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Fosamax Plus D

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Fosamax Plus D

CLINICAL PHARMACOLOGY

Mechanism of Action

Alendronate Sodium

Animal studies have indicated the following mode of action. At the cellular level, alendronate shows preferential localization to sites of bone resorption, specifically under osteoclasts. The osteoclasts adhere normally to the bone surface but lack the ruffled border that is indicative of active resorption. Alendronate does not interfere with osteoclast recruitment or attachment, but it does inhibit osteoclast activity. Studies in mice on the localization of radioactive [3H]alendronate in bone showed about 10-fold higher uptake on osteoclast surfaces than on osteoblast surfaces. Bones examined 6 and 49 days after [3H]alendronate administration in rats and mice, respectively, showed that normal bone was formed on top of the alendronate, which was incorporated inside the matrix. While incorporated in bone matrix, alendronate is not pharmacologically active. Thus, alendronate must be continuously administered to suppress osteoclasts on newly formed resorption surfaces. Histomorphometry in baboons and rats showed that alendronate treatment reduces bone turnover (i.e., the number of sites at which bone is remodeled). In addition, bone formation exceeds bone resorption at these remodeling sites, leading to progressive gains in bone mass.

Cholecalciferol

Vitamin D3 is produced in the skin by photochemical conversion of 7-dehydrocholesterol to previtamin D3 by ultraviolet light. This is followed by non-enzymatic isomerization to vitamin D3. In the absence of adequate sunlight exposure, vitamin D3 is an essential dietary nutrient. Vitamin D3 in skin and dietary vitamin D3 (absorbed into chylomicrons) is converted to 25-hydroxyvitamin D3 in the liver. Conversion to the active calcium-mobilizing hormone 1,25-dihydroxyvitamin D3 (calcitriol) in the kidney is stimulated by both parathyroid hormone and hypophosphatemia. The principal action of 1,25-dihydroxyvitamin D3 is to increase intestinal absorption of both calcium and phosphate as well as regulate serum calcium, renal calcium and phosphate excretion, bone formation and bone resorption.

Vitamin D is required for normal bone formation. Vitamin D insufficiency develops when both sunlight exposure and dietary intake are inadequate. Insufficiency is associated with negative calcium balance, increased parathyroid hormone levels, bone loss, and increased risk of skeletal fracture. In severe cases, deficiency results in more severe hyperparathyroidism, hypophosphatemia, proximal muscle weakness, bone pain and osteomalacia.

Pharmacodynamics

Alendronate Sodium

Alendronate is a bisphosphonate that binds to bone hydroxyapatite and specifically inhibits the activity of osteoclasts, the bone-resorbing cells. Alendronate reduces bone resorption with no direct effect on bone formation, although the latter process is ultimately reduced because bone resorption and formation are coupled during bone turnover.

Daily oral doses of alendronate (5, 20, and 40 mg for six weeks) in postmenopausal women produced biochemical changes indicative of dose-dependent inhibition of bone resorption, including decreases in urinary calcium and urinary markers of bone collagen degradation (such as deoxypyridinoline and crosslinked N-telopeptides of type I collagen). These biochemical changes tended to return toward baseline values as early as 3 weeks following the discontinuation of therapy with alendronate and did not differ from placebo after 7 months.

Long-term treatment of osteoporosis with FOSAMAX 10 mg/day (for up to five years) reduced urinary excretion of markers of bone resorption, deoxypyridinoline and cross-linked N-telopeptides of type l collagen, by approximately 50% and 70%, respectively, to reach levels similar to those seen in healthy premenopausal women. The decrease in the rate of bone resorption indicated by these markers was evident as early as one month and at three to six months reached a plateau that was maintained for the entire duration of treatment with FOSAMAX. In osteoporosis treatment studies FOSAMAX 10 mg/day decreased the markers of bone formation, osteocalcin and bone specific alkaline phosphatase by approximately 50%, and total serum alkaline phosphatase by approximately 25 to 30% to reach a plateau after 6 to 12 months. Similar reductions in the rate of bone turnover were observed in postmenopausal women during one-year studies with once weekly FOSAMAX 70 mg for the treatment of osteoporosis. These data indicate that the rate of bone turnover reached a new steady-state, despite the progressive increase in the total amount of alendronate deposited within bone.

