risedronate sodium

Two Consecutive Days per Month

The safety of risedronate sodium 75 mg administered on two consecutive days per month for the treatment of postmenopausal osteoporosis was assessed in a double-blind, multicenter study in postmenopausal women aged 50 to 86 years. The duration of the trial was two years; 613 patients were exposed to risedronate sodium 5 mg daily and 616 were exposed to risedronate sodium 75 mg two consecutive days per month. Patients with preexisting gastrointestinal disease and concomitant use of non-steroidal anti-inflammatory drugs, proton pump inhibitors, and H₂ antagonists were included in this clinical trial. All women received 1,000 mg of elemental calcium plus 400 to 800 international units of vitamin D supplementation per day.

The incidence of all-cause mortality was 1% for the risedronate sodium 5 mg daily group and 0.5% for the risedronate sodium 75 mg two consecutive days per month group. The incidence of serious adverse events was 10.8% in the risedronate sodium 5 mg daily group and 14.4% in the risedronate sodium 75 mg two consecutive days per month group. The percentage of patients who withdrew from treatment due to adverse events was 14.2% in the risedronate sodium 5 mg daily group and 13% in the risedronate sodium 75 mg two consecutive days per month group. The overall safety and tolerability profiles of the two dosing regimens were similar.

Acute Phase Reactions : Symptoms consistent with acute phase reaction have been reported with bisphosphonate use. The overall incidence of acute phase reaction was 3.6% of patients on risedronate sodium 5 mg daily and 7.6% of patients on risedronate sodium 75 mg two consecutive days per month. These incidence rates are based on reporting of any of 33 acute phase reaction-like symptoms within 5 days of the first dose. Fever or influenza-like illness with onset within the same period were reported by 0% of patients on risedronate sodium 5 mg daily and 0.6% of patients on risedronate sodium 75 mg two consecutive days per month.

Gastrointestinal Adverse Events : The risedronate sodium 75 mg two consecutive days per month group resulted in a higher incidence of discontinuation due to vomiting (1% versus 0.2%) and diarrhea (1% versus 0.3%) compared to the risedronate sodium 5 mg daily group. Most of these events occurred within a few days of dosing.

Ocular Adverse Events : None of the patients treated with risedronate sodium 75 mg two consecutive days per month reported ocular inflammation such as uveitis, scleritis, or iritis; 1 patient treated with risedronate sodium 5 mg daily reported uveitis.

Laboratory Test Findings : When risedronate sodium 5 mg daily and risedronate sodium 75 mg two consecutive days per month were compared in postmenopausal women with osteoporosis, the mean percent changes from baseline at 24 months were 0.2% and 0.8% for serum calcium, -1.9% and -1.3% for phosphate, and -10.4% and -17.2% for PTH, respectively. Compared to the risedronate sodium 5 mg daily group, risedronate sodium 75 mg two consecutive days per month resulted in a slightly higher incidence of hypocalcemia at the end of the first month of treatment (4.5% versus 3%). Thereafter, the incidence of hypocalcemia with these regimens was similar at approximately 2%.

Once-a-Month

The safety of risedronate sodium 150 mg administered once-a-month for the treatment of postmenopausal osteoporosis was assessed in a double-blind, multicenter study in postmenopausal women aged 50 to 88 years. The duration of the trial was one year, with 642 patients exposed to risedronate sodium 5 mg daily and 650 exposed to risedronate sodium 150 mg once-a-month. Patients with preexisting gastrointestinal disease and concomitant use of non-steroidal anti-inflammatory drugs, proton pump inhibitors, and H₂ antagonists were included in this clinical trial. All women received 1,000 mg of elemental calcium plus up to 1,000 international units of vitamin D supplementation per day.

The incidence of all-cause mortality was 0.5% for the risedronate sodium 5 mg daily group and 0% for the risedronate sodium 150 mg once-a-month group. The incidence of serious adverse events was 4.2% in the risedronate sodium 5 mg daily group and 6.2% in the risedronate sodium 150 mg once-a-month group. The percentage of patients who withdrew from treatment due to adverse events was 9.5% in the risedronate sodium 5 mg daily group and 8.6% in the risedronate sodium 150 mg once-a-month group. The overall safety and tolerability profiles of the two dosing regimens were similar.

