Real-life risks and benefits of fracture-reducing drugs

STAR and RUTH trials

Study of Tamoxifen and Raloxifene

The STAR trial reported by Vogel et al involved 19,747 postmenopausal women enrolled on the basis of their high risk for breast cancer. The patients were randomized to tamoxifen (already approved for breast cancer prevention) or raloxifene.

Over 5 years of study, the incidence of invasive breast cancer was virtually identical in both groups. However, the raloxifene group had statistically significant lower numbers of thromboembolic events, cataracts, hysterectomies performed, and endometrial hyperplasias. A 38% reduction in endometrial cancer in the raloxifene group had not reached statistical significance but was trending in that direction.

Studies of fracture reduction in populations with existing osteoporosis include the Fracture Intervention Trial, which enrolled women with low bone mass and existing vertebral fractures. Clinical vertebral and other fractures were substantially reduced in the treatment group

Raloxifene Use in The Heart

The RUTH trial reported by Barrett-Connor et al involved 10,101 post-menopausal women selected for multiple risks for coronary heart disease.

Although there was no reduction in coronary heart disease, there was no increase, unlike the estrogen and progesterone arm of the Women’s Health Initiative (WHI). Additionally, however, there was a 44% reduction in invasive breast cancer (95% CI 0.38–0.83). Remember, these women were chosen for their risk of heart disease. The rate of breast cancer in the placebo group was 2.7 cases per 1,000 women per year, and thus the 44% reduction means the rate in the treatment group was 1.5 cases per 1,000 women per year.

Consider the context

For comparison purposes, consider an average-risk group in the WHI, where the incidence of breast cancer was 3.3 cases per 1,000 women per year. Contrast this rate to that of a high-risk group, such as the placebo group in the original breast cancer prevention trial (BCPT), where the incidence was 6.8 cancers per 1,000 women per year.

A case in point

I believe that such information must be available to clinicians and must be factored into your decision when contemplating a bone drug. A recent anecdote underscores the problem.

4 out of 10 Caucasian women over age 50 will fracture a hip, spine, or wrist sooner or later

1 of every 5 who fracture a hip ends up in a nursing home

DXA T-score of -2.0 in the hip and atypical ductal hyperplasia

An internist called me to discuss a mutual patient whom I had placed on raloxifene 2 years earlier. His comment was that raloxifene does not work in the hip. Our mutual patient had a T-score on DXA in the hip of -2.0 and in the spine of -0.7 (falsely improved by some osteophytes). In addition, she had been diagnosed with atypical ductal hyperplasia of the breast 2 years earlier.

I pointed out to him that studies of hip fracture reduction with bisphosphonate were all performed in women with osteoporosis. Furthermore, after the NHANES III correction, a sizable number of women in the MORE trial were not osteoporotic. In fact, the fracture incidence in the MORE trial placebo group was 0.7%—an extremely low risk—compared with 2.2% in the treatment group in the Fracture Intervention Trial I, and 3.0% in the treatment group in the Hip Intervention Program.

Stated another way, the incidence of hip fracture in the MORE placebo group was less than that in the treated groups in the Fracture Intervention Trial I and the Hip Intervention Program.

But perhaps the most important point in my anecdotal case is that the woman had a diagnosis of atypical ductal hyperplasia of the breast, a lesion that significantly increases her risk of invasive breast cancer. For these reasons, raloxifene was a much better choice for her fracture reduction pharmacotherapy. Her internist was unaware of these breast effects and had not taken this into account.

3 Estrogen for bone protection: Time for a comeback?

Stefanick ML, Anderson GL, Margolis KL, et al. Effects of conjugated equine estrogens on breast cancer and mammography screening in postmenopausal women with hysterectomy. JAMA. 2006;295:1647–1657.

Jackson RD, Wactawski-Wende J, LaCroix AZ, et al. Effects of conjugated equine estrogen on risk of fractures and BMD in postmenopausal women with hysterectomy: results from the Women’s Health Initiative randomized trial. J Bone Miner Res. 2006;6:817–828.

It may be time to revisit our initial reaction to the WHI. Although most estrogens are FDA-approved for treatment of osteoporosis, recommendations since the WHI have generally been that we should reserve hormone therapy or estrogen therapy for disruptive transitional symptoms (hot flashes, night sweats, etc.), and prescribe the lowest dose possible for the shortest time possible, consistent with the patient’s treatment goals.