Alendronate is used in the treatment and prevention of osteoporosis in postmenopausal women; the drug also is used to increase bone mass in men with osteoporosis.
Osteoporosis, a systemic skeletal disease characterized by low bone mass and microarchitectural deterioration of bone tissue with consequent increased bone fragility and susceptibility to fracture (usually of the spine, hip, and wrist), is observed in a large proportion of postmenopausal women. Adult women have less bone mass than men at all ages, and decreased production of estrogen at menopause is associated with accelerated bone loss, particularly from the lumbar spine, for about 5 years, during which time skeletal mass loss averages 3% per year. Osteoporosis from age-related bone loss can also develop in men. While the risk of osteoporosis and resulting fractures cannot be quantified by a single clinical finding or test result, many risk factors have been identified, with the probability of developing osteoporosis increasing with multiple risk factors. Risk factors include early menopause, advanced age, low bone mineral density (BMD), low body mass index (BMI), previous fracture or family history of fracture/osteoporosis, excessive alcohol intake, smoking, inadequate physical activity, low calcium and vitamin D intake, certain drugs (e.g., glucocorticoids), and medical conditions or diseases (e.g., rheumatoid arthritis, diabetes mellitus, Cushing syndrome, hyperparathyroidism).
In addition to lifestyle modifications (e.g., regular weight-bearing exercise, avoidance of excessive alcohol and tobacco use), adequate intake of calcium (1-1.2 g daily) and vitamin D (800-1000 units daily) is essential in the prevention and treatment of osteoporosis and is recommended for all postmenopausal women and men 50 years of age or older. Additional pharmacologic therapy should be considered in such patients with high risk of fractures (generally those who have experienced a previous hip or vertebral fracture or who have low BMD). Pharmacologic therapy also may be considered in postmenopausal women and in men 50 years of age or older who have low bone mass, although there is less evidence supporting overall fracture risk reduction in such patients. When selecting an appropriate pharmacologic agent, experts recommend use of a drug with proven antifracture efficacy; available options include bisphosphonates (e.g., alendronate, risedronate, zoledronic acid, ibandronate), denosumab, raloxifene, calcitonin, or teriparatide with varying levels of recommendation given in expert guidelines based on the evidence supporting fracture risk reduction for each drug. While estrogen/hormone therapy was commonly used in the past for the treatment of osteoporosis in postmenopausal women, there is some evidence indicating that such therapy is associated with an increased risk of breast cancer, cardiovascular, cerebrovascular, and thromboembolic events. Choice of osteoporosis therapy should be individualized based on the potential benefits and adverse effects of therapy as well as patient preferences, comorbidities, and risk factors.
Prevention in Postmenopausal Women
Alendronate is used for the prevention of osteoporosis in postmenopausal women. The drug is used adjunctively with other measures (e.g., diet, calcium, vitamin D, weight-bearing exercise, physical therapy, avoidance of excessive cigarette smoking and/or alcohol consumption) to retard further bone loss and the progression of osteoporosis in postmenopausal women. The goal of preventive therapy is preservation of bone mass and a resultant decrease in fracture risk.
Alendronate has been evaluated for the prevention of osteoporosis in postmenopausal women in 2 double-blind, placebo-controlled studies of 2 or 3 years' duration that included 2056 women (40-60 years of age). In these studies, therapy with alendronate 5 mg daily increased BMD, as determined by dual-energy radiographic absorption (DXA) measurements, in the lumbar spine, femoral neck, trochanter bone, and total body. While women receiving placebo lost approximately 1% of BMD per year, substantial increases in BMD were observed in women receiving alendronate. In one of the studies that included postmenopausal women who had experienced menopause 6-36 months before initiation of the study, administration of alendronate (5 or 10 mg daily given for 3 years or, alternatively, 20 mg daily given for 2 years, followed by administration of placebo daily for 1 year) at 3 years was associated with a 1-4% increase in lumbar spine, femoral neck, and trochanter BMD and 0.3-1% increase in total body BMD compared with baseline, while placebo recipients lost about 2-4% BMD in these sites; a lower dosage (1 mg daily) of alendronate for 3 years attenuated but did not fully prevent losses in BMD relative to those in women receiving placebo. Limited data indicate that alendronate (5 mg daily) reduced the rate of bone loss on forearm by about half relative to placebo. In a 1-year controlled study in postmenopausal women with osteoporosis, alendronate 70 mg once weekly produced increases in BMD similar to those observed with a dosage of 10 mg daily.
