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OVARIAN HORMONE THERAPY
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Long term considerations
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Hormone therapy and fracture
Remember: Bone density is only a surrogate endpoint

The first thing to consider before getting into the efficacy or otherwise of hormones in preventing fractures, is the question Is Osteoporosis a Menopausal Disease?
 

July 9, 2002 
Despite the estrogen/progestin (Prempro) arm of the long-awaited "definitive" WHI study being halted early because of "the evidence of overall health risks exceeding any benefits", one slight benefit was in fact a one-third reduction in hip fracture rates and a 24 percent reduction in total fractures.  This benefit however must by offset by the definite risks associated with such use.
http://www.nhlbi.nih.gov/new/press/02-07-09.htm
NHLBI Stops Trial of Estrogen Plus Progestin
Due to Increased Breast Cancer Risk, Lack of Overall Benefit 
Longer term use or use for disease prevention must be re-evaluated given the multiple adverse effects noted in WHI," said Jacques Rossouw, M.D., acting director of the WHI.

Aug 15, 2001
http://jama.ama-assn.org/issues/v286n7/abs/jci10033.html
Bone Mineral Density Response to Estrogen Replacement
This is a study reported by its authors to be limited by its small size (45 on E/HRT - 11 dropouts, 22 placebo - 2 dropouts) short duration (9 months) inclusion of only frail elderly (over 75 with "frailty" factors) and use of surrogate endpoint (BMD) rather than a clinical one (fractures).
They conclude:
In summary, HRT has significant osteogenic effects in very old, physically frail women. However, fracture risk in very old women is due to multiple factors in addition to low BMD, including sensory and neuromuscular impairments, medications, and environmental hazards. Further research is therefore necessary to elucidate the effectiveness of HRT, alone and in combination with fall-prevention measures, in reducing fracture rates and postponing disability in elderly women.
A statement in the body of the text says:
Because socioeconomic factors are the chief determinants of estrogen use by elderly women, the benefits of HRT in observational studies may have been related to other lifestyle factors. 
Despite the authors cautions and disclaimers, press releases about this study predictably presented it is as definite evidence for the desirability of HRT use, and failed to mention the high drop out rate due to side effects.
June 2001: An editorial in JAMA at http://jama.ama-assn.org/issues/v285n22/ffull/jed10034.html
Postmenopausal Hormone Therapy for Prevention of Fractures asks
 How Good Is the Evidence? Deborah Grady, MD, MPH; Steven R. Cummings, MD

Not that good apparently.... The article includes the statements:

....This meta-analysis highlights the fact that evidence about the efficacy of postmenopausal estrogen for prevention of osteoporotic fractures is weak.
and
.....Since women in their 50s who do not have osteoporosis have a relatively low risk of fracture, the benefit of long-term treatment with estrogen to prevent bone loss and fractures may not exceed the risks.
The publication of the survey above was quickly followed by a front page article in USA Today which does a good rundown on the reasons for the escalating doubts of the usefulness of HRT. It includes the significant statement
Apparently, though, the latest research about HRT's effects has not trickled down to many doctors who care for postmenopausal women, nor, as a result, to the women themselves.
Extract from a "case study based educational exercise about "Hormone Replacement Therapy" commissioned by the Australian National Prescribing Service" athttp://www.healthyskepticism.org/editions/IN0108hrt3.htm

Our comment: 

The impact of HRT on fracture rates is probably known and may be mildly beneficial. 
Explanation: 
All of the evidence from RCTs is consistent with the belief that long term HRT reduces fracture risk but the benefit may be small.  One RCT has suggested that in women with established osteoporosis, HRT may reduce the rate of lower vertebral fractures.[2]  However, hip fractures are more important for patients.  We are not aware of any direct evidence from RCTs of a reduction in hip fractures from HRT even in women with osteoporosis.  Reports of two trials of HRT for women without osteoporosis claim lower rates of non-vertebral fractures of borderline statistical significance.  However the first of these trials used questionable statistical “adjustments”.[3]  The second trial found significantly less forearm fractures in the HRT group but there was no significant difference in the total number of fractures.[4]  Most of the participants in this trial were not randomised and there was no placebo so the results are not reliable. 

