Letters to the Editor - March 1, 2000 - American Academy of Family Physicians

Letters to the Editor

Raloxifene Therapy in the Reduction of Fractures

TO THE EDITOR: The article by Dr. Ullom-Minnich¹ is a nice review of osteoporotic fractures and includes a cost analysis of various pharmacologic agents. However, the author mentions that no published data were available at the time of publication that demonstrated a benefit of raloxifene in reducing fracture risk.

A study² of raloxifene showed a dose-related reduction in the incidence of fractures of the hip, total body and radius in 143 postmenopausal women who were followed for one year. Additionally, the Multiple Outcomes of Raloxifene Evaluation (MORE) study³ showed a significant reduction in the incidence of recurrent vertebral fracture at 30-month follow-up of 7,700 postmenopausal women. This reduction in fracture risk is equivalent to that shown for alendronate after three years of follow-up.⁴ Although the increase in bone mineral density produced by raloxifene at all bone sites is somewhat less than that of estrogen, the increase over the short term is impressive in postmenopausal women.⁵

Raloxifene's ability to provide a short-term effect on bone density is important because the "window of opportunity" to improve bone density using traditional estrogen therapy is limited, and because the efficacy of this treatment decreases during postmenopause. Estrogen improves bone density best over a period of many years, and although its use puts some postmenopausal women at a higher risk for endometrial cancer and, possibly, breast cancer, estrogen therapy may additionally reduce cardiovascular morbidity in women. This benefit may outweigh the risks, because cardiovascular disease is the leading cause of death among women, while breast and uterine cancer account for a much smaller percentage of deaths. Before the release of raloxifene and in instances where cardiovascular risk was minimal, the addition of a bisphosphonate to calcium, vitamin D and exercise seemed to be the next logical steps.

Further, the author mentioned that randomized trials should elucidate the extent to which uterine and breast cancer may complicate and increase the cost of therapy. This cost may turn out to be significant, considering the high cost of treating women with breast cancer. The results of clinical trials elucidating raloxifene's cost-effectiveness related to breast and uterine cancer might also be interesting, considering: (1) the results of the MORE trial³ indicated that raloxifene caused no increase in the incidence of uterine bleeding or thickness compared with placebo, (2) raloxifene's positive effect on serum lipids and coagulation factors⁶ and (3) raloxifene reduced the risk of breast cancer by 76 percent compared with placebo.³

Raloxifene may also prove to play a significant role in cardiovascular risk reduction when the results of the Raloxifene Use for the Heart (RUTH) study are released in several years.

If the current studies prove that raloxifene reduces cardiovascular risk, that information, along with the beneficial effects of raloxifene and other selective estrogen receptor modulators on the breast, the uterus, bone mineral density and reduced vertebral fracture risk, could make the use of traditional estrogens obsolete.

CHARLES A. CEFALU, M.D., M.S.
Louisiana State University Medical Center
1542 Tulane Ave.
New Orleans, LA 70112-2822

REFERENCES

Ullom-Minnich PD. Prevention of osteoporosis and fractures. Am Fam Physician 1999;60:194-202.

Lufkin EG, Whitaker MD, Nickelsen T, Argueta R, Caplan RH, Knickerbocker RK, et al. Treatment of established postmenopausal osteoporosis with raloxifene: a randomized trial. J Bone Miner Res 1998;13:1747-54.

Ettiger B, Black DM, Mitlak BH, Knickerbocker RK, Nickelsen T, Genant HK, et al. Reduction of vertebral fracture risk in postmenopausal women with osteoporosis treated with raloxifene: results from a 3-year randomized clinical trial. Multiple Outcomes of Raloxifene Evaluation (MORE). JAMA 1999; 282:637-45.

Black DM, Cummings, SR, Karpf DB, Cauley JA, Thompson DE, Nevitt MC, et al. Randomised trial of effect of alendronate on risk of fracture in women with existing vertebral fractures. Fracture Intervention Trial Research Group. Lancet 1996; 348:1535-41.

Delmas PD, Bjarnason NH, Mitlak BH, Ravoux AC, Shah AS, Huster WJ, et al. Effects of raloxifene on bone mineral density, serum cholesterol concentrations, and uterine endometrium in postmenopausal women. N Engl J Med 1997;337:1641-7.

Walsh BW, Kuller LH, Wild RA, Paul S, Farmer M, Lawrence JB, et al. Effects of raloxifene on serum lipids and coagulation factors in healthy postmenopausal women. JAMA 1998;279:1445-51.

IN REPLY: Dr. Cefalu's point is well taken. Evidence regarding raloxifene's impact on fractures is growing. The trial by Lufkin,¹ however, does not provide good evidence of raloxifene's effect. Dr. Cefalu's claim of a "dose-related reduction in the incidence of fractures of the hip, total body and radius" is not supported by any claim in this published account.¹ This small trial found that no statistical difference existed between overall or vertebral fracture rates. Even subgroup analysis did not address the fractures mentioned in Dr. Cefalu's letter, but rather a subset of severe vertebral fractures not discussed.

In August 1999, a large published trial² provided evidence that raloxifene reduces overall vertebral fracture incidence. This account of the Multiple Outcomes of Raloxifene Evaluation (MORE) trial is the published version associated with the data mentioned by Dr. Cefalu. More than 7,700 postmenopausal women with osteoporosis or vertebral fractures participated in the three-year trial. With a daily dose of raloxifene (60 mg), the relative risk of vertebral fracture dropped by 65 percent. Nonspinal fractures were not affected.

