Menopause

Romosozumab, a monoclonal antibody that targets the osteoblast inhibitor sclerostin, increased bone mineral density and bone formation while decreasing bone resorption in a phase II clinical trial in 419 postmenopausal women with low bone mass, according to a report published online Jan. 13 in the New England Journal of Medicine.

"The consequence of these divergent effects on bone formation and bone resorption ... is a strongly positive balance in bone turnover, accounting for the rapid and large increases in bone mineral density that we observed," said Dr. Michael R. McClung of the Oregon Osteoporosis Center, Portland, and his associates.

After 1 year of periodic subcutaneous injections of romosozumab, BMD at the lumbar spine was significantly greater than it was with placebo injections, regardless of the dose frequency or dose level of the active drug. Total hip and femoral neck BMD also were significantly greater with romosozumab.

These improvements in BMD also were significantly greater than those obtained with two comparator drugs used open-label in this trial, alendronate and teriparatide, Dr. McClung and his colleagues noted.

Sclerostin is a glycoprotein secreted by osteocytes that is known to be a key regulator of bone formation, capable of impeding osteoblast proliferation and function. Expression of the gene that encodes sclerostin is confined to skeletal tissue, which suggests that a drug that targets sclerostin should have minimal effects on other tissues.

Patients who have a genetic deficiency of sclerostin have greater than average bone mass, with corresponding bone strength and resistance to fractures. And, in animal models of estrogen deficiency, treatment with antisclerostin antibodies restored bone mass and bone strength to higher than normal levels.

In a previous phase I study, single injections of the humanized monoclonal antisclerostin antibody increased BMD, stimulated bone formation, and decreased bone resorption. Dr. McClung and his associates now report the results of their phase II study assessing the efficacy and safety of a variety of doses of romosozumab in postmenopausal women aged 55-85 years who had low bone mass.

The study participants were treated and followed at 28 medical centers in Europe, five dosing regimens of romosozumab (70 mg, 140 mg, or 210 mg injected once monthly; or 140 mg or 210 mg injected once every 3 months); or to 70 mg oral alendronate weekly; or to 20 mcg teriparatide injected daily; or to placebo injections that mirrored the dosing schedules of romosozumab.

A total of 383 women (91%) completed the 1-year study; 86% were white, and the mean T scores were –2.29 at the lumbar spine, –1.53 at the total hip, and –1.93 at the femoral neck.

The primary endpoint was change in BMD at the lumbar spine at 1 year. Participants in the pooled romosozumab groups showed a significant increase in this measure, compared with those pooled in the placebo groups, regardless of dose frequency or dose level.

Similarly, each of the romosozumab groups showed a significant increase in this measure when compared with the pooled placebo groups. Women who received romosozumab also showed significantly greater increases in BMD at the total hip and the femoral neck, but not at the wrist.

The greatest improvements were noted among women who received the highest monthly dose of romosozumab (210 mg), who showed a mean increase of 11.3% at the lumbar spine, 4.1% at the total hip, and 3.7% at the femoral neck at 1 year, the investigators said (N. Engl. J. Med. 2014 [doi:10.1056/NEJMoa1305224]).

The improvements in BMD with romosozumab also were significantly greater than those with alendronate and teriparatide.

The onset of action for romosozumab was swift. "The increase in BMD at the lumbar spine and proximal femur was rapid and substantial with romosozumab by 3 months, and by 6 months, the increase was greater with the 210-mg monthly dose of romosozumab than with either active comparator," Dr. McClung and his associates said.

The increase in BMD was accompanied by a significant decrease in bone resorption. This dual action differs markedly from the effects of bisphosphonates and other agents, which reduce both bone formation and bone resorption, they noted.

Overall, romosozumab’s effects on bone formation were strong but transitory, diminishing after 6 months even though the participants continued taking the drug. In contrast, romosozumab’s effects on bone resorption were more moderate but more sustained, continuing throughout the study period.

The study population was too small to allow adequate assessment of the drug’s safety, the investigators noted.

The overall incidence of adverse events and of serious adverse events was similar among all the study groups, except that mild injection-site reactions were more common with romosozumab. No serious adverse events were considered to be related to any of the treatments, and none of the study subjects showed any notable changes in vital signs, laboratory values, or ECG factors.

This study was funded by Amgen and UCB Pharma, makers of romosozumab. Dr. McClung reported receiving fees and honoraria from Amgen, Eli Lilly, Merck, Novartis, and Warner Chilcott, and his associates reported ties to numerous industry sources.

Romosozumab, a monoclonal antibody that targets the osteoblast inhibitor sclerostin, increased bone mineral density and bone formation while decreasing bone resorption in a phase II clinical trial in 419 postmenopausal women with low bone mass, according to a report published online Jan. 13 in the New England Journal of Medicine.

"The consequence of these divergent effects on bone formation and bone resorption ... is a strongly positive balance in bone turnover, accounting for the rapid and large increases in bone mineral density that we observed," said Dr. Michael R. McClung of the Oregon Osteoporosis Center, Portland, and his associates.

After 1 year of periodic subcutaneous injections of romosozumab, BMD at the lumbar spine was significantly greater than it was with placebo injections, regardless of the dose frequency or dose level of the active drug. Total hip and femoral neck BMD also were significantly greater with romosozumab.

These improvements in BMD also were significantly greater than those obtained with two comparator drugs used open-label in this trial, alendronate and teriparatide, Dr. McClung and his colleagues noted.

Sclerostin is a glycoprotein secreted by osteocytes that is known to be a key regulator of bone formation, capable of impeding osteoblast proliferation and function. Expression of the gene that encodes sclerostin is confined to skeletal tissue, which suggests that a drug that targets sclerostin should have minimal effects on other tissues.

Patients who have a genetic deficiency of sclerostin have greater than average bone mass, with corresponding bone strength and resistance to fractures. And, in animal models of estrogen deficiency, treatment with antisclerostin antibodies restored bone mass and bone strength to higher than normal levels.

In a previous phase I study, single injections of the humanized monoclonal antisclerostin antibody increased BMD, stimulated bone formation, and decreased bone resorption. Dr. McClung and his associates now report the results of their phase II study assessing the efficacy and safety of a variety of doses of romosozumab in postmenopausal women aged 55-85 years who had low bone mass.

The study participants were treated and followed at 28 medical centers in Europe, five dosing regimens of romosozumab (70 mg, 140 mg, or 210 mg injected once monthly; or 140 mg or 210 mg injected once every 3 months); or to 70 mg oral alendronate weekly; or to 20 mcg teriparatide injected daily; or to placebo injections that mirrored the dosing schedules of romosozumab.

A total of 383 women (91%) completed the 1-year study; 86% were white, and the mean T scores were –2.29 at the lumbar spine, –1.53 at the total hip, and –1.93 at the femoral neck.

The primary endpoint was change in BMD at the lumbar spine at 1 year. Participants in the pooled romosozumab groups showed a significant increase in this measure, compared with those pooled in the placebo groups, regardless of dose frequency or dose level.

Similarly, each of the romosozumab groups showed a significant increase in this measure when compared with the pooled placebo groups. Women who received romosozumab also showed significantly greater increases in BMD at the total hip and the femoral neck, but not at the wrist.

The greatest improvements were noted among women who received the highest monthly dose of romosozumab (210 mg), who showed a mean increase of 11.3% at the lumbar spine, 4.1% at the total hip, and 3.7% at the femoral neck at 1 year, the investigators said (N. Engl. J. Med. 2014 [doi:10.1056/NEJMoa1305224]).

The improvements in BMD with romosozumab also were significantly greater than those with alendronate and teriparatide.

The onset of action for romosozumab was swift. "The increase in BMD at the lumbar spine and proximal femur was rapid and substantial with romosozumab by 3 months, and by 6 months, the increase was greater with the 210-mg monthly dose of romosozumab than with either active comparator," Dr. McClung and his associates said.

The increase in BMD was accompanied by a significant decrease in bone resorption. This dual action differs markedly from the effects of bisphosphonates and other agents, which reduce both bone formation and bone resorption, they noted.

Overall, romosozumab’s effects on bone formation were strong but transitory, diminishing after 6 months even though the participants continued taking the drug. In contrast, romosozumab’s effects on bone resorption were more moderate but more sustained, continuing throughout the study period.

The study population was too small to allow adequate assessment of the drug’s safety, the investigators noted.

The overall incidence of adverse events and of serious adverse events was similar among all the study groups, except that mild injection-site reactions were more common with romosozumab. No serious adverse events were considered to be related to any of the treatments, and none of the study subjects showed any notable changes in vital signs, laboratory values, or ECG factors.

This study was funded by Amgen and UCB Pharma, makers of romosozumab. Dr. McClung reported receiving fees and honoraria from Amgen, Eli Lilly, Merck, Novartis, and Warner Chilcott, and his associates reported ties to numerous industry sources.

Romosozumab, a monoclonal antibody that targets the osteoblast inhibitor sclerostin, increased bone mineral density and bone formation while decreasing bone resorption in a phase II clinical trial in 419 postmenopausal women with low bone mass, according to a report published online Jan. 13 in the New England Journal of Medicine.

"The consequence of these divergent effects on bone formation and bone resorption ... is a strongly positive balance in bone turnover, accounting for the rapid and large increases in bone mineral density that we observed," said Dr. Michael R. McClung of the Oregon Osteoporosis Center, Portland, and his associates.

After 1 year of periodic subcutaneous injections of romosozumab, BMD at the lumbar spine was significantly greater than it was with placebo injections, regardless of the dose frequency or dose level of the active drug. Total hip and femoral neck BMD also were significantly greater with romosozumab.

These improvements in BMD also were significantly greater than those obtained with two comparator drugs used open-label in this trial, alendronate and teriparatide, Dr. McClung and his colleagues noted.

Sclerostin is a glycoprotein secreted by osteocytes that is known to be a key regulator of bone formation, capable of impeding osteoblast proliferation and function. Expression of the gene that encodes sclerostin is confined to skeletal tissue, which suggests that a drug that targets sclerostin should have minimal effects on other tissues.

Patients who have a genetic deficiency of sclerostin have greater than average bone mass, with corresponding bone strength and resistance to fractures. And, in animal models of estrogen deficiency, treatment with antisclerostin antibodies restored bone mass and bone strength to higher than normal levels.

In a previous phase I study, single injections of the humanized monoclonal antisclerostin antibody increased BMD, stimulated bone formation, and decreased bone resorption. Dr. McClung and his associates now report the results of their phase II study assessing the efficacy and safety of a variety of doses of romosozumab in postmenopausal women aged 55-85 years who had low bone mass.

The study participants were treated and followed at 28 medical centers in Europe, five dosing regimens of romosozumab (70 mg, 140 mg, or 210 mg injected once monthly; or 140 mg or 210 mg injected once every 3 months); or to 70 mg oral alendronate weekly; or to 20 mcg teriparatide injected daily; or to placebo injections that mirrored the dosing schedules of romosozumab.

A total of 383 women (91%) completed the 1-year study; 86% were white, and the mean T scores were –2.29 at the lumbar spine, –1.53 at the total hip, and –1.93 at the femoral neck.

The primary endpoint was change in BMD at the lumbar spine at 1 year. Participants in the pooled romosozumab groups showed a significant increase in this measure, compared with those pooled in the placebo groups, regardless of dose frequency or dose level.

Similarly, each of the romosozumab groups showed a significant increase in this measure when compared with the pooled placebo groups. Women who received romosozumab also showed significantly greater increases in BMD at the total hip and the femoral neck, but not at the wrist.

The greatest improvements were noted among women who received the highest monthly dose of romosozumab (210 mg), who showed a mean increase of 11.3% at the lumbar spine, 4.1% at the total hip, and 3.7% at the femoral neck at 1 year, the investigators said (N. Engl. J. Med. 2014 [doi:10.1056/NEJMoa1305224]).

The improvements in BMD with romosozumab also were significantly greater than those with alendronate and teriparatide.

The onset of action for romosozumab was swift. "The increase in BMD at the lumbar spine and proximal femur was rapid and substantial with romosozumab by 3 months, and by 6 months, the increase was greater with the 210-mg monthly dose of romosozumab than with either active comparator," Dr. McClung and his associates said.

The increase in BMD was accompanied by a significant decrease in bone resorption. This dual action differs markedly from the effects of bisphosphonates and other agents, which reduce both bone formation and bone resorption, they noted.

Overall, romosozumab’s effects on bone formation were strong but transitory, diminishing after 6 months even though the participants continued taking the drug. In contrast, romosozumab’s effects on bone resorption were more moderate but more sustained, continuing throughout the study period.

The study population was too small to allow adequate assessment of the drug’s safety, the investigators noted.

The overall incidence of adverse events and of serious adverse events was similar among all the study groups, except that mild injection-site reactions were more common with romosozumab. No serious adverse events were considered to be related to any of the treatments, and none of the study subjects showed any notable changes in vital signs, laboratory values, or ECG factors.

This study was funded by Amgen and UCB Pharma, makers of romosozumab. Dr. McClung reported receiving fees and honoraria from Amgen, Eli Lilly, Merck, Novartis, and Warner Chilcott, and his associates reported ties to numerous industry sources.

CASE: AFTER 3 YEARS OF HT, A PATIENT ASKS WHETHER IT’S TIME TO QUIT

My menopausal patient is a 57-year-old woman with a body mass index (BMI) of 21 kg/m². Her mother, who also was slender, suffered a hip fracture at age 74.

When this patient was 53, approximately 8 months after her last menstrual period, she scheduled a problem visit to discuss bothersome hot flushes, which occurred primarily at night. These symptoms were associated with sleep disruption and irritability. At that problem visit, the patient and I discussed the benefits and risks of menopausal hormone therapy (HT), and she elected to initiate it, choosing transdermal estradiol using an 0.05-mg patch, combined with oral micronized progesterone 100-mg (one capsule) at bedtime. Two months later, she telephoned my office to report that she was experiencing only moderate relief of her symptoms. I increased the dose of estradiol to 0.075 mg. On her next well-woman visit, the patient remarked that her symptoms were largely resolved and said that she wished to continue the regimen.

Now, as she presents for her well-woman visit 3 years later, she asks how long she should continue the HT.

How would you counsel such a patient?

Although the duration of HT is still marked by controversy, clinicians often encounter the issue in practice. As the North American Menopause Society (NAMS) notes in a recent Practice Pearl and in its 2012 Position Statement on hormone therapy, the determination of the optimal duration of HT can be a challenge for clinicians and patients.^1,2

In this article, I discuss indications for HT and consider variables that may influence its duration. I also offer practical guidance on therapeutic options for women who elect to use HT for an extended duration.

HOT FLUSHES CAN BE A LONG-TERM CONCERN
Moderate to severe vasomotor symptoms (VMS) are the most common indication for systemic combination estrogen-progestin or estrogen-only HT—and HT is the most effective treatment for VMS.²

Some experts have cautioned that “it remains prudent to keep the…duration of treatment short” or that HT “may serve a useful role in short-term symptom management.”^3,4 However, for many menopausal women, VMS are a long-term concern. The Penn Ovarian Aging Study was conducted to estimate the duration of moderate-to-severe VMS and found a median duration of such symptoms of more than 10 years. In this landmark cohort study, the median duration of VMS, which began near the time of the menopausal transition, was almost 12 years.⁵

In a study of older menopausal women (mean age, 67 years; mean time since menopause, 19 years), 11.8% reported “clinically significant” hot flushes and “more than half of these women who complained of significant hot flushes at baseline continued to report bothersome symptoms after 3 years.”⁶

These observations underscore the fact that, in many women, short-term use (3–5 years) of HT will not be sufficient to control bothersome VMS.

SYSTEMIC HT ALSO BENEFITS BONE
The standard daily dose of HT (eg, conjugated equine estrogens [CEE], 0.625 mg; micronized estradiol, 1.0 mg; or transdermal estradiol, 0.05 mg) for relief of VMS also prevents osteoporosis,² with many HT formulations approved for prevention of this condition. Randomized trial data from the Women’s Health Initiative (WHI) also have confirmed that a standard dose of HT prevents fractures in menopausal women.²

However, in menopausal women, doses of estrogen therapy substantially lower than those commonly used to treat VMS can still maintain or improve bone mineral density (BMD). For example, serum estradiol levels remain in the menopausal range during use of the weekly estradiol ultra-low-dose patch (0.014 mg).⁷ In a clinical trial of women (mean age, 66 years) with an intact uterus, use of this ultra-low-dose estradiol patch for 2 years without progestin did not increase the risk of endometrial hyperplasia⁷—although this patch does appear to increase the incidence of endometrial proliferation.⁸ For this reason, periodic endometrial monitoring may be appropriate in women using the 0.014-mg estradiol patch over the long term, including vaginal ultrasound assessment of endometrial thickness. Package labeling for this patch recommends that women with an intact uterus be given a progestogen for 14 days every 6 to 12 months.⁹

Related Article: Update on Osteoporosis Steven R. Goldstein, MD (December 2013)

Although the ultra-low-dose estradiol patch is approved for the prevention of osteoporosis, its efficacy in treating VMS is uncertain. For instance, in a study of this patch in women aged 60 to 80 years, with skeletal health and safety as the primary outcomes, 16% of participants reported VMS at baseline. The 0.014-mg estradiol patch did not reduce VMS more than placebo.¹⁰ However, in a trial of the 0.014-mg estradiol patch in which impact on VMS was the primary outcome, the ultra-low-dose patch did relieve VMS.¹¹ (The ultra-low-dose patch currently is not approved to treat VMS.) Low-dose CEE (0.3 mg, 0.45 mg) and low-dose oral estradiol (0.5 mg) have been found to be effective in the treatment of VMS.^12,13

Data on the risk of osteoporotic fractures among women using the ultra-low-dose estradiol patch are not available.