As a result of inhibition of bone resorption, asymptomatic reductions in serum calcium and phosphate concentrations were also observed following treatment with FOSAMAX. In the long-term studies, reductions from baseline in serum calcium (approximately 2%) and phosphate (approximately 4 to 6%) were evident the first month after the initiation of FOSAMAX 10 mg. No further decreases in serum calcium were observed for the five-year duration of treatment; however, serum phosphate returned toward prestudy levels during years three through five. In one-year studies with once weekly FOSAMAX 70 mg, similar reductions were observed at 6 and 12 months. The reduction in serum phosphate may reflect not only the positive bone mineral balance due to FOSAMAX but also a decrease in renal phosphate reabsorption.

Osteoporosis in Men

Treatment of men with osteoporosis with FOSAMAX 10 mg/day for two years reduced urinary excretion of cross-linked N-telopeptides of type I collagen by approximately 60% and bone-specific alkaline phosphatase by approximately 40%. Similar reductions were observed in a one-year study in men with osteoporosis receiving once weekly FOSAMAX 70 mg.

Cholecalciferol

Vitamin D is required for normal bone formation. Vitamin D insufficiency is associated with negative calcium balance, leading to increased parathyroid hormone levels and worsening of bone loss associated with osteoporosis. When taken without vitamin D, alendronate is also associated with a reduction in serum calcium concentrations and increased parathyroid hormone levels. In a 15-week trial, 717 postmenopausal women and men, mean age 67 years, with osteoporosis (lumbar spine bone mineral density [BMD] of at least 2.5 standard deviations below the premenopausal mean) were randomized to receive either weekly FOSAMAX PLUS D 70 mg/2800 international units vitamin D or weekly FOSAMAX 70 mg alone with no vitamin D supplementation. Patients who were vitamin D deficient (25-hydroxyvitamin D less than 9 ng/mL) at baseline were excluded. Treatment with FOSAMAX PLUS D 70 mg/2800 international units resulted in a smaller reduction in serum calcium levels (-0.9%) when compared to FOSAMAX 70 mg alone (-1.4%). As well, treatment with FOSAMAX PLUS D 70 mg/2800 international units resulted in a significantly smaller increase in parathyroid hormone levels when compared to FOSAMAX 70 mg alone (14% and 24%, respectively).

The sufficiency of patients' vitamin D status is best assessed by measuring 25-hydroxyvitamin D levels. In the 15-week trial mentioned above, baseline 25-hydroxyvitamin D levels were 22.2 ng/mL in the FOSAMAX PLUS D group and 22.1 ng/mL in the FOSAMAX only group. After 15 weeks of treatment, the mean levels were 23.1 ng/mL and 18.4 ng/mL in the FOSAMAX PLUS D and FOSAMAX only groups, respectively. The final levels of 25-hydroxyvitamin D at Week 15 are summarized in Table 4.

Table 4: 25-hydroxyvitamin D Levels after Treatment with FOSAMAX PLUS D (70 mg/2800 international units) or FOSAMAX 70 mg at Week 15*

25-hydroxyvitamin D Ranges (ng/mL) Number (%) of Patients
< 9 9-14 15-19 20-24 25-29 30-62
FOSAMAX PLUS D (70 mg/2800 international units) (N=357) 4 (1.1) 37 (10.4) 87 (24.4) 84 (23.5) 82 (23.0) 63 (17.7)
FOSAMAX 70 mg (N=351) 46 (13.1) 66 (18.8) 108 (30.8) 58 (16.5) 37 (10.5) 36 (10.3)
* Patients who were vitamin D deficient (25-hydroxyvitamin D less than 9 ng/mL) at baseline were excluded.

Patients (n=652) who completed the above 15-week trial continued in a 24-week extension in which all received FOSAMAX PLUS D (70 mg/2800 international units) and were randomly assigned to receive either additional once weekly vitamin D3 2800 international units (Vitamin D3 5600 international units group) or matching placebo (Vitamin D3 2800 international units group). After 24 weeks of extended treatment (Week 39 from original baseline), the mean levels of 25-hydroxyvitamin D were 27.9 ng/mL and 25.6 ng/mL in the vitamin D3 5600 international units group and vitamin D3 2800 international units group, respectively. The percentage of patients with hypercalciuria at Week 39 was not statistically different between treatment groups.

