 mg
n = 323
Placebo
n = 599
5 mg
n = 606
Placebo
n = 161
5 mg
n = 148
Placebo
n = 191
5 mg
n = 193
Lumbar Spine 1.0 6.6 0.8 5.0 0.0 4.0 0.2 4.8
Femoral Neck -1.4 1.6 -1.0 1.4 -1.1 1.3 0.1 2.4
Femoral
Trochanter
-1.9 3.9 -0.5 3.0 -0.6 2.5 1.3 4.0
Midshaft Radius -1.5* 0.2* -1.2* 0.1* ND ND a
The endpoint value is the value at the study's last time point for all patients who had BMD measured at that time; otherwise the last postbaseline BMD value prior to the study's last time point is used. b
The duration of the studies was 3 years. c
The duration of the studies was 1. 5 to 2 years.
* BMD of the midshaft radius was measured in a subset of centers in VERT MN (placebo, n = 222;
5 mg, n = 214) and VERT NA (placebo, n = 310; 5 mg, n = 306)
ND = analysis not done
Histology/ Histomorphometry: Bone biopsies from 110 postmenopausal women were obtained at endpoint. Patients had received daily ACTONEL (2. 5 mg or 5 mg) or placebo for 2 to 3 years. Histologic evaluation (n
= 103) showed no osteomalacia, impaired bone mineralization, or other adverse effects on bone in ACTONEL-treated women. These findings demonstrate that bone formed during ACTONEL administration is of normal quality. The histomorphometric parameter mineralizing surface, an index of bone turnover, was assessed based upon baseline and post-treatment biopsy samples from 23 patients treated with ACTONEL 5 mg and 21 treated with placebo. Mineralizing surface decreased moderately in ACTONEL-treated patients (median percent change: ACTONEL 5 mg, -74%; placebo, -21%), consistent with the known effects of treatment on bone turnover.
Prevention of Osteoporosis in Postmenopausal Women: ACTONEL 5 mg daily prevented bone loss in a majority of postmenopausal women (age range 42 to 63 years) within 3 years of menopause in a 2-year, double-blind, placebo-controlled study in 383 patients (ACTONEL 5 mg, n = 129). All patients in this study received supplemental calcium 1000 mg/ day. Increases in BMD were observed as early as 3 months following initiation of ACTONEL treatment. ACTONEL 5 mg produced significant mean increases in BMD at the lumbar spine, femoral neck, and trochanter compared to placebo at the end of the study (Figure 2). ACTONEL 5 mg daily was also effective in patients with lower baseline lumbar spine BMD (more than 1 SD below the premenopausal mean) and in those with normal baseline lumbar spine BMD. Bone mineral density at the distal radius decreased in both ACTONEL and placebo-treated women following 1 year of treatment. Figure 2 Change in BMD from Baseline
2-Year Prevention Study -3
-2
-1
0
1
2
3
4 Placebo ACTONEL 5 mg BMD
( Mean % Change ± SE) Lumbar Spine Femoral Neck Femoral Trochanter 5
n = 92 n = 91 n = 91
n = 101
n = 103 n = 103 -4
Combined Administration with Hormone Replacement Therapy: The effects of combining ACTONEL 5 mg daily with conjugated estrogen 0.625 mg daily (n = 263) were compared to the effects of conjugated estrogen alone (n = 261) in a 1-year, randomized, double-blind study of women ages 37 to 82 years, who were on average 14 years postmenopausal. The BMD results for this study are presented in Table 3. Table 3 Percent Change from Baseline in BMD
After 1 Year of Treatment
Estrogen 0.625 mg
n = 261 ACTONEL 5 mg +
Estrogen 0.625 mg
n = 263
Lumbar Spine 4.6 + 0.20 5.2 + 0.23
Femoral Neck 1. 8 + 0.25 2.7 + 0.25
Femoral Trochanter 3.2 + 0.28 3.7 + 0.25
Midshaft Radius 0.4 + 0.14 0.7 + 0.17
Distal Radius 1.7 + 0.24 1.6 + 0.28
