Clinical Review

MENOPAUSE

OBG Manag. 2007 May;19(5):59-70

References

1. Kaunitz AM. Update on menopause. OBG Management. 2006;18(5):45-54.

2. Rossouw JE, Anderson GL, Prentice RL, et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women. Principal results from the Women’s Health Initiative. Writing Group for the Women’s Health Initiative. JAMA. 2002;288:321-333.

3. Berry D, et al. Presented at the 29th annual San Antonio Breast Cancer Symposium, December 14, 2006, San Antonio, Tex.

4. Anderson GL, Limacher M, Assaf AR, et al. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women’s Health Initiative randomized controlled trial. Women’s Health Initiative Steering Committee. JAMA. 2004;291:1701-1712.

5. Kaunitz AM. Hormone therapy and breast cancer risk—trumping fear with facts. Menopause. 2006;13:160-163.

6. Collins JA, Blake JM, Crosignani PE. Breast cancer risk with postmenopausal hormonal treatment. Hum Reprod Update. 2005;11:545-560.

7. de Laet C, Oden A, Johansson H, Johnell O, Jonsson B, Kanis JA. The impact of the use of multiple risk indicators for fracture on case-finding strategies: a mathematical approach. Osteoporosis Int. 2005;16:313-318.

8. McClung MR. Do current management strategies and guidelines adequately address fracture risk? Bone. 2006;38(Suppl 2):S13-S17.

9. Mellstrom DD, Sorensen OH, Goemaere S, Roux C, Johnson TD, Chines AA. Seven years of treatment with risedronate in women with postmenopausal osteoporosis. Calcif Tissue Int. 2004;75:462-468.

10. Bone HG, Hosking D, Devogelaer JP, et al. For the Alendronate Phase III Osteoporosis Treatment Study Group. Ten years’ experience with alendronate for osteoporosis in postmenopausal women. N Engl J Med. 2004;350:1189-1199.

11. Black DM, Schwartz AV, Ensrud KE, et al. For the FLEX Research Group. Effects of continuing or stopping alendronate after 5 years of treatment: the Fracture Intervension Trial Long-term Extension (FLEX): a randomized trial. JAMA. 2006;296:2927-2938.

12. Odvina CV, Zerwekh JE, Rao DS, Maalouf N, Gottschalk FA, Pak CY. Severely suppressed bone turnover: a potential complication of alendronate therapy. J Clin Edocrinol Metab. 2005;90:1294-1301.

13. Ste-Marie LG, Sod E, Johnson T, Chines A. Five years of treatment with risedronate and its effects on bone safety in women with postmenopausal osteoporosis. Calcif Tissue Int. 2004;75:469-476.

14. Cummings SR, Black DM, Thompson DE, et al. Effect of alendronate on risk of fracture in women with low bone density but without vertebral fractures: results from the Fracture Intervention Trial. JAMA. 1998;280:2077-2082.

15. Black DM, Cummings SR, Karpf DB, et al. Randomised trial of effect of alendronate on risk of fracture in women with existing vertebral fractures. Lancet. 1996;348:1535-1541.

Dr. Kaunitz has received funding from Barr Laboratories, Berlex, Medical Diagnostic Laboratories, Organon, and Warner Chilcott. He is a speaker or consultant for the American College of Obstetricians and Gynecologists, Barr Laboratories, Berlex, Johnson & Johnson, Merck, Noven Organon, and Warner-Chilcott. He holds stock with Barr, Johnson & Johnson, Procter & Gamble, Roche, and Sanofi-Aventis.

Dr. McClung receives grant/research support from and is a consultant to Amgen, Lilly, Merck, Novartis, Proctor & Gamble, Roche, and Sanofi-Aventis. He is a speaker for Lilly, Merck, Procter & Gamble, and Sanofi-Aventis.

Grady D. Clinical practice. Management of menopausal symptoms. N Engl J Med. 2006;355:2338–2347.

Grady D, Cohen B, Tice J, et al. Ineffectiveness of sertraline for treatment of menopausal hot flushes: a randomized controlled trial. Obstet Gynecol. 2007;109:823–830.

Loprinzi CL, Kugler JW, Barton DL, et al. Phase III trial of gabapentin alone or in conjunction with an antidepressant in the management of hot flashes in women who have inadequate control with an antidepressant alone: NCCTG N03C5. J Clin Oncol. 2007;25:308–312.