Acute Phase Reactions : Symptoms consistent with acute phase reaction have been reported with bisphosphonate use. The overall incidence of acute phase reaction was 1.1% in the risedronate sodium 5 mg daily group and 5.2% in the risedronate sodium 150 mg once-a-month group. These incidence rates are based on reporting of any of 33 acute phase reaction-like symptoms within 3 days of the first dose and for a duration of 7 days or less. Fever or influenza-like illness with onset within the same period were reported by 0.2% of patients on risedronate sodium 5 mg daily and 1.4% of patients on risedronate sodium 150 mg once-a-month.

Gastrointestinal Adverse Events : A greater percentage of patients experienced diarrhea with risedronate sodium 150 mg once-a-month compared to 5 mg daily (8.2% versus 4.7%, respectively). The risedronate sodium 150 mg once-a-month group resulted in a higher incidence of discontinuation due to abdominal pain upper (2.5% versus 1.4%) and diarrhea (0.8% versus 0%) compared to the risedronate sodium 5 mg daily regimen. All of these events occurred within a few days of the first dose. The incidence of vomiting that led to discontinuation was the same in both groups (0.3% versus 0.3%).

Ocular Adverse Events : None of the patients treated with risedronate sodium 150 mg once-a-month reported ocular inflammation such as uveitis, scleritis, or iritis; 2 patients treated with risedronate sodium 5 mg daily reported iritis.

Laboratory Test Findings : When risedronate sodium 5 mg daily and risedronate sodium 150 mg once-a-month were compared in postmenopausal women with osteoporosis, the mean percent changes from baseline at 12 months were 0.1% and 0.3% for serum calcium, -2.3% and -2.3% for phosphate, and 8.3% and 4.8% for PTH, respectively. Compared to the risedronate sodium 5 mg daily regimen, risedronate sodium 150 mg once-a-month resulted in a slightly higher incidence of hypocalcemia at the end of the first month of treatment (0.2% versus 2.2%). Thereafter, the incidence of hypocalcemia with these regimens was similar at approximately 2%.

6.2 Postmarketing Experience

Because these adverse reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Hypersensitivity Reactions

Hypersensitivity and skin reactions have been reported rarely, including angioedema, generalized rash and bullous skin reactions, some severe.

Gastrointestinal Adverse Events

Events involving upper gastrointestinal irritation, such as esophagitis and esophageal or gastric ulcers, have been reported [see Warnings and Precautions (5.1)].

Musculoskeletal Pain

Bone, joint, or muscle pain, described as severe or incapacitating, have been reported rarely [see Warnings and Precautions (5.4)].

Eye Inflammation

Reactions of eye inflammation including iritis and uveitis have been reported rarely.

Jaw Osteonecrosis

Osteonecrosis of the jaw has been reported rarely [see Warnings and Precautions (5.3)].

Pulmonary

Asthma exacerbations

7 DRUG INTERACTIONS

No specific drug-drug interactionstudies were performed. Risedronate is not metabolized and does not induce orinhibit hepatic microsomal drug-metabolizing enzymes (for example, CytochromeP450).

7.1 Calcium Supplements/Antacids

Coadministration of risedronate sodium and calcium,antacids, or oral medications containing divalent cations will interfere withthe absorption of risedronate sodium.

7.2 Hormone Replacement Therapy

One study of about 500 earlypostmenopausal women has been conducted to date in which treatment with risedronate sodium 5 mg daily plusestrogen replacement therapy was compared to estrogen replacement therapyalone. Exposure to study drugs was approximately 12 to 18 months and theprimary endpoint was change in BMD. If considered appropriate, risedronate sodium may be usedconcomitantly with hormone replacement therapy.

7.3 Aspirin/Nonsteroidal Anti-Inflammatory Drugs

Of over 5,700 patients enrolled in the risedronate sodium Phase 3 osteoporosis studies, aspirin use was reported by 31% of patients, 24% of whom were regular users (3 or more days per week). Forty-eight percent of patients reported NSAID use, 21% of whom were regular users. Among regular aspirin or NSAID users, the incidence of upper gastrointestinal adverse experiences in placebo-treated patients (24.8%) was similar to that in risedronate sodium-treated patients (24.5%).

7.4 H2 Blockers and Proton Pump Inhibitors (PPIs)

Of over 5,700 patients enrolled in the risedronate sodium Phase 3 osteoporosis studies, 21% used H₂ blockers and/or PPIs. Among these patients, the incidence of upper gastrointestinal adverse experiences in the placebo-treated patients was similar to that in risedronate sodium-treated patients.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category C: There areno adequate and well-controlled studies of risedronate sodium in pregnant women. Risedronate sodium should be used during pregnancy only if the potentialbenefit justifies the potential risk to the mother and fetus.

