Binosto Drug Information
Generic name: ALENDRONATE SODIUM
Uses of Binosto
Treatment of Osteoporosis in Postmenopausal Women
BINOSTO effervescent tablet 70 mg is indicated for the treatment of osteoporosis in postmenopausal women. For the treatment of osteoporosis, alendronate sodium increases bone mass and reduces the incidence of fractures, including those of the hip and spine (vertebral compression fractures).
Treatment to Increase Bone Mass in Men With Osteoporosis
BINOSTO is indicated for treatment to increase bone mass in men with osteoporosis .
Important Limitations of Use
The optimal duration of use has not been determined. The safety and effectiveness of BINOSTO for the treatment of osteoporosis are based on clinical data of four years duration. All patients on bisphosphonate therapy should have the need for continued therapy re-evaluated on a periodic basis.
Patients at low-risk for fracture should be considered for drug discontinuation after 3 to 5 years of use. Patients who discontinue therapy should have their risk for fracture re-evaluated periodically.
Dosage & Administration of Binosto
Treatment of Osteoporosis in Postmenopausal Women
The recommended dosage is one 70 mg effervescent tablet once weekly.
Treatment to Increase Bone Mass in Men With Osteoporosis
The recommended dosage is one 70 mg effervescent tablet once weekly.
Important
Administration Instructions Instruct patients to do the following to assure adequate drug absorption and to decrease the risk of esophageal adverse reactions: Take BINOSTO upon arising for the day and at least 30 minutes before the first food, beverage, or medication of the day. Patients should not swallow the undissolved effervescent tablet, should not chew the effervescent tablet or allow the effervescent tablet to dissolve in their mouths because of the risk for oropharyngeal irritation. Dissolve the effervescent tablet in 4 ounces room temperature plain water only (not mineral water or flavored water). Wait at least 5 minutes after the effervescence stops and then stir the buffered solution for approximately 10 seconds and ingest.
Avoid lying down for at least 30 minutes after taking BINOSTO and until after their first food of the day. Do not take BINOSTO at bedtime or before arising for the day. Failure to follow these instructions may increase the risk of esophageal adverse reactions .
Recommendations for Calcium and Vitamin D Supplementation Instruct patients to take supplemental
calcium and vitamin D if dietary intake is inadequate . Patients at increased risk for vitamin D insufficiency (e.g., over the age of 70 years, nursing home-bound, or chronically ill) may need vitamin D supplementation. Patients with gastrointestinal malabsorption syndromes may require higher doses of vitamin D supplementation and measurement of 25-hydroxyvitamin D should be considered.
Administration Instructions for Missed Doses
If the once-weekly dose is missed, instruct patients to take one dose on the morning after they remember. They should not take 2 doses on the same day but should return to taking one dose once a week, as originally scheduled on their chosen day.
Side Effects of Binosto
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. The safety of BINOSTO (alendronate sodium) effervescent tablet 70 mg is based on clinical trial data of alendronate sodium 10 mg daily and alendronate sodium 70 mg weekly. Treatment of Osteoporosis in Postmenopausal Women Daily Dosing The safety of alendronate sodium 10 mg daily in the treatment of postmenopausal osteoporosis was assessed in four clinical trials that enrolled 7453 women aged 44-84 years.
Study 1 and Study 2 were identically designed, three-year, placebo-controlled, double-blind, multicenter studies (United States and Multinational n=994); Study 3 was the three year vertebral fracture cohort of the Fracture Intervention Trial (n=2027) and Study 4 was the four-year clinical fracture cohort of FIT (n=4432). Overall, 3620 patients were exposed to placebo and 3432 patients exposed to alendronate. Patients with pre-existing gastrointestinal disease and concomitant use of non-steroidal anti-inflammatory drugs were included in these clinical trials. In Study 1 and Study 2 all women received 500 mg elemental calcium as carbonate.
In Study 3 and Study 4 all women with dietary calcium intake less than 1000 mg per day received 500 mg calcium and 250 IU Vitamin D per day. Among patients treated with alendronate 10 mg or placebo in Study 1 and Study 2, and all patients in Study 3 and Study 4, the incidence of all-cause mortality was 1.8% in the placebo group and 1.8% in the alendronate group. The incidence of serious adverse events was 30.7% in the placebo group and 30.9% in the alendronate group.
