Risedronate sodium tablets are a pyridinyl bisphosphonate that inhibits osteoclast-mediated bone resorption and modulates bone metabolism. Each Risedronate sodium tablet for oral administration contains the equivalent of 5, 30, or 35 mg of anhydrous Risedronate sodium in the form of the monohydrate. The chemical name of Risedronate sodium is [1-hydroxy-2-(3-pyridinyl)ethylidene]bis[phosphonic acid] monosodium salt. The chemical structure of Risedronate sodium monohydrate is the following:
C7H10NO7P2 Na·H2O M.W. Monohydrate: 323.10
Risedronate sodium monohydrate is a white to off-white powder. It is soluble in water and in aqueous solutions, and essentially insoluble in common organic solvents.
Inactive Ingredients
Colloidal silicon dioxide, D&C yellow #10 lake (5 mg tablets only), FD&C yellow #6 aluminum lake (35 mg tablets only), hypromellose, iron oxide red (35 mg tablets only), iron oxide yellow (5 and 35 mg tablets only), lactose monohydrate, magnesium stearate, polyethylene glycol, polysorbate 80, pregelatinized starch, sodium stearyl fumarate, starch, and titanium dioxide.
Risedronate - Clinical Pharmacology
Mechanism of Action
Risedronate has an affinity for hydroxyapatite crystals in bone and acts as an antiresorptive agent. At the cellular level, Risedronate 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 Risedronate treatment reduces bone turnover (activation frequency, i.e., the rate at which bone remodeling sites are activated) and bone resorption at remodeling sites.
Pharmacokinetics
Absorption
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 to 30 mg; multiple dose, from 2.5 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. Risedronate is effective when administered at least 30 minutes before breakfast.
Distribution
The mean steady-state volume of distribution is 6.3 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%.
Metabolism
There is no evidence of systemic metabolism of Risedronate.
Elimination
Approximately half of the absorbed dose is excreted in urine within 24 hours, and 85% of an intravenous dose is recovered in the urine over 28 days. Mean renal clearance is 105 mL/min (CV = 34%) and mean total clearance is 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. Once Risedronate is absorbed, the serum concentration-time profile is multi-phasic, with an initial half-life of about 1.5 hours and a terminal exponential half-life of 480 hours. This terminal half-life is hypothesized to represent the dissociation of Risedronate from the surface of bone.
Special Populations
Pediatric
Risedronate pharmacokinetics have not been studied in 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. Risedronate 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.
Pharmacodynamics
Treatment and Prevention of Osteoporosis in Postmenopausal Women
Osteoporosis is characterized by decreased bone mass and increased fracture risk, most commonly at the spine, hip, and wrist.
The diagnosis can be confirmed by the finding of low bone mass, evidence of fracture on x-ray, a history of osteoporotic fracture, or height loss or kyphosis indicative of vertebral fracture. Osteoporosis occurs in both men and women but is more common among women following menopause. In healthy humans, bone formation and resorption are closely linked; old bone is resorbed and replaced by newly-formed bone. In postmenopausal osteoporosis, bone resorption exceeds bone formation, leading to bone loss and increased risk of bone fracture. After menopause, the risk of fractures of the spine and hip increases; approximately 40% of 50 year-old women will experience an osteoporosis-related fracture during their remaining lifetimes. After experiencing 1 osteoporosis-related fracture, the risk of future fracture increases 5 fold compared to the risk among a non-fractured population.
Risedronate treatment decreases the elevated rate of bone turnover that is typically seen in postmenopausal osteoporosis. In clinical trials, administration of Risedronate 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 Risedronate for the treatment of osteoporosis in postmenopausal women, Risedronate sodium tablets 5 mg daily and Risedronate sodium tablets 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 Risedronate sodium tablets 5 mg daily and Risedronate sodium tablets 35 mg once a week groups, respectively. When postmenopausal women with osteoporosis were treated for 1 year with Risedronate sodium tablets 5 mg daily, urinary collagen cross-linked N-telopeptide was decreased by 54% and serum bone-specific alkaline phosphatase was reduced by 36%. Risedronate is not an estrogen and does not have the benefits and risks of estrogen therapy.