Values shown are mean (+ SEM) percent change from baseline. Histology/ Histomorphometry: Bone biopsies from 53 postmenopausal women were obtained at endpoint. Patients had received ACTONEL 5 mg plus estrogen or estrogen alone once daily for 1 year. Histologic evaluation (n = 47) demonstrated that the bone of patients treated with ACTONEL plus estrogen was of normal lamellar structure and normal mineralization. The histomorphometric parameter mineralizing surface, a measure of bone turnover, was assessed based upon baseline and post-treatment biopsy samples from 12 patients treated with ACTONEL plus estrogen and 12 treated with estrogen alone. Mineralizing surface decreased in both treatment groups (median percent change: ACTONEL plus estrogen, -79%; estrogen alone, -50%), consistent with the known effects of these agents on bone turnover. Glucocorticoid-Induced Osteoporosis: Bone Mineral Density: Two 1-year, double-blind, placebo-controlled trials in patients who were taking prednisone or equivalent demonstrated that ACTONEL 5 mg once daily was effective in the prevention and treatment of glucocorticoid-induced osteoporosis in men and women who were either initiating or continuing glucocorticoid therapy. The prevention study enrolled 228 patients (ACTONEL 5 mg, n = 76) (18 to 85 years of age), each of whom had initiated glucocorticoid therapy (mean daily dose of prednisone 21 mg) within the previous 3 months (mean duration of use prior to study 1.8 months) for rheumatic, skin, and pulmonary diseases. The mean lumbar spine BMD was normal at baseline (average T score 0.684). All patients in this study received supplemental calcium 500 mg/ day. By the third month of treatment, and continuing through the year-long treatment, the placebo group experienced losses in BMD at the lumbar spine, femoral neck, and trochanter, while BMD was maintained or increased in the ACTONEL 5-mg group. At each skeletal site there were statistically significant differences between the ACTONEL 5-mg group and the placebo group at all timepoints (Months 3, 6, 9, and 12). The treatment differences increased with continued treatment. Although BMD increased at the distal radius in the ACTONEL 5-mg group compared to the placebo group, the difference was not statistically significant. The differences between placebo and ACTONEL 5 mg after 1 year were 3.8% at the lumbar spine, 4.1% at the femoral neck, and 4.6% at the trochanter, as shown in Figure 3. The results at these skeletal sites were similar to the overall results when the subgroups of men and postmenopausal women, but not premenopausal women, were analyzed separately. ACTONEL was effective at the lumbar spine, femoral neck, and trochanter regardless of age (< 65 vs. glucocorticoid dose, or baseline BMD. Positive treatment effects were also observed in patients taking glucocorticoids for a broad range of rheumatologic disorders, the most common of which were rheumatoid arthritis, temporal arteritis, and polymyalgia rheumatica. The treatment study of similar design enrolled 290 patients (ACTONEL 5 mg, n = 100) (19 to 85 years of age) with continuing, long-term use prior to study 60 months; mean daily dose of prednisone 15 mg) for rheumatic, skin, and pulmonary diseases. The baseline mean lumbar spine BMD was low (1. 63 SD below the young healthy population mean), with 28% of the patients more than 2. 5 SD below the mean. All patients in this study received supplemental calcium 1000 mg/ day and vitamin D 400 IU/ day. After 1 year of treatment, the BMD of the placebo group was within ±1% of baseline levels at the lumbar spine, femoral neck, and trochanter. ACTONEL 5 mg increased BMD at the lumbar spine (2. 9%), femoral neck (1. 8%), and trochanter (2. 4%). The differences between ACTONEL and placebo were 2.7% at the lumbar spine, 1.9% at the femoral neck, and 1.6% at the trochanter as shown in Figure 4. The differences were statistically significant for the lumbar spine and femoral neck, but not at the femoral trochanter. ACTONEL was similarly effective on lumbar
spine BMD regardless of age (< 65 vs. study glucocorticoid dose. Positive treatment effects were also observed in patients taking glucocorticoids for a broad range of rheumatologic disorders, the most common of which were rheumatoid arthritis, temporal arteritis, and polymyalgia rheumatica. Figure 3 Change in BMD from Baseline
Patients Recently Initiating Glucocorticoid Therapy -4
-3
-2
-1
0
1
2
3
4