In osteoporosis prevention studies that evaluated alendronate therapy (Early Postmenopausal Intervention Cohort Study) for 24 months, raloxifene (European trial), or various estrogen/progestin combinations for hormone replacement therapy (HRT), alendronate (5 mg daily) therapy was associated with 1.3-1.9% increases in hip BMD compared with baseline, raloxifene hydrochloride therapy (60 mg daily) was associated with 1.6% increases, and HRT was associated with 1.8-3.2% increases. In these studies, alendronate, raloxifene, or HRT was associated with increases in BMD of lumbar spine of 2.9-3.5%, 1.6%, or 4-5.1%, respectively, compared with baseline.
Treatment in Postmenopausal Women
Alendronate is used alone or in fixed combination with cholecalciferol (vitamin D3) for the treatment of osteoporosis in postmenopausal women.
In several double-blind, placebo-controlled trials in postmenopausal women with osteoporosis (defined as lumbar spine BMD values at least 2 standard deviations below premenopausal mean values), therapy with alendronate 10 mg daily for 2-3 years substantially increased BMD in the lumbar spine, femoral neck, and trochanter; total body BMD also increased, suggesting that BMD increases in the spine and hip did not occur at the expense of other skeletal sites. In long-term trials (e.g., 3 years with several extensions up to 10 years), increases in BMD were apparent as early as 3 months after initiation of alendronate therapy and continued throughout therapy. Results of some studies indicate that some therapeutic effects on bone mass are maintained for up to 5 years following withdrawal of alendronate therapy (following 5 years of treatment) at the lumbar spine, trochanter, and total body; after discontinuance of therapy, BMD decreased appreciably at the femoral neck and forearm over the next 5 years of follow-up. Bone histology studies in postmenopausal women with osteoporosis treated with alendronate 1-20 mg daily for 1, 2, or 3 years indicate that bone formed during treatment with the drug is of normal quality. Among women who had sustained a vertebral fracture, alendronate therapy reduced the risk of new vertebral fractures, including women at high risk for further vertebral fractures (e.g., those with severe osteoporosis, those 75 years or older).
Analysis of pooled data from several US and multinational placebo-controlled trials in postmenopausal women indicates that alendronate therapy (5 or 10 mg daily for 3 years, or 20 mg daily for 2 years followed by 5 mg daily for 1 year) was associated with a reduced incidence of vertebral fractures (a 48% relative risk reduction) and, because of a reduction in the frequency and severity of fractures, less height loss than that occurring with placebo, even among patients who sustained a vertebral fracture. Several large, placebo-controlled clinical trials have noted a reduced incidence of vertebral and other types of fractures (e.g., hip, wrist) in postmenopausal women, most of whom had osteoporosis. In a large, placebo-controlled clinical trial in women with osteoporosis who had an existing vertebral fracture, alendronate therapy (5 or 10 mg once daily given concomitantly with calcium and vitamin D supplementation) reduced the incidence of hip fracture by 51% and wrist fracture by 48% at 3 years; the proportion of patients requiring hospitalization also was reduced (31 or 25% with placebo or alendronate, respectively). The frequency of adverse effects, including GI disorders, also was similar between alendronate or placebo. In another large, long-term (4-year), placebo-controlled trial in women with low BMD but without vertebral fractures, alendronate (5 mg daily for 2 years, then 10 mg daily thereafter) reduced the risk of clinical fractures in women with osteoporosis (baseline femoral neck BMD exceeding 2.5 standard deviations below the normal adult mean) but not in those with higher BMDs. The incidence of atrial fibrillation in these 2 placebo-controlled trials was numerically higher in the alendronate-treated groups compared with that observed in the placebo-treated groups.
