Mechanism of Action
ACTONEL has an affinity for hydroxyapatite crystals in bone and acts as an antiresorptive agent. At the cellular level, ACTONEL inhibits osteoclasts. The osteoclasts adhere normally to the bone surface, but show evidence of reduced active resorption (e.g., lack of ruffled border). Histomorphometry in rats, dogs, and minipigs showed that ACTONEL treatment reduces bone turnover (activation frequency, i.e., the rate at which bone remodeling sites are activated) and bone resorption at remodeling sites.
ACTONEL treatment decreases the elevated rate of bone turnover that is typically seen in postmenopausal osteoporosis. In clinical trials, administration of ACTONEL to postmenopausal women resulted in decreases in biochemical markers of bone turnover, including urinary deoxypyridinoline/creatinine and urinary collagen cross-linked N-telopeptide (markers of bone resorption) and serum bone-specific alkaline phosphatase (a marker of bone formation). At the 5 mg dose, decreases in deoxypyridinoline/creatinine were evident within 14 days of treatment. Changes in bone formation markers were observed later than changes in resorption markers, as expected, due to the coupled nature of bone resorption and bone formation; decreases in bone-specific alkaline phosphatase of about 20% were evident within 3 months of treatment. Bone turnover markers reached a nadir of about 40% below baseline values by the sixth month of treatment and remained stable with continued treatment for up to 3 years. Bone turnover is decreased as early as 14 days and maximally within about 6 months of treatment, with achievement of a new steady-state that more nearly approximates the rate of bone turnover seen in premenopausal women. In a 1-year study comparing daily versus weekly oral dosing regimens of ACTONEL for the treatment of osteoporosis in postmenopausal women, ACTONEL 5 mg daily and ACTONEL 35 mg once-a-week decreased urinary collagen cross-linked N-telopeptide by 60% and 61%, respectively. In addition, serum bone-specific alkaline phosphatase was also reduced by 42% and 41% in the ACTONEL 5 mg daily and ACTONEL 35 mg once-a-week groups, respectively. When postmenopausal women with osteoporosis were treated for 1 year with ACTONEL 5 mg daily or ACTONEL 75 mg two consecutive days per month, urinary collagen cross-linked N-telopeptide was decreased by 54% and 52%, respectively, and serum bone-specific alkaline phosphatase was reduced by 36% and 35%, respectively. In a 1–year study comparing ACTONEL 5 mg daily versus ACTONEL 150 mg once a month in women with postmenopausal osteoporosis, urinary collagen cross-linked N-telopeptide was decreased by 52% and 49%, respectively, and serum bone-specific alkaline phosphatase was reduced by 31% and 32%, respectively.
Osteoporosis in Men
In a 2-year study of men with osteoporosis, treatment with ACTONEL 35 mg once-a-week resulted in a mean decrease from baseline compared to placebo of 16% (placebo 20%; ACTONEL 35 mg 37%) for the bone resorption marker urinary collagen cross-linked N-telopeptide, 45% (placebo -6%; ACTONEL 35 mg 39%) for the bone resorption marker serum C-telopeptide, and 27% (placebo -2%; ACTONEL 35 mg 25%) for the bone formation marker serum bone-specific alkaline phosphatase.
Osteoporosis with glucocorticoid use 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.
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.
In pagetic patients treated with ACTONEL 30 mg daily 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).
Based on simultaneous modeling of serum and urine data, absorption after an oral dose is relatively rapid (tmax ~1 hour) and occurs throughout the upper gastrointestinal tract. The fraction of the dose absorbed is independent of dose over the range studied (single dose, from 2.5 mg to 30 mg; multiple dose, from 2.5 mg to 5 mg). Steady-state conditions in the serum are observed within 57 days of daily dosing. Mean absolute oral bioavailability of the 30 mg tablet is 0.63% (90% CI: 0.54% to 0.75%) and is comparable to a solution. The extent of absorption of a 30 mg dose (three 10 mg tablets) when administered 0.5 hours before breakfast is reduced by 55% compared to dosing in the fasting state (no food or drink for 10 hours prior to or 4 hours after dosing). Dosing 1 hour prior to breakfast reduces the extent of absorption by 30% compared to dosing in the fasting state. Dosing either 0.5 hours prior to breakfast or 2 hours after dinner (evening meal) results in a similar extent of absorption. ACTONEL is effective when administered at least 30 minutes before breakfast.