The percentage of patients who discontinued the study due to any clinical adverse event was 9.5% in the placebo group and 8.9% in the alendronate group. Adverse reactions from these studies considered by the investigators as possibly, probably, or definitely drug related in greater than or equal to 1% of patients treated with either alendronate or placebo are presented in Table 1. Table 1 Osteoporosis Treatment Studies in Postmenopausal Women Adverse Reactions Considered Possibly, Probably, or Definitely Drug Related by the Investigators and Reported in Greater Than or Equal to 1% of Patients United States/Multinational Studies Fracture Intervention Trial Alendronate Sodium 10 mg/day for three years Placebo Alendronate Sodium 5 mg/day for 2 years and 10 mg/day for either 1 or 2 additional years Placebo % (N = 196) % (N = 397) % (N = 3236) % (N = 3223) Gastrointestinal Abdominal pain 6.6 4.8 1.5
Nausea 3.6 4.0 1.1 1.5 Dyspepsia 3.6 3.5 1.1 1.2 Constipation 3.1
1.8 0.0
Diarrhea 3.1 1.8 0.6 0.3 Flatulence 2.6 0.5 0.2 0.3 Acid regurgitation
2.0 4.3 1.1
Esophageal ulcer 1.5 0.0 0.1 0.1 Vomiting 1.0 1.5 0.2 0.3 Dysphagia
1.0 0.0 0.1
Abdominal distention 1.0 0.8 0.0 0.0 Gastritis 0.5 1.3 0.6 0.7 Musculoskeletal
Musculoskeletal (bone, muscle or joint) pain 4.1 2.5 0.4
Rarely, rash and erythema have occurred. Gastrointestinal Adverse Reactions: One patient treated
with alendronate sodium (10 mg/day), who had a history of peptic ulcer disease and gastrectomy and who was taking concomitant aspirin developed an anastomotic ulcer with mild hemorrhage, which was considered drug related. Aspirin and alendronate sodium were discontinued and the patient recovered. In the Study 1 and Study 2 populations, 49-54% had a history of gastrointestinal disorders at baseline and 54-89% used nonsteroidal anti-inflammatory drugs or aspirin at some time during the studies.
Laboratory Test Findings: In double-blind, multicenter, controlled studies, asymptomatic, mild, and transient decreases in serum calcium and phosphate were observed in approximately 18% and 10%, respectively, of patients taking alendronate versus approximately 12% and 3% of those taking placebo. However, the incidences of decreases in serum calcium to less than 8.0 mg/dL (2.0 mM) and serum phosphate to less than or equal to 2.0 mg/dL (0.65 mM) were similar in both treatment groups. Weekly Dosing The safety of alendronate sodium 70 mg once weekly for the treatment of postmenopausal osteoporosis was assessed in a one-year, double-blind, multicenter study comparing alendronate 70 mg once weekly and alendronate 10 mg daily.
The overall safety and tolerability profiles of once weekly alendronate 70 mg and alendronate 10 mg daily were similar. The adverse reactions considered by the investigators as possibly, probably, or definitely drug related in greater than or equal to 1% of patients in either treatment group are presented in Table 2. Table 2 Osteoporosis Treatment Studies in Postmenopausal Women Adverse Reactions Considered Possibly, Probably, or Definitely Drug Related by the Investigators and Reported in Greater Than or Equal to 1% of Patients Once Weekly Alendronate Sodium 70 mg % (N = 519) Once Daily Alendronate Sodium 10 mg % (N = 370) Gastrointestinal Abdominal pain 3.7
Dyspepsia 2.7 2.2 Acid regurgitation 1.9 2.4 Nausea 1.9 2.4 Abdominal distention
1.0
Musculoskeletal Musculoskeletal (bone, muscle, joint) pain 2.9 3.2 Muscle cramp 0.2 1.1
Osteoporosis in Men In two placebo-controlled, double-blind, multicenter studies in men (a two-year study of alendronate sodium 10 mg/day and a one-year study of once weekly alendronate sodium 70 mg) the rates of discontinuation of therapy due to any clinical adverse event were 2.7% for alendronate 10 mg/day vs. 10.5% for placebo, and 6.4% for once weekly alendronate 70 mg vs. 8.6% for placebo. The adverse reactions considered by the investigators as possibly, probably, or definitely drug related in greater than or equal to 2% of patients treated with either alendronate or placebo are presented in the following table. Table 3 Osteoporosis Studies in Men Adverse Reactions Considered Possibly, Probably, or Definitely Drug Related by the Investigators and Reported in Greater Than or Equal to 2% of Patients Two-Year Study One-Year Study Once Daily Alendronate Sodium Once Weekly Alendronate Sodium 10 mg % (N = 146) Placebo % (N = 95) 70 mg % (N = 109) Placebo % (N = 58) Gastrointestinal Acid regurgitation 4.1 3.2 0.0
Flatulence 4.1 1.1 0.0 0.0 Gastroesophageal reflux disease 0.7 3.2 2.8 0.0
Dyspepsia 3.4 0.0 2.8
Diarrhea 1.4 1.1 2.8 0.0 Abdominal pain 2.1 1.1 0.9 3.4 Nausea
2.1 0.0 0.0 0.0
Post-Marketing Experience
The following adverse reactions have been identified during post-approval use of alendronate sodium or bisphosphonate products. Because these 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. Body as a Whole : hypersensitivity reactions including urticaria and angioedema.
