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PubMed2000

Therapeutic equivalence of alendronate 70 mg once-weekly and alendronate 10 mg daily in the treatment of osteoporosis. Alendronate Once-Weekly Study Group.

Dosing convenience is a key element in the effective management of any chronic disease, and is particularly important in the long-term management of osteoporosis. Less frequent dosing with any medication may enhance compliance, thereby maximizing the effectiveness of therapy. Animal data support the rationale that once-weekly dosing with alendronate 70 mg (7 times the daily oral treatment dose) could provide similar efficacy to daily dosing with alendronate 10 mg due to its long duration of effect in bone. In addition, dog studies suggest that the potential for esophageal irritation, observed with daily oral bisphosphonates, may be substantially reduced with once-weekly dosing. This dosing regimen would provide patients with increased convenience and would be likely to enhance patient compliance. We compared the efficacy and safety of treatment with oral once-weekly alendronate 70 mg (N=519), twice-weekly alendronate 35 mg (N=369), and daily alendronate 10 mg (N=370) in a one-year, double-blind, multicenter study of postmenopausal women (ages 42 to 95) with osteoporosis (bone mineral density [BMD] of either lumbar spine or femoral neck at least 2.5 SDs below peak premenopausal mean, or prior vertebral or hip fracture). The primary efficacy endpoint was the comparability of increases in lumbar spine BMD, using strict pre-defined equivalence criteria. Secondary endpoints included changes in BMD at the hip and total body and rate of bone turnover, as assessed by biochemical markers. Both of the new regimens fully satisfied the equivalence criteria relative to daily therapy. Mean increases in lumbar spine BMD at 12 months were: 5.1% (95% CI 4.8, 5.4) in the 70 mg once-weekly group, 5.2% (4.9, 5.6) in the 35 mg twice-weekly group, and 5.4% (5.0, 5.8) in the 10 mg daily treatment group. Increases in BMD at the total hip, femoral neck, trochanter, and total body were similar for the three dosing regimens. All three treatment groups similarly reduced biochemical markers of bone resorption (urinary N-telopeptides of type I collagen) and bone formation (serum bone-specific alkaline phosphatase) into the middle of the premenopausal reference range. All treatment regimens were well tolerated with a similar incidence of upper GI adverse experiences. There were fewer serious upper GI adverse experiences and a trend toward a lower incidence of esophageal events in the once-weekly dosing group compared to the daily dosing group. These data are consistent with preclinical animal models, and suggest that once-weekly dosing has the potential for improved upper GI tolerability. Clinical fractures, captured as adverse experiences, were similar among the groups. We conclude that the alendronate 70 mg once-weekly dosing regimen will provide patients with a more convenient, therapeutically equivalent alternative to daily dosing, and may enhance compliance and long-term persistence with therapy.

Administration, Oral↗
PubMed2007

Superiority of a combined treatment of Alendronate and Alfacalcidol compared to the combination of Alendronate and plain vitamin D or Alfacalcidol alone in established postmenopausal or male osteoporosis (AAC-Trial).

