14.1 Treatment of Osteoporosis in Postmenopausal Women
Daily Dosing
The efficacy of Alendronate 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 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 (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 resulted in statistically significant reductions in fracture incidence at three years as shown in Table 6.
* Number evaluable for vertebral fractures: Alendronate, n=984; placebo, n=966
† p<0.001, ‡ p=0.007, § p<0.01, ¶ p<0.05
Furthermore, in this population of patients with baseline vertebral fracture, treatment with Alendronate 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, p=0.047. Figure 1 displays the cumulative incidence of hip fractures in this study.
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. 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 7 for the patients with osteoporosis.
* Baseline femoral neck BMD at least 2 SD below the mean for young adult women
† Number evaluable for vertebral fractures: Alendronate, n=1426; placebo, n=1428
‡ p<0.001, § p=0.035, ¶ p=0.01,
# Not significant. This study was not powered to detect differences at these sites.
Fracture Results Across Studies
In the Three-Year Study of FIT, Alendronate 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 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 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 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 10 mg once daily in postmenopausal women, 44 to 84 years of age, with osteoporosis (lumbar spine bone mineral density [BMD] of at least 2 standard deviations below the premenopausal mean) was demonstrated in four double-blind, placebo-controlled clinical studies of two or three years’ duration.
Figure 2 shows the mean increases in BMD of the lumbar spine, femoral neck, and trochanter in patients receiving Alendronate 10 mg/day relative to placebo-treated patients at three years for each of these studies.
At three 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 three months and continued throughout the three years of treatment. (See Figure 3 for lumbar spine results). In the two-year extension of these studies, treatment of 147 patients with Alendronate 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 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).
In patients with postmenopausal osteoporosis treated with Alendronate 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.
Bone Histology
Bone histology in 270 postmenopausal patients with osteoporosis treated with Alendronate at doses ranging from 1 to 20 mg alendronate/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 is of normal quality.
Effect on Height
Alendronate, 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 70 mg (n=519) and Alendronate 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 one 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 two 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.
Concomitant Use with Estrogen/Hormone Replacement Therapy (HRT)
The effects on BMD of treatment with Alendronate 10 mg once daily and conjugated estrogen (0.625 mg/day) either alone or in combination were assessed in a two-year, double-blind, placebo-controlled study of hysterectomized postmenopausal osteoporotic women (n=425). At two years, the increases in lumbar spine BMD from baseline were significantly greater with the combination (8.3%) than with either estrogen or Alendronate alone (both 6.0%).
The effects on BMD when Alendronate was added to stable doses (for at least one year) of HRT (estrogen ± progestin) were assessed in a one-year, double-blind, placebo-controlled study in postmenopausal osteoporotic women (n=428). The addition of Alendronate 10 mg once daily to HRT produced, at one year, significantly greater increases in lumbar spine BMD (3.7%) vs. HRT alone (1.1%).
In these studies, significant increases or favorable trends in BMD for combined therapy compared with HRT alone were seen at the total hip, femoral neck, and trochanter. No significant effect was seen for total body BMD.
Histomorphometric studies of transiliac biopsies in 92 subjects showed normal bone architecture. Compared to placebo there was a 98% suppression of bone turnover (as assessed by mineralizing surface) after 18 months of combined treatment with Alendronate and HRT, 94% on Alendronate alone, and 78% on HRT alone. The long-term effects of combined Alendronate and HRT on fracture occurrence and fracture healing have not been studied.
14.3 Treatment to Increase Bone Mass in Men with Osteoporosis
The efficacy of Alendronate 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 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 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 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 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 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 70 mg enrolled a total of 167 men between the ages of 38 and 91 (mean, 66). Patients in the study had either 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 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 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 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 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).
14.4 Treatment of Glucocorticoid-Induced Osteoporosis
The efficacy of Alendronate 5 and 10 mg once daily in men and women receiving glucocorticoids (at least 7.5 mg/day of prednisone or equivalent) was demonstrated in two, one-year, double-blind, randomized, placebo-controlled, multicenter studies of virtually identical design, one performed in the United States and the other in 15 different countries (Multinational [which also included Alendronate 2.5 mg/day]). These studies enrolled 232 and 328 patients, respectively, between the ages of 17 and 83 with a variety of glucocorticoid-requiring diseases. Patients received supplemental calcium and vitamin D. Figure 5 shows the mean increases relative to placebo in BMD of the lumbar spine, femoral neck, and trochanter in patients receiving Alendronate 5 mg/day for each study.
After one year, significant increases relative to placebo in BMD were seen in the combined studies at each of these sites in patients who received Alendronate 5 mg/day. In the placebo-treated patients, a significant decrease in BMD occurred at the femoral neck (-1.2%), and smaller decreases were seen at the lumbar spine and trochanter. Total body BMD was maintained with Alendronate 5 mg/day. The increases in BMD with Alendronate 10 mg/day were similar to those with Alendronate 5 mg/day in all patients except for postmenopausal women not receiving estrogen therapy. In these women, the increases (relative to placebo) with Alendronate 10 mg/day were greater than those with Alendronate 5 mg/day at the lumbar spine (4.1% vs. 1.6%) and trochanter (2.8% vs. 1.7%), but not at other sites. Alendronate was effective regardless of dose or duration of glucocorticoid use. In addition, Alendronate was similarly effective regardless of age (less than 65 vs. greater than or equal to 65 years), race (Caucasian vs. other races), gender, underlying disease, baseline BMD, baseline bone turnover, and use with a variety of common medications.
Bone histology was normal in the 49 patients biopsied at the end of one year who received Alendronate at doses of up to 10 mg/day.
Of the original 560 patients in these studies, 208 patients who remained on at least 7.5 mg/day of prednisone or equivalent continued into a one-year double-blind extension. After two years of treatment, spine BMD increased by 3.7% and 5.0% relative to placebo with Alendronate 5 and 10 mg/day, respectively. Significant increases in BMD (relative to placebo) were also observed at the femoral neck, trochanter, and total body.
After one year, 2.3% of patients treated with Alendronate 5 or 10 mg/day (pooled) vs. 3.7% of those treated with placebo experienced a new vertebral fracture (not significant). However, in the population studied for two years, treatment with Alendronate (pooled dosage groups: 5 or 10 mg for two years or 2.5 mg for one year followed by 10 mg for one year) significantly reduced the incidence of patients with a new vertebral fracture (Alendronate 0.7% vs. placebo 6.8%).
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