Transient symptoms of myalgia, malaise, asthenia and fever have been reported with alendronate, typically in association with initiation of treatment. Symptomatic hypocalcemia has occurred, generally in association with predisposing conditions. Peripheral edema.
Gastrointestinal : esophagitis, esophageal erosions, esophageal ulcers, esophageal stricture or perforation, and oropharyngeal ulceration. Gastric or duodenal ulcers, some severe and with complications have also been reported . Dental : Localized osteonecrosis of the jaw, generally associated with tooth extraction and/or local infection with delayed healing, has been reported . Musculoskeletal : bone, joint, and/or muscle pain, occasionally severe and incapacitating ; joint swelling; low-energy femoral shaft and subtrochanteric fractures, and atypical fractures of other bones . Nervous system : dizziness and vertigo. Pulmonary: acute asthma exacerbations Skin : rash (occasionally with photosensitivity), pruritus, alopecia, severe skin reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis.
Special Senses : uveitis, scleritis or episcleritis. Cholesteatoma of the external auditory canal (focal osteonecrosis).
Warnings & Cautions for Binosto
Upper Gastrointestinal Adverse Reactions
BINOSTO, like other bisphosphonates administered orally, may cause local irritation of the upper gastrointestinal mucosa. Because of these possible irritant effects and a potential for worsening of the underlying disease, caution should be used when BINOSTO is given to patients with active upper gastrointestinal problems (such as known Barrett's esophagus, dysphagia, other esophageal diseases, gastritis, duodenitis, or ulcers). Esophageal adverse experiences, such as esophagitis, esophageal ulcers and esophageal erosions, occasionally with bleeding and rarely followed by esophageal stricture or perforation, have been reported in patients receiving treatment with oral bisphosphonates including alendronate sodium. In some cases these have been severe and required hospitalization.
Physicians should therefore be alert to any signs or symptoms signaling a possible esophageal reaction and patients should be instructed to discontinue BINOSTO and seek medical attention if they develop dysphagia, odynophagia, retrosternal pain or new or worsening heartburn. The risk of severe esophageal adverse experiences appears to be greater in patients who lie down after taking oral bisphosphonates including alendronate sodium, and/or who continue to take oral bisphosphonates including alendronate sodium after developing symptoms suggestive of esophageal irritation. Therefore, it is very important that the full dosing instructions are provided to, and understood by, the patient . In patients who cannot comply with dosing instructions due to mental disability, therapy with BINOSTO should be used under appropriate supervision.
There have been post-marketing reports of gastric and duodenal ulcers with oral bisphosphonate use, some severe and with complications, although no increased risk was observed in controlled clinical trials .
Mineral Metabolism Hypocalcemia must be corrected before initiating therapy with
BINOSTO. Other disorders affecting mineral metabolism (such as vitamin D deficiency) should also be effectively treated. In patients with these conditions, serum calcium and symptoms of hypocalcemia should be monitored during therapy with BINOSTO. Presumably due to the effects of BINOSTO on increasing bone mineral, small, asymptomatic decreases in serum calcium and phosphate may occur. Patients should receive adequate calcium and vitamin D intake.
Musculoskeletal Pain
In post-marketing experience, severe and occasionally incapacitating bone, joint, and/or muscle pain has been reported in patients taking bisphosphonates that are approved for the treatment of osteoporosis . This category of drugs includes BINOSTO. Most of the patients were postmenopausal women. The time to onset of symptoms varied from one day to several months after starting the drug. Discontinue use if severe symptoms develop.
Most patients had relief of symptoms after stopping. A subset had recurrence of symptoms when rechallenged with the same drug or another bisphosphonate. In placebo-controlled clinical studies of alendronate sodium, the percentages of patients with these symptoms were similar in the alendronate sodium and placebo groups.
Osteonecrosis of the Jaw Osteonecrosis of the jaw (ONJ), which can occur
spontaneously, is generally associated with tooth extraction and/or local infection with delayed healing, and has been reported in patients taking bisphosphonates, including alendronate sodium. Known risk factors for osteonecrosis of the jaw include invasive dental procedures (e.g., tooth extraction, dental implants, boney surgery), diagnosis of cancer, concomitant therapies (e.g., chemotherapy, corticosteroids, angiogenesis inhibitors), poor oral hygiene, and co-morbid disorders (e.g., periodontal and/or other pre-existing dental disease, anemia, coagulopathy, infection, ill-fitting dentures). The risk of ONJ may increase with duration of exposure to bisphosphonates. For patients requiring invasive dental procedures, discontinuation of bisphosphonate treatment may reduce the risk for ONJ. Clinical judgment of the treating physician and/or oral surgeon should guide the management plan of each patient based on individual benefit/risk assessment.
