The efficacy of FOSAMAX in men with hypogonadal or idiopathic osteoporosis was demonstrated in two clinical studies.

A two-year, double-blind, placebo-controlled, multicenter study of FOSAMAX 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 ≤ -2 at the femoral neck and ≤ -1 at the lumbar spine, or 2) a baseline osteoporotic fracture and a BMD T-score ≤ -1 at the femoral neck. At two years, the mean increases relative to placebo in BMD in men receiving FOSAMAX 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 FOSAMAX also reduced height loss (FOSAMAX, -0.6 mm vs. placebo, -2.4 mm).

A one-year, double-blind, placebo-controlled, multicenter study of once weekly FOSAMAX 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 ≤ -2 at the femoral neck and ≤ -1 at the lumbar spine, 2) a BMD T-score ≤ -2 at the lumbar spine and ≤ -1 at the femoral neck, or 3) a baseline osteoporotic fracture and a BMD T-score ≤ -1 at the femoral neck. At one year, the mean increases relative to placebo in BMD in men receiving FOSAMAX 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 (≥ 65 years vs. <65 years), gonadal function (baseline testosterone <9 ng/dL vs. ≥ 9 ng/dL), or baseline BMD (femoral neck and lumbar spine T-score ≤ -2.5 vs. >-2.5).

Prevention of osteoporosis in postmenopausal women

Prevention of bone loss was demonstrated in two double-blind, placebo-controlled studies of postmenopausal women 40-60 years of age. One thousand six hundred nine patients (FOSAMAX 5 mg/day; n=498) who were at least six months postmenopausal were entered into a two-year study without regard to their baseline BMD. In the other study, 447 patients (FOSAMAX 5 mg/day; n=88), who were between six months and three years postmenopause, were treated for up to three years. In the placebo-treated patients BMD losses of approximately 1% per year were seen at the spine, hip (femoral neck and trochanter) and total body. In contrast, FOSAMAX 5 mg/day prevented bone loss in the majority of patients and induced significant increases in mean bone mass at each of these sites (see figures below). In addition, FOSAMAX 5 mg/day reduced the rate of bone loss at the forearm by approximately half relative to placebo. FOSAMAX 5 mg/day was similarly effective in this population regardless of age, time since menopause, race and baseline rate of bone turnover.

Osteoporosis Prevention Studies in Postmenopausal Women

The therapeutic equivalence of once weekly FOSAMAX 35 mg (n=362) and FOSAMAX 5 mg daily (n=361) was demonstrated in a one-year, double-blind, multicenter study of postmenopausal women without osteoporosis. In the primary analysis of completers, the mean increases from baseline in lumbar spine BMD at one year were 2.9% (2.6, 3.2%; 95% CI) in the 35-mg once-weekly group (n=307) and 3.2% (2.9, 3.5%; 95% CI) in the 5-mg daily group (n=298). 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.

Bone histology

Bone histology was normal in the 28 patients biopsied at the end of three years who received FOSAMAX at doses of up to 10 mg/day.

Concomitant use with estrogen/hormone replacement therapy (HRT)

The effects on BMD of treatment with FOSAMAX 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 FOSAMAX alone (both 6.0%).

The effects on BMD when FOSAMAX 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 FOSAMAX 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 FOSAMAX and HRT, 94% on FOSAMAX alone, and 78% on HRT alone. The long-term effects of combined FOSAMAX and HRT on fracture occurrence and fracture healing have not been studied.

Glucocorticoid-induced osteoporosis

The efficacy of FOSAMAX 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 FOSAMAX 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. The following figure shows the mean increases relative to placebo in BMD of the lumbar spine, femoral neck, and trochanter in patients receiving FOSAMAX 5 mg/day for each study.

Studies in Glucocorticoid - Treated Patients
Increase in BMD
FOSAMAX 5 mg/day at One Year

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 FOSAMAX 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 FOSAMAX 5 mg/day. The increases in BMD with FOSAMAX 10 mg/day were similar to those with FOSAMAX 5 mg/day in all patients except for postmenopausal women not receiving estrogen therapy. In these women, the increases (relative to placebo) with FOSAMAX 10 mg/day were greater than those with FOSAMAX 5 mg/day at the lumbar spine (4.1% vs. 1.6%) and trochanter (2.8% vs. 1.7%), but not at other sites. FOSAMAX was effective regardless of dose or duration of glucocorticoid use. In addition, FOSAMAX was similarly effective regardless of age (<65 vs. ≥ 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 FOSAMAX 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 FOSAMAX 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 FOSAMAX 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 FOSAMAX (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 (FOSAMAX 0.7% vs. placebo 6.8%).

Paget's disease of bone

The efficacy of FOSAMAX 40 mg once daily for six months was demonstrated in two double-blind clinical studies of male and female patients with moderate to severe Paget's disease (alkaline phosphatase at least twice the upper limit of normal): a placebo-controlled, multinational study and a U.S. comparative study with etidronate disodium 400 mg/day. The following figure shows the mean percent changes from baseline in serum alkaline phosphatase for up to six months of randomized treatment.

Studies in Paget's Disease of Bone
Effect on Serum Alkaline Phosphatase of FOSAMAX 40 mg/day Versus Piacebo or Etidronate 400 mg/day

At six months the suppression in alkaline phosphatase in patients treated with FOSAMAX was significantly greater than that achieved with etidronate and contrasted with the complete lack of response in placebo-treated patients. Response (defined as either normalization of serum alkaline phosphatase or decrease from baseline ≥ 60%) occurred in approximately 85% of patients treated with FOSAMAX in the combined studies vs. 30% in the etidronate group and 0% in the placebo group. FOSAMAX was similarly effective regardless of age, gender, race, prior use of other bisphosphonates, or baseline alkaline phosphatase within the range studied (at least twice the upper limit of normal).

Bone histology was evaluated in 33 patients with Paget's disease treated with FOSAMAX 40 mg/day for 6 months. As in patients treated for osteoporosis (see Clinical Studies, Treatment of osteoporosis in postmenopausal women, Bone histology), FOSAMAX did not impair mineralization, and the expected decrease in the rate of bone turnover was observed. Normal lamellar bone was produced during treatment with FOSAMAX, even where preexisting bone was woven and disorganized. Overall, bone histology data support the conclusion that bone formed during treatment with FOSAMAX is of normal quality.

ANIMAL PHARMACOLOGY

The relative inhibitory activities on bone resorption and mineralization of alendronate and etidronate were compared in the Schenk assay, which is based on histological examination of the epiphyses of growing rats. In this assay, the lowest dose of alendronate that interfered with bone mineralization (leading to osteomalacia) was 6000-fold the antiresorptive dose. The corresponding ratio for etidronate was one to one. These data suggest that alendronate administered in therapeutic doses is highly unlikely to induce osteomalacia.

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