A combined therapy with the strongly antiresorptive Alendronate and the pleiotropically acting D-hormone analogue Alfacalcidol may have additive effects on bone quality, falls and fracture risk in established osteoporosis. The aim of this study (Alfacalcidol Alendronate Combined-AAC) was to compare the efficacy and safety of a combined parallel therapy with Alendronate and Alfacalcidol to the treatment with either Alendronate in combination with plain vitamin D or Alfacalcidol alone in patients with established postmenopausal or male osteoporosis. Ninety patients were included as matched triplets to receive randomly either 1 microg Alfacalcidol daily + 500 mg calcium (group A, n = 30) or 70 mg Alendronate weekly + 1,000 mg calcium + 1,000 IU vitamin D daily (group B, n = 30) or 1 microg Alfacalcidol daily + 70 mg Alendronate weekly + 500 mg calcium daily (group C, n = 30). Patients were recruited in one centre and were followed up for 24 months. Analysis was intention-to-treat and the primary outcome was lumbar spine and total hip bone mineral density (measured observer blind). BMD was measured at the lumbar spine and at the proximal femur with dual energy X-ray absorptiometry (LUNAR Prodigy, GE, USA) at the beginning and after 12 and 24 months. During the 2-year-study we observed descriptively significant increases at the lumbar spine of 3.0% in group A compared to baseline, of 5.4% in group B and of 9.6% in group C, respectively. The superiority of the Alendronate + Alfacalcidol treatment group over Alfacalcidol alone and over Alendronate + vitamin D was of more than large rele-vance (both tests: MW > 0.71; CI-LB > 0.64; P < 0.001). We also observed median increases of the BMD at the total hip of 1.5% in group A, of 2.4% in group B and of 3.8% in group C, respectively. The superiority of group C over group A and over group B again was relevant and statistically significant in a descriptive sense. After 2 years there was a tendency towards higher rates of vertebral and non-vertebral fractures in group A and B as compared to C. Taking both fracture types together we observed 9, 10 and 2 "osteoporotic fractures" in groups A, B and C, respectively. The comparison of group C with pooled groups A and B and with each single group gave a relevantly lower fracture rate for the combination of Alendronate and Alfacalcidol. Furthermore a lower rate of falls was observed for the combination Alendronate plus Alfacalcidol versus Alendronate + vitamin D, but not versus Alfacalcidol alone. We found 80% of the patients in the Alendronate + Alfacalcidol group free from back pain at month 24, compared to 30% in the Alendronate + vitamin D and 43% in the Alfacalcidol monotherapy group. The superiority is relevant (both tests: MW > 0.64; CI-LB > 0.56; P < 0.003). Pain decrease also occurred more rapidly in the Alendronate + Alfacalcidol group than in the other groups. In general side effects in all groups were mild, and only four cases of moderate hypercalcuria in group A and one in group C were reported, but no case of hypercalcemia was documented. In conclusion, the combination therapy with Alendronate and Alfacalcidol exhibited superiority in terms of BMD, overall fractures, rate of falls and back pain over either Alendronate in combination with plain vitamin D or Alfacalcidol alone. The overall safety profiles of the three treatment regimens were found to be not different in this study.

Aged↗
PubMed2000

A comparison of continuous alendronate, cyclical alendronate and cyclical etidronate with calcitriol in the treatment of postmenopausal vertebral osteoporosis: a randomized controlled trial.

A number of drugs are now available for the treatment of established osteoporosis and have been shown to significantly increase bone mineral density (BMD). There are, however, few comparative treatment studies and, furthermore, adverse events remain a problem with some of the newer agents, particularly in the elderly, in everyday clinical practice. We report a 12 month, open labeled, randomized controlled, prospective treatment study in 140 postmenopausal women with established vertebral osteoporosis, comparing the effect of continuous alendronate, cyclical alendronate and cyclical etidronate with calcitriol in terms of gain in BMD, reduction in bone turnover markers and adverse event profile. The mean percentage increases in BMD at 12 months, at the spine and hip respectively, were: continuous alendronate 5.7%, 2.6%; cyclical alendronate 4.1%, 1.6%; cyclical etidronate 4.9%, 2.0% (p<0.0 1) and calcitriol 2.0%, 0.4% (NS). In comparison with calcitriol, the mean changes in BMD at the spine and hip respectively were greater in the other groups; continuous alendronate: 3.7% (95% CI 1.4 to 8.3), 2.2% (95% CI 0.7 to 4.0); cyclical alendronate: 2.1% (95% CI 1.2 to 6.4), 1.2% (95% CI -0.3 to 3.0); cyclical etidronate: 2.9% (95% CI 1.9 to 6.5), 1.6% (95% CI 0.9 to 3.1)). The reduction in bone turnover markers was between 26% and 32% in the alendronate and etidronate groups (p<0.01), with a trend toward greater reduction in the continuous alendronate group. Eight patients discontinued the study: 6 in the continuous alendronate group, 1 in the cyclical alendronate group and 1 in the calcitriol group. Two patients in the cyclical etidronate group were unable to tolerate the Cacit component, but continued on substituting Cacit with Calcichew. In summary, 12 months of treatment with continuous alendronate, cyclical alendronate and cyclical etidronate are effective in terms of the gain in BMD at the anteroposterior spine and total hip in a comparable treatment population. These treatments are more effective than calcitriol and were generally well tolerated. Continuous alendronate showed a trend toward a larger gain in BMD and greater suppression of bone turnover markers than the other treatment groups, but had a higher incidence of adverse events, particularly within the older subgroup. Cyclical alendronate offers a lower adverse event profile and appears to be effective in comparison with continuous treatment, and may possibly be an alternative in the elderly. However, further studies are necessary, but more importantly with fracture end-points.

Administration, Oral↗
PubMed2000

Alendronate in early postmenopausal women: effects on bone mass during long-term treatment and after withdrawal. Alendronate Osteoporosis Prevention Study Group.

