DSI Newsletter: Osteoporosis

DSI Newsletters, Issue 13:
Osteoporosis

On July 17, 2002, JAMA, the Journal of the American Medical Association, published the WHI (Women's Health Initiative), the results of which will make postmenopausal women and their doctors think harder about why to use combination HRT (Hormone Replacement Therapy) for how long, in which women, and with what other concomitant treatments.
The WHI was the first randomized trial to directly address whether Prempro (combination of Premarin-estrogen and Provera-progestin) has a favorable or unfavorable effect on CHD (Coronary Heart Disease) incidence and on overall risks and benefits in primary prevention in a predominently healthy cohort of women.
In the past, there have been other trials that made HRT appear good. In 1996, the PEPI trial (Postmenopausal Estrogen/Progestin Intervention) showed us that if a woman has a uterus, she will need the progestin, Provera to stop the Premarin from increasing the risk of uterine cancer. There have been studies in other primates, observational studies, and secondary prevention trials in women who already have heart disease that show HRT has a favorable effect on Cholesterol. It was found to lower the bad LDL-C 12.7% and raise the good HDL-C 7.3%. It should follow that lowering the cholesterol should translate to fewer heart attacks. This data goes along with that found in the PEPI trial and the HERS trial (Heart and Estrogen/progestin Replacement Study). In HERS, 2,763 post-menopausal with CHD (Coronary Heart Disease) were given Prempro (Wyeth Ayerst) vs. Placebo (dummy sham pill). There was an increase in risk of CHD the first year only, but no overall risk long-term. So, their cholesterols got better, but their hearts got worse for some unclear reason.
In America, the majority (62%) of postmenopausal women already chose not to use HRT to treat their menopause. Some groups already look at the cessation of menstruation as no more of a disease entity as the beginning of it. Their main fear is that of Breast Cancer. The fear is many times greater than the actual event. It makes sense that estrogen should be related to Breast Cancer. Observational studies have shown that the more estrogen a woman has for more years, the higher the resultant risk of developing Breast Cancer.

WHI was first conceived in 1991 and began enrolling research volunteers in its different arms between 1993 and 1998. In the Prempro combo arm, there were 16,608 subjects, 8,506 in the Prempro group and 8,102 in the Placebo group. It was supposed to be an 8.5 year study, but it was terminated early by the DSMB at the end of 5.2 years to the excess risk of Breast Cancer in the Prempro group compared with the Placebo group. Other risk factors that were trending elevated included: Heart Disease, Stroke, Blood Clots (Pulmonary Embolism and Phlebitis).

Cases per 1,000 women per year

Breast Cancer: 3.8 (HRT), 3.0 (Placebo), +26% (Difference)
Heart Disease: 3.7 (HRT), 3.0 (Placebo), +23% (Difference)
Stroke: 2.9 (HRT), 2.1 (Placebo), +38% (Difference)
Blood Clots: 2.6 (HRT), 1.3 (Placebo), +100% (Difference)
Hip Fracture: 1.0 (HRT), 1.5 (Placebo), -33% (Difference)
Colon Cancer: 1.0 (HRT), 1.6 (Placebo), -37% (Difference)

So, the DSMB (Data and Safety Monitoring Board) concluded that the evidence for an increased risk of CHD, Stroke, and Blood Clots outweighed the possible benefits from decreasing Hip Fractures and Colon Cancer over the average 5.2 year follow-up period and the Prempro arm was discontinued. The Premarin alone arm continues in women who have had a hysterectomy as no significant early trends have turned up as of yet.
During the past year, for every 10,000 women taking Prempro, one would expect to find:

7 more CHD events
8 more invasive Breast Cancers
8 more Strokes
8 more Pulmonary Embolisms (Blood Clots)
6 fewer Colorectal Cancers
5 fewer Hip Fractures