Bisphosphonates are incorporatedinto the bone matrix, from which they are gradually released over periods ofweeks to years. The amount of bisphosphonate incorporation into adult bone, andhence, the amount available for release back into the systemic circulation, isdirectly related to the dose and duration of bisphosphonate use. There are nodata on fetal risk in humans. However, there is a theoretical risk of fetalharm, predominantly skeletal, if a woman becomes pregnant after completing acourse of bisphosphonate therapy. The impact of variables such as time betweencessation of bisphosphonate therapy to conception, the particularbisphosphonate used, and the route of administration (intravenous versus oral)on this risk has not been studied.

In animal studies, pregnant ratsreceived risedronate sodium during organogenesis at doses 1 to 26 times thehuman dose of 30 mg/day. Survival of neonates was decreased in rats treatedduring gestation with oral doses approximately 5 times the human dose and bodyweight was decreased in neonates from dams treated with approximately 26 timesthe human dose. The number of fetuses exhibiting incomplete ossification ofsternebrae or skull from dams treated with approximately 2.5 times the humandose was significantly increased compared to controls. Both incompleteossification and unossified sternebrae were increased in rats treated with oraldoses approximately 5 times the human dose. A low incidence of cleft palate wasobserved in fetuses from female rats treated with oral doses approximatelyequal to the human dose. The relevance of this finding to human use of risedronate sodium is unclear.

No significant fetalossification effects were seen in rabbits treated with oral doses approximately7 times the human dose (the highest dose tested). However, 1 of 14 litters wereaborted and 1 of 14 litters were delivered prematurely.

Similar to otherbisphosphonates, treatment during mating and gestation with doses ofrisedronate sodium approximately the same as the 30 mg/day human dose resultedin periparturient hypocalcemia and mortality in pregnant rats allowed to deliver.

Dosing multiples provided aboveare based on the recommended human dose of 30 mg/day and normalized using bodysurface area (mg/m²). Actual animal doses were 3.2, 7.1 and 16mg/kg/day in the rat and 10 mg/kg/day in the rabbit.

8.3 Nursing Mothers

Risedronate was detected infeeding pups exposed to lactating rats for a 24-hour period post-dosing,indicating a small degree of lacteal transfer. It is not known whether risedronate sodium is excreted inhuman milk. Because many drugs are excreted in human milk and because of thepotential for serious adverse reactions in nursing infants from risedronate sodium, a decision shouldbe made whether to discontinue nursing or to discontinue the drug, taking intoaccount the importance of the drug to the mother.

8.4 Pediatric Use

Risedronate sodiumis not indicated for use in pediatric patients.

The safety and effectiveness ofrisedronate was assessed in a one-year, randomized, double-blind, placebocontrolled study of 143 pediatric patients (94 received risedronate) withosteogenesis imperfecta (OI). The enrolled population was predominantlypatients with mild osteogenesis imperfecta (85% Type-I), aged 4 to less than 16years, 50% male and 82% Caucasian, with a mean lumbar spine BMD Z-score of-2.08 (2.08 standard deviations below the mean for age-matched controls).Patients received either a 2.5 mg (less than or equal to 30 kg body weight) or5 mg (greater than 30 kg body weight) daily oral dose. After one year, anincrease in lumbar spine BMD in the risedronate group compared to the placebogroup was observed. However, treatment with risedronate did not result in areduction in the risk of fracture in pediatric patients with osteogenesisimperfecta. In risedronatesodium-treated subjects, no mineralization defectswere noted in paired bone biopsy specimens obtained at baseline and month 12.

The overall safety profile ofrisedronate in OI patients treated for up to 12 months was generally similar tothat of adults with osteoporosis. However, there was an increased incidence ofvomiting compared to placebo. In this study, vomiting was observed in 15% ofchildren treated with risedronate and 6% of patients treated with placebo.Other adverse events reported in greater than or equal to 10% of patientstreated with risedronate and with a higher frequency than placebo were: pain inthe extremity (21% with risedronate versus 16% with placebo), headache (20%versus 8%), back pain (17% versus 10%), pain (15% versus 10%), upper abdominalpain (11% versus 8%), and bone pain (10% versus 4%).