The distribution of the final levels of 25-hydroxyvitamin D at Week 39 is summarized in Table 5.

Table 5: 25-hydroxyvitamin D Levels after Treatment with FOSAMAX PLUS D at Week 39

  Number (%) of Patients
25-hydroxyvitamin D Ranges (ng/mL) < 9 9-14 15-19 20-24 25-29 30-59
FOSAMAX PLUS D (Vitamin D3 5600 international units group)* (N=321) 0 10 (3.1) 29 (9.0) 79 (24.6) 87 (27.1) 116 (36.1)
FOSAMAX PLUS D (Vitamin D3 2800 international units group)1†(N=320) 1 (0.3) 17 (5.3) 56 (17.5) 80 (25.0) 74 (23.1) 92 (28.8)
* Patients received FOSAMAX 70 mg or FOSAMAX PLUS D (70 mg/2800 international units) for the 15-week base study followed by FOSAMAX PLUS D (70 mg/2800 international units) and 2800 international units additional vitamin D3 for the 24-week extension study.
† Patients received FOSAMAX 70 mg or FOSAMAX PLUS D (70 mg/2800 international units) for 15-week base study followed by FOSAMAX PLUS D (70 mg/2800 international units) and placebo for the additional vitamin D3 for 24-week extension study.

Pharmacokinetics

Absorption

Alendronate Sodium

Relative to an intravenous reference dose, the mean oral bioavailability of alendronate in women was 0.64% for doses ranging from 5 to 70 mg when administered after an overnight fast and two hours before a standardized breakfast. Oral bioavailability of the 10-mg tablet in men (0.59%) was similar to that in women when administered after an overnight fast and 2 hours before breakfast.

In a study, the alendronate in the FOSAMAX PLUS D (70 mg/2800 international units) tablet and the FOSAMAX (alendronate sodium) 70-mg tablet were found to be equally bioavailable. In a separate study, the alendronate in the FOSAMAX PLUS D (70 mg/5600 international units) tablet was found to be equally bioavailable to the alendronate in the FOSAMAX (alendronate sodium) 70-mg tablet.

A study examining the effect of timing of a meal on the bioavailability of alendronate was performed in 49 postmenopausal women. Bioavailability was decreased (by approximately 40%) when 10 mg alendronate was administered either 0.5 or 1 hour before a standardized breakfast, when compared to dosing 2 hours before eating. In studies of treatment and prevention of osteoporosis, alendronate was effective when administered at least 30 minutes before breakfast.

Bioavailability was negligible whether alendronate was administered with or up to two hours after a standardized breakfast. Concomitant administration of alendronate with coffee or orange juice reduced bioavailability by approximately 60%.

Cholecalciferol

Following administration of FOSAMAX PLUS D (70 mg/2800 international units) after an overnight fast and two hours before a standard meal, the baseline adjusted mean area under the serum-concentrationtime curve (AUC0-120 hrs) for vitamin D3 was 120.7 ng-hr/mL. The baseline adjusted mean maximal serum concentration (Cmax) of vitamin D3 was 4.0 ng/mL, and the baseline adjusted mean time to maximal serum concentration (Tmax) was 10.6 hrs. The bioavailability of the 2800 international units vitamin D3 in FOSAMAX PLUS D is similar to 2800 international units vitamin D3 administered alone.

In a separate study, the baseline adjusted mean AUC0-80 hrs and baseline adjusted mean Cmax for vitamin D3 were 355.6 ng-hr/mL and 10.8 ng/mL, respectively. The baseline adjusted mean Tmax was 9.2 hrs. The bioavailability of the 5600 international units vitamin D3 in the FOSAMAX PLUS D is similar to 5600 international units vitamin D3 administered as two 2800 international units vitamin D3 tablets.

Distribution

Alendronate Sodium

Preclinical studies (in male rats) show that alendronate transiently distributes to soft tissues following 1 mg/kg intravenous administration but is then rapidly redistributed to bone or excreted in the urine. The mean steady-state volume of distribution, exclusive of bone, is at least 28 L in humans. Concentrations of drug in plasma following therapeutic oral doses are too low (less than 5 ng/mL) for analytical detection. Protein binding in human plasma is approximately 78%.

