Therapeutic equivalence of alendronate 35 milligrams once weekly and 5 milligrams daily in the prevention of postmenopausal osteoporosis

doi:10.1016/S0029-7844(03)00008-5

Obstetrics & Gynecology

Volume 101, Issue 4, April 2003, Pages 711-721

https://doi.org/10.1016/S0029-7844(03)00008-5 Get rights and content

Abstract

Objective

To evaluate the efficacy and safety of alendronate 35 mg once weekly compared with alendronate 5 mg daily in the prevention of osteoporosis.

Methods

We compared the efficacy and safety of treatment with alendronate 35 mg once weekly (n = 362) and alendronate 5 mg daily (n = 361) in a 1-year, double-blind, multicenter study of postmenopausal women (6 months or greater), aged 40–70 years, with lumbar spine and femoral neck bone mineral density T-scores between −2.5 and 1. The primary efficacy end point was the comparability of lumbar spine bone mineral density increases, defined by strict prespecified criteria.

Results

Mean increases in lumbar spine bone mineral density at 12 months were equivalent (difference between the alendronate 35-mg once-weekly group and the alendronate 5-mg daily group [90% confidence interval] at month 12 was −0.3% [−0.6, 0.1], well within the prespecified bounds of ±1.0%). Bone mineral density increases at other skeletal sites and effects on bone turnover were also virtually identical for the two dosing regimens. Both treatment regimens were well tolerated, and the larger weekly unit dose was not associated with an increased frequency of upper gastrointestinal events.

Conclusion

Alendronate 35 mg once weekly is therapeutically equivalent to alendronate 5 mg daily and provides patients with greater dosing convenience, in addition to the proven efficacy of alendronate and good tolerability.

Section snippets

Materials and methods

To be eligible for the study, women had to be 40–70 years of age and postmenopausal, as diagnosed by a history of the absence of menstrual periods during the 6 months preceding randomization; for those women whose last menstrual period occurred 6–12 months before study start, serum follicle-stimulating hormone levels were confirmed to be in the reference range for postmenopausal women. Other entry criteria included bone mineral density T-score (standard deviation difference from the normal

Results

Women randomized to the two treatment groups had similar baseline characteristics in terms of age, years since menopause, body mass index, dietary calcium intake, prior vertebral fracture, history of upper gastrointestinal disease, and prior nonsteroidal antiinflammatory drugs or aspirin use (Table 1). Although women with radiologic fractures of the lumbar spine were excluded at screening based on local review of spine radiographs, small, comparable proportions of women enrolled in the two

Discussion

In two major studies employing daily regimens of alendronate enrolling a total of 2056 postmenopausal women without osteoporosis, treatment with alendronate 5 mg daily resulted in significant increases in lumbar spine bone mineral density (an average increase of 3% in the first year, which was maintained in subsequent years of treatment), as well as smaller yet significant increases in hip and total body bone mineral density. By contrast, the placebo groups experienced progressive bone loss at

Acknowledgements

The authors thank Marianne Daley and Christine Peverly for their outstanding contributions in overseeing the conduct of this trial, and Douglas Tracey and Andrea Dynder for expert data coordination and statistical programming support.

References (28)

J.R Tucci et al.
Effect of three years of oral alendronate treatment in postmenopausal women with osteoporosis
Am J Med
(1996)
C.H Chesnut et al.
Alendronate treatment of the postmenopausal osteoporotic womanEffect of multiple dosages on bone mass and bone remodeling
Am J Med
(1995)
H.G Bone et al.
Weekly administration of alendronateRationale and plan for clinical assessment
Clin Ther
(2000)
P Garnero et al.
Decreased bone turnover in oral contraceptive users
Bone
(1995)
J.E Bailey et al.
Risk factors for antihypertensive medication refill failure by patients under medicaid managed care
Clin Ther
(1996)
J.A Sbarbaro
Strategies to improve compliance with therapy
Am J Med
(1985)
J.A Simon et al.
Patient preference for once-weekly alendronate 70 mg versus once-daily alendronate 10 mg: A multicenter, randomized, open-label, crossover study
Clin Ther
(2002)
E.A Chrischilles et al.
A model of lifetime osteoporosis impact
Arch Intern Med
(1991)
L.J Melton et al.
How many women have osteoporosis?
J Bone Miner Res
(1992)
P.D Ross et al.
Pre-existing fractures and bone mass predict vertebral fracture incidence in women
Ann Intern Med
(1991)

S.H Gehlbach et al.

Recognition of osteoporosis by primary care physicians

Am J Public Health

(2002)

J.G Seedor et al.

The bisphosphonate alendronate (MK-217) inhibits bone loss due to ovariectomy in rats

J Bone Miner Res

(1991)

R Balena et al.

The effects of 2-year treatment with the aminobisphosphonate alendronate on bone metabolism, bone histomorphometry, and bone strength in ovariectomized nonhuman primates

J Clin Invest

(1993)

G.A Rodan et al.