8.5 Geriatric Use

Of the patients receiving risedronate sodium in postmenopausal osteoporosis studies [see Clinical Studies (14)], 47% were between 65 and 75 years of age, and 17% were over 75. No overall differences in efficacy between geriatric and younger patients were observed in these studies. In the male osteoporosis trial, 28% of patients receiving risedronate sodium were between 65 and 75 years of age and 9% were over 75. The lumbar spine BMD response for risedronate sodium compared to placebo was 5.6% for subjects less than 65 years and 2.9% for subjects greater than or equal to 65 years. No overall differences in safety between geriatric and younger patients were observed in the risedronate sodium trials, but greater sensitivity of some older individuals cannot be ruled out.

8.6 Renal Impairment

Risedronate sodiumis not recommended for use in patients with severerenal impairment (creatinine clearance less than 30 mL/min) because of lack of clinical experience. No dosage adjustmentis necessary in patients with a creatinine clearance greater than or equal to 30mL/min. 

8.7 Hepatic Impairment

No studies have been performed to assess risedronate’ssafety or efficacy in patients with hepatic impairment. Risedronate is notmetabolized in human liver preparations. Dosage adjustment is unlikely to beneeded in patients with hepatic impairment.

10 OVERDOSAGE

Decreases in serum calcium and phosphorus following substantial overdose may be expected in some patients. Signs and symptoms of hypocalcemia may also occur in some of these patients. Milk or antacids containing calcium should be given to bind risedronate sodium and reduce absorption of the drug.

In cases of substantial overdose, gastric lavage may be considered to remove unabsorbed drug. Standard procedures that are effective for treating hypocalcemia, including the administration of calcium intravenously, would be expected to restore physiologic amounts of ionized calcium and to relieve signs and symptoms of hypocalcemia.

Lethality after single oral doses was seen in female rats at 903 mg/kg and male rats at 1,703 mg/kg. The minimum lethal dose in mice and rabbits was 4,000 mg/kg and 1,000 mg/kg, respectively. These values represent 320 to 620 times the 30 mg human dose based on surface area (mg/m²).

11 DESCRIPTION

Risedronate sodium tablets are pyridinyl bisphosphonate that inhibits osteoclast-mediated bone resorption and modulates bone metabolism. Each risedronate sodium tablet, USP for oral administration contains the equivalent of 75 mg, or 150 mg of anhydrous risedronate sodium in the form of the hemi-pentahydrate. The molecular formula for risedronate sodium hemi-pentahydrate, USP is C₇H₁₀NO₇P₂Na •2.5 H₂O. The chemical name of risedronate sodium is [1-hydroxy-2-(3-pyridinyl)ethylidene]bis[phosphonic acid] monosodium salt. The chemical structure of risedronate sodium hemi-pentahydrate is the following:

Risedronate sodium is a fine, white to off-white, odorless, crystalline powder. It is soluble in water and in aqueous solutions, and essentially insoluble in common organic solvents.

Inactive Ingredients

All dose strengths contain: mannitol, microcrystalline cellulose, croscarmellose sodium, pregelatinized starch, colloidal silicon dioxide, magnesium stearate, polyvinyl alcohol, titanium dioxide, polyethylene glycol, talc.

Dose strength-specific ingredients include: 75 mg— iron oxide red; 150 mg—FD&C blue #2 aluminum lake.
For 75 mg and 150 mg strengths - USP dissolution test pending.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Risedronate sodium has anaffinity for hydroxyapatite crystals in bone and acts as an antiresorptiveagent. At the cellular level, risedronate sodium inhibits osteoclasts. Theosteoclasts adhere normally to the bone surface, but show evidence of reducedactive resorption (for example,lack of ruffled border). Histomorphometry in rats, dogs, and minipigs showedthat risedronate sodium treatment reduces bone turnover (activation frequency, that is, the rate at which boneremodeling sites are activated) and bone resorption at remodeling sites.

12.2 Pharmacodynamics

Risedronate sodium treatment decreases the elevated rate of bone turnover that is typically seen in postmenopausal osteoporosis. In clinical trials, administration of risedronate sodium 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 sodium for the treatment of osteoporosis in postmenopausal women, risedronate sodium 5 mg daily and risedronate sodium 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 5 mg daily and risedronate sodium 35 mg once-a-week groups, respectively. When postmenopausal women with osteoporosis were treated for 1 year with risedronate sodium 5 mg daily or risedronate sodium 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 risedronate sodium 5 mg daily versus risedronate sodium 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.

12.3 Pharmacokinetics

Absorption

Based on simultaneous modeling of serum and urine data, peak absorption after an oral dose is achieved at approximately 1 hour (T_max) 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.

Food Effect

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 sodium is effective when administered at least 30 minutes before breakfast.