Alendronate has been used concomitantly with various estrogen or estrogen/progestin combinations and calcium to increase bone mass in postmenopausal women with osteoporosis. In several clinical trials in postmenopausal women with osteoporosis, the combination of estrogen-containing hormone replacement therapy (HRT) and alendronate resulted in a greater degree of suppression of bone turnover than either therapy given alone. In a long-term, placebo-controlled trial comparing therapy with alendronate (10 mg once daily), conjugated estrogens (0.625 mg daily), or the combination of these drugs in postmenopausal women with osteoporosis who had undergone hysterectomy and were not currently receiving antiresorptive therapy, combination therapy increased lumbar spine and femoral neck BMD to a greater degree than either agent alone or placebo at 2 years. All women received supplementation with calcium 500 mg daily. Bone histology studies in these patients indicated that the bone formed during therapy was of normal quality. Compared with placebo, bone turnover after 18 months was suppressed by 98% with combined alendronate and HRT, 94% with alendronate therapy alone, and 78% with HRT alone. In another comparative study in postmenopausal women who had osteoporosis despite receiving estrogen or estrogen plus progestin (medroxyprogesterone) HRT for at least 1 year (mean duration almost 10 years), the addition of alendronate (10 mg once daily) to supplementation with daily vitamin D and calcium (if baseline calcium intake was less than 1000 mg daily) increased BMD in the lumbar spine and hip trochanter compared with HRT alone. In either trial, the incidence of new fractures was similar across treatment groups. However, the size and duration of these studies may have been inadequate to detect differences in fracture incidence for combination therapy compared with alendronate or placebo, and further studies are needed. The safety of combination therapy reportedly was consistent with that of each antiresorptive agent alone. However, some clinicians state that concomitant hormone replacement therapy currently is not recommended in patients receiving alendronate because of lack of clinical experience with such use.
Treatment in Men
Alendronate also is used alone or in fixed combination with cholecalciferol (vitamin D3) for the treatment of osteoporosis in men. In a double-blind, placebo-controlled trial in men 31-87 years of age (mean age: 63) with hypogonadal or idiopathic osteoporosis, therapy with alendronate (10 mg daily) substantially increased BMD in the lumbar spine, hip, femoral neck, and trochanter; total body BMD also increased, suggesting that BMD increases in the spine and hip did not occur at the expense of other skeletal sites. Osteoporosis in these men was defined as a femoral neck BMD value at least 2 standard deviations below the mean in healthy young men and a lumbar spine BMD value at least 1 standard deviation below the mean in healthy young men, or a femoral neck BMD of at least 1 standard deviation below the mean value in healthy young men and at least one sustained fracture. All patients in the study received supplemental calcium (500 mg daily as calcium carbonate) and vitamin D (400-450 units daily). Increases in BMD were apparent as early as 6 months after initiation of alendronate therapy and continued throughout therapy. Alendronate therapy was associated with a reduced incidence of new vertebral fractures and, because of a reduction in the frequency of fractures, less height loss than that occurring with calcium and vitamin D supplementation only.
In another double-blind, placebo-controlled trial in men 38-91 years of age (mean age: 66 years) with hypogonadal or idiopathic osteoporosis, therapy with alendronate (70 mg once weekly for 1 year) substantially increased BMD in the lumbar spine, femoral neck, trochanter, and total body. Osteoporosis in these men was defined as a femoral neck BMD value at least 2 standard deviations below the mean for healthy young men and a lumbar spine BMD value at least 1 standard deviation below the mean for healthy young men; a lumbar spine BMD of at least 2 standard deviations below the mean value for healthy young men and a femoral neck BMD value at least 1 standard deviation below the mean for healthy young men; or at least one sustained fracture and a femoral neck BMD value at least 1 standard deviation below the mean for healthy young men. The increases in BMD with weekly therapy were similar to those seen at 1 year in patients receiving 10 mg of alendronate daily. Among men receiving alendronate in both studies (daily or weekly therapy), response to therapy was similar regardless of age (65 years of age or older, younger than 65 years of age), gonadal function (baseline testosterone concentrations of at least 9 ng/dL, less than 9 ng/dL), or baseline BMD (femoral neck and lumbar spine BMD at least 2.5 standard deviations from the mean for young men, less than 2.5 standard deviations from the mean).
