/ EDITORIAL

Cyclic Etidronate: Has the Rose Lost Its Bloom? ROBERT MARCUS, M.D., Stanford and Palo Alto, California

F ew events in the annals of osteoporosis research have elicited such widespread interest as did

the independent reports, 2 years ago, that cyclic administration of etidronate (Didronel), a geminal bisphosphonate, increases vertebral bone mass and reduces the incidence of vertebral fracture in post- menopausal women with osteoporosis [1,2]. This news was enthusiastically received by the medical community and hailed by the mass media as a major therapeutic breakthrough. Its impact on patients was immediate and dramatic, In my own clinic, pa- tients arrived bearing news clippings and request- ing prescriptions. Informed that there was no estab- lished rationale for adding a bisphosphonate to estrogen, some patients asked to terminate hor- mone replacement in order to receive the new drug. During the subsequent 2 years, Food and Drug Ad- ministration (FDA) approval of etidronate for os- teoporosis was requested, and the pharmaceutical industry rushed to develop second- and third-gen-’ eration bisphosphonates for this purpose.

In the current issue, Harris and colleagues [3] present a follow-up report on the skeletal effects of cyclic etidronate. The results, although encourag- ing, warrant considerably more interpretive re- straint than greeted the initial report. Gains in bone mass achieved by 2 years persisted and increased slightly during Year 3 of treatment. However, the dramatic improvement in overall vertebral fracture incidence that one anticipated from the 2-year re- sults did not achieve statistical significance follow- ing Year 3. This finding reflects a stable fracture rate in the control subjects and an increased frac- ture rate in the etidronate-treated subjects during the third year. However, when post-hoc analysis of women at particularly high risk for fracture was carried out, significant reductions in total and new vertebral fractures were observed. This subgroup consisted of women who, at baseline, had three or more vertebral fractures and a spinal bone mineral density that was below the 50th percentile for the group as a whole. It is important to note that this percentile refers not to healthy postmenopausal

From the Department of Medicine, Stanford University, Stanford, Cali- fornia, and Veterans Administration Medical Center, Palo Alto, California.

Requests for reprints should be addressed to Robert Marcus, M.D.

Manuscript submitted October 22,1992, and accepted June 17,1993.

women, but to the median of a group who, by virtue of having established osteoporosis, already have a reduced bone mass.

Should cyclic etidronate therefore be considered potentially useful only for patients at the most ex- treme jeopardy for fracture? I think not. Although the results failed to achieve significance, a trend toward reduced fracture incidence was observed in women at lower risk. Because of the relatively mod- est number of incident fractures in both controls and drug-treated subjects in this subgroup, a type II error seems highly likely. It is risky, of course, to rely on post-hoc analysis in clinical trials, so it will be important to confirm this interpretation with a prospective trial of sufficient size and duration to permit valid conclusions not only regarding women with lower risk for recurrent vertebral fracture, but also regarding nonvertebral fractures.

It must be remembered that this study was con- ducted in osteoporotic women who were considera- bly beyond menopause. Cyclic etidronate was therefore tested in subjects who predictably show low rates of bone turnover. The cyclic regimen was adopted to minimize the risk of osteomalacia that may result from long-term etidronate use. There are other patients, however, for whom bisphos- phonate therapy may be rational, but for whom cyclic therapy may not be the optimal initial strate- gy. Examples include men with high-turnover os- teoporosis, women at menopause who cannot take estrogen, or patients commencing treatment with high-dose glucocorticoids, such as transplant recip- ients. In these situations, antiresorptive therapy with calcitonin or bisphosphonate will conserve bone mass, and if a bisphosphonate is selected, it might be more effective as daily therapy for several months to maximize suppression of bone turnover. The newer, more potent, bisphosphonates do not show the osteomalacic potential of etidronate, so cyclic administration of these agents may never be necessary.

Timely, sustained administration of replacement estrogen remains the single most powerful pharma- cologic intervention for conserving bone and mini- mizing fracture. When estrogen is inappropriate, we can select from several antiresorptive agents, in- cluding calcitonin and bisphosphonates. Since bone remodeling is a coupled process, reduction in bone resorption will ultimately decrease bone formation.

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Thus, antiresorptive therapy will produce only modest increases in bone mass that level off after a few years, a phenomenon confirmed again by Harris et ali [3J. The goal of finding an agent that produces major, sustained increases in bone mass remains elusive.

The study of Harris et al [3] emphasizes the diffi- culty of proving antifracture efficacy. To validate a reduction in hip fracture incidence, for example, it may be necessary to treat thousands of persons for several years. Such trials will be very expensive. The results of recent meetings between academic and industry scientists and the FDA suggest that bone density changes may not be accepted as a sur- rogate endpoint for fracture incidence for purposes

of drug approval. Although there is a reasonable basis to entertain such a position, there is a high risk that such a policy will have a chilling effect on fur- ther drug development in this field. One hopes that the FDA will be sensitive to this concern before a final policy is formulated.

REFERENCES 1. Storm T, Thamsborg G, Steiniche T, Genant HK, Ssrenson OH. Effect of

intermittent cyclical etidronate therapy on bone mass and fracture rate in women with postmenopausal osteoporosis. N Engl J Med 1990; 322: 1265-71. 2. Watts NB, Harris ST, Genant HK, et al. Intermittent cyclical etidronate treat- ment of postmenopausal osteoporosis. N Engl J Med 1990; 323: 73-9.

3. Harris ST, Watts NB, Jackson RD, eta/. Four-year study of intermittent cyclic etidronate treatment of postmenopausal osteoporosis: three years of blinded

therapy followed by one year of open therapy. Am J Med 1993; 95: 557-67.

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