Patients who develop osteonecrosis of the jaw while on bisphosphonate therapy should receive care by an oral surgeon. In these patients, extensive dental surgery to treat ONJ may exacerbate the condition. Discontinuation of bisphosphonate therapy should be considered based on individual benefit/risk assessment.
Atypical Fractures Including Femoral Fractures Atypical, low-energy, or low trauma fractures of
the femoral shaft have been reported during treatment with bisphosphonates, including alendronate sodium, in patients with osteoporosis. Atypical femur and other fractures most commonly occur with minimal or no trauma to the affected area. These fractures occurred anywhere in the femoral shaft from just below the lesser trochanter to above the supracondylar flare and are transverse or short oblique in orientation without evidence of comminution.
Atypical fractures of other bones have also been reported. They may be bilateral. These fractures can also occur in osteoporotic patients who have not been treated with bisphosphonates.
Concomitant treatment with glucocorticoids may also induce these fractures. Prodromal pain in the affected area, usually presenting as dull, aching pain, weeks to months before a complete fracture occurs was reported by patients. Any patient with a history of bisphosphonate exposure who presents with thigh or groin pain should be suspected of having an atypical fracture and should be evaluated to rule out an incomplete femur fracture.
Bone pain in other locations should also be considered for evaluation of atypical fracture. Patients presenting with an atypical fracture should also be assessed for symptoms and signs of fracture in the contralateral limb. Risk/benefit of continuing bisphosphonate therapy should be re-evaluated in these patients and interruption of bisphosphonate therapy should be considered.
Renal Impairment
BINOSTO is not recommended for patients with creatinine clearance <35 mL/min.
Patients Sensitive to High Sodium Intake Each
BINOSTO effervescent tablet contains 603 mg of sodium, equivalent to approximately 1532 mg of salt (NaCl). Use caution in patients who must restrict their sodium intake, including some patients with a history of heart failure, hypertension, or other cardiovascular diseases.
Drug Interactions with Binosto
Calcium Supplements/Antacids Co-administration of
BINOSTO and calcium, antacids, or oral medications containing multivalent cations will interfere with absorption of BINOSTO. Therefore, instruct patients to wait at least one-half hour after taking BINOSTO before taking any other oral medications.
Aspirin
In clinical studies, the incidence of upper gastrointestinal adverse events was increased in patients receiving concomitant therapy with daily doses of alendronate sodium greater than 10 mg and aspirin-containing products.
Nonsteroidal Anti-inflammatory Drugs (NSAIDs)
BINOSTO may be administered to patients taking NSAIDs. In a 3-year, controlled, clinical study (n=2027) during which a majority of patients received concomitant NSAIDs, the incidence of upper gastrointestinal adverse events was similar in patients taking alendronate sodium 5 or 10 mg/day compared to those taking placebo. However, since NSAID use is associated with gastrointestinal irritation, caution should be used during concomitant use with BINOSTO.
Levothyroxine
The bioavailability of alendronate was slightly decreased when BINOSTO and levothyroxine were co-administered to healthy subjects .
Pregnancy Safety for Binosto
Pregnancy Risk Summary Available data on the use of BINOSTO in pregnant women are insufficient to inform a drug-associated risk of adverse maternal or fetal outcomes. Discontinue BINOSTO when pregnancy is recognized. In animal reproduction studies, daily oral administration of alendronate to rats from before mating through the end of gestation or lactation showed decreased postimplantation survival and decreased pup body weight gain starting at doses equivalent to less than half of the highest recommended 40 mg clinical daily dose (based on body surface area, mg/m 2 ). Oral administration of alendronate to rats during organogenesis resulted in reduced fetal ossification starting at doses 3 times the 40 mg clinical daily dose.
No similar fetal effects were observed in pregnant rabbits dosed orally during organogenesis at doses equivalent to approximately 10 times the 40 mg clinical daily dose. Delayed or failed delivery of offspring, protracted parturition, and late pregnancy maternal and fetal deaths due to maternal hypocalcemia occurred in rats at oral doses as low as one tenth the 40 mg clinical daily dose (See Data ). Bisphosphonates are incorporated into the bone matrix, from which they are gradually released over a period of years. The amount of bisphosphonate incorporated into adult bone and available for release into the systemic circulation is directly related to the dose and duration of bisphosphonate use.