HRT does reduce loss of bone density.[5]  However, contrary to popular belief, bone density is not good for predicting who is or is not at high risk of fractures as shown in the graph below.[6]  We should also remember that fractures result from many causes and bone density is just one factor along with balance, environment, sedating medications, etc.

Numbers in brackets refer to references available through above URL

Here is an extract from a 1998 article which is actually looking at effect of endogenous (produced by the body) estrogen on fracture risk but which has relevance to decision making on supplementation by the drug variety.
http://www.nejm.org/content/1998/0339/0011/0733.html
The New England Journal of Medicine -- September 10, 1998 -- Volume 339, Number 11
Endogenous Hormones and the Risk of Hip and Vertebral Fractures among Older Women
Steven R. Cummings, Warren S. Browner, Douglas Bauer, Katie Stone, Kristine Ensrud, Sophie Jamal, Bruce Ettinger, for the Study of Osteoporotic Fractures Research Group 
In postmenopausal women, the serum concentrations of endogenous sex hormones and vitamin D might influence the risk of hip and vertebral fractures. In a study of a cohort of women 65 years of age or older, we compared the serum hormone concentrations at base line in 133 women who subsequently had hip fractures and 138 women who subsequently had vertebral fractures with those in randomly selected control women from the same cohort. Women who were taking estrogen were excluded. The results were adjusted for age and weight. 
From highly recommended editorial at http://www.nejm.org/content/1998/0339/0011/0767.asp which is alas no longer available without subscription
Surprisingly, there was no effect of increasing serum estradiol concentrations on the risk of fracture among women who had detectable concentrations (>5 pg per milliliter [18 pmol per liter]) at base line, all of whom had relative risks of fracture of 0.3 to 0.5 as compared with women with undetectable concentrations. On the other hand, there was a linear relation between serum concentrations of sex hormone-binding globulin and the risk of fracture, which was three times as high for women in the highest quintile as for those in the lowest. Serum sex hormone-binding globulin binds both androgens and estrogens, and higher levels would presumably decrease the bioavailability of both hormones to skeletal tissues. 
<snip> 
Do the low, but detectable, concentrations in postmenopausal women have an effect on bone metabolism, or are the undetectable concentrations simply a marker of some other metabolic difference in this group of postmenopausal women? A study of the effects of low doses of estradiol on bone turnover in postmenopausal women who have undetectable serum estradiol concentrations at base line would help to resolve these questions. 
Press reports of this study used it to suggest that lower doses of estrogen might be adequate. My question is why any* dose for women with detectable levels? Tishy] 

1996 Extract from
http://www.ti.ubc.ca/pages/letter14.htm#note2
Does hormone therapy prevent fractures associated with osteoporosis?  (1996)

Menopause is associated with an accelerated decline in bone mass, which may lead to osteoporosis and bone fractures in susceptible women. 

Only hip fracture has an effect on longevity; a menopausal woman has a 15% lifetime chance of sustaining and 1.5% chance of dying of a hip fracture (median age, 79) 

Even if the evidence is accepted and we pool all studies to get a RR of 0.75, the absolute risk reduction is small (see Table 2), estrogens also reduce the risk of vertebral and wrist fractures (3), which may cause significant morbidity. The benefits probably outweigh the risks in patients with established osteoporosis (previous low trauma fracture) or patients with greater than 5 risk factors for hip fracture(10). 

The same site points out that in the case of unopposed estrogen therapy (no progestin), it has been calculated that it would be necessary to treat 250 women for 10 years in order to prevent one hip fracture. At the same time, treating only 167 women for the same period would produce one more breast cancer.
OVARIAN HORMONE THERAPY
General - risks, definition Which OHT?  Deciding on it  Getting off it  "Natural" hormones Long term considerations
Long term considerations
heart and cardiovascular bone brain breast in general
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July 19, 2002
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