Since publication of the initial WHI findings in 2002,² interest in nonhormonal management of vasomotor symptoms has increased among menopausal women and their clinicians. The botanical black cohosh and “nutraceutical” soy or isoflavone supplements represent the nonprescription remedies most widely used for relief of hot flashes. Unfortunately, accumulating evidence does not support the efficacy of these popular remedies.

In a recent NIH-funded, randomized, double-blind, placebo-controlled clinical trial, Newton and colleagues compared the following interventions:

black cohosh, 160 mg daily
daily multibotanical supplement that included 200 mg of black cohosh and 9 other ingredients
the multibotanical supplement plus counseling regarding dietary soy
conjugated equine estrogen, 0.625 mg daily (with or without 2.5 mg of medroxyprogesterone acetate)
placebo

The study involved 351 perimenopausal or postmenopausal women aged 45 to 55 years with 2 or more vasomotor symptoms daily.

The findings: At 3, 6, and 12 months, women allocated to estrogen (with or without progestin) had statistically significant relief of symptoms. In contrast, women allocated to botanical and/or herbal supplements experienced minimal relief, comparable to the effects of placebo.

The findings of this important study, as well as those of Grady, are discouraging: Black cohosh, botanicals, and encouraging increased soy intake are ineffective in the treatment of vasomotor symptoms.

Evidence on antidepressants is inconclusive

Selective serotonin reuptake inhibitors (SSRIs) and the antidepressant venlafaxine have been assessed for their effects on menopausal vasomotor symptoms, particularly in breast cancer survivors. In a recent review and also a randomized trial, Grady reports that the SSRIs citalopram and sertraline do not appear to be effective, and the findings in regard to the SSRI fluoxetine and venlafaxine have been inconsistent. Compared with placebo, the SSRI paroxetine has eased vasomotor symptoms to a modest degree in breast cancer survivors, but had little effect in women who have not had the disease.

Breast cancer survivors often take tamoxifen or aromatase inhibitors, medications that can induce or aggravate hot flashes. Breast cancer survivors also have a higher prevalence of mood disorders. These factors suggest that the experience and treatment of menopausal symptoms differ between breast cancer survivors and the general population.

Overall, Grady notes, for women with bothersome vasomotor symptoms who have no history of breast cancer, clinical trials of antidepressants have not been encouraging.

Gabapentin is more effective than antidepressants, but with a price

Clinical trials of gabapentin suggest that this anticonvulsant is moderately effective in the nonhormonal treatment of vasomotor symptoms, and the phase III trial by Loprinzi and colleagues finds it to be more effective therapy for vasomotor symptoms than antidepressants.

The drawback? This drug must be taken 2 or 3 times daily, and side effects (including fatigue) limit its attractiveness.

When deciding whom to treat, consider risk as well as BMD

Sanders KM, Nicholson GC, Watts JJ, et al. Half the burden of fragility fractures in the community occur in women without osteoporosis. When is fracture prevention cost-effective? Bone. 2006;38:694–700.

The diagnosis of osteoporosis in postmenopausal women is now based on a threshold bone mineral density (BMD) T-score of –2.5. However, BMD is only one of several important risk factors for fracture, and most patients who experience a fracture related to osteoporosis do not have BMD values in the range consistent with osteoporosis, as Sanders and colleagues observe. Therefore, clinicians are faced with this question: Which patients who do not have osteoporosis should be treated to prevent fracture?

The World Health Organization (WHO) task force on fracture risk assessment, under the leadership of Professor John Kanis, has developed an algorithm to estimate fracture probability in individual patients.⁷ This algorithm is based on a sophisticated analysis of almost all of the large epidemiological studies performed worldwide that have assessed relationships between clinical risk factors and fracture risk. By including the 3 major risk factors (age, BMD, and fracture history), as well as weaker risk factors (family history of hip fracture, current smoking, excess alcohol intake, and history of chronic glucocorticoid use), the absolute risk of developing a fracture of the spine, wrist, hip, or shoulder over the next 10 years will be estimated. This information will be the basis for revised guidelines by the National Osteoporosis Foundation (NOF) and other organizations. The new guidelines will include recommendations for treating patients at or above a certain threshold of fracture risk rather than a certain BMD threshold. The new treatment threshold will be based on a combination of cost- and clinical effectiveness.