We studied the effect on bone mass of alendronate treatment for 5 yr and its withdrawal. Four hundred and forty-seven postmenopausal women with normal bone mass entered a 3-yr randomized trial followed by a 2-yr open label extension. Three hundred and eleven women completed the first 3 yr, and 263 consented to continue and completed the extension. We are reporting data from groups using the dose of alendronate currently approved for osteoporosis prevention (5 mg) or from the group in which alendronate treatment was withdrawn: 52 women received alendronate (5 mg) for 5 yr (group I), 56 received 3 yr of placebo followed by alendronate (5 mg) for 2 yr (group II), and 52 received alendronate (20 mg) for 2 yr followed by 3 yr off therapy (group III). In group I, alendronate (5 mg) increased bone mineral density (BMD) at the spine and trochanter by 2.5-3.2% (P < 0.001 vs. baseline) and stabilized total body and femoral neck BMD (change vs. baseline, P = NS) over 5 yr. By the end of 5 yr, BMD was comparable at the spine, hip, and total body in groups I and III. The 3-yr decrease in BMD after withdrawal of alendronate (20 mg) in group III was 1.8-5.7% (P < 0.01 vs. baseline) and similar to the 3-yr decrease in BMD in group II during the initial 3 yr. In conclusion, alendronate (5 mg) for 5 yr or alendronate (20 mg) for 2 yr followed by 3 yr off therapy prevented postmenopausal bone loss. After withdrawal of alendronate (20 mg), bone loss resumed at the normal early postmenopausal rate.

Absorptiometry, Photon↗
PubMed1999

A double-masked multicenter comparative study between alendronate and alfacalcidol in Japanese patients with osteoporosis. The Alendronate Phase III Osteoporosis Treatment Research Group.

To evaluate the efficacy and safety of alendronate, a double-masked, active (alfacalcidol) controlled comparative study for 48 weeks was carried out in a total of 210 Japanese patients with osteoporosis. The doses of alendronate and alfacalcidol were 5 mg/day and 1 microgram/day, respectively. The lumbar bone mineral density (LBMD) values observed at 12, 24, 36 and 48 weeks after the initiation of alendronate treatment were 3.53 +/- 0.53%, 5.37 +/- 0.62%, 5.87 +/- 0.74% and 6.21 +/- 0.59% (mean +/- SE), respectively, higher than the baseline value. Corresponding values in the alfacalcidol group were 1.50 +/- 0.43%, 0.69 +/- 0.63%, 1.12 +/- 0.60% and 1.36 +/- 0. 63%, respectively. There was a significant difference between the two groups at each time point (p<0.05 or p<0.001). The bone turnover markers were depressed during treatment in the alendronate group: -32.2% for alkaline phosphatase, -53.7% for N-terminal osteocalcin and -45.0% for urinary deoxypyridinoline compared with the corresponding baseline values. On the contrary, no notable changes in these parameters were observed in the alfacalcidol group. Treatment with alendronate caused a transient decrease in serum calcium concentrations associated with an increase in the serum level of intact parathyroid hormone. In contrast, treatment with alfacalcidol resulted in a tendency of these parameters to change in the opposite direction. No difference in fracture incidence between the two groups was observed. The overall safety of alendronate was comparable to that of alfacalcidol. In conclusion, although it was a relatively short-term study of 48 weeks, the results of the present study indicate that alendronate at the daily dose of 5 mg was effective in increasing LBMD and that no serious drug-related adverse events were observed in the alendronate-treated patients. Alendronate is more efficacious than alfacalcidol in increasing bone mineral density, although the mechanisms of the actions of the two drugs are apparently different.

Aged↗
PubMed2002

Patient preference for once-weekly alendronate 70 mg versus once-daily alendronate 10 mg: a multicenter, randomized, open-label, crossover study.