Consequently, based on the mechanism of action of bisphosphonates, there is a potential risk of fetal harm, predominantly skeletal, if a woman becomes pregnant after completing a course of bisphosphonate therapy. The impact of variables such as time between cessation of bisphosphonate therapy to conception, the particular bisphosphonate used, and the route of administration (intravenous versus oral) on the risk has not been studied. The estimated background risk of major birth defects and miscarriage for the indicated population(s) is unknown.
All pregnancies have a background risk of birth defects, loss, or other adverse outcomes. In the U.S. general population, the estimated background risks of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Data Animal Data Reproduction studies in rats dosed orally from before mating to the end of gestation or lactation showed decreased postimplantation survival starting at 2 mg/kg/day and decreased body weight gain starting at 1 mg/kg/day, doses equivalent to less than half the 40 mg clinical daily dose based on body surface area, mg/m 2. Incidence of incomplete fetal ossification in vertebral, skull, and sternebral bones were increased in rats dosed orally during organogenesis starting at 10 mg/kg/day (approximately 3 times the 40 mg clinical daily dose). No similar fetal effects were observed in pregnant rabbits dosed orally during organogenesis at up to 35 mg/kg/day (equivalent to approximately 10 times the 40 mg clinical daily dose). Both total and ionized calcium decreased in pregnant rats dosed orally with 15 mg/kg/day alendronate (approximately 4 times the 40 mg clinical daily dose) resulting in delays and failures of delivery.
Protracted parturition due to maternal hypocalcemia was observed when rats were treated from before mating through gestation starting at 0.5 mg/kg/day (approximately one tenth the 40 mg clinical daily dose). Maternotoxicity (late pregnancy deaths) also occurred in female rats treated orally with 15 mg/kg/day (approximately 4 times the 40 mg clinical daily dose) for varying gestational time periods. These maternal deaths were lessened but not eliminated by cessation of treatment. Calcium supplementation in the drinking water or by subcutaneous minipump to rats dosed orally with 15 mg/kg/day alendronate could not ameliorate the hypocalcemia or prevent the dystocia-related maternal and neonatal deaths.
However, intravenous calcium supplementation prevented maternal, but not neonatal deaths.
Pediatric Use of Binosto
Pediatric Use BINOSTO is not indicated for use in pediatric patients. The safety and efficacy of alendronate sodium were examined in a randomized, double-blind, placebo-controlled two-year study of 139 pediatric patients, aged 4-18 years, with severe osteogenesis imperfecta (OI). One-hundred-and-nine patients were randomized to 5 mg alendronate sodium daily (weight less than 40 kg) or 10 mg alendronate sodium daily (weight greater than or equal to 40 kg) and 30 patients to placebo. The mean baseline lumbar spine BMD Z-score of the patients was -4.5. The mean change in lumbar spine BMD Z-score from baseline to Month 24 was 1.3 in the alendronate-treated patients and 0.1 in the placebo- treated patients.
Treatment with alendronate sodium did not reduce the risk of fracture. Sixteen percent of the alendronate-treated patients who sustained a radiologically-confirmed fracture by Month 12 of the study had delayed fracture healing (callus remodeling) or fracture non-union when assessed radiographically at Month 24 compared with 9% of the placebo-treated patients. In alendronate-treated patients, bone histomorphometry data obtained at Month 24 demonstrated decreased bone turnover and delayed mineralization time; however, there were no mineralization defects.
There were no statistically significant differences between the alendronate sodium and placebo groups in reduction of bone pain. The oral bioavailability in children was similar to that observed in adults. The overall safety profile of alendronate sodium in osteogenesis imperfecta patients treated for up to 24 months was generally similar to that of adults with osteoporosis treated with alendronate sodium.
However, there was an increased occurrence of vomiting in osteogenesis imperfecta patients treated with alendronate sodium compared to placebo. During the 24-month treatment period, vomiting was observed in 32 of 109 (29.4%) patients treated with alendronate sodium and 3 of 30 (10%) patients treated with placebo. In a pharmacokinetic study, 6 of 24 pediatric osteogenesis imperfecta patients who received a single oral dose of alendronate sodium 35 or 70 mg developed fever, flu-like symptoms, and/or mild lymphocytopenia within 24 to 48 hours after administration.
These events, lasting no more than 2 to 3 days and responding to acetaminophen, are consistent with an acute-phase response that has been reported in patients receiving bisphosphonates, including alendronate sodium.
