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The pendulum swings from fear to understanding

May 2005 · Vol. 17, No. 5

Time and study make a difference. So does careful review and reappraisal of existing data. In the past year, the pendulum has swung away from fear of hormone therapy to a better understanding of indications, risks and benefits—an understanding driven largely by the evidence-based position statements of the North American Menopause Society (NAMS).

A meta-analysis of randomized controlled trials of phytoestrogens attested to lack of efficacy or weak effect, which helps clear the picture on soy and red clover, but the researchers stressed that the lack of quality control does not rule out the possibility that some products might carry steroidal effects and potential risk.

And another year has brought even more evidence that diet, exercise, smoking cessation and the like really do improve health and quality of life.

Advisory on hormone therapy and “bio-identicals”

The NAMS Hormone Therapy Panel concluded definitively that bio-identical hormones should be considered in the same category as all the sex steroids, which, in the absence of specific safety and efficacy studies, carry the same risks and benefits as related products.

On the other hand, alternatives do exist for specific indications, such as bisphosphonates for bone conservation.

The new NAMSPosition Statement stresses individualized treatment based on the recommendations below.

The full report is available at

  • Treatment of moderate to severe menopausal symptoms is the primary indications for systemic therapy. Every systemic product is FDA-approved for this indication.
  • Every systemic and local product is approved for moderate vulvar and vaginal atrophy. For this indication alone, local ET is generally advised.
  • Duration should be for the lowest effective dose and shortest time consistent with treatment goals.
  • If the woman is well aware of potential risks and benefits, and if there is clinical supervision, extended use of the lowest effective ET/EPT dose for treatment goals is acceptable in women who believe the benefits outweigh the risks, for those at high risk of osteoporotic fracture who also have moderate to severe menopause symptoms, for further prevention of established bone loss when alternate therapies are not appropriate or cause side effects, or when outcomes of extended use of those therapies are not known.
  • Although specific compounds, doses, and routes of administration may have different outcomes, clinical trial results for one agent should be generalized to all agents within the same family in the absence of data for each specific product. This proviso also applies to the so-called bioidentical products.

Question marks

The Hormone Therapy panel could not agree unanimously on these questions:

  • Should women who are doing well on long-term HT discontinue?
  • What is the best way to discontinue HT, abrupt cessation or tapering?
  • Is the effect of continuous-combined EPT different from that of continuous estrogen with sequential progestogen?
  • How definitive is the evidence on early increased CHD risk with HT?
  • Conflicting data precluded a consensus on adverse breast cancer and cardiovascular outcomes associated with ET/EPT.


The following commentaries on key papers are from the NAMS First To Knowemail program for members. I thank the members of NAMS who have taken time out to provide these objective reviews of the studies presented here, and Phil Lammers, NAMS Medical Editor.

OSTEOPOROSISCurb your enthusiasm—no need to rush bone drugs if risk is low

McClung MR, Wasnich RD, Hosking DJ, et al, on behalf of the Early Postmenopausal Intervention Cohort (EPIC) study group. Prevention of postmenopausal bone loss: six-year results from the early postmenopausal intervention cohort study. J Clin Endocrinol Metab 2004;89:4879-4885. LEVEL 1 EVIDENCE: Randomized, controlled trial


In this 6-year study of women in their 50s, the placebo group lost an inconsequential amount of bone mass. Not surprisingly, women using alendronate had some increase in BMD and some reduction in bone turnover markers.

Women in their 50s are not melting away. Their bones are not dissolving out from under them, contrary to what many media reports would have ObGyns and patients believe. Still, many clinicians are enthusiastic about prescribing bone drugs like bisphosphonates to women in their 50s who are generally healthy. (And there is no doubt that we do have bone drugs found to be safe and effective in well-designed trials, including the EPIC study.)

Yet there has been a major shift away from starting osteoporosis prevention drugs soon after menopause. EPIC data add support for a “go slow” strategy for drug intervention in healthy women in their 50s.

The EPIC study involved a total of 1,609 women ages 45 to 59, who received alendronate or placebo in a double-blind, randomized design. BMD was measured annually. The 4-year results were reported previously, and the 6-year results were published just last fall. Not surprisingly, women using alendronate had some increase in BMD and some reduction in bone turnover markers. But the results in the women who took placebo are of singular interest.

After 6 years, women on placebo had lost very little bone. The amount lost was statistically significant, but clinically inconsequential. The average BMD in women on placebo decreased 3% in the spine and 2% in the hip. Thus, the average rate of bone loss was about 0.5% per year.

A bone mass decrease of this extent represents a decline of about -0.3 T score, which is negligible. In the EPIC study, the 6-year fracture benefit, based on any type of fracture, boils down to lowering the risk from 1 in 11 on placebo to 1 in 9 on alendronate. These healthy women in their 50s had a very low risk of fracture, and taking a drug for 6 years had very little benefit for fracture reduction.

Women in their 50s typically have about 10% to 15% less bone mass than women of 25 to 30, when bone mass is at its peak. That 10% to 15% lower BMD translates to a T score of –1 to –1.2 , which is currently being labeled as osteopenic. Many patients and physicians have come to feel that osteopenia must always be treated with our newer drugs.