Alendronate is used in the treatment of glucocorticoid-induced osteoporosis. The manufacturer recommends use of alendronate in men and women receiving a daily dosage equivalent to at least 7.5 mg of prednisone who have low BMD; risks versus benefits of alendronate therapy in patients receiving a lower dosage of glucocorticoids have not been established. Alendronate also has been used in the prevention of glucocorticoid-induced osteoporosis.
Osteoporosis and related fractures are some of the most serious complications of long-term glucocorticoid therapy. More than 10% of patients are diagnosed with a fracture and 30-40% have radiographic evidence of vertebral fractures during long-term glucocorticoid use. The risk of fracture is both dose and duration dependent, with higher daily or cumulative doses of glucocorticoids and longer durations of use associated with greater risk. A high glucocorticoid dosage generally is considered a daily dosage equivalent to more than 7.5 mg of prednisone. However, some studies have reported an increased risk of fracture with daily dosages as low as 2.5-7.5 mg of prednisolone or equivalent, while others have found no appreciable decline in bone density with prednisone dosages averaging 8 mg daily or dosages of less than 5 mg daily. Because glucocorticoid-induced osteoporosis can be effectively prevented, the American College of Rheumatology (ACR) recommends that appropriate preventive therapy be considered for patients in whom the benefits of such therapy outweigh the potential harms. ACR recommendations are based on a risk-stratification approach in which an individual's risk level for developing a fracture (low, moderate, or high) is determined based on predisposing factors including the individual's preexisting or anticipated glucocorticoid dosage. An initial clinical fracture risk assessment is recommended within 6 months of initiating long-term glucocorticoid therapy with reassessments recommended every 12 months during continued treatment. Lifestyle modifications (e.g., diet, smoking cessation, weight-bearing or resistance-training exercise) and calcium/vitamin D intake should be optimized in all patients receiving long-term (at least 3 months) glucocorticoid therapy at a daily dosage equivalent to at least 2.5 mg of prednisone. The need for additional pharmacologic therapy should be determined based on the patient's risk for fractures. ACR recommends an oral bisphosphonate in adults receiving long-term glucocorticoid therapy who are considered to be at moderate-to-high risk of fracture. Oral bisphosphonates generally are preferred because of their demonstrated benefits in reducing fracture risk as well as their safety and low cost; other options include IV bisphosphonates, teriparatide, denosumab, and raloxifene (for postmenopausal women if no other therapy is appropriate). ACR states that the available data on fracture risk and risk reduction are more limited in children and adults younger than 40 years of age; however, treatment with oral bisphosphonates and calcium/vitamin D is recommended because the possible benefits appear to outweigh the risks. For additional information on the prevention and treatment of glucocorticoid-induced osteoporosis,
Alendronate has been evaluated for the treatment of glucocorticoid-induced osteoporosis in men and women with a variety of underlying diseases (e.g., rheumatoid arthritis, systemic lupus erythematosus, polymyalgia rheumatica, inflammatory myopathy, inflammatory bowel disease, asthma) and usually with low bone mineral density (e.g., 1-2 standard deviations below the mean for healthy young adults in more than 70% of those studied) who were receiving glucocorticoid therapy (e.g., a daily dosage of at least 7.5 mg of prednisone or equivalent) in 2 placebo-controlled, double-blind, randomized studies of 1 year's duration and an extension of one of these studies for a total duration of 2 years. In these studies, therapy with alendronate 5 or 10 mg daily (given concomitantly with calcium and vitamin D supplementation) increased BMD, as determined by DXA measurements in the lumbar spine, femoral neck, trochanter bone, and total body; 2 years after initiating alendronate therapy, lumbar BMD was increased by 2.8-3.9 and trochanter BMD also was increased and femoral neck BMD maintained relative to baseline values. While patients receiving placebo lost approximately 0.4, 0.7, or 1.2% of BMD within about 1 year at the lumbar spine, trochanter bone, or femoral neck, respectively, and 0.8% with 2 years at the lumbar spine; BMD either increased or was maintained in these sites in patients receiving alendronate for such periods of time. Administration of alendronate 5 mg daily was associated with a 2.1, 1.1, or 1.2% increase in lumbar spine, trochanter bone, or femoral neck, respectively, and administration of alendronate 10 mg daily was associated with a 2.9, 2.7, or 1% increase in lumbar spine, trochanter bone, and femoral neck, respectively, after 1 year. Total body BMD was maintained with 5 mg of alendronate daily after 1 year but was increased with 5 or 10 mg of the drug daily after 2 years.