BACKGROUND: Alendronate, an oral bisphosphonate, is available for the treatment of osteoporosis in a 70-mg once-weekly and a 10-mg once-daily formulation. OBJECTIVES: This study aimed to determine patient preference for once-weekly versus once-daily dosing with alendronate, and to determine which treatment regimen the patients believed was more convenient and would be easier to comply with for a long period. METHODS: This was a multicenter, randomized, open-label, preference study in which postmenopausal women with osteoporosis were enrolled to receive 9 weeks of treatment in crossover fashion (4 weeks with each study regimen separated by a 1-week washout period). The study regimens included once-weekly alendronate 70 mg and once-daily alendronate 10 mg. The primary and secondary end points were assessed with a questionnaire completed by the patient. Adverse events (AEs) were recorded to assess patient tolerability of the study medications. RESULTS: A total of 324 patients met the eligibility requirements; 288 were randomized to treatment, 287 (mean age, 64.8 years) received treatment, 272 completed the questionnaire, and 266 completed the study. Of the patients who completed the questionnaire, 235 patients preferred the 70-mg once-weekly dosing regimen compared with the 10-mg once-daily regimen (86.4% vs 9.2%; P < 0.001). Most patients also believed that once-weekly dosing was more convenient than once-daily dosing (89.0% vs 7.7%; P < 0.001) and would allow them to achieve better long-term compliance (87.5% vs 8.5%; P < 0.001). Clinical AEs were reported in 30.7% of patients treated with once-weekly alendronate and 30% of patients treated with once-daily alendronate, with no significant differences between treatments. CONCLUSION: When once-weekly alendronate 70 mg was compared with once-daily alendronate 10 mg in this study, 70-mg once-weekly alendronate was the preferred dosing regimen.

Administration, Oral↗
PubMed1998

Alendronate prevents postmenopausal bone loss in women without osteoporosis. A double-blind, randomized, controlled trial. Alendronate Osteoporosis Prevention Study Group.

BACKGROUND: Preventing bone loss associated with menopause and aging and maintaining the normal micro-architecture of bone provide important opportunities for the prevention of osteoporosis and fractures. OBJECTIVE: To determine the safety and efficacy of alendronate, an aminobisphosphonate, for preventing postmenopausal bone loss. DESIGN: 3-year double-blind, randomized, placebo-controlled trial. SETTING: 15 osteoporosis centers throughout the world. PARTICIPANTS: 447 women who had recently experienced menopause (6 to 36 months before study entry). INTERVENTION: Participants were randomly assigned to one of five regimens: oral placebo; oral alendronate, 1, 5, or 10 mg/d; or oral alendronate, 20 mg/d for 2 years followed by placebo during the third year (20/0 mg/d). MEASUREMENTS: Bone mineral density was measured by dual-energy x-ray absorptiometry. Bone turnover and bone quality were assessed with biochemical markers and bone histomorphometry. RESULTS: Alendronate at 5, 10, and 20/0 mg/d increased bone mineral density from baseline at the lumbar spine, femoral neck, and trochanter by 1% to 4% and in the total body by 0.3% to 1.0%; placebo led to losses of 2% to 4% at these sites. Alendronate, 1 mg/d, attenuated losses relative to those seen with placebo. Alendronate decreased markers of bone resorption to a new steady state by 3 months and decreased markers of bone formation by 6 to 12 months. Bone quality remained normal. At all dosages studied, alendronate had a safety and tolerability profile similar to that of placebo. CONCLUSIONS: In early postmenopausal women, alendronate given for 3 years at dosages of 5 mg/d or greater prevented the loss of bone mineral density at the spine and hip and in the total body. Alendronate seems to be a safe and effective nonhormonal option for prevention of postmenopausal bone loss.

Adult↗
PubMed2005

Patient preference for once-monthly ibandronate versus once-weekly alendronate in a randomized, open-label, cross-over trial: the Boniva Alendronate Trial in Osteoporosis (BALTO).

OBJECTIVE: Ibandronate, a potent nitrogen-containing bisphosphonate, can be administered with extended interval dosing. Patient preferences were assessed for once-monthly versus once-weekly bisphosphonate treatment using a previously developed, open-label, cross-over trial design. RESEARCH DESIGN AND METHODS: This was a 6-month, prospective, randomized, open-label, multi-center study with a two-period and two-sequence cross-over treatment design. After screening, eligible patients (postmenopausal women with osteoporosis) were randomized to once-monthly ibandronate 150 mg followed by once-weekly alendronate 70 mg for a total of 6 months (Sequence A) or once-weekly alendronate followed by once-monthly ibandronate for a total of 6 months (Sequence B). The primary objective was to evaluate patient-reported preference for either the once-monthly ibandronate regimen or the once-weekly alendronate regimen based on responses to a preference questionnaire. RESULTS: A total of 342 patients were enrolled into this study (Sequence A, 170; Sequence B, 172). In the primary analysis of patient preference, 71.4% of women selected once-monthly ibandronate and 28.6% of women selected once-weekly alendronate. Overall, 66.1% preferred the once-monthly ibandronate regimen to the once-weekly alendronate regimen (26.5%) and 7.4% of participants stated no preference for either regimen. The preference rate for once-monthly ibandronate was statistically significant (p < 0.0001). 'Ease of following a treatment regimen for a long time' was the most common reason given for patient preference for both the once-monthly ibandronate (61%, 169/276) and once-weekly alendronate (25%, 70/276) regimens. Additionally, 17% (47/276) of patients who preferred once-monthly ibandronate chose 'it is easier to tolerate side effects' as did 4.3% (12/276) of patients who preferred alendronate. Significantly more women found once-monthly ibandronate to be more convenient (p < 0.0001). CONCLUSIONS: Significantly more women with postmenopausal osteoporosis preferred once-monthly ibandronate therapy to once-weekly alendronate therapy, and found the once-monthly regimen to be more convenient. Ease of following a treatment regimen for a long time was the most common reason given for the patients' preferences.