Placebo ACTONEL 5 mg BMD ( Mean % Change ± SE) Lumbar Spine Femoral Neck Femoral Trochanter
n = 52
n = 60
n = 56 n = 58
n = 56 n = 58 -1
0 1
2
3
4
5 Figure 4 Change in BMD from Baseline
Patients on Long-Term Glucocorticoid Therapy BMD ( Mean % Change ± SE) Lumbar Spine Femoral Neck Femoral Trochanter
Placebo ACTONEL 5 mg
n = 66
n = 77
n = 77 n = 79 n = 67 n = 67 Vertebral Fractures: In the prevention study of patients initiating glucocorticoids, the incidence of vertebral fractures at 1 year was reduced from 17% in the placebo group to 6% in the ACTONEL group. In the treatment study of patients continuing glucocorticoids, the incidence of vertebral fractures was reduced from 15% in the placebo group to 5% in the ACTONEL group (Figure 5). The statistically significant reduction in vertebral fracture incidence in the analysis of the combined studies corresponded to an absolute risk reduction of 11% and a relative risk reduction of 70%. All vertebral fractures were diagnosed radiographically; some of these fractures also were associated with symptoms (i. e., clinical fractures). Placebo ACTONEL 5 mg
0
6
12
18 Incidence ( % ) Patients Continuing
Glucocorticoid Treatment
Patients Initiating
Glucocorticoid Treatment
Combined Figure 5 Incidence of Vertebral Fractures in Patients
Initiating or Continuing Glucocorticoid Therapy n= 59 n= 58 n= 53 n= 52 n= 111
n= 111 24 Histology/ Histomorphometry: Bone biopsies from 40 patients on glucocorticoid therapy were obtained at endpoint. Patients had received daily ACTONEL (2. 5 mg or 5 mg) or placebo for 1 year. Histologic evaluation (n = 33) showed that bone formed during treatment with ACTONEL was of normal lamellar structure and normal mineralization, with no bone or marrow abnormalities observed. The histomorphometric parameter mineralizing surface, a measure of bone turnover, was assessed based upon baseline and post-treatment biopsy samples from 10 patients treated with ACTONEL 5 mg. Mineralizing surface decreased 24% (median percent change) in these patients. Only a small number of placebo-treated patients had both baseline and post-treatment biopsy samples, precluding a meaningful quantitative assessment. Treatment of Paget's Disease: The efficacy of ACTONEL was demonstrated in 2 clinical studies involving 120 men and 65 women. In a double-blind, active-controlled study of patients with moderate-to-severe Paget's disease (serum alkaline phosphatase levels of at least 2 times the upper limit of normal), patients were treated with ACTONEL 30 mg daily for 2 months or Didronel ® (etidronate disodium) 400 mg/ day for 6 months. At Day 180, 77% (43/ 56) of ACTONEL-treated patients achieved normalization of serum alkaline phosphatase levels, compared to 10. 5% (6/ 57) of patients treated with Didronel (p< 0.001). At Day 540, 16 months after discontinuation of therapy, 53% (17/ 32) of ACTONEL-treated patients and 14% (4/ 29) of Didronel-treated patients with available data remained in biochemical remission. During the first 180 days of the active-controlled study, 85% (51/ 60) of ACTONEL-treated patients demonstrated a (difference between measured level and midpoint of the normal range) with 2 months of treatment compared to 20% (12/ 60) in the Didronel-treated group with 6 months of treatment (p< 0.001). Changes in serum alkaline phosphatase excess over time (shown in Figure 6) were significant following only 30 days of treatment, with a 36% reduction in serum alkaline phosphatase excess at that time compared to only a 6% reduction seen with Didronel treatment at the same time point (p< 0. 01). -120
-100
-80
-60
-40
-20
0
20 0 60 120 180 240 300 360 420 480 540 600
Visit Days Treatment Follow-Up Extended Follow-Up n = 29
n = 56
n = 32 n = 50 n = 53 Percentage ( % ) n = 57 ACTONEL 30 mg DIDRONEL 400 mg
Figure 6 Mean Percent Change from Baseline in
Serum Alkaline Phosphatase Excess by Visit Response to ACTONEL therapy was similar in patients with mild to very severe Paget's disease.
