Evolving Toward a New Paradigm for Prevention of Osteoporosis— The Time Is Upon Us

Clifford Rosen

St. Joseph Hospital, Bangor, Maine

Address correspondence and requests for reprints to: John P. Bilezikian, M.D., Professor of Medicine and Pharmacology, Department of Medicine, College of Physicians & Surgeons, Columbia University, 630 West 168th Street, PH8W-864, New York, New York 10032.


    Introduction
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 Introduction
 References
 
The treatment of chronic diseases has always been a most frustrating and challenging part of medicine. Prevention of chronic diseases and their complications has been an even greater challenge. For many disorders, the best a physician could hope for was to manage what inevitably would progress to a regrettable outcome. In the last two decades, however, a new therapeutic paradigm aimed at preventing the long-term complications of chronic diseases has emerged. This model has evolved into preemptive pharmacological strikes against phenotypical markers that characterize preclinical components of the disease process. The prototypical example of this strategy appeared in the late 1970s with aggressive blood pressure control. In the 1980s, serum cholesterol became a major target for the new interventionalists. By the mid-1990s virtually all endocrinologists were pursuing a course of vigorously controlling blood glucose in diabetics. With respect to blood pressure, glucose, and cholesterol control, epidemiologic evidence has reinforced the value of these interventions by demonstrating favorable reductions in morbidity and mortality from complications associated with these clinical markers.

Osteoporosis has also been subject to this paradigm, with good documentation that estrogen replacement therapy prevents bone loss in postmenopausal women (1). It can be argued that estrogen treatment is different from control of blood pressure, cholesterol, and glucose because it is a replacement strategy rather than a pharmacological intervention. Nevertheless, it is clear that postmenopausal women on estrogen replacement are at lower risk for osteoporosis and its complications (2). Despite a more favorable outcome when estrogen is used for prevention, compliance is a monumental problem. Many patients do not fill their prescriptions, or they take estrogen for only a few months before stopping (3, 4). Troubling short-term side effects such as weight gain, bloatedness, mastalgia, and long-term fears of breast cancer drive many women away from this effective preventive approach.

With this issue of the journal (see page 2784, Meunier et al. (5) present data to suggest that bisphosphonates, which have already been established as effective therapies for established osteoporosis, may also be useful for the prevention of bone loss in postmenopausal women. In this relatively small but important study, healthy postmenopausal women (i.e. defined in skeletal terms by spine and hip bone mineral density (BMD) between -2.0 and +2.0 standard deviations (SD) from young normal subjects) were treated for 2 yr with etidronate, a first generation bisphosphonate. Fifty-four women (53 ± 2.8 yr old and 2.3 ± 1.3 yr postmenopausal) were treated with a cyclic regimen of etidronate, 400 mg/day for 14 days, followed by supplemental calcium only for the next 11 weeks. This cycle was repeated for 24 months in a study design that was double-blinded and placebo controlled. The results showed a significant difference in spinal BMD (+2.93%; P < 0.02) and in femoral neck (+2.02%; P < 0.03) compared with controls. Markers of bone resorption and bone formation were reduced, as expected, by 20–30% for most of the 2-yr treatment period. In a 1-yr period of open observational follow up, these markers returned to baseline. There were no further changes in the 1-yr follow-up period with respect to BMD of the lumbar spine or femoral neck, suggesting that discontinuing etidronate was associated with a return of bone metabolism to that of the untreated postmenopausal group. Etidronate was extremely well tolerated. This study was limited by being short-term and by employing a very small number of subjects. However, a larger study by Pouilles et al. (6) substantiates the results of this study. The studies by Meunier et al. (5) and Pouilles et al.(6) used a bisphosphonate that, although approved for the therapy of osteoporosis in many countries, has not yet been approved in the United States. This report, nevertheless, is supported by a much larger study of alendronate, a more potent bisphosphonate that has been approved in the United States as well as in many other countries for the therapy of osteoporosis. The more recent data on the use of alendronate as a preventive for bone loss are based upon the EPIC (Early Post-Menopausal Intervention Cohort) study (7, 8). On the strength of these data, the Food and Drug Administration (FDA) in the United States has approved alendronate at the 5 mg daily dose for prevention of bone loss in early postmenopausal women. The results of the EPIC study of 1400 women are similar to those reported by Meunier et al. After 2 yr, there was a 5% difference in spine density between women taking 5 mg alendronate and those taking placebo (7). Likewise, there was a 3% difference between treatment groups for total hip bone mineral density. In contrast to the etidronate-treated women in the Meunier study, the magnitude of increase from baseline for spine BMD was 5-fold higher for alendronate (+3.0% vs. +0.6%). Alendronate was well tolerated in EPIC, and the rate of serious adverse events did not differ from placebo.

In summary, three randomized double-blind placebo controlled trials now provide very compelling evidence that bisphosphonates can prevent bone loss in healthy early postmenopausal women.