Distribution

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%.

Metabolism

There is no evidence of systemic metabolism of risedronate.

Excretion

 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%).

Specific Populations

Pediatric: Risedronate sodium is not indicated for use in pediatric patients [see Pediatric Use (8.4)].

Gender: Bioavailability and pharmacokinetics following oral administration are similar in men and women.

Geriatric: Bioavailability and disposition are similar in elderly (greater than 60 years of age) and younger subjects. No dosage adjustment is necessary.

Race: Pharmacokinetic differences due to race have not been studied.

Renal Impairment : 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 sodium is not recommended for use in patients with severe renal impairment (creatinine clearance less than 30 mL/min) because of lack of clinical experience. No dosage adjustment is necessary in patients with a creatinine clearance greater than or equal to 30 mL/min.

Hepatic Impairment : 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 (less than 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.

Drug Interactions: No specific drug-drug interaction studies were performed. Risedronate is not metabolized and does not induce or inhibit hepatic microsomal drug-metabolizing enzymes (Cytochrome P450) [see Drug Interactions (7)].

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis 

In a 104-week carcinogenicity study, rats were administered daily oral doses up to approximately 8 times the maximum recommended human daily dose. There were no significant drug-induced tumor findings in male or female rats. The high dose male group 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 approximately 6.5 times the human dose. There were no significant drug-induced tumor findings in male or female mice.

Mutagenesis 

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 (greater than 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 approximately 5 times the human dose. Decreased implantation was noted in female rats treated with doses approximately 2.5 times the human dose. In male rats, testicular and epididymal atrophy and inflammation were noted at approximately 13 times the human dose. Testicular atrophy was also noted in male rats after 13 weeks of treatment at oral doses approximately 5 times the human dose. There was moderate-to-severe spermatid maturation block after 13 weeks in male dogs at an oral dose approximately 8 times the human dose. These findings tended to increase in severity with increased dose and exposure time.

Dosing multiples provided above are based on the recommended human dose of 30 mg/day and normalized using body surface area (mg/m²). Actual doses were 24 mg/kg/day in rats, 32 mg/kg/day in mice, and 8, 16 and 40 mg/kg/day in dogs.

13.2 Animal Toxicology and/or Pharmacology

Risedronate demonstrated potentanti-osteoclast, antiresorptive activity in ovariectomized rats and minipigs.Bone mass and biomechanical strength were increased dose-dependently at dailyoral doses up to 4 and 25 times the human recommended oral dose of 5 mg forrats and minipigs, respectively. Risedronate treatment maintained the positivecorrelation between BMD and bone strength and did not have a negative effect onbone structure or mineralization. In intact dogs, risedronate induced positivebone balance at the level of the bone remodeling unit at oral doses rangingfrom 0.5 to 1.5 times the 5 mg/day human daily dose.

In dogs treated with an oral dose approximately 5 timesthe human daily dose, risedronate caused a delay in fracture healing of theradius. The observed delay in fracture healing is similar to otherbisphosphonates. This effect did not occur at a dose approximately 0.5 timesthe human daily dose.

The Schenk rat assay, based onhistologic examination of the epiphyses of growing rats after drug treatment,demonstrated that risedronate did not interfere with bone mineralization evenat the highest dose tested, which was approximately 3,500 times the lowestantiresorptive dose in this model (1.5 mcg/kg/day) and approximately 800 timesthe human daily dose of 5 mg. This indicates that risedronate sodium administeredat the therapeutic dose is unlikely to induce osteomalacia.

Dosing multiples provided above are based on therecommended human dose of 5 mg/day and normalized using body surface area (mg/m²).

14 CLINICAL STUDIES

14.1 Treatment of Osteoporosis in Postmenopausal Women

The fracture efficacy of risedronate sodium 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 4,000 postmenopausal women under similar protocols. The Multinational study (VERT MN) (risedronate sodium 5 mg, N = 408) was conducted primarily in Europe and Australia; a second study was conducted in North America (VERT NA) (risedronate sodium 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 1,000 mg/day. Patients with low 25-hydroxyvitamin D3 levels (approximately 40 nmol/L or less) also received supplemental vitamin D 500 international units/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 (that is, 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 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 Risedronate Sodium on the Risk of Vertebral Fractures

