Elsevier

The Lancet

Volume 348, Issue 9041, 7 December 1996, Pages 1535-1541
The Lancet

Articles
Randomised trial of effect of alendronate on risk of fracture in women with existing vertebral fractures

https://doi.org/10.1016/S0140-6736(96)07088-2Get rights and content

Summary

Background

Previous studies have shown that alendronate can increase bone mineral density (BMD) and prevent radiographically defined (morphometric) vertebral fractures. The Fracture Intervention Trial aimed to investigate the effect of alendronate on the risk of morphometric as well as clinically evident fractures in postmenopausal women with low bone mass.

Methods

Women aged 55–81 with low femoral-neck BMD were enrolled in two study groups based on presence or absence of an existing vertebral fracture. Results for women with at least one vertebral fracture at baseline are reported here. 2027 women were randomly assigned placebo (1005) or alendronate (1022) and followed up for 36 months. The dose of alendronate (initially 5 mg daily) was increased (to 10 mg daily) at 24 months, with maintenance of the double blind. Lateral spine radiography was done at baseline and at 24 and 36 months. New vertebral fractures, the primary endpoint, were defined by morphometry as a decrease of 20% (and at least 4 mm) in at least one vertebral height between the baseline and latest follow-up radiograph. Non-spine clinical fractures were confirmed by radiographic reports. New symptomatic vertebral fractures were based on self-report and confirmed by radiography.

Findings

Follow-up radiographs were obtained for 1946 women (98% of surviving participants). 78 (8·0%) of women in the alendronate group had one or more new morphometric vertebral fractures compared with 145 (15·0%) in the placebo group (relative risk 0·53 [95% CI 0·41–0·68]). For clinically apparent vertebral fractures, the corresponding numbers were 23 (2·3%) alendronate and 50 (5·0%) placebo (relative hazard 0·45 [0·27–0·72]). The risk of any clinical fracture, the main secondary endpoint, was lower in the alendronate than in the placebo group (139 [13·6%] vs 183 [18·2%]; relative hazard 0·72 [0·58–0·90]). The relative hazards for hip fracture and wrist fracture for alendronate versus placebo were 0·49 (0·23–0·99) and 0·52 (0·31–0·87). There was no significant difference between the groups in numbers of adverse experiences, including upper-gastrointestinal disorders.

Interpretation

We conclude that among women with low bone mass and existing vertebral fractures, alendronate is well tolerated and substantially reduces the frequency of morphometric and clinical vertebral fractures, as well as other clinical fractures.

Introduction

Osteoporosis is a common disorder that is a contributing factor in about 1·5 million fractures per year among women in the USA alone, with an estimated treatment cost of more than US$10 billion.1 On average, a 50-year-old white woman has a risk of hip fracture during her remaining lifetime of about 16%.2 About 1·7 million hip fractures occurred world wide in 1990.3

Randomised trials have shown increases in bone mass with several treatments, including oestrogen,4, 5 calcitonin,6 calcitriol,7 sodium fluoride,8, 9 and bisphosphonates.10, 11, 12 Trials of some of these drugs have also reported reductions in the incidence of vertebral fracture,4, 9, 11, 12 although some were small and of short duration, and in some the outcome was decrease in vertebral height. Only about a third of radiographically diagnosed vertebral fractures cause symptoms;13 the effect of these agents on clinically evident fractures is uncertain. A combination of calcium and vitamin D reduced the incidence of hip and non-spine fracture in very elderly women in nursing homes,14 and long-term use of oestrogen has been associated with reduced risk of hip fracture in observational studies.15 No randomised trial has shown, however, a reduction in risk of hip fracture in community-dwelling women.

Liberman and colleagues12 reported that the aminobisphosphonate alendronate sodium (alendronate) increases bone mineral density (BMD) at the spine and hip and in the whole body and reduces the risk of radiographically defined vertebral fracture in women with low BMD. Their study did not, however, have sufficient power to demonstrate a significant effect on non-vertebral fractures.

The Fracture Intervention Trial was designed to find out the effect of alendronate on the frequencies of vertebral and non-vertebral fractures in postmenopausal women with low bone mass.16 The investigation was carried out as two separate studies in women with and without vertebral fractures at baseline. We report here the results among women with at least one vertebral fracture at recruitment.

Section snippets

Methods

Participants were recruited from population-based listings in 11 metropolitan areas of the USA. All women in the Fracture Intervention Trial were aged between 55 and 81 years at baseline, had been postmenopausal for at least 2 years, and had femoral-neck BMD of 0·68 g/cm2 or less (QDR-2000 Hologic, Waltham, MA, USA), about 2·1 SDs below peak bone mass based on the manufacturer's normative data. Details of the study design and methods have been published previously.16 We excluded women with

Results

2027 women were recruited into the vertebral fracture arm of the Fracture Intervention Trial, 1022 to alendronate and 1005 to placebo (figure 1). Potential confounding variables were similarly distributed between the treatment groups (table 1). 97% of participants identified themselves as Caucasian, 1% as Asian, and 1% as African-American.

The average follow-up time was 2·9 years in both groups (range 0·7–3·5 alendronate, 0·3–3·5 placebo). Closeout information was obtained either in clinic or by

Discussion

We found that postmenopausal women with low bone mass and pre-existing vertebral fractures who received alendronate had a lower incidence of several types of fractures than women who received placebo. Our findings confirm those of Liberman and colleagues,12 and show in addition to the effect on radiographically defined vertebral fractures, effects on symptomatic vertebral fractures, hip fractures, and wrist fractures.

This randomised trial found a significant reduction in the risk of hip

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