Contraindications for Binosto
is contraindicated in patients with the following conditions: Abnormalities of the esophagus which delay esophageal emptying such as stricture or achalasia Inability to stand or sit upright for at least 30 minutes Do not administer BINOSTO to patients at increased risk of aspiration Hypocalcemia Hypersensitivity to any component of this product. Hypersensitivity reactions including urticaria and angioedema have been reported . Abnormalities of the esophagus which delay emptying such as stricture or achalasia Inability to stand/sit upright for at least 30 minutes Increased risk of aspiration. Hypocalcemia Hypersensitivity to any component of this product
Overdosage Information for Binosto
Significant lethality after single oral doses was seen in female rats and mice at 552 mg/kg (3256 mg/m 2 ) and 966 mg/kg (2898 mg/m 2 ), respectively. In males, these values were slightly higher, 626 and 1280 mg/kg, respectively. There was no lethality in dogs at oral doses up to 200 mg/kg (4000 mg/m 2 ). No specific information is available on the treatment of overdosage with BINOSTO. Hypocalcemia, hypophosphatemia, and upper gastrointestinal adverse events, such as upset stomach, heartburn, esophagitis, gastritis, or ulcer, may result from oral overdosage.
Milk or antacids should be given to bind alendronate. Due to the risk of esophageal irritation, vomiting should not be induced and the patient should remain fully upright. Dialysis would not be beneficial.
Clinical Studies of Binosto
Treatment of Osteoporosis in Postmenopausal Women
BINOSTO (alendronate sodium) effervescent tablet 70 mg is bioequivalent to alendronate sodium tablet 70 mg. The fracture reduction efficacy and bone mineral density changes attributed to BINOSTO are based on clinical trial data of alendronate sodium 10 mg daily and alendronate sodium 70 mg weekly. Daily Dosing The efficacy of alendronate sodium 10 mg daily was assessed in four clinical trials.
Study 1, a three-year, multicenter double-blind, placebo-controlled, US clinical study enrolled 478 patients with a BMD T-score at or below minus 2.5 with or without a prior vertebral fracture; Study 2, a three-year, multicenter double blind placebo controlled Multinational clinical study enrolled 516 patients with a BMD T-score at or below minus 2.5 with or without a prior vertebral fracture; Study 3, the Three-Year Study of the Fracture Intervention Trial (FIT) a study which enrolled 2027 postmenopausal patients with at least one baseline vertebral fracture; and Study 4, the Four-Year Study of FIT: a study which enrolled 4432 postmenopausal patients with low bone mass but without a baseline vertebral fracture. Effect on Fracture Incidence To assess the effects of alendronate sodium on the incidence of vertebral fractures (detected by digitized radiography; approximately one third of these were clinically symptomatic), the U.S. and Multinational studies were combined in an analysis that compared placebo to the pooled dosage groups of alendronate sodium (5 or 10 mg for three years or 20 mg for two years followed by 5 mg for one year). There was a statistically significant reduction in the proportion of patients treated with alendronate experiencing one or more new vertebral fractures relative to those treated with placebo (3.2% vs. 6.2%; a 48% relative risk reduction). A reduction in the total number of new vertebral fractures (4.2 vs. 11.3 per 100 patients) was also observed. In the pooled analysis, patients who received alendronate had a loss in stature that was statistically significantly less than was observed in those who received placebo (-3.0 mm vs. -4.6 mm). The Fracture Intervention Trial (FIT) consisted of two studies in postmenopausal women: the Three-Year Study of patients who had at least one baseline radiographic vertebral fracture and the Four-Year Study of patients with low bone mass but without a baseline vertebral fracture.
In both studies of FIT, 96% of randomized patients completed the studies (i.e., had a closeout visit at the scheduled end of the study); approximately 80% of patients were still taking study medication upon completion. Fracture Intervention Trial: Three-Year Study (patients with at least one baseline radiographic vertebral fracture) This randomized, double-blind, placebo-controlled, 2027-patient study (alendronate, n=1022; placebo, n=1005) demonstrated that treatment with alendronate sodium resulted in statistically significant reductions in fracture incidence at three years as shown in Table 4. Table 4 Effect of Alendronate Sodium on Fracture Incidence in the Three-Year Study of FIT (Patients With Vertebral Fracture at Baseline) Percent of Patients Alendronate Sodium (N = 1022) Placebo (N = 1005) Absolute Reduction in Fracture Incidence Relative Reduction in Fracture Risk % Patients with: Vertebral fractures (diagnosed by X-ray) Number evaluable for vertebral fractures: alendronate, n=984; placebo, n=966 ≥1 new vertebral fracture 7.9 15.0 7.1 47 p<0.001, ≥2 new vertebral fractures 0.5 4.9 4.4 90 Clinical (symptomatic) fractures Any clinical (symptomatic) fracture 13.8 18.1 4.3 26 p=0.007, ≥1 clinical (symptomatic) vertebral fracture 2.3 5.0 2.7 54 p<0.01, Hip fracture 1.1 2.2 1.1 51 p<0.05 Wrist (forearm) fracture 2.2 4.1 1.9 48 Furthermore, in this population of patients with baseline vertebral fracture, treatment with alendronate sodium significantly reduced the incidence of hospitalizations (25.0% vs. 30.7%). In the Three-Year Study of FIT, fractures of the hip occurred in 22 (2.2%) of 1005 patients on placebo and 11 (1.1%) of 1022 patients on alendronate sodium, p=0.047. Figure 1 displays the cumulative incidence of hip fractures in this study. Figure 1 Cumulative Incidence of Hip Fractures in the Three-Year Study of FIT (Patients With Radiographic Vertebral Fracture at Baseline) Figure 1 Fracture Intervention Trial: Four-Year Study (patients with low bone mass but without a baseline radiographic vertebral fracture) This randomized, double-blind, placebo-controlled, 4432-patient study (alendronate, n=2214; placebo, n=2218) further investigated the reduction in fracture incidence due to alendronate sodium.
