The Use of Alendronate to Prevent Bone Loss


Synopsis: In postmenopausal women younger than 60 years, alendronate increases bone mineral density but not as much as estrogen-progestin.

Source: Hosking D, et al. N Engl J Med 1998;338:485-492.

The purpose of this study was to determine whether low doses of alendronate could prevent bone loss in women younger than 60 years-similar to estrogen-progestin supplementation. Hosking and colleagues studied 1174 postmenopausal women who were not on hormone replacement and had no evidence of osteoporosis. These patients were randomized to receive either placebo, 2.5 mg daily alendronate, or 5 mg daily alendronate. This portion of the study was blinded. An additional 435 women received estrogen-progestin supplementation (unblinded). Appropriate exclusions were applied. The study took place at four sites, including ones in the United States and Europe. If estimated calcium intake from diet was less than 500 mg/d, calcium supplementation was advised.

Initial bone mineral density (BMD) was measured using dual-energy x-ray absorptiometry (DEXA) scans. Lumbar spine, hip, forearm, and total body BMD were measured. Appropriate statistical techniques were used to examine the collected data.

In patients treated with alendronate, the BMD of the lumbar spine increased. The amount of increase with 5 mg of daily alendronate was greater than with 2.5 mg. The group receiving the placebo lost lumbar spine BMD. Although the gains during the first year were greater than the second year, there were increases with treatment during the second year. The response to estrogen-progestin was greater than the response to 5 mg of alendronate daily.

Similar results were reported when hip BMD was measured. Forearm BMD, however, decreased slightly in both the placebo and treated groups, as well as in those receiving estrogen. Total body BMD decreased in the placebo group, increased slightly in the alendronate treated group, and increased in the estrogen-progestin group.

Hosking et al carefully recorded all side effects. Interestingly, upper gastrointestinal tract symptoms were virtually identical in the alendronate-treated groups, the estrogen-progestin-treated group, and the placebo-treated group. There were more drug-related withdrawals in the estrogen-progestin treatment group than in the other groups.


The use of estrogen to prevent bone loss in postmenopausal women is well known and documented. Several other drugs have been developed and used to treat osteoporosis and/or to prevent BMD loss in these women. Unfortunately, many of the previous drugs had serious side effects associated with them or were inconvenient. Alendronate is the first bisphosphonate to be clinically useful for both the prevention and treatment of osteoporosis. Like other bisphosphonates, it is poorly absorbed, but the small amount of drug that reaches the circulation is rapidly deposited in bone and remains there relatively forever. Longer term studies have shown that fractures are markedly reduced in individuals with osteoporosis who are placed on a regimen of alendronate.

However, previous studies (mostly using 10 mg of alendronate/day) have reported significant upper gastrointestinal tract side effects, including a few significant esophageal ulcers, in some patients. This has caused many clinicians to avoid its use.

I was happy to see this study published because it both establishes that alendronate in relatively low doses is a useful method to prevent bone loss in postmenopausal women younger than age 60, and it underscores the fact that the drug is well tolerated. While estrogen-progestin is preferable for most women because of similar prevention of osteoporosis as well as prevention of cardiovascular disease and Alzheimer's disease, there are many women who cannot or will not take hormone replacement therapy. For these women, treatment with alendronate appears to be a safe alternative.


This is the first study to assess prevention of bone loss in women in the early postmenopausal age with the use of alendronate. It is quite clear that alendronate in the 5 mg dose can prevent bone loss, and, therefore, we expect it to reduce the risk of fracture in older women. The difference in bone gain with alendronate of approximately 2% compared to estrogen-progestin is somewhat similar to the situation with raloxifene. At the end of a two-year trial, raloxifene was associated with an average gain in bone density of 2%, in contrast to an approximate 6% gain in bone with estrogen. Therefore, the difference between the drug and hormone therapy was even greater. The critical question is whether these differences in bone density will produce a difference in fracture protection later in life. Although we know that fracture risk correlates with bone density, we truly do not know where these percentage changes will translate into a difference in fracture rates when they occur later in life. At the present time, it seems reasonable to conclude that alendronate and raloxifene prevent bone loss in postmenopausal women, but it is possible that, ultimately, protection against fractures will be slightly less than that with hormone therapy.

By now, it is well recognized that the major problem with alendronate is the side effect of esophageal ulceration. This reaction is minimized, if not eliminated, by the proper taking of alendronate with a full glass of water on an empty stomach in the morning and remaining upright for at least one-half hour. The side effects with the 5 mg dose of alendronate were similar to those of the placebo group. About 10-15% of women on standard doses of hormone therapy will still lose bone. The reasons for this are not clear. It is certainly possible that adding alendronate to those individuals will prevent this bone loss. This is a subject deserving of study, but, in the meantime, it is a reason to screen bone densities in women in their late 60s even if they are on hormone therapy. The clinical trial measuring the effect of combined alendronate estrogen therapy is not yet over. We have reason to believe that the combination will be more effective than either agent alone, because a similar combination trial with atigeronate indicated an additive effect.

We now have two options available to us for patients who are unwilling to take estrogen or cannot take estrogen. Of course, these are alendronate and raloxifene. Each has its advantages and disadvantages. Alendronate has the disadvantage of being uni-dimensional, having an effect only on bone loss, and the further disadvantage of the necessity for a rigorous method of pill taking. Raloxifene has the disadvantage of stimulating hot flashes. Alendronate will have no beneficial effects on the cardiovascular system, and we have reason to believe the same will be true of raloxifene. When all is said and done, alendronate and raloxifene cannot match the broad spectrum of effects associated with postmenopausal estrogen therapy, and treatment with alendronate or raloxifene is far more expensive.