Use of HT to prevent osteoporosis is appropriate for women who have other indications for HT, such as VMS. For women using HT who no longer experience VMS, long-term use of HT for osteoporosis is controversial. However, it may be considered for women at elevated risk for osteoporosis when skeleton-specific treatments (eg, bisphosphonates) are not tolerated or when such women prefer not to use skeleton-specific therapy.

FDA package labeling for systemic HT indicates that, “When prescribing solely for the prevention of postmenopausal osteoporosis, therapy only should be considered for women at significant risk of osteoporosis, and non-estrogen medications should be carefully considered.”¹⁴

The NAMS 2012 Position Statement on HT states: “Provided that the woman is well aware of the potential benefits and risks and has clinical supervision, extending [estrogen-progestin therapy] use with the lowest effective dose is acceptable under some circumstances, including 1) for the woman who has determined that the benefits of menopause symptom relief outweigh risks, notably after failing an attempt to stop [estrogen-progestin therapy], and 2) for the woman at high risk of fracture for whom alternate therapies are not appropriate or cause unacceptable adverse effects.”²

A 2014 Practice Bulletin from the American College of Obstetricians and Gynecologists (ACOG) on the management of menopausal symptoms states: “The decision to continue HT should be individualized and be based on a woman’s symptoms and the risk–benefit ratio, regardless of age. Because some women aged 65 years and older may continue to need systemic HT for the management of vasomotor symptoms, ACOG recommends against routine discontinuation of systemic estrogen at age 65. As with younger women, use of HT and estrogen therapy should be individualized based on each woman’s risk–benefit ratio and clinical presentation.”¹⁵

As I have detailed, doses of HT that are lower than those used to treat VMS can prevent loss of BMD. Accordingly, clinicians prescribing HT for the sole indication of osteoporosis prevention should use doses lower than those for standard HT. Moreover, clinicians prescribing HT specifically to prevent osteoporosis should recognize the elevated risk of breast cancer with estrogen-progestin therapy. Extended use of estrogen-only therapy is more appropriate for this indication.

Related Article: Your menopausal patient's breast biopsy reveals atypical hyperplasia JoAnn V. Pinkerton, MD (Cases in Menopause, May 2013)

While estrogen-only therapy is common in women following hysterectomy, ultra-low-dose estrogen therapy with regular endometrial monitoring also can be considered in women with an intact uterus.

Also be aware that BMD declines rapidly after discontinuation of HT (in contrast with bisphosphonates), so alternative agents to maintain BMD should be considered when HT is stopped.¹⁶

HOW SAFE IS EXTENDED USE OF SYSTEMIC HT?
The incidence of breast cancer and mortality from breast cancer increase after 3 to 5 years of estrogen-progestin therapy, and the risk of stroke remains elevated throughout use of combination as well as estrogen-only HT.² Women with an intact uterus who choose to extend the duration of combination therapy beyond 5 years for control of VMS or protection against osteoporosis, or both, need to be candidly counseled about these concerns. No increase in the risk of breast cancer was observed in the estrogen-only arm of the WHI randomized, clinical trial (mean duration of CEE therapy of 7.1 years).¹⁷

James A. Simon, MD:
Not only was there no increase in the risk of breast cancer in the estrogen-only arm, but the therapy was associated with a decrease in risk that persisted even following discontinuation of the therapy.

 JoAnn V. Pinkerton, MD:
Yes, after 7 years of follow-up, women taking CEE (0.625 mg daily) had a reduction in the risk of breast cancer that translated into a decrease in mortality.¹⁷

Related Article: Stop enforcing a 5-year rule for menopausal hormone therapy Robert L. Reid, MD (Stop/Start, December 2013)

Long-term risks of oral estrogen
Among women who initiate HT at the time of menopause, long-term use does not appear to increase the risk of coronary heart disease (CHD), although follow-up in clinical trials has not extended beyond 7 years for estrogen-progestin therapy, and midlife may bring increases in a woman’s baseline cardiovascular risk.² However, in the WHI, women who initiated oral estrogen-only or estrogen-progestin therapy later in menopause experienced an increased risk of CHD,¹⁸ underscoring the need for caution and individualization in this patient population.

Oral HT increases the risk of venous thromboembolism (VTE) and stroke.² In addition, age is an independent risk factor for these two outcomes. Observational studies suggest that, in contrast with oral estrogen, transdermal HT does not increase the risk of VTE.^19–24 Randomized trial data are lacking.

Similarly, one observational study suggests that low-dose (≤0.05 mg) transdermal estradiol does not appear to increase the risk of stroke,²⁵ but, again, clinical trial data are unavailable.

Given these apparent safety advantages, transdermal estrogen therapy would appear to be preferable to oral estrogen in older, long-term users, a perspective supported by ACOG.²⁶

Related Article: Is one oral estrogen formulation safer than another for menopausal women? Andrew M. Kaunitz, MD (Examining the Evidence, January 2014)

In regard to VTE, oral estradiol appears to be safer than CEE.²⁷ Accordingly, oral estradiol may be preferable for older long-term users who don’t tolerate transdermal estradiol due to local skin reactions or costs. Oral estradiol also is less expensive than CEE.

What to expect when your patient discontinues systemic HT
VMS may recur is as many as 50% of women after they discontinue HT. The likelihood of recurring VMS does not appear to vary between abrupt and tapered discontinuation.²

Some HT users may be reluctant to reduce their dose or discontinue HT, particularly those who experienced severe VMS originally. In my clinical experience, many of these women are receptive to a trial of lower-dose HT, especially when I advise them that they can resume their original (higher) dose should bothersome VMS recur.

JoAnn V. Pinkerton, MD:
I use a similar approach with my patients, advising them to try 3 months off HT with the understanding that they can resume the therapy if they develop bothersome symptoms.

Individualized assessment of HT benefits and risks and shared decision-making play important roles in the management of these patients. As the dose of HT declines, or systemic HT is discontinued, symptoms of genital atrophy may become more prominent and, in the absence of indications for systemic HT (bothersome VMS or prevention of osteoporosis), may best be addressed with vaginal estrogen therapy or ospemifene.

Extended use of vaginal estrogen
Unlike VMS, untreated genital atrophy may continue to progress as women age, ­sometimes necessitating use of vaginal estrogen. Because the clinical trials that served as the basis for FDA approval of vaginal estrogen formulations did not find an elevated risk of endometrial hyperplasia, routine use of a progestin to prevent endometrial proliferation in women with an intact uterus is not recommended.28 However, these trials were too limited in duration to assure long-term endometrial safety. All postmenopausal women using vaginal ET should be advised to report any vaginal bleeding, and that bleeding should be evaluated appropriately.

JoAnn V. Pinkerton, MD:
I recommend transvaginal ultrasound and endometrial biopsy for women using vaginal estrogen who report spotting or bleeding.

Although low-dose local or vaginal estrogen therapy has not been studied in clinical trials beyond 1 year, it is thought to carry significantly fewer risks than systemic HT.28 Several studies have confirmed that serum estrogen levels remain in the postmenopausal range in women using low-dose vaginal estrogen, specifically the 3-month estradiol ring (2 mg) or twice-weekly estradiol tablets (10 µg).²⁸

Besides relieving vaginal dryness and dyspareunia, low-dose vaginal estrogen also may improve overactive bladder and reduce the incidence of recurrent urinary tract infection.^29,30

CASE: RESOLVED
The 57-year-old patient has been essentially symptom-free for the past 3 years using an estradiol patch (0.075 mg) with progesterone (100 mg nightly). Now she asks how long she should continue HT, and I explain that the duration of bothersome VMS is different in each woman. I also counsel her that hot flushes do resolve over time in almost all women. When she asks how likely it is that bothersome VMS will recur if she simply stops HT, I explain that bothersome symptoms often last 10 years or longer, and I remind her that her VMS began some 4 years earlier.

I also briefly review HT benefits (treatment of VMS as well as prevention of vulvovaginal atrophy and osteoporosis) and risks (small increased risk of breast cancer and stroke). I suggest a reduction in her HT dose as a reasonable method to determine her ongoing need for HT, telling her that she should know within about 1 month how she feels on the lower dose (0.05-mg patch). I also advise her to call my office if bothersome VMS recur on the lower dose so that I can increase the dose back to its original level.

After her estradiol dose is reduced, the patient reports only minimal VMS, and she opts to continue the estradiol patch (0.05 mg) with nightly progesterone (100 mg) for another 2 years.

At age 59, during her well-woman visit, she decides to lower the estradiol further, transitioning to a 0.0375-mg patch but maintaining the nightly progesterone (100 mg). She reports no VMS on this new regimen.

At age 61, because of her maternal history of osteoporosis and her own low BMI, the patient undergoes BMD assessment with dual x-ray absorptiometry (DXA). In average-risk women, NAMS recommends that BMD assessment be performed at age 65.³¹ The results of BMD assessment are normal.

After further discussion, the patient agrees to an even lower dose of estradiol, switching to an 0.025-mg patch, with progesterone (100 mg nightly) administered for 2 weeks in every 3-month interval. She reports no VMS or vaginal bleeding on this lower-dose HT regimen.

After 12 months on this new regimen, the patient undergoes vaginal sonography, revealing an endometrial thickness of 3 mm. She continues this regimen, including annual vaginal ultrasound assessment of the endometrium, without problems until her well-woman visit at age 65.

At that visit, I explain that discontinuation of HT is unlikely to trigger recurred VMS but may cause her to lose BMD rapidly for several years, and may also result in unpleasant symptoms from vulvovaginal atrophy including sexual discomfort. She decides to switch to an 0.014-mg estradiol patch without progesterone, and to undergo ultrasound assessment of her endometrium every 1 to 2 years.

Do you have a troubling case in menopause?
Suggest it to our expert panel. They may address your management dilemma in a future issue!
Email us at [email protected]

BOTTOM LINE: INDIVIDUALIZE THE DURATION OF HT
Although published data on extended use of HT are few, many clinicians caring for menopausal women are asked to make a recommendation. Because extended use of estrogen-progestin HT increases the risk of breast cancer, estrogen-only HT has a more favorable benefit-risk ratio. If a patient uses estrogen-progestin HT for an extended duration, periodic discussions about the elevated risk of breast cancer are appropriate.

JoAnn V. Pinkerton, MD:
The risk of breast cancer associated with extended use of estrogen-progestin HT likely is reduced if lower doses are given. Overall, however, the risk appears to be both dose- and duration-dependent.

We lack randomized trial data on CHD and other risks in women who begin HT at the time of menopause and continue it for decades. In older women who use HT for an extended duration, transdermal estrogen may be safer in regard to the risk of VTE and stroke.

As the systemic estrogen dose is lowered, it is possible to reduce the dose of the progestin (the sole function of which is to protect the endometrium from estrogen stimulation). Intermittent dosing can be used, although we lack long-term safety data, and periodic endometrial evaluation should be considered.

Remember also that, with intermittent or daily dosing of a progestin, you are relying on the patient to take this medication to protect the endometrium.

Extended use of low-dose vaginal estrogen HT may be necessary to treat symptoms of vulvovaginal atrophy, which tend to worsen over time. Administration of a progestin is not currently recommended with use of vaginal estrogen, but long-term use may increase the risk of endometrial stimulation.

Read other CASES IN MENOPAUSE
Your postmenopausal patient reports a history of migraine James A. Simon, MD (October 2013)
Your menopausal patient's breast biopsy reveals atypical hyperplasia JoAnn V. Pinkerton, MD (May 2013)

WE WANT TO HEAR FROM YOU!
Drop us a line and let us know what you think about current articles, which topics you'd like to see covered in future issues, and what challenges you face in daily practice. Tell us what you think by emailing us at: [email protected]

CASE: AFTER 3 YEARS OF HT, A PATIENT ASKS WHETHER IT’S TIME TO QUIT

My menopausal patient is a 57-year-old woman with a body mass index (BMI) of 21 kg/m². Her mother, who also was slender, suffered a hip fracture at age 74.

When this patient was 53, approximately 8 months after her last menstrual period, she scheduled a problem visit to discuss bothersome hot flushes, which occurred primarily at night. These symptoms were associated with sleep disruption and irritability. At that problem visit, the patient and I discussed the benefits and risks of menopausal hormone therapy (HT), and she elected to initiate it, choosing transdermal estradiol using an 0.05-mg patch, combined with oral micronized progesterone 100-mg (one capsule) at bedtime. Two months later, she telephoned my office to report that she was experiencing only moderate relief of her symptoms. I increased the dose of estradiol to 0.075 mg. On her next well-woman visit, the patient remarked that her symptoms were largely resolved and said that she wished to continue the regimen.

Now, as she presents for her well-woman visit 3 years later, she asks how long she should continue the HT.

How would you counsel such a patient?

Although the duration of HT is still marked by controversy, clinicians often encounter the issue in practice. As the North American Menopause Society (NAMS) notes in a recent Practice Pearl and in its 2012 Position Statement on hormone therapy, the determination of the optimal duration of HT can be a challenge for clinicians and patients.^1,2

In this article, I discuss indications for HT and consider variables that may influence its duration. I also offer practical guidance on therapeutic options for women who elect to use HT for an extended duration.

HOT FLUSHES CAN BE A LONG-TERM CONCERN
Moderate to severe vasomotor symptoms (VMS) are the most common indication for systemic combination estrogen-progestin or estrogen-only HT—and HT is the most effective treatment for VMS.²

Some experts have cautioned that “it remains prudent to keep the…duration of treatment short” or that HT “may serve a useful role in short-term symptom management.”^3,4 However, for many menopausal women, VMS are a long-term concern. The Penn Ovarian Aging Study was conducted to estimate the duration of moderate-to-severe VMS and found a median duration of such symptoms of more than 10 years. In this landmark cohort study, the median duration of VMS, which began near the time of the menopausal transition, was almost 12 years.⁵

In a study of older menopausal women (mean age, 67 years; mean time since menopause, 19 years), 11.8% reported “clinically significant” hot flushes and “more than half of these women who complained of significant hot flushes at baseline continued to report bothersome symptoms after 3 years.”⁶

These observations underscore the fact that, in many women, short-term use (3–5 years) of HT will not be sufficient to control bothersome VMS.

SYSTEMIC HT ALSO BENEFITS BONE
The standard daily dose of HT (eg, conjugated equine estrogens [CEE], 0.625 mg; micronized estradiol, 1.0 mg; or transdermal estradiol, 0.05 mg) for relief of VMS also prevents osteoporosis,² with many HT formulations approved for prevention of this condition. Randomized trial data from the Women’s Health Initiative (WHI) also have confirmed that a standard dose of HT prevents fractures in menopausal women.²

However, in menopausal women, doses of estrogen therapy substantially lower than those commonly used to treat VMS can still maintain or improve bone mineral density (BMD). For example, serum estradiol levels remain in the menopausal range during use of the weekly estradiol ultra-low-dose patch (0.014 mg).⁷ In a clinical trial of women (mean age, 66 years) with an intact uterus, use of this ultra-low-dose estradiol patch for 2 years without progestin did not increase the risk of endometrial hyperplasia⁷—although this patch does appear to increase the incidence of endometrial proliferation.⁸ For this reason, periodic endometrial monitoring may be appropriate in women using the 0.014-mg estradiol patch over the long term, including vaginal ultrasound assessment of endometrial thickness. Package labeling for this patch recommends that women with an intact uterus be given a progestogen for 14 days every 6 to 12 months.⁹

Related Article: Update on Osteoporosis Steven R. Goldstein, MD (December 2013)

Although the ultra-low-dose estradiol patch is approved for the prevention of osteoporosis, its efficacy in treating VMS is uncertain. For instance, in a study of this patch in women aged 60 to 80 years, with skeletal health and safety as the primary outcomes, 16% of participants reported VMS at baseline. The 0.014-mg estradiol patch did not reduce VMS more than placebo.¹⁰ However, in a trial of the 0.014-mg estradiol patch in which impact on VMS was the primary outcome, the ultra-low-dose patch did relieve VMS.¹¹ (The ultra-low-dose patch currently is not approved to treat VMS.) Low-dose CEE (0.3 mg, 0.45 mg) and low-dose oral estradiol (0.5 mg) have been found to be effective in the treatment of VMS.^12,13

Data on the risk of osteoporotic fractures among women using the ultra-low-dose estradiol patch are not available.

Use of HT to prevent osteoporosis is appropriate for women who have other indications for HT, such as VMS. For women using HT who no longer experience VMS, long-term use of HT for osteoporosis is controversial. However, it may be considered for women at elevated risk for osteoporosis when skeleton-specific treatments (eg, bisphosphonates) are not tolerated or when such women prefer not to use skeleton-specific therapy.

FDA package labeling for systemic HT indicates that, “When prescribing solely for the prevention of postmenopausal osteoporosis, therapy only should be considered for women at significant risk of osteoporosis, and non-estrogen medications should be carefully considered.”¹⁴

The NAMS 2012 Position Statement on HT states: “Provided that the woman is well aware of the potential benefits and risks and has clinical supervision, extending [estrogen-progestin therapy] use with the lowest effective dose is acceptable under some circumstances, including 1) for the woman who has determined that the benefits of menopause symptom relief outweigh risks, notably after failing an attempt to stop [estrogen-progestin therapy], and 2) for the woman at high risk of fracture for whom alternate therapies are not appropriate or cause unacceptable adverse effects.”²

A 2014 Practice Bulletin from the American College of Obstetricians and Gynecologists (ACOG) on the management of menopausal symptoms states: “The decision to continue HT should be individualized and be based on a woman’s symptoms and the risk–benefit ratio, regardless of age. Because some women aged 65 years and older may continue to need systemic HT for the management of vasomotor symptoms, ACOG recommends against routine discontinuation of systemic estrogen at age 65. As with younger women, use of HT and estrogen therapy should be individualized based on each woman’s risk–benefit ratio and clinical presentation.”¹⁵

As I have detailed, doses of HT that are lower than those used to treat VMS can prevent loss of BMD. Accordingly, clinicians prescribing HT for the sole indication of osteoporosis prevention should use doses lower than those for standard HT. Moreover, clinicians prescribing HT specifically to prevent osteoporosis should recognize the elevated risk of breast cancer with estrogen-progestin therapy. Extended use of estrogen-only therapy is more appropriate for this indication.