Proportion of Patients with Fracture (%)Calculated by Kaplan-Meier methodology
VERT NA	Placebo N = 678	Risedronate Sodium 5 mg N = 696	Absolute Risk Reduction (%)	Relative Risk Reduction (%)
New and Worsening
0 to 1 Year	7.2	3.9	3.3	49
0 to 2 Years	12.8	8	4.8	42
0 to 3 Years	18.5	13.9	4.6	33
New
0 to 1 Year	6.4	2.4	4	65
0 to 2 Years	11.7	5.8	5.9	55
0 to 3 Years	16.3	11.3	5	41
VERT MN	Placebo N = 346	Risedronate Sodium 5 mg N = 344	Absolute Risk Reduction(%)	Relative Risk Reduction(%)
New and Worsening
0 to 1 Year	15.3	8.2	7.1	50
0 to 2 Years	28.3	13.9	14.4	56
0 to 3 Years	34	21.8	12.2	46
New
0 to 1 Year	13.3	5.6	7.7	61
0 to 2 Years	24.7	11.6	13.1	59
0 to 3 Years	29	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. Risedronate sodium 5 mg daily significantly reduced the incidence of nonvertebral osteoporosis-related fractures over 3 years in VERT NA (8% versus 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 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 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. In both VERT studies (VERT MN and VERT NA), risedronate sodium 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 Risedronate Sodium 5 mg or Placebo at Endpoint^a

	VERT MNThe duration of the studies was 3 years		VERT NAThe duration of the studies was 3 years		BMD MNThe duration of the studies was 1.5 to 2 years		BMD NAThe duration of the studies was 1.5 to 2 years
	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	6.6	0.8	5	0	4	0.2	4.8
Femoral Neck	-1.4	1.6	-1	1.4	-1.1	1.3	0.1	2.4
Femoral Trochanter	-1.9	3.9	-0.5	3	-0.6	2.5	1.3	4
Midshaft Radius	-1.5BMD 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)	0.2BMD 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)	-1.2BMD 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)	0.1BMD 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		ND
aThe 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.

ND = analysis not done

Risedronate sodium 35 mg once-a-week (N = 485) was shown to be non-inferior to risedronate sodium 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% (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 risedronate sodium 75 mg two consecutive days per month (N = 616) was shown to be non-inferior to risedronate sodium 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.

Risedronate sodium 150 mg once-a-month (N = 650) was shown to be non-inferior to risedronate sodium 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, 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.

Histology/Histomorphometry 
Bone biopsies from 110 postmenopausal women were obtained at endpoint. Patients had received placebo or daily risedronate sodium (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 risedronate sodium-treated women. These findings demonstrate that bone formed during risedronate sodium 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 risedronate sodium 5 mg. Mineralizing surface decreased moderately in risedronate sodium-treated patients (median percent change: placebo, -21%; risedronate sodium 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 risedronate sodium and placebo-treated groups lost height during the studies. Patients who received risedronate sodium 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 risedronate sodium 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 risedronate sodium 5 mg daily group.

14.2 Prevention of Osteoporosis in Postmenopausal Women

The safety and effectiveness of risedronate sodium 5 mg daily for the prevention of postmenopausal osteoporosis were demonstrated in a 2-year, double-blind, placebo-controlled study of 383 postmenopausal women (age range 42 to 63 years) within three years of menopause (risedronate sodium 5 mg, N = 129). All patients in this study received supplemental calcium 1,000 mg/day. Increases in BMD were observed as early as 3 months following initiation of risedronate sodium treatment. Risedronate sodium 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). Risedronate sodium 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 sodium and placebo-treated women following 1 year of treatment.

Figure 2 Change in BMD from Baseline 2-Year Prevention Study

The safety and effectiveness of risedronate sodium 35 mg once-a-week for the prevention postmenopausal osteoporosis were demonstrated in a 1-year, double-blind, placebo-controlled study of 278 patients (risedronate sodium 35 mg, N = 136). All patients were supplemented with 1,000 mg elemental calcium and 400 international units 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). Risedronate sodium 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%). Risedronate sodium 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%; risedronate +0.22%), and trochanter of +1.8% (placebo -0.74%; risedronate +1.07%).

Combined Administration with Hormone Replacement Therapy

The effects of combining risedronate sodium 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.

Values shown are mean (± SEM) percent change from baseline.

Histology/Histomorphometry

Bone biopsies from 53 postmenopausal women were obtained at endpoint. Patients had received risedronate sodium 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 sodium 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 sodium plus estrogen and 12 treated with estrogen alone. Mineralizing surface decreased in both treatment groups (median percent change: risedronate sodium plus estrogen, -79%; estrogen alone, -50%), consistent with the known effects of these agents on bone turnover.