The increases in BMD in patients receiving 10 mg of alendronate daily were similar to those receiving alendronate 5 mg except in postmenopausal women not receiving estrogen replacement therapy. In these women, BMD increases (relative to placebo) at the lumbar spine were 4.1 or 1.6% in patients receiving 10 or 5 mg of alendronate daily, respectively, while at the trochanter bone, BMD increases were 2.8 or 1.7% in patients receiving 10 or 5 mg of alendronate daily, respectively; at other sites, increases in BMD were similar when using the different dosages of alendronate. In these studies, greatest increase in BMD occurred in the first year of therapy and only maintenance or smaller increases in BMD were reported in the second year of therapy with alendronate. In addition, the efficacy of alendronate reportedly was not affected by age, gender, race, underlying disease, previous duration or current dosage of corticosteroid therapy, baseline BMD, baseline bone turnover or concomitant administration of other drugs. Bone histology was normal in several patients (receiving alendronate 10 mg daily for 1 year) who underwent bone biopsy. In these studies after 1 year of therapy, patients receiving alendronate (5 or 10 mg daily), had fewer new vertebral fractures than those receiving placebo (2.3 versus 3.7%, respectively), but the difference was not significant. Analysis of pooled data indicates that after 2 years of therapy, the incidence of a new vertebral fracture was 0.7 or 6.8% in patients receiving alendronate (5 or 10 mg daily for 2 years, or 2.5 mg for 1 year followed by 10 mg for the second year) or placebo, respectively. However, these findings were based on very few fractures occurring mainly in postmenopausal women.
Paget Disease of Bone
Alendronate also is used orally in the treatment of moderate to severe Paget disease of bone (osteitis deformans). In most patients with Paget disease, only small areas of bone are involved and patients are usually asymptomatic; mild symptoms in these patients usually can be controlled with analgesics. Treatment with alendronate should be considered in patients with serum alkaline phosphatase concentrations at least twice the upper limit of normal, those who are symptomatic, or those at risk for future complications from their disease.
In clinical trials in males and females with moderate to severe Paget disease of bone (serum alkaline phosphatase concentrations at least twice the upper limit of normal), suppression of alkaline phosphatase (i.e., either normalization of serum concentrations or a decrease of at least 60% compared with baseline concentrations) after 6 months of therapy occurred in a substantially greater percentage of patients receiving alendronate (40 mg daily) than in those receiving etidronate disodium (400 mg daily) or placebo. Bone histology studies in patients with Paget disease of bone treated with alendronate 40 mg daily for 6 months indicate that bone formed during treatment with the drug is of normal quality. In placebo-controlled trials, the decreased bone turnover associated with bisphosphonate therapy has resulted in pain relief.
Retreatment with alendronate may be considered, following a 6-month posttreatment evaluation period, in patients with Paget disease of bone who have relapsed (as determined by an increase in serum alkaline phosphatase concentration). The manufacturer states that while clinical data on retreatment with alendronate currently are lacking, responses to initial therapy with the drug in patients who had or had not received prior bisphosphonate therapy have been similar.