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Alendronate

An Update of its Use in Osteoporosis

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Summary

Abstract

Alendronate (alendronic acid) is a nitrogen-containing bisphosphonate which binds to bone surfaces and inhibits bone resorption by osteoclasts.

Oral alendronate 5 or 10 mg/day produces sustained increases in bone mineral density (BMD) in postmenopausal women with or without osteoporosis, in men with primary osteoporosis and in both men and women with or without osteoporosis receiving systemic corticosteroid therapy. Histomorphometric analyses have found that alendronate does not appear to impair bone quality. Alendronate reduced the risk of radiographic vertebral fracture, clinical vertebral fracture or hip fracture by 47 to 56% in postmenopausal women who had ≥1 existing vertebral fracture and in those with no existing vertebral fractures but who had osteoporosis. In a number of comparative trials in postmenopausal women with osteoporosis, alendronate 10 mg/day was found to be more effective at inducing sustained increases in BMD than intranasal calcitonin, and at least as effective as conjugated estrogens and raloxifene. Alendronate 70mg administered once weekly and 35mg twice weekly are as effective at increasing BMD as 10 mg/day in this patient group.

In clinical trials, alendronate was generally well tolerated when taken as recommended. Adverse events tended to be transient and associated with the upper GI tract, most commonly including abdominal pain, nausea, dyspepsia, acid regurgitation and musculoskeletal pain. No statistically significant differences between alendronate 10 mg/day and placebo have been found in the incidence of upper GI adverse events in large clinical trials. However, postmarketing surveillance reported a low incidence of adverse events related to the oesophagus. Specific instructions aimed at reducing the risk of upper GI adverse events have been provided by the manufacturer.

Conclusions: Alendronate is effective and generally well tolerated in the treatment of women or men with primary (including postmenopausal) or corticosteroid-induced osteoporosis and in the prevention of osteoporosis in postmenopausal women. The drug has been associated with upper GI tract adverse events, although the extent to which alendronate is responsible for these events has not been clearly established. Alendronate should be considered a treatment of choice in postmenopausal women with osteoporosis. Alendronate is also a suitable treatment option for primary osteoporosis in men and for corticosteroid-induced osteoporosis in both men and women.

Pharmacodynamic Properties

Mechanism of Action

Alendronate (alendronic acid), a nitrogen-containing bisphosphonate, binds to bone surfaces and inhibits bone resorption by osteoclasts, possibly through inhibition of the mevalonate pathway.

Biochemical Markers of Bone Turnover

Continuous oral alendronate 10 mg/day significantly reduced levels of serum markers of bone formation and urinary markers of bone resorption compared with placebo for at least 7 years in postmenopausal women with osteoporosis. Alendronate had similar effects on bone turnover markers in men with primary osteoporosis or osteoporosis associated with low serum testosterone levels, both men and women with corticosteroid-induced osteoporosis and postmenopausal women without osteoporosis.

Generally, the decreases in markers of bone resorption and formation associated with alendronate 5 or 10 mg/day were significantly larger than those associated with intranasal calcitonin or alfacalcidol and similar or larger than those associated with raloxifene, conjugated estrogens, calcitriol, estradiol plus norethisterone acetate, conjugated estrogens plus medroxyprogesterone or cyclical etidronate when compared directly, suggesting that alendronate is at least as (or more) effective in reducing rates of bone turnover as these agents.

Bone Quality and Biomechanical Properties

Histomorphometric analyses have confirmed that alendronate over 1 to 3 years decreases bone turnover in patients with either postmenopausal or corticosteroid-induced osteoporosis and does not appear to impair bone quality. Alendronate appears to increase bone mineral density (BMD) and bone strength by increasing bone mineralisation rather than increasing bone volume.

Adverse Upper GI Effects

Short term endoscopic studies in humans have given conflicting results as to whether alendronate causes upper GI damage. The relevance of these studies to clinical events is unknown: alendronate and placebo had a similar incidence of upper GI adverse events in large clinical trials (tolerability summary). The results of 3 double-blind, randomised, placebo-controlled endoscopic studies carried out in 32 to 277 healthy female or male volunteers suggest that alendronate 10 mg/day for 15 days or 1 month or 70mg once weekly for 10 weeks does not cause upper GI damage. In contrast, alendronate 10 mg/day for 14 days was found to cause gastric mucosal damage in a nonblind, crossover, randomised, placebo-controlled study in 24 healthy male and female volunteers.

Pharmacokinetic Properties

The oral bioavailability of alendronate is <1% in postmenopausal women. Absorption and disposition of alendronate over the dosage range 5 to 80mg are linear. Beverages (other than water), food and calcium supplements all reduce absorption of alendronate.

The drug is either excreted by the kidneys, the only route of elimination, or taken up and sequestered by bone, from where it is slowly released. The mean steady-state volume of distribution of alendronate, excluding bone, is estimated to be at least 28L.

The renal clearance rate of the drug is 4.26 L/h and alendronate is not metabolised. Excretion involves multiple phases that are initially rapid, then become very slow as alendronate is released from bone. The estimated mean terminal elimination half-life of alendronate is 10.5 years.

