Update on nonhormonal approaches to menopausal management

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Bone health

Many alternatives to systemic HT exist for maintaining bone health, including calcium and vitamin D supplementation, bisphosphonates, selective estrogen receptor modulators, calcitonin, recombinant human parathyroid hormone, and ultralow-dose transdermal estradiol. Beyond calcium and vitamin D supplementation, the most appropriate options for most women will likely be bisphosphonates or transdermal estradiol.

Ultralow-dose (0.014 mg/day) transdermal estradiol has been shown to significantly increase bone mineral density (BMD) at both the hip and the spine in post-menopausal women compared with placebo.33 However, the only agent that has demonstrated fracture risk reduction in women who do not otherwise have osteoporosis is standard-dose estrogen therapy (eg, 0.625 mg conjugated equine estrogens). Lower doses of estrogen, which may maintain bone density, do not have data on fracture risk reduction. Although lower doses of estrogen have been found to increase BMD, there is a dose-dependent response, with higher doses producing more of an increase.34,35

Bisphosphonates. The oral bisphosphonates, alendronate and risedronate, have proven efficacy in reducing hip fracture rates in women who already have osteoporosis. Risedronate recently gained FDA approval for administration in a regimen involving two 75-mg tablets taken on a monthly (consecutive-day) basis, and a 150-mg monthly risedronate tablet is expected soon.

Zoledronic acid, an injectable bisphosphonate, recently gained FDA approval for administration as a once-yearly intravenous infusion after this regimen was shown in a large 3-year placebo-controlled trial to significantly reduce the risk of morphometric spine, hip, nonvertebral, wrist, and rib fractures in postmenopausal women with osteoporosis.36 In this trial, atrial fibrillation was more common in women treated with zoledronic acid than in those who received placebo. However, any link between zoledronic acid and atrial fibrillation is uncertain, since episodes of atrial fibrillation tended to occur more than 30 days after the infusion and since circulating active levels of zoledronic acid persist for only up to 1 week. (A history of arrhythmia or atrial fibrillation is not listed in FDA-approved labeling as a contraindication to zoledronic acid.) Also, there was no increased risk of jaw osteonecrosis in subjects treated with zoledronic acid.36

Intravenous dosing can be helpful when patients have intolerable gastrointestinal side effects or other contraindications to oral dosing, as well as to ensure adherence.

Ibandronate is another bisphosphonate that has been shown to reduce the risk of vertebral fractures. It is administered as a once-monthly oral dose or as an intravenous injection given every 3 months. Although these less-frequent dosing regimens can be more convenient for patients and the injectable form can eliminate gastrointestinal side effects, widespread use of ibandronate has been limited somewhat by a lack of evidence for reduction of nonvertebral and hip fractures.37

Raloxifene is the only selective estrogen receptor modulator (SERMs, which the FDA recently requested be called “estrogen agonists/estrogen antagonists”) approved for the prevention and treatment of osteoporosis in postmenopausal women. Raloxifene reduced the vertebral fracture rate by 40% to 50% over 2 to 4 years of use but did not reduce nonvertebral fracture rates. Raloxifene also reduces the risk of invasive breast cancer development.38,39 It has not been shown to lower the risk of coronary events or overall stroke risk but was instead associated with an increased risk of VTE and fatal stroke.

Synthetic recombinant human parathyroid hormone (PTH[1–34]; teriparatide) is currently the sole available agent in the new class of bone anabolic agents, although others are on the horizon. PTH(1–34) is given as a once-daily subcutaneous injection for up to 2 years of therapy. It is associated with a reduction in the risk of vertebral and nonvertebral fractures and is indicated for postmenopausal women (and men) with osteoporosis who are at high risk for fracture, as well as those in whom other medications have failed or are not tolerated.

Although rat studies revealed a potential increased risk for osteosarcoma with PTH(1–34) use, this has not been seen in any human studies or in postmarketing surveillance. As the risk was dependent on dose and duration of therapy, use of PTH(1–34) is not recommended for more than 2 years or in patients at increased risk for osteosarcoma.

Concomitant use of PTH(1–34) with a bisphosphonate seems to blunt its effect and is therefore to be avoided. Resumption of bisphosphonate use after 2 years of PTH(1–34) therapy seems to prevent the loss of densitometric gains that ensues upon cessation of PTH(1–34).40

Calcitonin is an older agent administered mainly as a nasal spray. It reduces vertebral fracture risk in postmenopausal women and is FDA-approved for the treatment, but not prevention, of osteoporosis. Calcitonin has questionable mild analgesic effects in compression fracture treatment. Because of its expense and inferior efficacy relative to other therapies, it is generally reserved for patients who cannot tolerate other agents.41

Therapies on the horizon for osteoporosis prevention and/or treatment in postmenopausal women include strontium ranelate, third-generation SERMs or estrogen agonists/antagonists (ie, bazedoxifene and lasofoxifene), and combination estrogen/SERM therapies.


The risk-benefit assessment for management of vasomotor symptoms and other menopause-related health issues should be tailored to formulate the most efficacious and safe treatment plan for each individual woman. The most appropriate management is guided by the individual patient’s own assessment of her most bothersome symptom(s) and her preferences and comfort level regarding various risks and quality-of-life issues. To best inform these patient choices, physicians must strive to clearly and accurately present the risks and benefits of the various available treatment options.

For most symptomatic menopausal women, HT remains the best treatment. However, for women unable or unwilling to take HT, there are alternatives for the treatment of vasomotor symptoms and bone loss. Low doses of local vaginal estrogen remain an option for treatment of genitourinary atrophy, even in women in whom systemic HT may be contraindicated.

Reassessment of current data and ongoing clinical trials will assist clinicians and patients in decision-making regarding menopausal HT. Nonhormonal therapies for menopausal symptoms should be used to provide effective treatment options for those menopausal patients unwilling or unable to take HT.

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Case studies and clinical considerations in menopausal management

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