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. Risedronate decreases bone resorption without directly inhibiting bone formation.
In two 1 year clinical trials in the treatment and prevention of glucocorticoid-induced osteoporosis, Risedronate sodium tablets 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
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 Risedronate sodium tablets 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). 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 Risedronate treatment. In addition, histomorphometric data provide further support that Risedronate can lead to a more normal bone structure in these patients.
Radiographs taken at baseline and after 6 months from patients treated with Risedronate sodium tablets 30 mg daily demonstrate that Risedronate 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 Risedronate sodium tablets 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) (Risedronate sodium tablets 5 mg, n = 408) was conducted primarily in Europe and Australia; a second study was conducted in North America (VERT NA) (Risedronate sodium tablets 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.
Effect on Vertebral Fractures
Fractures of previously undeformed vertebrae (new fractures) and worsening of preexisting 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. Risedronate sodium tablets 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.
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. Risedronate sodium tablets 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: 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 Risedronate- and placebo-treated groups lost height during the studies. Patients who received Risedronate 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 Risedronate sodium tablets 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 Risedronate sodium tablets 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 Risedronate sodium tablets 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 Risedronate reverses the loss of BMD, a central factor in the progression of osteoporosis. In both VERT studies (VERT MN and VERT NA), Risedronate sodium tablets 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.
Risedronate sodium tablets 35 mg once a week (n = 485) was shown to be non-inferior to Risedronate sodium tablets 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% (-0.4, 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.
Histology/Histomorphometry
Bone biopsies from 110 postmenopausal women were obtained at endpoint. Patients had received daily Risedronate sodium tablets (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 Risedronate-treated women. These findings demonstrate that bone formed during Risedronate 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 Risedronate sodium tablets 5 mg and 21 treated with placebo. Mineralizing surface decreased moderately in Risedronate-treated patients (median percent change: Risedronate sodium tablets 5 mg, -74%; placebo, -21%), consistent with the known effects of treatment on bone turnover.
Prevention of Osteoporosis in Postmenopausal Women
Risedronate sodium tablets 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 (Risedronate sodium tablets 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 Risedronate treatment. Risedronate sodium tablets 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). Risedronate sodium tablets 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 Risedronate- and placebo-treated women following 1 year of treatment.
Figure 2: Change in BMD From Baseline 2 Year Prevention Study
Combined Administration with Hormone Replacement Therapy
The effects of combining Risedronate sodium tablets 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.
Histology/Histomorphometry
Bone biopsies from 53 postmenopausal women were obtained at endpoint. Patients had received Risedronate sodium tablets 5 mg plus estrogen or estrogen alone once daily for 1 year. Histologic evaluation (n = 47) demonstrated that the bone of patients treated with Risedronate 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 Risedronate plus estrogen and 12 treated with estrogen alone. Mineralizing surface decreased in both treatment groups (median percent change: Risedronate 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 ≥ 7.5 mg/day of prednisone or equivalent demonstrated that Risedronate sodium tablets 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 (Risedronate sodium tablets 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 Risedronate sodium tablets 5 mg group. At each skeletal site there were statistically significant differences between the Risedronate sodium tablets 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 Risedronate sodium tablets 5 mg group compared to the placebo group, the difference was not statistically significant. The differences between placebo and Risedronate sodium tablets 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. Risedronate 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 (Risedronate sodium tablets 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. Risedronate sodium tablets 5 mg increased BMD at the lumbar spine (2.9%), femoral neck (1.8%), and trochanter (2.4%). The differences between Risedronate 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. Risedronate 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
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 Risedronate 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 Risedronate 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
Histology/Histomorphometry
Bone biopsies from 40 patients on glucocorticoid therapy were obtained at endpoint. Patients had received daily Risedronate sodium tablets (2.5 mg or 5 mg) or placebo for 1 year. Histologic evaluation (n = 33) showed that bone formed during treatment with Risedronate 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 Risedronate sodium tablets 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 Risedronate 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 Risedronate sodium tablets 30 mg daily for 2 months or etidronate disodium tablets 400 mg daily for 6 months. At Day 180, 77% (43/56) of Risedronate-treated patients achieved normalization of serum alkaline phosphatase levels, compared to 10.5% (6/57) of patients treated with etidronate disodium tablets (p < 0.001). At Day 540, 16 months after discontinuation of therapy, 53% (17/32) of Risedronate-treated patients and 14% (4/29) of etidronate disodium-treated patients with available data remained in biochemical remission.