Cholecalciferol

Following absorption, vitamin D3 enters the blood as part of chylomicrons. Vitamin D3 is rapidly distributed mostly to the liver where it undergoes metabolism to 25-hydroxyvitamin D3, the major storage form. Lesser amounts are distributed to adipose tissue and stored as vitamin D3 at these sites for later release into the circulation. Circulating vitamin D3 is bound to vitamin D-binding protein.

Metabolism

Alendronate Sodium

There is no evidence that alendronate is metabolized in animals or humans.

Cholecalciferol

Vitamin D3 is rapidly metabolized by hydroxylation in the liver to 25-hydroxyvitamin D3, and subsequently metabolized in the kidney to 1,25-dihydroxyvitamin D3, which represents the biologically active form. Further hydroxylation occurs prior to elimination. A small percentage of vitamin D3 undergoes glucuronidation prior to elimination.

Excretion

Alendronate Sodium

Following a single intravenous dose of [14C] alendronate, approximately 50% of the radioactivity was excreted in the urine within 72 hours and little or no radioactivity was recovered in the feces. Following a single 10-mg intravenous dose, the renal clearance of alendronate was 71 mL/min (64, 78; 90% confidence interval [CI]), and systemic clearance did not exceed 200 mL/min. Plasma concentrations fell by more than 95% within 6 hours following intravenous administration. The terminal half-life in humans is estimated to exceed 10 years, probably reflecting release of alendronate from the skeleton. Based on the above, it is estimated that after 10 years of oral treatment with FOSAMAX (10 mg daily) the amount of alendronate released daily from the skeleton is approximately 25% of that absorbed from the gastrointestinal tract.

Cholecalciferol

When radioactive vitamin D3 was intravenously administered to healthy subjects, the mean urinary excretion of radioactivity after 48 hours was 2.4% of the administered dose, and the mean fecal excretion of radioactivity after 48 hours was 4.9% of the administered dose. In both cases, the excreted radioactivity was almost exclusively as metabolites of the parent. The mean half-life of baseline adjusted vitamin D3 in the serum following an oral dose of FOSAMAX PLUS D is approximately 14 hours.

Specific Populations

Gender: Bioavailability and the fraction of an intravenous dose of alendronate excreted in urine were similar in men and women.

Geriatric

Alendronate Sodium

Bioavailability and disposition of alendronate (urinary excretion) were similar in elderly and younger patients. No dosage adjustment of alendronate is necessary.

Cholecalciferol

Dietary requirements of vitamin D3 are increased in the elderly.

Race: Pharmacokinetic differences due to race have not been studied.

Renal Impairment

Alendronate Sodium

Preclinical studies show that, in rats with kidney failure, increasing amounts of drug are present in plasma, kidney, spleen, and tibia. In healthy controls, drug that is not deposited in bone is rapidly excreted in the urine. No evidence of saturation of bone uptake was found after 3 weeks dosing with cumulative intravenous doses of 35 mg/kg in young male rats. Although no formal renal impairment pharmacokinetic study has been conducted in patients, it is likely that, as in animals, elimination of alendronate via the kidney will be reduced in patients with impaired renal function. Therefore, somewhat greater accumulation of alendronate in bone might be expected in patients with impaired renal function.

No dosage adjustment is necessary for patients with creatinine clearance 35 to 60 mL/min. FOSAMAX PLUS D is not recommended for patients with creatinine clearance less than 35 mL/min due to lack of experience with alendronate in renal failure.

Cholecalciferol

Patients with renal insufficiency will have decreased ability to form the active 1,25-dihydroxyvitamin D3 metabolite.

Hepatic Impairment

Alendronate Sodium

As there is evidence that alendronate is not metabolized or excreted in the bile, no studies were conducted in patients with hepatic impairment. No dosage adjustment is necessary.

Cholecalciferol

Vitamin D3 may not be adequately absorbed in patients who have malabsorption due to inadequate bile production.

Drug Interactions

Alendronate Sodium

Intravenous ranitidine was shown to double the bioavailability of oral alendronate. The clinical significance of this increased bioavailability and whether similar increases will occur in patients given oral H2-antagonists is unknown.

In healthy subjects, oral prednisone (20 mg three times daily for five days) did not produce a clinically meaningful change in the oral bioavailability of alendronate (a mean increase ranging from 20 to 44%). Products containing calcium and other multivalent cations are likely to interfere with absorption of alendronate.

