Michelle P. Warren, MD Columbia University Medical Center, New York, New York mpw1@columbia.edu
Dr Warren serves as a consultant on advisory boards to Depomed, Pfizer, QuatRx, Wolters Kluwer, and Yoplait; is on the speakers bureau of Upsher Smith and Amgen; and has received research support from Ferring, Pfizer, and Wyeth.
Editorial support for this manuscript was provided by Bo Choi, PhD, and funded by Wyeth, which was acquired by Pfizer in October 2009. The author was not compensated and retained full editorial control over the content of the manuscript.
The Journal of Family Practice no longer accepts articles whose authors have received writing assistance from commercially sponsored third parties. This article was accepted prior to implementation of this policy.
Nonhormonal therapy for bone health. For women who are not candidates for HT, therapeutic options for maintaining bone health include bisphosphonates, raloxifene, teriparatide, and calcitonin.22 In addition to calcium and vitamin D supplementation, the NAMS guidelines recommend bisphosphonates as first-line treatment, followed by raloxifene, for postmenopausal women with low bone mass or younger postmenopausal women with osteoporosis who are at greater risk of spine fracture than hip fracture.23 Teriparatide is generally reserved for women at high risk of fracture.23 Calcitonin, typically administered as a nasal spray, is approved for osteoporosis treatment, but not prevention. It is generally considered an alternative for patients who cannot tolerate other therapies.23 Denosumab, a monoclonal antibody, is a new drug indicated in women at high risk for fracture or who cannot tolerate other therapies.
What are the potential risks of HT?
Risk factors associated with HT relate to a woman’s baseline disease risks: age; age at menopause; cause of menopause; time elapsed since menopause; prior use of any hormone; types, routes of administration, and doses of HT used; and medical conditions emerging during treatment.5 When assessing the benefit–risk profile of HT for any patient, take into account the woman’s health profile as well as the chance of harm associated with any particular therapy.
Cardiovascular disease: Timing of HT matters Estrogen therapy. Although observational studies,24,25 such as the Nurses’ Health Study, suggest a reduced risk of cardiovascular events with ET, randomized clinical trials16,26 have shown either no effect or increased risk of cardiovascular disease among women using ET. In the ET arm of the WHI study,16,26,27 there was an increased risk of stroke and a trend toward increased risk of peripheral arterial disease, but no effect on the incidence of coronary heart disease (including myocardial infarction and coronary death).
The disparity between observational and randomized clinical trial results is now believed to be a result of differences in patient characteristics (particularly age) and timing of initiation of HT in both types of studies.5 Demographic or biologic differences influence the effects of HT on cardiovascular risk. This timing hypothesis is supported by data from an observational study,28 meta-analysis of clinical trials,29 secondary analyses from the WHI,30 and a substudy of the WHI (WHI-Coronary Artery Calcium Study).31
Estrogen-progestin therapy. As with ET, observational studies24,25 have indicated a reduced risk of cardiovascular events with EPT, whereas randomized clinical trials1,26,32 have shown either no effect or increased risk of cardiovascular disease in women using EPT. A recent observational study of women taking primarily EPT (87%; 13% on ET) for a mean duration of 8.3 years found no significant difference in the risk of cardiovascular disease between groups exposed to HT and those unexposed (relative risk, 0.84; 95% confidence interval [CI], 0.16-4.13).33
The WHI study demonstrated an increase in cardiovascular event risk with EPT, particularly during the first year of treatment.1 However, when results were adjusted for age and time since menopause, this risk was isolated to women ≥20 years past menopause, contrasting with a trend toward reduced risk of coronary heart disease in women who initiated HT within 10 years of menopause.30
In the Women’s International Study of Long Duration Oestrogen After Menopause (WISDOM), there was a significant increase in the number of major cardiovascular events with EPT vs placebo.32 However, as in the original WHI study, most women in the WISDOM study were age 65 or older and thus did not fall into the younger age category that experiences cardiovascular benefit from HT.
Influence of age on cardiovascular risk. In the WHI and WISDOM studies,1,16,32 women tended to be at least 10 years postmenopause, whereas the observational studies included younger women who started HT sooner after menopause. The WHI data have shown no increased risk of cardiovascular disease with ET overall and have shown lower coronary artery disease risk in women ages 50 to 59 years.26 There was also a trend for reduced cardiovascular risk with EPT among women who were up to 10 years postmenopause.30
FAST TRACK
Increased risk for cardiovascular disease with EPT is seen mostly in older women years after the onset of menopause.
In a meta-analysis34 of randomized studies, there was a reduction in the risk of cardiovascular events with HT in women younger than 60 years, but an increased risk of events during the first year of treatment in older women. HT has been associated with reduced blood pressure in women who are <5 years postmenopause but not in women ≥5 years postmenopause.35 Thus, the data appear to support the hypothesis of a “therapeutic window” during which ET or EPT may be cardioprotective in younger, newly menopausal women, and an increased risk for cardiovascular disease with EPT, principally confined to older women at an increased distance from menopause.
