Objective. The objective of this review is to present the clinical profiles of the once-weekly and once-daily dosing formulations of alendronate and risedronate, the 2 bisphosphonates currently available in the United States for the prevention and treatment of postmenopausal osteoporosis.Data Source/Study Selection. Data were obtained from a MEDLINE literature search of all English language articles published between January 1996 and April 2004 using generic names of the bisphosphonates alendronate and risedronate. Results were refined by incorporating terms such as “osteoporosis,” “bone mineral density,” “fracture risk,” and “adverse events.” Randomized, controlled trials of once-daily and once-weekly bisphosphonate therapies were selected. Also selected for review were post hoc analyses and extension studies of the original controlled trials, including more recent data from published abstracts from scientific meetings.Data Extraction. Relevant portions of articles obtained from the literature search were used to summarize the efficacy and tolerability of the 2 therapies.Conclusions. In prospective trials, both bisphosphonates were effective in reducing vertebral and hip fractures in women with postmenopausal osteoporosis. In the only prospective trial evaluating hip fracture risk reduction as the primary end point, risedronate was effective at reducing hip fracture vs placebo. Both alendronate and risedronate are available in once-weekly formulations that have efficacy and tolerability profiles similar to the once-daily doses. Clinicians should review all available data for both agents as well as the medical history of the patient to make the most appropriate treatment choice.Introduction
Osteoporosis is characterized by low bone mass and a disruption in skeletal microarchitecture. The disease typically progresses without symptoms until a fracture occurs and has, therefore, been labeled a silent disease. Osteoporosis and low bone mass are estimated to be health concerns for more than 50% of people aged 50 years and older in the United States. Of the affected population, almost 70% are women with postmenopausal osteoporosis.
Fracture is the most serious clinical consequence of osteoporosis. Vertebral fracture can lead to significant back pain, disability, disfigurement, decreased quality of life, and an increased mortality rate.[2,3] Moreover, women with at least 1 vertebral fracture have a 1 in 5 chance of sustaining another vertebral fracture within the following year, demonstrating the characteristic rapid progression of osteoporosis. Fractures of the wrist and humerus are also associated with disability. Moreover, all fractures, including fractures of the wrist, increase the risk of future fractures.
Hip fracture commonly results in profound physical disability, a need for short- or long-term nursing care, and loss of independence. One quarter of patients aged 50 years and older who fracture their hip die in the year following their fracture, and another 25% who were ambulatory before the hip fracture require long-term care afterward. Therefore, reduction of fracture risk is the most important goal of treatment for osteoporosis.
Because osteoporosis can be asymptomatic, compliance and persistence with medication dosing are not optimal. Poor daily compliance and lack of persistence are major issues for most patients with chronic asymptomatic diseases.[10-12] Another potential detriment to compliance is the dosing regimen; that is, inflexible daily dosing schedules. For the bisphosphonates alendronate and risedronate, which are considered to be 2 of the most effective therapies for osteoporosis, this includes having to take the medication 30 minutes before the first meal or beverage other than water while remaining in an upright position.
Medications for the treatment of postmenopausal osteoporosis in the United States include the bisphosphonates alendronate, risedronate, and ibandronate; the selective estrogen receptor modulator raloxifene; salmon calcitonin nasal spray; and teriparatide. Alendronate, risedronate, and raloxifene are also approved for the prevention of postmenopausal osteoporosis, as well as various estrogen (Premarin, Alora, Climara) and estrogen plus progestin (Prempro, femhrt, Prefest, Vivelle) preparations. Although it is approved by the US Food and Drug Administration for the prevention and treatment of postmenopausal osteoporosis, ibandronate is not marketed in the United States. Only alendronate and risedronate are available in daily and once-weekly formulations.[13,14] Raloxifene, salmon calcitonin, and teriparatide are currently available only in the daily formulation.[15-17] Administration of hormone therapy may be once daily[18-21] or continuous (transdermal).[22-24]
In this article, the clinical profiles of the once-weekly and once-daily dosing formulations of alendronate and risedronate are reviewed. Data discussed are from a MEDLINE literature search conducted using the generic names of the bisphosphonates alendronate and risedronate. English language articles published between January 1996 and April 2004 were included. Terms such as “osteoporosis,” “bone mineral density,” “fracture risk,” and “adverse events” were added to further refine the search results. All placebo-controlled trials evaluating once-daily alendronate and risedronate for postmenopausal osteoporosis were included in this review, with an emphasis on those studies that included fracture end points. Studies evaluating the once-weekly regimens included head-to-head comparisons with the once-daily regimens. Data from post hoc analyses of the pivotal trials and long-term extensions were also discussed, including data obtained from published abstracts from recent scientific meetings. The patients evaluated in these studies were predominantly white postmenopausal women. Data pertaining to other ethnic groups were not available.
