The Latest on Osteoporosis Research
By Leon Speroff, MD
The reports at the annual meeting of the American Society for Bone and Mineral Research in December 1998 provide us with the latest data from the on going studies of alendronate and raloxifene.
The effect of alendronate on osteoporosis-related fractures was reported from the follow-up of 4432 women for an average of 4.2 years.1 A statistically significant reduced risk of fracture was demonstrated only in women with initial T-scores of -2.5 or less, with 36% reduction in all fractures, and a 50% reduction in vertebral fractures. Calcium and vitamin D supplementation with alendronate treatment had no added effect as long as women have a minimal intake of 800 mg daily. (See Table 1.)2
| Table 1 | ||
| Effect of Alendronate on Osteoporosis-Related Fractures | ||
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Adapted from: Bonnick S, et al. 1998;http://www.asbmr.org. _________________________________________________________________ |
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There are two important interpretations of these data:
• Treatment obviously benefits women who already have an osteoporotic low bone density or previous vertebral fractures, meaning, women who already have osteoporosis; and
• If alendronate benefits women who do not already have osteoporosis, it will take more than four years of treatment to observe the effect. This is a reasonable prediction, based on the recognized positive impact of alendronate on bone density.
The Early Postmenopausal Interventional Cohort (EPIC) study indicated that over a four-year period, alendronate and hormone therapy in the United States produced similar bone density results.3 The greater increase noted in Europe with hormone therapy probably reflects the use of 19-nortestosterone progestins, which are known to have an additive effect on bone density when combined with estrogen. (See Table 2.)
| Table 2 | ||
| Results of the EPIC Study | ||
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| Placebo |
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| Alendronate, 5 mg |
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| E/P, USA |
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| E/P, Europe |
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Adapted from: Ravn P, et al. 1998;http://www.asbmr.org. ___________________________________________________ |
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Combining alendronate and hormone therapy produces an added gain in bone density. When women who were already taking hormone therapy also received alendronate (10 mg) for one year, the gain in bone density ranged from 0.9% in the femoral neck to 2.6% in the spine.4 In women with osteopenia, combined therapy with alendronate 10 mg and 0.625 mg conjugated estrogens produced a 1-2% greater gain in bone density over a two-year period of treatment.5 However, it is by no means certain that these findings will translate into a difference in the incidence of fractures later in life. Indeed, it is unlikely. There is a further theoretical concern that oversuppression of resorption can ultimately yield more brittle bones. This emphasizes the importance of long-term follow-up studies with fracture outcomes. Unfortunately, most bone studies end after about four years when bone density differences are demonstrated.
Compliance with alendronate has been overestimated by the clinical trials. It is well-recognized that participants in clinical trials are better motivated, better supported, and perform better. In the Kaiser Permanente Medical Care Program in California, about one-third of patients had acid-related complaints and one in eight required treatment.6 About 50% of patients do not comply with instructions and about 50% discontinue therapy by one year.6,7 These compliance data are a strong argument for the use of bone marker or bone density measurements to assess the effectiveness of treatment.
The Multiple Outcomes of Raloxifene Evaluation (MORE) study of raloxifene administration to osteoporotic women has now accumulated results from two and three years of follow-up. (See Table 3.)8
| Table 3 | ||
| Results of the MORE Study | ||
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| Low T-score |
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| Previous vertebral fracture |
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Adapted from: Ensrud KE, et al. Bone 1998;23(Suppl 5):S174. __________________________________________________________ |
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Women with low T-scores or previous vertebral fractures have approximately a 50% reduction in vertebral fractures with raloxifene treatment. Thus far, there has been no evidence of a reduction in hip fractures. The reduction in vertebral fractures is similar to that seen with alendronate. Why is there no decrease in hip fractures, despite a bone density response that is only slightly less than that associated with alendronate? Is it because the slight difference in bone density comparing raloxifene with alendronate is clinically significant?9,10 Like alendronate, we have no fracture data in treated women who originally had normal bone densities. Will the effect of alendronate and raloxifene in osteoporotic women be similar to that achieved with long-term treatment of normal women?
A Scandinavian assessment of cost effectiveness concluded that it is not cost effective to treat a 55-year-old woman of average risk for fractures if the only benefit is skeletal.11 If this woman already has osteopenia, then it is cost effective, and a treatment that has multiple benefits is also cost effective. (See Table 4.)
| Table 4 | |
| Cost of Treating a 55-year-old Woman | |
| Effect |
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| Hip fracture only |
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| Hip fx + CVD |
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| Hip fx + CVD + breast |
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| Hip fx only, osteopenia |
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Adapted from: Jönsson B, et al. Bone 1998;23(Suppl 5):S203. __________________________________________________ |
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These data reinforce my belief that the treatment of choice for the early postmenopausal years (age 50-65) is hormone therapy because of its broad spectrum of benefits—most notably, symptomatic relief and protection against cardiovascular disease and also because we have no current data that confirm alendronate and raloxifene given to women with normal bone densities will prevent fractures in old age and, if they do, how they compare to hormone therapy. Around age 65, I recommend measurement of bone density. Low bone density should be treated with a drug chosen during a clinician-patient dialogue reviewing the advantages and disadvantages of each drug (estrogen, alendronate, raloxifene).
References
1. Cummings SR, et al. JAMA 1998;280:2077-2082.
2. Bonnick S, et al. 1998;http://www.asbmr.org.
3. Ravn P, et al. 1998;http://www.asbmr.org.
4. Lindsay R, et al. Osteoporos Int 1998;8(Suppl 3):12.
5. Greenspan S, et al. Bone 1998;23(Suppl 5):S174.
6. Ettinger B, et al. 1998;http://www.asbmr.org.
7. Faulkner DL, et al. Osteoporos Int 1998;8(Suppl 3):21.
8. Ensrud KE, et al. Bone 1998;23(Suppl 5):S174.
9. Meunier PJ, et al. Bone 1998;23(Supp 5):S295.
10. Bjarnason NH, et al. Osteoporos Int 1998; 8(Suppl3):11.
11. Jönsson B, et al. Bone 1998;23(Suppl 5):S203.
Dr. Speroff is Professor of Obstetrics and Gynecology, Oregon Health Sciences University, Portland.
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