Related Article: Your menopausal patient's breast biopsy reveals atypical hyperplasia JoAnn V. Pinkerton, MD (Cases in Menopause, May 2013)

While estrogen-only therapy is common in women following hysterectomy, ultra-low-dose estrogen therapy with regular endometrial monitoring also can be considered in women with an intact uterus.

Also be aware that BMD declines rapidly after discontinuation of HT (in contrast with bisphosphonates), so alternative agents to maintain BMD should be considered when HT is stopped.¹⁶

HOW SAFE IS EXTENDED USE OF SYSTEMIC HT?
The incidence of breast cancer and mortality from breast cancer increase after 3 to 5 years of estrogen-progestin therapy, and the risk of stroke remains elevated throughout use of combination as well as estrogen-only HT.² Women with an intact uterus who choose to extend the duration of combination therapy beyond 5 years for control of VMS or protection against osteoporosis, or both, need to be candidly counseled about these concerns. No increase in the risk of breast cancer was observed in the estrogen-only arm of the WHI randomized, clinical trial (mean duration of CEE therapy of 7.1 years).¹⁷

James A. Simon, MD:
Not only was there no increase in the risk of breast cancer in the estrogen-only arm, but the therapy was associated with a decrease in risk that persisted even following discontinuation of the therapy.

 JoAnn V. Pinkerton, MD:
Yes, after 7 years of follow-up, women taking CEE (0.625 mg daily) had a reduction in the risk of breast cancer that translated into a decrease in mortality.¹⁷

Related Article: Stop enforcing a 5-year rule for menopausal hormone therapy Robert L. Reid, MD (Stop/Start, December 2013)

Long-term risks of oral estrogen
Among women who initiate HT at the time of menopause, long-term use does not appear to increase the risk of coronary heart disease (CHD), although follow-up in clinical trials has not extended beyond 7 years for estrogen-progestin therapy, and midlife may bring increases in a woman’s baseline cardiovascular risk.² However, in the WHI, women who initiated oral estrogen-only or estrogen-progestin therapy later in menopause experienced an increased risk of CHD,¹⁸ underscoring the need for caution and individualization in this patient population.

Oral HT increases the risk of venous thromboembolism (VTE) and stroke.² In addition, age is an independent risk factor for these two outcomes. Observational studies suggest that, in contrast with oral estrogen, transdermal HT does not increase the risk of VTE.^19–24 Randomized trial data are lacking.

Similarly, one observational study suggests that low-dose (≤0.05 mg) transdermal estradiol does not appear to increase the risk of stroke,²⁵ but, again, clinical trial data are unavailable.

Given these apparent safety advantages, transdermal estrogen therapy would appear to be preferable to oral estrogen in older, long-term users, a perspective supported by ACOG.²⁶

Related Article: Is one oral estrogen formulation safer than another for menopausal women? Andrew M. Kaunitz, MD (Examining the Evidence, January 2014)

In regard to VTE, oral estradiol appears to be safer than CEE.²⁷ Accordingly, oral estradiol may be preferable for older long-term users who don’t tolerate transdermal estradiol due to local skin reactions or costs. Oral estradiol also is less expensive than CEE.

What to expect when your patient discontinues systemic HT
VMS may recur is as many as 50% of women after they discontinue HT. The likelihood of recurring VMS does not appear to vary between abrupt and tapered discontinuation.²

Some HT users may be reluctant to reduce their dose or discontinue HT, particularly those who experienced severe VMS originally. In my clinical experience, many of these women are receptive to a trial of lower-dose HT, especially when I advise them that they can resume their original (higher) dose should bothersome VMS recur.

JoAnn V. Pinkerton, MD:
I use a similar approach with my patients, advising them to try 3 months off HT with the understanding that they can resume the therapy if they develop bothersome symptoms.

Individualized assessment of HT benefits and risks and shared decision-making play important roles in the management of these patients. As the dose of HT declines, or systemic HT is discontinued, symptoms of genital atrophy may become more prominent and, in the absence of indications for systemic HT (bothersome VMS or prevention of osteoporosis), may best be addressed with vaginal estrogen therapy or ospemifene.

Extended use of vaginal estrogen
Unlike VMS, untreated genital atrophy may continue to progress as women age, ­sometimes necessitating use of vaginal estrogen. Because the clinical trials that served as the basis for FDA approval of vaginal estrogen formulations did not find an elevated risk of endometrial hyperplasia, routine use of a progestin to prevent endometrial proliferation in women with an intact uterus is not recommended.28 However, these trials were too limited in duration to assure long-term endometrial safety. All postmenopausal women using vaginal ET should be advised to report any vaginal bleeding, and that bleeding should be evaluated appropriately.

JoAnn V. Pinkerton, MD:
I recommend transvaginal ultrasound and endometrial biopsy for women using vaginal estrogen who report spotting or bleeding.

Although low-dose local or vaginal estrogen therapy has not been studied in clinical trials beyond 1 year, it is thought to carry significantly fewer risks than systemic HT.28 Several studies have confirmed that serum estrogen levels remain in the postmenopausal range in women using low-dose vaginal estrogen, specifically the 3-month estradiol ring (2 mg) or twice-weekly estradiol tablets (10 µg).²⁸

Besides relieving vaginal dryness and dyspareunia, low-dose vaginal estrogen also may improve overactive bladder and reduce the incidence of recurrent urinary tract infection.^29,30

CASE: RESOLVED
The 57-year-old patient has been essentially symptom-free for the past 3 years using an estradiol patch (0.075 mg) with progesterone (100 mg nightly). Now she asks how long she should continue HT, and I explain that the duration of bothersome VMS is different in each woman. I also counsel her that hot flushes do resolve over time in almost all women. When she asks how likely it is that bothersome VMS will recur if she simply stops HT, I explain that bothersome symptoms often last 10 years or longer, and I remind her that her VMS began some 4 years earlier.

I also briefly review HT benefits (treatment of VMS as well as prevention of vulvovaginal atrophy and osteoporosis) and risks (small increased risk of breast cancer and stroke). I suggest a reduction in her HT dose as a reasonable method to determine her ongoing need for HT, telling her that she should know within about 1 month how she feels on the lower dose (0.05-mg patch). I also advise her to call my office if bothersome VMS recur on the lower dose so that I can increase the dose back to its original level.

After her estradiol dose is reduced, the patient reports only minimal VMS, and she opts to continue the estradiol patch (0.05 mg) with nightly progesterone (100 mg) for another 2 years.

At age 59, during her well-woman visit, she decides to lower the estradiol further, transitioning to a 0.0375-mg patch but maintaining the nightly progesterone (100 mg). She reports no VMS on this new regimen.

At age 61, because of her maternal history of osteoporosis and her own low BMI, the patient undergoes BMD assessment with dual x-ray absorptiometry (DXA). In average-risk women, NAMS recommends that BMD assessment be performed at age 65.³¹ The results of BMD assessment are normal.

After further discussion, the patient agrees to an even lower dose of estradiol, switching to an 0.025-mg patch, with progesterone (100 mg nightly) administered for 2 weeks in every 3-month interval. She reports no VMS or vaginal bleeding on this lower-dose HT regimen.

After 12 months on this new regimen, the patient undergoes vaginal sonography, revealing an endometrial thickness of 3 mm. She continues this regimen, including annual vaginal ultrasound assessment of the endometrium, without problems until her well-woman visit at age 65.

At that visit, I explain that discontinuation of HT is unlikely to trigger recurred VMS but may cause her to lose BMD rapidly for several years, and may also result in unpleasant symptoms from vulvovaginal atrophy including sexual discomfort. She decides to switch to an 0.014-mg estradiol patch without progesterone, and to undergo ultrasound assessment of her endometrium every 1 to 2 years.

Do you have a troubling case in menopause?
Suggest it to our expert panel. They may address your management dilemma in a future issue!
Email us at [email protected]

BOTTOM LINE: INDIVIDUALIZE THE DURATION OF HT
Although published data on extended use of HT are few, many clinicians caring for menopausal women are asked to make a recommendation. Because extended use of estrogen-progestin HT increases the risk of breast cancer, estrogen-only HT has a more favorable benefit-risk ratio. If a patient uses estrogen-progestin HT for an extended duration, periodic discussions about the elevated risk of breast cancer are appropriate.

JoAnn V. Pinkerton, MD:
The risk of breast cancer associated with extended use of estrogen-progestin HT likely is reduced if lower doses are given. Overall, however, the risk appears to be both dose- and duration-dependent.

We lack randomized trial data on CHD and other risks in women who begin HT at the time of menopause and continue it for decades. In older women who use HT for an extended duration, transdermal estrogen may be safer in regard to the risk of VTE and stroke.

As the systemic estrogen dose is lowered, it is possible to reduce the dose of the progestin (the sole function of which is to protect the endometrium from estrogen stimulation). Intermittent dosing can be used, although we lack long-term safety data, and periodic endometrial evaluation should be considered.

Remember also that, with intermittent or daily dosing of a progestin, you are relying on the patient to take this medication to protect the endometrium.

Extended use of low-dose vaginal estrogen HT may be necessary to treat symptoms of vulvovaginal atrophy, which tend to worsen over time. Administration of a progestin is not currently recommended with use of vaginal estrogen, but long-term use may increase the risk of endometrial stimulation.

Read other CASES IN MENOPAUSE
Your postmenopausal patient reports a history of migraine James A. Simon, MD (October 2013)
Your menopausal patient's breast biopsy reveals atypical hyperplasia JoAnn V. Pinkerton, MD (May 2013)

WE WANT TO HEAR FROM YOU!
Drop us a line and let us know what you think about current articles, which topics you'd like to see covered in future issues, and what challenges you face in daily practice. Tell us what you think by emailing us at: [email protected]

CASE: AFTER 3 YEARS OF HT, A PATIENT ASKS WHETHER IT’S TIME TO QUIT

My menopausal patient is a 57-year-old woman with a body mass index (BMI) of 21 kg/m². Her mother, who also was slender, suffered a hip fracture at age 74.

When this patient was 53, approximately 8 months after her last menstrual period, she scheduled a problem visit to discuss bothersome hot flushes, which occurred primarily at night. These symptoms were associated with sleep disruption and irritability. At that problem visit, the patient and I discussed the benefits and risks of menopausal hormone therapy (HT), and she elected to initiate it, choosing transdermal estradiol using an 0.05-mg patch, combined with oral micronized progesterone 100-mg (one capsule) at bedtime. Two months later, she telephoned my office to report that she was experiencing only moderate relief of her symptoms. I increased the dose of estradiol to 0.075 mg. On her next well-woman visit, the patient remarked that her symptoms were largely resolved and said that she wished to continue the regimen.

Now, as she presents for her well-woman visit 3 years later, she asks how long she should continue the HT.

How would you counsel such a patient?

Although the duration of HT is still marked by controversy, clinicians often encounter the issue in practice. As the North American Menopause Society (NAMS) notes in a recent Practice Pearl and in its 2012 Position Statement on hormone therapy, the determination of the optimal duration of HT can be a challenge for clinicians and patients.^1,2

In this article, I discuss indications for HT and consider variables that may influence its duration. I also offer practical guidance on therapeutic options for women who elect to use HT for an extended duration.

HOT FLUSHES CAN BE A LONG-TERM CONCERN
Moderate to severe vasomotor symptoms (VMS) are the most common indication for systemic combination estrogen-progestin or estrogen-only HT—and HT is the most effective treatment for VMS.²

Some experts have cautioned that “it remains prudent to keep the…duration of treatment short” or that HT “may serve a useful role in short-term symptom management.”^3,4 However, for many menopausal women, VMS are a long-term concern. The Penn Ovarian Aging Study was conducted to estimate the duration of moderate-to-severe VMS and found a median duration of such symptoms of more than 10 years. In this landmark cohort study, the median duration of VMS, which began near the time of the menopausal transition, was almost 12 years.⁵

In a study of older menopausal women (mean age, 67 years; mean time since menopause, 19 years), 11.8% reported “clinically significant” hot flushes and “more than half of these women who complained of significant hot flushes at baseline continued to report bothersome symptoms after 3 years.”⁶

These observations underscore the fact that, in many women, short-term use (3–5 years) of HT will not be sufficient to control bothersome VMS.

SYSTEMIC HT ALSO BENEFITS BONE
The standard daily dose of HT (eg, conjugated equine estrogens [CEE], 0.625 mg; micronized estradiol, 1.0 mg; or transdermal estradiol, 0.05 mg) for relief of VMS also prevents osteoporosis,² with many HT formulations approved for prevention of this condition. Randomized trial data from the Women’s Health Initiative (WHI) also have confirmed that a standard dose of HT prevents fractures in menopausal women.²

However, in menopausal women, doses of estrogen therapy substantially lower than those commonly used to treat VMS can still maintain or improve bone mineral density (BMD). For example, serum estradiol levels remain in the menopausal range during use of the weekly estradiol ultra-low-dose patch (0.014 mg).⁷ In a clinical trial of women (mean age, 66 years) with an intact uterus, use of this ultra-low-dose estradiol patch for 2 years without progestin did not increase the risk of endometrial hyperplasia⁷—although this patch does appear to increase the incidence of endometrial proliferation.⁸ For this reason, periodic endometrial monitoring may be appropriate in women using the 0.014-mg estradiol patch over the long term, including vaginal ultrasound assessment of endometrial thickness. Package labeling for this patch recommends that women with an intact uterus be given a progestogen for 14 days every 6 to 12 months.⁹

Related Article: Update on Osteoporosis Steven R. Goldstein, MD (December 2013)

Although the ultra-low-dose estradiol patch is approved for the prevention of osteoporosis, its efficacy in treating VMS is uncertain. For instance, in a study of this patch in women aged 60 to 80 years, with skeletal health and safety as the primary outcomes, 16% of participants reported VMS at baseline. The 0.014-mg estradiol patch did not reduce VMS more than placebo.¹⁰ However, in a trial of the 0.014-mg estradiol patch in which impact on VMS was the primary outcome, the ultra-low-dose patch did relieve VMS.¹¹ (The ultra-low-dose patch currently is not approved to treat VMS.) Low-dose CEE (0.3 mg, 0.45 mg) and low-dose oral estradiol (0.5 mg) have been found to be effective in the treatment of VMS.^12,13

Data on the risk of osteoporotic fractures among women using the ultra-low-dose estradiol patch are not available.

Use of HT to prevent osteoporosis is appropriate for women who have other indications for HT, such as VMS. For women using HT who no longer experience VMS, long-term use of HT for osteoporosis is controversial. However, it may be considered for women at elevated risk for osteoporosis when skeleton-specific treatments (eg, bisphosphonates) are not tolerated or when such women prefer not to use skeleton-specific therapy.

FDA package labeling for systemic HT indicates that, “When prescribing solely for the prevention of postmenopausal osteoporosis, therapy only should be considered for women at significant risk of osteoporosis, and non-estrogen medications should be carefully considered.”¹⁴

The NAMS 2012 Position Statement on HT states: “Provided that the woman is well aware of the potential benefits and risks and has clinical supervision, extending [estrogen-progestin therapy] use with the lowest effective dose is acceptable under some circumstances, including 1) for the woman who has determined that the benefits of menopause symptom relief outweigh risks, notably after failing an attempt to stop [estrogen-progestin therapy], and 2) for the woman at high risk of fracture for whom alternate therapies are not appropriate or cause unacceptable adverse effects.”²

A 2014 Practice Bulletin from the American College of Obstetricians and Gynecologists (ACOG) on the management of menopausal symptoms states: “The decision to continue HT should be individualized and be based on a woman’s symptoms and the risk–benefit ratio, regardless of age. Because some women aged 65 years and older may continue to need systemic HT for the management of vasomotor symptoms, ACOG recommends against routine discontinuation of systemic estrogen at age 65. As with younger women, use of HT and estrogen therapy should be individualized based on each woman’s risk–benefit ratio and clinical presentation.”¹⁵

As I have detailed, doses of HT that are lower than those used to treat VMS can prevent loss of BMD. Accordingly, clinicians prescribing HT for the sole indication of osteoporosis prevention should use doses lower than those for standard HT. Moreover, clinicians prescribing HT specifically to prevent osteoporosis should recognize the elevated risk of breast cancer with estrogen-progestin therapy. Extended use of estrogen-only therapy is more appropriate for this indication.

Related Article: Your menopausal patient's breast biopsy reveals atypical hyperplasia JoAnn V. Pinkerton, MD (Cases in Menopause, May 2013)

While estrogen-only therapy is common in women following hysterectomy, ultra-low-dose estrogen therapy with regular endometrial monitoring also can be considered in women with an intact uterus.

Also be aware that BMD declines rapidly after discontinuation of HT (in contrast with bisphosphonates), so alternative agents to maintain BMD should be considered when HT is stopped.¹⁶

HOW SAFE IS EXTENDED USE OF SYSTEMIC HT?
The incidence of breast cancer and mortality from breast cancer increase after 3 to 5 years of estrogen-progestin therapy, and the risk of stroke remains elevated throughout use of combination as well as estrogen-only HT.² Women with an intact uterus who choose to extend the duration of combination therapy beyond 5 years for control of VMS or protection against osteoporosis, or both, need to be candidly counseled about these concerns. No increase in the risk of breast cancer was observed in the estrogen-only arm of the WHI randomized, clinical trial (mean duration of CEE therapy of 7.1 years).¹⁷

James A. Simon, MD:
Not only was there no increase in the risk of breast cancer in the estrogen-only arm, but the therapy was associated with a decrease in risk that persisted even following discontinuation of the therapy.

