Effect of Alendronate on Risk of Fracture in Women With Low Bone Density but Without Vertebral Fractures
ABSTRACT & COMMENTARY
Synopsis: Alendronate decreases the risk of fractures only in women with low bone mass or those who already have a fracture.
Source: Cummings SR, et al. JAMA 1998;280: 2077-2082.
A previous study showed that alendronate use for three years reduced the risk of hip and wrist fractures by about 50% in women who had low bone mineral density (BMD) and vertebral fractures. This follow-up study tested the hypothesis that alendronate would also reduce the risk of clinical fractures in postmenopausal women who have low BMD but not vertebral fractures. A total of 4432 postmenopausal women not taking hormone replacement therapy (HRT) with low femoral neck BMD (lower than or equal to 0.68 g/cm3) were randomized to placebo or alendronate for four years. The dose of alendronate was 5 mg daily for the first two years and 10 mg daily for the last two years. BMD was measured at the hip, spine, and whole body using a Hologic densitometer (dual energy x-ray absorptiometry [DEXA]). A subset had wrist BMD assessed. The hip and spine assessments were anually repeated. Vertebral fractures were assessed by clinical criteria and by radiographic morphometry. A decrease of 20% or 4 mm in vertebral height was classified as a compression fracture.
Compared with the placebo, alendronate use resulted in a similar increase in BMD in all women, regardless of initial BMD. However, alendronate use decreased the overall fracture rate only in women with femoral neck BMD less than -2.5 standard deviations below normal young adult mean based on results obtained by the Third National Health and Nutritional Examination Survey (T-score). The overall relative hazard was 0.64 for women with a T-score of less than or equal to -2.5 but 1.03 for those with a T-score higher than -2.5 and lower than -2.0. The risk of vertebral fracture detected radiographically was also reduced in women with an initial T-score less than or equal to -2.5. The relative hazard for vertebral compression fracture was 0.50 in this group, but 0.54 (confidence interval, 0.28-1.04) for those with a T-score higher than -2.5 and lower than -.0 and 0.82 or a T-score greater than or equal to -2.0 (CI, 0.33-2.07).
COMMENT BY SARAH L. BERGA, MD
This study is interesting for many reasons. First, it suggests that alendronate should not be used universally as prophylaxis against future fractures. Second, the study enrolled only women not using HRT, so at least two important questions remain unanswered. One is whether the concomitant use of HRT and alendronate makes sense for any group of postmenopausal women. The other question is whether HRT or alendronate is better for the prevention of fractures in postmenopausal women with osteoporosis. Third, the study found that an astonishing 82% of women had dietary calcium intakes of less than 1000 mg/d.
In his accompanying editorial (JAMA 1998;280:2119-2120), Robert Heaney, MD, highlights another interesting feature of the study, that osteoporosis is defined as skeletal fragility due to low bone mass, microarchitectural deterioration, or both. However, the practical definition of osteoporosis is based only on BMD as radiographically assessed. Not all women with low BMD have architectural fragility. The best indication of fragility is a clinically evident fracture. The prior study of women with a history of vertebral fractures assessed the effects of alendronate in women with osteoporosis due to low bone mass and fragility. But not all women with low BMD also have fragility, so, in this study, those without fragility may have benefited less and also diluted the treatment effect of alendronate. Heaney points out that there currently is no biochemical test for fragility. Personal and family histories are the best clues. He suggests that the reasonable clinician will implement bisphosphonate therapy in those with low BMD (T-score less than or equal to -2.5) and a clinical history of bone fragility or glucocorticoid use. To prevent loss of bone mass in others, he suggests HRT, exercise, and appropriate dietary calcium and vitamin D intake. Given that 82% of enrollees had inadequate dietary intakes of calcium, the prudent clinician should do what it takes to make sure that all patients get the message to get enough dietary calcium and vitamin D. Since HRT has benefits above and beyond the prevention of fractures, its use should be strongly encouraged. Like nutritional intake, HRT use is woefully low. We should concentrate on understanding why and figuring out what it will take to make HRT more acceptable and tolerable to a larger group of women. It is unsatisfying to wait for fracture to occur before starting an intervention, because, by that time, the loss of microarchitectural integrity can never be fully reversed. To Heaney, that is a lot like waiting for a stroke before treating hypertension. However, the present data do not suggest that alendronate should be given as the first line of defense for prophylaxis from osteoporosis.
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