Clinical Efficacy of the Bisphosphonates: Once-Daily RegimensAlendronate
The antifracture efficacy and safety of daily administered alendronate for the treatment of postmenopausal osteoporosis have been reported in 3 randomized, placebo-controlled trials.[25-27] Patients received 5 mg, 10 mg, or 20 mg alendronate daily, or placebo. In addition to the study drug, patients also received a calcium supplement of 500 mg per day. The Fracture Intervention Trial (FIT) was conducted in 2 separate arms — a 3-year arm that enrolled 2027 subjects with existing vertebral fractures at baseline (FIT I) and a 4-year arm that included 4432 subjects without vertebral fractures at baseline (FIT II), one third of whom had osteoporosis based on femoral neck bone mineral density (BMD) — and investigated the effect of alendronate on fracture incidence in postmenopausal women with low femoral neck BMD (= 0.68 g/cm2, about -1.6 standard deviations [SDs] below peak bone mass). Excluded from the studies were women with recent peptic ulcer disease or ulcers requiring hospitalization, and dyspepsia requiring daily treatment. Women with past or current histories of upper gastrointestinal tract disease requiring less frequent treatment were eligible. Patients treated with nonsteroidal anti-inflammatory drugs were not excluded for the same reason. Lateral spine radiographs were obtained to detect morphometric vertebral fractures at 2 and 3 years (FIT I) and at 4 years (FIT II).
After 3 and 4 years of treatment in the FIT I and II studies, alendronate reduced vertebral fracture risk by 47% (P -2.5), hip fracture was reduced by 56% (P The efficacy of alendronate was also evaluated in 2 nearly identical 3-year dose-ranging studies of postmenopausal women with osteoporosis (lumbar spine T-score = -2.5). Women with active peptic ulcer disease were excluded from these studies. Subjects were randomized to receive alendronate 5 mg or 10 mg daily for 3 years, alendronate 20 mg daily for 2 years, followed by 5 mg daily in the third year, or placebo for 3 years.
Alendronate 10 mg/day and alendronate 20 mg/day for 2 years followed by 5 mg/day for the third year were found to be more effective than the 5-mg/day dose at building BMD. A significant reduction in new vertebral fractures vs placebo was observed when all patients receiving alendronate were pooled (48%; P = .03).
The long-term efficacy and tolerability of alendronate were evaluated in two 2-year extensions, followed by a 3-year extension of the dose-ranging studies. During the first 2-year extension, patients receiving placebo in the original studies were switched to alendronate 10 mg/day for years 4 and 5. During the second 2-year extension, patients who received the 20-mg/day followed by the 5-mg/day regimen were switched to placebo and remained on placebo during the following 3-year extension. Patients receiving placebo during the original study were not eligible for enrollment into the second and third extensions.[31,32]
In patients receiving continuous treatment (alendronate 5 mg/day or 10 mg/day), bone density continued to increase over the 10-year evaluation period. Patients receiving alendronate 20 mg/day for 2 years, followed by alendronate 5 mg/day for 1 year of the original study and 2 years of the first extension, and then placebo for years 6 to 10, showed no significant change in BMD at both the lumbar spine and total body during the 5 years in which they received placebo. Because the first extension was not placebo-controlled, fracture risk reduction for years 4 to 10 could not be calculated.Risedronate
The antifracture efficacy and safety of the 5-mg daily regimen of risedronate in postmenopausal women with osteoporosis have been demonstrated in 3 large, multicenter, double-blind clinical trials.[33-35] Patients were randomly assigned to treatment with either oral risedronate (2.5 mg/day or 5.0 mg/day) or placebo. In the vertebral fracture trials discussed here, osteoporosis was defined as the presence of at least 2 vertebral fractures or a lumbar spine BMD T-score of In two 3-year, placebo-controlled trials, the Vertebral Efficacy With Risedronate Therapy-Multinational (VERT-MN) and -North America (VERT-NA) trials, the risk of new vertebral fractures in postmenopausal women with osteoporosis was significantly reduced by 61% to 65%, respectively, (P= .001; Table 1) after 1 year of risedronate 5-mg/day therapy vs placebo.[33,34] Furthermore, in pooled analyses, risedronate 5 mg/day significantly reduced clinical vertebral and nonvertebral fracture risk after 6 months of treatment (P A post hoc analysis combining the 3-year data from the VERT-MN study and a 2-year extension of the same study found that antifracture efficacy was sustained during 5 years of treatment, with a 50% reduction in vertebral fracture risk vs placebo (P The placebo-controlled 2-year extension described earlier was followed by an open-label 2-year extension. During years 6 and 7, BMD continued to increase, similar to the findings over 7 years in a study of alendronate. Reduction of fracture risk could not be calculated for the second 2-year risedronate extension trial because it was not placebo-controlled.