 JoAnn V. Pinkerton, MD:
Yes, after 7 years of follow-up, women taking CEE (0.625 mg daily) had a reduction in the risk of breast cancer that translated into a decrease in mortality.¹⁷

Related Article: Stop enforcing a 5-year rule for menopausal hormone therapy Robert L. Reid, MD (Stop/Start, December 2013)

Long-term risks of oral estrogen
Among women who initiate HT at the time of menopause, long-term use does not appear to increase the risk of coronary heart disease (CHD), although follow-up in clinical trials has not extended beyond 7 years for estrogen-progestin therapy, and midlife may bring increases in a woman’s baseline cardiovascular risk.² However, in the WHI, women who initiated oral estrogen-only or estrogen-progestin therapy later in menopause experienced an increased risk of CHD,¹⁸ underscoring the need for caution and individualization in this patient population.

Oral HT increases the risk of venous thromboembolism (VTE) and stroke.² In addition, age is an independent risk factor for these two outcomes. Observational studies suggest that, in contrast with oral estrogen, transdermal HT does not increase the risk of VTE.^19–24 Randomized trial data are lacking.

Similarly, one observational study suggests that low-dose (≤0.05 mg) transdermal estradiol does not appear to increase the risk of stroke,²⁵ but, again, clinical trial data are unavailable.

Given these apparent safety advantages, transdermal estrogen therapy would appear to be preferable to oral estrogen in older, long-term users, a perspective supported by ACOG.²⁶

Related Article: Is one oral estrogen formulation safer than another for menopausal women? Andrew M. Kaunitz, MD (Examining the Evidence, January 2014)

In regard to VTE, oral estradiol appears to be safer than CEE.²⁷ Accordingly, oral estradiol may be preferable for older long-term users who don’t tolerate transdermal estradiol due to local skin reactions or costs. Oral estradiol also is less expensive than CEE.

What to expect when your patient discontinues systemic HT
VMS may recur is as many as 50% of women after they discontinue HT. The likelihood of recurring VMS does not appear to vary between abrupt and tapered discontinuation.²

Some HT users may be reluctant to reduce their dose or discontinue HT, particularly those who experienced severe VMS originally. In my clinical experience, many of these women are receptive to a trial of lower-dose HT, especially when I advise them that they can resume their original (higher) dose should bothersome VMS recur.

JoAnn V. Pinkerton, MD:
I use a similar approach with my patients, advising them to try 3 months off HT with the understanding that they can resume the therapy if they develop bothersome symptoms.

Individualized assessment of HT benefits and risks and shared decision-making play important roles in the management of these patients. As the dose of HT declines, or systemic HT is discontinued, symptoms of genital atrophy may become more prominent and, in the absence of indications for systemic HT (bothersome VMS or prevention of osteoporosis), may best be addressed with vaginal estrogen therapy or ospemifene.

Extended use of vaginal estrogen
Unlike VMS, untreated genital atrophy may continue to progress as women age, ­sometimes necessitating use of vaginal estrogen. Because the clinical trials that served as the basis for FDA approval of vaginal estrogen formulations did not find an elevated risk of endometrial hyperplasia, routine use of a progestin to prevent endometrial proliferation in women with an intact uterus is not recommended.28 However, these trials were too limited in duration to assure long-term endometrial safety. All postmenopausal women using vaginal ET should be advised to report any vaginal bleeding, and that bleeding should be evaluated appropriately.

JoAnn V. Pinkerton, MD:
I recommend transvaginal ultrasound and endometrial biopsy for women using vaginal estrogen who report spotting or bleeding.

Although low-dose local or vaginal estrogen therapy has not been studied in clinical trials beyond 1 year, it is thought to carry significantly fewer risks than systemic HT.28 Several studies have confirmed that serum estrogen levels remain in the postmenopausal range in women using low-dose vaginal estrogen, specifically the 3-month estradiol ring (2 mg) or twice-weekly estradiol tablets (10 µg).²⁸

Besides relieving vaginal dryness and dyspareunia, low-dose vaginal estrogen also may improve overactive bladder and reduce the incidence of recurrent urinary tract infection.^29,30

CASE: RESOLVED
The 57-year-old patient has been essentially symptom-free for the past 3 years using an estradiol patch (0.075 mg) with progesterone (100 mg nightly). Now she asks how long she should continue HT, and I explain that the duration of bothersome VMS is different in each woman. I also counsel her that hot flushes do resolve over time in almost all women. When she asks how likely it is that bothersome VMS will recur if she simply stops HT, I explain that bothersome symptoms often last 10 years or longer, and I remind her that her VMS began some 4 years earlier.

I also briefly review HT benefits (treatment of VMS as well as prevention of vulvovaginal atrophy and osteoporosis) and risks (small increased risk of breast cancer and stroke). I suggest a reduction in her HT dose as a reasonable method to determine her ongoing need for HT, telling her that she should know within about 1 month how she feels on the lower dose (0.05-mg patch). I also advise her to call my office if bothersome VMS recur on the lower dose so that I can increase the dose back to its original level.

After her estradiol dose is reduced, the patient reports only minimal VMS, and she opts to continue the estradiol patch (0.05 mg) with nightly progesterone (100 mg) for another 2 years.

At age 59, during her well-woman visit, she decides to lower the estradiol further, transitioning to a 0.0375-mg patch but maintaining the nightly progesterone (100 mg). She reports no VMS on this new regimen.

At age 61, because of her maternal history of osteoporosis and her own low BMI, the patient undergoes BMD assessment with dual x-ray absorptiometry (DXA). In average-risk women, NAMS recommends that BMD assessment be performed at age 65.³¹ The results of BMD assessment are normal.

After further discussion, the patient agrees to an even lower dose of estradiol, switching to an 0.025-mg patch, with progesterone (100 mg nightly) administered for 2 weeks in every 3-month interval. She reports no VMS or vaginal bleeding on this lower-dose HT regimen.

After 12 months on this new regimen, the patient undergoes vaginal sonography, revealing an endometrial thickness of 3 mm. She continues this regimen, including annual vaginal ultrasound assessment of the endometrium, without problems until her well-woman visit at age 65.

At that visit, I explain that discontinuation of HT is unlikely to trigger recurred VMS but may cause her to lose BMD rapidly for several years, and may also result in unpleasant symptoms from vulvovaginal atrophy including sexual discomfort. She decides to switch to an 0.014-mg estradiol patch without progesterone, and to undergo ultrasound assessment of her endometrium every 1 to 2 years.

Do you have a troubling case in menopause?
Suggest it to our expert panel. They may address your management dilemma in a future issue!
Email us at [email protected]

BOTTOM LINE: INDIVIDUALIZE THE DURATION OF HT
Although published data on extended use of HT are few, many clinicians caring for menopausal women are asked to make a recommendation. Because extended use of estrogen-progestin HT increases the risk of breast cancer, estrogen-only HT has a more favorable benefit-risk ratio. If a patient uses estrogen-progestin HT for an extended duration, periodic discussions about the elevated risk of breast cancer are appropriate.

JoAnn V. Pinkerton, MD:
The risk of breast cancer associated with extended use of estrogen-progestin HT likely is reduced if lower doses are given. Overall, however, the risk appears to be both dose- and duration-dependent.

We lack randomized trial data on CHD and other risks in women who begin HT at the time of menopause and continue it for decades. In older women who use HT for an extended duration, transdermal estrogen may be safer in regard to the risk of VTE and stroke.

As the systemic estrogen dose is lowered, it is possible to reduce the dose of the progestin (the sole function of which is to protect the endometrium from estrogen stimulation). Intermittent dosing can be used, although we lack long-term safety data, and periodic endometrial evaluation should be considered.

Remember also that, with intermittent or daily dosing of a progestin, you are relying on the patient to take this medication to protect the endometrium.

Extended use of low-dose vaginal estrogen HT may be necessary to treat symptoms of vulvovaginal atrophy, which tend to worsen over time. Administration of a progestin is not currently recommended with use of vaginal estrogen, but long-term use may increase the risk of endometrial stimulation.

Read other CASES IN MENOPAUSE
Your postmenopausal patient reports a history of migraine James A. Simon, MD (October 2013)
Your menopausal patient's breast biopsy reveals atypical hyperplasia JoAnn V. Pinkerton, MD (May 2013)

WE WANT TO HEAR FROM YOU!
Drop us a line and let us know what you think about current articles, which topics you'd like to see covered in future issues, and what challenges you face in daily practice. Tell us what you think by emailing us at: [email protected]

Although numerous investigators, including the Women’s Health Initiative (WHI) team, have compared cardiovascular risks in women using menopausal hormone therapy (HT) versus nonusers, few researchers have addressed the comparative safety of different oral estrogen formulations.

Related Article: Update on Menopause (Andrew M. Kaunitz, MD, June 2013)

In this case-control study, Smith and colleagues compared the safety of oral estradiol and CEE in menopausal members of a large US Health Maintenance Organization who were using these oral estrogens between 2003 and 2009.

Details of the study
Cases were women diagnosed with deep venous thrombosis, including pulmonary embolism; myocardial infarction; or ischemic stroke. Women in the control group had no history of cardiovascular events. The endogenous thrombin potential-based normalized activated protein C sensitivity ratio (nAPCsr), which has been shown to predict venous thromboembolism (VTE) in the setting of estrogen therapy, was measured in the control group.

Between 2003 and 2009, incident VTE, MI, and stroke were diagnosed in 68, 67, and 49 cases, respectively, and 201 controls were identified. Cases were more likely than controls to have cardiovascular risk factors.

More than 90% of participants were white, with a mean age ranging from 63.2 to 67.6 years.

Among women in the control group, those using oral estradiol had slightly more cardiovascular risk factors than those using CEE, although age, body mass index, and the recency of HT initiation were similar among women using the two oral estrogens.

Although the ORs for VTE and MI were elevated among CEE users, the risk for ischemic stroke was similar for estradiol and CEE users. Women using CEE had higher nAPCsrs (P <.001), however, suggesting a greater tendency to clot.

WHAT THIS EVIDENCE MEANS FOR PRACTICE
Although the risk of VTE appears to be higher among users of oral estrogen than among those using a transdermal formulation,¹ many menopausal women prefer oral estrogen for its convenience and because patch adherence can sometimes be an issue.
Oral estradiol and oral CEE appear to be equally effective in relieving menopausal symptoms. However, there is a significant cost differential: A 1-month supply of 1-mg estradiol tablets costs $4 at some chain pharmacies, whereas 0.625-mg tablets of CEE cost $84.92 (according to goodrx.com). Therefore, for menopausal women who elect to use an oral estrogen formulation, estradiol appears to be a wise choice for both safety and  economy.
Andrew M. Kaunitz, MD

WE WANT TO HEAR FROM YOU. Tell us what you think.

Although numerous investigators, including the Women’s Health Initiative (WHI) team, have compared cardiovascular risks in women using menopausal hormone therapy (HT) versus nonusers, few researchers have addressed the comparative safety of different oral estrogen formulations.

Related Article: Update on Menopause (Andrew M. Kaunitz, MD, June 2013)

In this case-control study, Smith and colleagues compared the safety of oral estradiol and CEE in menopausal members of a large US Health Maintenance Organization who were using these oral estrogens between 2003 and 2009.

Details of the study
Cases were women diagnosed with deep venous thrombosis, including pulmonary embolism; myocardial infarction; or ischemic stroke. Women in the control group had no history of cardiovascular events. The endogenous thrombin potential-based normalized activated protein C sensitivity ratio (nAPCsr), which has been shown to predict venous thromboembolism (VTE) in the setting of estrogen therapy, was measured in the control group.

Between 2003 and 2009, incident VTE, MI, and stroke were diagnosed in 68, 67, and 49 cases, respectively, and 201 controls were identified. Cases were more likely than controls to have cardiovascular risk factors.

More than 90% of participants were white, with a mean age ranging from 63.2 to 67.6 years.

Among women in the control group, those using oral estradiol had slightly more cardiovascular risk factors than those using CEE, although age, body mass index, and the recency of HT initiation were similar among women using the two oral estrogens.

Although the ORs for VTE and MI were elevated among CEE users, the risk for ischemic stroke was similar for estradiol and CEE users. Women using CEE had higher nAPCsrs (P <.001), however, suggesting a greater tendency to clot.

WHAT THIS EVIDENCE MEANS FOR PRACTICE
Although the risk of VTE appears to be higher among users of oral estrogen than among those using a transdermal formulation,¹ many menopausal women prefer oral estrogen for its convenience and because patch adherence can sometimes be an issue.
Oral estradiol and oral CEE appear to be equally effective in relieving menopausal symptoms. However, there is a significant cost differential: A 1-month supply of 1-mg estradiol tablets costs $4 at some chain pharmacies, whereas 0.625-mg tablets of CEE cost $84.92 (according to goodrx.com). Therefore, for menopausal women who elect to use an oral estrogen formulation, estradiol appears to be a wise choice for both safety and  economy.
Andrew M. Kaunitz, MD

WE WANT TO HEAR FROM YOU. Tell us what you think.

Although numerous investigators, including the Women’s Health Initiative (WHI) team, have compared cardiovascular risks in women using menopausal hormone therapy (HT) versus nonusers, few researchers have addressed the comparative safety of different oral estrogen formulations.

Related Article: Update on Menopause (Andrew M. Kaunitz, MD, June 2013)

In this case-control study, Smith and colleagues compared the safety of oral estradiol and CEE in menopausal members of a large US Health Maintenance Organization who were using these oral estrogens between 2003 and 2009.

Details of the study
Cases were women diagnosed with deep venous thrombosis, including pulmonary embolism; myocardial infarction; or ischemic stroke. Women in the control group had no history of cardiovascular events. The endogenous thrombin potential-based normalized activated protein C sensitivity ratio (nAPCsr), which has been shown to predict venous thromboembolism (VTE) in the setting of estrogen therapy, was measured in the control group.

Between 2003 and 2009, incident VTE, MI, and stroke were diagnosed in 68, 67, and 49 cases, respectively, and 201 controls were identified. Cases were more likely than controls to have cardiovascular risk factors.

More than 90% of participants were white, with a mean age ranging from 63.2 to 67.6 years.

Among women in the control group, those using oral estradiol had slightly more cardiovascular risk factors than those using CEE, although age, body mass index, and the recency of HT initiation were similar among women using the two oral estrogens.

Although the ORs for VTE and MI were elevated among CEE users, the risk for ischemic stroke was similar for estradiol and CEE users. Women using CEE had higher nAPCsrs (P <.001), however, suggesting a greater tendency to clot.

WHAT THIS EVIDENCE MEANS FOR PRACTICE
Although the risk of VTE appears to be higher among users of oral estrogen than among those using a transdermal formulation,¹ many menopausal women prefer oral estrogen for its convenience and because patch adherence can sometimes be an issue.
Oral estradiol and oral CEE appear to be equally effective in relieving menopausal symptoms. However, there is a significant cost differential: A 1-month supply of 1-mg estradiol tablets costs $4 at some chain pharmacies, whereas 0.625-mg tablets of CEE cost $84.92 (according to goodrx.com). Therefore, for menopausal women who elect to use an oral estrogen formulation, estradiol appears to be a wise choice for both safety and  economy.
Andrew M. Kaunitz, MD

WE WANT TO HEAR FROM YOU. Tell us what you think.

"WHAT IS THE GYNECOLOGIST'S ROLE IN THE CARE OF BRCA PREVIVORS?"
ROBERT L. BARBIERI, MD (EDITORIAL, SEPTEMBER 2013)

Young women with a BRCA mutation need not pass it to their offspring

One consideration that wasn't mentioned in Dr. Barbieri's editorial is the possibility that a woman with a BRCA mutation will pass it to her offspring. Any patient with such a mutation who has not yet completed childbearing should be advised that, with in vitro fertilization and preimplantation genetic diagnosis, we now have the capabiity to break this familial curse.

Mark Perloe, MD
Atlanta, Georgia

DR. BARBIERI RESPONDS

I agree with Dr. Perloe. I neglected to mention that, for women who are BRCA carriers who are planning a pregnancy, consultation with a fertility specialist to explore the use of assisted reproductive technology and preimplantation genetic testing is an important aspect of their health care.

WE WANT TO HEAR FROM YOU. Tell us what you think.   

"WHAT IS THE GYNECOLOGIST'S ROLE IN THE CARE OF BRCA PREVIVORS?"
ROBERT L. BARBIERI, MD (EDITORIAL, SEPTEMBER 2013)

Young women with a BRCA mutation need not pass it to their offspring

One consideration that wasn't mentioned in Dr. Barbieri's editorial is the possibility that a woman with a BRCA mutation will pass it to her offspring. Any patient with such a mutation who has not yet completed childbearing should be advised that, with in vitro fertilization and preimplantation genetic diagnosis, we now have the capabiity to break this familial curse.

Mark Perloe, MD
Atlanta, Georgia

DR. BARBIERI RESPONDS

I agree with Dr. Perloe. I neglected to mention that, for women who are BRCA carriers who are planning a pregnancy, consultation with a fertility specialist to explore the use of assisted reproductive technology and preimplantation genetic testing is an important aspect of their health care.

WE WANT TO HEAR FROM YOU. Tell us what you think.   

