Addition of Alendronate to Ongoing HRT in the Treatment of Osteoporosis: A Randomized, Controlled Trial

abstract & commentary

Synopsis: In postmenopausal women with low bone density on hormone therapy, the addition of alendronate leads to further increases in bone density.

Source: Lindsay R, et al. J Clin Endocrinol Metab 1999;84:3076-3081.

This study sought to determine if the concurrent use of the bisphosphonate, alendronate, and standard doses of hormone replacement therapy (HRT) would yield greater bone mineral density (BMD) than the use of HRT alone. A total of 428 postmenopausal women with BMD less than two standard deviation (SD) below the mean for a reference population of young women and who had used HRT for at least one year were randomized to receive either alendronate 10 mg po qd or placebo. Outcome variables included BMD determined by dual-energy x-ray absorptiometry, bone-specific alkaline phosphatase as a marker of bone formation, N-telopeptide as a marker of bone resorption, and adverse events were assessed before and at six and 12 months. At 12 months, the increase in the lumbar spine was 3.6% for combination therapy vs. 1.0% for HRT alone (P < 0.001). At the trochanter (hip), it was 2.7% vs. 0.5% (P < 0.001). The most commonly used estrogen preparations were conjugated equine estrogens (75%), micronized estradiol (10%), and transdermal estradiol (8%). Patients responded similarly to treatments regardless of age and duration of previous HRT. Overall, the incidence of side effects and adverse events was similar in both groups. In particular, the incidence of drug-related gastrointestinal side effects was identical in both groups. There were no hip or symptomatic vertebral fractures in either group during the study.

COMMENT by Sarah L. Berga, MD

The previous dictum regarding the concomitant use of a bisphosphonate and HRT was that, since both were antiresorptives, no additional gain in bone mineral density was to be expected from the use of both. Further, there was the concern that concomitant use might oversuppress osteoclastic function (the cells that resorb), thereby severely depressing osteoblastic function, resulting in too steep of a decrease in bone turnover. Since bone turnover, in addition to density, is important to skeletal structural integrity, too little is undesirable. This study suggests that, contrary to expectations, the use of both alendronate and standard doses of HRT increased bone density at both the spine and the hip trochanter. Two small studies that used etidronate found similar results, but this study is the only one that used a prospective, randomized design with such a large population of postmenopausal women.

Based on this study, one can be reasonably confident in recommending the use of both therapies in women with established osteoporosis or osteopenia. I envision the following as the most parsimonious approach for most women. Initiate HRT as the first line of defense in women with low bone mass because of the multiple other associated salutary benefits. One of these benefits is maintenance of mental speed of processing, an attribute implicated in the pathogenesis of falls. Then, if bone density does not increase or declines, add a bisphosphonate. Of course, to know whom to treat demands that one know the bone density.

It is preferable to know BMD before initiating HRT, so that the response to it can be gauged. A woman on a low dose of estrogen would also have the option of increasing the estrogen dose, regardless of whether a bisphosphonate is begun, if the skeletal response to the initial dose of HRT was insufficient. In the past, the clinical recommendation was to choose between HRT and bisphosphonates. An either/or approach is no longer dictated. For instance, women with severe osteoporosis might want to start both concomitantly, if they are not already on HRT. The population in this study involved women with a mean duration of HRT use of 10 years. All had a bone density at hip or spine of less than 2.0 SD and had already had a fracture.

While the group treated with both HRT and alendronate showed somewhat greater gains in BMD, it is important to note that even women on long-term HRT continued to accrue some BMD while in the HRT arm. I think most practitioners believe that HRT will stabilize BMD. Certainly, that is an appropriate goal in someone with adequate BMD, but women with a history of fracture and severe osteopenia and osteoporosis benefit from a more ambitious treatment goal. Rather than relying on increasing the estrogen dose in those taking HRT, one now also has the option of adding a bisphosphonate.

The combined use of alendronate and standard doses of HRT therapy yielded which of the following?

a. Greater bone mass in the lumbar spine than that achieved with HRT alone

b. Reduced fracture rates in the lumbar spine compared with HRT alone

c. More side effects than with HRT alone

d. Better lipoprotein profile than with HRT alone

e. Less risk of dementia than HRT alone