The Hip Intervention Program study specifically examined the effect of risedronate therapy on the risk of hip fracture over 3 years. In women aged 70 to 79 years with confirmed osteoporosis (femoral neck BMD more than 3 SDs below young adult women), once-daily risedronate (2.5- and 5-mg groups combined) significantly reduced the risk of hip fracture by 40% (P = .009) vs placebo. In women with confirmed osteoporosis and 1 or more vertebral fractures at baseline, risedronate reduced the risk of hip fracture by 60% (P = .003). Risedronate therapy had no significant effect (P = .35) on hip fracture risk in the group of women aged >/= 80 years that were selected primarily on the basis of nonskeletal risk factors.
Clinical Efficacy of the Bisphosphonates: Once-Weekly AdministrationAlendronate
A randomized, placebo-controlled trial comparing once-daily, twice-weekly, and once-weekly alendronate was conducted on 1258 women aged 42 to 95 years with postmenopausal osteoporosis over a period of 2 years.[40,41] Patients enrolled in the study had prior vertebral or hip fracture, or BMD of the lumbar spine or femoral neck of at least -2.5 SD below the normal reference mean. Patients were randomized to receive alendronate 70 mg once weekly, 35 mg twice weekly, or 10 mg/day. Patients also received calcium 500 mg/day and vitamin D 250 IU/day. Results of this study showed similar reductions in bone turnover marker assays and increases in BMD among the 3 groups (Table 3). After 2 years of therapy, patients in the weekly and twice-weekly alendronate (70 mg and 35 mg, respectively) groups had a mean increase in lumbar spine BMD of 6.8% and 7.0%, respectively; patients in the daily alendronate (10 mg) group experienced a 7.4% increase. Differences in BMD at the lumbar spine and hip were not statistically significant among the 3 groups. Effects of alendronate on bone turnover markers were seen as early as 1 month after initiation of therapy regardless of the dosing regimen. All the treatment regimens resulted in a reduction of bone turnover marker levels to the premenopausal reference range. Clinical fractures captured as adverse events were similar among the 3 groups. Reductions in bone turnover and increases in lumbar spine BMD continued to be similar among the once-daily, twice-weekly, and once-weekly regimens over a second year. Incidence rates of clinical fractures also continued to be similar during the 1-year extension.Risedronate
In a multicenter, randomized, double-blind study, the efficacy and safety of risedronate administered once weekly (35 mg/week or 50 mg/week) was compared with the 5-mg once-daily risedronate regimen in 1456 postmenopausal women with osteoporosis (lumbar spine BMD T-score of In a retrospective comparison by Watts and colleagues, fracture risk reduction with risedronate 35 mg once weekly was evaluated using historical risedronate 5 mg/day and placebo-controlled groups constructed by matching patients from the VERT-MN and -NA studies to patients in the once-weekly trial using the once-weekly trial’s enrollment criteria. No statistically significant differences in vertebral fracture incidence were observed between the 5-mg/day groups from the phase 3 (1.7%; VERT-MN and -NA) and once-weekly (1.5%) studies. Relative reduction in the risk of new vertebral fractures with risedronate once weekly (77%) was similar to the 1-year reductions (65% and 61%) reported for once-daily risedronate.[33,34] Fracture risk reduction with risedronate 35 mg once weekly continued to be significant over 2 years compared with placebo.