We are discovering that starting healthy women in their 50s on osteoporosis prevention drugs carries an extremely high cost per fracture avoided. During the 10 years since the startup of the EPIC study, support for early drug intervention in healthy women still in their 50s has dwindled. Now, expert groups, including the National Osteoporosis Foundation and the US Preventive Services Task Force, advise waiting until age 65 before starting osteoporosis risk evaluation or considering drug intervention in women who are otherwise healthy.

In my practice, I give healthy women in their 50s permission not to take drugs if their risk of fracture within the next 5 to 10 years is low. The picture is quite different in postmenopausal women in their 50s who do have high fracture risk, such as those who have already had a fracture, or who have very low bone density or high exposure to glucocorticoids.

EPIC data support the concept that the rate of bone loss is quite slow after a year or 2 has elapsed after menopause.

We need to avoid medicalizing these patients simply because we have drugs that reduce bone loss or because women in their 50s have less bone mass than 25-year-olds.


Hosking D, Chilvers CE, Christiansen C, et al. Prevention of bone loss with alendronate in postmenopausal women under 60 years of age. Early Postmenopausal Intervention Cohort Study Group. N Engl J Med. 1998;338:485-492.

Wasnich RD, Bagger YZ, Hosking DJ, et al. Changes in bone density and turnover after alendronate or estrogen withdrawal. Menopause. 2004;11:622-630.

Siris ES, Bilezikian JP, Rubin MR, et al. Pins and plasters aren’t enough: a call for the evaluation and treatment of patients with osteoporotic fractures. J Clin Endocrinol Metab. 2003;88:3482-3486.

Rosen CJ, Black DM, Greenspan SL. Vignettes in osteoporosis: a road map to successful therapeutics. J Bone Miner Res. 2004;19:3-10.

HORMONE THERAPYDoes age affect mortality rate in postmenopausal women using HT?

Salpeter SR, Walsh JME, Greyber E, Ormiston TM, Salpeter EE. Mortality associated with hormone replacement therapy in younger and older women. J Gen Intern Med. 2004;19:791–804. META-ANALYSIS


  • This study is sure to incite yet another round of debate about postmenopausal hormone therapy, but it does suggest that we can provide substantial reassurance about safety in younger women considering hormone therapy for menopause-related symptoms.

This study attempted to discover whether the age of the postmenopausal woman using hormone therapy affects mortality. Investigators performed a meta-analysis of clinical trials that reported mortality rates associated with use of postmenopausal hormone therapy, and analyzed the results based on mean ages.

They reported a significant trend between increasing risk of mortality and increasing mean age of the women using hormone therapy—raising the possibility of a health benefit for younger postmenopausal women.

The studies included in the metaanalysis varied in entry criteria, outcomes assessed, number of subjects, and HT type and dosage. Furthermore, because age groups were defined by mean age in each trial rather than actual age of pooled participants, some overlap in ages likely occurred between the analyses of younger and older women.

In postmenopausal women younger than 60, the total mortality rate was reduced by 39% in women taking estrogen-containing hormone therapy, which was significant; in women older than 60, there was no significant effect on total mortality.

The data were from 30 randomized, controlled clinical trials published between 1966 and 2002, and included 26,708 women taking estrogen (ET) or estrogen plus progestogen (EPT). Data were pooled to determine total mortality and mortality due to specific causes such as cardiovascular disease and cancer. The mean trial duration was 4.5 years, and the mean age was 62.2 years.

When the study population was divided into younger and older age groups based on mean ages, it was found that those younger than 60 (mean age, 53.9) had a significantly reduced OR for total mortality of 0.61 (95% CI, 0.39–0.95) and those older than age 60 (mean age, 64.6) had an OR of 1.03 (95% CI, 0.90–1.18).

For specific causes, the OR for cardiovascular disease mortality associated with ET/EPT was 1.10 (95% CI, 0.90–1.34). For overall cancer mortality, the OR was 1.03 (95% CI, 0.82–1.29) and for breast cancer mortality, the OR was 1.03 (95% CI, 0.29–3.67).

For causes other than cardiovascular disease or cancer, mortality was significantly lower in women on HT: OR 0.67 (95% CI, 0.51–0.88). When divided into younger and older age groups, ET/EPT was not associated with a significant change in mortality, with the exception of reduced mortality from causes other than cardiovascular disease and cancer in the older age group (OR, 0.68; 95% CI, 0.56–0.91).

Does HT improve insulin resistance?

Margolis KL, Bonds DE, Rodabough RJ, et al, for the Women’s Health Initiative Investigators. Effect of oestrogen plus progestin on the incidence of diabetes in postmenopausal women: results from the Women’s Health Initiative Hormone Trial. Diabetologia. 2004;47:1175–1187. LEVEL 1 EVIDENCE: Randomized, controlled trial


Decreased insulin and fasting glucose

  • Combined estrogen plus progestogen may reduce the incidence of diabetes, possibly by mediating a decrease in insulin resistance.

Hormone therapy, compared with placebo, was associated with 15 fewer cases of diabetes per 10,000 women per year. Fasting glucose and insulin decreased compared with placebo, and may suggest improved insulin resistance. Although others have reported similar results, it is unlikely that hormone therapy will be prescribed to prevent diabetes, given its greater risk than benefit for other outcomes observed in other WHI analyses.

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