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    <head><title>Estrogen and Osteoporosis</title></head>
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        <h1>
            Estrogen and Osteoporosis
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        The government declared victory in the war on cancer, though the age-specific death rate from cancer keeps
        increasing. In the equally well publicized effort to prevent disability and death from osteoporosis, no one is
        declaring victory, because the only trend in its incidence that has been reported is an increase. The
        estrogen-promoting culture tells us that this is because of the aging of the population, but the age corrected
        numbers still show a great increase--for example, in Finland between 1970 and 1995, the number of women (for a
        given population of women older than 60) breaking their forearm because of osteoporosis more than doubled
        (Palvanen, et al., 1998). That this happened during a time when the use of estrogen had become much more common
        doesn't present a good argument for the protective effects of estrogen treatment. (And during this period there
        was a large increase in the consumption of estrogenic soy products.) Recently our local newspaper had a story at
        the bottom of the front page reporting that lean women who used estrogen and synthetic progestins had an 80%
        higher rate of breast cancer. Several days later, across the top of the front page, there was a rebuttal
        article, quoting some doctors including a "world class expert on hormone replacement therapy" and a woman who
        has taken Premarin for forty years and urges everyone to take it. The "protection against osteoporosis" and
        against heart disease, they said, must be weighed against a trifle such as the 80% increase in cancer. It
        appeared that the newspaper was apologizing for reporting a fact that could make millions of women nervous. (Jan
        26, Register-Guard). Medical magazines, like the mass media, don't like to miss any opportunity to inform the
        public about the importance of using estrogen to prevent osteoporosis. Their attention to the bone-protective
        effect of progesterone has been noticeably less than their mad campaign to sell estrogen, despite the evidence
        that progesterone can promote bone rebuilding, rather than just slowing its loss. Although I have spoken about
        progesterone and osteoporosis frequently in the last 25 years, I have only occasionally considered what estrogen
        does to bones; generally, I described estrogen as a stress-promoting and age-promoting hormone. In the 1970s,
        pointing out progesterone's protective antagonism to excessive amounts of other hormones, and that the catabolic
        glucocorticoids tend to increase with aging, I began referring to progesterone as the "anticatabolic" hormone
        that should be used to prevent stress-induced atrophy of skin, bones, brain, etc. A former editor of Yearbook of
        Endocrinology had reviewed a series of studies showing that excess prolactin can cause osteoporosis. Then, he
        presented a group of studies showing how estrogen promotes the secretion of prolactin, and can cause
        hyperprolactinemia. In that review, he wryly wondered how something that increases something that causes
        osteoporosis could prevent osteoporosis. Women have a higher incidence of osteoporosis than men do. Young women
        have thinner more delicate bones than young men. The women who break bones in old age are generally the women
        who had the thinnest bones in youth. Menstrual irregularities, and luteal defects, that involve relatively high
        estrogen and low progesterone, increase bone loss. Fatter women are less likely to break bones than thinner
        women. Insulin, which causes the formation of fat, also stimulates bone growth. Estrogen however, increases the
        level of free fatty acids in the blood, indicating that it antagonizes insulin (insulin decreases the level of
        free fatty acids), and the fatty acids themselves strongly oppose the effects of insulin. Estrogen dominance is
        widely thought to predispose women to diabetes. Between the ages of 20 and 40, there is a very considerable
        increase in the blood level of estrogen in women. However, bone loss begins around the age of 23, and progesses
        through the years when estrogen levels are rising. Osteoarthritis, which involves degeneration of the bones
        around joints, is strongly associated with high levels of estrogen, and can be produced in animals with estrogen
        treatment. Thirty years ago, when people were already claiming that estrogen would prevent or cure osteoporosis,
        endocrinologists pointed out that there was no x-ray evidence to support the claim. Estrogen can cause a
        positive calcium balance, the retention of more calcium than is excreted, and the estrogen promoters argued that
        this showed it was being stored in the bones, but the endocrine physiologists showed that estrogen causes the
        retention of calcium by soft tissues. There are many reasons for not wanting calcium to accumulate in the soft
        tissues; this occurs normally in aging and stress. Then, it was discovered that, although estrogen doesn't
        improve the activity of the cells that build bone, it can reduce the activity of the cells that remove bone, the
        osteoclasts. The osteoclast is a type of phagocytic cell, and is considered to be a macrophage, the type of cell
        that can be found in any organ, which can eat any sort of particle, and which secretes substances (cytokines,