During the first 180 days of the active-controlled study, 85% (51/60) of Risedronate-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 etidronate disodium-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 etidronate disodium tablet 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 Risedronate 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.
Response to Risedronate 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, etidronate disodium) responded to treatment with Risedronate sodium tablets 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 Risedronate.
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/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 (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 Risedronate administered at the therapeutic dose is unlikely to induce osteomalacia.
Indications and Usage for Risedronate
Postmenopausal Osteoporosis
Risedronate sodium tablets are indicated for the treatment and prevention of osteoporosis in postmenopausal women.
Treatment of Osteoporosis
In postmenopausal women with osteoporosis, Risedronate sodium tablets increase BMD and reduce the incidence of vertebral fractures and a composite endpoint of nonvertebral osteoporosis-related fractures (see CLINICAL STUDIES). Osteoporosis may be confirmed by the presence or history of osteoporotic fracture, or by the finding of low bone mass (for example, at least 2 SD below the premenopausal mean).
Prevention of Osteoporosis
Risedronate sodium tablets may be considered in postmenopausal women who are at risk of developing osteoporosis and for whom the desired clinical outcome is to maintain bone mass and to reduce the risk of fracture.
Factors such as family history of osteoporosis, previous fracture, smoking, BMD (at least 1 SD below the premenopausal mean), high bone turnover, thin body frame, Caucasian or Asian race, and early menopause are associated with an increased risk of developing osteoporosis and fractures. The presence of these risk factors may be important when considering the use of Risedronate sodium tablets for prevention of osteoporosis.
Glucocorticoid-Induced Osteoporosis
Risedronate sodium tablets are indicated for the prevention and treatment of glucocorticoid-induced osteoporosis in men and women who are either initiating or continuing systemic glucocorticoid treatment (daily dosage equivalent to 7.5 mg or greater of prednisone) for chronic diseases. Patients treated with glucocorticoids should receive adequate amounts of calcium and vitamin D.
Paget's Disease
Risedronate sodium tablets are indicated for treatment of Paget's disease of bone in men and women. Treatment is indicated in patients with Paget's disease of bone (1) who have a level of serum alkaline phosphatase at least 2 times the upper limit of normal, or (2) who are symptomatic, or (3) who are at risk for future complications from their disease, to induce remission (normalization of serum alkaline phosphatase).
Contraindications
- Hypocalcemia (see PRECAUTIONS, Mineral Metabolism)
- Known hypersensitivity to any component of this product
- Inability to stand or sit upright for at least 30 minutes
Warnings
Bisphosphonates may cause upper gastrointestinal disorders such as dysphagia, esophagitis, and esophageal or gastric ulcer (see PRECAUTIONS).
Precautions
Mineral Metabolism
Hypocalcemia and other disturbances of bone and mineral metabolism should be effectively treated before starting Risedronate therapy. Adequate intake of calcium and vitamin D is important in all patients, especially in patients with Paget's disease in whom bone turnover is significantly elevated. Risedronate is not recommended for use in patients with severe renal impairment (creatinine clearance < 30 mL/min).
Upper Gastrointestinal Effects
Bisphosphonates have been associated with gastrointestinal disorders such as dysphagia, esophagitis, and esophageal or gastric ulcers. This association has been reported for bisphosphonates in postmarketing experience, but has not been found in most pre-approval clinical trials, including those conducted with Risedronate. Patients should be advised that taking the medication according to the instructions is important to minimize the risk of these events. They shoul
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