The mean steady-state volume of distribution for risedronate is 13.8 L/kg in humans. Human plasma protein binding of drug is about 24%. Preclinical studies in rats and dogs dosed intravenously with single doses of [14C] risedronate indicate that approximately 60% of the dose is distributed to bone. The remainder of the dose is excreted in the urine. After multiple oral dosing in rats, the uptake of risedronate in soft tissues was in the range of 0.001% to 0.01%.
There is no evidence of systemic metabolism of risedronate.
In young healthy subjects, approximately half of the absorbed dose of risedronate was excreted in urine within 24 hours, and 85% of an intravenous dose was recovered in the urine over 28 days. Based on simultaneous modeling of serum and urine data, mean renal clearance was 105 mL/min (CV = 34%) and mean total clearance was 122 mL/min (CV = 19%), with the difference primarily reflecting nonrenal clearance or clearance due to adsorption to bone. The renal clearance is not concentration dependent, and there is a linear relationship between renal clearance and creatinine clearance. Unabsorbed drug is eliminated unchanged in feces. In osteopenic postmenopausal women, the terminal exponential half-life was 561 hours, mean renal clearance was 52 mL/min (CV=25%), and mean total clearance was 73 mL/min (CV=15%).
Pediatric: Risedronate pharmacokinetics have not been studied in pediatric patients (<18 years of age).
Gender: Bioavailability and pharmacokinetics following oral administration are similar in men and women.
Geriatric: Bioavailability and disposition are similar in elderly (>60 years of age) and younger subjects. No dosage adjustment is necessary.
Race: Pharmacokinetic differences due to race have not been studied.
Renal Insufficiency: Risedronate is excreted unchanged primarily via the kidney. As compared to persons with normal renal function, the renal clearance of risedronate was decreased by about 70% in patients with creatinine clearance of approximately 30 mL/min. ACTONEL is not recommended for use in patients with severe renal impairment (creatinine clearance <30 mL/min) because of lack of clinical experience. No dosage adjustment is necessary in patients with a creatinine clearance ≥30 mL/min.
Hepatic Insufficiency: No studies have been performed to assess risedronate's safety or efficacy in patients with hepatic impairment. Risedronate is not metabolized in rat, dog, and human liver preparations. Insignificant amounts (<0.1% of intravenous dose) of drug are excreted in the bile in rats. Therefore, dosage adjustment is unlikely to be needed in patients with hepatic impairment.
Carcinogenesis, Mutagenesis, Impairment of Fertility
In a 104-week carcinogenicity study, rats were administered daily oral doses up to 24 mg/kg/day (approximately 7.7 times the maximum recommended human daily dose of 30 mg based on surface area, mg/m2). There were no significant drug-induced tumor findings in male or female rats. The high dose male group of 24 mg/kg/day was terminated early in the study (Week 93) due to excessive toxicity, and data from this group were not included in the statistical evaluation of the study results. In an 80-week carcinogenicity study, mice were administered daily oral doses up to 32 mg/kg/day (approximately 6.4 times the 30 mg/day human dose based on surface area, mg/m2). There were no significant drug-induced tumor findings in male or female mice.
Risedronate did not exhibit genetic toxicity in the following assays: In vitro bacterial mutagenesis in Salmonella and E. coli (Ames assay), mammalian cell mutagenesis in CHO/HGPRT assay, unscheduled DNA synthesis in rat hepatocytes and an assessment of chromosomal aberrations in vivo in rat bone marrow. Risedronate was positive in a chromosomal aberration assay in CHO cells at highly cytotoxic concentrations (>675 mcg/mL, survival of 6% to 7%). When the assay was repeated at doses exhibiting appropriate cell survival (29%), there was no evidence of chromosomal damage.