"WHAT IS THE GYNECOLOGIST'S ROLE IN THE CARE OF BRCA PREVIVORS?"
ROBERT L. BARBIERI, MD (EDITORIAL, SEPTEMBER 2013)

Young women with a BRCA mutation need not pass it to their offspring

One consideration that wasn't mentioned in Dr. Barbieri's editorial is the possibility that a woman with a BRCA mutation will pass it to her offspring. Any patient with such a mutation who has not yet completed childbearing should be advised that, with in vitro fertilization and preimplantation genetic diagnosis, we now have the capabiity to break this familial curse.

Mark Perloe, MD
Atlanta, Georgia

DR. BARBIERI RESPONDS

I agree with Dr. Perloe. I neglected to mention that, for women who are BRCA carriers who are planning a pregnancy, consultation with a fertility specialist to explore the use of assisted reproductive technology and preimplantation genetic testing is an important aspect of their health care.

WE WANT TO HEAR FROM YOU. Tell us what you think.   

The bisphosphonate zolendronate didn't improve survival in patients with chemoresistant breast cancer, according to results from the phase III NATAN trial.

In an interview at the San Antonio Breast Cancer Symposium, Dr. Gunter von Minckwitz discusses the trial's results and clinical implications, and whether a role remains for bisphosphonates in postmenopausal patients.

The bisphosphonate zolendronate didn't improve survival in patients with chemoresistant breast cancer, according to results from the phase III NATAN trial.

In an interview at the San Antonio Breast Cancer Symposium, Dr. Gunter von Minckwitz discusses the trial's results and clinical implications, and whether a role remains for bisphosphonates in postmenopausal patients.

The bisphosphonate zolendronate didn't improve survival in patients with chemoresistant breast cancer, according to results from the phase III NATAN trial.

In an interview at the San Antonio Breast Cancer Symposium, Dr. Gunter von Minckwitz discusses the trial's results and clinical implications, and whether a role remains for bisphosphonates in postmenopausal patients.

A novel agent shown in clinical trials to improve sex drive in women has been turned down by the Food and Drug Administration, leaving clinicians with no approved treatment options for a commonly reported disorder unless a manufacturer appeal proves successful.

Flibanserin, a drug originally investigated in the 1990s as an antidepressant, was later studied as a treatment for hypoactive sexual desire disorder (HSDD) in premenopausal women.

HSDD is characterized by a stress-inducing loss of sex drive without an identifiable physical or psychological cause. Flibanserin works by increasing dopamine and norepinephrine, both associated with sexual excitement, and by decreasing serotonin, which is associated with sexual inhibition. In studies, 100 mg of flibanserin daily was associated with statistically significant improvements in the number of satisfying sexual episodes per month as well as improvements in reported sexual desire over placebo, and reduction in stress associated with sexual dysfunction.

Sheryl Kingsberg, Ph.D., chief of behavioral medicine at University Hospitals Case Medical Center in Cleveland, and an investigator on some of the flibanserin research submitted to the FDA, said in an interview that there remains a "huge vacuum" in options for women with HSDD.

"For women for whom the primary loss of sexual desire is drive, which is the biological component to desire, there is nothing," she said. "For postmenopausal women for whom drive is related to declining testosterone, testosterone is an option – but off-label. There are no FDA-approved testosterone options for women."

The FDA cited concerns about flibanserin’s risks compared with its "modest" effect size, according to Sprout Pharmaceuticals, which has already moved to appeal the agency’s decision. In one manufacturer-sponsored randomized controlled trial published this year (n = 1,087), the results of which were submitted to the FDA, flibanserin was seen increasing satisfying sexual events per month by an average of 2.5, compared with 1.5 for placebo (J. Sex. Med. 2013;10:1807-15 [doi: 10.1111/jsm.12189]).

"I know the data very well, and I was convinced that it hit every endpoint," Dr. Kingsberg said. "FDA says they’re concerned about the modest efficacy in light of a risk profile not different from an SSRI [selective serotonin reuptake inhibitor], or even an antihistamine. How much more can women be expected to have in terms of number of events? Any more would push them to be having sex more than women without sexual desire problems."

To Dr. Kingsberg, the FDA’s reluctance to approve flibanserin harks back to 2004, when the FDA said it was unconvinced by the evidence in support of Intrinsa, a transdermal testosterone patch also shown to significantly increase satisfying sexual episodes per month in surgically menopausal women. Then, too, the FDA cited concerns about a modest effect size in light of risk.

In trials, the most frequently reported adverse events associated with flibanserin were somnolence, dizziness, and nausea.

Dr. James A. Simon, clinical professor of obstetrics and gynecology at George Washington University in Washington, said in an interview that he was concerned about what he considered a "double standard for men and women in the regulatory process."

Both flibanserin and the testosterone patch were shown to work in women, he noted, yet both met regulatory obstacles. Meanwhile, dozens of treatments have been approved in the past 20 years for male sexual dysfunction.

HSDD "is a common problem; it’s not a made-up issue," Dr. Simon said. "But right now all we have to try and treat it with are testosterone, some antidepressants that work on dopamine, and some drugs for restless legs syndrome. None of them is approved for this indication."

Dr. Kingsberg disclosed a consulting relationship with Sprout Pharmaceuticals. Dr. Simon disclosed he was a coauthor on several studies of flibanserin, and a former consultant for Sprout.

Dr. Jan Shifren, director of the Midlife Women’s Health Center at Massachusetts General Hospital, Boston, said that she found the FDA’s position understandable, but agreed that there appeared to be higher hurdles for women’s sexual health interventions. Dr. Shifren was an investigator in manufacturer-sponsored trials of flibanserin in postmenopausal women but does not have a consulting relationship with the company.

Testosterone replacement treatments for men received fast approval and are in widespread use, she noted, despite lingering safety concerns.

Dr. Shifren said that she was uncertain as to why flibanserin’s manufacturer would aim first to approve the drug for premenopausal women, when studies have found that women in midlife are more likely to report distress related to sexual dysfunction.

In Dr. Shifren and colleagues’ 2008 survey study (Obstet. Gynecol. 2008;112:970-8) in which they evaluated responses from more than 30,000 women, they learned that distress related to low sex drive is more commonly reported by women aged 45-64 years (14.8%) than by younger women (10.8%).

A novel agent shown in clinical trials to improve sex drive in women has been turned down by the Food and Drug Administration, leaving clinicians with no approved treatment options for a commonly reported disorder unless a manufacturer appeal proves successful.

Flibanserin, a drug originally investigated in the 1990s as an antidepressant, was later studied as a treatment for hypoactive sexual desire disorder (HSDD) in premenopausal women.

HSDD is characterized by a stress-inducing loss of sex drive without an identifiable physical or psychological cause. Flibanserin works by increasing dopamine and norepinephrine, both associated with sexual excitement, and by decreasing serotonin, which is associated with sexual inhibition. In studies, 100 mg of flibanserin daily was associated with statistically significant improvements in the number of satisfying sexual episodes per month as well as improvements in reported sexual desire over placebo, and reduction in stress associated with sexual dysfunction.

Sheryl Kingsberg, Ph.D., chief of behavioral medicine at University Hospitals Case Medical Center in Cleveland, and an investigator on some of the flibanserin research submitted to the FDA, said in an interview that there remains a "huge vacuum" in options for women with HSDD.

"For women for whom the primary loss of sexual desire is drive, which is the biological component to desire, there is nothing," she said. "For postmenopausal women for whom drive is related to declining testosterone, testosterone is an option – but off-label. There are no FDA-approved testosterone options for women."

The FDA cited concerns about flibanserin’s risks compared with its "modest" effect size, according to Sprout Pharmaceuticals, which has already moved to appeal the agency’s decision. In one manufacturer-sponsored randomized controlled trial published this year (n = 1,087), the results of which were submitted to the FDA, flibanserin was seen increasing satisfying sexual events per month by an average of 2.5, compared with 1.5 for placebo (J. Sex. Med. 2013;10:1807-15 [doi: 10.1111/jsm.12189]).

"I know the data very well, and I was convinced that it hit every endpoint," Dr. Kingsberg said. "FDA says they’re concerned about the modest efficacy in light of a risk profile not different from an SSRI [selective serotonin reuptake inhibitor], or even an antihistamine. How much more can women be expected to have in terms of number of events? Any more would push them to be having sex more than women without sexual desire problems."

To Dr. Kingsberg, the FDA’s reluctance to approve flibanserin harks back to 2004, when the FDA said it was unconvinced by the evidence in support of Intrinsa, a transdermal testosterone patch also shown to significantly increase satisfying sexual episodes per month in surgically menopausal women. Then, too, the FDA cited concerns about a modest effect size in light of risk.

In trials, the most frequently reported adverse events associated with flibanserin were somnolence, dizziness, and nausea.

Dr. James A. Simon, clinical professor of obstetrics and gynecology at George Washington University in Washington, said in an interview that he was concerned about what he considered a "double standard for men and women in the regulatory process."

Both flibanserin and the testosterone patch were shown to work in women, he noted, yet both met regulatory obstacles. Meanwhile, dozens of treatments have been approved in the past 20 years for male sexual dysfunction.

HSDD "is a common problem; it’s not a made-up issue," Dr. Simon said. "But right now all we have to try and treat it with are testosterone, some antidepressants that work on dopamine, and some drugs for restless legs syndrome. None of them is approved for this indication."

Dr. Kingsberg disclosed a consulting relationship with Sprout Pharmaceuticals. Dr. Simon disclosed he was a coauthor on several studies of flibanserin, and a former consultant for Sprout.

Dr. Jan Shifren, director of the Midlife Women’s Health Center at Massachusetts General Hospital, Boston, said that she found the FDA’s position understandable, but agreed that there appeared to be higher hurdles for women’s sexual health interventions. Dr. Shifren was an investigator in manufacturer-sponsored trials of flibanserin in postmenopausal women but does not have a consulting relationship with the company.

Testosterone replacement treatments for men received fast approval and are in widespread use, she noted, despite lingering safety concerns.

Dr. Shifren said that she was uncertain as to why flibanserin’s manufacturer would aim first to approve the drug for premenopausal women, when studies have found that women in midlife are more likely to report distress related to sexual dysfunction.

In Dr. Shifren and colleagues’ 2008 survey study (Obstet. Gynecol. 2008;112:970-8) in which they evaluated responses from more than 30,000 women, they learned that distress related to low sex drive is more commonly reported by women aged 45-64 years (14.8%) than by younger women (10.8%).

A novel agent shown in clinical trials to improve sex drive in women has been turned down by the Food and Drug Administration, leaving clinicians with no approved treatment options for a commonly reported disorder unless a manufacturer appeal proves successful.

Flibanserin, a drug originally investigated in the 1990s as an antidepressant, was later studied as a treatment for hypoactive sexual desire disorder (HSDD) in premenopausal women.

HSDD is characterized by a stress-inducing loss of sex drive without an identifiable physical or psychological cause. Flibanserin works by increasing dopamine and norepinephrine, both associated with sexual excitement, and by decreasing serotonin, which is associated with sexual inhibition. In studies, 100 mg of flibanserin daily was associated with statistically significant improvements in the number of satisfying sexual episodes per month as well as improvements in reported sexual desire over placebo, and reduction in stress associated with sexual dysfunction.

Sheryl Kingsberg, Ph.D., chief of behavioral medicine at University Hospitals Case Medical Center in Cleveland, and an investigator on some of the flibanserin research submitted to the FDA, said in an interview that there remains a "huge vacuum" in options for women with HSDD.

"For women for whom the primary loss of sexual desire is drive, which is the biological component to desire, there is nothing," she said. "For postmenopausal women for whom drive is related to declining testosterone, testosterone is an option – but off-label. There are no FDA-approved testosterone options for women."

The FDA cited concerns about flibanserin’s risks compared with its "modest" effect size, according to Sprout Pharmaceuticals, which has already moved to appeal the agency’s decision. In one manufacturer-sponsored randomized controlled trial published this year (n = 1,087), the results of which were submitted to the FDA, flibanserin was seen increasing satisfying sexual events per month by an average of 2.5, compared with 1.5 for placebo (J. Sex. Med. 2013;10:1807-15 [doi: 10.1111/jsm.12189]).

"I know the data very well, and I was convinced that it hit every endpoint," Dr. Kingsberg said. "FDA says they’re concerned about the modest efficacy in light of a risk profile not different from an SSRI [selective serotonin reuptake inhibitor], or even an antihistamine. How much more can women be expected to have in terms of number of events? Any more would push them to be having sex more than women without sexual desire problems."

To Dr. Kingsberg, the FDA’s reluctance to approve flibanserin harks back to 2004, when the FDA said it was unconvinced by the evidence in support of Intrinsa, a transdermal testosterone patch also shown to significantly increase satisfying sexual episodes per month in surgically menopausal women. Then, too, the FDA cited concerns about a modest effect size in light of risk.

In trials, the most frequently reported adverse events associated with flibanserin were somnolence, dizziness, and nausea.

Dr. James A. Simon, clinical professor of obstetrics and gynecology at George Washington University in Washington, said in an interview that he was concerned about what he considered a "double standard for men and women in the regulatory process."

Both flibanserin and the testosterone patch were shown to work in women, he noted, yet both met regulatory obstacles. Meanwhile, dozens of treatments have been approved in the past 20 years for male sexual dysfunction.

HSDD "is a common problem; it’s not a made-up issue," Dr. Simon said. "But right now all we have to try and treat it with are testosterone, some antidepressants that work on dopamine, and some drugs for restless legs syndrome. None of them is approved for this indication."

Dr. Kingsberg disclosed a consulting relationship with Sprout Pharmaceuticals. Dr. Simon disclosed he was a coauthor on several studies of flibanserin, and a former consultant for Sprout.

Dr. Jan Shifren, director of the Midlife Women’s Health Center at Massachusetts General Hospital, Boston, said that she found the FDA’s position understandable, but agreed that there appeared to be higher hurdles for women’s sexual health interventions. Dr. Shifren was an investigator in manufacturer-sponsored trials of flibanserin in postmenopausal women but does not have a consulting relationship with the company.

Testosterone replacement treatments for men received fast approval and are in widespread use, she noted, despite lingering safety concerns.

Dr. Shifren said that she was uncertain as to why flibanserin’s manufacturer would aim first to approve the drug for premenopausal women, when studies have found that women in midlife are more likely to report distress related to sexual dysfunction.

In Dr. Shifren and colleagues’ 2008 survey study (Obstet. Gynecol. 2008;112:970-8) in which they evaluated responses from more than 30,000 women, they learned that distress related to low sex drive is more commonly reported by women aged 45-64 years (14.8%) than by younger women (10.8%).

Immediately after the worrisome initial findings of the Women’s Health Initiative (WHI) were published in July 2002,¹ leading organizations and experts in menopausal medicine began advising practitioners to prescribe the “lowest dose of hormones for the shortest period of time.” News headlines that cited menopausal hormone therapy (HT) as a risk factor for myocardial infarction, venous thromboembolism (VTE), gall blad­der disease, stroke, urinary incontinence, dementia, and cancers of the breast and lung fueled fear among the lay public and led to a burgeoning market for alternative therapies to address menopausal symptoms.² Companies that marketed alternative therapies, including bioidentical hormones, often exaggerated the reported risks of menopausal HT and implied that their products were safe and effective, although supporting evidence was lacking.³

More than a decade later, despite a growing body of data reinforcing the safety and efficacy of HT for recently menopausal women,⁴ many medical professionals remain reluctant to prescribe HT—and when they do prescribe it, they push for a 5-year limit.^4,5 This has led to needless suffering and reduced quality of life among thousands of women entering the menopausal ­transition.^6,7

THE IMPORTANCE OF TARGETING HT TO THE APPROPRIATE POPULATION
Over the past decade, experts have conducted in-depth analyses of WHI findings and other contemporary data on the benefits and risks of HT. One fact is clear: The original reports and the way the data were portrayed in the media overstated the risks of HT in newly menopausal women.^2,8 Reanalysis has shown that when HT is initiated within 10 years of menopause, the risks are few and generally are outweighed by benefits.^9–11 When HT is initiated by women in their 60s and 70s, however, the reverse may be true.

HT is the best therapy for menopausal vasomotor symptoms and has a secondary benefit of preventing osteoporosis.¹² HT also may offer cardiovascular benefits in younger menopausal women, although no ­appropriately powered randomized, clinical trial has yet confirmed this presumption.^9,13

Related Article: In young hysterectomized women, does unopposed estrogen therapy increase overall survival? Andrew M. Kaunitz, MD (Examining the Evidence, October 2013)

HT AND BREAST CANCER: CONTEXT IS CRITICAL
The original WHI publication and the news reports that followed emphasized that women using combination estrogen-progestin HT experienced a 24% increase in the incidence of breast cancer, which became apparent in the fifth year of therapy.¹ A closer look at the data reveals that the increased incidence of breast cancer reported in this arm of the WHI involved just 38 breast cancers per 10,000 women using HT per year, compared with 30 breast cancers per 10,000 women using placebo. The absolute risk increased by eight breast cancers per 10,000 women, or 0.08%, for each year of use. In the WHI, the 75% of women who were new users of HT actually had no increased risk of breast cancer (hazard ratio [HR], 1.06; 95% confidence interval [CI], 0.81–1.38).

Related Article: Osteoporosis treatment and breast cancer prevention: Two goals, one treatment? Robert L. Barbieri, MD (Editorial, November 2013)

It is important to put this degree of increased risk into perspective. An increase of 0.08% per year is less than one-tenth of a percentage point and is comparable to the risk of breast cancer that a woman accepts if she drinks alcohol regularly, allows herself to become overweight during perimenopause, or fails to exercise at least three times a week.¹⁴ Cumulative data from a number of observational studies suggest that the effect of estrogen alone (without a progestin) on breast cancer is even lower, and that estrogen can be taken for many years before any effect is seen. Indeed, among women receiving estrogen alone in the WHI, the risk of breast cancer did not increase. In fact, there was a statistically significant decrease in breast cancer in this population.