Preclinical pharmacology of alendronate

Osteoporos Int

(1993)

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Chronic administration of phenytoin (PHT) has been associated with bone loss. Bisphosphonates [alendronate (ALD), ibandronate (IBD) and risedronate (RSD)] are potential candidates to prevent PHT-induced bone disorders, and the present study evaluated their effect on the antiepileptic efficacy of PHT. The PHT-induced depletion in folic acid (FA), vitamin B6 and vitamin B12 results in hyperhomocysteinemia. The elevated circulating homocysteine (hcy) could be a risk indicator for micronutrient-deficiency-related osteoporosis via generation of free radicals. Thus, an attempt was also made to unravel the PHT's and bisphosphonates' effect on hcy. Male mice received PHT (35 mg/kg, p.o.) for 90 days to induce bone loss. ALD, RSD and IBD were administered orally at doses 0.65 mg/kg, 0.33 mg/kg, and 0.17 mg/kg respectively, for prevention and 1.3 mg/kg, 0.65 mg/kg, and 0.33 mg/kg respectively, for treatment of PHT-induced bone loss. The bone loss was confirmed by bone mineral density (BMD) analysis and bone turnover markers. Serum levels of hcy and FA were estimated along with hydrogen peroxide levels and total antioxidant capacity in order to assess the antioxidant profile of bisphosphonates. The induction of bone loss by PHT was marked by lowered BMD and altered bone turnovers. ALD and RSD administration to PHT treated groups significantly reverted the bony adverse effects. No such effects were observed with IBD. In the bisphosphonates treated groups, hcy levels were statistically at par with the control group. PHT at 35 mg/kg, p.o. could compromise bone mass and thus, could be a model of bone demineralization in mice. The ALD, IBD and RSD have no pharmacodynamic interaction when administered along with PHT at the experimental level. Thus, their usage in the management of PHT-induced bone disease could be worthwhile if clinically approved.
Treatment of osteoporosis with bisphosphonates. Differences by mechanism of action. Data on long-term efficacy and safety
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These data demonstrate that monthly ibandronate is effective in preventing bone loss at the LS and proximal femur in young postmenopausal women with low BMD. The average BMD decreased modestly in both the spine and proximal femur in the participants receiving only calcium and vitamin D (placebo group), as has been seen in other studies involving young postmenopausal women [8–13]. BMD increases of 1.1–3.7% were observed by DXA at the spine (adjusted for baseline LS BMD and time since menopause) and proximal femur sites after 12 months of therapy with monthly ibandronate.
Monthly oral ibandronate has been shown to increase bone mineral density (BMD) and reduce bone turnover in postmenopausal women with osteoporosis, but its efficacy has not been investigated in women with low bone mass. The objective of this study was to examine the efficacy and safety of monthly oral ibandronate (150 mg) treatment in postmenopausal women with low bone mass.
This 1-year, double-blind, placebo-controlled, randomized study enrolled ambulatory postmenopausal women aged 45–60 years with baseline lumbar spine (LS) BMD T-score < − 1.0 and > − 2.5 and baseline T-score > − 2.5 at the total hip, trochanter, and femoral neck (collectively defined as the proximal femur) and no prior vertebral or low-trauma osteoporotic fractures at baseline. Subjects received either 150 mg monthly oral ibandronate or placebo. All subjects received calcium and vitamin D supplements. The primary endpoint was the relative change from baseline (%) in mean LS BMD at 1 year (intent-to-treat population). Treatment groups were compared by means of a two-way ANOVA model which adjusted for independent factors including treatment group, baseline LS BMD T-score, and time since menopause. Responder analyses examined the percentage of participants with changes from baseline in LS BMD and proximal femur BMD ≥ 0%. Adverse events and safety laboratory parameters were monitored continuously.
A total of 77 women received monthly ibandronate and 83 women received placebo. Subjects treated with ibandronate achieved larger increases in LS BMD after 1 year compared with subjects receiving placebo (3.7% vs − 0.4% [difference of 4.1%, p < 0.0001]). After 3 months, median serum C-terminal telopeptide of type I collagen levels were reduced by > 55% in the ibandronate group compared with ∼ 4% in the placebo group. At 1 year, 88.2% of the participants treated with ibandronate achieved increases in LS BMD ≥ 0% compared with 38.6% of subjects receiving placebo. Treatment regimens were well tolerated in both the ibandronate-treated and placebo groups.
Monthly ibandronate therapy prevents bone loss in postmenopausal women with low bone mass.
Oral ibandronate in the management of postmenopausal osteoporosis: Review of upper gastrointestinal safety
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Oral daily bisphosphonates carry a potential for gastrointestinal (GI) adverse events, which has been partly addressed by introducing once-weekly regimens. Nevertheless, the need to follow inconvenient dosing instructions every week could still hinder long-term compliance and therapeutic outcome. In addition, survey data indicates that many patients would prefer a once-monthly rather than once-weekly bisphosphonate dosing regimen. Ibandronate is a potent, nitrogen-containing bisphosphonate specifically developed for less frequent administration. In a pivotal study in postmenopausal osteoporosis, oral ibandronate, administered daily or with a between-dose interval of >2 months, demonstrated robust antifracture efficacy and an overall incidence of upper GI adverse events similar to placebo, even in patients at increased risk of such events. This and other clinical studies conducted in postmenopausal women demonstrate that oral ibandronate has an excellent upper GI safety profile.