Impairment of Fertility
In female rats, ovulation was inhibited at an oral dose of 16 mg/kg/day (approximately 5.2 times the 30 mg/day human dose based on surface area, mg/m2). Decreased implantation was noted in female rats treated with doses ≥7 mg/kg/day (approximately 2.3 times the 30 mg/day human dose based on surface area, mg/m2). In male rats, testicular and epididymal atrophy and inflammation were noted at 40 mg/kg/day (approximately 13 times the 30 mg/day human dose based on surface area, mg/m2). Testicular atrophy was also noted in male rats after 13 weeks of treatment at oral doses of 16 mg/kg/day (approximately 5.2 times the 30 mg/day human dose based on surface area, mg/m2). There was moderate-to-severe spermatid maturation block after 13 weeks in male dogs at an oral dose of 8 mg/kg/day (approximately 8 times the 30 mg/day human dose based on surface area, mg/m2). These findings tended to increase in severity with increased dose and exposure time.
Animal Toxicology and/or Pharmacology
Risedronate demonstrated potent anti-osteoclast, antiresorptive activity in ovariectomized rats and minipigs. Bone mass and biomechanical strength were increased dose-dependently at daily oral doses up to 4 and 25 times the human recommended oral dose of 5 mg based on surface area (mg/m2) 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 daily dose of 5 mg based on surface area (mg/m2).
In dogs treated with an oral dose of 1 mg/kg/day (approximately 5 times the human daily dose of 5 mg based on surface area, mg/m2), 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 daily dose of 5 mg based on surface area, mg/m2).
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 in this model (1.5 mcg/kg/day) and approximately 800 times the human daily dose of 5 mg based on surface area (mg/m2). This indicates that ACTONEL administered at the therapeutic dose is unlikely to induce osteomalacia.
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 BMD levels. All patients in these studies received supplemental calcium 1000 mg/day. Patients with low 25-hydroxyvitamin D3 levels (approximately 40 nmol/L or less) also received supplemental vitamin D 500 IU/day.
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 3). 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 3 The Effect of ACTONEL on the Risk of Vertebral Fractures
|Proportion of Patients|
with Fracture (%)a
a Calculated by Kaplan-Meier methodology.
n = 678
|ACTONEL 5 mg|
n = 696
|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|
| 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|
n = 346
|ACTONEL 5 mg|
n = 344
|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|
| 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|
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.
Figure 1 Nonvertebal Osteoporosis-Related Fractures Cumulative Incidence Over 3 Years Combined VERT MN and VERT NA
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 4 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 4 Mean Percent Increase in BMD from Baseline in Patients Taking ACTONEL 5 mg or Placebo at Endpointa
|VERT MNb||VERT NAb||BMD MNc||BMD NAc|
n = 323
n = 323
n = 599
n = 606
n = 161
n = 148
n = 191
n = 193
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 post-baseline 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
ACTONEL 35 mg once-a-week (n = 485) was shown to be non-inferior 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 once-a-week was 0.1% (-0.4, 0.6; 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.
In a double-blind, multicenter study of postmenopausal women with osteoporosis, treatment with ACTONEL 75 mg two consecutive days per month (n = 616) was shown to be non-inferior to ACTONEL 5 mg daily (n = 613). In the primary efficacy analysis of completers, the mean increases from baseline in lumbar spine BMD at 1 year were 3.6% (3.3, 3.9; 95% CI) in the 5 mg daily group (n = 527) and 3.4% (3.1, 3.7; 95% CI) in the 75 mg two days per month group (n = 524) with a mean difference between groups being 0.2% (-0.2, 0.6; 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.
ACTONEL 150 mg once-a-month (n = 650) was shown to be non-inferior to ACTONEL 5 mg daily (n = 642) in a 1-year, double-blind, multicenter study of postmenopausal women with osteoporosis. The primary efficacy analysis was conducted in all randomized patients with baseline and post-baseline lumbar spine BMD values (modified intent-to-treat population) using last observation carried forward. The mean increases from baseline in lumbar spine BMD at 1 year were 3.4% (3.0, 3.8; 95% CI) in the 5 mg daily group (n = 561), and 3.5% (3.1, 3.9; 95% CI) in the 150 mg once-a-month group (n = 578) with a mean difference between groups being -0.1% (-0.5, 0.3; 95% CI). The results of the completers analysis were consistent with the primary efficacy analysis. The 2 treatment groups were also similar with regard to BMD increases at other skeletal sites.