        hormone-like proteins) that modify the functions of other cells. When estrogen was found to impair the activity
        of this kind of cell, there wasn't much known about macrophage cytokines. With the clear evidence that estrogen
        inhibits the osteoclasts without activating the bone-building osteoblasts, estrogen was said to "prevent bone
        loss," and from that point on we never heard again about estrogen promoting a positive calcium balance. Calcium
        retention by soft tissues has come to be an accepted marker of tissue aging, tissue damage, excitotoxicity, and
        degeneration. Positive calcium balance had been the essence of the argument for using estrogen to prevent
        osteoporosis: "Women are like chickens, estrogen makes them store calcium in their bones." But if everyone now
        recognizes that calcium isn't being stored in bones, it's better for the estrogen industry if we forget about
        the clearly established positive calcium balance produced by estrogen. The toxic effects of excessive
        intracellular calcium (decreased respiration and increased excitation) are opposed by magnesium. Both thyroid
        and progesterone improve magnesium retention. Estrogen dominance is often associated with magnesium deficiency,
        which can be an important factor in osteoporosis (Abraham and Grewal, 1990; Muneyyirci-Delale, et al., 1999). As
        part of the campaign to get women to use estrogen, an x-ray (bone density) test was devised which can supposedly
        measure changes in the mineral content of bone. However, it happens that fat and water interfere with the
        measurements. Estrogen changes the fat and water content of tissues. By chance, the distortions produced by fat
        and water happen to be such that estrogen could appear to be increasing the density of a bone, when it is really
        just altering the soft tissues. Ultrasound measurements can provide very accurate measurements of bone density,
        without the fat and water artifacts that can produce misleading results in the x-ray procedure, and don't expose
        the patient to radiation, but the ultrasound method is seldom used. In recent years, there has been quite a lot
        of research into the effects of the macrophage cytokines. Immune therapy for cancer was considered quackery when
        Lawrence Burton identified some substances in blood serum that could cause massive tumors in rodents to
        disappear in just a few hours. One of the serum factors was called Tumor Necrosis Factor, TNF. An official
        committee was formed to evaluate his work, but it reported that there was nothing to it. A member of the
        committee later became known as "the authority" on tumor necrosis factor, which was thought to have great
        potential as an anticancer drug. However, used by itself, TNF killed only a few cancers, but it damaged every
        organ of the body, usually causing the tissues to waste away. Other names, lymphotoxin and cachectin, reflected
        its toxic actions on healthy tissues. Aging involves many changes that tend to increase the inflammatory
        reaction, and generally the level of TNF increases with aging. Although cancer, heart failure, AIDS, and extreme
        hormone deficiency (from loss of the pituitary or thyroid gland, for example) can cause cachexia of an extreme
        and rapid sort, ordinary aging is itself a type of cachexia. Progeria, or premature aging, is a kind of wasting
        disease that causes a child's tissues (including bones) to atrophy, and to change in many of the ways that would
        normally occur in extreme old age. Recent studies have found that both men and women lose minerals from their
        bones at the rate of about 1% per year. Although men have lower estrogen in youth than women do, their bones are
        much heavier. During aging, as their bones get thinner, men's estrogen levels keep rising. Besides having weaker
        bones, old people have weaker muscles, and are more likely to injure themselves in a fall because their muscles
        don't react as well. Muscle loss occurs at about the rate of 1% per year. Women's muscles, like their bones, are
        normally smaller than men's, and estrogen contributes significantly to these differences. TNF can produce very
        rapid loss of tissue including bone, and in general, it rises with aging. Some of the people who like to say
        that "osteoporosis is caused by estrogen deficiency" know about the destructive actions of TNF, and argue that
        it rises at menopause "because of estrogen deficiency." There are very good reasons for rejecting that argument;
        the experiments sometimes seem to have been designed purely for propaganda purposes, using toxic levels of
        estrogen for a specific result. One researcher noted that the effects of estrogen on cells in vitro are
        biphasic: Low doses increased TNF, high doses decreased TNF. Everyone knows that unphysiologically high doses
        (50 or 100 or more times above the physiological level of around 0.25 micrograms per liter) of estrogen are
        toxic to cells, producing functional and structural changes, and even rapid death. So, when a researcher who
        wants to show estrogen's "bone protective" effect of lowering TNF adds a lethal dose of estrogen to his cell
        culture, he can conclude that "estrogen inhibits TNF production." But the result is no more interesting than the
        observation that a large dose of cyanide inhibits breathing. TNF is produced by endotoxin, and estrogen
        increases the amount of endotoxin in the blood. Even without endotoxin, though, estrogen can stimulate the
        production of TNF. Lactic acid and unsaturated fats and hypoxia can stimulate increased formation of TNF.