The intent of the study was to recruit women with osteoporosis, defined as a baseline femoral neck BMD at least two standard deviations below the mean for young adult women. However, due to subsequent revisions to the normative values for femoral neck BMD, 31% of patients were found not to meet this entry criterion and thus this study included both osteoporotic and non-osteoporotic women. The results are shown in Table 5 for the patients with osteoporosis.
Table 5 Effect of Alendronate on Fracture Incidence in Osteoporotic Baseline femoral neck BMD at least 2 SD below the mean for young adult women Patients in the Four-Year Study of FIT (Patients Without Vertebral Fracture at Baseline) Percent of Patients Alendronate Sodium (N = 1545) Placebo (N = 1521) Absolute Reduction in Fracture Incidence Relative Reduction in Fracture Risk % Patients with: Vertebral fractures (diagnosed by X-ray) Number evaluable for vertebral fractures: alendronate, n=1426; placebo, n=1428 ≥1 new vertebral fracture 2.5 4.8 2.3 48 p<0.001, ≥2 new vertebral fractures 0.1 0.6 0.5 78 p=0.035, Clinical (symptomatic) fractures Any clinical (symptomatic) fracture 12.9 16.2 3.3 22 p=0.01 ≥1 clinical (symptomatic) vertebral fracture 1.0 1.6 0.6 41(NS) Not significant. This study was not powered to detect differences at these sites. Hip fracture 1.0 1.4 0.4 29(NS) Wrist (forearm) fracture 3.9 3.8 -
NS Fracture Results Across Studies
In the Three-Year Study of FIT, alendronate sodium reduced the percentage of women experiencing at least one new radiographic vertebral fracture from 15.0% to 7.9% (47% relative risk reduction, p<0.001); in the Four-Year Study of FIT, the percentage was reduced from 3.8% to 2.1% (44% relative risk reduction, p=0.001); and in the combined U.S./Multinational studies, from 6.2% to 3.2% (48% relative risk reduction, p=0.034). Alendronate sodium reduced the percentage of women experiencing multiple (two or more) new vertebral fractures from 4.2% to 0.6% (87% relative risk reduction, p<0.001) in the combined U.S./Multinational studies and from 4.9% to 0.5% (90% relative risk reduction, p<0.001) in the Three-Year Study of FIT. In the Four-Year Study of FIT, alendronate sodium reduced the percentage of osteoporotic women experiencing multiple vertebral fractures from 0.6% to 0.1% (78% relative risk reduction, p=0.035). Thus, alendronate sodium reduced the incidence of radiographic vertebral fractures in osteoporotic women whether or not they had a previous radiographic vertebral fracture. Effect on Bone Mineral Density The bone mineral density efficacy of alendronate sodium 10 mg once daily in postmenopausal women, 44 to 84 years of age, with osteoporosis (lumbar spine bone mineral density of at least 2 standard deviations below the premenopausal mean) was demonstrated in 4 double-blind, placebo-controlled clinical studies of 2 or 3 years' duration. Figure 2 shows the mean increases in BMD of the lumbar spine, femoral neck, and trochanter in patients receiving alendronate sodium 10 mg/day relative to placebo-treated patients at three years for each of these studies.
Figure 2 Osteoporosis Treatment Studies in Postmenopausal Women Increase in BMD Alendronate Sodium 10 mg/day at Three Years At 3 years significant increases in BMD, relative both to baseline and placebo, were seen at each measurement site in each study in patients who received alendronate 10 mg/day. Total body BMD also increased significantly in each study, suggesting that the increases in bone mass of the spine and hip did not occur at the expense of other skeletal sites. Increases in BMD were evident as early as 3 months and continued throughout the 3 years of treatment. ( See figures below for lumbar spine results.) In the 2-year extension of these studies, treatment of 147 patients with alendronate sodium 10 mg/day resulted in continued increases in BMD at the lumbar spine and trochanter (absolute additional increases between years 3 and 5: lumbar spine, 0.94%; trochanter, 0.88%). BMD at the femoral neck, forearm and total body were maintained.
