No studies have had sufficient power to show that combination antiresorptive therapy—bisphosphonate and estrogen replacement—reduces fracture risk and increases bone mass. Greenspan and colleagues designed a study to determine the effect of combination therapy in a group of elderly, community-dwelling women.

Patients in this randomized, double-blind study took alendronate, hormone therapy (estrogen alone or with progesterone, depending on whether the patient had an intact uterus), both drugs, or neither drug. A run-in phase was completed by 373 women, aged 65 to 90 years. Outcomes included bone mineral density (BMD) measurements of the hip, lumbar spine, and radius at baseline, randomization, and six-month intervals for three years. Weight, height, body mass index, and activity and mental status parameters were secondary outcomes.

All groups were similar at baseline. After three years, hip BMD increased 5.9 percent in the combination therapy group, 4.3 percent in the alendronate group, and 3 percent in the hormone group, while patients in the placebo group maintained their BMD. Similar trends were found when measuring density at the femoral neck and greater trochanter. All treatment groups had increased BMD in the posteroanterior lumbar spine and the lumbar spine; women in the combination therapy group had the greatest increase in vertebral BMD and the greatest rate of change from baseline. Although the effects of combination therapy were superior to the effects of each agent when taken alone, the benefits were not additive. There was considerable variation in response rate among the active-treatment groups, with older participants generally responding less often than younger patients.

Combination therapy with alendronate and hormone therapy improved BMD in community-dwelling elderly women better than therapy with either agent alone. Although direct measurement of impact on fractures was not part of this study, the authors estimate that combination therapy would reduce fractures by an additional 10 percent compared with hormone therapy alone and by an additional 8 percent compared with alendronate alone. The risks of including estrogen replacement in the therapeutic regimen must be weighed against the benefits of potential fracture reduction, especially in women who do not respond to monotherapy.