Table 4 shows the mean percent reduction from baseline at Day 180 in excess serum alkaline phosphatase in patients with mild, moderate, or severe disease. Table 4 Mean Percent Reduction from Baseline at Day 180 in
Total Serum Alkaline Phosphatase Excess by Disease Severity
ACTONEL 30 mg DIDRONEL 400 mg
Subgroup:
Baseline Disease
Severity (AP) n Baseline
Serum
AP (U/ L)*
Mean %
Reduction n Baseline
Serum
AP (U/ L)*
Mean %
Reduction
>2, <3x ULN 32 271.6 + 5. 3 -88.1 22 277.9 + 7. 45 -44.6
>3, <7x ULN 14 475.3 + 28. 8 -87.5 25 480.5 + 26. 44 -35.0
>7x ULN 8 1336.5 + 134.19 -81.8 6 1331.5 + 167.58 -47.2
*Values shown are mean + SEM; ULN = upper limit of normal. Response to ACTONEL therapy was similar between patients who had previously received anti-pagetic therapy and those who had not. In the active-controlled study, 4 patients previously non-responsive to 1 or more courses of anti-pagetic therapy (calcitonin, Didronel) responded to treatment with ACTONEL 30 mg daily (defined by at least a 30% change from baseline). Each of these patients achieved at least 90% reduction from baseline in serum alkaline phosphatase excess, with 3 patients achieving normalization of serum alkaline phosphatase levels. Histomorphometry of the bone was studied in 14 patients with bone biopsies: 9 patients had biopsies from pagetic bone lesions and 5 patients from non-pagetic bone. Bone biopsy results in non-pagetic bone did not reveal osteomalacia, impairment of bone remodeling, or induction of a
significant decline in bone turnover in patients treated with ACTONEL. ANIMAL PHARMACOLOGY AND/ OR TOXICOLOGY Risedronate demonstrated potent anti-osteoclast, antiresorptive activity in ovariectomized rats and minipigs. Bone mass and biomechanical strength were increased dose-dependently at oral doses up to 4 and 25 times the human recommended oral dose of 5 mg based on surface area, (mg/ m 2 ) for rats and minipigs, respectively. Risedronate treatment maintained the positive correlation between BMD and bone strength and did not have a negative effect on bone structure or mineralization. In intact dogs, risedronate induced positive bone balance at the level of the bone remodeling unit at oral doses ranging from 0.35 to 1. 4 times the human 5-mg dose based on surface area (mg/ m 2 ). In dogs treated with an oral dose of 1 mg/ kg/ day (approximately 5 times the human 5-mg dose based on surface area, mg/ m 2 ), risedronate caused a delay in fracture healing of the radius. The observed delay in fracture healing is similar to other bisphosphonates. This effect did not occur at a dose of 0.1 mg/ kg/ day (approximately 0.5 times the human 5-mg dose based on surface area, mg/ m 2 ). The Schenk rat assay, based on histologic examination of the epiphyses of growing rats after drug treatment, demonstrated that risedronate did not interfere with bone mineralization even at the highest dose tested (5 mg/ kg/ day, subcutaneously), which was approximately 3500 times the lowest antiresorptive dose (1. 5 mcg/ kg/ day in this model) and approximately 8 times the human 5-mg dose based on surface area (mg/ m 2 ). This indicates that ACTONEL administered at the therapeutic dose is unlikely to induce osteomalacia. Page: << Prev | 1 | 2 | 3 | 4 | 5
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