Adult↗
PubMed1998

[Comparative study in postmenopausal women with osteoporosis (sodium alendronate, calcium and HRT vs sodium alendronate and calcium].

In 1995 Alendronate was approved by the FDA for the treatment of Post-Menopause Osteoporosis. Their use for the preventive treatment on Osteopenic patients is approved in 1996. Calcium is a very important element in the treatment of Osteoporosis, because it is the only one that acts in the mineralization phase. It is well known that the first line to stop the loss of DMO in Post-Menopausic women are Estrogens. If we add TRH to the therapy, the effects of Alendronate will raise significantly. The first group (A) of 32 patients received Alendronate, Calcium and TRH. In the second group (B), there were 35 patients and they received Alendronate and Calcium. The groups were statistically compared and selected. In both groups the lumbar column was more affected than the hips. The use of TRH associated with Alendronate for the lumbar column significantly raised the percentage of change of DMO in 24 months. The change percentage was of 9% of DMO for group A and 5.25% for group B, giving a significant difference of 3.75% of DMO. For the hips the use of TRH associated with Alendronate did not have any difference in raise between both groups. In the next twelve months there was a change of 3.2% of DMO more in group A than in group B. In 24 months the change of DMO in the hips was of 7.95% in group A and 4.75% for group B. The TRH decrease the vasomotor symptoms, and improves the hormonal levels (FSH and Estradiol) keeping their benefits effective (Cardioprotectors, Neuroprotectors, etc.) but it potentiates the decrease of the bone reabsorption shown by the Alendronate. This significantly increases the change of percentage of DMO, obtaining densiometrics and clinical improvements in less time than using only Alendronate and Calcium. Also decreases the price of the treatment and the risk of fracture in less time, offering in that way a better quality of life to our patients.

Alendronate↗
PubMed1996

Alendronate stimulation of nocturnal parathyroid hormone secretion: a mechanism to explain the continued improvement in bone mineral density accompanying alendronate therapy.

The major effect of currently available antiresorptive therapy for osteoporosis is to slow or arrest bone loss. Although antiresorptive therapies demonstrate increases in bone mineral density, the effect is usually transient, and a plateau in bone mineral density usually emerges at 1 year. A unique and unexplained feature of treatment with the antiresorptive agent alendronate is continued, and steady improvement in bone mineral density occurs in years 2 and 3. We postulated that a potential mechanism for this unanticipated effect might be an exaggerated nocturnal increase in parathyroid hormone (PTH), which can act as an anabolic agent. We examined day-night levels and diurnal variation of PTH, serum calcium, ionized calcium, and markers of bone formation (osteocalcin) and resorption (N-telopeptide cross-links) over 24 hours in a randomly selected subset of 38 women (placebo: N = 13; mean age +/- SD, 69 +/- 3 years; alendronate: N = 25; mean age +/- SD, 69 +/- 3 years) who had completed 12 to 15 months of a larger (N = 120), randomized, double-blind, placebo-controlled trial with alendronate, 5 mg/day. By month 12, increases in the bone density of the spine (4.6%) and femoral neck (2.7%) were observed in the group treated with alendronate compared with placebo, (spine, 2.2%, p = .05; femoral neck, -0.2%, p < or = .05). Mean nocturnal PTH (10 PM-8 AM) was 21% higher (39 versus 32 pg/ml), and nocturnal serum calcium averaged 3% lower (8.7 versus 9.0 mg/dL) in the alendronate-versus-placebo group (both p < or = .05). Daytime levels (8 AM-10 PM) of PTH did not differ significantly between groups. We observed accompanying decreases in coupled markers of bone formation (osteocalcin, 38% lower, p < or = .01) and resorption (N-telopeptide cross-links, 50% lower, p < or = .01) in the alendronate group. Significant diurnal variations of PTH, serum calcium, and osteocalcin were present in both groups. We conclude that following 1 year of alendronate therapy, women have significant increases in bone mineral density and in nocturnal PTH levels, associated with decreases in nocturnal serum calcium and markers of bone turnover with maintenance of the diurnal variation. The nocturnal increase in PTH may mimic the anabolic effect of low-dose intermittent PTH administration to stimulate bone formation. Therefore, the increase might be a potential mechanism to explain the continued improvement in bone density following more than 1 year of alendronate therapy.