        Estrogen increases production of nitric oxide systemically, and nitric oxide can stimulate TNF formation. How
        does TNF work, to produce tissue damage and wasting? It causes cells to take up too much calcium, which makes
        them hypermetabolic before it kills them. It increases formation of nitric oxide and carbon monoxide, blocking
        respiration. TNF can cause a 19.5 fold increased in the enzyme which produces carbon monoxide (Rizzardini, et
        al., 1993), which blocks respiration. All of the normal conditions associated with high estrogen also are found
        to involve increased production of TNF, and treatment of animals with estrogen clearly increases their TNF.
        Premature ovarian failure (with low estrogen levels) leads to reduced TNF, as does treatment with antiestrogens.
        If bone resorption is significantly regulated by TNF, then it should be concluded that increased estrogenic
        influence will tend to produce osteoporosis. Tamoxifen, which has some estrogenic effects, including the
        inhibition of osteoclasts, can kill osteoclasts when the dose is high enough. The inhibition of osteoclast
        activity by either estrogen or tamoxifen is probably a toxic action, that has been characterized as "beneficial"
        by the estrogen industry simply because they didn't have any better argument for getting women to use their
        products. Some types of dementia, such as Alzheimer's disease, involve a life-long process of degeneration of
        the brain, with an inflammatory component, that probably makes them comparable to osteoporosis and
        muscle-wasting. (In the brain, the microglia, which are similar to macrophages, and the astrocytes, can produce
        TNF.) The importance of the inflammatory process in Alzheimer's disease was appreciated when it was noticed that
        people who used aspirin regularly had a low incidence of that dementia. Aspirin inhibits the formation of TNF,
        and aspirin has been found to retard bone loss. In the case of osteoporosis (A. Murrillo-Uribe, 1999), as in
        Alzheimer's disease, the incidence is two or three times as high in women as in men. In both Alzheimer's disease
        and osteoporosis, the estrogen industry is arguing that the problems are caused by a suddenly developing
        estrogen deficiency, rather than by prolonged exposure to estrogen. Similar arguments were made fifty years ago
        regarding the nature of the menopause itself--that it was caused by a sudden decrease in estrogen production.
        The evidence that has accumulated in the last forty years has decisively settled that argument: Menopause is the
        result of prolonged exposure to estrogen. (Even one large dose destroys certain areas in the brain, and chronic,
        natural levels damage the nerves that regulate the pituitary. Overactivity of the pituitary leads to many other
        features of aging.) The links between estrogen and TNF appear to be essential factors in aging and its diseases.
        Each of these substances has its constructive, but limited, place in normal physiology, but as excitatory
        factors, they must operate within the appropriate constraints. The basic constraint is that resources, including
        energy and oxygen, must be available to terminate their excitatory actions. Adequate oxygen, a generous supply
        of carbon dioxide, saturated fats, thyroid, and progesterone restrain TNF, while optimizing other cytokines and
        immune functions, including thymic protection. In the development of the organism and its adaptive functions,
        there are patterned processes, functional systems, that can clarify the interactions of growth and atrophy. The
        respiratory production of energy and carbon dioxide, and the respiratory defect in which lactic acid is
        produced, correspond to successful adaptation, and to stressful/excitotoxic maladaptation, respectively.
        Excitotoxicity, and Meerson's work on the protective functions of the antistress hormones, have to be understood
        in this framework. This framework integrates the understanding of cancer metabolism with the other stress
        metabolisms, and with the metabolism of normal growth. Unsaturated fats, iron, and lactic acid are closely
        related to the actions and regulation of TNF, and therefore they strongly influence the nature of stress and the
        rate of aging. The fact that cancer depends on the presence of polyunsaturated fats probably relates to the
        constructive and destructive actions of TNF: The destructive effects such as multiple organ failure/congestive
        heart failure/shock-lung, etc., apparently involve arachidonic acid and its metabolites, which are based on the
        so-called essential fatty acids. When oxygen and the correct nutrients are available, the hypermetabolism
        produced by TNF could be reparative (K. Fukushima, et al., 1999), rather than destructive. Stimulation in the
        presence of oxygen produces carbon dioxide, allowing cells to excrete calcium and to deposit it in bones, but
        stimulation in the absence of oxygen produces lactic acid and causes cellular calcium uptake. It is in this
        context that the therapeutic effects of saturated fats, carbon dioxide, progesterone, and thyroid can be
        understood. They restore stability to a system that has been stimulated beyond its capacity to adapt without
        injury.

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