Related Article: USPSTF recommends tamoxifen or raloxifene to reduce breast cancer risk in high-risk patients (October 2013)

WHY A 5-YEAR LIMIT IS INAPPROPRIATE
As I explained above, the increase in the incidence of breast cancer observed in the estrogen-progestin arm of the WHI after 5 years represents an increase in the ­absolute risk of breast cancer of only 0.08% per year. Although HT carries other small potential risks, most experts agree that they are outweighed by the potential benefits among most perimenopausal women. Because an individual’s risks and benefits probably vary according to her personal and family history, clinicians can mitigate the risks, in part, by tailoring the dose, regimen, and route of delivery to the individual’s situation. The risk of VTE is greatest during the first year of HT and approaches background rates thereafter. The risk of stroke in newly menopausal women who initiated HT in the WHI was approximately 1/1,000.¹³

Health-care practitioners also can minimize the risks of HT by monitoring outcomes, such as blood pressure, unscheduled bleeding, and so on.¹⁵ It also may be helpful to counsel patients about interventions for other conditions that contribute to risk, including obesity, smoking, inactivity, hypertension, and hyperlipidemia.

Quality of life was largely ignored in the decade after publication of the initial WHI findings because it was thought that the lives saved by avoiding HT would justify some level of distress.^6,7 There also was a presumption—promoted by advocates of natural products and alternative therapies—that interventions such as acupuncture, paced respiration, and herbal remedies were safe and effective at alleviating hot flashes, night sweats, mood swings, and sleep disruption. Complaints of vaginal dryness and dyspareunia from urogenital atrophy often were inadequately addressed because local estrogen was incorrectly thought to increase the risk of hormone-induced breast cancer. Rates of osteoporosis and hip fracture also have risen over the past decade as the protective effect of systemic HT for many women was lost.¹⁶

Although most postmenopausal women (60%) experience hot flashes for less than 7 years, as many as 15% report that hot flashes persist for 15 years or longer. The symptoms that can accompany hot flashes (including sweating, palpitations, apprehension, and anxiety) contribute to a woman’s discomfort, inconvenience, and distress, particularly when the hot flashes are frequent, and can be a significant contributor to sleep disturbance. Vasomotor symptoms adversely affect quality of life for 20% to 25% of women, primarily due to the physical discomfort and social embarrassment that they evoke—although night sweats and sleep disturbance also are reported to exert a negative impact.^17–19

THE BOTTOM LINE
Nothing magical happens after 5 years of HT to increase a woman’s risk of breast cancer. Any cumulative effect of combination HT on the risk of breast cancer is gradual and small. It is not appropriate to demand that a patient stop HT after 5 years if it affords dramatic improvement in her quality of life, provided she has been correctly informed about potential risks and chooses to continue with therapy.

Immediately after the worrisome initial findings of the Women’s Health Initiative (WHI) were published in July 2002,¹ leading organizations and experts in menopausal medicine began advising practitioners to prescribe the “lowest dose of hormones for the shortest period of time.” News headlines that cited menopausal hormone therapy (HT) as a risk factor for myocardial infarction, venous thromboembolism (VTE), gall blad­der disease, stroke, urinary incontinence, dementia, and cancers of the breast and lung fueled fear among the lay public and led to a burgeoning market for alternative therapies to address menopausal symptoms.² Companies that marketed alternative therapies, including bioidentical hormones, often exaggerated the reported risks of menopausal HT and implied that their products were safe and effective, although supporting evidence was lacking.³

More than a decade later, despite a growing body of data reinforcing the safety and efficacy of HT for recently menopausal women,⁴ many medical professionals remain reluctant to prescribe HT—and when they do prescribe it, they push for a 5-year limit.^4,5 This has led to needless suffering and reduced quality of life among thousands of women entering the menopausal ­transition.^6,7

THE IMPORTANCE OF TARGETING HT TO THE APPROPRIATE POPULATION
Over the past decade, experts have conducted in-depth analyses of WHI findings and other contemporary data on the benefits and risks of HT. One fact is clear: The original reports and the way the data were portrayed in the media overstated the risks of HT in newly menopausal women.^2,8 Reanalysis has shown that when HT is initiated within 10 years of menopause, the risks are few and generally are outweighed by benefits.^9–11 When HT is initiated by women in their 60s and 70s, however, the reverse may be true.

HT is the best therapy for menopausal vasomotor symptoms and has a secondary benefit of preventing osteoporosis.¹² HT also may offer cardiovascular benefits in younger menopausal women, although no ­appropriately powered randomized, clinical trial has yet confirmed this presumption.^9,13

Related Article: In young hysterectomized women, does unopposed estrogen therapy increase overall survival? Andrew M. Kaunitz, MD (Examining the Evidence, October 2013)

HT AND BREAST CANCER: CONTEXT IS CRITICAL
The original WHI publication and the news reports that followed emphasized that women using combination estrogen-progestin HT experienced a 24% increase in the incidence of breast cancer, which became apparent in the fifth year of therapy.¹ A closer look at the data reveals that the increased incidence of breast cancer reported in this arm of the WHI involved just 38 breast cancers per 10,000 women using HT per year, compared with 30 breast cancers per 10,000 women using placebo. The absolute risk increased by eight breast cancers per 10,000 women, or 0.08%, for each year of use. In the WHI, the 75% of women who were new users of HT actually had no increased risk of breast cancer (hazard ratio [HR], 1.06; 95% confidence interval [CI], 0.81–1.38).

Related Article: Osteoporosis treatment and breast cancer prevention: Two goals, one treatment? Robert L. Barbieri, MD (Editorial, November 2013)

It is important to put this degree of increased risk into perspective. An increase of 0.08% per year is less than one-tenth of a percentage point and is comparable to the risk of breast cancer that a woman accepts if she drinks alcohol regularly, allows herself to become overweight during perimenopause, or fails to exercise at least three times a week.¹⁴ Cumulative data from a number of observational studies suggest that the effect of estrogen alone (without a progestin) on breast cancer is even lower, and that estrogen can be taken for many years before any effect is seen. Indeed, among women receiving estrogen alone in the WHI, the risk of breast cancer did not increase. In fact, there was a statistically significant decrease in breast cancer in this population.

Related Article: USPSTF recommends tamoxifen or raloxifene to reduce breast cancer risk in high-risk patients (October 2013)

WHY A 5-YEAR LIMIT IS INAPPROPRIATE
As I explained above, the increase in the incidence of breast cancer observed in the estrogen-progestin arm of the WHI after 5 years represents an increase in the ­absolute risk of breast cancer of only 0.08% per year. Although HT carries other small potential risks, most experts agree that they are outweighed by the potential benefits among most perimenopausal women. Because an individual’s risks and benefits probably vary according to her personal and family history, clinicians can mitigate the risks, in part, by tailoring the dose, regimen, and route of delivery to the individual’s situation. The risk of VTE is greatest during the first year of HT and approaches background rates thereafter. The risk of stroke in newly menopausal women who initiated HT in the WHI was approximately 1/1,000.¹³

Health-care practitioners also can minimize the risks of HT by monitoring outcomes, such as blood pressure, unscheduled bleeding, and so on.¹⁵ It also may be helpful to counsel patients about interventions for other conditions that contribute to risk, including obesity, smoking, inactivity, hypertension, and hyperlipidemia.

Quality of life was largely ignored in the decade after publication of the initial WHI findings because it was thought that the lives saved by avoiding HT would justify some level of distress.^6,7 There also was a presumption—promoted by advocates of natural products and alternative therapies—that interventions such as acupuncture, paced respiration, and herbal remedies were safe and effective at alleviating hot flashes, night sweats, mood swings, and sleep disruption. Complaints of vaginal dryness and dyspareunia from urogenital atrophy often were inadequately addressed because local estrogen was incorrectly thought to increase the risk of hormone-induced breast cancer. Rates of osteoporosis and hip fracture also have risen over the past decade as the protective effect of systemic HT for many women was lost.¹⁶

Although most postmenopausal women (60%) experience hot flashes for less than 7 years, as many as 15% report that hot flashes persist for 15 years or longer. The symptoms that can accompany hot flashes (including sweating, palpitations, apprehension, and anxiety) contribute to a woman’s discomfort, inconvenience, and distress, particularly when the hot flashes are frequent, and can be a significant contributor to sleep disturbance. Vasomotor symptoms adversely affect quality of life for 20% to 25% of women, primarily due to the physical discomfort and social embarrassment that they evoke—although night sweats and sleep disturbance also are reported to exert a negative impact.^17–19

THE BOTTOM LINE
Nothing magical happens after 5 years of HT to increase a woman’s risk of breast cancer. Any cumulative effect of combination HT on the risk of breast cancer is gradual and small. It is not appropriate to demand that a patient stop HT after 5 years if it affords dramatic improvement in her quality of life, provided she has been correctly informed about potential risks and chooses to continue with therapy.

Immediately after the worrisome initial findings of the Women’s Health Initiative (WHI) were published in July 2002,¹ leading organizations and experts in menopausal medicine began advising practitioners to prescribe the “lowest dose of hormones for the shortest period of time.” News headlines that cited menopausal hormone therapy (HT) as a risk factor for myocardial infarction, venous thromboembolism (VTE), gall blad­der disease, stroke, urinary incontinence, dementia, and cancers of the breast and lung fueled fear among the lay public and led to a burgeoning market for alternative therapies to address menopausal symptoms.² Companies that marketed alternative therapies, including bioidentical hormones, often exaggerated the reported risks of menopausal HT and implied that their products were safe and effective, although supporting evidence was lacking.³

More than a decade later, despite a growing body of data reinforcing the safety and efficacy of HT for recently menopausal women,⁴ many medical professionals remain reluctant to prescribe HT—and when they do prescribe it, they push for a 5-year limit.^4,5 This has led to needless suffering and reduced quality of life among thousands of women entering the menopausal ­transition.^6,7

THE IMPORTANCE OF TARGETING HT TO THE APPROPRIATE POPULATION
Over the past decade, experts have conducted in-depth analyses of WHI findings and other contemporary data on the benefits and risks of HT. One fact is clear: The original reports and the way the data were portrayed in the media overstated the risks of HT in newly menopausal women.^2,8 Reanalysis has shown that when HT is initiated within 10 years of menopause, the risks are few and generally are outweighed by benefits.^9–11 When HT is initiated by women in their 60s and 70s, however, the reverse may be true.

HT is the best therapy for menopausal vasomotor symptoms and has a secondary benefit of preventing osteoporosis.¹² HT also may offer cardiovascular benefits in younger menopausal women, although no ­appropriately powered randomized, clinical trial has yet confirmed this presumption.^9,13

Related Article: In young hysterectomized women, does unopposed estrogen therapy increase overall survival? Andrew M. Kaunitz, MD (Examining the Evidence, October 2013)

HT AND BREAST CANCER: CONTEXT IS CRITICAL
The original WHI publication and the news reports that followed emphasized that women using combination estrogen-progestin HT experienced a 24% increase in the incidence of breast cancer, which became apparent in the fifth year of therapy.¹ A closer look at the data reveals that the increased incidence of breast cancer reported in this arm of the WHI involved just 38 breast cancers per 10,000 women using HT per year, compared with 30 breast cancers per 10,000 women using placebo. The absolute risk increased by eight breast cancers per 10,000 women, or 0.08%, for each year of use. In the WHI, the 75% of women who were new users of HT actually had no increased risk of breast cancer (hazard ratio [HR], 1.06; 95% confidence interval [CI], 0.81–1.38).

Related Article: Osteoporosis treatment and breast cancer prevention: Two goals, one treatment? Robert L. Barbieri, MD (Editorial, November 2013)

It is important to put this degree of increased risk into perspective. An increase of 0.08% per year is less than one-tenth of a percentage point and is comparable to the risk of breast cancer that a woman accepts if she drinks alcohol regularly, allows herself to become overweight during perimenopause, or fails to exercise at least three times a week.¹⁴ Cumulative data from a number of observational studies suggest that the effect of estrogen alone (without a progestin) on breast cancer is even lower, and that estrogen can be taken for many years before any effect is seen. Indeed, among women receiving estrogen alone in the WHI, the risk of breast cancer did not increase. In fact, there was a statistically significant decrease in breast cancer in this population.

Related Article: USPSTF recommends tamoxifen or raloxifene to reduce breast cancer risk in high-risk patients (October 2013)

WHY A 5-YEAR LIMIT IS INAPPROPRIATE
As I explained above, the increase in the incidence of breast cancer observed in the estrogen-progestin arm of the WHI after 5 years represents an increase in the ­absolute risk of breast cancer of only 0.08% per year. Although HT carries other small potential risks, most experts agree that they are outweighed by the potential benefits among most perimenopausal women. Because an individual’s risks and benefits probably vary according to her personal and family history, clinicians can mitigate the risks, in part, by tailoring the dose, regimen, and route of delivery to the individual’s situation. The risk of VTE is greatest during the first year of HT and approaches background rates thereafter. The risk of stroke in newly menopausal women who initiated HT in the WHI was approximately 1/1,000.¹³

Health-care practitioners also can minimize the risks of HT by monitoring outcomes, such as blood pressure, unscheduled bleeding, and so on.¹⁵ It also may be helpful to counsel patients about interventions for other conditions that contribute to risk, including obesity, smoking, inactivity, hypertension, and hyperlipidemia.

Quality of life was largely ignored in the decade after publication of the initial WHI findings because it was thought that the lives saved by avoiding HT would justify some level of distress.^6,7 There also was a presumption—promoted by advocates of natural products and alternative therapies—that interventions such as acupuncture, paced respiration, and herbal remedies were safe and effective at alleviating hot flashes, night sweats, mood swings, and sleep disruption. Complaints of vaginal dryness and dyspareunia from urogenital atrophy often were inadequately addressed because local estrogen was incorrectly thought to increase the risk of hormone-induced breast cancer. Rates of osteoporosis and hip fracture also have risen over the past decade as the protective effect of systemic HT for many women was lost.¹⁶

Although most postmenopausal women (60%) experience hot flashes for less than 7 years, as many as 15% report that hot flashes persist for 15 years or longer. The symptoms that can accompany hot flashes (including sweating, palpitations, apprehension, and anxiety) contribute to a woman’s discomfort, inconvenience, and distress, particularly when the hot flashes are frequent, and can be a significant contributor to sleep disturbance. Vasomotor symptoms adversely affect quality of life for 20% to 25% of women, primarily due to the physical discomfort and social embarrassment that they evoke—although night sweats and sleep disturbance also are reported to exert a negative impact.^17–19

THE BOTTOM LINE
Nothing magical happens after 5 years of HT to increase a woman’s risk of breast cancer. Any cumulative effect of combination HT on the risk of breast cancer is gradual and small. It is not appropriate to demand that a patient stop HT after 5 years if it affords dramatic improvement in her quality of life, provided she has been correctly informed about potential risks and chooses to continue with therapy.

SAN DIEGO – The mortality-reducing benefit of colorectal cancer screening persists long term, according to an updated analysis of the randomized Minnesota Fecal Occult Blood Trial.

Investigators led by Dr. Aasma Shaukat, a gastroenterologist with the University of Minnesota, Minneapolis, analyzed data for more than 46,000 participants aged 50-80 years who were assigned to screening with the fecal occult blood test (FOBT) or no screening.

After the first 18 years, the cumulative colorectal cancer mortality rate was reduced by one-third with annual screening and by one-fifth with biennial screening as compared with no screening, according to initially reported results (J. Natl. Cancer Inst. 1999;91:434-7).

The updated results, now after 30 years of follow-up – the longest of any such trial to date – showed that the reductions in risk with screening were essentially unchanged, Dr. Shaukat reported at the annual meeting of the American College of Gastroenterology.

"Screening for colon cancer using fecal occult blood testing consistently reduces colorectal cancer mortality..., and this effect is sustained through 30 years of follow-up," she commented. "This suggests the effect of polypectomy, because [if] fecal occult blood testing [detected only] early cancers, most of the benefit would be seen in the first 8-10 years. The sustained benefit suggests that these individuals underwent removal of polyps that would have turned into cancer and resulted in a death at 30 years."

In additional trial findings, the benefit of screening appeared to be greater for men than women and greater for those who began screening after the age of 60 years.

Session attendee Dr. Samir Gupta, of the University of California, San Diego, asked, "After the initial 10 or 15 years of protocolized screening, is it possible that screening was going on in the control group" and that might explain the lesser benefit in younger individuals, as they would have had more time to be screened.

"During the trial, through 1998, the screening in the control group was less than 5%, so there wasn’t much screening going on in the control group," Dr. Shaukat replied. However, "after the trial ended, we don’t have information on people’s screening behavior. And screening became popular, particularly in the last two decades. So there is a possibility that a large number of people that were in the control group underwent screening, and that’s diluting the effects that we would have otherwise seen."

She offered a few possible additional reasons for the smaller benefit in the younger group. "One is that group doesn’t have a higher risk of colon cancer and of dying from colon cancer, and hence, we are just not seeing the effect of screening," she said. "The second is that perhaps fecal occult blood testing is fairly insensitive in that age group; that’s something that needs to be explored further."

Session comoderator Dr. Jonathan A. Leighton of the Mayo Clinic in Scottsdale, Ariz., asked, "Why do you think there was that benefit in men over women?"

"That’s something that’s actually been shown in several natural history and modeling studies," Dr. Shaukat replied. "Men have a higher incidence of colon cancer and they have a higher risk of dying from colon cancer compared to women. So it bears to reason that we would see a larger effect of screening among men compared to women." That said, subgroup analyses should be considered hypothesis generating and require confirmation, she acknowledged.

Dr. Carol Burke of the Cleveland Clinic, who also attended the session, asked whether the screening benefit would have been even greater in analyses restricted to adherent patients.