Aged↗
PubMed1998

A placebo-controlled, single-blind study to determine the appropriate alendronate dosage in postmenopausal Japanese patients with osteoporosis. The Alendronate Research Group.

Alendronate (4-amino-1-hydroxybutylidene-1,1-bisphosphonate) is a potent inhibitor of bone resorption. The efficacy and safety of 36 weeks of treatment with alendronate were evaluated in Japanese women with osteoporosis, osteoporotic osteopenia or artificial menopause. The bone mineral density (BMD) of the lumbar vertebrae, markers of bone and calcium metabolism and clinical symptoms were monitored. A total of 113 randomly selected patients with osteoporosis or osteopenia were enrolled in the study, of whom 12 were excluded from the analyses because of lack of data. As a result, 101 patients were evaluated for the safety of the drug. Since eight patients were excluded from the efficacy analysis, 93 were evaluated. The incidence of adverse effects in the placebo (P), alendronate 2.5 mg/day (L) and alendronate 10 mg/day (H) groups increased with increasing dose of alendronate, being 6.1, 14.3 and 18.2%, respectively. The most common adverse effects were gastrointestinal symptoms, none of which was serious. Lumbar BMD increased after 36 weeks of drug administration to 5.21%, 5.64% and -0.90% in the L, H and P groups, respectively (P < 0.001, L vs. P and H vs. P). Serum alkaline phosphatase activity, serum osteocalcin and urinary deoxypyridinoline excretion were significantly decreased in a dose-related manner. Serum calcium and phosphorus were also significantly decreased after alendronate administration. Serum intact PTH was transiently increased. The present results indicate that alendronate effectively decreases bone turnover in a dose-related manner and increases lumbar BMD at a dosage of 2.5 mg/day, the lowest dose used in this study, in Japanese patients with osteoporosis.

Adult↗
PubMed2006

Bioequivalence and pharmacokinetics of 70 mg alendronate sodium tablets by measuring alendronate in plasma.

The bioequivalence and pharmacokinetics of alendronate sodium tablets were examined by determining the plasma concentration of alendronate. Two groups, consisting of 24 healthy volunteers, each received a 70 mg reference alendronate sodium tablet and a test tablet in a 2x2 crossover study. There was a 6-day washout period between doses. The plasma alendronate concentration was monitored for 7 h after the dose, using HPLC-Fluorescence Detector (FD). The area under the plasma concentration-time curve from time 0 to the last sampling time at 7 h (AUC(0-7h) was calculated using the linear-log trapezoidal rule. The maximum plasma drug concentration (Cmax) and the time to reach Cmax (Tmax) were derived from the plasma concentration-time data. Analysis of variance was performed using logarithmically transformed AUC(0-7h) and Cmax, and untransformed Tmax. For the test medication versus the reference medication, the AUC(0-7h) were 87.63 +/- 29.27 vs. 102.44 +/- 69.96 ng x h x mL(-1) and the Cmax values were 34.29 +/- 13.77 vs. 38.47 +/- 24.39 ng x mL(-1), respectively. The 90% confidence intervals of the mean differences of the logarithmic transformed AUC(0-7h) and Cmax values were log 0.8234-log 1.1597 and log 0.8222-log 1.1409, respectively, satisfying the bioequivalence criteria guidelines of both the U.S. Food and Drug Administration and the Korea Food and Drug Administration. The other pharmacokinetic parameters for the test drug versus reference drug, respectively, were: t(1/2), 1.87 +/- 0.62 vs. 1.77 +/- 0.54 h; V/F, 2061.30 +/- 986.49 vs. 2576.45 +/- 1826.05 L; CL/F, 835.32 +/- 357.35 vs. 889.48 +/- 485.87 L x h(-1); K(el), 0.42 +/- 0.14 vs. 0.40 +/- 0.18 h(-1); Ka, 4.46 +/- 3.63 vs. 3.80 +/- 3.64 h(-1); and Tlag, 0.19 +/- 0.09 vs. 0.18 +/- 0.06 h. These results indicated that two alendronate formulations (70-mg alendronate sodium) were biologically equivalent and can be prescribed interchangeably.