Cholecalciferol

Olestra, mineral oils, orlistat, and bile acid sequestrants (e.g., cholestyramine, colestipol) may impair the absorption of vitamin D. Anticonvulsants, cimetidine, and thiazides may increase the catabolism of vitamin D.

Animal Toxicology and/or 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.

Clinical Studies

Treatment of Osteoporosis in Postmenopausal Women

FOSAMAX Daily

The efficacy of FOSAMAX 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, doubleblind, 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 FOSAMAX 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 FOSAMAX (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 FOSAMAX 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 FOSAMAX 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 (FOSAMAX, n=1022; placebo, n=1005) demonstrated that treatment with FOSAMAX resulted in statistically significant reductions in fracture incidence at three years as shown in Table 6.

Table 6: Effect of FOSAMAX on Fracture Incidence in the Three-Year Study of FIT (patients with vertebral fracture at baseline)

  Percent of Patients
FOSAMAX
(n=1022)
Placebo
(n=1005)
Absolute Reduction in Fracture Incidence Relative Reduction in FractureRisk %
Patients with:
Vertebral fractures (diagnosed by X-ray)*
   ≥ 1 new vertebral fracture 7.9 15.0 7.1 47†
   ≥ 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‡
   ≥ 1 clinical (symptomatic) vertebral fracture 2.3 5.0 2.7 54§
Hip fracture 1.1 2.2 1.1 51¶
Wrist (forearm) fracture 2.2 4.1 1.9 48¶
*Number evaluable for vertebral fractures: FOSAMAX, 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 FOSAMAX 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 FOSAMAX, 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)

Cumulative Incidence of Hip Fractures in the Three-Year Study of FIT - Illustration

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 (FOSAMAX, n=2214; placebo, n=2218) further investigated the reduction in fracture incidence due to FOSAMAX. 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 below for the patients with osteoporosis.

Table 7: Effect of FOSAMAX on Fracture Incidence in Osteoporotic* Patients in the Four- Year Study of FIT (patients without vertebral fracture at baseline)

  Percent of Patients
FOSAMAX
(n=1545)
Placebo
(n=1521)
Absolute Reduction in Fracture Incidence Relative Reduction in Fracture Risk (%)
Patients with:
Vertebral fractures (diagnosed by X-ray)1
   ≥ 1 new vertebral fracture 2.5 4.8 2.3 48‡
   ≥ 2 new vertebral fractures 0.1 0.6 0.5 78§
Clinical (symptomatic) fractures
  Any clinical (symptomatic) fracture 12.9 16.2 3.3 22¶
   ≥ 1 clinical (symptomatic) vertebral fracture 1.0 1.6 0.6 41 (NS)#
Hip fracture 1.0 1.4 0.4 29 (NS)#
Wrist (forearm) fracture 3.9 3.8 -0.1 NS#
*Baseline femoral neck BMD at least 2 SD below the mean for young adult women
†Number evaluable for vertebral fractures: FOSAMAX, 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, FOSAMAX 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).

FOSAMAX 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, FOSAMAX reduced the percentage of osteoporotic women experiencing multiple vertebral fractures from 0.6% to 0.1% (78% relative risk reduction, p=0.035).

Thus, FOSAMAX 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 FOSAMAX 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 atients receiving FOSAMAX 10 mg/day relative to placebo-treated patients at three years for each of these studies.

Figure 2

Mean increases in BMD of the lumbar spine -\ Illustration

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 FOSAMAX 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 FOSAMAX 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. FOSAMAX 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

Time Course of Effect of FOSAMAX - Illustration

In patients with postmenopausal osteoporosis treated with FOSAMAX 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 FOSAMAX 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 FOSAMAX is of normal quality.

Effect on Height

FOSAMAX, 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.

FOSAMAX Once-Weekly

The therapeutic equivalence of once-weekly FOSAMAX 70 mg (n=519) and FOSAMAX 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

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, placebocontrolled 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.

Treatment to Increase Bone Mass in Men with Osteoporosis

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

FOSAMAX Daily

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 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 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).

FOSAMAX Once-Weekly

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 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 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 oncedaily 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).

Last reviewed on RxList: 11/22/2013
This monograph has been modified to include the generic and brand name in many instances.

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