Therapeutic Use

Treatment of Postmenopausal Osteoporosis

In randomised, double-blind, multicentre studies of 1 or 3 years’ duration, oral alendronate 10 mg/day significantly increased BMD from baseline at the lumbar spine and femoral neck (5.0 to 9.59% and 2.3 to 4.8%, respectively) compared with placebo in postmenopausal women with osteoporosis. In the double-blind, randomised, multicentre Fracture Intervention Trial (FIT), alendronate 5 mg/day for 2 years followed by 10 mg/day for about 1 to 2 years reduced the risk of radiographic vertebral fracture, clinical vertebral fracture or hip fracture by 47 to 56% (a statistically significant extent) in postmenopausal women who already had a vertebral fracture and in those with no existing vertebral fractures but with osteoporosis (a femoral neck BMD T-score of ≤−2.5). The drug increased BMD throughout 7 years at the lumbar spine and maintained initial increases in BMD at the hip, forearm and total body of postmenopausal women with osteoporosis. The alternative regimens 70mg once weekly and 35mg twice weekly increased BMD to the same extent as 10 mg/day in women with postmenopausal osteoporosis over 1 year.

Alendronate 10 mg/day was more effective at increasing BMD than intranasal calcitonin or estradiol plus norethisterone acetate and at least as effective as conjugated estrogens and raloxifene. Combination therapy with alendronate plus estrogen or the selective estrogen receptor modulator raloxifene achieved significantly greater increases in BMD at the femoral neck and lumbar spine than any of these agents administered alone with the exception of 1 comparison: raloxifene plus alendronate achieved similar increases to alendronate monotherapy at the lumbar spine.

Prevention of Postmenopausal Osteoporosis

In 2 well designed studies, alendronate 5mg administered daily to postmenopausal women without osteoporosis increased BMD from baseline by 0.9 to 3.7% whereas placebo decreased BMD by -2.7 to −1.7%. The increases in lumbar spine BMD produced by alendronate 5 mg/day were not as large as those produced by cyclical estradiol plus norethisterone acetate or conjugated estrogens plus medroxyprogesterone. According to evidence from FIT, alendronate lowers the risk of vertebral fracture, but not the risk of any clinical fracture or hip fracture, in postmenopausal women with low BMD but without osteoporosis (T-score of>−2.5 to ≤−1.6).

Male Osteoporosis

Alendronate 10 mg/day was effective in increasing BMD in men with primary osteoporosis or osteoporosis associated with low serum testosterone levels, increasing BMD to a significantly greater extent than placebo at all sites measured in a 2-year, randomised, double-blind, multicentre trial and a 3-year, randomised trial (n = 92 and 241). The incidence of vertebral fractures measured quantitatively was significantly lower with alendronate than with placebo.

Corticosteroid-Induced Osteoporosis

According to the combined results from 2 multicentre, double-blind, placebo-controlled studies (n = 560) with similar protocols, alendronate 5 or 10 mg/day over 1 year significantly increases BMD at the lumbar spine and femoral neck (by 1.0 to 2.9% vs −0.4 to −1.2% with placebo) in men and women with or without osteoporosis receiving systemic corticosteroid therapy (prednisone ≥7.5 mg/day or equivalent). In a subset of these patients participating in a study extension, alendronate 5 or 10 mg/day significantly increased BMD and reduced the incidence of morphometrically defined vertebral fracture (0.7 vs 6.8%, p < 0.05) over 2 years. Alendronate may also be able to prevent corticosteroid-induced osteoporosis in patients initiating systemic corticosteroid therapy for sarcoidosis, according to a preliminary study.

Tolerability

Alendronate 5 or 10 mg/day is generally well tolerated for at least 5 to 7 years in postmenopausal women with osteoporosis and at least 4 to 5 years in postmenopausal women without osteoporosis. The most common adverse events reported in clinical trials that are related or possibly related to alendronate use include abdominal pain, nausea, dyspepsia and acid regurgitation. Essentially similar profiles of events are seen in men with osteoporosis and men and women with corticosteroid-induced osteoporosis.

Alendronate has been associated with adverse events of the upper GI tract when administration instructions have not been followed. No statistically significant differences between alendronate 10 mg/day and placebo have been found in the incidence of upper GI adverse events in large clinical trials. However, 199 adverse events related to the oesophagus were reported from postmarketing surveillance from an estimated 470 000 patients receiving alendronate. In order to minimise any adverse events, manufacturer recommendations have been made regarding posture, medication, food and beverages during administration. Alendronate 70mg once and 35mg twice weekly produced similar incidences of upper GI adverse events to 10mg once daily in a randomised trial.

Pharmacoeconomics

Alendronate is more cost effective in patient groups at higher risk of osteoporotic fractures compared with lower risk patients.

Dosage and Administration

Oral alendronate 10 mg/day is indicated for the treatment of postmenopausal osteoporosis and, in some countries, men with osteoporosis. The alternative regimen of 70mg once weekly is approved in a number of countries. Five or 10 mg/day is recommended for the prevention of postmenopausal osteoporosis in at-risk women and for the treatment of patients with corticosteroid-induced osteoporosis resulting from dosages of corticosteroid equivalent to prednisone ≥7.5 mg/day.

Alendronate should be taken with about 170 to 230ml of plain water upon arising in the morning, at least 30 minutes before the first food, beverage or oral medication of the day. After taking the drug, patients must not lie down for 30 minutes and until the first food of the day has been eaten. Calcium and vitamin D supplements need to be administered if dietary intake of these is inadequate.

Alendronate should not be administered to individuals with hypocalcaemia, abnormalities of the oesophagus which delay oesophageal emptying or inability to stand or sit upright for at least 30 minutes. The drug must also be administered with caution to patients with upper GI problems.

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    Miriam Sharpe, Stuart Noble & Caroline M. Spencer

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Sharpe, M., Noble, S. & Spencer, C.M. Alendronate. Drugs 61, 999–1039 (2001). https://doi.org/10.2165/00003495-200161070-00010

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