Administration, Oral↗
PubMed1995

Effect of oral alendronate on bone mineral density and the incidence of fractures in postmenopausal osteoporosis. The Alendronate Phase III Osteoporosis Treatment Study Group.

BACKGROUND: Postmenopausal osteoporosis is a serious health problem, and additional treatments are needed. METHODS: We studied the effects of oral alendronate, an aminobisphosphonate, on bone mineral density and the incidence of fractures and height loss in 994 women with postmenopausal osteoporosis. The women were treated with placebo or alendronate (5 or 10 mg daily for three years, or 20 mg for two years followed by 5 mg for one year); all the women received 500 mg of calcium daily. Bone mineral density was measured by dual-energy x-ray absorptiometry. The occurrence of new vertebral fractures and the progression of vertebral deformities were determined by an analysis of digitized radiographs, and loss of height was determined by sequential height measurements. RESULTS: The women receiving alendronate had significant, progressive increases in bone mineral density at all skeletal sites, whereas those receiving placebo had decreases in bone mineral density. At three years, the mean (+/- SE) differences in bone mineral density between the women receiving 10 mg of alendronate daily and those receiving placebo were 8.8 +/- 0.4 percent in the spine, 5.9 +/- 0.5 percent in the femoral neck, 7.8 +/- 0.6 percent in the trochanter, and 2.5 +/- 0.3 percent in the total body (P < 0.001 for all comparisons). The 5-mg dose was less effective than the 10-mg dose, and the regimen of 20 mg followed by 5 mg was similar in efficacy to the 10-mg dose. Overall, treatment with alendronate was associated with a 48 percent reduction in the proportion of women with new vertebral fractures (3.2 percent, vs. 6.2 percent in the placebo group; P = 0.03), a decreased progression of vertebral deformities (33 percent, vs. 41 percent in the placebo group; P = 0.028), and a reduced loss of height (P = 0.005) and was well tolerated. CONCLUSIONS: Daily treatment with alendronate progressively increases the bone mass in the spine, hip, and total body and reduces the incidence of vertebral fractures, the progression of vertebral deformities, and height loss in postmenopausal women with osteoporosis.

Aged↗
PubMed1997

Prevention of nonvertebral fractures by alendronate. A meta-analysis. Alendronate Osteoporosis Treatment Study Groups.

OBJECTIVE: To evaluate the effect of treatment with alendronate sodium, a potent aminobisphosphonate, on the incidence of nonvertebral fractures in postmenopausal women with osteoporosis. DATA SOURCES: Published data and data on file at Merck Research Laboratories. STUDY SELECTION: All completed prospective, randomized, placebo-controlled alendronate trials of at least 2 years' duration (5 studies). DATA EXTRACTION: All subjects were women with osteoporosis between the ages of 42 and 85 years, postmenopausal at least 4 years, with lumbar spine bone mineral density (measured using dual-energy x-ray absorptiometry) at least 2.0 SD below the mean for young adult women. All women randomized to treatment with placebo or alendronate at a dose higher than 1 mg per day for at least 2 years were included. DATA SYNTHESIS: In the placebo group (n=590), 60 women reported nonvertebral fractures during 1347 patient-years at risk (overall rate, 4.45 women with fractures per 100 patient-years at risk). In the alendronate group (n = 1012), 73 women reported nonvertebral fractures during 2240 patient-years-at risk (overall rate, 3.26 women with fractures per 100 patient-years at risk). The estimated cumulative incidence of nonvertebral fractures after 3 years was 12.6% in the placebo group and 9.0% in alendronate group. The relative risk for nonvertebral fracture estimated using the Cox proportional hazards model was 0.71 (95% confidence interval,0.502-0.997) (P=.048). A reduction in risk was consistent across each of the studies and at each major site of osteoporotic fracture, including the hip and wrist. CONCLUSION: In postmenopausal women with osteoporosis, treatment with alendronate reduces the risk of nonvertebral fractures over at least 3 years.

Adult↗
PubMed2006

Synthesis and study of alendronate derivatives as potential prodrugs of alendronate sodium for the treatment of low bone density and osteoporosis.

Alendronate derivatives were evaluated as potential prodrugs for the osteoporosis drug alendronate sodium in an attempt to enhance the systemic exposure after oral administration. An investigation of the chemical behavior of alendronate derivatives led to development of practical synthetic strategies and prediction of each structural class's prodrug potential. Pharmacokinetic studies of N-myristoylalendronic acid revealed that 25% have been converted in vivo after i.v. administration in rat, providing an important proof-of-concept for this strategy.