"Compliance-adjusted estimates ... are a lot larger, to the magnitude of about a 40% reduction in colorectal cancer mortality," Dr. Shaukat replied.

"What effect do you think FIT [fecal immunochemical test] would have on the magnitude [of benefit] – similar for FIT or better because of adherence?" Dr. Burke further queried.

"These fecal occult blood tests were rehydrated, so their sensitivity is comparable to modern-day FIT. So we expect FIT to do the same if not better," Dr. Shaukat replied.

In the trial, 46,551 participants in the Minnesota Colon Cancer Control Study were assigned to annual or biennial screening or no screening between 1976 and 1992. Those with positive FOBT results underwent colonoscopy with polypectomy if needed. All groups had annual follow-up thereafter through 1998.

Adherence to screening was high in the trial, with 90% of participants in the screening groups completing at least one FOBT, and no difference between men and women, according to Dr. Shaukat.

At each screening, 10% of participants had positive results, and 83% of this subset overall underwent colonoscopy. The complication rate from colonoscopy was low, at less than 0.1%.

In the updated analysis, 71% of trial participants had died as ascertained from the National Death Index.

In intention-to-treat analyses, the risk of colorectal cancer mortality was a significant 32% lower in the group screened annually (relative risk, 0.68) and 22% lower in the group screened biennially (RR, 0.78) as compared with the nonscreened group, according to data reported at the meeting and recently published (N. Engl. J. Med. 2013;369:1106-14).

"We don’t know what happened after 1998," Dr. Shaukat reminded attendees. "At best, the effects that we are seeing might be dilute, and if truly the control group had remained unscreened, we would have seen perhaps larger differences."

The absolute cumulative colorectal cancer mortality rates were 0.02 with annual screening, 0.02 with biennial screening, and 0.03 with no screening. "This separation [in curves] started at about 13 years of follow-up and persisted through 30 years of follow-up," she pointed out.

All-cause mortality was statistically indistinguishable between groups, although the trial was underpowered to assess this outcome.

In subgroup analyses, there was a near-significant interaction of screening with sex (P = .06), whereby the benefit was greater among men (RR, 0.62) than among women (RR, 0.83).

Additionally, among men, there was a significant interaction with age (P = .04), whereby screening was most beneficial among those 60-69 years old at baseline (RR, 0.46). The benefit among women appeared to be restricted to those who started screening at age 60 or later.

"We don’t have information on the incidence of colon cancer, and hence we can’t comment on right- versus left-sided colon cancer mortality," Dr. Shaukat noted.

Dr. Shaukat disclosed no conflicts of interest.

SAN DIEGO – The mortality-reducing benefit of colorectal cancer screening persists long term, according to an updated analysis of the randomized Minnesota Fecal Occult Blood Trial.

Investigators led by Dr. Aasma Shaukat, a gastroenterologist with the University of Minnesota, Minneapolis, analyzed data for more than 46,000 participants aged 50-80 years who were assigned to screening with the fecal occult blood test (FOBT) or no screening.

After the first 18 years, the cumulative colorectal cancer mortality rate was reduced by one-third with annual screening and by one-fifth with biennial screening as compared with no screening, according to initially reported results (J. Natl. Cancer Inst. 1999;91:434-7).

The updated results, now after 30 years of follow-up – the longest of any such trial to date – showed that the reductions in risk with screening were essentially unchanged, Dr. Shaukat reported at the annual meeting of the American College of Gastroenterology.

"Screening for colon cancer using fecal occult blood testing consistently reduces colorectal cancer mortality..., and this effect is sustained through 30 years of follow-up," she commented. "This suggests the effect of polypectomy, because [if] fecal occult blood testing [detected only] early cancers, most of the benefit would be seen in the first 8-10 years. The sustained benefit suggests that these individuals underwent removal of polyps that would have turned into cancer and resulted in a death at 30 years."

In additional trial findings, the benefit of screening appeared to be greater for men than women and greater for those who began screening after the age of 60 years.

Session attendee Dr. Samir Gupta, of the University of California, San Diego, asked, "After the initial 10 or 15 years of protocolized screening, is it possible that screening was going on in the control group" and that might explain the lesser benefit in younger individuals, as they would have had more time to be screened.

"During the trial, through 1998, the screening in the control group was less than 5%, so there wasn’t much screening going on in the control group," Dr. Shaukat replied. However, "after the trial ended, we don’t have information on people’s screening behavior. And screening became popular, particularly in the last two decades. So there is a possibility that a large number of people that were in the control group underwent screening, and that’s diluting the effects that we would have otherwise seen."

She offered a few possible additional reasons for the smaller benefit in the younger group. "One is that group doesn’t have a higher risk of colon cancer and of dying from colon cancer, and hence, we are just not seeing the effect of screening," she said. "The second is that perhaps fecal occult blood testing is fairly insensitive in that age group; that’s something that needs to be explored further."

Session comoderator Dr. Jonathan A. Leighton of the Mayo Clinic in Scottsdale, Ariz., asked, "Why do you think there was that benefit in men over women?"

"That’s something that’s actually been shown in several natural history and modeling studies," Dr. Shaukat replied. "Men have a higher incidence of colon cancer and they have a higher risk of dying from colon cancer compared to women. So it bears to reason that we would see a larger effect of screening among men compared to women." That said, subgroup analyses should be considered hypothesis generating and require confirmation, she acknowledged.

Dr. Carol Burke of the Cleveland Clinic, who also attended the session, asked whether the screening benefit would have been even greater in analyses restricted to adherent patients.

"Compliance-adjusted estimates ... are a lot larger, to the magnitude of about a 40% reduction in colorectal cancer mortality," Dr. Shaukat replied.

"What effect do you think FIT [fecal immunochemical test] would have on the magnitude [of benefit] – similar for FIT or better because of adherence?" Dr. Burke further queried.

"These fecal occult blood tests were rehydrated, so their sensitivity is comparable to modern-day FIT. So we expect FIT to do the same if not better," Dr. Shaukat replied.

In the trial, 46,551 participants in the Minnesota Colon Cancer Control Study were assigned to annual or biennial screening or no screening between 1976 and 1992. Those with positive FOBT results underwent colonoscopy with polypectomy if needed. All groups had annual follow-up thereafter through 1998.

Adherence to screening was high in the trial, with 90% of participants in the screening groups completing at least one FOBT, and no difference between men and women, according to Dr. Shaukat.

At each screening, 10% of participants had positive results, and 83% of this subset overall underwent colonoscopy. The complication rate from colonoscopy was low, at less than 0.1%.

In the updated analysis, 71% of trial participants had died as ascertained from the National Death Index.

In intention-to-treat analyses, the risk of colorectal cancer mortality was a significant 32% lower in the group screened annually (relative risk, 0.68) and 22% lower in the group screened biennially (RR, 0.78) as compared with the nonscreened group, according to data reported at the meeting and recently published (N. Engl. J. Med. 2013;369:1106-14).

"We don’t know what happened after 1998," Dr. Shaukat reminded attendees. "At best, the effects that we are seeing might be dilute, and if truly the control group had remained unscreened, we would have seen perhaps larger differences."

The absolute cumulative colorectal cancer mortality rates were 0.02 with annual screening, 0.02 with biennial screening, and 0.03 with no screening. "This separation [in curves] started at about 13 years of follow-up and persisted through 30 years of follow-up," she pointed out.

All-cause mortality was statistically indistinguishable between groups, although the trial was underpowered to assess this outcome.

In subgroup analyses, there was a near-significant interaction of screening with sex (P = .06), whereby the benefit was greater among men (RR, 0.62) than among women (RR, 0.83).

Additionally, among men, there was a significant interaction with age (P = .04), whereby screening was most beneficial among those 60-69 years old at baseline (RR, 0.46). The benefit among women appeared to be restricted to those who started screening at age 60 or later.

"We don’t have information on the incidence of colon cancer, and hence we can’t comment on right- versus left-sided colon cancer mortality," Dr. Shaukat noted.

Dr. Shaukat disclosed no conflicts of interest.

SAN DIEGO – The mortality-reducing benefit of colorectal cancer screening persists long term, according to an updated analysis of the randomized Minnesota Fecal Occult Blood Trial.

Investigators led by Dr. Aasma Shaukat, a gastroenterologist with the University of Minnesota, Minneapolis, analyzed data for more than 46,000 participants aged 50-80 years who were assigned to screening with the fecal occult blood test (FOBT) or no screening.

After the first 18 years, the cumulative colorectal cancer mortality rate was reduced by one-third with annual screening and by one-fifth with biennial screening as compared with no screening, according to initially reported results (J. Natl. Cancer Inst. 1999;91:434-7).

The updated results, now after 30 years of follow-up – the longest of any such trial to date – showed that the reductions in risk with screening were essentially unchanged, Dr. Shaukat reported at the annual meeting of the American College of Gastroenterology.

"Screening for colon cancer using fecal occult blood testing consistently reduces colorectal cancer mortality..., and this effect is sustained through 30 years of follow-up," she commented. "This suggests the effect of polypectomy, because [if] fecal occult blood testing [detected only] early cancers, most of the benefit would be seen in the first 8-10 years. The sustained benefit suggests that these individuals underwent removal of polyps that would have turned into cancer and resulted in a death at 30 years."

In additional trial findings, the benefit of screening appeared to be greater for men than women and greater for those who began screening after the age of 60 years.

Session attendee Dr. Samir Gupta, of the University of California, San Diego, asked, "After the initial 10 or 15 years of protocolized screening, is it possible that screening was going on in the control group" and that might explain the lesser benefit in younger individuals, as they would have had more time to be screened.

"During the trial, through 1998, the screening in the control group was less than 5%, so there wasn’t much screening going on in the control group," Dr. Shaukat replied. However, "after the trial ended, we don’t have information on people’s screening behavior. And screening became popular, particularly in the last two decades. So there is a possibility that a large number of people that were in the control group underwent screening, and that’s diluting the effects that we would have otherwise seen."

She offered a few possible additional reasons for the smaller benefit in the younger group. "One is that group doesn’t have a higher risk of colon cancer and of dying from colon cancer, and hence, we are just not seeing the effect of screening," she said. "The second is that perhaps fecal occult blood testing is fairly insensitive in that age group; that’s something that needs to be explored further."

Session comoderator Dr. Jonathan A. Leighton of the Mayo Clinic in Scottsdale, Ariz., asked, "Why do you think there was that benefit in men over women?"

"That’s something that’s actually been shown in several natural history and modeling studies," Dr. Shaukat replied. "Men have a higher incidence of colon cancer and they have a higher risk of dying from colon cancer compared to women. So it bears to reason that we would see a larger effect of screening among men compared to women." That said, subgroup analyses should be considered hypothesis generating and require confirmation, she acknowledged.

Dr. Carol Burke of the Cleveland Clinic, who also attended the session, asked whether the screening benefit would have been even greater in analyses restricted to adherent patients.

"Compliance-adjusted estimates ... are a lot larger, to the magnitude of about a 40% reduction in colorectal cancer mortality," Dr. Shaukat replied.

"What effect do you think FIT [fecal immunochemical test] would have on the magnitude [of benefit] – similar for FIT or better because of adherence?" Dr. Burke further queried.

"These fecal occult blood tests were rehydrated, so their sensitivity is comparable to modern-day FIT. So we expect FIT to do the same if not better," Dr. Shaukat replied.

In the trial, 46,551 participants in the Minnesota Colon Cancer Control Study were assigned to annual or biennial screening or no screening between 1976 and 1992. Those with positive FOBT results underwent colonoscopy with polypectomy if needed. All groups had annual follow-up thereafter through 1998.

Adherence to screening was high in the trial, with 90% of participants in the screening groups completing at least one FOBT, and no difference between men and women, according to Dr. Shaukat.

At each screening, 10% of participants had positive results, and 83% of this subset overall underwent colonoscopy. The complication rate from colonoscopy was low, at less than 0.1%.

In the updated analysis, 71% of trial participants had died as ascertained from the National Death Index.

In intention-to-treat analyses, the risk of colorectal cancer mortality was a significant 32% lower in the group screened annually (relative risk, 0.68) and 22% lower in the group screened biennially (RR, 0.78) as compared with the nonscreened group, according to data reported at the meeting and recently published (N. Engl. J. Med. 2013;369:1106-14).

"We don’t know what happened after 1998," Dr. Shaukat reminded attendees. "At best, the effects that we are seeing might be dilute, and if truly the control group had remained unscreened, we would have seen perhaps larger differences."

The absolute cumulative colorectal cancer mortality rates were 0.02 with annual screening, 0.02 with biennial screening, and 0.03 with no screening. "This separation [in curves] started at about 13 years of follow-up and persisted through 30 years of follow-up," she pointed out.

All-cause mortality was statistically indistinguishable between groups, although the trial was underpowered to assess this outcome.

In subgroup analyses, there was a near-significant interaction of screening with sex (P = .06), whereby the benefit was greater among men (RR, 0.62) than among women (RR, 0.83).

Additionally, among men, there was a significant interaction with age (P = .04), whereby screening was most beneficial among those 60-69 years old at baseline (RR, 0.46). The benefit among women appeared to be restricted to those who started screening at age 60 or later.

"We don’t have information on the incidence of colon cancer, and hence we can’t comment on right- versus left-sided colon cancer mortality," Dr. Shaukat noted.

Dr. Shaukat disclosed no conflicts of interest.

CASE: ACTIVE, HEALTHY, OSTEOPOROTIC, AND AT-RISK FOR BREAST CANCER
Your patient, a 58-year-old, G0 healthy and active woman underwent early menopause at 44 years. She recently had a bone mineral density test, results of which showed a T-score of –2.8 at the spine and –2.5 at the hip. She is taking vitamin D and calcium. She is an exceptionally active woman who plays tennis and walks more than 5 miles daily. Two years earlier, at age 56, she had abnormal mammography results, and a breast biopsy revealed atypical hyperplasia. Her mother has a history of Paget disease of the breast.

Prior to selecting a bone medicine to treat this woman’s osteoporosis, should you assess her risk of breast cancer?

In this editorial, I make the argument that, yes, you should assess this patient’s risk of breast cancer prior to selecting treatment for her osteoporosis, as her level of breast cancer risk can help determine the optimal osteoporosis therapy.  

An expert panel convened by the American Society of Clinical Oncology noted that far too few American women are being assessed for their risk of breast cancer, and too few American women at increased risk for breast cancer are being offered pharmacologic preventive therapy.¹ One small step to increase the frequency of risk assessment and counseling regarding preventive therapy is to assess breast cancer risk in women with osteoporosis to help guide the selection of a bone medicine.

Options for osteoporosis treatment
Most experts recommend that menopausal women with osteoporosis (T-score ≤–2.5) should be offered a bone medicine in addition to the standard prescription therapy of vitamin D and calcium, exercise, and smoking cessation.

The most commonly prescribed bone medicines are bisphosphonates, estrogen, and raloxifene. Following the publication of the Women’s Health Initiative (WHI) in 2002, the use of estrogen and raloxifene for the treatment of osteoporosis decreased significantly. Both the bisphosphonates and estrogen are believed to be slightly more effective at increasing bone density than raloxifene, but there are no direct head-to-head, large-scale fracture-reduction studies comparing these agents.² In one large retrospective database study, women taking alendronate or raloxifene were reported to have similar vertebral and nonvertebral fracture rates.³

Unlike the bisphosphonates and estrogen, raloxifene has been demonstrated to reduce the risk of breast cancer by about 50%. For women with newly diagnosed osteoporosis and an above-average risk of developing breast cancer, raloxifene may represent an optimal pharmacologic intervention. But, how would you know if your patient with newly diagnosed osteoporosis is at increased risk for breast cancer?

Assessing breast cancer risk
The Gail breast cancer risk assessment tool is often used in clinical practice to identify women who are at above-average risk for breast cancer (defined as a 5-year risk of developing breast cancer ≥1.66%).⁴ For the patient described in the opening case, the Gail tool predicts that her 5-year risk of breast cancer is 6%, compared with 1.7% for a woman of the same age who is at average risk. In addition, the Gail tool predicts that for the woman in this case, her lifetime risk of breast cancer, to age 90, is 30.1%, compared with 9.5% for a woman of the same age who is at average risk.

The woman in this case is clearly at increased risk for breast cancer. What are her choices for reducing her risk of developing breast cancer?

Options for preventing breast cancer
There are many strategies to prevent breast cancer, including lifestyle interventions, pharmacotherapy, and mastectomy. Lifestyle interventions that may reduce the risk of breast cancer in postmenopausal women include: maintain a body weight in the normal range,⁵ reduce or eliminate the consumption of alcoholic beverages,⁶ exercise daily,⁷ and quit smoking.⁸

Mastectomy has been demonstrated to reduce the risk of breast cancer in women at very high risk (BRCA positive), but it is seldom used in women at moderate risk for breast cancer.

Pharmacologic interventions for the prevention of breast cancer include tamoxifen, raloxifene, and exemestane.¹ All three agents reduce the risk of breast cancer by about 50%.  In fact, the US Preventive Services Task Force (USPSTF) recently recommended the use of tamoxifen or raloxifene to reduce breast cancer risk in patients at high risk. (See “USPSTF recommends tamoxifen or raloxifene to reduce breast cancer risk in high-risk patients”.)

Exemestane is an aromatase inhibitor that causes bone loss. Consequently, this agent would not be an optimal choice for use in a woman with osteoporosis. Like raloxifene, tamoxifen is thought to increase bone density and decrease the risk of osteoporotic fracture.^9,10 Consequently, for a woman with osteoporosis, with an elevated risk of breast cancer, raloxifene or tamoxifen could be prescribed with the dual goals of reducing the risk of osteoporoticfracture and reducing the risk of breast cancer.