An open-label study evaluated changes in BMD and tolerability to risedronate 30 mg once weekly over a period of 2 years.[46,47] Mean increases in BMD were significantly higher in year 2 than in year 1 (P
Data from the 2 FIT trials showed a similar incidence of upper gastrointestinal adverse events in the alendronate group when compared with the placebo group. The incidences for upper gastrointestinal events vs placebo were 41.3% and 40.0%, respectively, in the trial evaluating women with existing vertebral fractures and 47.5% and 47.2%, respectively, in the trial in women with low bone density but no fractures. Incidences of upper gastrointestinal adverse events were similar with alendronate 10 mg/day and 70 mg once weekly (23.5% and 22.4%, respectively) at 1 year, and at 2 years (30.0% and 29.3%, respectively).Risedronate
In the comparison between risedronate 5 mg once daily and risedronate 35 mg or 50 mg once weekly, the percentage of women who reported adverse events, and specifically upper gastrointestinal adverse events, was similar among all 3 treatment groups; 17.5%, 18.4%, and 18.7% for risedronate 5 mg/day, 35 mg once weekly, and 50 mg once weekly, respectively. Thus, risedronate once daily and risedronate once weekly are equally well-tolerated in women with postmenopausal osteoporosis.Alendronate vs Risedronate
Following approval when alendronate was first used in the clinical practice setting, patients reported upper gastrointestinal distress more frequently than expected.[49-54] Adverse events included acute esophagitis with exudative inflammation, ulcerations, upper gastrointestinal bleeding, and esophageal stricture requiring dilation. The relatively high incidence of postmarketing reports may have been related to poor patient instruction and an underappreciation by physicians of proper bisphosphonate dosing techniques. A recent review of upper gastrointestinal event data indicates that clinical reports of esophagitis appear to have declined and suggests that the decline may be due to proper bisphosphonate administration.
Special Dosing Considerations for Bisphosphonates
As with other second- and third-generation oral bisphosphonates, alendronate and risedronate should be taken at least 30 minutes to 1 hour before the first food or drink of the day to avoid interference with absorption. Both medications should be swallowed whole with a full glass of plain water while the patient is in an upright position to minimize the potential for upper gastrointestinal irritation. The patient should not lie down for 30 minutes after taking the medication. Patients should receive supplemental calcium and, if dietary intake is inadequate, supplemental vitamin D. However, the potential for interference with the absorption of alendronate and risedronate necessitates administration of calcium supplements, as well as any calcium-, aluminum-, and magnesium-containing medication, at a different time of the day from the bisphosphonate dose.
The bisphosphonates are not recommended for use in patients with severe renal impairment (defined as creatinine clearance
Costs of Treatment
Costs of treatment for the once-daily and once-weekly regimens of the bisphosphonates are similar. The monthly costs for all available osteoporosis therapies approved for the treatment and/or prevention of postmenopausal osteoporosis are provided in Table 5.
Once a patient has been identified to be at risk of fracture, the most important therapeutic goal is to reduce this risk as quickly as possible. The bisphosphonates alendronate and risedronate have consistently been shown to be effective therapies for the prevention and treatment of osteoporosis. Both alendronate and risedronate have consistently reduced the risk of morphometric vertebral fractures in patients treated for at least 3 years, and prospective risedronate trials demonstrated reductions in morphometric vertebral fracture risk as early as 1 year. Reductions in clinical vertebral fractures were observed after 1 year of treatment with alendronate and risedronate. Significant reductions in nonvertebral fractures with both bisphosphonates were also seen after 1 year of treatment.
Less frequent administration of a chronic medication may improve patient compliance (as shown by fluoxetine). For some women, long-term compliance with treatment for postmenopausal osteoporosis may be more convenient with a once-weekly dosage regimen. The tolerability profiles of once-weekly bisphosphonate regimens are similar to the once-daily.[40,41,43] Risedronate once daily is well-tolerated in women with postmenopausal osteoporosis, including those at increased risk of upper gastrointestinal adverse events due to preexisting upper gastrointestinal disease or the concomitant use of potentially ulcerogenic agents. In a head-to-head trial of the 2 bisphosphonates, alendronate 10 mg/day was associated with a higher incidence of gastric and esophageal ulcers than risedronate 5 mg/day. EGD scores were also higher. However, in a second study, with a higher dose of both bisphosphonates and longer duration of treatment, endoscopic gastric ulcers were similar in both bisphosphonate treatment groups.
In conclusion, once-weekly administration of alendronate or risedronate provides efficacy (increasing BMD and decreasing markers of bone turnover) and safety similar to once-daily administration in the treatment of postmenopausal women with osteoporosis. Because of the differences in trial protocols and the paucity of head-to-head comparisons between these bisphosphonates, clinicians should be aware of the data available for both bisphosphonates when considering a treatment option.