Alendronate sodium was similarly effective regardless of age, race, baseline rate of bone turnover, and baseline BMD in the range studied (at least 2 standard deviations below the premenopausal mean). Figure 3 Osteoporosis Treatment in Studies in Postmenopausal Women Time Course Effect of Alendronate Sodium 10 mg/day Versus Placebo: Lumbar Spine BMD Percent Change From Baseline In patients with postmenopausal osteoporosis treated with alendronate sodium 10 mg/day for one or two years, the effects of treatment withdrawal were assessed. Following discontinuation, there were no further increases in bone mass and the rates of bone loss were similar to those of the placebo groups. Figure 2 Figure 3 Bone Histology Bone histology in 270 postmenopausal patients with osteoporosis treated with alendronate sodium at doses ranging from 1 to 20 mg/day for one, two, or three years revealed normal mineralization and structure, as well as the expected decrease in bone turnover relative to placebo.
These data, together with the normal bone histology and increased bone strength observed in rats and baboons exposed to long-term alendronate treatment, support the conclusion that bone formed during therapy with alendronate sodium is of normal quality. Effect on height Alendronate sodium, over a three- or four-year period, was associated with statistically significant reductions in loss of height vs. placebo in patients with and without baseline radiographic vertebral fractures. At the end of the FIT studies the between-treatment group differences were 3.2 mm in the Three-Year Study and 1.3 mm in the Four-Year Study.
Weekly dosing The therapeutic equivalence of once weekly alendronate sodium 70 mg (n=519) and alendronate sodium 10 mg daily (n=370) was demonstrated in a one-year, double-blind, multicenter study of postmenopausal women with osteoporosis. In the primary analysis of completers, the mean increases from baseline in lumbar spine BMD at 1 year were 5.1% (4.8, 5.4%; 95% CI) in the 70 mg once-weekly group (n=440) and 5.4% (5.0, 5.8%; 95% CI) in the 10 mg daily group (n=330). The 2 treatment groups were also similar with regard to BMD increases at other skeletal sites. The results of the intention-to-treat analysis were consistent with the primary analysis of completers.
Treatment to Increase Bone Mass in Men with Osteoporosis
The efficacy of alendronate sodium in men with hypogonadal or idiopathic osteoporosis was demonstrated in two clinical studies. Daily Dosing A two-year, double-blind, placebo-controlled, multicenter study of alendronate sodium 10 mg once daily enrolled a total of 241 men between the ages of 31 and 87 (mean, 63). All patients in the trial had either: 1) a BMD T-score less than or equal to -2 at the femoral neck and less than or equal to -1 at the lumbar spine, or 2) a baseline osteoporotic fracture and a BMD T-score less than or equal to -1 at the femoral neck. At two years, the mean increases relative to placebo in BMD in men receiving alendronate sodium 10 mg/day were significant at the following sites: lumbar spine, 5.3%; femoral neck, 2.6%; trochanter, 3.1%; and total body, 1.6%. Treatment with alendronate sodium also reduced height loss (alendronate, -0.6 mm vs. placebo, -2.4 mm). Weekly dosing A one-year, double-blind, placebo-controlled, multicenter study of once weekly alendronate sodium 70 mg enrolled a total of 167 men between the ages of 38 and 91 (mean, 66). Patients in the study had either: 1) a BMD T-score less than or equal to -2 at the femoral neck and less than or equal to -1 at the lumbar spine, 2) a BMD T-score less than or equal to -2 at the lumbar spine and less than or equal to -1 at the femoral neck, or 3) a baseline osteoporotic fracture and a BMD T-score less than or equal to -1 at the femoral neck.
At one year, the mean increases relative to placebo in BMD in men receiving alendronate sodium 70 mg once weekly were significant at the following sites: lumbar spine, 2.8%; femoral neck, 1.9%; trochanter, 2.0%; and total body, 1.2%. These increases in BMD were similar to those seen at one year in the alendronate sodium 10 mg once-daily study. In both studies, BMD responses were similar regardless of age (greater than or equal to 65 years vs. less than 65 years), gonadal function (baseline testosterone less than 9 ng/dL vs. greater than or equal to 9 ng/dL), or baseline BMD (femoral neck and lumbar spine T-score less than or equal to -2.5 vs. greater than -2.5).
Drug information sourced from the FDA. This content is for informational purposes only and does not constitute medical advice. Consult a healthcare professional before making any medication decisions.
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