Alendronate↗
PubMed1999

Biochemical markers can predict the response in bone mass during alendronate treatment in early postmenopausal women. Alendronate Osteoporosis Prevention Study Group.

Data from the Danish cohort (n = 67) of a multicenter trial of oral alendronate in the prevention of postmenopausal osteoporosis were used to evaluate the capacity of the biochemical markers to predict changes in bone mineral density (BMD). A panel of markers were measured: serum N-terminal midfragment osteocalcin (N-MID OC); serum total osteocalcin (total OC); bone-specific alkaline phosphatase (BSAP); serum and urine C-telopeptides of type I collagen (sCL and uCL); urine N-telopeptide crosslinks of type I collagen (NTX); and deoxypyridinoline (dPyr). The correlation between change from baseline at months 3-12 in total OC, N-MID OC, sCL, uCL, and NTX and 2 year response in spine BMD ranged from r = -0.45 to r = -0.78 (p < 0.001), and from r = -0.38 to r = 0.10 (n.s. to p < 0.002) for BSAP and dPyr. Sensitivity and specificity were used to assess the accuracy of change from baseline at month 6 in the biochemical markers for predicting prevention of bone loss in the spine over 2 years. The cutpoints used were a 30% (N-MID OC) or 50% (all other markers) decrease from baseline. Sensitivity levels were 82% (N-MID OC), 98% (total OC), 78% (sCL and NTX), and 89% (uCL). Specificities were 91% (N-MID OC), 59% (total OC), 100% (sCL), 71% (uCL), and 84% (NTX). Positive predictive values were 95% (N-MID OC), 82% (total OC), 100% (sCL), 87% (uCL), and 90% (NTX). In comparison, the predictive capacities of change from baseline at year 2 in hip BMD in predicting prevention of bone loss at the spine were similar: sensitivity, 82%; specificity, 55%; and positive predictive value, 79%. In conclusion, short-term changes in biochemical markers were valid predictors of long-term changes in BMD. Short-term changes in the sensitive biochemical markers revealed a predictive capacity similar to bone densitometry at the hip measured over 2 years. The sensitive biochemical markers offered a fast and valid alternative to bone densitometry for monitoring of alendronate treatment.

Absorptiometry, Photon↗
PubMed1997

Dose-response relationships for alendronate treatment in osteoporotic elderly women. Alendronate Elderly Osteoporosis Study Centers.

Alendronate (ALN) is an aminobisphosphonate employed as an antiresorptive agent in the treatment of osteoporosis. The present study was carried out to determine dose-response relationships, particularly the effects of relatively low doses of ALN, on bone mineral density (BMD), biochemical indexes of bone and mineral metabolism, and bone histology, with particular attention to effects in elderly women. This prospective, randomized, double blind, 2-yr multicenter study compared the effects of placebo with those of 1.0, 2.5, or 5.0 mg ALN daily. All subjects received supplemental calcium (500 mg daily) as the carbonate. We studied 359 women with lumbar spine BMD at least 2.0 SD below the peak young adult mean. Subjects were stratified by age, with 135 aged 60-69 yr and 224 aged 70-85 yr. Histomorphometry was performed on transiliac bone biopsies obtained from 104 subjects after 1 yr and from 83 subjects after 2 yr. This study elucidated the previously uninvestigated lower region of the dose-response curve for ALN in osteoporosis. Over 2 yr, treatment with 1.0, 2.5, or 5.0 mg/day increased lumbar spine BMD, on the average, by 0.65%, 3.54%, and 5.67%, respectively, compared with that in the placebo group (P < 0.001 vs. placebo for the 2.5 and 5 mg groups). Significant dose-related increases were also seen in BMD at appendicular sites and in total body BMD. Dose-dependent reductions in bone turnover to new steady states were indicated by serum and urine biochemical markers as well as by histomorphometry. There was also a dose-related reduction in the proportion of subjects suffering nonvertebral fractures (P < 0.05). Safety profiles were similar for the ALN and placebo groups and for both age strata. Efficacy was similar for both age strata. There was no evidence of impaired mineralization or other histological abnormalities due to ALN treatment. We conclude that treatment with ALN over a period of 2 yr was well tolerated and produced dose-dependent increases in BMD without evidence of a plateau over the dose range of 1.0-5.0 mg daily. One milligram daily did not result in a significant effect on BMD, and 5.0 mg daily produced favorable effects at all sites measured. Other studies have demonstrated somewhat greater effects on 10 mg daily. ALN, was equally effective and well tolerated in osteoporotic women over 70 yr old as in younger women with the same condition.

Aged↗