Bone biopsies from 110 postmenopausal women were obtained at endpoint. Patients had received placebo or daily ACTONEL (2.5 mg or 5 mg) 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 21 treated with placebo and 23 patients treated with ACTONEL 5 mg. Mineralizing surface decreased moderately in ACTONEL-treated patients (median percent change: placebo, -21%; ACTONEL 5 mg, -74%), consistent with the known effects of treatment on bone turnover.
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 -2.4 mm/yr in the placebo group compared to -1.3 mm/yr in the ACTONEL 5 mg daily group. In VERT NA, the median annual height change was -1.1 mm/yr in the placebo group compared to -0.7 mm/yr in the ACTONEL 5 mg daily group.
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 daily 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
ACTONEL 35 mg once-a-week prevented bone loss in postmenopausal women (age range 44 to 64 years) without osteoporosis in a 1-year, double-blind, placebo-controlled study in 278 patients (ACTONEL 35 mg, n = 136). All patients were supplemented with 1000 mg elemental calcium and 400 IU vitamin D per day. The primary efficacy measure was the percent change in lumbar spine BMD from baseline after 1 year of treatment using LOCF (last observation carried forward). ACTONEL 35 mg once-a-week resulted in a statistically significant mean difference from placebo in lumbar spine BMD of +2.9% (least square mean for placebo -1.05%; risedronate +1.83%). ACTONEL 35 mg once-a-week also showed a statistically significant mean difference from placebo in BMD at the total proximal femur of +1.5% (placebo -0.53%; risedronate +1.01%), femoral neck of +1.2% (placebo -1.00%; risedronate +0.22%), and trochanter of +1.8% (placebo -0.74%; risedronate +1.07%).
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 5.
Table 5 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
Values shown are mean (± SEM) percent change from baseline.
|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|
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.
Men with Osteoporosis
The effects of ACTONEL 35 mg once-a-week on BMD were examined in a 2-year, double-blind, placebo-controlled, multinational study in 285 men with osteoporosis (ACTONEL, n = 192). The patients had a mean age of 60.6 years (range 36 to 84 years) and 95% were Caucasian. At baseline, mean lumbar spine T-score was -3.2 and mean femoral neck T-score was -2.4. All patients in the study had either, 1) a BMD T-score ≤-2 at the femoral neck and ≤-1 at the lumbar spine, or 2) a BMD T-score ≤-1 at the femoral neck and ≤-2.5 at the lumbar spine. All patients were supplemented with calcium 1000 mg/day and vitamin D 400 to 500 IU/day. ACTONEL 35 mg once-a-week produced significant mean increases in BMD at the lumbar spine, femoral neck, trochanter, and total hip compared to placebo after 2 years of treatment (treatment difference: lumbar spine, 4.5%; femoral neck, 1.1%; trochanter, 2.2%; total proximal femur, 1.5%).
Bone Mineral Density
Two 1-year, double-blind, placebo-controlled trials in patients who were taking ≥7.5 mg/day of prednisone or equivalent demonstrated that ACTONEL 5 mg 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 efficacy of ACTONEL therapy for glucocorticoid-induced osteoporosis beyond one year has not been studied.
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 -0.7). 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 placebo group and the ACTONEL 5 mg 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. ≥65), gender, prior and concomitant 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 (≥6 months) use of glucocorticoids (mean duration of 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. ≥65), gender, or pre-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
Figure 4 Change in BMD from Baseline Patients on Long-Term Glucocorticoid Therapy
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).
Figure 5 Incidence of Vertebral Fractures in Patients Initiating or Continuing Glucocorticoid Therapy
Bone biopsies from 40 patients on glucocorticoid therapy were obtained at endpoint. Patients had received placebo or daily ACTONEL (2.5 mg or 5 mg) 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 daily 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 ≥75% reduction from baseline in serum alkaline phosphatase excess (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).
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 6 shows the mean percent reduction from baseline at Day 180 in excess serum alkaline phosphatase in patients with mild, moderate, or severe disease.
Table 6 Mean Percent Reduction from Baseline at Day 180 in Total Serum Alkaline Phosphatase Excess by Disease Severity
|ACTONEL 30 mg||DIDRONEL 400 mg|
|Mean % Reduction||n||Baseline|
|Mean % Reduction|
*Values shown are mean± SEM; ULN = upper limit of normal.
|>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|
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.