The report of Meunier et al. (5), Poilles et al.(6), and the results of the EPIC study (7, 8) sharpen several key questions regarding prevention therapy. For example, who should be treated? This is a short but complicated question. While the bisphosphonates can be regarded as bona fide alternatives to prevention with estrogen, they are certainly not interchangeable with estrogen. Prevention of bone loss with estrogen, the true gold standard, encompasses a compendium of other preventive features (cardiovascular, hot flashes, sense of well being, mucous membranes, and perhaps cognitive function), whereas the bisphosphonates are unidimensional, affecting the skeleton only. The question, who should be treated, is answered by addressing a corollary question: who is at risk, specifically, for bone loss? Certainly, individuals who are at substantial risk for postmenopausal bone loss are more serious candidates for prevention with bisphosphonates than women who are not at substantial risk. For each postmenopausal woman, therefore, risk should be evaluated on an individual basis. If the risk is high and the individual chooses not to or can not take estrogen, the case for bisphosphonate use is clear. However, ascertaining risk is not easily quantified. We do know many risk factors that contribute to the overall risk profile for bone loss. These include race, life style, exercise, calcium intake, body size, family history, history of previous fractures, concomitant diseases, and of course, BMD. While the FDA did not specifically recommend bone mass measurement in this setting, knowledge of bone density can be extremely helpful in the overall assessment of risk. Bone mass measurement is the single most important risk factor for fracture. In this regard, dual energy x-ray absorptiometry of specific sites at risk (i.e. lumbar spine, femoral neck, distal forearm) are recommended because surrogate sites, such as the heel or the phalanges do not necessarily reflect bone density at these more important sites. Bone mass measurement can also be extremely helpful in ensuring compliance as preventive therapy implies long-term use. Long-term therapies carry with them the need for patients to know that their regimen is effective. Monitoring BMD at appropriate intervals can be extremely helpful for this purpose.

Algorithms have not yet been established by which clinicians can be confidently guided to know who are serious candidates for pharmacological intervention to prevent osteoporosis. Recommendations will also have to take into account the age of the individual and the proper timing of the "preemptive preventive strike." Any set of recommendations will include sufficient calcium and vitamin D, an appropriate exercise regimen, and other ingredients for a "bone healthy" life style. Such guidelines will inevitably have to come to grips with issues of cost effectiveness, although one ideally would like to set up guidelines for prevention of osteoporosis that are riveted primarily on the medical issues that define individuals who are at risk. Guidelines are currently being actively considered by major organizations such as the American Society for Bone and Mineral Research and the National Osteoporosis Foundation.

The manuscript by Meunier et al. and upcoming publications, including the EPIC data, highlight the preventive approach to osteoporosis (5, 6, 7, 8). Although the message from these studies is clear, application of this message to the practice of prevention is not. For the present, at least the dialogue has begun. Ultimately, the questions raised by the work of Meunier et al. and others will serve ultimately to benefit both patients and practitioners. Osteoporosis is rapidly joining many other disorders of aging for which the best therapeutic dictum is prevention.

Received June 9, 1997.

Accepted June 12, 1997.


    References
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 Introduction
 References
 

  1. Hillard TC, Whitcroft SJ, Marsh MS, et al. 1994 Long-term effects of transdermal and oral hormone replacement therapy on postmenopausal bone loss. Osteoporosis Int. 4:341–348.[Medline]
  2. Cauley JA, Seeley DG, Ensrudt D, Ettinger B, Black D, Cummings SR. 1995 Estrogen replacement therapy and fractures in older women: the study of osteoporotic fractures research group. Ann Int Med. 122:9–16.[Abstract/Free Full Text]
  3. Ravnikar VA. 1987 Compliance with hormone therapy. Am J Obstet Gynecol. 156:1332–1334.[Medline]
  4. Ettinger B, De-Kun L, Klein R. 1996 Continuation of postmenopausal hormone replacement therapy: comparison of cyclic versus continuous combined schedules. Menopause. 185–189.
  5. Meunier PJ, Confavreux E, Tupinon I, Hardouin C, Delmas PD, Balena R. 1997 Prevention of postmenopausal bone loss with cyclical etidronate therapy. J Clin Endocrinol Metab. 82:2784–2791.[Abstract/Free Full Text]
  6. Pouilles JM, Tremollieres F. Roux C, et al. 1997 Effects of cyclical etidronate therapy on bone loss in early postmenopausal women who are not undergoing hormonal replacement therapy. Osteoporosis Int. 7:213–218.[Medline]
  7. Hosking DJ, McClung MR, Ravn P, et al. 1996 Alendronate in the prevention of osteoporosis: EPIC study two-year results. J Bone Miner Res. S133.
  8. Hosking D, Chilvers CED, Christiansen C, et al. 1997 For the early postmenopausal intervention cohort study group (EPIC): prevention of early postmenopausal bone loss with oral alendronate. N Engl J Med. In press.




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