Strategies for the prevention and treatment of osteoporosis during early postmenopause
2006, American Journal of Obstetrics and Gynecology
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Importantly, BMD continues to increase at the lumbar spine and hip through 10 years of treatment.65 The once weekly, 35-mg dosage of alendronate has been shown to be equivalent to the once daily, 5-mg dosage in terms of BMD increases at the lumbar spine in early postmenopausal women (mean age: 56 years.)66 Risedronate has been shown to reduce the risk of vertebral and nonvertebral fractures early in the course of therapy (within 6 months of initiation) in postmenopausal women67,68 with sustained protection through up to 7 years of therapy in multiple, large clinical trials: Vertebral Efficacy with Risedronate Therapy–North America, Vertebral Efficacy with Risedronate Therapy–Multinational, and the Hip Intervention Program.36,38,40,69-71
During the perimenopause, both the quantity and quality of bone decline rapidly, resulting in a dramatic increase in the risk of fracture in postmenopausal women. Although many factors are known to be associated with osteoporotic fractures, measures to identify and treat women at risk are underused in clinical practice. Consequently, osteoporosis is frequently not detected until a fracture occurs. Identification of postmenopausal women at high risk of fracture therefore is a priority and is especially important for women in early postmenopause who can benefit from early intervention to maintain or to increase bone mass and, thus, reduce the risk of fracture. Most authorities recommend risk-factor assessment for all postmenopausal women, followed by bone mineral density measurements for women at highest risk (ie, all women aged ≥65 years, postmenopausal women aged <65 years with ≥1 additional risk factors for osteoporosis, and postmenopausal women with fragility fractures). All postmenopausal women can benefit from nonpharmacologic interventions to reduce the risk of fracture, including a balanced diet with adequate intake of calcium and vitamin D, regular exercise, measures to prevent falls or to minimize their impact, smoking cessation, and moderation of alcohol intake. Several pharmacologic agents, including the bisphosphonates (eg, alendronate, risedronate, and ibandronate) and the selective estrogen receptor modulator, raloxifene, have been shown to increase bone mass, to reduce fracture risk, and to have acceptable side-effect profiles. Women who have discontinued hormone therapy are in particular need of monitoring for fracture risk, in light of the accelerated bone loss and increased risk of fracture that occurs after withdrawal of estrogen treatment.
Postmenopausal osteoporosis and alendronate
2004, Maturitas
Osteoporosis is a systemic metabolic disorder associated with a decreased bone mass and resistance. Bisphosphonates suppress bone resorption and bone turnover by a mechanism that depends on their structure. They are characterized by low gastrointestinal absorption. In postmenopausal women, alendronate (ALN) reduces bone resorption markers and increases bone mineral density (BMD) in the lumbar spine, femoral neck, and total body. Individuals receiving ALN have been studied for up to 10 years with an apparent linear increase in BMD over that time period estimated at 13.7% at the lumbar spine. Treatment with ALN reduced the risk of both vertebral and non-vertebral fractures, including hip fractures, in postmenopausal women with osteoporosis. Direct comparisons of the results obtained with different antiresortive agents is difficult, because the designs of the respective studies, populations and other factors. However, the meta-analysis of available publications seems to indicate that ALN reduces the relative risk of vertebral fractures in a greater proportion than any other agent. Furthermore, ALN prevents the reduction in BMD after hormone replacement therapy discontinuation.

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Original researchTherapeutic equivalence of alendronate 35 milligrams once weekly and 5 milligrams daily in the prevention of postmenopausal osteoporosis

Abstract

Objective

Methods

Results

Conclusion

Section snippets

Materials and methods

Results

Discussion

Acknowledgements

Am J Med

Am J Med

Clin Ther

Bone

Clin Ther

Am J Med

Clin Ther

A model of lifetime osteoporosis impact

Arch Intern Med

How many women have osteoporosis?

J Bone Miner Res

Pre-existing fractures and bone mass predict vertebral fracture incidence in women

Ann Intern Med

Recognition of osteoporosis by primary care physicians

Am J Public Health

The bisphosphonate alendronate (MK-217) inhibits bone loss due to ovariectomy in rats

J Bone Miner Res

The effects of 2-year treatment with the aminobisphosphonate alendronate on bone metabolism, bone histomorphometry, and bone strength in ovariectomized nonhuman primates

J Clin Invest

Preclinical pharmacology of alendronate

Osteoporos Int

Original research
Therapeutic equivalence of alendronate 35 milligrams once weekly and 5 milligrams daily in the prevention of postmenopausal osteoporosis