Two good options: Raloxifene and tamoxifen
Raloxifene and tamoxifen are both good choices for treating osteoporosis in women at high risk for breast cancer. For women with a uterus, raloxifene is the preferred agent because tamoxifen can cause endometrial cancer. For women without a uterus, either raloxifene or tamoxifen could be utilized. 

What is the benefit-to-risk ratio for these agents?
Dr. Gabriel Hortobagyi and Dr. Powel Brown have provided a snapshot of the pros and cons of using raloxifene and tamoxifen for breast cancer prophylaxis by estimating benefits and risks in 1,000 women treated for 5 years with an additional 2 years of follow-up (7 years of observation).¹¹ In their analysis it was assumed that the women had a 5-year risk of developing breast cancer of 4% (the mean risk for “high risk” subjects entered into the STAR P-2 Trial).

They calculated that after 7 years of observation, treating 1,000 women with tamoxifen 20 mg daily for 5 years will prevent 20 invasive and 20 noninvasive breast cancers and cause 2.25 endometrial cancers and 3.3 thromboembolic events. Treating 1,000 women with raloxifene 60 mg daily for 5 years will prevent15 invasive and 16 noninvasive breast cancers and cause no cases of endometrial cancer and 2.47 thromboembolic events. They concluded that for these major events, tamoxifen caused 40 beneficial events and 5.55 adverse events for a benefit-to-risk ratio of approximately 7. Raloxifene caused 31 beneficial events and 2.47 adverse events for a benefit-to-risk ratio of approximately 13.

Be aware of treatment-specific adverse effects
Raloxifene and tamoxifen treatment cause different patterns of symptom side effects and gynecologic problems. Tamoxifen treatment results in more vasomotor symptoms, leg cramps, and bladder control problems than treatment with raloxifene. Raloxifene is associated with more dyspareunia, lower libido, and more vaginal dryness, weight gain, and musculoskeletal problems than tamoxifen.¹²

Tamoxifen treatment results in more problems with leiomyomata, endometriosis, endometrial polyps, and endometrial cancer than treatment with raloxifene.¹³ In turn, this results in more gynecologic surgical procedures, such as endometrial biopsy, oophorectomy, laparoscopy, and hysteroscopy being performed on women taking tamoxifen than on women taking raloxifene. In the largest clinical trial, adherence to treatment was greater for raloxifene than tamoxifen.¹² For women with an intact uterus, raloxifene is likely the better choice for breast cancer prevention.

CASE: I WOULD RECOMMEND RALOXIFENE TO THE CASE PATIENT
For the woman presented in this case—who has osteoporosis and a 5-year risk for breast cancer of 6%, as well as an intact uterus—a 5-year course of raloxifene would be an appropriate treatment both to reduce her risk of breast cancer and to treat her osteoporosis.

To achieve the goal of the American Society of Clinical Oncology to increase the use of chemoprevention in women at increased risk of breast cancer, ObGyns will need to take a lead role in assessing our patients for breast cancer risk and counseling them about chemopreventive options.  

We want to hear from you!  Tell us what you think.

CASE: ACTIVE, HEALTHY, OSTEOPOROTIC, AND AT-RISK FOR BREAST CANCER
Your patient, a 58-year-old, G0 healthy and active woman underwent early menopause at 44 years. She recently had a bone mineral density test, results of which showed a T-score of –2.8 at the spine and –2.5 at the hip. She is taking vitamin D and calcium. She is an exceptionally active woman who plays tennis and walks more than 5 miles daily. Two years earlier, at age 56, she had abnormal mammography results, and a breast biopsy revealed atypical hyperplasia. Her mother has a history of Paget disease of the breast.

Prior to selecting a bone medicine to treat this woman’s osteoporosis, should you assess her risk of breast cancer?

In this editorial, I make the argument that, yes, you should assess this patient’s risk of breast cancer prior to selecting treatment for her osteoporosis, as her level of breast cancer risk can help determine the optimal osteoporosis therapy.  

An expert panel convened by the American Society of Clinical Oncology noted that far too few American women are being assessed for their risk of breast cancer, and too few American women at increased risk for breast cancer are being offered pharmacologic preventive therapy.¹ One small step to increase the frequency of risk assessment and counseling regarding preventive therapy is to assess breast cancer risk in women with osteoporosis to help guide the selection of a bone medicine.

Options for osteoporosis treatment
Most experts recommend that menopausal women with osteoporosis (T-score ≤–2.5) should be offered a bone medicine in addition to the standard prescription therapy of vitamin D and calcium, exercise, and smoking cessation.

The most commonly prescribed bone medicines are bisphosphonates, estrogen, and raloxifene. Following the publication of the Women’s Health Initiative (WHI) in 2002, the use of estrogen and raloxifene for the treatment of osteoporosis decreased significantly. Both the bisphosphonates and estrogen are believed to be slightly more effective at increasing bone density than raloxifene, but there are no direct head-to-head, large-scale fracture-reduction studies comparing these agents.² In one large retrospective database study, women taking alendronate or raloxifene were reported to have similar vertebral and nonvertebral fracture rates.³

Unlike the bisphosphonates and estrogen, raloxifene has been demonstrated to reduce the risk of breast cancer by about 50%. For women with newly diagnosed osteoporosis and an above-average risk of developing breast cancer, raloxifene may represent an optimal pharmacologic intervention. But, how would you know if your patient with newly diagnosed osteoporosis is at increased risk for breast cancer?

Assessing breast cancer risk
The Gail breast cancer risk assessment tool is often used in clinical practice to identify women who are at above-average risk for breast cancer (defined as a 5-year risk of developing breast cancer ≥1.66%).⁴ For the patient described in the opening case, the Gail tool predicts that her 5-year risk of breast cancer is 6%, compared with 1.7% for a woman of the same age who is at average risk. In addition, the Gail tool predicts that for the woman in this case, her lifetime risk of breast cancer, to age 90, is 30.1%, compared with 9.5% for a woman of the same age who is at average risk.

The woman in this case is clearly at increased risk for breast cancer. What are her choices for reducing her risk of developing breast cancer?

Options for preventing breast cancer
There are many strategies to prevent breast cancer, including lifestyle interventions, pharmacotherapy, and mastectomy. Lifestyle interventions that may reduce the risk of breast cancer in postmenopausal women include: maintain a body weight in the normal range,⁵ reduce or eliminate the consumption of alcoholic beverages,⁶ exercise daily,⁷ and quit smoking.⁸

Mastectomy has been demonstrated to reduce the risk of breast cancer in women at very high risk (BRCA positive), but it is seldom used in women at moderate risk for breast cancer.

Pharmacologic interventions for the prevention of breast cancer include tamoxifen, raloxifene, and exemestane.¹ All three agents reduce the risk of breast cancer by about 50%.  In fact, the US Preventive Services Task Force (USPSTF) recently recommended the use of tamoxifen or raloxifene to reduce breast cancer risk in patients at high risk. (See “USPSTF recommends tamoxifen or raloxifene to reduce breast cancer risk in high-risk patients”.)

Exemestane is an aromatase inhibitor that causes bone loss. Consequently, this agent would not be an optimal choice for use in a woman with osteoporosis. Like raloxifene, tamoxifen is thought to increase bone density and decrease the risk of osteoporotic fracture.^9,10 Consequently, for a woman with osteoporosis, with an elevated risk of breast cancer, raloxifene or tamoxifen could be prescribed with the dual goals of reducing the risk of osteoporoticfracture and reducing the risk of breast cancer.

Two good options: Raloxifene and tamoxifen
Raloxifene and tamoxifen are both good choices for treating osteoporosis in women at high risk for breast cancer. For women with a uterus, raloxifene is the preferred agent because tamoxifen can cause endometrial cancer. For women without a uterus, either raloxifene or tamoxifen could be utilized. 

What is the benefit-to-risk ratio for these agents?
Dr. Gabriel Hortobagyi and Dr. Powel Brown have provided a snapshot of the pros and cons of using raloxifene and tamoxifen for breast cancer prophylaxis by estimating benefits and risks in 1,000 women treated for 5 years with an additional 2 years of follow-up (7 years of observation).¹¹ In their analysis it was assumed that the women had a 5-year risk of developing breast cancer of 4% (the mean risk for “high risk” subjects entered into the STAR P-2 Trial).

They calculated that after 7 years of observation, treating 1,000 women with tamoxifen 20 mg daily for 5 years will prevent 20 invasive and 20 noninvasive breast cancers and cause 2.25 endometrial cancers and 3.3 thromboembolic events. Treating 1,000 women with raloxifene 60 mg daily for 5 years will prevent15 invasive and 16 noninvasive breast cancers and cause no cases of endometrial cancer and 2.47 thromboembolic events. They concluded that for these major events, tamoxifen caused 40 beneficial events and 5.55 adverse events for a benefit-to-risk ratio of approximately 7. Raloxifene caused 31 beneficial events and 2.47 adverse events for a benefit-to-risk ratio of approximately 13.

Be aware of treatment-specific adverse effects
Raloxifene and tamoxifen treatment cause different patterns of symptom side effects and gynecologic problems. Tamoxifen treatment results in more vasomotor symptoms, leg cramps, and bladder control problems than treatment with raloxifene. Raloxifene is associated with more dyspareunia, lower libido, and more vaginal dryness, weight gain, and musculoskeletal problems than tamoxifen.¹²

Tamoxifen treatment results in more problems with leiomyomata, endometriosis, endometrial polyps, and endometrial cancer than treatment with raloxifene.¹³ In turn, this results in more gynecologic surgical procedures, such as endometrial biopsy, oophorectomy, laparoscopy, and hysteroscopy being performed on women taking tamoxifen than on women taking raloxifene. In the largest clinical trial, adherence to treatment was greater for raloxifene than tamoxifen.¹² For women with an intact uterus, raloxifene is likely the better choice for breast cancer prevention.

CASE: I WOULD RECOMMEND RALOXIFENE TO THE CASE PATIENT
For the woman presented in this case—who has osteoporosis and a 5-year risk for breast cancer of 6%, as well as an intact uterus—a 5-year course of raloxifene would be an appropriate treatment both to reduce her risk of breast cancer and to treat her osteoporosis.

To achieve the goal of the American Society of Clinical Oncology to increase the use of chemoprevention in women at increased risk of breast cancer, ObGyns will need to take a lead role in assessing our patients for breast cancer risk and counseling them about chemopreventive options.  

We want to hear from you!  Tell us what you think.

CASE: ACTIVE, HEALTHY, OSTEOPOROTIC, AND AT-RISK FOR BREAST CANCER
Your patient, a 58-year-old, G0 healthy and active woman underwent early menopause at 44 years. She recently had a bone mineral density test, results of which showed a T-score of –2.8 at the spine and –2.5 at the hip. She is taking vitamin D and calcium. She is an exceptionally active woman who plays tennis and walks more than 5 miles daily. Two years earlier, at age 56, she had abnormal mammography results, and a breast biopsy revealed atypical hyperplasia. Her mother has a history of Paget disease of the breast.

Prior to selecting a bone medicine to treat this woman’s osteoporosis, should you assess her risk of breast cancer?

In this editorial, I make the argument that, yes, you should assess this patient’s risk of breast cancer prior to selecting treatment for her osteoporosis, as her level of breast cancer risk can help determine the optimal osteoporosis therapy.  

An expert panel convened by the American Society of Clinical Oncology noted that far too few American women are being assessed for their risk of breast cancer, and too few American women at increased risk for breast cancer are being offered pharmacologic preventive therapy.¹ One small step to increase the frequency of risk assessment and counseling regarding preventive therapy is to assess breast cancer risk in women with osteoporosis to help guide the selection of a bone medicine.

Options for osteoporosis treatment
Most experts recommend that menopausal women with osteoporosis (T-score ≤–2.5) should be offered a bone medicine in addition to the standard prescription therapy of vitamin D and calcium, exercise, and smoking cessation.

The most commonly prescribed bone medicines are bisphosphonates, estrogen, and raloxifene. Following the publication of the Women’s Health Initiative (WHI) in 2002, the use of estrogen and raloxifene for the treatment of osteoporosis decreased significantly. Both the bisphosphonates and estrogen are believed to be slightly more effective at increasing bone density than raloxifene, but there are no direct head-to-head, large-scale fracture-reduction studies comparing these agents.² In one large retrospective database study, women taking alendronate or raloxifene were reported to have similar vertebral and nonvertebral fracture rates.³

Unlike the bisphosphonates and estrogen, raloxifene has been demonstrated to reduce the risk of breast cancer by about 50%. For women with newly diagnosed osteoporosis and an above-average risk of developing breast cancer, raloxifene may represent an optimal pharmacologic intervention. But, how would you know if your patient with newly diagnosed osteoporosis is at increased risk for breast cancer?

Assessing breast cancer risk
The Gail breast cancer risk assessment tool is often used in clinical practice to identify women who are at above-average risk for breast cancer (defined as a 5-year risk of developing breast cancer ≥1.66%).⁴ For the patient described in the opening case, the Gail tool predicts that her 5-year risk of breast cancer is 6%, compared with 1.7% for a woman of the same age who is at average risk. In addition, the Gail tool predicts that for the woman in this case, her lifetime risk of breast cancer, to age 90, is 30.1%, compared with 9.5% for a woman of the same age who is at average risk.

The woman in this case is clearly at increased risk for breast cancer. What are her choices for reducing her risk of developing breast cancer?

Options for preventing breast cancer
There are many strategies to prevent breast cancer, including lifestyle interventions, pharmacotherapy, and mastectomy. Lifestyle interventions that may reduce the risk of breast cancer in postmenopausal women include: maintain a body weight in the normal range,⁵ reduce or eliminate the consumption of alcoholic beverages,⁶ exercise daily,⁷ and quit smoking.⁸

Mastectomy has been demonstrated to reduce the risk of breast cancer in women at very high risk (BRCA positive), but it is seldom used in women at moderate risk for breast cancer.

Pharmacologic interventions for the prevention of breast cancer include tamoxifen, raloxifene, and exemestane.¹ All three agents reduce the risk of breast cancer by about 50%.  In fact, the US Preventive Services Task Force (USPSTF) recently recommended the use of tamoxifen or raloxifene to reduce breast cancer risk in patients at high risk. (See “USPSTF recommends tamoxifen or raloxifene to reduce breast cancer risk in high-risk patients”.)

Exemestane is an aromatase inhibitor that causes bone loss. Consequently, this agent would not be an optimal choice for use in a woman with osteoporosis. Like raloxifene, tamoxifen is thought to increase bone density and decrease the risk of osteoporotic fracture.^9,10 Consequently, for a woman with osteoporosis, with an elevated risk of breast cancer, raloxifene or tamoxifen could be prescribed with the dual goals of reducing the risk of osteoporoticfracture and reducing the risk of breast cancer.

Two good options: Raloxifene and tamoxifen
Raloxifene and tamoxifen are both good choices for treating osteoporosis in women at high risk for breast cancer. For women with a uterus, raloxifene is the preferred agent because tamoxifen can cause endometrial cancer. For women without a uterus, either raloxifene or tamoxifen could be utilized. 

What is the benefit-to-risk ratio for these agents?
Dr. Gabriel Hortobagyi and Dr. Powel Brown have provided a snapshot of the pros and cons of using raloxifene and tamoxifen for breast cancer prophylaxis by estimating benefits and risks in 1,000 women treated for 5 years with an additional 2 years of follow-up (7 years of observation).¹¹ In their analysis it was assumed that the women had a 5-year risk of developing breast cancer of 4% (the mean risk for “high risk” subjects entered into the STAR P-2 Trial).

They calculated that after 7 years of observation, treating 1,000 women with tamoxifen 20 mg daily for 5 years will prevent 20 invasive and 20 noninvasive breast cancers and cause 2.25 endometrial cancers and 3.3 thromboembolic events. Treating 1,000 women with raloxifene 60 mg daily for 5 years will prevent15 invasive and 16 noninvasive breast cancers and cause no cases of endometrial cancer and 2.47 thromboembolic events. They concluded that for these major events, tamoxifen caused 40 beneficial events and 5.55 adverse events for a benefit-to-risk ratio of approximately 7. Raloxifene caused 31 beneficial events and 2.47 adverse events for a benefit-to-risk ratio of approximately 13.

Be aware of treatment-specific adverse effects
Raloxifene and tamoxifen treatment cause different patterns of symptom side effects and gynecologic problems. Tamoxifen treatment results in more vasomotor symptoms, leg cramps, and bladder control problems than treatment with raloxifene. Raloxifene is associated with more dyspareunia, lower libido, and more vaginal dryness, weight gain, and musculoskeletal problems than tamoxifen.¹²

Tamoxifen treatment results in more problems with leiomyomata, endometriosis, endometrial polyps, and endometrial cancer than treatment with raloxifene.¹³ In turn, this results in more gynecologic surgical procedures, such as endometrial biopsy, oophorectomy, laparoscopy, and hysteroscopy being performed on women taking tamoxifen than on women taking raloxifene. In the largest clinical trial, adherence to treatment was greater for raloxifene than tamoxifen.¹² For women with an intact uterus, raloxifene is likely the better choice for breast cancer prevention.

CASE: I WOULD RECOMMEND RALOXIFENE TO THE CASE PATIENT
For the woman presented in this case—who has osteoporosis and a 5-year risk for breast cancer of 6%, as well as an intact uterus—a 5-year course of raloxifene would be an appropriate treatment both to reduce her risk of breast cancer and to treat her osteoporosis.

To achieve the goal of the American Society of Clinical Oncology to increase the use of chemoprevention in women at increased risk of breast cancer, ObGyns will need to take a lead role in assessing our patients for breast cancer risk and counseling them about chemopreventive options.  

We want to hear from you!  Tell us what you think.