Several medications have been used in similar three-year trials of postmenopausal and osteoporotic women. Raloxifene² prevented one vertebral fracture for every 45 patients treated. This appears slightly less efficacious than etidronate,³ which required treating 32 patients per fracture. Alendronate⁴ and calcium⁵ reduced vertebral as well as nonspinal fractures. Alendronate prevented one fracture for every 21 patients.⁴ Calcium prevented one for every 15 patients treated.⁵ The cost of these agents remains an important consideration for patients. According to data from the MORE trial and average wholesale costs, the cost per vertebral fracture prevented would be more than $97,000 with raloxifene.^2,6 Etidronate and alendronate cost $16,700 and $58,300 per fracture prevented, respectively.^3,4,6 The cost per fracture prevented with calcium is only $1,000.^5,6

The data supporting the use of raloxifene for prevention of fractures is indeed growing. While it is one appropriate alternative at the present time, it appears to be less effective and much less cost-effective in the above populations, compared with the alternatives.

PAUL D. ULLOM-MINNICH, M.D., M.P.H.
Partners in Family Care
Moundridge, KS 67107

REFERENCES

Lufkin EG, Whitaker MD, Nickelsen T, Argueta R, Caplan RH, Knickerbocker RK, et al. Treatment of established postmenopausal osteoporosis with raloxifene: a randomized trial. J Bone Miner Res 1998;13:1747-54.

Ettiger B, Black DM, Mitlak BH, Knickerbocker RK, Nickelsen T, Genant KH, et al. Reduction of vertebral fracture risk in postmenopausal women with osteoporosis treated with raloxifene: results from a 3-year randomized clinical trial. Multiple Outcomes of Raloxifene Evaluation (MORE). JAMA 1999; 282:637-45.

Harris ST, Watts NB, Jackson RD, Genant HK, Wasnich RD, Ross P, et al. 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.

Black DM, Cummings SR, Karpf DB, Cauley JA, Thompson DE, Nevitt MC, et al. Randomised trial of effect of alendronate on risk of fracture in women with existing vertebral fractures. Fracture Intervention Trial Research Group. Lancet 1996;348:1535-41.

Chapuy MC, Arlot ME, Delmas PD, Meunier PJ. Effect of calcium and cholecalciferol treatment for three years on hip fractures in elderly women. BMJ 1994;308:1081-2.

Red Book. Montvale, N.J.: Medical Economics, 1998.

Use of the Word 'Accident' in Injury-Causing Events

TO THE EDITOR: I would like to thank Dr. Butler and colleagues for the article on post-traumatic stress reactions following motor vehicular trauma.¹ Those who work in injury care and/or injury control know that the long-term effects of trauma are often occult and diverse in presentation. The National Center for Healthcare Statistics within the Centers for Disease Control and Prevention continually reminds us that trauma is the leading cause of death in persons between one and 44 years of age in the United States.² Dr. Butler's article and the accompanying patient education sheet are timely and needed.

However, I would like to encourage the readers of American Family Physician and Dr. Butler and colleagues to adopt the more acceptable substitutions for the word "accident." There is a concentrated effort on the part of professionals who care for trauma patients to avoid the word "accident" in their verbal and written communications. More than just a semantic exercise, choosing the words "crash," "incident," "collision," or even "wreck" over "accident" allows one to describe a traumatic event without implying that it occurs serendipitously. Every traffic crash has a cause and effect. Implying that crashes and the subsequent injuries are "luck," "acts of God" or "accidents" hampers efforts to lower the incidence of injury-related death and disability in the United States. Please consider an editorial review standard that disallows the word "accident" to describe events such as motor vehicle collision that lead to trauma.

DEB DOYLE, R.N., M.S.N.
Trauma/Emergency Services
Memorial Hermann Hospital
Texas Medical Center
Houston, TX 77030-1501

REFERENCES

Butler DJ, Moffic HS, Turkal NW. Post-traumatic stress reactions following motor vehicle accidents. Am Fam Physician 1999;60:524-31.

Injury prevention: meeting the challenge. The National Committee for Injury Prevention and Control. Am J Prev Med 1989;5(3 suppl):1-303.

Corrections

Question 12 in the "Clinical Quiz" of the October 15, 1999, issue (page 1633), pertaining to the article "Pediatric Advanced Life Support: A Review of the AHA Recommendations," contained a typographical error. Rather than saying "60 mg per kg of crystalloid," the question should refer to "60 mL per kg of crystalloid."

Table 4 in the article "Endometrial Cancer" (June 1999, page 3069) contained data that were misaligned in the fourth and fifth columns: the "80 percent" specificity cited in the fifth column should have aligned with "patients with bleeding: 82" in the fourth column. In the same article, an incorrect title was given in the references. The correct title of the third reference is "Contemporary Issues in the Management of Endometrial Cancer."

*These corrections have been made to the online version of AFP. The links above will take you to the corrected items, which remain part of the online issues in which they were originally published.

Send letters to Jay Siwek, M.D., Editor, American Family Physician, 11400 Tomahawk Creek Parkway, Leawood, KS 66211-2672; fax:913-906-6080; e-mail: afplet@aafp.org. Please include your complete address, telephone number and fax number. Letters should be double-spaced, fewer than 500 words and limited to one table or figure and six references. Please submit a word count. Letters submitted for publication in AFP must not be submitted to any other publication. Possible conflicts of interest must be disclosed at time of submission. Submission of a letter constitutes transfer of copyright to the American Academy of Family Physicians. The editors may edit letters to meet style and space requirements.

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