From the above, you can see there will be 31 extra bad events per year for each 10,000 women on Prempro and a simultaneous 11 fewer bad events. This leaves an excess of 20 more women experiencing a harmful event. This is why the results are big news and why the study was stopped early. Now, what should practicing physicians and the 38% of postmenopausal women taking HRT do as we enter the "post-HRT era"? Well, keep in mind that the absolute excess risk attributable to Prempro was low. The majority of women didn't increase any adverse events (side effects). However, the whole purpose of healthy women taking long term estrogen/progestin therapy is to preserve health and prevent disease. The results of WHI provide strong evidence that the opposite is happening even if the absolute risk is low.
What can a postmenopausal woman do to prevent heart disease?
Instead of HRT, stress the use of low fat diet, regular exercise, and cholesterol lowering.
What can a postmenopausal woman do to prevent Osteoporosis?
Even though it's clear that HRT works well for this indication, there are other alternatives that appear not to share the same side effects. Calcium supplements; bisphonates like Fosamax and Actonel; SERMS like Evista and weight bearing exercise can all favorable effect tisk of Osteoporosis.
What can a postmenopausal woman do to prevent Colon Cancer?
Even though the women in WHI experienced less Colon Cancer, one can diminish her risk by: getting a colonoscopy; focal occult blood testing; eating fruits and vegetables; and regularly exercising.
What can a postmenopausal woman do to keep her skin looking healthy?
Skin cells lose their elasticity and youthful appearance when the estrogen level falls with menopause. The hair can become dryer and thinner. Alternatives include: creams and moistures; and cosmetic surgery.
What can a postmenopausal woman do to decrease the chance of developing Breast Cancer?
HRT does indeed raise the risk of developing invasive Breast Cancer. Mammography, regular GYN visits, along with breast self-exam, can help prevent disease.
What can a postmenopausal woman do to minimize the chance of Stroke?
As the estrogen level falls, the blood vessels age and become less flexible, leading to a buildup of plaque, which can cause a Stroke. HRT can help this, but its tendency to promote blood clots looks like it caused more Strokes than it prevented.
What can a postmenopausal woman do to decrease her chances of getting Alzheimer's Disease?
Even though some studies show HRT may help, there are other treatments available, like: Aricept and Reminyl.
What can a postmenopausal woman do to treat the Hot Flashes?
Maybe, short-term HRT will be the way to go for a year or so, and then wean down the dose and stop. Other treatments for the sweating and flushing include: natural plant-based estrogen, including Black Cohosh, Soy Products, and Wild Yams. These may provide some relief. But you have to check the reliability of the alternative medicines and the estrogen in them may also be harmful.
What can a postmenopausal woman do to treat Vaginal Dryness?
When the vaginal tissue is deprived of estrogen, it loses its suppleness and becomes dry and irritated. Itching discomfort and dysparunia can result. Options include: vaginal creams, flexible hormonal rings, vitamin E, both orally and topically.
What can a postmenopausal woman do to treat Mood Swings?
The drop in estrogen can cause Mood Swings that are manifested by: irritability; depression; and insomnia. Tiredness can cause changes in personality. Short term HRT, relaxation exercises, meditation or massage can help. In more severe cases, antidepressants like Prozac can be useful.
In conclusion, the possibilities of these small absolute risks must be balanced against the severity of the woman's symptoms and the benefits of the treatments. It's obvious that in the next year, less than 38% of postmenopausal women will be taking HRT. If you already had a hysterectomy and you don't have a uterus, you might benefit from staying on the Premarin alone. To find out for sure, we'll have to wait for the full results of the WHI to be out in 2005. Until then, doctors that believe "primun non nocere" (first do no harm) and patients who fear even small risks of drugs are going to have to deal with this brave new post-HRT world!
Click here to find out how best to prevent Osteoporosis.
The National Institutes of Health announced in March 2004 preliminary findings from the estrogen-alone study arm which showed the estrogen therapy:

Decreased the risk of Hip Fracture.
Did not increase the risk of Breast Cancer.
No effect of Coronary Artery Disease.
Increased the risk of Stroke.

In conclusion, Estrogen along is less dangerous than combining it with a progestin. However, it is clearly not as good as we once thought it was.

Sincerely:

Joseph Saponaro, MD, DABIM, FACP, CPI, CCI, CCRI, CCRC, CCRP
Board Certified Internist, JPMC
Principal Investigator, DSI
Diplomat American Board of Internal Medicine
Fellow American College of Physicians
Certified Physician Investigator by the AAPP
Certified Clinical Investigator by the DIA
Certified Clinical Research Investigator by the ACRP
Certified Clinical Research Coordinator by the ACRP
Certified Clinical Research Professional by SoCRA
Member: The American College of Preventive Medicine

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